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magnitude can be calculated as m = −2.5log 10 F + zp, where F is the integrated flux of an object. Note that the single-epoch images have both astrometric and photometric residuals even though we can correct them in the catalogs. If the user wants higher accuracies for the astrometry and photometry from images, one should apply the residual maps to the coordinates and magnitudes 13 . The astrometric correction can be as much as 0 ′′ .04 for both BASS and MzLS. The photometric correction can be as much as 0.02 and 0.05 mag for BASS and MzLS, respectively. The stacked images cannot be used for accurate photometric measurements because they are combined from many single-epoch images with different qualities. Each stacked image has a weight image. We adopt standard WCS parameters with a simple "TAN" projection. The zero-points are fixed to 30. Catalogs The co-added catalogs provide the deepest and most accurate magnitude measurements for objects with multiple exposures. A co-added catalog covers an area of about 0.68×0.68 deg 2 with an 0 • .02 overlap with other neighboring blocks. For each source in the catalog, we provide the minimums, maximums, and averages of modified Julian date, seeing in FWHM, sky brightness, and zero-point from single-epoch observations, and provide the total exposure time and number of exposures in each band. The catalogs include Galactic reddening from the map of Schlegel et al. (1998), some measurements from stacked images derived by SExtractor, such as shape parameters and star/galaxy classification (marked with a postfix " Stack"), | 3,069,500 | 119462399 | 0 | 16 |
and "Mag Auto" magnitudes for three bands. These measurements are only recorded and much less accurate. The other measurements in the catalogs are obtained by co-adding parameters from single-epoch images by our own photometric code. For each band, there are coordinates, shape parameters (e.g. half major/minor axis length, ellipticity, PA and Kron radius), all kinds of fluxes and magnitudes, and flags. For the magnitude error, we provide both normal parameter error and standard error. The standard error is related to the magnitude rms of multiple observations. It contains information of light variation, which can be useful for variable objects. Shape parameters are directly computed from the images. They are not intrinsic due to the seeing effect. The single-epoch catalogs contains the measurements for objects detected on stacked images. The object ID is unique in the co-added catalogs, while objects in single-epoch catalogs use the same ID. This means that the ID in single-epoch catalogs can be duplicated for objects with multiple observations. All fluxes in the catalogs are in nanomaggy, where magnitudes can be calculated as −2.5log 10 F + 22.5. We recommend the PSF magnitude for point sources and Kron magnitudes for extended sources. For very large galaxies with apparent diameters larger than about 1 ′ , they might be fragmented due to foreground stars and their substructures, which might mean the photometry might not be reliable. For star/galaxy separation, the column "Type Stack" gives a median of class parameters from stacked images derived by SExtractor. We can also identify point sources from the reduced | 3,069,501 | 119462399 | 0 | 16 |
χ 2 of PSF fitting. The reduced χ 2 can be computed as the ratio of "Chi2 PSF" and "DOF PSF" columns in the catalogs. If it is close to 1, the object is likely to be a point-like source. In addition, the ellipticity, color, and magnitude difference between PSF and Kron magnitudes can be also useful for classification. The user can even combine all these parameters to separate objects. We expect a classification to be added in the next data release. Summary The BASS made its first data release be public in 2017 January. It only includes the BASS g-band and r-band observations taken before 2016 July. This paper describes the details of our second data release, which include new datasets and updates to the data reduction. We summa-rize these updates as follows: (a) The DR2 includes the data taken as of 2017 July. This release includes the MzLS data. The BASS and MzLS have respectively completed about 72% and 76% of their observations over the footprint of over 5000 deg 2 . (b) BASS and MzLS data are reduced by the same pipeline, which includes some updates from DR1, such as bias correction of 2015 BASS data, identification of cosmic rays, crosstalk correction, and subtraction of pattern noise in MzLS images. (c) Gaia DR1 catalogs are utilized to derive astrometric solutions. The global astrometric error is about 0 ′′ .03. This is much better than DR1, where SDSS DR9 was used as the reference catalog. (d) External photometric zero-points are calculated using point-source catalogs | 3,069,502 | 119462399 | 0 | 16 |
of PS1, the same as in DR1. To improve the accuracy of flux calibrations, internal zero-points are computed by comparing the magnitude differences of common objects in different exposures. (e) Source detection is implemented in stacked images and photometry is made in single-epoch images. We provide circular aperture, Isophotal, Kron elliptical aperture, and PSF magnitudes. The median depths over the whole coverage are 24.05, 23.61, and 23.10 mag for the g, r, and z bands, respectively. The MzLS finished its observations in February of 2018 and the BASS will complete the observations in of 2019 January. The next data release (DR3) is expected to include all BASS and MzLS survey data. Furthermore, we will have some new features in DR3, such as astrometry by Gaia DR2, a new source detecting algorithm, a stargalaxy separation, a flag to mark objects close to bright stars and large galaxies, new PSF modeling, and Galactic extinction from Planck dust map. | 3,069,503 | 119462399 | 0 | 16 |
Laparoscopic Hepatectomy: Current State in Japan Based on the 4th Nationwide Questionnaire Purpose. Since laparoscopic hepatectomy (LH) became covered by national health insurance in April 2010 in Japan, the numbers of applied cases and institutions performing it have increased and the indication has expanded. We surveyed the current state and safety of LH in Japan. Methods. A questionnaire survey was performed in 41 institutions related to the Japanese Endoscopic Liver Surgery Study Group and 747 institutions certified by the Japanese Society of Gastroenterological Surgery, and responses concerning all 2962 cases of LH performed by August 2011 were obtained. Results. The surgical procedure employed was hemihepatectomy in 234 (8%), segmentectomy in 88 (3%), left lateral segmentectomy in 434 (15%), segmentectomy in 156 (5%), and partial resection in 1504 (51%) cases. The approach was pure laparoscopy in 1835 (63%), hand-assisted laparoscopic surgery in 201 (7%), and laparoscopy-assisted surgery in 926 (31%). Regarding perioperative complications, surgery was switched to laparotomy in 59 (2.0%), reoperation was performed in 4 (0.1%), and surgery-related death occurred in 2 (0.07%). Intraoperative accidents occurred in 68 (2.3%), and postoperative complications developed in 94 (3.2%). Conclusions. When the selection of cases is appropriate, LH for liver diseases can be safely performed. Introduction Laparoscopic hepatectomy (LH) was initially performed to resect a benign liver tumor by Reich et al. in 1991 [1]. LH requires a large incision to mobilize the liver in addition to the resection of the liver parenchyma. Moreover, the liver is surrounded by the costal bones, and securing a visual field is difficult. | 3,069,504 | 17066471 | 0 | 16 |
Performing these procedures in the abdominal cavity under laparoscopy reduces the size of the incision and burden on the patient [2]. Based on this concept, LH has recently spread rapidly throughout the world, and now, it is applied for not only surgery of malignant tumors but also donor surgery in living donor liver transplantation. The procedures of LH were already established and reported by institutions whose staff had encountered many cases overseas [3]. An international consensus meeting was held in Louisville in November 2008, in which the surgical procedure and safety of LH were widely discussed and the guidance for the development of the current LH was presented [4]. In Japan, since LH was initially applied for liver cancer by Hashizume et al. in 1995 andKaneko et al. in 1996, cases resected by LH have occasionally been reported [5,6]. In April 2010, partial resection and lateral segmentectomy became covered by national health insurance, and the numbers of cases and institutions performing LH are rapidly increasing. The current state of LH in Japan has been surveyed every year by the Japanese Endoscopic Liver Surgery Study Group since 2007 [7][8][9]. The 4th Annual Meeting of the Japanese Endoscopic Liver Surgery Study Group (chairman: M. Yamamoto) was held in November 2010. This questionnaire survey was performed by this Study Group to investigate the current state of LH in Japan and its safety. We report the results of this survey. Methods The questionnaire survey has been performed by the Japanese Endoscopic Liver Surgery Study Group since 2009, and this was | 3,069,505 | 17066471 | 0 | 16 |
the 4th survey. The questionnaire was sent by post mail to 41 institutions related to the Study Group and 747 institutions certified by the Japanese Society of Gastroenterological Surgery. The subjects of the survey were all patients who underwent the first laparoscopic hepatectomy at the institutions by August 31, 2011. Results Four hundred sixty-four institutions (59%) responded to the questionnaire, 113 (14.3%) of these perform LH, and the total number of cases was 2962. The intraoperative pneumoperitoneum pressure was 12 mmHg or higher in 8 institutions (7%), 10-12 mmHg in 29 (26%), 8-10 mmHg in 71 (63%), and lower than 8 mmHg in 2 (2%) ( Figure 5). institutions performing these may be increasing. The questionnaire survey has been performed since 2009 when the Japanese Endoscopic Liver Surgery Study Group was established, and this was the 4th survey. The first and second surveys were performed in institutions related to the study group [7,8], but institutions certified by the Japanese Society of Gastroenterological Surgery were additionally included from the previous 3rd survey [9]. Of the 464 institutions (59%) which responded, 113 (14.3%) performed LH, and the total number of LH-resected cases increased by 640 to 2899 per year, although the number of responder institutions decreased. This increase may have been due to the marked influence of coverage by national health insurance one year and 4 months ago. Discussion HCC and Meta cases accounted for 60 and 25%, respectively, and HCC cases decreased and Meta cases increased from those in the previous survey [9] (HCC: 64.9%, Meta: 20.0%). | 3,069,506 | 17066471 | 0 | 16 |
The approach was Pure-LH in 59.6% and Hybrid-LH in 32.7% in the previous survey [9], and cases employing Pure-LH slightly increased and those employing Hybrid-LH decreased. The surgical procedure was partial resection in 52%, lateral segmentectomy in 15%, subsegmentectomy in 5%, and segmentectomy (excluding lateral segmentectomy) in 3%, showing that partial resection and lateral segmentectomy covered by national health insurance accounted for 67% of all cases. Cases treated with lateral segmentectomy and unilateral lobectomy increased, and those treated with partial resection decreased compared to those in the previous year. The surgical procedure and approach tended to shift from Hybrid-LH to Pure-LH and from partial to systematic resection, respectively. LH advanced with the improvement of operators' techniques and progression of various devices. As of several years after coverage by national health insurance, the installation of various devices may have progressed with the improvement of operators' techniques. In the future, the number of LH cases may rapidly increase and the shifts from Hybrid-LH to Pure-LH and from partial to systematic resection may become marked. When the surgical procedure was investigated by the approach, while Pure-LH and Hybrid-LH were employed in 1835 (63%) and 863 (30%) of all cases, respectively, these were employed in 398 (43.6%) and 472 (51.8%) cases of systematic resection and 986 (65.6%) and 389 (25.9%) of partial resection, respectively, showing that Hybrid-LH tended to be selected for systematic resection and Pure-LH tend to be selected for partial resection (Table 1). When systematic resection employing each surgical procedure was analyzed by the approach in HCC and | 3,069,507 | 17066471 | 0 | 16 |
Meta cases ( Table 2), while unilateral lobectomy was performed in 26% of all cases, it was performed in only 16% of HCC cases and 28% of Meta cases, which is nearly the same rate in all cases. Lateral segmentectomy was performed under Pure-LH in 259 (59.7%) and Hybrid-LH in 151 (34.8%) of all cases. It was performed under Pure-LH and Hybrid-LH in 150 (52.4%) and 122 (42.7%) of HCC cases and 77 (83.7%) and 6 (6.5%) of Meta cases, respectively, suggesting that major resection is tended to be avoided in HCC cases because of the risk of hemorrhage due to the presence of chronic hepatitis and background liver cirrhosis and due to the selection of small-range resection to conserve the residual liver function. Since unilateral lobectomy is not necessarily technically more advanced than subsegmentectomy, a high rate of employing segmentectomy and subsegmentectomy may continue to conserve the residual liver function, even though techniques will progress in the future. Partial resection was performed under complete laparoscopy in 986 cases (66%), and this rate did not change in the HCC and Meta cases. The most frequently resected region was S6 (374 cases, 25%) followed by S3 (315 cases, 20.9%) and S5 (204 cases, 14%). When these cases were divided into HCC and Meta, the most frequently resected region was S6 followed by S3 and S5, showing the same order. S6, S3, and S5 are located in the marginal region on the liver foot side considered to be relatively easy to resect, and the findings were as expected. | 3,069,508 | 17066471 | 0 | 16 |
On the other hand, partial resections of S7 and S8 on the dorsal liver head side are considered relatively difficult to resect, but these were performed in 109 (7%) and 167 (11%) cases, respectively, not being markedly low. S1 was resected in 12 (0.8%), showing the lowest rate. Although this region is not necessarily difficult to resect, its resection tended to be avoided, possibly because the visual field is restricted (Table 3). Regarding perioperative complications, the procedure was switched to laparotomy in 59 (2.0%), reoperation was performed in 4 (0.1%), and surgery-related death occurred in 2 (0.07%). No marked change from those in the previous survey [9] was noted. The frequency of switching to laparotomy of 2% was lower (0.66-8.1%, mean: 4.9%) [10] than that of laparoscopic cholecystectomy, which is widely performed with a standardized technique in Japan. The most commonly expressed reason is that we have an established system of endoscopic surgical skill qualification by the Japan Society for Endoscopic Surgery. And we have an institute authorization system of laparoscopic hepatectomy on covering by insurance. Therefore, we believe that surgical skill can be kept at a high level due to these credentialing and authorization systems. Another reason may be a problem with the definition of switching to laparotomy. For example, when hemorrhage from the transected liver surface cannot be controlled in Pure-LH and laparotomy is added to stop the bleeding, opinions differ on whether it is regarded as switching to laparotomy or Hybrid-LH. One more reason may be inaccurate data extraction from the database of | 3,069,509 | 17066471 | 0 | 16 |
each institution to the respond to the questionnaire, which is a disadvantage of questionnaire surveys. It is possible that complications and accidents are not accurately reported. It is necessary to establish accurate databases in cooperation with the Japan Surgical Society-based database, the National Clinical Database (NCD). The intraoperative pneumoperitoneum pressure was 12 mmHg or higher in 8 institutions (7%), 10-12 mmHg in 29 (26%), 8-10 mmHg in 71 (63%), and lower than 8 mmHg in 2 (2%). Attention should be paid to it even in laparoscopic hepatectomy because gas embolism by carbon dioxide entering through the hepatic vein is problematic, but carbon dioxide embolism as an intraoperative accident has been reported to be rare in Western countries [11]. Complication by gas embolism occurred in 2 cases in the survey, and the incidence was 0.06%, being very rare. In animal experiments, gas embolism in the heart can be observed by transesophageal echocardiography in all animals treated with LH [12,13]. In an experiment in which LH was performed at various central venous pressures (CVP), gas embolism affecting the circulatory dynamics was observed only in the low CVP group [14]. Control of the pneumoperitoneum pressure and CVP by consulting with an anesthesiologist may prevent serious gas embolism. Control of the pneumoperitoneum pressure is also useful for hemostasis, which is a merit of LH, in addition to the prevention of gas embolism. However, an excess pneumoperitoneum pressure may cause gas embolism, to which attention should be paid, and adjustment while judging the circulatory dynamics and grade of hemorrhage is necessary. | 3,069,510 | 17066471 | 0 | 16 |
Bile leakage as a postoperative complication occurred in 15 cases (0.05%). Transection in LH largely depends on an energy device, and delayed bile leakage due to deep cauterization conducted more than necessary is of concern [15], but the incidence is not high compared to that after laparotomy [16]. The mortality was as low as that in the previous survey, and it was much lower than that in Western countries [17]. Not all episodes may have been accurately reported, as described above, and there may have been more fatal cases. Close investigation using the NCD database is necessary. | 3,069,511 | 17066471 | 0 | 16 |
TP53-Mutated Myelodysplastic Syndrome and Acute Myeloid Leukemia: Biology, Current Therapy, and Future Directions Abstract TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) form a distinct group of myeloid disorders with dismal outcomes. TP53-mutated MDS and AML have lower response rates to either induction chemotherapy, hypomethylating agent–based regimens, or venetoclax-based therapies compared with non–TP53-mutated counterparts and a poor median overall survival of 5 to 10 months. Recent advances have identified novel pathogenic mechanisms in TP53-mutated myeloid malignancies, which have the potential to improve treatment strategies in this distinct clinical subgroup. In this review, we discuss recent insights into the biology of TP53-mutated MDS/AML, current treatments, and emerging therapies, including immunotherapeutic and nonimmune-based approaches for this entity. Significance: Emerging data on the impact of cytogenetic aberrations, TP53 allelic burden, immunobiology, and tumor microenvironment of TP53-mutated MDS and AML are further unraveling the complexity of this disease. An improved understanding of the functional consequences of TP53 mutations and immune dysregulation in TP53-mutated AML/MDS coupled with dismal outcomes has resulted in a shift from the use of cytotoxic and hypomethylating agent–based therapies to novel immune and nonimmune strategies for the treatment of this entity. It is hoped that these novel, rationally designed combinations will improve outcomes in this area of significant unmet need. INTRODUCTION TP53 is a tumor suppressor gene that encodes for the transcription factor p53, appropriately coined the "guardian of the genome." TP53 is the most frequently mutated gene across all human cancers and carries an adverse prognosis with suboptimal responses to conventional therapies across multiple cancer | 3,069,512 | 252816471 | 0 | 16 |
