Effectiveness of autocrosslinked hyaluronic acid gel after laparoscopic myomectomy in infertile patients: a prospective, randomized, controlled study.
To assess the efficacy of autocrosslinked hyaluronic gel in postsurgical adhesion prevention after laparoscopic myomectomy. Prospective, randomized, controlled study. University of Naples "Federico II".Thirty-six infertile women with symptomatic myomas were randomly divided into two groups of 18 patients each. Laparoscopic myomectomy with subserous sutures or interrupted figure 8 sutures, with (group A) or without (group B) application of autocrosslinked hyaluronic acid (HA) gel. Rate of postsurgical adhesions at 60-90 days of follow-up. The rate of subjects who developed postoperative adhesions was significantly lower in group A in comparison with group B (27.8% vs. 77.8%). In both groups, the rate of adhesions was significantly higher in patients treated with interrupted figure 8 sutures than with subserous sutures. Autocrosslinked HA gel is a promising resorbable agent barrier for the reduction of postoperative adhesions after laparoscopic myomectomy. Moreover, the type of suture is a factor influencing the postsurgical adhesion formation.


[Analysis of RECQL4 gene variant in a child with Rothmund-Thomson syndrome].
To explore the genetic basis for a child with Rothmund-Thomson syndrome (RTS). The child has featured poikeloderma, short stature, cataract, sparse hair and skeletal malformation. Peripheral blood samples of the child and her family members were collected and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. The child was found to harbor compound heterozygous variants of the RECQL4 gene, namely c.1048_1049delAG and c.2886-1G>A, among which c.2886-1G>A was unreported previously. According to the ACMG guidelines, the c.1048_1049delAG was predicted to be pathogenic (PVS1+PM3_Strong+PM2), while the c.2886-1G>A was predicted to be likely pathogenic (PVS1+PM2). The compound heterozygous variants of the RECQL4 gene probably underlay the pathogenesis of RTS in this patient. Above finding has enriched the mutational spectrum of the RECQL4 gene.


Tweeting about public health policy: Social media response to the UK Government's announcement of a Parliamentary vote on draft standardised packaging regulations.
Standardised tobacco packaging has been, and remains, a contentious policy globally, attracting corporate, public health, political, media and popular attention. In January 2015, the UK Government announced it would vote on draft regulations for the policy before the May 2015 General Election. We explored reactions to the announcement on Twitter, in comparison with an earlier period of little UK Government activity on standardised packaging. We obtained a random sample of 1038 tweets in two 4-week periods, before and after the UK Government's announcement. Content analysis was used to examine the following Tweet characteristics: support for the policy, purpose, Twitter-user's geographical location and affiliation, and evidence citation and quality. Chi-squared analyses were used to compare Tweet characteristics between the two periods. Overall, significantly more sampled Tweets were in favour of the policy (49%) in comparison to those opposed (19%). Yet, at Time 2, following the announcement, a greater proportion of sampled tweets opposed standardised packaging compared to the period sampled at Time 1, prior to the announcement (p<0.001). The quality of evidence and research cited in URLs linked at Time 2 was significantly lower than at Time 1 (p<0.001), with peer-reviewed research more likely to be shared in positive Tweets (p<0.001) and in Tweets linking to URLs originating from the health sector (p<0.001). The decline in the proportion of positive Tweets was mirrored by a reduction in Tweets by health sector Twitter-users at Time 2 (p<0.001). Microblogging sites can reflect offline policy debates and are used differently by policy proponents and opponents dependent on the policy context. Twitter-users opposed to standardised packaging increased their activity following the Government's announcement, while those in support broadly maintained their rate of Twitter engagement. The findings offer insight into the public health community's options for using Twitter to influence policy and disseminate research. In particular, proliferation of Twitter activity following pro-public health policy announcements could be considered to ensure pro-health messages are not overshadowed by anti-regulation voices.


Comparative metabolism of 7-methyl- and 7-ethylbenz[a]anthracene by rat-liver preparations.
The metabolism of 7-ethyl (7-EBA) and 7-methylbenz[a]anthracene (7-MBA) to dihydrodiols has been compared in incubations with hepatic microsomal fractions prepared from untreated rats. Although both hydrocarbons were found to be metabolised to similar extents, the relative proportions of their diols that were detected differed. For 7-MBA, the principal diols identified were the 8,9- and 5,6-derivatives, whereas for 7-EBA the 8,9- and 1,2-diols predominated; the 5,6-diol was only present as a minor product. These results imply that the presence of the sterically bulky ethyl group at position seven in the benz[a]anthracene ring system may, when compared to the analogous methyl derivative, enhance diol formation on the angular 1,2,3,4 benzo-ring, at the expense of metabolism at the K-region.


Myelosarcomatosis of the skin preceding leukemic generalization of acute myelomonocytic leukemia.
A case report of a patient with myelosarcomatosis of the skin six months preceding leukemic generalization of acute myelomonocytic leukemia is presented. To the best of our knowledge this is the first case of a myelosarcoma with generalized skin involvement diagnosed before development of an overt myeloproliferative disease.


Correction to: Review of global neurosurgery education: Horizon of Neurosurgery in the Developing Countries.
[This corrects the article DOI: 10.1186/s41016-020-00194-1.].