types (1). Response to cytotoxic chemotherapy is highly dependent on the presence of intact p53 to enable the induction of apoptosis (2,3). Consequently, TP53mutated cancers respond poorly to cytotoxic chemotherapy. Despite being one of the most studied genes since its initial discovery about 40 years ago, it has so far been considered "undruggable." Similar to many TP53-mutated malignancies, TP53-mutated myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain long-standing therapeutic challenges, with a dismal median survival of 5 to 10 months, irrespective of therapies used (4)(5)(6). In the last few years, some of the novel immune-harnessing and p53 structuremodulating agents have demonstrated encouraging early clinical activity in TP53-mutated AML/MDS, and are now being advanced in phase II/III registration studies. In this review, we summarize the key biological implications of TP53 mutations, their prognostic relevance to MDS and AML, and outcomes with currently approved therapies, and we discuss current and future directions for drug development for TP53-mutated AML/MDS. TP53 MUTATION AND CANCER TP53 is a 20-kb gene located on chromosome 17p13.1, which codes for at least 15 different isoforms and has two paralogs, p63 and p73, with similar structures and overlapping but distinct functions and upstream pathways (7). It presides over a highly connected intracellular hub involving multiple signal transduction pathways and consequently is affected by and in turn regulates numerous cellular processes. Some of the major functions of p53 include the regulation of genomic stability, cell cycling, proliferation, differentiation, apoptosis, senescence, autophagy, metabolism, and stem cell homeostasis throughout human life, highlighting the central role of this | 3,069,513 | 252816471 | 0 | 16 |
pathway in the healthy state ( Fig. 1; refs. 8,9). More than 90% of cancer-related TP53 mutations have structural losses of both alleles, and most result in loss or decreased function of genes in the p53 regulatory network, many of which are critical for growth arrest, routine apoptosis, and suppressing neoplasia (10). Mutations in TP53 can be somatic or germline, can be contact or structural, and based on their functional consequences can be divided into the most frequent complete or partial loss of function to rarely silent or potentially gain of function (1,11,12). A majority of TP53 hotspot mutations lead to loss of function, causing Figure 1. Different subunits of the p53 are coded by a gene located on chromosome 17p13.1. p53 resides over a highly connected hub involving multiple signal transduction pathways, including DNA damage response, oncogene activation, cellular stress, and its positive and negative regulators. In turn, p53 regulates numerous key cellular processes including cell cycling, genomic stability, cell metabolism, differentiation, proliferation, apoptosis, senescence, and others. In addition, downstream signaling through p53 influences the tumor microenvironment through a direct effect on several immunologic targets. APC, antigen-presenting cell; NK, natural killer; Treg, regulatory T cell. an inability to trigger p21, downregulation of genes associated with apoptosis, and upregulation of proteins involved in cell-cycle progression (e.g., cyclin B1, cyclin E1, FOXM1, CDK1) and those involved in DNA damage response (CHK2, MSH6; ref. 10). However, the gain-of-function hypothesis has been challenged by elegant work demonstrating a dominantnegative effect of missense TP53 mutations leading to the disruption of | 3,069,514 | 252816471 | 0 | 16 |
activity of the remaining wild-type p53 after tetramerization (13,14). This was further supported by clinical analysis showing lack of a more aggressive phenotype, a similar comutational landscape, and comparable clinical outcomes and response to therapy between patients harboring missense and truncating TP53 mutations, throwing doubt on the gain-of-function hypothesis. Seventy percent of all TP53 mutations are nonhotspot mutations, and out of those, around 30% of the mutations, for example, those involving E180 and R181, while tumorigenic, behave very differently from p53-null and hotspot mutations (15). These partial loss-of-function mutant p53 proteins can retain 10% to 50% of transcriptional activity compared with wild-type p53, and accumulation of these mutants can rescue the transcriptional apoptosis defect and sensitize leukemia cells to chemotherapy (15). In contrast, mutations in other tumor suppressors, such as RB1 and VHL, more homogenously lead to no protein expression at all (16). More recently, it has been noted that TP53 mutations also modulate diverse aspects of the innate and adaptive immune systems. Loss or dysfunction of p53 in solid tumors promotes tumor immune tolerance through downregulating antigen presentation, decreasing Toll-like receptor-mediated apoptosis, and increasing PD-L1 expression (17). However, mutant p53 also favorably modulates immune response by increasing NF-κB activity, increasing tumor-associated macrophage infiltration, eliciting B-cell response, and activating T cells-effects that potentially could be modulated with therapeutic intent (17). The differential impact of cytotoxic therapy on TP53mutated cancer cells and TP53 wild-type immune cells in the tumor microenvironment further adds to the stochastic complexity of these immune interactions and may affect cytokine production, immune synapse | 3,069,515 | 252816471 | 0 | 16 |
formation between antigenpresenting cells and T cells, and T-cell fate (18)(19)(20). With these diverse effects on various components of both the adaptive and innate immune systems, p53 is increasingly being recognized as a "guardian of immune integrity" (21). TP53 MUTATION IN MDS AND AML Clonal hematopoiesis is noted in the blood of 2% to 6% of patients with cancer, including clonal TP53 variants that could represent a precursor lesion in diverse malignancies (22,23). TP53 abnormalities occur in nearly 5% to 10% of patients with de novo MDS and AML (24)(25)(26). This frequency is much lower than several other solid tumors-for example, uterine carcinosarcoma, esophageal adenocarcinoma, and lung squamous cell cancers in which TP53 alterations are noted in more than 80% of cases. However, the frequency in AML/MDS goes up to 20% to 40% in older patients or those with therapy-related myeloid malignancies (6,27). The frequency of TP53 abnormalities further increases to 70% to 80% in patients with complex karyotype and in patients with loss of chromosome 17/17p, 5/5q, or 7/7q (28,29). Therapy for a previous cancer, including radiation or chemotherapy, does not directly induce TP53 mutations. Rather, preexisting progenitors that carry mutant TP53 and are resistant to DNA damage expand under selective pressure from radiation or chemotherapy to give rise to TP53mutated AML/MDS later in life (5,30,31). Although more than 70% of TP53 abnormalities are missense substitutions clustering within the DNA-binding domain, diverse genetic aberrations in TP53 with complex and varied functional consequences have been described in MDS and AML (1). These include chromosomal alterations leading | 3,069,516 | 252816471 | 0 | 16 |
to allelic gains or losses or frameshift insertions or deletions. The impact of these disruptions ranges from partial loss of function to complete loss of function (1,26,27). Among TP53-mutated MDS, "multihit" involvement with more than one genomic and/or chromosome 17 abnormality is noted in the majority of patients, including multiple mutations in 24% of patients, mutations with concomitant deletions in 22% of patients, and mutations with concomitant copy-number loss of heterozygosity in 21% of patients (26). Notably, recent data strongly support that TP53 mutations, particularly multihit, results in similarly poor clinical outcomes, regardless of whether classified as MDS or AML, arguing for a revised TP53 mutant myeloid entity encompassing both MDS and AML if the blast count is 10% to 19% (MDS/AML) or AML with mutated TP53 if blasts are 20% to recognize this highly adverse-risk myeloid pathology (32)(33)(34)(35). Multihit TP53-mutated MDS/AML often represents a distinct stem cell disorder with a paucity of comutations in other myeloid malignancy-related genes, with comutations occurring in less than 25% of cases (36). This is consistent with TP53 mutations being early truncal events in the MDS/ AML pathogenesis in such cases, and consequently multihit TP53 mutations or biallelic defects evolve to become dominant clones conferring resistance to current standard therapies and therefore carry a worse prognosis (26). Monoallelic TP53 mutations (33%) on the other hand frequently have comutations in other genes, most commonly TET2 (29%), SF3B1 (27%), ASXL1 (16%), and DNMT3A (16%), and are likely to be late subclonal events with varying impacts on outcomes (26). As accurate multihit analysis | 3,069,517 | 252816471 | 0 | 16 |
requires the determination of the allelic state by loss-of-heterozygosity mapping, clinically available conventional and cytogenetic techniques currently do not capture all biallelic patients. However, a reasonable determination of multihit state can be made if there is the presence of more than one TP53 mutation, TP53 mutation(s) in the setting of a missing chromosome 17p locus, or a variant allele frequency (VAF) >50%, which are 75% concordant with copy-neutral loss-of-heterozygosity variants (26). Nuclear p53 accumulation assessed by IHC may also serve as a surrogate for TP53 mutation and copy-number status (37). Recent reports further show that blast count does not distinguish clinical course, and patients with TP53 mutation with complex karyotype have similarly dismal outcomes irrespective of the initial diagnosis of AML or MDS or the baseline bone marrow blast percentage (32,33). As a result, the International Consensus Classification has categorized TP53-mutated MDS with excess blasts and TP53-mutated AML as a group of high-risk myeloid neoplasms harboring TP53 mutations to facilitate clinical trial conduct and regulatory approval for new drugs targeting this patient population. Chromothripsis, or chromosome shattering, is a catastrophic event leading to extensive chromosomal rearrangement (38). Chromothripsis serves as an additional adverse-risk biological characteristic associated with TP53 mutation and complex karyotype in AML/MDS. Such massive shattering and reassembly of chromosomes correlates with genomic instability and defines a subset of complex karyotype AML/MDS with even worse outcomes (39,40). In a recent survey of more than 500 TP53-mutant AML cases, three quarters harbored a missense variant, most commonly R248, R273, and Y220, with other variants, such as | 3,069,518 | 252816471 | 0 | 16 |
TP53 deletion as well as frameshift and nonsense alterations being less common. It was also found that TP53 copy-number loss was extremely prevalent-identified in 70% of AML cases with a concomitant TP53 abnormality (37). AML survival appeared worse for patients who had either a concomitant TP53 mutation and TP53 copy-number loss or when multiple TP53 mutations were present. It is possible that certain TP53 hotspot variants confer a biological fitness advantage, especially if the restraining effect of the wild-type allele is also lost. Alternatively, deletion of chromosome 17p may result in an allelic loss of other haploinsufficient tumor suppressors that may further enhance the oncogenic potential of mutant TP53 via p53 independent mechanisms (41). Experimental CRISPR/ Cas9 genome modeling has demonstrated that human AML cell lines expressing TP53 missense/+ have a competitive growth advantage in vivo over haploinsufficient TP53 +/− isogenic lines, suggesting a dominant-negative effect (13). TP53 missense/− cells, however, were also competitively more potent than TP53 missense/+ cells with the wild-type allele retained, consistent with clinical observations in which p53 loss of heterozygosity is often selected for at the time of clinical progression, including after venetoclax-based therapy (42). The biological dominance of TP53 missense variants in AML supports the ongoing therapeutic search for new compositions with therapeutic potential to revert aberrant p53 protein function to normal. TP53 mutational burden has also emerged as a significant prognostic factor in AML and MDS, with a correlation with response to certain standard therapies. A VAF over 6% is associated with inferior overall survival (OS) and progression-free survival | 3,069,519 | 252816471 | 0 | 16 |
in lower-risk MDS. In high-risk MDS (HR-MDS), increasing VAF strongly correlates with risk of complex cytogenetics, and a VAF >40% was an independent covariate for poor OS (43,44). These data were validated in a larger cohort that showed that the hazard of death increased by 1.02 per 1% increase in VAF among all MDS (45). In patients with newly diagnosed AML with monoallelic TP53 mutations, an increasing VAF (<20% vs. 20%-40% vs. >40%) did not affect the response rates or the overall dismal survival with hypomethylating agent (HMA)-based therapies, with or without venetoclax, but an increasing VAF was associated with progressively lower response rates and inferior OS in the context of cytarabine-based regimens (46,47). p53 also plays a vital role in the normal function and homeostasis of hematopoietic stem cells (HSC) and the bone marrow microenvironment. During normal hematopoiesis, intact p53 mediates the quiescence of HSCs and preservation of genomic stability. Loss or dysfunction of p53 leads to enhanced self-renewal of HSCs, and other supporting oncogenic aberrations can lead to their transformation into leukemia stem cells (LSC; ref. 36). p53 is activated in response to DNA damage with consequent transcriptional activation of several genes, resulting in DNA repair or cell-cycle arrest and apoptosis (2). An impaired apoptosis pathway likely contributes to resistance to cytotoxic chemotherapy or venetoclaxbased therapies in multihit TP53-mutated MDS/AML (46,48,49). Haploinsufficiency of genes located on chromosome 5qfor example, CSNK1A1, EGR1, APC-cooperate with loss of or mutations in TP53 to confer a survival advantage in HSCs (50,51). Degradation of the remaining CK1α leading to | 3,069,520 | 252816471 | 0 | 16 |
increased p53-mediated apoptosis is the key mechanism of benefit with lenalidomide in MDS with del(5q) (52). Expansion of preexisting clones or emergence of new clones with TP53 mutations consequently contributes to treatment failure and disease progression in lower-risk MDS with del(5q) treated with lenalidomide (53,54). Other notable genomic associations with TP53-mutated MDS/AML include amplifications involving EPOR/JAK2 in patients with acute erythroid leukemia, which is characterized by multihit TP53 mutations (55,56). Germline mutations in ERCC excision repair 6 like 2 (ERCC6L2) have been linked to genomic instability and somatic TP53 mutations leading to AML with erythroid differentiation (57). Poor outcomes with available therapies prompted investigations into the immune architecture and cytokine milieu of TP53-mutated MDS/AML, with the goal of identifying potential immunotherapeutic approaches. TP53-mutated MDS and AML have an enrichment of immunoinhibitory checkpoints including PD-L1 on HSCs, TIM3 on myeloid-derived suppressor cells (MDSC), and LAG3 and TIGIT on bulk bone marrow blasts (20,58,59). Furthermore, TP53-mutated MDS and AML have an immune-dampened microenvironment with upregulation of FOXP3 transcription, an increase in ICOS hi (activated) regulatory T cells and PD-1 lo MDSCs, a decrease in OX40 + cytotoxic T cells and ICOS + and 4-1BB + natural killer cells, as well as marked impairment of CD3−CD28-stimulated T cells to secrete immune-effector Th1 cytokines (polyfunctionality; refs. 20, 58, 60). IFNγ signaling is well recognized as a major driver of response to immune-checkpoint inhibition in solid tumors. Although studies in TP53-mutated AML show that IFNγ signaling may be a biomarker of response to the CD123 × CD3ε dual-affinity receptor targeting (DART) | 3,069,521 | 252816471 | 0 | 16 |
antibody flotetuzumab, there is debate about whether the increased IFNγ signal is a reflection of T-cell fitness in the tumor microenvironment or a sequela of increased inflammation in response to cell death after chemotherapy causing heightened IFNγ production (20,60). Although bulk RNA analysis of bone marrow has shown high IFNγ signaling before therapy in TP53-mutated AML responders to flotetuzumab, single-cell CD3-CD28-stimulated T-cell cytokine profiling has suggested decreased IFNγ and Th1 cytokine secretion by T cells in newly diagnosed and relapsed or refractory (R/R) TP53-mutated AML (20,60). In addition, TP53-mutated AML showed upregulation of proinflammatory Th17 genes, NF-κB, PI3K-AKT signaling, and other markers of immune senescence. One could postulate that these aspects may not only affect response to standard therapies but also potentially abrogate the development of a robust graft-versusleukemia effect (20). In summary, these data point toward a profound immune dysregulation, with features of immunosenescence with an overall immune-evasive phenotype, which could potentially be leveraged to develop novel immunotherapy approaches for TP53-mutated MDS/AML. CURRENT THERAPIES FOR TP53-MUTATED MDS AND AML HMAs are the current standard approach for newly diagnosed HR-MDS and offer an overall response rate (ORR) of 17% to 77% [encompassing complete remission (CR), marrow complete remission (mCR), partial response (PR), and hematologic improvement (HI)] in patients with TP53-mutated MDS, with International Working Group (IWG) CR in 10% to 25%, and a median OS of 8.2 to 12.4 months, with one study reporting an ORR of 100% (n = 9) with the 10-day regimen of decitabine (45,61,62). In MDS, TP53 deletions are associated with significantly | 3,069,522 | 252816471 | 0 | 16 |
lower response rates to HMAs, and TP53 VAF more than 40% confer significantly worse outcomes with a median OS of 4.1 to 7.7 months with HMA therapy (Table 1; refs. 29,45). In a large cohort of patients with MDS and oligoblastic AML who underwent sequential genomic testing during HMA therapy, TP53 mutation was a strong negative predictor with a median OS of 9.7 months (HR, 2.33; P = 0.001). Importantly, a clearance of TP53 mutations (i.e., to VAF of <5%) was a strong predictor of improved outcomes to HMA therapy, particularly in patients who were bridged to allogeneic stem cell transplantation (allo-SCT; HR 0.28; P = 0.001; ref. 44). In TP53-mutated AML, first-line therapy with low-intensity chemotherapies-for example, HMAs or low-dose cytarabinebased regimens-demonstrated an ORR of 14% to 62% with a median OS of 2.1 to 8.1 months. The rates of response with the 5-day versus 10-day regimen of decitabine were similar (29% vs. 47%, P = 0.40) in a single-institution randomized study (6,(63)(64)(65)(66). Intensive chemotherapy-based approaches offered similar outcomes with an ORR of 47% to 55% and a median OS of 6.8 to 10.1 months, often with more toxicities, longer hospital stays, and prolonged myelosuppresion (6,63,64,67). Baseline TP53 VAF was prognostic for response to cytarabine-based regimens with VAF >40% associated with an inferior CR and CR with incomplete hematologic recovery (CRi) rate of 35% and median OS of 4.7 months compared with a CR/CRi rate of 79% and median OS of 7.3 months in patients with TP53 VAF ≤40% (47). TP53 VAF, however, did not | 3,069,523 | 252816471 | 0 | 16 |
seem to affect response rates and median OS in the context of HMA-based regimens for AML, unlike the trend observed in TP53-mutated MDS with HMA (47). TP53 mutations confer resistance to venetoclax-based regimens in AML through alterations in mitochondrial homeostasis by inhibiting mitochondrial stress response and increasing oxidative phosphorylation (68). Leukemia cells with TP53 loss have an increased threshold for BAX/BAK activation, and although this can be suppressed initially by venetoclax, over time they are able to escape BCL-2 inhibition due to competitive advantage (49). HMA with venetoclax did show encouraging responses in first-line, TP53-mutated, poor cytogenetic risk AML, with a CR/CRi rate of 41% (CR rate of 20%) versus a CR/CRi rate of 17% (CR rate of 11%) with HMA alone, as noted in subset analysis from the phase IB study of HMA with venetoclax and the VIALE-A trial (46,48,(69)(70)(71). However, the median OS in older/unfit patients with AML treated with venetoclax and HMA was 6.5 months, which was similar to the 6.7 months with HMA alone. Given prior data suggesting 10-day decitabine may have a specific benefit in TP53-mutated AML, one study combining decitabine for 10 days with venetoclax showed a CR/CRi rate of 57% (CR rate 37%) but a median OS of only 5.2 months (46). A high 60-day mortality rate of 26% was observed with decitabine plus venetoclax, mainly due to refractory disease, and contributed to poor long-term OS. Nonetheless, venetoclax may still have a role in combination with novel therapies in TP53-mutated AML, harnessing independent mechanisms of synergy. Combined inhibition of | 3,069,524 | 252816471 | 0 | 16 |
BCL-2 and MCL1 as well as blockade of extrinsic and intrinsic apoptotic pathways may also offer a novel approach that preclinically appears to be effective against TP53-mutated AML (49,72). ROLE OF ALLO-SCT IN TP53-MUTATED AML Multiple analyses have shown that patients with TP53mutated AML/MDS harbor an 80% to 90% higher risk of relapse and death after allo-SCT compared with TP53 wildtype patients (25,73,74). A majority of these relapses and death following allo-SCT occur in patients with concomitant chromosome 17 abnormality or complex karyotype, leading to multihit disease (75). However, among patients with TP53mutated AML, allo-SCT in first remission (CR1) can reduce the risk of relapse by up to 80% and risk of death by up to 70% (47). However, only a minority of patients with TP53mutated AML, regardless of age or fitness, are able to proceed to allo-SCT in CR1, ranging from 0 to 33% across different published series, with lower response rates, poor count recovery, increased rates of early mortality, and early relapse being the predominant barriers to allo-SCT in this population (46,47,66). A case could be made for limiting allo-SCT only in TP53-mutated patients with AML who achieve at least a morphologic remission (i.e., <5% marrow blasts), as outcomes in patients not in morphologic remission before allo-SCT are poor in general and even more inferior in TP53-mutated patients. Clearance of TP53 mutation prior to allo-SCT has been shown to be a favorable prognostic marker, and patients who achieve TP53 mutation clearance or <5% by next-generation sequencing should be strongly considered for transition to allo-SCT | 3,069,525 | 252816471 | 0 | 16 |
in otherwise suitable candidates (76). Although augmented reduced-intensity conditioning with fludarabine/amsacrine/cytarabine-busulphan has not been shown to improve outcomes over a fludarabine-based reduced-intensity conditioning regimen, a myeloablative conditioning regimen has been shown to improve survival over reduced-intensity conditioning in patients with AML with measurable residual disease (MRD; refs. 77, 78). Even with allo-SCT in TP53-mutated MDS and AML, the risk of relapse remains very significant and long-term survival remains low at less than 20% (28,29). Nevertheless, allo-SCT still appears to offer the best chances of improving outcomes and achieving long-term survival in appropriately selected patients, with up-front noncytotoxic strategies to attain remissions without severe toxicities, early transition to allo-SCT in suitable candidates, close peritransplant monitoring for TP53-mutated clones, and the use of rational maintenance therapies after transplant to improve outcomes in TP53-mutated patients (75). To this end, novel mutant p53-directed therapies such REVIEW NOVEMBER 2022 CANCER DISCOVERY | 2521 as eprenetapopt in combination with azacitidine have shown promising results as maintenance therapy after allo-SCT. In patients with TP53-mutated AML/MDS following allo-SCT, this combination showed a median relapse-free survival of 14.5 months and a median OS of 20.6 months, which compared favorably with historical expectations (79). EMERGING STRATEGIES FOR TP53-MUTATED MDS AND AML Recent progress in immunotherapeutics and mutant p53directed approaches offer the hope of potentially improving outcomes in these patients ( Fig. 2; ref. 80). In this section, we discuss emerging data with four promising agents in this space, namely, magrolimab, flotetuzumab, sabatolimab, and eprenetapopt, and have briefly described other emerging strategies with potential for the field | 3,069,526 | 252816471 | 0 | 16 |
of TP53-mutated MDS/AML ( Table 2). Magrolimab CD47 is an integrin-associated antiphagocytic protein that is overexpressed in cancer cells and correlates with poor outcomes in AML. It binds to the signal receptor protein-α (SIRPα) on macrophages and dendritic cells and enables immune evasion by inhibiting prophagocytic receptors like complement receptor 3, Fc receptors, and SLAMF7 from initiating phagocytosis (81). Magrolimab (Hu5F9-G4) is a first-in-class humanized IgG4 monoclonal antibody against CD47 and prompts cancer cell phagocytosis by macrophages through disruption of the CD47-SIRPα inhibitory checkpoint, thereby blocking the "don't eat me signal." CD47 is also an LSC marker, and targeting CD47 can potentially eliminate LSCs while sparing normal HSCs. Preclinical studies showed synergism between azacitidine and magrolimab in AML cell lines, and this combination was tested in a phase Ib trial that enrolled older/unfit patients with newly diagnosed AML ineligible for induction therapy and newly diagnosed intermediate-to high-risk MDS. Among older/unfit patients with TP53-mutated AML treated on this trial (n = 72), azacitidine with magrolimab showed an ORR of 49% (n = 35/72) and a CR rate of 33% (n = 24/72; ref. 82). The median duration of response (DOR) was 8.7 months, and the median OS was 10.8 months (82). In 25 patients with TP53-mutated Flotetuzumab CD123 serves as the receptor for IL3, and its downstream signaling promotes hematopoietic progenitor cell proliferation through activation of the PI3K/MAPK pathway and upregulation of antiapoptotic proteins (86). CD123 is differentially expressed in about 90% of patients with AML, and overexpression on AML blasts is associated with inferior outcomes (87,88). | 3,069,527 | 252816471 | 0 | 16 |
Flotetuzumab is a CD123 × CD3ε DART molecule that mediates T-cell activation and proliferation, resulting in the eradication of CD123-expressing primary AML blasts in vitro and in vivo (86,89). Flotetuzumab was evaluated in a phase I/II study in R/R AML, enriched for patients with AML with primary induction failure or early relapse (within 6 months of response; ref. 90). Among patients with TP53-mutated R/R AML, the ORR was 47% (n = 7/15) with an encouraging median OS of 10.3 months in responding patients (20). The relatively short durability of response outside of patients who were bridged quickly to allo-SCT remains a challenge with a DOR of 2 to 5 months in nontransplanted patients. CD123 expression did not correlate with response or cytokine release syndrome with flotetuzumab. Transcriptomic analysis suggested that an IFNγ-enriched, immuneinfiltrated tumor microenvironment predicted response to flotetuzumab, and an immunosuppressed tumor microenvironment could be rejuvenated by flotetuzumab through T cell-driven mechanisms (90). Specifically among TP53mutated patients, higher bulk RNA expression of FOXP3, PD-1, and inflammatory chemokines correlated with a response along with CD8B and IFNG (20,90). Vibecotamab (XmAb14045) is another CD123 × CD3 bispecific T-cell engager (BiTE) that showed a modest ORR of 14% (n = 7/51) in R/R AML (91). Multiple CD33-directed BiTEs are currently in the dose-escalation phase and have yielded modest responses in R/R AML. There are several other bispecific antibody platforms targeting CD123, CD33, CD135, CLEC12A, as well as novel natural killer (NK) cell-directed bispecific engager and trispecific engagers in early clinical development and if found to be effective and | 3,069,528 | 252816471 | 0 | 16 |
safe may be interesting to evaluate for TP53-mutated AML given their potential mutation-agnostic mechanism of actions. Eprenetapopt Eprenetapopt (APR-246) is a first-in-class agent that binds covalently to cysteine residues in the core DNA domain of mutant p53 and is postulated to cause refolding and restoration of an active wild type-like conformation and function of p53 (16). Other proposed mechanisms of this class of agents include induction of cell death via reactive oxygen species, ferroptosis, depletion of deoxyribonucleotides, and triggering of unfolded protein responses through depletion of antioxidants (92)(93)(94)(95). Two studies evaluated eprenetapopt with azacitidine in newly diagnosed adults with HMA-naïve low-to high-risk MDS, AML, and MDS/myeloproliferative neoplasm (MPN; refs. 96,97). In a pooled analysis of the two trials, significantly higher rates of CR were noted in patients with isolated TP53 mutations (CR rate of 52% vs. 30%), and in patients with biallelic TP53 mutation or complex karyotype (CR rate of 49% vs. 8%; ref. 98). Additionally, patients with complete or partial remission and/or clearing TP53 mutation (VAF sensitivity 1%) and proceeding to allo-SCT had favorable outcomes with the median OS not reached. In the overall AML, MDS, MPN population, IHC of bone marrow mononuclear cells showing more than 10% staining for p53 was associated with a higher CR rate (66% vs. 13%, P = 0.01; ref. 96). Reduction of mutant TP53 VAF below 0.1% was associated with improved OS (not reached vs. 10.7 months, P = 0.05; ref. 97). However, in a randomized trial in newly diagnosed patients with TP53-mutated MDS, azacitidine with eprenetapopt versus azacitidine | 3,069,529 | 252816471 | 0 | 16 |
with placebo did not meet the primary endpoint in spite of a numerically improved CR rate (33% vs. 22%, P = 0. 13; refs. 99, 100). Preliminary results of a triple combination of eprenetapopt in combination with venetoclax and azacitidine in previously untreated TP53-mutated AML (n = 30) showed a CR/CRi rate of 53% and a CR rate of 37%, and accrual is ongoing (101). A nextgeneration oral p53 reactivator, APR-548, is currently under preclinical development. Mutant-specific p53 activators, such as PC14586 for p.Y220C, are currently under investigation for solid tumors (NCT04585750; ref. 102). Sabatolimab The potential for immunotherapeutic agents to act in a p53-agnostic manner and potentially circumvent some of the p53-associated resistance mechanisms, as well as growing insights into immune microenvironmental remodeling by TP53-mutant AML/MDS, has led to an increasing interest in evaluating other immunotherapies in TP53-mutant AML/ MDS. TIM3 is another checkpoint that forms part of a coinhibitory receptor module expressed on exhausted T cells and is preferentially overexpressed on MDS/AML LSCs (103,104). TIM3 is involved in an autocrine signaling loop via galectin-9, which promotes LSC renewal, and antibodies blocking TIM3 could therefore selectively eradicate AML LSCs (105,106). Sabatolimab (MBG453) is a humanized, high-affinity IgG4targeting TIM3 being evaluated in solid tumors and hematologic malignancies. A phase Ib trial evaluated sabatolimab with HMA in newly diagnosed patients with HR-MDS by the Revised International Prognostic Scoring System (IPSS-R; n = 53) or AML unfit for intensive therapy (n = 48; ref. 107). The adverse event profile of the combination was consistent with that of HMA | 3,069,530 | 252816471 | 0 | 16 |
alone with few and mostly lower-grade immune-related adverse events noted. In patients with HR-MDS, this combination demonstrated an ORR of 57% (CR rate 20%) and a median DOR of 17.1 months. Among patients with newly diagnosed AML, this combination yielded a CR/ CRi rate of 30%, a CR rate of 25%, and a median DOR of 12.6 months. Specifically, in patients with HR-MDS with adverse-risk mutations TP53, RUNX1, and ASXL1, the CR/ mCR rate was 43% and the median DOR was encouraging at 21.5 months in 10 of 14 responders. In patients with newly diagnosed TP53-mutant AML, the CR/CRi was 40% with a median DOR of 6.4 months. OTHER IMMUNOTHERAPEUTIC APPROACHES SIRPα α-directed therapies to the macrophage ligand SIRPα offer another approach to disrupt the CD47-SIRPα immune checkpoint and modulate MDSCs. These agents may potentially mitigate on-target adverse effects of anti-CD47 antibody (e.g., anemia). Such therapies including anti-SIRPα antibodies (e.g., OSE-172 and CC-95251) and SIRPα fusion proteins (e.g., ALX148 and TT-621) are currently in phase I trials, with ALX418 and TTI-621 being evaluated in combination with HMA in MDS and in combination with HMA with venetoclax in AML. Immune-checkpoint inhibitor-based regimens have overall yielded modest results in MDS/AML so far. The initial report with single-agent ipilimumab yielded a CR in 42% of patients (n = 5/12) with relapsed AML after allo-SCT, generating a great deal of excitement for this field in AML and MDS (108). Blockade of PD-1 or PD-1 and CTLA-4 with azacitidine or high-dose cytarabine in all R/R AML yielded modest CR/ CRi rates | 3,069,531 | 252816471 | 0 | 16 |
of 14% to 36% in patients. The median OS was 6.3 to 10.5 months, with an ORR of 23% in TP53-mutated R/R AML in these PD-1-based combinations (109,110). In the first-line setting, nivolumab with idarubicin and cytarabine yielded a CR/CRi of 50% in patients with TP53-mutated AML (n = 4/8; ref. 67). Unfortunately, no significant improvement in CR/CRi rates or in OS in first-line higher-risk MDS (n = 84) or first-line older/unfit AML (n = 129) was noted in a randomized, first-line phase II study of azacitidine with or without the anti-PD-L1 antibody durvalumab, resulting in tempered enthusiasm and uncertain future for PD-1/PD-L1/ CTLA-4-based therapies in myeloid malignancies (111,112). Cellular therapy approaches have been challenging to develop due to the hostile milieu of the bone marrow niche in AML (80). Chimeric antigen receptor (CAR) T-cell therapies directed at myeloid antigens, including CD33, CD38, CD70, CD123, CD135, CD371, CLL1, FLT3, TIM3, LILRB4, NKG2D, Lewis Y, and others, are still in early development, with modest responses ranging from isolated blast count reductions to brief CR/CRi in up to 50% of patients in the dose-escalation cohorts (28,113). One second-generation CAR-T targeting CLL1 has shown promising outcomes in pediatric AML with CR/CRi in six of eight patients without any grade 3/4 cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome (114). Although CLL1 is not expressed in HSCs, its expression on granulocytes and monocytes led to associated neutropenia, which resolved only after the eradication of CLL1 CAR-T cells. Novel approaches to safely improve CAR-T efficacy through targeting multiple antigens with | 3,069,532 | 252816471 | 0 | 16 |
novel gating strategies, enhancing fitness and in vivo persistence, overcoming the immunosuppressive microenvironment, and developing allogeneic CAR-based approaches will hopefully lead to better cellular therapies for AML (115). Development of T-cell receptor-like antibodies against mutant p53 and the potential for engineering similar adoptive T-cell approaches are in early preclinical development (116,117). Off-the-shelf modified NK cell-based approaches have shown early promise in R/R AML with no dose-limiting toxicities or cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, or graft-versus-host disease. In a phase I trial of FT516/538 (an induced pluripotent stem cellderived high-affinity, noncleavable CD16 expressing NK cell) in 12 patients with R/R AML with a median of three prior lines of therapy, the ORR was 42% with durable remissions in two patients lasting >6 months without subsequent interventions after NK infusions (118). If successful, such strategies may find an important role in traditionally difficult-to-treat molecular and cytogenetic subsets such as TP53, RUNX1, and inv3q and other subsets of AML/MDS. Such approaches may be especially attractive in patients with low-burden disease, MRD + disease, or potentially as maintenance after AML therapy or after allo-SCT in high-risk patients in remission, as these patients are likely to have a more favorable tumor microenvironment potentially not rendered deranged by the presence of highvolume aberrant myeloid cells. Other similar adoptive cellular therapies rapidly entering the clinic for AML/MDS include gamma-delta T cells, and invariant NKT cells are currently in preclinical development (refs. 119-121). OTHER NONIMMUNOLOGIC APPROACHES COTI-2 is a thiosemicarbazone compound with effects like eprenetapopt. It binds to mutant p53 and | 3,069,533 | 252816471 | 0 | 16 |
reverses conformation to a wild-type form, thus restoring DNA-binding function and normalizing wild-type p53 target gene expression (16). It can also act independently through inducing DNA damage, causing replication stress, activating AMP-activated protein kinase, and inhibiting the mTOR pathway. It showed acceptable safety in a phase I trial in gynecologic malignancies (NCT02433626; ref. 122). Other similar mutant p53 reactivators including PK110007, HO-3867, and PK7088 are in various stages of development. Other miscellaneous approaches with potential application to TP53-mutated MDS/AML include arsenic trioxidebased approaches to induce proteasomal degradation of mutant p53 (arsenic trioxide has been shown to structurally stabilize p53 mutants and transcriptionally rescue a subset of mutants through a cryptic allosteric site; ref. 123), statinbased approaches to promote mutant p53 degradation via inhibition of the mevalonate pathway, and restoring zinc to zinc-deficient p53 mutants (16,27,124,125). Future approaches directed toward TP53 mutations may include promotion of premature termination codon readthrough enabling the production of full-length p53 and gene replacement therapies (16,27). In addition, rational combinations or sequential approaches of previously mentioned strategies with the integration of allo-SCT as a part of the continuum of therapy may be needed to improve response durability and survival of TP53mutated MDS and AML. CONCLUSION Four decades of cumulative discoveries have brought us to what is hopefully the cusp of important breakthroughs in the field of TP53-mutated cancers, with many of these efforts culminating in clinical trials being initiated in myeloid malignancies. With the increasing recognition of TP53mutated MDS and AML as distinct stem cell disorders, we are beginning to better understand | 3,069,534 | 252816471 | 0 | 16 |