Impacts of wind stilling on solar radiation variability in China.
Solar dimming and wind stilling (slowdown) are two outstanding climate changes occurred in China over the last four decades. The wind stilling may have suppressed the dispersion of aerosols and amplified the impact of aerosol emission on solar dimming. However, there is a lack of long-term aerosol monitoring and associated study in China to confirm this hypothesis. Here, long-term meteorological data at weather stations combined with short-term aerosol data were used to assess this hypothesis. It was found that surface solar radiation (SSR) decreased considerably with wind stilling in heavily polluted regions at a daily scale, indicating that wind stilling can considerably amplify the aerosol extinction effect on SSR. A threshold value of 3.5 m/s for wind speed is required to effectively reduce aerosols concentration. From this SSR dependence on wind speed, we further derived proxies to quantify aerosol emission and wind stilling amplification effects on SSR variations at a decadal scale. The results show that aerosol emission accounted for approximately 20% of the typical solar dimming in China, which was amplified by approximately 20% by wind stilling.


Marijuana-Related Posts on Instagram.
Instagram is a highly visual social networking site whose audience continues to grow, especially among young adults. In the present study, we examine marijuana-related content on Instagram to better understand the varied types of marijuana-related social networking occurring on this popular social media platform. We collected 417,561 Instagram posts with marijuana-related hashtags from November 29 to December 12, 2014. We assessed content of a random sample (n = 5000) of these posts with marijuana-related hashtags. Approximately 2136 (43 %) were explicit about marijuana and further analyzed. Of the 2136 marijuana-related posts, images of marijuana were common (n = 1568). Among these 1568 marijuana images, traditional forms (i.e., buds/leaves) were the most common (63 %), followed by some novel forms of marijuana, including marijuana concentrates (20 %). Among the 568 posts that displayed marijuana being ingested, 20 % showed someone dabbing marijuana concentrates. Marijuana-related advertisements were also observed among the 2136 marijuana-related posts (9 %). Our findings signal the promotion of marijuana use in its traditional plant-based form; trendy and novel modes of marijuana ingestion were also endorsed. This content along with the explicit marketing of marijuana that we observed on Instagram have potential to influence social norms surrounding marijuana use.


Loss of tyrosine hydroxylase, motor deficits and elevated iron in a mouse model of phospholipase A2G6-associated neurodegeneration (PLAN).
Phospholipase A2G6-associated neurodegeneration (PLAN) is a rare early-onset monogenic neurodegenerative movement disorder which targets the basal ganglia and other regions in the central and peripheral nervous system; presenting as a series of heterogenous subtypes in patients. We describe here a B6.C3-Pla2g6m1J/CxRwb mouse model of PLAN which presents with early-onset neurodegeneration at 90 days which is analogous of the disease progression that is observed in PLAN patients. Homozygous mice had a progressively worsening motor deficit, which presented as tremors starting at 65 days and progressed to severe motor dysfunction and increased falls on the wire hang test at 90 days. This motor deficit positively correlated with a reduction in tyrosine hydroxylase (TH) protein expression in dopaminergic neurons of the substantia nigra (SN) without any neuronal loss. Fluorescence imaging of Thy1-YFP revealed spheroid formation in the SN. The spheroids in homozygous mice strongly mirrors those observed in patients and were demonstrated to correlate strongly with the motor deficits as measured by the wire hang test. The appearance of spheroids preceded TH loss and increased spheroid numbers negatively correlated with TH expression. Perls/DAB staining revealed the presence of iron accumulation within the SN of mice. This mouse model captures many of the major hallmarks of PLAN including severe-early onset neurodegeneration, a motor deficit that correlates directly to TH levels, spheroid formation and iron accumulation within the basal ganglia. Thus, this mouse line is a useful tool for further research efforts to improve understanding of how these disease mechanisms give rise to the disease presentations seen in PLAN patients as well as to test novel therapies.


A unique substrate binding mode discriminates membrane type-1 matrix metalloproteinase from other matrix metalloproteinases.
In our study, we characterized the substrate recognition properties of membrane type-1 matrix metalloproteinase (MT1-MMP; also known as MMP-14), a key enzyme in tumor cell invasion and metastasis. A panel of optimal peptide substrates for MT1-MMP was identified using substrate phage display. The substrates can be segregated into four groups based on their degree of selectivity for MT1-MMP. Substrates with poor selectivity for MT1-MMP are comprised predominately of the Pro-X-X- downward arrow-X(Hy) motif that is recognized by a number of MMPs. Highly selective substrates lack the characteristic Pro at the P(3) position; instead they contain an Arg at the P(4) position. This P(4) Arg is essential for efficient hydrolysis and for selectivity for MT1-MMP. Molecular modeling indicates that the selective substrates adopt a linear conformation that extends along the entire catalytic pocket of MT1-MMP, whereas non-selective substrates are kinked at the conserved P(3) Pro residue. Importantly, the selective substrates can be made non-selective by insertion of a proline kink at P(3), without significantly reducing overall k(cat)/K(m) values. Altogether the study provides a structural basis for selective and non-selective substrate recognition by MT1-MMP. The findings in this report are likely to explain several aspects of MT1-MMP biology.


Portal flow augmentation for liver cirrhosis.
Portal hypertension due to chronic liver disease is a major cause of death worldwide. Orthotopic liver transplantation offers the best therapeutic option but is available to only a minority of patients. In the past few years mechanically pumping portal venous inflow has been reported to reduce portal hypertension and improve liver function. A review of the published data on augmented portal perfusion for the treatment of portal hypertension in cirrhosis was carried out by searching Medline and other online databases. From each published study portal pressure and blood flow data before and after augmented portal perfusion were used to calculate the change in mean intrahepatic portal vascular resistance (IHPR). The standardized data were then combined to allow meta-analysis. Seven papers were identified on normal and cirrhotic animal and human livers with augmented flow (50% to fourfold over baseline) for 30-180 min. Meta-analysis revealed that the increased portal venous inflow was associated with a significant rise in portal venous pressure on the hepatic side (P < 0.001), a significant reduction on the mesenteric side (P < 0.001) and a significant reduction in IHPR (P = 0.013). Limited data were available to support improved liver function. Detailed in vivo cirrhotic liver studies on augmented portal flow in experimental models assessing haemodynamic and functional changes are required before clinical evaluation.