the diverse genetic and immune landscape of TP53 alterations, their functional consequences on both the tumor and the immune microenvironment, and the heterogenous nature of TP53 mutations with varied prognostic consequences. Clearly, it is now well recognized that TP53-mutant MDS/AML disease represents a singular entity with poor outcomes necessitating dedicated clinical interventions with the hope of developing and optimizing the first TP53-specific agents. Encouraging early results of novel innate and adaptive immunotherapeutic approaches and mutant p53 reactivators in combination with HMA with or without venetoclax are showing encouraging efficacy that needs to be confirmed in randomized registration studies. If successful, new questions will emerge regarding predictive biomarkers, time and role of allo-SCT, resistance mechanisms, side effect management, and optimal combination and sequencing strategies as well as maintenance applications of such novel strategies with the eventual hope of improving survival in this extremely difficult patient population. Authors' Disclosures N.G. Daver reports grants and personal fees from Gilead, Pfizer, AbbVie, Shattuck Labs, Bristol Myers Squibb, Kite, Genentech, Daiichi Sankyo, Astellas, Novartis, Immunogen, Hanmi, and Servier and grants from Fate and KAHR Therapeutics outside the submitted work. A. Maiti reports other support from BioSight, Sanofi, and Astex Pharmaceuticals outside the submitted work. T.M. Kadia reports grants and personal fees from AbbVie, Jazz, and Genentech, personal fees from Agios and Daichii Sankyo, and grants from | 3,069,535 | 252816471 | 0 | 16 |
A systematic review and meta-analysis on the prevalence of stigma in infectious diseases, including COVID-19: a call to action Infectious diseases, including COVID-19, are crucial public health issues and may lead to considerable fear among the general public and stigmatization of, and discrimination against, specific populations. This meta-analysis aimed to estimate the pooled prevalence of stigma in infectious disease epidemics. We systematically searched PubMed, PsycINFO, Embase, MEDLINE, Web of Science, and Cochrane databases since inception to June 08, 2021, and reported the prevalence of stigma towards people with infectious diseases including SARS, H1N1, MERS, Zika, Ebola, and COVID-19. A total of 50 eligible articles were included that contributed 51 estimates of prevalence in 92722 participants. The overall pooled prevalence of stigma across all populations was 34% [95% CI: 28−40%], including enacted stigma (36% [95% CI: 28−44%]) and perceived stigma (31% [95% CI: 22−40%]). The prevalence of stigma in patients, community population, and health care workers, was 38% [95% CI: 12− 65%], 36% [95% CI: 28−45%], and 30% [95% CI: 20−40%], respectively. The prevalence of stigma in participants from low- and middle-income countries was 37% [95% CI: 29−45%], which is higher than that from high-income countries (27% [95% CI: 18−36%]) though this difference was not statistically significant. A similar trend of prevalence of stigma was also observed in individuals with lower education (47% [95% CI: 23−71%]) compared to higher education level (33% [95% CI: 23−4%]). These findings indicate that stigma is a significant public health concern, and effective and comprehensive interventions are needed to counteract the damaging | 3,069,536 | 237638484 | 0 | 16 |
effects of the infodemics during infectious disease epidemics, including COVID-19, and reduce infectious disease-related stigma. INTRODUCTION The outbreak of the coronavirus disease 2019 (COVID- 19) around the world has brought public attention to infectious disease epidemics again [1]. In fact, infectious diseases have become more frequent and more complex in recent years, with notable examples such as severe acute respiratory syndrome (SARS), influenza A subtype H5N1, Zika, Ebola, and Middle East respiratory syndrome coronavirus (MERS-CoV) [2], which pose a health threat to the general public and are issues of concern for public health professionals in terms of preventing their spread, promoting public awareness, and educating the public about the diseases [3][4][5]. In view of the possibility of the rapid spread of infectious diseases, infodemics (the rapid and far-reaching dissemination of information of questionable quality) during epidemics and subsequent protracted physical and psychological morbidity and mortality, epidemic-related stigma emerges consequently [6][7][8][9]. Stigma is described as an attribute that is deeply discreditable or undesirable [10] and is further conceptualized as a social process of labeling, stereotyping, and prejudices that lead to segregation, devaluation, and discrimination [10]. Various layers of stigma are explored, including enacted (experienced) stigma and perceived public (anticipated) stigma. Enacted stigma refers to actual negative actions taken against someone due to their infection status [11]. Perceived public stigma refers to the perception of being stigmatized and the anticipation of being discriminated against [12]. Populations vulnerable to stigma during infectious disease epidemics involve both infected individuals and health care workers, especially frontline medical staff [9]. Substantial incidents | 3,069,537 | 237638484 | 0 | 16 |
of stigmatization of healthcare workers and patients have come up during the COVID-19 pandemic across the world [13]. Some patients were fearful of being shamed and accused by others [14], which will bring extra psychological burden to patients and can hinder their social adaptation after recovery. As for frontline medical workers, they were at higher risk of being exposed to COVID-19 virus when working in the hospitals or clinics. Stigma from their families and friends might increase their psychological stress and interfere with their normal work [9]. It was even reported that patients recovered from COVID-19 infection and medical workers were denied access to public transportation, assaulted on the street or in the ordinary course of work, and forced to move out of their rented houses [15,16]. However, these over-generalized applications of stereotypes should be differentiated from realistic fear caused by epidemics. In this case, negative reactions to involved populations does not necessarily mean stigmatization. Some kind of avoidance or social distancing measures during epidemics (e.g., imposing shelter-inplace orders, restricting dining-in at restaurants, home isolation) are required and have been shown effective in containing the spread of the virus [17]. Stigma and discrimination may cause mental stress, physical harm, and loss of jobs and educational opportunities for involved populations, and further pose a serious threat to the control of epidemics and the recovery and development of the economy and society [13,18,19]. Evidence has suggested that stigma contributed to psychological distress and acute and posttraumatic stress (PTSD) of affected patients and healthcare workers during SARS, H1N1, MERS, | 3,069,538 | 237638484 | 0 | 16 |
Ebola, and COVID-19 outbreaks [20][21][22][23]. A cross-sectional study also found that higher level of depression and anxiety were significantly associated with the experience of health facility-related stigma among Ebola survivors [24]. Therefore, stigma can be a hindrance for the public to have an accurate understanding of the disease and can act as a barrier for them to adopt health promoting behavior, seek health care and adhere to treatment, which may lead to suboptimal control of epidemics [25,26]. As COVID-19 might be a continuing threat for the human society, stigma related to this pandemic would be a long-term concern for wellbeing, social recovery, and development in a long time [27]. The rapid spread of the pandemic was associated with high levels of fear [28,29]. From a public health perspective, fear and its associated stigma constituted the high impact of the pandemic [30]. Stigma is a barrier to help-seeking. That means people may not use services (diagnostics, prevention, and/or treatment) in order to avoid labeling/stigma. Therefore, fear associated with stigma and discrimination has significantly compromised the public health efforts [31,32]. Identifying the influence of stigma during the pandemic would be helpful not only for the mental health of affected patients, but also for policy making and social support services globally. However, there is a lack of quantitative estimate of stigma profiles and risk factors among affected individuals during infectious disease epidemics. Therefore, this systematic review and meta-analysis aimed to evaluate the prevalence of stigma during infectious disease epidemics, including COVID-19, to raise public health concern and call for | 3,069,539 | 237638484 | 0 | 16 |
actions to promote the development of effective and comprehensive interventions to reduce infectious disease-related stigma. Search strategy and selection criteria We performed a systematic review and meta-analysis in accordance with preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines (Table S1) [33]. The protocol was registered in International Prospective Register of Systematic Reviews (PROSPERO CRD42020206287 at www.crd.york.ac.uk/PROSPERO). We searched the PubMed, PsycINFO, Embase, MEDLINE, Web of Science, and Cochrane databases to identify studies that reported the prevalence of stigma during infectious disease epidemics, including SARS, MERS, H1N1, H5N1, Zika, Yellow fever, Ebola, Viral Haemorrhagic fevers, and COVID-19, since inception to June 8, 2021. However, other infectious diseases like tuberculosis were not included in our study, as we focused on the infectious diseases that cause a sudden increase in the number of infected cases in a short period of time, of which the outbreak has posed serious public health threats and has been associated with stigma and discrimination against related populations. The search terms were shown in the Appendix. The literature search was limited to English. We also checked the reference lists and review articles for additional studies that might meet the inclusion criteria. Three researchers (Huang XL, Zhang YX, and Huang YT) independently assessed the articles for their eligibility for inclusion. The studies that met the following criteria were included: (1) cross-sectional or cohort studies on the epidemics of infectious diseases including SARS, MERS, H1N1, H5N1, Zika, Yellow fever, Ebola, Viral Haemorrhagic fevers, and COVID-19; (2) defining stigma via self-reported perception or questionnaires; and (3) | 3,069,540 | 237638484 | 0 | 16 |
directly providing prevalence of stigma or sufficient data to calculate the prevalence. Exclusion criteria were as follows: (1) guidelines, book sections, case-reports, commentaries, and conference abstracts; and (2) studies that measured stigma as a numerical variable without cut-off value and the prevalence could not be calculated. If the same population was used in more than one publication, only one publication with the most comprehensive information would be included. The process of identifying eligible studies and the reasons for exclusion are shown in Fig. 1 and eTable 1 in Appendix. Data extraction The data were independently extracted from eligible papers by researchers (Huang XL, Huang YT, Zhong Y, and Wang YJ) and the extracted data were subsequently cross-checked. Discrepancies were discussed until a consensus was reached. The following information was extracted from each study: (1) first author, (2) year of publication, (3) study design, (4) research site (country), (5) total sample size, (6) type of epidemics of infectious diseases, (7) sex proportion of participants, (8) type of study population (patients, community population, and health care workers), and (9) measurement of stigma (question or scale), classification of stigma (enacted stigma, and perceived stigma), etc. (see Table 1). Assessment of study quality Two researchers (Huang XL and Su SZ) assessed the quality of the studies using the Australia's Joanna Briggs Institute (JBI) critical appraisal checklist for prevalence studies [34]. It consists of nine items, and four options (yes, no, unclear, and not applicable) were used for evaluating items (see eTable 2 in Appendix). Disagreements were discussed with and resolved | 3,069,541 | 237638484 | 0 | 16 |
by a third author (Zhang YX). (1) you are treated with less courtesy or respect than other people; (2) Statistical analysis The primary outcomes of interest were the overall prevalence estimates of stigma which were calculated across all studies by using a random-effects model. Subgroups and meta-regression analyses were conducted to explore the potential sources of heterogeneity, including the following variables: study population, region, the levels of economic development, sex, and the proportion of tertiary education. Q and I [2] were calculated to assess heterogeneity across all studies and within subgroups, with I 2 ≥ 50% indicating significant heterogeneity. Egger's test and the funnel plot were used to evaluate publication bias. A bilateral significance level less than 0.05 was considered to be statistically significant. All analyses were calculated with Stata version 15. As some studies included in our studies used items and the left used scales to measure stigma, we further performed subgroup analysis in terms of the measurement tools. Forty studies clearly described stigma items, and 10 studies used modified scales for measuring stigma. One study contributed two estimates of prevalence [24] ( Table 1). The estimated prevalence of stigma was 34% [95% CI: 27-40%] in studies using items and 37% [95% CI: 22-53%] in studies using scales, respectively. The metaregression analysis indicated that the pooled prevalence of stigma based on measurement tools had no significant difference (p = 0.942) (Figs. 3 and S7). The Egger's tests and funnel plots (Fig. 4) did not show a publication bias (p > 0.05). A sensitivity analysis that | 3,069,542 | 237638484 | 0 | 16 |
was used for examining the impact of each study on the overall results showed similar estimates of stigma prevalence after excluding any single study, indicating that any study included in the present metaanalysis was unlikely to have a disproportionate impact on the reported prevalence estimates. DISCUSSION To our knowledge, this systematic review and meta-analysis provides the first quantitative estimate of stigma of affected individuals during infectious disease epidemics. We found that over a third of vulnerable populations reported infectious disease epidemic-related stigma, mainly involving infected patients, community members, and health care workers. People from low-and middle-income countries or with lower education are vulnerable populations who may have a greater risk of reporting stigma (enacted stigma or perceived public stigma). The results indicate that stigma is a significant public health concern during infectious disease epidemics, including COVID-19, and calls for actions to raise public health concern and develop effective and Fig. 3 Subgroup analysis of prevalence estimates across variables. We performed subgroup analyses with regard to stigma type, countries, type of infectious outbreak, gender, education level, and measurement tools. Meta-regression showed that the estimated prevalence based on different characteristics subgroup had no significant difference (p > 0.05). comprehensive interventions to reduce infectious disease-related stigma. The rapid spread of an epidemic is typically associated with high levels of fear, which is manifested as stigma of and discrimination against affected individuals. Stigma can be a hindrance for the public to have an accurate understanding of the disease and can impose an adverse effect on the control of infectious disease | 3,069,543 | 237638484 | 0 | 16 |
epidemics. For example, during the COVID-19 epidemic, patients were reluctant to disclose their symptoms and see doctors at the early stage when COVID-19 became a social stigma [81]. Patients recovered from COVID-19 infections were even denied to take public transportation, assaulted on the street, or interfered with in their normal work [15,16], which might increase their psychological stress and negatively affect the control of the pandemic. Although there is limited information in the extant literature, effective and accurate educational interventions and protecting policies of affected individuals are needed to counteract the damaging effects of infectious diseaserelated stigma, promote the control of infectious diseases, improve public mental and physical health, and facilitate the social stability and development ultimately. Stigma was commonly reported by patients, community population, and health care workers during the epidemics, which can have a long-term adverse impact on their well-being and willingness to engage with health care. In the general population, enacted stigma (36%) was a little higher than their perceived stigma (31%). This could mean that perceptions were optimistic, underestimating the prevalence of enacted stigma that actually occurred. In community populations, the prevalence was 38% for enacted stigma, and 34% for perceived stigma, respectively. Residents living in places where the outbreak first occurred would be accused of spreading the virus, considered infectious, and thus further subjected to discrimination and stigmatization [83,106]. On the other hand, people may endorse stigma when accepting survivors back into communities. However, variance in epidemicrelated stigma across communities exists and some communitylevel factors may account for this. For example, | 3,069,544 | 237638484 | 0 | 16 |
communities with higher knowledge of the disease and high mobilization efforts were less likely to endorse stigma, while communities that were concerned about providing assistance and care during the epidemics were more likely to endorse stigma (i.e., enacted stigma) [71,107]. Community-level interventions are needed to increase awareness and knowledge of the epidemics among community populations. The high prevalence of enacted stigma (28%) and perceived stigma (31%) among health care workers also indicated that they not only expressed discrimination against some particular groups related to infectious diseases, but also were discriminated more seriously by the general public. During the epidemic of infectious diseases, health care workers are at high risk of infection. Physical and mental exhaustion, fear of infection, worries about passing the infection to their friends and families, as well as medical violence (the conflicting doctor-patient relationship, especially in China) during the pandemic of COVID-19 were main complaints of medical workers [108][109][110]. Moreover, an increasing proportion of medical staffs reported suffering from isolation and avoidance from the community population. They described the feelings of rejection in their neighborhood because of hospital work or the feelings of being treated differently because others knew they might have contacted patients with infectious diseases [60,64]. The stigma they experienced had adverse effects on their mental health. Therefore, more social support policies and mental health services are urgently needed for health care workers to protect their wellbeing and effectively control the epidemics. The finding that individuals with higher levels of education had a lower prevalence of stigma is consistent with our | 3,069,545 | 237638484 | 0 | 16 |