Effect of adjuvant radiotherapy on local recurrence in stage II rectal cancer.
Prospective trials have demonstrated that chemotherapy combined with radiotherapy decreases local recurrence rates in stage II and stage III rectal cancer. Some patients with stage II lesions, however, have relatively low risks of local recurrence. We evaluated the effect of radiotherapy on local recurrence in patients with stage IIA rectal cancer. From the colorectal cancer database, we identified 390 stage IIA rectal cancer patients who underwent curative resection followed by adjuvant therapy from 1995 to 2002; a total of 72 patients who received preoperative chemoradiotherapy and who did not receive adjuvant therapy were excluded. Mean follow-up period was 65 months (range, 2-133 months). Of the 390 patients, 110 had primary tumors in the upper rectum, 136 in the midrectum, and 144 in the lower rectum. Lymphovascular invasion was observed in 35 patients (9.0%). Mean (+/- SD) number of examined lymph nodes was 18 (+/- 12). Adjuvant chemotherapy was provided to 180 patients (46.2%), and chemotherapy plus radiotherapy was provided to 210 patients (53.8%). Radiotherapy was significantly more common in younger patients (P = .01) and those with lower rectal cancer (P < .001). Local recurrence rate did not differ between patients who did and did not receive radiotherapy. In patients with mid and lower rectal cancer, the local recurrence rate was not affected by radiotherapy. Radiotherapy did not seem to provide additional benefit in decreasing local recurrence rate of stage IIA rectal cancers. In selected patients, however, the role of radiotherapy needs to be carefully evaluated.


Loss of LncRNA DUXAP8 synergistically enhanced sorafenib induced ferroptosis in hepatocellular carcinoma via SLC7A11 de-palmitoylation.
Ferroptosis is an important iron-dependent form of cell death in hepatocellular carcinoma (HCC). Sorafenib, a potent ferroptosis inducer, is used to treat advanced HCC but its efficacy is limited by the development of drug resistance. The effects of DUXAP8 expression on HCC progression were evaluated by TCGA database, Kaplan-Meier analysis, and in situ hybridization analysis. Sorafenib resistant HCC cell lines were modeled in vitro to study the regulation of DUXAP8 on ferroptosis in HCC induced by sorafenib. We used RNA pull-down, immunofluorescence assays, acyl-biotinyl exchange assay and mass spectrometry analysis to assess the molecular mechanism of ferroptosis regulation by DUXAP8. Syngeneic subcutaneous and orthotopic CDX models were used to assess whether DUXAP8 inhibition improves HCC in vivo. LncRNA DUXAP8, which is highly expressed in liver cancer and associated with poor prognosis, contributes to sorafenib resistance through suppression of ferroptosis. In vitro tests revealed that DUXAP8 reduced the sensitivity of HCC to sorafenib-induced ferroptosis by acting on SLC7A11, a subunit of the amino acid antiporter system xc-. DUXAP8 facilitates SLC7A11 palmitoylation and impedes its lysosomal degradation, thereby enhancing SLC7A11 action and suppressing ferroptosis. RNA pull-down and immunofluorescence assays confirmed that DUXAP8 decreased membrane translocation and promoted sorting of de-palmitoylated SLC7A11 to lysosomes by binding of DUXAP8 to SLC7A11. In addition, mass spectrometric analysis found that the Cys414 residue of SLC7A11 might be the predominant mutant site responsible for molecular masking of SLC7A11 lysosomal sorting. Further, the antitumor effect of DUXAP8 knockdown was verified in orthotopic and subcutaneous CDX models. Our findings suggest that a novel translational strategy combining sorafenib with DUXAP8 silencing to overcome drug resistance may improve treatment efficacy in patients with advanced HCC.


Human parainfluenza virus surveillance in pediatric patients with lower respiratory tract infections: a special view of parainfluenza type 4.
Characterize the role of human parainfluenza virus and its clinical features in Brazilian children under 2 years of age presenting with acute lower respiratory tract infections. Real-time assays were used to identify strains of human parainfluenza virus and other common respiratory viruses in nasopharyngeal aspirates. One thousand and two children presenting with acute lower respiratory tract illnesses were enrolled from February 2008 to August 2010. One hundred and four (10.4%) patients were human parainfluenza virus positive, of whom 60 (57.7%) were positive for human parainfluenza virus-3, 30 (28.8%) for human parainfluenza virus-4, 12 (11.5%) for human parainfluenza virus-1, and two (1.9%) for human parainfluenza virus-2. Seven (6.7%) patients had more than one strain of human parainfluenza virus detected. The most frequent symptoms were tachypnea and cough, similar to other viral respiratory infections. Clinical manifestations did not differ significantly between human parainfluenza virus-1, -2, -3, and -4 infections. Human parainfluenza virus-1, -3, and -4 were present in the population studied throughout the three years of surveillance, with human parainfluenza virus-3 being the predominant type identified in the first two years. Human parainfluenza viruses contribute substantially to pediatric acute respiratory illness (ARI) in Brazil, with nearly 30% of this contribution attributable to human parainfluenza virus-4.


Endodontic application of cone-beam computed tomography in South Korea.
This study aimed to investigate the incidence of cone-beam computed tomography (CBCT) associated with endodontic procedures during 2009 in South Korea and to retrospectively evaluate information from CBCT with large field of view (FOV), which is popular in South Korea. The Health Insurance Review and Assessment agency, which reviews all medical and dental expenses covered under the Korean National Health Insurance (NHI) system, was queried for data on the nationwide number of CBCTs associated with some treatment procedures. To compare digital periapical radiography and CBCT retrospectively, 470 roots of 257 root canal-infected teeth were enrolled. In total, 13,209 cases of NHI-covered CBCT were performed in South Korea during 2009, excluding cases for implant restoration and orthodontics. In total, 1253 and 95 CBCT cases were combined with root canal length measuring and apicoectomy, respectively. In a retrospective comparison, CBCT with large FOV provided more information about the presence of apical periodontitis, distortion of cortical bone, and identification of root compared with digital periapical radiography. CBCT with large FOV is useful in nonsurgical endodontic treatment and provides more information compared with digital periapical radiography.


Effects of hemolysis and lipemia on the COBAS salicylate and acetaminophen assays compared to GDS assays.
We compared the COBAS(R) acetaminophen and salicylate assays (Roche Diagnostics) with the Stanbio GDS assays (Stanbio Laboratories) that are currently used in our laboratory with respect to interferences from hemolysis and lipemia. Acetaminophen and salicylate were added into human serum with varying concentrations of hemoglobin or Intralipid to generate a range of acetaminophen and salicylate concentrations. Then the COBAS and GDS assays were used to measure the apparent drug concentrations; the H and L indices were measured to determine the extent of hemolysis and lipemia present in each specimen. Both hemolysis and lipemia have less effect on the COBAS(R) acetaminophen and salicylate assays than on the GDS assays. The COBAS assays for acetaminophen and salicylate are preferable to the current GDS assays in clinical toxicology laboratories.


Nomogram to diagnosis of obstructive sleep apnoea-hypopnoea syndrome in high-risk Chinese adult patients.
Many scales are designed to screen for obstructive sleep apnoea-hypopnoea syndrome (OSAHS); however, there is a lack of an efficiently and easily diagnostic tool, especially for Chinese. Therefore, we conduct a cross-sectional study in China to develop and validate an efficient and simple clinical diagnostic model to help screen patients at risk of OSAHS. This study based on 782 high-risk patients (aged >18 years) admitted to the Sleep Medicine department of the Sixth Affiliated Hospital, Sun Yat-sen University from 2015 to 2021. Totally 34 potential predictors were evaluated. We divided all patients into training and validation dataset to develop diagnostic model. The univariable and multivariable logistic regression model were used to build model and nomogram was finally built. Among 602 high-risk patients with median age of 46 (37, 56) years, 23.26% were women. After selecting using the univariate logistic model, 15 factors were identified. We further used the stepwise method to build the final model with five factors: age, BMI, total bilirubin levels, high Berlin score, and symptom of morning dry mouth or mouth breathing. The AUC was 0.780 (0.711, 0.848), with sensitivity of 0.848 (0.811, 0.885), specificity of 0.629 (0.509, 0.749), accuracy of 0.816 (0.779, 0.853). The discrimination ability had been verified in the validation dataset. Finally, we established a nomogram model base on the above final model. We developed and validated a predictive model with five easily acquire factors to diagnose OSAHS patient in high-risk population with well discriminant ability. Accordingly, we finally build the nomogram model.


Inside out: the role of nucleocytoplasmic transport in ALS and FTLD.
Neurodegenerative diseases are characterized by the presence of protein inclusions with a different protein content depending on the type of disease. Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are no exceptions to this common theme. In most ALS and FTLD cases, the predominant pathological species are RNA-binding proteins. Interestingly, these proteins are both depleted from their normal nuclear localization and aggregated in the cytoplasm. This key pathological feature has suggested a potential dual mechanism with both nuclear loss of function and cytoplasmic gain of function being at play. Yet, why and how this pathological cascade is initiated in most patients, and especially sporadic cases, is currently unresolved. Recent breakthroughs in C9orf72 ALS/FTLD disease models point at a pivotal role for the nuclear transport system in toxicity. To address whether defects in nuclear transport are indeed implicated in the disease, we reviewed two decades of ALS/FTLD literature and combined this with bioinformatic analyses. We find that both RNA-binding proteins and nuclear transport factors are key players in ALS/FTLD pathology. Moreover, our analyses suggest that disturbances in nucleocytoplasmic transport play a crucial initiating role in the disease, by bridging both nuclear loss and cytoplasmic gain of functions. These findings highlight this process as a novel and promising therapeutic target for ALS and FTLD.


Rate of exchange of esterified cholesterol between human plasma low and high density lipoproteins.
In vitro incubations of human low density lipoproteins (LDL), high density lipoproteins (HDL) and lipoprotein-free plasma at 37 degrees for 6 h revealed no significant net mass transfers of esterified cholesterol from either lipoprotein fraction to the other. Observed transfers of esterified [3H]cholesterol from LDL to HDL must, therefore, have represented a process of molecular exchange between the two fractions. The time course of the esterified [3H]cholesterol transfers indicated that, from the point of view of the exchange process, the pools of esterified cholesterol in LDL and HDL were (mathematically) homogeneous, thus permitting a precise calculation of the rate of the exchange between the two fractions. In incubations of lipoproteins isolated from the plasma of 9 clinically normal human subjects, there was an hourly exchange of 8-12% and 7-31% of the pools of esterified cholesterol in LDL and HDL respectively, which, in molar terms, represented an exchange of 108-301 mumol/l plasma/h between the two fractions. The exchange of esterified cholesterol between human LDL and HDL is, therefore, rapid when considered in relation to other parameters of esterified cholesterol and lipoprotein metabolism.