expectations, though no significant difference was observed possibly due to the limited number and heterogeneity of studies included. An overabundance of news and mixed messages is a key driver of stigma in our time, especially during large-scale disasters like COVID-19 [111][112][113]. With a higher level of education, individuals may have better access to accurate knowledge about infectious diseases and have a better understanding of the situation, so that they could distinguish between factual information and misinformation. This may be more difficult for those with lower education level, who may be more easily misled by biased or false information provided by traditional media, social media, and self-proclaimed experts [114]. As previous studies reported, education, clear and correct communication have the potential to significantly improve the knowledge, attitudes, and behaviors related to infectious diseases, such as Ebola and COVID-19, and reduce infectious disease-related stigma [115,116]. Therefore, it is important to improve public awareness of the nature of the disease to reduce fear and anxiety, and subsequently reduce the stigma [117]. In addition, the higher educational level is always associated with high socio-economic status, which could explain the fact that people with higher income level may be less worried and less likely to stigmatize others, especially in high-income countries [118]. However, there were few studies on infectious disease-related stigma from high-income countries, and more studies are needed in the future. Differences in infectious disease-related stigma hinge on the features related to infectious diseases. Among various infectious diseases, stigma related to human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS) has been | 3,069,546 | 237638484 | 0 | 16 |
the most salient and widely studied [119]. However, in our present study, we excluded the infectious diseases like HIV/AIDS that do not cause an outbreak. Compared with infectious diseases like SARS and COVID-19, the means of infection and disease course of HIV/AIDS differ substantially [120]. HIV/AIDS has been perceived as a fatal condition with little hope of recovery since the infection [8], while epidemic-related infectious diseases may be cured by antiviral medications or controlled just by physical distancing. Therefore, the disease course of HIV/AIDS is chronic, while that of epidemic-related infectious diseases is usually acute and timelimited. Furthermore, HIV/AIDS is always being stigmatized with negative connotations such as drug abuse, sex work, poverty, or incarceration, which are considered to be deviant and disapproved by the society [121]. In contrast, epidemic-related diseases such as SARS and COVID-19 are caused mainly by external factors that are not considered as morally reprehensible. Therefore, stigmatization of these infectious diseases is mainly driven by the fear of the disease itself, and will be reduced as the perceived threat level decreases [26,65]. To tackle social stigma derived from infectious disease epidemics, many health authorities and academic associations across the world have appealed to stop stigmatizing and discriminating against certain populations, such as survivors and those from high-risk areas [122,123], highlighting the negative consequences of stigma that compromise efforts to treat the disease and reduce its further transmission. As COVID-19 is still a continuing threat for the human society, several crucial actions are needed to reduce COVID-19-related stigma. First, governments and authorities need | 3,069,547 | 237638484 | 0 | 16 |
to work closely to stop racism and xenophobia toward specific countries and areas at high epidemic level [124]. Evidence shows that disease outbreaks have always been accompanied by an increase in xenophobic or racist sentiment [125]. The COVID-19 is a global public health issue and united efforts are crucial to win the worldwide battle against it. Second, proper public health education with scientific-based information and an anti-stigma campaign appear to be the most effective ways to prevent social harassment of at-risk groups [13,126]. This would also help create an appropriate environment to work together to contain this pandemic. Third, the government and health authorities should appeal for the public to access COVID-19 information from reliable sources like the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). Fourth, community leaders and public health officials should maintain the privacy and confidentiality of survivors, avoid using negative languages that may cause stigmatization, and provide community and social support to challenge stereotypes and stigmatization [123]. Fifth, more research using scales to estimate the prevalence of stigma are needed and more standardized scales should be developed for routine assessment of infectious disease-related stigma in at-risk groups and necessary support should be provided for those who may feel stigmatized [127]. Last but not least, the long-term impact of COVID-19 on stigma should be examined and the effectiveness of protection measures and interventions should be explored in further studies. This study had several limitations that compromise the interpretation of the findings. First, the lack of reliable and valid | 3,069,548 | 237638484 | 0 | 16 |
instruments of infectious disease-related stigma used in the populations studied is a major limitation for both research and practice. Only 10 studies [24,59,73,75,80,82,85,91,97,105] used modified scales for measuring stigma. And these measure tools, such as the Ebola-related stigma Questionnaire, seven-item EVDrelated stigma index, varied widely in terms of measurement development, the groups surveyed and the domains assessed (i.e., knowledge, attitude, and behavior). Moreover, other studies without valid scales measured the prevalence of infectious disease-related stigma by using one or more items. We defined the (combined) proportion of "Yes" of one item or several items in studies as the (combined) prevalence of stigma in these studies. Standardized scales should be developed to assess infectious disease-related stigma in further studies. Second, although we initially searched for all major infectious disease epidemics, the majority of eligible studies (47 out of 50) mainly focused on Ebola, SARS, and COVID-19, resulting in insufficient data to allow subgroup analysis of the prevalence of stigma in other infectious diseases. Furthermore, the literature search in the present study was limited to English, which may omit some useful studies related to the stigmatization of infectious diseases in other languages. Finally, there was high heterogeneity in the estimated prevalence of stigma with an I 2 of more than 99%, possibly because of the vastly diverse and non-standardized scales used in the included studies as mentioned above. Furthermore, we also took measures to find out other sources of heterogeneity, including using random-effect models, subgroup analysis, and meta-regression analysis. Sensitivity analyses were also conducted to identify the influence | 3,069,549 | 237638484 | 0 | 16 |
of individual studies on the pooled estimates by excluding each of the studies from the pooled estimate. Nonetheless, the remaining unexplained heterogeneity was still substantial. More research is needed to provide us with more accurate information about the prevalence of infectious disease-related stigma. CONCLUSIONS In conclusion, individuals reported infectious disease-related stigma, including enacted stigma and perceived stigma, exceeded one-third, with the highest prevalence of stigma observed in infected patients, followed by community populations and health care workers. Our findings indicate that infectious disease-related stigma is a significant public health concern during infectious disease epidemics, including COVID-19. Governments and public health authorities need to pay more attention to take comprehensive and effective measures and strategies to eliminate or reduce threats of infectious disease-related stigma. | 3,069,550 | 237638484 | 0 | 16 |
Lifting decoders for classical codes to decoders for quantum codes The design of decoding algorithms is a significant technological component in the development of fault-tolerant quantum computers. Often design of quantum decoders is inspired by classical decoding algorithms, but there are no general principles for building quantum decoders from classical decoders. Given any pair of classical codes, we can build a quantum code using the hypergraph product, yielding a hypergraph product code. Here we show we can also lift the decoders for these classical codes. That is, given oracle access to a minimum weight decoder for the relevant classical codes, the corresponding [[ n, k, d ]] quantum code can be efficiently decoded for any error of weight smaller than ( d − 1) / 2 . The quantum decoder requires only O ( k ) oracle calls to the classical decoder and O ( n 2 ) classical resources. The lift and the correctness proof of the decoder have a purely algebraic nature that draws on the discovery of some novel homological invariants of the hypergraph product codespace. While the decoder works perfectly for adversarial errors, it is not suitable for more realistic stochastic noise models and therefore can not be used to establish an error correcting threshold. The construction of quantum codes often takes classical codes as a starting point. The CSS construction is one method for combining a pair of classical codes into a quantum code. However, the CSS recipe only works when the pair of classical codes are dual to each other. | 3,069,551 | 233864693 | 0 | 16 |
Unfortunately, some of the best known classical code families, such as those based on expander graphs, do not come in convenient dual pairs. The hypergraph product is a different recipe that allows a pair of arbitrary classical codes to form the basis of a quantum code [1]. Crucially, when the hypergraph product uses families of classical low-density parity check (LDPC) codes, it leads to families of quantum-LDPC codes. The quantum-LDPC property eases the experimental difficulty of implementation and, combined with suitably growing distance, ensures the existence of an error correction threshold [2]. Two of the most widely known quantum codes, the toric and surface codes, are hypergraph product codes that use the classical repetition code as their seed classical code. The decoding problem for the surface code can be recast as a minimum-weight perfect-matching problem, which is efficiently solved by the blossom algorithm [3,4] and the union-find algorithm [5]. Another interesting class of hypergraph product codes uses classical expander codes as their seed, with the resulting offspring called quantum expander codes [6], which are quantum-LDPC codes achieving both constant rate and Ω( √ n) distance. The classical expander codes can be decoded by a very simple bit-flip algorithm discovered by Spiser and Spielman [7]. This inspired the small-set flip decoder for quantum expander codes, which follows a similar idea but is slightly modified, and has been shown to correct adversarial errors [6], stochastic errors [8] and also to operate as a single-shot decoder [9]. However, there are a broad range of hypergraph product codes that are | 3,069,552 | 233864693 | 0 | 16 |
neither surface codes nor quantum expander codes, for which there is no general propose strategy for decoder design that is proven to work across the whole code family. For classical LDPC codes, using a belief propagation decoder (BP) works well in practice, though it is a heuristic without any rigorously established performance promises. Furthermore, the classical BP decoder cannot be used out of the box on quantum-LDPC codes. In fact, whenever a decoding instance has more than one minimum weight solution, it is degenerate, BP does not converge and yields a decoding failure. Degeneracy is the quintessential feature of quantum codes and therefore some workarounds are needed to use BP on quantum-LDPC codes [10,11]. The literature offers many examples of BP inspired decoders for quantum-LDPC codes which show an error correcting threshold [12][13][14][15][16][17], however, as for the classical BP, none of them come with a correctness proof. Recently, a union-find like decoder has been proposed to decode quantum-LDPC codes [18]. The authors in [18] prove that their union-find decoder corrects for all errors of weight up to a polynomial in the distance for three classes of quantum-LDPC codes: codes with linear confinement (see [19,20]), D-dimensional hyperbolic codes and D-dimensional toric codes for D ≥ 3. The decoder in [18] is therefore provably correct for adversarial noise, nonetheless a comprehensive investigation of its performance under stochastic noise is still missing. Here we introduce the ReShape decoder for generic hypergraph product codes. Given a hypergraph product built using classical codes with parity matrices δ A and δ B | 3,069,553 | 233864693 | 0 | 16 |
, we assume access to a minimum weight decoder for parity matrices δ A , δ B , δ T A and δ T B . The ReShape decoder calls these classical decoders as blackbox oracles without any modification or knowledge of their internal working, and furthermore only requires O(k) oracle calls, and only a polynomial amount of additional classical computation. Under these conditions we prove that ReShape works in the adversarial setting, correcting errors (up to stabilisers) of weight less than half the code distance. Therefore, ReShape lifts the classical decoders to the status of a quantum decoder, providing the first general purpose hypergraph product codes decoder proven to correct adversarial errors. Formally we prove: Theorem 1. Any [[n, k, d]] hypergraph product code constructed from the classical parity check matrices δ A and δ B can be successfully decoded from error of weight up to (d − 1)/2 using O(k) oracle calls to classical decoders for the seed matrices and their transpose plus O(n 2 ) classical operations. Theorem 1 though, does not state anything about stochastic noise or error correcting thresholds. Families of n-qubit hypergraph product codes have distance of at most O( √ n) and so they are bad codes in the sense that the distance is sub-linear. However, given a stochastic noise model with each qubit affected independently with probability p, the typical error size will be pn. Thus, for n > (d/2p), the most likely errors will not necessarily be corrected by ReShape and there is no guarantee that a | 3,069,554 | 233864693 | 0 | 16 |
threshold will be observed. Indeed, we implemented ReShape for several code families and found evidence that ReShape fails to provide a threshold (see Fig. 3). A clear open problem is whether there exists a similar general lifting procedure, or modification of ReShape, for which one can prove good performance in the stochastic settings. Hence, if on one hand Theorem 1 provides a solution to the adversarial decoding problem for hypergraph product codes, on the other, a stronger, difficult and much longed-for result is desirable. Namely, the solution of the stochastic decoding problem for hypergraph product codes both on a theoretical level (proof of a threshold) and on a practical one (numerical observation of a high correcting threshold). Even so, if we contrast ReShape with what said on BP and union-find like decoders, we see that ReShape improves on the former in that it is provably correct and on the latter because its correction capability are optimal, (d − 1)/2 against a polynomial in d. I. PRELIMINARIES AND NOTATION A classical [n, k, d] linear code is compactly described by its parity check matrix H. The matrix H is a binary matrix of size m × n such that the codespace C(H) ⊆ F n 2 is described by: The codespace C(H) has dimension k = n − rank(H) and distance d defined as: where |v| is the Hamming weight of the binary vector v. Whenever the parity check matrix has columns and rows of small weight we say that it is a low density parity check | 3,069,555 | 233864693 | 0 | 16 |
(LDPC) matrix; when H has constant column and row weight w c , w r we shortly say that it is a (w c , w r )-matrix. The classical decoding problem can be stated as: given a syndrome vector s ∈ F m 2 , find the minimum weight solution e r ∈ F n 2 to the equation It is easy to show that the optimal decoder for any classical linear code can correct errors of weight up to half the code distance (see, for instance, [21]). A quantum [[n, k, d]] stabiliser code [22] is a subspace of dimension 2 k of the Hilbert space (C 2 ) ⊗n . It is described as the common +1 eigenspace of its stabiliser group S, an Abelian subgroup of the Pauli group P n such that −1 ∈ S. The Pauli group on n qubits is the group generated by the n-fold tensor product of single qubit Pauli operators. The weight |P | of a Pauli operator P ∈ P n is the number of its non-identity factors. We indicate by N (S) the normaliser of S i.e. the group of Paulis which commute with the stabiliser group S. Because S ⊆ N (S), the quotient group L = N (S) /S is well defined. Elements [P ] of L are equivalence classes with respect to the congruence modulo multiplication by stabiliser operators: Each Pauli P such that [P ] = 0 in L is an operator that preserves the codespace and has non-trivial action | 3,069,556 | 233864693 | 0 | 16 |
on it. We refer to such code operators modulo S as logical Pauli operators; with slight abuse of notation we write P ∈ L, meaning [P ] ∈ L. Two logical operators P, Q are said to be homologically equivalent, or just equivalent, if and only if [P ] = [Q]. Importantly, for a code of dimension k, L P k . The distance d of the code is the minimum weight of any non-trivial logical operator in L. Any generating set of the stabiliser group S induces a syndrome map σ. Namely, if S = S 1 , . . . , S m , the associated syndrome function σ maps any Pauli P ∈ P n in a binary vector s = (s 1 , . . . , s m ) T ∈ F m 2 such that s i = 0 if and only if P commutes with S i and 1 otherwise. We refer to the vector s as the syndrome. Conventionally, when considering a stabiliser code, it is always intended that a generating set {S 1 , . . . , S m } for the stabiliser group is chosen and with it a syndrome map. We say that a stabiliser code is LDPC if each S i has low weight and each qubit is in the support of only a few generators. The decoding problem for stabiliser codes can be stated as: given a syndrome vector s ∈ F m 2 , find an operator E r ∈ P | 3,069,557 | 233864693 | 0 | 16 |
n such that (i) σ(E r ) = s and (ii) where E min is a minimum weight operator with syndrome s. We call any operator that satisfies (i) a valid solution of the syndrome equation and operators for which both (i) and (ii) are true, correct solutions. Pauli operators can be put into a one-to-one correspondence with binary vectors, if we discard the phase factor ±i. In fact, any Pauli P can be written as: from which it follows: This correspondence between binary vectors and Pauli operators is particularly handy when dealing with CSS codes [23,24]. CSS codes are stabiliser codes for which the stabiliser group can be generated by two disjoint sets S x and S z of X and Z type operators respectively. . . , Z[w mz ]} and we define H X and H Z as the matrices whose rows are the v i s and the w i s respectively, then the commutation relation on the stabilisers generators translate in to the binary constraint H X H T Z = 0. Using Eq. (4), it is easy to show that the syndrome for a Pauli error E = X[e x ]Z[e z ] is described by the two binary vectors s z = H Z e x and s x = H X e z . Since these two linear equations are independent, we can treat the X-part and Z-part of the error separately. For CSS codes, we define the X-distance d x as the minimum weight of an operator | 3,069,558 | 233864693 | 0 | 16 |