Variation is function: Are single cell differences functionally important?: Testing the hypothesis that single cell variation is required for aggregate function.
There is a growing appreciation of the extent of transcriptome variation across individual cells of the same cell type. While expression variation may be a byproduct of, for example, dynamic or homeostatic processes, here we consider whether single-cell molecular variation per se might be crucial for population-level function. Under this hypothesis, molecular variation indicates a diversity of hidden functional capacities within an ensemble of identical cells, and this functional diversity facilitates collective behavior that would be inaccessible to a homogenous population. In reviewing this topic, we explore possible functions that might be carried by a heterogeneous ensemble of cells; however, this question has proven difficult to test, both because methods to manipulate molecular variation are limited and because it is complicated to define, and measure, population-level function. We consider several possible methods to further pursue the hypothesis that variation is function through the use of comparative analysis and novel experimental techniques.


Green Chemistry and Environmental Management Systems: Relationships, Synergies, Advantages and Barriers of Joint Implementation at Universities.
Environmental Management Systems (EMS) based on international standard ISO 14001 are recognized as a tool to improve the environment and the sustainability of organizations. Green Chemistry (GC) seeks to reduce the use and generation of hazardous substances in chemical processes. This paper studies the relationship between EMS based on ISO 14001 and GC. We have analysed their similarities, difficulties, advantages, and synergies that can be developed with a joint implementation in general and in particular on university campuses. The results show that both disciplines have in common the philosophy of Continuous Improvement in the Processes (CIP) and that their joint application is possible, since each principle of GC are related to, at least, one clause of ISO 14001. It is shown that this joint application to different university areas can generate benefits, such as the reduction of hazardous waste and the promotion of green purchases, which favour the environmental improvement of universities. However, there are problems in their joint application related to the lack of specific knowledge and the difficulty of identifying products manufactured following the criteria of GC. Furthermore, a case study in the San Jorge University showing that both disciplines can be treated together is shown. Results were the following: seven GC initiatives (proposed by a small group of GC students) were submitted to the EMS office; only one was considered nonviable and two were implemented, achieving two main goals: Reduction of the environmental impact of laboratories and promotion of green purchasing in the laboratories of San Jorge University.


Comparative analysis of NK cell subsets in menstrual and peripheral blood of patients with unexplained recurrent spontaneous abortion and fertile subjects.
Natural killer (NK) cells play a fundamental role in maintaining pregnancy. Based on the availability and non-invasive method of collection of menstrual blood (MB), here we investigated for the first time a comparative analysis of NK cell subsets in MB and peripheral blood (PB) of women with recurrent spontaneous abortion (RSA) and fertile women. PB and MB of healthy fertile (n=15) and RSA women (n=15) were sampled simultaneously on the second day of the menstrual cycle. Proportions of CD56+CD3-CD16+/-, CD56+CD3-CCR7+/-, and CD56+CD3-CD45RO+/- cells were analyzed using flow cytometry. In the MB of both groups, proportions of CD16+ and CD45RO- NK cells were significantly lower than in the PB. In parallel, CD56+CD16+CCR7- and CCR7+ cells were present in significantly smaller amounts in MB than in PB. However, the amounts of CD56+CD16-CCR7- and CCR7+ cells were greater in MB. In comparison to the fertile group, the percentage of MB CD45RO+ NK cells was significantly lower and frequencies of PB CD16-, CD45RO- and CD56+CD16+CCR7+ subsets were significantly higher in RSA patients. Different subsets of NK cells are differentially distributed in MB in comparison with PB in women with RSA and fertile subjects. Population differences of NK cell subsets in RSA patients and normal controls were more clearly reflected at the systemic level.


SNP discovery in common bean by restriction-associated DNA (RAD) sequencing for genetic diversity and population structure analysis.
Researchers have made great advances into the development and application of genomic approaches for common beans, creating opportunities to driving more real and applicable strategies for sustainable management of the genetic resource towards plant breeding. This work provides useful polymorphic single-nucleotide polymorphisms (SNPs) for high-throughput common bean genotyping developed by RAD (restriction site-associated DNA) sequencing. The RAD tags were generated from DNA pooled from 12 common bean genotypes, including breeding lines of different gene pools and market classes. The aligned sequences identified 23,748 putative RAD-SNPs, of which 3357 were adequate for genotyping; 1032 RAD-SNPs with the highest ADT (assay design tool) score are presented in this article. The RAD-SNPs were structurally annotated in different coding (47.00 %) and non-coding (53.00 %) sequence components of genes. A subset of 384 RAD-SNPs with broad genome distribution was used to genotype a diverse panel of 95 common bean germplasms and revealed a successful amplification rate of 96.6 %, showing 73 % of polymorphic SNPs within the Andean group and 83 % in the Mesoamerican group. A slightly increased He (0.161, n = 21) value was estimated for the Andean gene pool, compared to the Mesoamerican group (0.156, n = 74). For the linkage disequilibrium (LD) analysis, from a group of 580 SNPs (289 RAD-SNPs and 291 BARC-SNPs) genotyped for the same set of genotypes, 70.2 % were in LD, decreasing to 0.10 %in the Andean group and 0.77 % in the Mesoamerican group. Haplotype patterns spanning 310 Mb of the genome (60 %) were characterized in samples from different origins. However, the haplotype frameworks were under-represented for the Andean (7.85 %) and Mesoamerican (5.55 %) gene pools separately. In conclusion, RAD sequencing allowed the discovery of hundreds of useful SNPs for broad genetic analysis of common bean germplasm. From now, this approach provides an excellent panel of molecular tools for whole genome analysis, allowing integrating and better exploring the common bean breeding practices.


Cerebellar impulsivity-compulsivity assessment scale.
The cerebellum has been identified as the key brain region that modulates reward processing in animal models. Consistently, we recently found that people with cerebellar ataxia have impulsive and compulsive behaviors (ICBs), the main symptoms related to abnormal reward processing. Due to the lack of a validated scale to quantitatively measure ICBs in cerebellar disorders, we aim to develop and validate a new scale, Cerebellar Impulsivity-Compulsivity Assessment (CIA). We recruited 62 cerebellar ataxia cases, categorized into those with ICBs and those without. We developed a preliminary version of CIA, containing 17 questions. We studied the internal consistency, test-retest reliability, and inter-rater reliability to formulate the final version of CIA, which constitutes only 10 questions. The receiver operating characteristic curve (ROC) was generated to assess the sensitivity and specificity of CIA. Cerebellar ataxia cases with ICBs have threefold higher total preliminary CIA scores than those without ICBs (12.06 ± 5.96 vs. 4.68 ± 3.50, p = 0.038). Cronbach's alpha revealed good internal consistency across all items (α > 0.70). By performing the test-retest reliability and inter-rater reliability on the preliminary version of CIA, we excluded seven questions (r < 0.70) and generated the final version of CIA. Based on the ROC, a score of 8.0 in CIA was chosen as the cut-off for ICBs in individuals with cerebellar ataxia with 81% sensitivity and 81% specificity. CIA is a novel tool to assess ICBs in cerebellar ataxia and broaden our understanding of the cerebellum-related cognitive and behavioral symptoms.


Inorganic Matrices Assisted Laser Desorption/Ionization Mass Spectrometry for Metabolic Analysis in Biofluids.
Metabolic analysis in biofluids interprets the end products in the bioprocess, emerging as an irreplaceable disease diagnosis and monitoring platform. Laser desorption/ionization mass spectrometry (LDI MS)-based metabolic analysis holds great potential for clinical applications in terms of high throughput, rapid signal readout, and minimal sample preparation. There are two essential elements to construct the LDI MS-based metabolic analysis: 1) well-designed nanomaterials as matrices; 2) machine learning algorithms for data analysis. This review highlights the development of various inorganic matrices to comprehend the advantages of LDI MS in metabolite detection and the recent diagnostic applications based on target metabolite detection and untargeted metabolic fingerprints in biological fluids.


Can computerized reminder systems have an impact on preventive services in practice?
This report reviews computerized reminder systems for tracking health maintenance in clinical practice and discusses the features of a useful, cost-effective system. Systems presently available are predominantly designed for large groups. The primary product of these systems is a health maintenance status report for the provider that is generated at each patient visit. Systems for smaller groups that will generate reminders for providers and patients at specified appropriate intervals and will easily send reminders to patients who do not have appointments or are inactive are not available. Necessary features of such "ideal" computerized tracking systems include: 1) Demographic data must be obtainable from the practice's billing system and not require separate data entry. 2) Data entry must be quick, preferably single-screen. 3) Multiple-entry options must be available for each procedure. 4) The system must generate reminders regardless of whether a patient has an appointment. 5) Providers must be able to specify or cancel patient reminders. 6) A status report must be created for the chart at specified intervals. 7) The frequency and description of indicated procedures must be modifiable without programmer assistance.


Clinicoradiological and therapeutic considerations in severe diffuse traumatic brain injury in children.
Forty-one children with severe head injuries and diffuse brain lesions were selected from a consecutive series of 62 children in traumatic coma (21 focal mass lesions) and studied. According to the CT pattern, two main types of intracranial lesions were considered: diffuse axonal injury (DAI) and diffuse brain swelling (DBS). High mortality, due to secondary increases of intracranial pressure (ICP), correlated well with the patterns of severe DBS, absence of perimesencephalic cisterns, and obliteration of the ventricles. However, children with normal CTs, and/or obvious shearing injuries indicative of DAI, had favorable outcomes; there was no mortality if increased ICP was not present. We conclude that although there does not seem to be any routine indications for ICP monitoring in children with pure DAI, early ICP monitoring and aggressive management of increasing ICP should be considered in comatose children with DBS, especially when associated with subarachnoid hemorrhage and respiratory or circulatory failure.


Tibial internal rotation is affected by lateral laxity in cruciate-retaining total knee arthroplasty: an intraoperative kinematic study using a navigation system and offset-type tensor.
The purpose of this study was to test the hypothesis that intraoperative soft-tissue balance assessed by an offset-type tensor influences post-operative knee kinematics after cruciate-retaining (CR) total knee arthroplasty (TKA). The influence of intraoperative soft-tissue balance on knee kinematics in CR-TKA was retrospectively analysed in 30 patients. Intraoperative soft-tissue balance parameters such as varus angle (varus ligament balance), joint component gap (centre gap), and medial and lateral compartment gaps were measured in the navigation system while applying 40-lb joint distraction force at 0°, 10°, 30°, 60°, 90°, and 120° of knee flexion using an offset-type tensor with the patella reduced. Tibial internal rotation and tibial anterior translation were measured as the differences between the values at 60° and 120° of flexion using the navigation system. Correlations between the soft-tissue parameters and post-operative knee kinematics were analysed. The varus ligament balance was positively correlated with tibial internal rotation at 60° and 90° of flexion (R = 0.54, P < 0.05; R = 0.60, P < 0.01, respectively). Furthermore, the joint component gap was positively correlated with tibial internal rotation at 90° of flexion (R = 0.44, P < 0.05), and the lateral compartment gap was positively correlated with tibial internal rotation at 60°, 90°, and 120° of knee flexion. The intraoperative varus ligament balance and joint component gap values were factors that predicted post-operative knee kinematics after CR-TKA. Lateral laxity at mid-to-deep knee flexion plays a significant role in tibial internal rotation. III.