X[v] which commutes with all the stabilisers in S z but does not belong to the group generated by S x . Note that the weight of an operator X[v] equates the Hamming weight |v| of the vector v. Therefore, combining Eq. (3), Eq. (4) and the definition of d x , we shortly say that d x is the minimum weight of a vector v in ker H Z which does not belong to the row span of Similarly, d z is the minimum weight of a vector in ker H X not in Im H T Z . The Z-error decoding problem for CSS code can be stated as: given a syndrome vector s ∈ F mx 2 , find a valid and correct solution e r ∈ F n 2 to the equation: [25,26]. In this article we focus on a sub-class of CSS codes, the hypergraph product codes [27][28][29][30]. We give a minimal description of these codes in Sec. II and we refer the reader to App. B for a more detailed presentation. We study some homology invariants for the logical operators of the hypergraph product codes in Sec. III A. These invariants are the algebraic core upon which we design a decoder for these codes, the ReShape decoder. We prove that ReShape is an efficient and correct decoder for adversarial noise in Sec. III B. We conclude with some consideration on the performance of ReShape under stochastic noise in Sec. III C. II. HYPERGRAPH PRODUCT CODES We here present a bottom-up | 3,069,559 | 233864693 | 0 | 16 |
overview on hypergraph product codes. The purpose of this Section is dual: we both want to describe the hypergraph product codes with the least possible technical overhead and introduce the notation necessary to motivate and give an intuition for the results presented in Sec. III. We refer the reader interested in the homology theory approach to App. B. The most well-known example of hypergraph product code is the toric code and its variations [31,32]. The toric code is conventionally represented by a square lattice where qubits sit on edges, X-stabilisers are identified with vertices and Z-stabilisers with faces. The first evident feature of this identification is that in a square lattice we have two kind of edges: vertical and horizontal edges. The second is that each vertex uniquely identifies a row of horizontal edges and a column of vertical one, starting from the four ones that are incident to it. The third is that faces, similarly to vertices, uniquely identify a column of horizontal edges and a row of vertical ones, starting from the four which lie on its boundary. Very similar attributes can be found in all the hypergraph product codes, as we now explain. Consider two classical parity check matrices δ A , δ B of size m a × n a and m b × n b ; we indicate with C(δ A , δ B ) their hypergraph product code and refer to the matrices δ A and δ B as seed matrices. The qubits of the code C(δ A , δ | 3,069,560 | 233864693 | 0 | 16 |
B ) can be labelled as left and right qubits. Left qubits can be placed in a n a × n b grid and right qubits in a m a × m b grid, see Fig. 1. Under this labelling, left and right qubits are uniquely identified by pair of indices (j a , j b ) and (i a , i b ) respectively, where j a , j b vary among the column indices of δ A , δ B while i a , i b vary among their row indices. Given a pair (L, R) of binary matrices, of size n a × n b and m a × m b respectively, we define the Z-operator: and similarly for X-operators. We refer to L as the left part of the operator and to R as its right part. The code C(δ A , δ B ) has m a × n b X-stabiliser generators which can be indexed by (i a , j b ). The Xstabiliser S x (ia,j b ) has support contained in the union of the j b th column of left qubits and the i a th row of right qubits. More precisely 1 , it acts as X[(δ A ) ia ] on the left qubits located at column j b and as X[(δ B ) j b ] on the right qubits located on row i a , see Fig. 1b. Using the X-version of Eq. (6), S x (i a , j b ) is | 3,069,561 | 233864693 | 0 | 16 |
uniquely represented by the pair of matrices, where E ia,j b is the all-zero m a × n b matrix but for the (i a , j b )th entry which is 1. From the characteristic 'cross' shape of the stabilisers generators S is uniquely represented by the pair of matrices: for E jai b of size m a × n b , with all entries 0 but for the (j a , i b )th entry which is 1. Given a Z-operator (L, R), its X-syndrome is the m a × n b binary matrix: (SE) 1 Here and in the following, for a m × n matrix δ we indicate by δ i ∈ F n 2 the transpose of its ith row, and by δ j ∈ F m 2 its jth column. It is easy to show that any Z-stabiliser has trivial X-syndrome, which is equivalent to X-stabilisers and Z-stabilisers commuting. As a consequence, C(δ A , δ B ) is a well-defined CSS code. A minimal generating set of logical Z-operators for C(δ A , δ B ) is given by : where: Here, given a vector space A for details. Similarly, a minimal generating set of logical X-operators is: where: The similarities in structure between general hypergraph product codes C(δ A , δ B ) and the toric codes (with and without boundaries) should now be clear: the toric code with boundaries (resp. without) of lattice size L is just the hypergraph product code C(δ L , δ L ) | 3,069,562 | 233864693 | 0 | 16 |
where δ L is the L − 1 × L (resp. L × L) parity check matrix of the classical repetition code. Left and right qubits correspond to vertical and horizontal edges; vertices and faces on the square lattice can be indexed in the natural way yielding the same stabiliser indexing of the general hypergraph product codes; string like (resp. loop like) logical operators correspond precisely to the left and right logical operators described above which have single column/single row support. In what follows, we focus on Z-errors and their correction. With slight abuse of notation, we will refer to pair of matrices (L, R) as operators (and vice versa sometimes) where the identification is clear via Eq. (6). The corresponding results for X-errors are easily obtained exploiting the dual structure of C(δ A , δ B ). : : : : III. RESULTS The ultimate aim of this Section is to exhibit the ReShape decoder for hypergraph product codes and prove Theorem 1. The correctness of ReShape strongly relies on the determination of some algebraic invariant for the logical operators of the code C(δ A , δ B ), which we now proceed to study. We will detail ReShape in Sec. III B and discuss its limitations in Sec. III C. All the proof of this Section are deferred to App. C. A. Invariants The characteristic shape of operators on the codespace of C(δ A , δ B ) and the structure of its stabilisers and logical operators, induces a canonical form for Z-operators in | 3,069,563 | 233864693 | 0 | 16 |
C(δ A , δ B ). More precisely, by combining the construction outlined in Sec. II and the definition of complement of a vector subspace (see App. A) we have proven the following: Proposition 1 (Canonical form). Let (L, R) be a Z-operator on the codespace of C(δ A , δ B ). Then its left part L can be expressed as a sum of a free part M L and a logical part O L such that every row of M L belongs to Im δ T B and every row of O L belongs to (Im δ T B ) ⊥ . Similarly, its right part R can be expressed as a sum of a free part M R and a logical part O R such that every column of M R belongs to Im δ A and every column of O R belongs to (Im δ A ) ⊥ . Hence, for (L, R) holds: (CF) We refer to the writing given by Eq. (CF) as canonical form of the operator (L, R). Crucially, as we detail in App. B, it is always possible to 'move' the support of the free part of an operator from the left qubits to the right qubits and vice versa. Opposite is the situation for the logical part: the support of the logical part of an operator cannot be moved from the left to the right qubits without changing its homology class. These two observations (see also Proposition 2) justify the name free and logical part in | 3,069,564 | 233864693 | 0 | 16 |
the canonical form of a Z-operator on C(δ A , δ B ). Given a Z-operator (L, R) we define its row-column weight as The primary significance of this novel notion of weight is explained by Proposition 2, which also represents a key result towards the construction of the ReShape decoder. . Corollary 1 below further specifies the structure of logical Z-operators and it is easily derived from the proof of Proposition 2, which is deferred to App. C. Equivalently, if (L, R) has canonical form given by for its logical row-column weight holds: The pivotal property of the logical row-column weight is expressed by Proposition 3. Proposition 3. The logical row-column weight of a Z-operator on C(δ A , δ B ) is an invariant of its homology class. Proposition 3 not only justifies the introduction of the notion of logical row-column weight but also constitutes the core resource upon which we prove the correctness of the ReShape decoder, which we now introduce. B. The ReShape decoder An hypergraph product code C(δ A , δ B ) is a CSS code and as such the decoding for X and Z error can be treated separately but in a symmetric way. Here we focus on Z-errors and therefore we measure a generating set of X-stabilisers. The Z-error decoding problem for C(δ A , δ B ) can be stated as: given a m a × n b syndrome matrix S, find a valid and correct solution (L,R) to the equation: where (L,R) is valid if σ(L,R) | 3,069,565 | 233864693 | 0 | 16 |
= S and it is correct if it belongs to the homology class of the minimum weight operator with syndrome S. The ReShape decoder for Z-errors is build upon two classical minimum weight decoding algorithms: D δ A and D δ T B . By this we mean that (i) the algorithms D δ A and D δ T B are optimal decoders for the classical linear code with parity check matrix δ A and δ T B respectively, and (ii) they solve the classical decoding problem of Eq. ReShape (Algorithm 1) works separately on the left part L and on the right part R of the operator (L, R) and in fact it could be run in parallel (lines 1-10 and lines [11][12][13][14][15][16][17][18][19][20]. Starting from a valid solution (L, R), it minimises its logical row-column weight by minimizing #row log (L) (lines 1-10) first and #col log (R) after (lines [11][12][13][14][15][16][17][18][19][20]. Because the logical row-column weight is an homology invariant for Z-operators (Proposition 3) and ReShape minimises it, this suffices to assure that ReShape is correct, as stated in Proposition 4. Split: Li = mi + µi ∈ Im δ T B ⊕ (Im δ T B ) ⊥ , as in (A1) 3: end for 4: ML ← matrix whose rows are mi 5: OL ← matrix whose rows are µi 6: for all O j L columns of OL do 7: Decode: ρ j = D δ A (O j L ) 8: end for 9:L ← matrix whose columns are ρ j | 3,069,566 | 233864693 | 0 | 16 |
10:L ←L + OL + ML 11: for all R j columns of R do 12: Split: R j = m j + µ j ∈ Im δA ⊕ (Im δA) ⊥ , as in (A1) 13: end for 14: MR ← matrix whose columns are m j 15: OR ← matrix whose columns are µ j 16: for all (OR) i rows of OR do We now detail how ReShape works on the left part L of the inputted valid solution (L, R) (lines 1-10) and refer the reader to the pseudocode in Algorithm 1 for the right part R. ReShape has two steps, each of which exploits a feature of the left part of Z-operators on the codespace of C(δ A , δ B ): (i) Split step: a Z-stabilizer (G L , G R ) has left part G L such that every row is in the image of δ T B ; (ii) Decode step: a logical Z-operator which acts non-trivially on the left qubits has a representative (L z , R z ) such that at least one column of L z is in ker δ A \ {0}. We now proceed to explain how these two steps are performed while specifying their computational cost. This analysis, together with Proposition 4, yields a proof of Theorem 1. Let (L, R) be any valid solution of (SE) given in input to ReShape. (i) Split. First, in lines 1-3, L is written in its canonical form with respect to the basis described by | 3,069,567 | 233864693 | 0 | 16 |
Eq. (A1): This operation has the cost of a n a × n b times n b × n b matrix multiplication and therefore the Split step of ReShape has cost O(n a n 2 b ). (ii) Decode. The second step performed by ReShape (lines 6-10) aims to minimise the logical rowcolumn weight of (L, R) by looking at non-homologically equivalent operators: If the computational cost of the classical decoder D δ A is O(c a ), the computational cost of the second step of ReShape is O(k b c a ). The Split and Decode steps described for the left part are replicated, with opportune modifications, for the right part. Proposition 4 below ensures that the recovery operator (L,R) found by ReShape is a correct solution of (SE), as long as the classical decoders D δ A and D δ T B succeed. σ(L, R) = S. (SE) Suppose that the minimum weight operator (L min , R min ) with syndrome S has (d a /2, d T b /2)-bounded logical row-column weight i.e. wt log rc (L min , R min ) = (#row log (L min ), #col log (R min )), is such that Then, on input D δ A , D δ T B , S and (L, R), ReShape outputs a correct solution (L,R) of (SE), provided that the classical decoders D δ A , D δ T B succeed. In other words, the solution (L,R) found by ReShape is in the same homology class as the minimum | 3,069,568 | 233864693 | 0 | 16 |
weight operator with syndrome S: It is important to note that the condition (10) on the weight of the original error is on its row-column weight, while usually decoding success is assessed depending on the weight of an operator, meaning the number of its non-identity factors. Obviously, for any operator (L, R) it holds: #row(L) ≤ |L| and #col(R) ≤ |R|. As a consequence, Proposition 4 entails that ReShape succeeds in correcting any Z-error of weight up to half the code distance d z = min{d A , d T B }. Combining this with the cost analysis of the Split and Decode steps detailed above, gives a proof of Theorem 1. It is worth to observe that actually ReShape can correct errors of weight strictly bigger than half the code distance, as long as they are not too 'spread'. In fact, whenever an error is homologically equivalent to an operator (L, R) such that L has 'few' non-zero rows and R has 'few' non-zero columns, ReShape succeeds. Formally, because by definition: #row(L) ≥ #row log (L) and #col(R) ≥ #col log (R). Proposition 4 yields Corollary 2. Provided that the classical decoders succeed, ReShape successfully corrects any Z-error (L, R) with bounded row-column weight: To sum up, ReShape successfully solves the decoding problem for any hypergraph product code requiring only k oracle calls to a classical decoder for the seed matrices, where k is the logical dimension of the code. Furthermore, it is able to correct for a vast class of errors of weight strictly | 3,069,569 | 233864693 | 0 | 16 |
bigger than half the code distance, provided that they have a 'good' shape. The next Section focuses on what happens when we cannot control the shape of the errors but we assume that the probability of a given error to occur decays exponentially in its weight. C. ReShape for Stochastic noise Up till now, we have focused on the adversarial noise model: errors on qubits are always correctable because we assume they have weight less than half the code distance. In real systems though, this is rarely the case and it is more faithful to assume that errors are sampled accordingly to a local stochastic noise model, where qubits errors have arbitrary location but the probability of a given error decays exponentially in its weight. More precisely the probability of a Pauli error E ∈ P n to occur is given by: Under the binomial distribution associated to Eq. (11), the expected error weight on the encoded state is pn. Because the best possible distance scaling for the hypergraph product codes is ∼ √ n (when the classical seed codes have linear distance), as n increases, we eventually find pn > √ n/2 ∼ d/2. Nonetheless, it is well known that LDPC hypergraph product codes do have a positive error correcting threshold [2]. A family of codes has threshold p th > 0 if, for noise rate below p th , non-correctable errors that destroy the logical information occur with probability p non−correctable which decays exponentially in the system size: for some α, β > 0. | 3,069,570 | 233864693 | 0 | 16 |
It is important to stress that Eq. (12) does not contrast with the fact that the typical error under the stochastic noise model will have weight pn. Instead, Eq. (12) entails that, among all the errors sampled, the non-correctable ones are only a small fraction. Beyond the theoretical threshold that Kovalev and Pryadko proved in [2], the literature offers several numerical evidence of decoders for hypergraph product or related families of codes which exhibit a threshold. Nonetheless these decoders either lack a correctness proof, e.g. BP in [14,17], or need some additional constraints on the seed matrices, e.g. expander codes with small-set flip decoder [8], or augmented surface codes with the union-find decoder in [33]. Split step Decode step Input Free part Logical part Output FIG. 2. Graphical representation of one instance of ReShape for Z-errors. The code considered is the planar code of distance 3 (toric code with boundaries) or, equivalently, the hypergraph product code C(δ, δ) for δ full-rank parity check matrix of the distance-3 repetition code. We use the same graphical representation used in Fig. 1. Input: the valid solution in input is (L, R), whose support is represented by the black qubits. Split step: (L, R) is written as sum of its free part (ML, MR), with support on the striped qubits; and its logical part (OL, OR) with support on the polkadot qubits. Decode step: the column (0, 1, 1) T of the polka-dot qubits is given in input to a decoder for the classical distance-3 repetition code. The solution found | 3,069,571 | 233864693 | 0 | 16 |
is (1, 1, 1) T , represented by the red qubits. Output: the output solution (L,R) is obtained by adding the input operator (L, R) and the operator found in the decode step, with support on the red qubits. The support of (L,R) is represented by the blue qubits. On the contrary, for any choice of the seed matrices in the hypergraph product, ReShape is provably correct for adversarial errors. Not surprisingly though, ReShape does not show a threshold and the reason behind its anti-threshold behaviour can be understood as follows. A common ingredient for decoders that exhibit a threshold on LDPC codes is their local nature on the syndrome graph, where nodes are stabiliser generators that are connected by an edge if and only if their support overlap. Roughly, local stochastic errors tend to form small disjoint clusters on the qubit graph 2 which do not destroy the logical information as long as they are (1) small enough (2) sufficiently far apart. If a decoder manages to mimic the error cluster distribution on the syndrome graph and finds recovery operators accordingly, then it is likely to show a threshold. ReShape, on the other hand, has a deeply global nature. The Split step groups all the clusters of flipped stabilisers scattered across the syndrome graph in a small pre-assigned region; a recovery is then chosen (Decode step) based on the syndrome information there contained. If we take the planar code as an example (see Fig. 2), the Split step groups the error (and the syndrome) weight | 3,069,572 | 233864693 | 0 | 16 |
on one column of the left qubits. The subsequent Decode step decodes that column and find a recovery operator with support there contained. Because for the planar code a logical Z-operator can be chosen to have support on only one column of the left qubits, this procedure can easily destroy the logical information. Our intuition on the performance of ReShape under stochastic noise finds confirmation in the plots reported in Fig. 3. Even if at first sight the plots in Fig. 3a and 3b could indicate the presence of a very low threshold (below 1%), a closer analysis suggests that this is not the case. In fact, as d increases, the crossing point between the dashed curve labelled d = 0 and the d-curves slips leftwards. Since the dashed curve is the locus of points where the failure probability p fail equates the noise rate p, it corresponds to the case of no encoding i.e. d = 0. The common crossing point, in other words, represents the pseudo-threshold of the code [34]. Importantly, if a code family has a threshold p th in the sense of Eq. (12), then all the codes of the family crosses the curve d = 0 at the same point of coordinates (p th , p th ). Fig. 3c clearly illustrates this left slipping phenomenon for the toric codes without boundaries. For close distances d = 6, 8, 10, there it seems to be a common crossing point with the d = 0 curve. However, the crossing point lowers if | 3,069,573 | 233864693 | 0 | 16 |