An optimized model for network intrusion detection systems in industry 4.0 using XAI based Bi-LSTM framework.
Industry 4.0 enable novel business cases, such as client-specific production, real-time monitoring of process condition and progress, independent decision making and remote maintenance, to name a few. However, they are more susceptible to a broad range of cyber threats because of limited resources and heterogeneous nature. Such risks cause financial and reputational damages for businesses, well as the theft of sensitive information. The higher level of diversity in industrial network prevents the attackers from such attacks. Therefore, to efficiently detect the intrusions, a novel intrusion detection system known as Bidirectional Long Short-Term Memory based Explainable Artificial Intelligence framework (BiLSTM-XAI) is developed. Initially, the preprocessing task using data cleaning and normalization is performed to enhance the data quality for detecting network intrusions. Subsequently, the significant features are selected from the databases using the Krill herd optimization (KHO) algorithm. The proposed BiLSTM-XAI approach provides better security and privacy inside the industry networking system by detecting intrusions very precisely. In this, we utilized SHAP and LIME explainable AI algorithms to improve interpretation of prediction results. The experimental setup is made by MATLAB 2016 software using Honeypot and NSL-KDD datasets as input. The analysis result reveals that the proposed method achieves superior performance in detecting intrusions with a classification accuracy of 98.2%.


The neuroprotective impact of the leak potassium channel TASK1 on stroke development in mice.
Oxygen depletion (O(2)) and a decrease in pH are initial pathophysiological events in stroke development, but secondary mechanisms of ischemic cell death are incompletely understood. By patch-clamp recordings of brain slice preparations we show that TASK1 and TASK3 channels are inhibited by pH-reduction (42+/-2%) and O(2) deprivation (36+/-5%) leading to membrane depolarization, increased input resistance and a switch in action potential generation under ischemic conditions. In vivo TASK blockade by anandamide significantly increased infarct volumes at 24 h in mice undergoing 30 min of transient middle cerebral artery occlusion (tMCAO). Moreover, blockade of TASK channels accelerated stroke development. Supporting these findings TASK1(-/-) mice developed significantly larger infarct volumes after tMCAO accompanied by worse outcome in functional neurological tests compared to wild type mice. In conclusion, our data provide evidence for an important role of functional TASK channels in limiting tissue damage during cerebral ischemia.


Role of the Collecting Duct Renin Angiotensin System in Regulation of Blood Pressure and Renal Function.
Recent evidence suggests that the renal tubular renin angiotensin system regulates urinary Na(+) and water excretion and blood pressure. Three key components of the tubular renin angiotensin system, namely renin, prorenin receptor, and angiotensin-II type 1 receptor, are localized to the collecting duct. This system may modulate collecting duct Na(+) and water reabsorption via angiotensin-II-dependent and angiotensin-II-independent pathways. Further, the system may be of greatest relevance in hypertensive states and particularly those characterized by high circulating angiotensin-II. In this review, we summarize the current knowledge on the synthesis, regulation, and function of collecting duct-derived renin angiotensin system components and examine recent developments with regard to regulation of blood pressure and renal fluid and Na(+) excretion.


Acquisition of submandibular gland nerve growth factor (SMG-NGF) responsiveness to thyroxine administration in neonatal mice.
The growth of the submandibular gland (SMG) was studied in newborn mice from birth to 15 days of age. Progressive changes in wet weight were observed to accompany changes in biochemical constituents such as RNA, protein, and lipid. Thyroxine (T4) administration from days 0-6 produced changes in SMG growth and SMG accumulation of RNA, protein, and lipid components relative to control pups treated with a similar volume of vehicle. This hormone regimen produced no measurable changes in SMG nerve growth factor (SMG-NGF) concentration. T4 responsiveness also was studied from days 0-15. Three patterns of T4 injection (from days 0-6, 7-14, and 0-14) were found to elicit a differential response in the three biochemical constituents measured, but treatment from days 7-14 and 0-14 elicited precocious increments in SMG-NGF concentrations on day 15. The effect of T4 injection from birth was more effective in augmenting SMG-NGF concentration than hormone treatment initiated from days 7-14. A persistent T4 effect on SMG-NGF also was observed on day 21 following hormone treatment from days 7-14 or 0-14. In summary, the acquisition of SMG-NGF responsiveness to T4 appears to develop during the neonatal period. The administration of T4 during this period also precociously stimulates the mechanisms that govern the normal ontogeny of SMG-NGF at the time of weaning.