we increase d more substantially, e.g. d = 20. The situation appears less clear in Fig. 3d because the pseudo-threshold seems to increase with the distance of the code. Still though, there is no common crossing point of the three curves; besides, we would expect the same trend as the one observed for the toric codes if codes of bigger distance were considered. In conclusion, ReShape is not suited to tackle stochastic errors in the regime where typical errors has weight exceeding the code distance bound. A family of hypergraph product codes C(δ, δ T ) where δ is a full-rank (3, 4)-matrix randomly generated, see [17]. IV. CONCLUSIONS AND OUTLOOK In this paper we determined some important homology invariants of hypergraph product codes. Exploiting these invariants, we designed the ReShape decoder. ReShape is the first decoder to efficiently decode for all errors up to half the code distance, across the whole spectrum of hypergraph product codes. We foresee two natural extensions of this work. The first is to adapt ReShape for it to work in the stochastic noise model settings. Because ReShape actually succeeds in correcting errors of weight substantially bigger than (d − 1)/2 (namely it corrects error of weight as big as ∼ d 2 , when they have the right shape!), this gives us some hope that ReShape would work under stochastic noise if paired with the right clustering technique. For instance, something on the line of the clustering methods used in the renormalisation group or the union-find decoders [5,18,35,36]. The second | 3,069,574 | 233864693 | 0 | 16 |
is to find the corresponding invariants for other families of homological product codes. Specifically, for the codes in [37], which have 'rectangular' shaped logical operators instead of 'string' like as the standard hypergraph product codes here studied; or the balanced product codes proposed in [38]. Once found, the right invariants could be plugged-in an appropriately modified version of ReShape and yield a provable correct decoder for these class of codes too. In this Appendix we review some known linear algebra facts that we use in our proofs. We refer the reader for instance to [39,40] for a detailed presentation on the topic. Consider a m × n binary matrix δ. If rank(δ) = rk then we can choose binary vectors v 1 , . . . , v rk in F m 2 whose span is Im δ: Let 1 be the m × m identity matrix. Perform Gaussian reduction on the (rk + m)-row matrix M : By selecting the pivot rows, we obtain a basis of F m 2 of the form: where the f i are unit vectors. Letting: we have: We refer to the space (Im δ) ⊥ as complement of the space Im δ. Appendix B: Hypergraph product codes CSS codes can be easily described in terms of homology theory [31,41,42] via the identification of the objects of the code with a chain complex [43]. For our purposes, a length chain complex is an object described by a sequence of + 1 vector spaces {C i } i over F 2 | 3,069,575 | 233864693 | 0 | 16 |
and binary matrices {∂ i : C i −→ C i+1 } i such that, for each i, ∂ i ∂ i−1 = 0. In the following, we use the symbol ∂ to indicate the maps of a chain complex of length > 1 and the symbol δ to indicate the map of a chain complex of length 1. Given a chain complex C: we can define a CSS code C by equating: Since ∂ 0 ∂ −1 = 0 by construction, X-type and Z-type operators do commute i.e. H X · H T Z = 0 and the code C associated to the chain complex (C) is well defined. The code C has length n = dim(C 0 ) and its dimension k equates to the dimension of the 0th homology group H 0 = ker ∂ 0 / Im ∂ −1 or, equivalently, to the dimension of the 0th co-homology group H * 0 = ker ∂ −1 / Im ∂ 0 . Its Z-distance and X-distance are given by the minimum Hamming weight of any representative of a non-zero element in H 0 and H * An hypergraph product code C(δ A , δ B ), which is a CSS code, can be easily defined in terms of product of chain complexes. Consider the two length-1 chain complexes defined by the seed matrices δ A and δ B : We define their homological product as follows. Take the tensor product spaces The chain complex C A,B : is well defined. In fact: Therefore, | 3,069,576 | 233864693 | 0 | 16 |
the complex (C A,B ) defines a valid CSS code, which we denote by C(δ A , δ B ) and refer to as the hypergraph product code of the seed matrices δ A and δ B . If the classical code with parity check δ , δ T has parameters [n , k , d ] and [n T , k T , d T ] respectively ( = A, B) then the hypergraph product code C(δ A , δ B ) has parameters: where d x = min{d T a , d b } and d z = min{d a , d T b }, see [42]. Reshaping of vectors One tool we make extensive use of, and from which our decoder takes its name, is the reshaping of vectors of a two-fold tensor product space into matrices (see, for instance, [42,44]). Consider a basis B of the vector space F n1 2 ⊗ F n2 2 : . . , n 1 and j = 1, . . . , n 2 }. Then any v ∈ F n1 2 ⊗ F n2 2 can be written as: for some v ij ∈ F 2 . We call the n 1 × n 2 matrix V with entries v ij the reshaping of the vector v. By this identification, if ϕ, θ are respectively m 1 × n 1 and m 2 × n 2 matrices, then (ϕ ⊗ θ)(V ) = ϕV θ T . The inner product between u ⊗ w | 3,069,577 | 233864693 | 0 | 16 |
and v in F n1 2 ⊗ F n2 2 can be computed as As we here detail, the identification of operators on the code space C(δ A , δ B ) with pairs of binary matrices that we used in the main text is rigorously justified by the reshaping of vectors into matrices. With slight abuse of notation, we refer to binary vectors and binary matrices as operators and vice versa, where the identification is clear via Eq. (6). Graphical representation Physical qubits of the code C(δ A , δ B ) are in one-to-one correspondence with basis element of the 1 of dimension n a , n b , m a , m b respectively, then the union of the two sets is a basis of C 0 . We refer to qubits associated to elements in B L , or its span, as left qubits and to those associated to B R , or its span, as right qubits. Since qubit operators are vectors in C 0 , by reshaping, they can be identified with pairs of matrices (L, R) where L has size n a × n b and R has size m a × m b ; in particular, L acts on the left qubits while R acts on the right qubits. A Z-stabilizer for the code associated to the complex (C A,B ) is any vector in Im ∂ −1 . A generating set for Z-stabilizers is: where e ja and e i b are unit vectors of C 0 | 3,069,578 | 233864693 | 0 | 16 |
A and C 1 B respectively, i.e. they are a basis of the two spaces. Let be the reshaping of (e ja ⊗ e i b ), i.e. it is the matrix with all zeros entries but for the (j a , i b )-th entry which is 1. The reshape of ∂ −1 (e ja ⊗ e i b ) is then given by the pair of matrices: Proof. Let (L, R) ∈ ker ∂ 0 . Then: Eq. (C1) yields: for some V ∈ C 1 A ⊗ C 0 B . Eq. (C2) entails that all columns of V belong to Im(δ A ) while its rows belong to Im δ T B . As a consequence, it must exists U ∈ C 0 A ⊗ C 1 B such that: Therefore Eq. (C2) can be re-written as: which yields: Equivalently, Eq. (C3) states that L + U δ B has columns in ker δ A : and therefore: as in the thesis. Similarly, we find In the main text, we have introduced the notions of row-column weight and logical row-column weight for a Z-operator on C(δ A , δ B ). The definition of these two quantities finds its explanation in Proposition 2, whose proof builds on the results of Lemma 1. Proof. If (L, R) is a non-trivial logical Z-operator, it must anti-commute with at least one logical Xoperator (L x , R x ). Because a Z-operator and a X-operator anti-commute if and only if their supports overlap on an | 3,069,579 | 233864693 | 0 | 16 |
odd number of positions, either L and L x or R and R x have odd overlap. Without loss of generality, we can assume that the former is verified and we can choose (L x , R x ) as a left operator of the form where f is a unit vector in (Im δ T A ) ⊥ and k ∈ ker δ B . In other words, we choose logical X-operator In particular, (L, R) belongs to ker ∂ 0 and thanks to Lemma 1, we can re-write it as: where columns of K A belong to ker δ A and rows ofK B belong to ker δ T B . Using Lemma 1's decomposition for (L, R) ∈ ker ∂ 0 , we can expand the matrix-vector product Lk as: Eq. (C5) entails Lk = K A k and therefore that Lk, being a linear combination of column-vectors in ker δ A , belongs to ker δ A itself. Furthermore, by Eq. (C4), Lk = 0. To sum up, Lk is a non-zero vector in ker δ A and therefore it must have Hamming weight at least d a . As a consequence, L is a matrix with at least d a rows: Similarly, we would have found: if we had assumed that (L, R) anti-commuted with a logical X-operator (0, R x ) inL right x . Corollary 1 follows easily. for some binary matrices N L , N R of size n a × m b . As done in the | 3,069,580 | 233864693 | 0 | 16 |
proof of Proposition 2, consider a logical X-operator (f ⊗ k, 0) such that it anti-commutes with (L, R). Combining the canonical form of L and Eq. (C5), yields: for some n a ×n b matrix K A with columns in ker δ A . By the same argument used in the proof of Proposition 2, we find: and in particular that O L has at least d a non-zero rows. Since by definition of canonical form the non-zero rows of O L are precisely those rows of L which do not belong to Im δ B , we have proven point (i). Point (ii) follows similarly in the case (L, R) anti-commutes with at least one logical X-operator of the form (0, R x ). Corollary 1, together with Proposition 3 below, justifies the definition of the logical row-column weight for Z-operators on C(δ A , δ B ) (Definition 2). The logical row-column weight of (L, R) is denoted by the symbol wt log rc (L, R) and stands for the integer pair (#row log (L), #col log (R)) where #row log (L) is the number of rows of L that are not in Im δ T B and #col log (R) is the number of columns of R which are not in Im δ A . Proposition 3, that we now prove, states that the logical row-column weight of a Z-operator on C(δ A , δ B ) is an homology invariant of the chain complex (C A,B ) and therefore it legitimates | 3,069,581 | 233864693 | 0 | 16 |
the name choice for this quantity. is a Z-stabiliser . The operator (G L , G R ) ∈ C 0 is a Z-stabilizer for C(δ A , δ B ) if and only if For some n a × m b binary matrix U . Eq. (C6) entails that any row of G L belongs to Im δ T B and any column of G R belongs to Im δ A . Therefore, if we write (L, R) in its canonical form: we see that we can 'delete' all the rows of M L by adding a stabiliser and hence 'move' part of the support of the operator (L, R) from the left qubits to the right qubits. Specifically, if M L = N L δ B for some n a × m b binary matrix N L , we consider the stabiliser G = (N L δ B , δ A N L ) and we obtain: Similarly, we could move the M R part of the operator (L, R) from the right qubits to the left qubits, by adding the stabilizer G = (N R δ B , δ A N R ), for a n a × m b matrix N R such that M R = δ A N R . On the other hand though, it is not possible to delete non-zero rows of O L via stabiliser addition. In other words, it is not possible to remove, via stabiliser addition, any of the rows of L that are not | 3,069,582 | 233864693 | 0 | 16 |
in Im δ T B . Hence, the number #row log (L) of non-zero rows of O L is an homology invariant. Likewise, we find that it is not possible to delete any column in O R by adding stabilisers and therefore #col log (R) is a logical invariant too. The proof of Proposition 3 actually entails a stronger result than the invariance of the row-column weight of Z-operators on C(δ A , δ B ). Namely, we have proven that the indices of the rows and the columns in the sets row log and col log respectively, are homology invariants of the reshaped Z-operators (L, R) on C(δ A , δ B ). However, because to prove the correctness of ReShape it is sufficient to look at the cardinality of the two sets row log and col log , we decided to state Proposition in this more compact and elegant form. We can now prove Proposition 4. Suppose that the minimum weight operator (L min , R min ) with syndrome S has (d a /2, d T b /2)-bounded logical row-column weight i.e. | 3,069,583 | 233864693 | 0 | 16 |
Pheromone trapping system for Rhynchophorus ferrugineus in Saudi Arabia : Optimization of trap contents and placement doi: 10.9755/ejfa.2017.v29.i12.1564 Despite the practices of RPW pheromone trapping being done since two decades, the holistic optimization of protocols with regards to the trap density, design, placement and various internal components including lure, co-attractant, food bait, insecticide, etc., are contemporary research topics as evident from recent studies (Vidyasagar et al., 2016;El-Shafie and Faleiro, 2017;Vacas et al., 2017).The traditional pheromone trapping systems for RPW in Saudi Arabia are based on broadly four components: bucket trap, aggregation pheromone, kairomone and insecticide.The bucket traps are in widespread use throughout the country.They are hung on palm trees and usually not placed on or buried in the ground (Hallett et al., 1993b;Rajapakse et al., 1998;Abraham et al., 2000;Vidyasagar et al., 2000b;Faleiro, 2005Faleiro, , 2006)).On the other hand, stump trap (Massoud et al., 2012;Hoddle et al., 2013) is gaining popularity where bucket trap is placed on the top of stump, which are essentially log pieces of date palm deadwood.In the present study, bucket trap placement on the tree (tree trap) was compared with that on the stump (stump trap).The trap color have already been studied extensively (Abuagla and Al-Deeb, 2012;Al-Saoud, 2013;Abdel-Azim et al., 2014;Avalos and Soto, 2015).The role of semiochemicals in management of a cryptic pest like RPW has been elaborated before (Soroker et al., 2015).The male produced aggregation pheromone of RPW, which attracts both the sexes, was reported to be a mixture of two compounds, 4-methyl-5-nonanol (major component, ferrugineol) and 4-methyl-5-nonanone (minor component, ferrugineone) (Hallet | 3,069,584 | 55478564 | 0 | 16 |
et al., 1993a) and use of both components in the lure (9:1 ratio) increased catches by 75 per cent (Abozuhairah et al., 1996).In Saudi Arabia, all the three readily available commercial pheromone lures, i.e.Ferrolure+™ (ChemTica), RHYFER™ (Alpha Scents) and RHYNCAP™ (Green Universe) are available as 9:1 mixture of the ferrugineol and ferrugineone.Hallet et al. (1999) reported 3 mg/day as effective release rate of ferrugineol but recently 4-5 mg/day was reported for maximum trap catches (Vacas et al., 2017).However, the emission rates of commercial pheromones in spite of same composition may differ due to the difference in the pheromone holding matrices used in the packaging.Therefore, in the present study, the three lures with different holding matrices were evaluated for their RPW attraction efficacy. If the trap is equipped with pheromone lure but not baited with food, weevil catches drop significantly.Several studies have highlighted the importance of food baits to sustain RPW pheromone trap catches (Faleiro and Chellapan, 1999;Hallett et al., 1999;Nair et al., 2000;Faleiro and Satarkar, 2003;Oehlschlager, 2007).The food baits used in Saudi Arabia are predominantly date fruits (fodder grade) with some growers also using date palm and sugarcane stem pieces.Therefore in the present study, the three food baits and their respective combination with ethyl acetate were evaluated for maximizing the trap catches.Regarding the food bait, the food components need to be wet and in a state of gradual degradation or fermentation for sustaining high RPW trap catches (Hallett et al., 1999;Oehlschlager, 2016).The wet food ferments faster and releases additional volatiles which are considered essential for short-range | 3,069,585 | 55478564 | 0 | 16 |
orientation of weevils towards traps (Gunawardena and Gunatilake, 1993;Avalos and Soto, 2015).If this is the case, expediting and/or facilitating the fermentation of food should increase the release rate and variety of food volatiles from the trap.Therefore, in the present study, fast fermenting food bait of fodder grade date fruits with yeast was evaluated to augment and sustain the RPW trap catches.Moreover, ethyl acetate is a known fermenting food volatile and therefore the food-baited traps with a dedicated ethyl acetate release source were also evaluated with and without yeast.No evaluation with regards to fourth trap component, insecticide, was undertaken in the present study as efforts are underway to make the trap organic and avoid the insecticide use.The results would strengthen the mass-trapping strategies by doing the suitable interventions in the current practices. Study location Three date palm orchards at Al Kharj Governorate (24° 8′ 54″ N latitude, 47° 18′ 18″ E longitude), 77 km south of Riyadh, Saudi Arabia, were chosen for this study.Based on the experimental design, the orchards with trees of similar age (10 to 15 years) and having moderate to severe infestation were selected for experiment.The routine trapping was halted for two weeks before initiating the experiments to offset the change in adult population due to emergence of adults thereby ensuring that the weekwise trap catches were nearly uniform before starting the field experiments. Standard Saudi trap Six liters, black-colored (Abdel-Azim et al., 2015) plastic buckets were fabricated into traps by making four 3x6 cm windows equidistant from each other and about 2 cm | 3,069,586 | 55478564 | 0 | 16 |
below the upper rim.To facilitate the climbing by weevils, a darkcolored rough jute cloth was wrapped around the bucket without obstructing the windows.The pheromone lure dispenser was hung on the inner side of the bucket lid by a wire.The Ferrolure+™ sachets (Chem Tica International, Costa Rica) loaded with 700 mg of aggregation pheromone components, 4-methyl-5-nonanol and 4-methyl-5nonanone in 9:1 ratio at 98% purity of enantiomeric mixture, were used as the standard pheromone lure.The bucket was filled with ~ 2 L of tap water and 2 g insecticide (Carbaryl, 10 % WP; Kafr Elzayat Pesticides and Chemicals Co., Egypt) was added to it.About 200 g of fodder grade date fruits were used as the standard food bait along with 3 g of yeast (Saccharomyces cerevisiae) powder (Saf-instant S.I.Lesaffre -59703 Marcq -France).For dispensing ethyl acetate, 12 ml (19x65 mm) amber glass vial (Agilent Technologies, USA) with a polyethylene lid having two 1 mm holes was filled with 10 ml ethyl acetate (> 99 % purity; Fisher Scientific UK) and suspended along side pheromone lure.As per the evaluated component/s in the experiments, the standard pheromone lure and food bait were replaced with other options, while yeast and ethyl acetate were removed.Shaded areas in the orchard were chosen for the trap placement to maintain a uniform and sustained release of volatiles from the trap while ensuring longer service life of pheromone lure under arid environment of Saudi Arabia.The traps were suspended on the palm trunks at a height of about 1.2 m by wire. Field experiment setup Total six sets | 3,069,587 | 55478564 | 0 | 16 |
of field experiments were conducted involving evaluation of trap placement and various trap contents including pheromone lures, kairomones, food baits and food fermenting agent.The traps were placed in random block design (RBD) while maintaining ~ 50 m spacing between treatments and ~ 200 m between replications.Each experiment was conducted within single orchard to obviate differences due to age of palm trees, level of RPW infestation and general agronomic practices.In each of the six experiments, the traps were examined for removing and recording dead or alive male and female adult catches, and replenishing the wet contents to their original level for the sake of uniformity.Since the experiments continued between 4 to 12 weeks, the pheromone lures, irrespective of the quantity of their contents, were also replaced in all traps after six weeks.In addition, to eliminate spot effect due to aggregation of weevils (Faleiro et al., 2002), the traps were shuffled within replications.Generally, the efficiency of pheromone trapping was correlated to the number of weevils captured in each trap during the experimental period. Stump trap In the first experiment of the present study, stump traps were evaluated by installing bucket traps on the top of the date palm stump (~ 75 cm height).Stumps for holding bucket traps were made from dry palm stems obtained from the neglected or discarded palms.The tree trunks were cut longitudinally in ~ 75 cm pieces by using a mechanical saw.Then a central hole was made manually on top of each stump using a sharp shovel to fit the standard Saudi bucket trap.The depth | 3,069,588 | 55478564 | 0 | 16 |
of the hole was made till the windows in the bucket trap.The stumps were then thoroughly treated with pesticide to avoid infestation from deviating weevils.In this experiment, the following treatments with standard Saudi trap were compared in the field: (1) Hanged on the trunk of a palm tree (about 1.2 above the ground level), hereafter referred as 'Tree Trap' and (2) Placed in the groove on the top of a date palm stump (about 25-35 cm radius and about 70 cm height), hereafter referred as 'Stump Trap'.The two treatments were applied with 13 replications each (26 traps) for 12 weeks.The trap catches were recorded every second week. Pheromone lure In the second field experiment, 18 standard Saudi trap described before were installed (3 treatments x 6 replications).Apart from standard lure used in the present study, two more commercially available RPW aggregation pheromone lures were evaluated for field efficacy.The Ferrolure+™ (ChemTica International Co., Costa Rica) is available in a porous and inert sachet (5 x 6 cm) loaded with 700 mg of pheromone mixture comprising 4-methyl-5nonanol (9 parts) + 4-methyl-5-nonanone (1 part) -purity 99.9%.The other two lures, RHYFER™ (Alpha Scents Inc., USA) and RHYNCAP™ (Green Universe Agriculture S.L., Spain) were same component-wise, but used paper material saturated with pheromone mixture and packed in permeable plastic bag as dispenser.While Alpha Scents lure used an absorbent matrix which is a round and thick paper disk (3.8 cm diameter x 0.2 cm thickness) loaded with 700 mg of pheromone mixture and packaged in inert permeable plastic bag, the RHYNCAP™ contained | 3,069,589 | 55478564 | 0 | 16 |
a thick but bigger and rectangular paper (6.8 x 6 x 0.2 cm) enclosed in impermeable aluminum bag (7.5 x 6.2 cm) with a permeable transparent plastic square (4.2 cm side) window on one side.Experiment was held for 10 weeks and trap catches were recorded every alternate week. Lure and ethyl acetate Based on the results from pheromone lure evaluation experiment, the two better performing lures, Ferrolure+™ and RHYFER™ were tested with and without ethyl acetate in the third experiment for the trap catches.The standard Saudi trap was used without yeast, and except lure and ethyl acetate, all other standard components were retained.The experiment was replicated nine times with four treatments (36 traps).A weekly record of the number of weevils trapped was maintained for the study period of four weeks. Kairomone The most common kairomone, ethyl acetate was evaluated against other potential kairomones including ethanol (Merck Millipore), and acetic acid (Merck Millipore) in the fourth experiment.Kairomones were also dispensed like ethyl acetate and suspended along side pheromone lure in the standard Saudi trap.In total, five treatments were tested in standard Saudi trap: (i) ethyl acetate; (ii) acetic acid; (iii) ethyl acetate and acetic acid (in separate vial dispensers); (iv) ethanol and (v) Control (water only; without kairomone).All tested kairomones were refilled in the vials when the quantity reached 5 ml mark.The treatments were replicated ten times and the trap catches were sexed and counted on a weekly basis for a total of five weeks. Food bait In the fifth experiment, the standard Saudi trap was used | 3,069,590 | 55478564 | 0 | 16 |
to evaluate three types of food baits, viz.date palm stem pieces, date fruits and sugarcane pieces, with and without ethyl acetate in a total of six treatments for their effect on trap catches.Like kairomone experiment, the treatments were replicated ten times and the trap catches were sexed and counted every week for five weeks. Yeast and ethyl acetate In the final experiment, four treatments were tested to assess the effect on trap catches due to addition of yeast to date fruits with and without ethyl acetate, which was compared with date fruits alone and in combination with ethyl acetate.The standard Saudi trap components were altered as per the four treatments except lure, water, insecticide and date fruits.Apart from (i) date fruits alone, three other combinations, (ii) date fruits with ethyl acetate, (iii) date fruits with yeast, and (iv) date fruits with yeast and ethyl acetate, were tested for six weeks and replicated ten times.Trap catches were sexed and counted. Statistical analysis All statistical analyses were performed using SPSS (SPSS Release 16.00).The data was evaluated for the normality and homoscedasticity (Homogeneity of variance test, P < 0.05) and required no transformation for the analyses.All trap capture data were presented as mean ± standard error and subjected to one-way ANOVA.The means were separated using Tukey's multiple test.The mean differences were considered significant at values P < 0.05 level.The confidence limit was 95%.To assess the statistical difference in the trap catches due to type of traps, an independent samples t-test was performed with significance level set at P < | 3,069,591 | 55478564 | 0 | 16 |
0.05. Stump trap This experiment lasted for 12 weeks.In the first four weeks, the stump trap catches were higher than the tree traps but not significantly as revealed by the t-test data of week 2 (t = 1.976; df = 24; P = 0.060(and week 4 (t = 1.495; df = 24; P = 0.148) (Fig. 1).However, the stump trap catches emerged significantly superior to the tree trap in week 6 (t = 2.732; df = 24; P < 0.05), week 8 (t = 2.406; df = 24; P < 0.05), week 10 (t = 2.695; df = 24; P < 0.05) and week 12 (t = 2.465; df = 24; P < 0.05).The total stump trap catches (mean = 9.91 ± 0.45) in 12 weeks were significantly higher (t = 5.451; df = 154; P < 0.05) than the total tree trap catches (mean = 6.33 ± 0.47).Notably, stump trap preparation demanded comparatively more effort due to handling and transportation.Once located, they were easy to install and service.Tree traps are more common due to their cost and handling ease.In Indonesia and United Arab Emirates, tree traps have been recommended (Hallett et al., 1993b).In case of tree traps, trap height from the ground level is an important consideration.In coconut plantations in India, 1.0 m height was reported to yield highest trap catches (Faleiro, 2005).In India, Muralidharan et al. (1999) hung the bucket traps on date palm trees at breast height, whereas in Sri Lanka, Rajapakse et al. (1998), chose 1.5 m height above ground to hang | 3,069,592 | 55478564 | 0 | 16 |
traps on coconut trees for mass trapping studies on RPW.In Saudi Arabia, 1.5 m height was recommended for placing pheromone traps on date palm trunks (Abraham et al., 1998).As high as 3m height has been reported for tethering traps on date palm trunks in Egypt (El-Garhy, 1996).On the contrary, ground level traps on coconut palms were found to be most effective with maximum trap catches in Indonesia (Hallet et al., 1999).It is important to note that placing the traps on young palm trees can potentially invite infestation (Faleiro, 2006).In order to avoid infestation in trees used for hanging pheromone traps, ground level traps away from the trees have been suggested (Hunsberger et al., 2000).For example, Oehlschlager (2006) suggested for Middle-eastern region to partially bury the pheromone traps in the ground away from the tree.Trap windows at ground level allow easier insect entry.Ground level traps are being used in several countries including Israel, Spain and UAE (Faleiro, 2006).Stump traps used in the present study, allow trap placement away from the tree and thus avoid or at least alleviate the potential risk of inviting infestation.Secondly, stump traps have easy accessibility from all sides for flying weevils and they are easier to service due to their position away from the tree and at nearly waist height.In addition, the stump provides a landing and climbing platform to weevils trying to trace the lure source.Thus, like buried ground traps where trap windows are at the ground level, in case of stump traps too, weevils don't need to climb steeply against gravity | 3,069,593 | 55478564 | 0 | 16 |
and can walk almost straight into the trap.But unlike ground traps, stump traps not subject to drainage from rain or irrigation water and are less likely to be damaged by workers accidentally or foraging animals.Notably, despite the stumps being insecticide-treated dead fibrous wood, the present study does not claim that no volatiles are produced by the stumps.Additionally, in pursuit of placing the stumps between the two tree rows, difficulty was faced sometimes in finding shaded spots for them.Although the release rate of the lures was not ascertained in the present study, it has been suggested previously that pheromone longevity is adversely affected if the traps are placed in direct sunlight (Faleiro et al., 1998). Pheromone lure The RPW pheromone lures have been used effectively in coconut and date plantations since the launch of first commercial product in the year 1994 as Ferrolure (Chem Tica International, Costa Rica).Many studies have reported lure comparison tests and most of them have included Ferrolure+™ as one of the tested lures.In the present study, no significant difference was observed between the weekwise trap catches of the three commercially available pheromone lures, Ferrolure+™, RHYFER™ and RHYNCAP™ (df=2, 44; F=1.498; P = 0.235) (Table 1), despite the differences in their dispensers.Similarly, a recent study reported comparison of four lures where no statistically significant difference in the trap catches from Ferrolure+™ was found when compared to three other commercially available pheromone lures, Pherobank RPW lure (Pherobank), IT189 ISCA™ Lure-ferrugineus (ISCA Technologies) and Rhylure™ WAT-700 (Russel IPM) despite the Rhylure™ sharing similar dispensing mechanism with | 3,069,594 | 55478564 | 0 | 16 |
Ferrolure+™ (El-Shafie and Faleiro, 2017).On the other hand, Ferrolure+™ was reported to be significantly better in catches when compared to the two-component (ferrugineol and ferrugineone) lures from Qualiube company, France and Sedq company, Spain (Abbas and Al-Nasser, 2012) or when compared to four lures containing four enantiomers of 4-methyl-5-nonanol (SciTech, Czech Republic and IPM Technologies, USA) (Kaakeh et al., 2001).Similarly, Faleiro and Chellapan (1999) reported significantly more Ferrolure+™ trap catches than lure of Agrisense, UK from coconut plantation in India.But in Saudi Arabia, Ferrolure+™ trap catches were found at par with lure of Agrisense, UK, though significantly more than Calliope lure formulation from France (Faleiro et al., 2000).However, Interestingly, only major component (ferrugineol) based pheromone lures are also available commercially, as role of ferrugineone is not clear.Although in Saudi Arabia, it was shown that the minor presence of 4-methyl-5-nonanone along with 4-methyl-5-nonanol significantly increases the trap catches (Abozuhairah et al., 1996;Oehlschlager, 2006), the role of ketone component in augmenting the catches is debated (Vacas et al., 2017).Nevertheless, many two-component formulations of the RPW pheromone lure are still available commercially. Lure and ethyl acetate The objective of the second experiment was to test the role of kairomone, ethyl acetate in synergizing the RPW attraction of pheromone lure -food bait combination, and thus augmenting the trap catches.Ferrolure+™ and RHYFER™ were chosen for this experiment as they performed slightly better over the third lure, RHYNCAP™ in the first experiment (Table 1).The trap catches from Ferrolure+™ and RHYFER™ were not significantly different from each other.But when their combinations with ethyl | 3,069,595 | 55478564 | 0 | 16 |
acetate were compared, Ferrolure+™ with ethyl acetate attracted significantly more number of weevils than the RHYFER™ and ethyl acetate combination in the first week and also in total of four-week catches (df = 3, 143; F = 38.022;P < 0.0001).When trap catches from pheromone alone were compared with their ethyl acetate combinations, the Ferrolure+™ and ethyl acetate combination showed highly significant increase in the trap catches in each of the four weeks as well as in mean of the total catches for the entire experiment.The RHYFER™ and ethyl acetate combination also showed similarly significant increase in trap catches over pheromone lure alone, except in the week 3 when the trap catches were not significantly different.Overall, combination of Ferrolure+™ with ethyl acetate attracted maximum weevils amongst the four tested treatments (Fig. 2). Many studies have found ethyl acetate synergizing the lure-food bait attraction of RPW (Oehlschlager, 1998;El-Sebay, 2003;Al-Shagag et al., 2008;Guarino et al., 2011;Al-Saoud, 2013;Giblin-Davis et al., 2013;Vacas et al., 2014Vacas et al., , 2017)).For example, in a latest study using food-baited wet bucket trap and a commercial product, Weevil Magnet™, Al Saoud (2013) showed that mean monthly RPW trap catches from ethyl acetate and lure combination were ~1.6 times higher than the traps without ethyl acetate.Similarly, in a comparison between Ferrolure+™ with and without ethyl acetate, 3 and 4 times higher trap catches for female and male weevils were reported, respectively, when ethyl acetate was present (Solaiman and Abd El-Latif, 2013).However, it is important to note that ethyl acetate is not a substitute of food (Faleiro, | 3,069,596 | 55478564 | 0 | 16 |
2006).Vacas et al. (2013) in experiments with Picusan® trap (Sansan Prodesing SL, Naquera, Valencia, Spain), showed that ethyl acetate doesn't synergizes the lure attraction in absence of food bait and alone it can't be considered for replacing the food bait.This in turn suggests obligatory and synergistic significance of additional kairomonal volatiles and their respective ratios from food bait apart from ethyl acetate.Therefore, though ethyl acetate is still considered indispensable as a co-attractant, efforts are targeted towards its combinations with other food fermentation volatiles, including ethanol, to replace the plant material in the trap (Vacas et al., 2017).Notably, apart from the lure-bait synergism by ethyl acetate for attracting RPW, the present study revealed subtle but significant differences in synergistic role of ethyl acetate for lures differing in the dispensing matrix.The differences in lure attraction may depend on two desired attributes: (i) stable release rate in the 4 to 5 mg per day range, and (ii) longevity (which includes longer chemical stabilization of the components).The sustained release of pheromone may affect the performance of the lure over the lifetime of the sachet.In the presence of a co-attractant and/or food kairomones, difference in the lure performance is magnified. Kairomone Four kairomones/combination were evaluated in the fourth field experiment.The total trap catch count showed ethyl acetate and acetic acid alone and together as the most effective co-attractants (df = 4, 449; F = 8.486; P < 0.0001). Ethanol was found to be the most feeble attractant amongst the tested kairomones.In the male -female segregated counts too, the combination of ethyl | 3,069,597 | 55478564 | 0 | 16 |
acetate and acetic acid attracted maximum weevils but not significantly more than either of them alone (df = 4, 249; F = 5.956; P < 0.0001 and df = 4, 249; F = 3.963; P < 0.001 for female and male adults, respectively).Ethanol though showed less trap catches of segregated adults than ethyl acetate and acetic acid but not became an exception to attracting more female than the male adults.Compared to control, ethanol attracted twice female adults (Table 2). The combination of aggregation pheromone with host kairomones have been reported to synergize the attractiveness for R. ferrugineus (Hallett et al., 1993a,b). The salient findings from the kairomone experiment of the present study endorsed both ethyl acetate and acetic acid as potential candidates for further evaluation.Acetic acid has previously been implicated as potential RPW kairomone in trapping studies done on Coconut (Kurian et al., 1984;Faleiro, 2005).It has been detected as a major component of sugarcane volatiles (Rochat et al., 2000) and from the infested Canary Island Palm (Phoenix canariensis) stem under anaerobic conditions and was shown to elicit high antennal response on electro-antennogram detector (Vacas et al., 2014).Additionally, in both the quoted studies, ethyl acetate and ethanol blends were tested as kairomonal mixtures to find the synergistic co-attractant composition for food bait-free traps.Interestingly, what Rochat et al. (2000) reported 16 years ago in their seminal study on the efficiency of ethyl acetate -ethanol blends for R. palmarum, was verified 14 years later by Vacas et al. (2014) in case of R. ferrugineus.In a recent multi-location study, ethanol-biased | 3,069,598 | 55478564 | 0 | 16 |
blend with ethyl acetate augmented the catches in food bait-free traps from 1.4 to 2.2 times (Vacas et al., 2017).Based on the results of the present study, the blends of ethyl acetate, acetic acid and ethanol can be tried in different ratios.The release rates were not recorded in the present experiment.However, ethanol emissions were higher than ethyl acetate as ethanol needed refill every 2 weeks whereas ethyl acetate and water were refilled back to 10 ml mark in the third week.Acetic acid needed refilling in the fourth week. Food bait Amongst the three food baits evaluated, date fruits attracted maximum number of weevils however not significantly different from the numbers attracted by date stem or sugarcane pieces.The same trend was observed in the female and male catches too.The difference between the food baits became significant, interestingly, in presence of ethyl acetate.The total catch of adult weevils in the traps having date fruits with ethyl acetate was recorded significantly higher (df = 5, 599; F = 7.304; P < 0.0001) than the traps having date stem or sugarcane pieces with ethyl acetate.Significantly more female adults were attracted towards date fruit + ethyl acetate combination than sugarcane with ethyl acetate but date stem pieces with ethyl acetate combination attracted similar numbers (df = 2, 299; F = 4.981; P < 0.0001).However, male catches were not different between the respective combinations of three tested food baits and ethyl acetate (df = 5, 299; F = 3.062; P < 0.010).In addition, the female adult catches in case of date fruits | 3,069,599 | 55478564 | 0 | 16 |
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