Exploratory investigation on antibodies to GluN1 and cognitive dysfunction in patients with chronic autoimmune psychosis.
Mild cognitive dysfunction has been implicated in a number of psychiatric diseases and affects social functioning. Although clinical criteria were recently proposed for autoimmune psychosis (AP), biomarkers have not yet been established for the severity and prognosis of cognitive dysfunction. We herein investigated the relationships between 3 types of serum antibodies and cognitive dysfunction in chronic psychiatric patients suspected of AP. We included 31 patients suspected of AP and obtained information on their clinical characteristics. Three types of autoantibodies (the anti-N-methyl-D-aspartate receptor (anti-NMDAR Ab), anti-N-terminal of GluN1 (anti-GluN1-NT Ab), and anti-thyroid antibodies) were evaluated in serum. Cognitive function was assessed using Wechsler Adult Intelligence Scale-III. We examined the relationships between serum autoantibodies and cognitive dysfunction in patients using multiple regression models. Serum titers of anti-GluN1-NT Ab significantly contributed to the estimated score of working memory (B= -55.85, β= -0.46, p= 0.01), while no correlation was observed between the other 2 types of antibodies and cognitive function. The present results indicate the potential of serum anti-GluN1-NT Ab as a biomarker for the severity and prognosis of cognitive dysfunction underlying various psychiatric symptoms in patients with AP. The pathological significance of anti-GluN1-NT Ab needs to be verified in future studies.


Evaluation of Agonal Cardiac Function for Sudden Cardiac Death in Forensic Medicine with Postmortem Brain Natriuretic Peptide (BNP) and NT-proBNP: A Meta-analysis.
Sudden cardiac death (SCD) is an unexpected death caused by a sudden loss of cardiac function, which is currently a global public health problem. Evaluation of the agonal cardiac function of the deceased is a quite important task for the diagnosis of SCD in forensic medicine. Brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are currently considered as significant biomarkers for the diagnosis of heart failure in both clinical and forensic practices. To investigate the postmortem evaluation roles of postmortem BNP and NT-proBNP levels for SCD, the present study meta-analyzed eight related studies from Embase, Cochrane Library, PubMed, China Biomedical Literature Database, China National Knowledge Infrastructure, and Wanfang Data. Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the included literature, and the meta-analysis was performed by RevMan 5.3.5 software. Postmortem NT-proBNP in pericardial fluid showed higher levels in the SCD group than that of the non-SCD group with the weighted mean difference = 3665.74, 95% confidence interval: 1812.89-5518.59, and p = 0.0001. However, postmortem levels of BNP in pericardial fluid and NT-proBNP in serum revealed no statistical difference between SCD and non-SCD subjects. The results of present meta-analysis demonstrated that postmortem NT-proBNP in the pericardial fluid could be used as an ancillary indicator for evaluation of agonal cardiac function in forensic medicine.


Type 1 diabetes management and outcomes: A multicenter study in Thailand.
The Thai Type 1 Diabetes and Diabetes Diagnosed Before Age 30 Years Registry, Care and Network was established in 2014 and involved 31 hospitals. The objective of the registry was to evaluate glycemic control and complications of patients with type 1 diabetes. Patients' demographics, clinical data, frequencies of daily self-monitoring of blood glucose (SMBG), glycemic control and complications were collected. Among the 1,907 type 1 diabetes patients, the mean age was 21.2 ± 11.3 years. The mean glycated hemoglobin level was 9.35 ± 2.41%, with significant variations among age groups (P < 0.001). Conventional insulin treatment and intensive insulin treatment were used in 43 and 57% of patients, respectively. Mean glycated hemoglobin levels were significantly higher in patients treated with conventional insulin treatment compared to those treated with intensive insulin treatment (9.63 ± 2.34 vs 9.17 ± 2.46%, P = 0.002). Compared to the conventional insulin treatment group, significantly more patients in the intensive insulin treatment group achieved good glycemic control (P < 0.001), and fewer had diabetic retinopathy (P = 0.031). The prevalence of microvascular complications increased significantly with age (P < 0.001). Multivariate analysis showed good glycemic control to be associated with age 25 to <45 years, intensive insulin treatment with SMBG three or more times daily and diabetes duration of 1 to <5 years. Most Thai type 1 diabetes patients were not meeting the recommended glycemic target. As a result of this study, the national program to improve the quality of diabetes treatment and education has been implemented, and the results are ongoing.


Costs of family planning programmes in fourteen developing countries by method of service delivery.
The cost effectiveness of several modes of family planning service delivery based on the cost per couple-year of protection (CYP), including commodity costs, is assessed for 1991-92 using programme and project data from fourteen developing countries (five in Africa, four in Asia, three in Latin America and two in the Middle East). More than 100 million CYP were provided through these family planning services during the 12 months studied. Sterilisation services provided both the highest volume (over 60% of total) and the lowest cost per CYP ($1.85). Social marketing programmes (CSM), delivering almost 9 million CYPs, had the next lowest cost per CYP on average ($2.14). Clinic-based services excluding sterilisation had an average cost of $6.10. The highest costs were for community-based distribution projects (0.7 million CYPs), which averaged $9.93, and clinic-based services with a community-based distribution component (almost 6 million CYPs), at a cost of $14.00 per CYP. Based on a weighted average, costs were lowest in the Middle East ($3.37 per CYP for all modes of delivery combined) and highest in Africa ($11.20).


Squamous cell carcinoma complicating chronic osteomyelitis: A systematic review and case series.
Squamous cell carcinoma (SCC) is a rare but serious complication of chronic osteomyelitis. This study aimed to determine an optimum approach to diagnosis and management. A systematic review was performed using Medline, Embase, CINAHL and Web of Science, from 1999-present. Additional cases, meeting the eligibility criteria, were added from our hospital database. Patient demographics (age, gender, co-morbidities), osteomyelitis diagnosis (location, duration), diagnosis of SCC (method, imaging, extent of disease) and management (amputation versus wide local excision versus palliation) as well as outcome at one and five years were collected. Nineteen studies involving 106 patients met strict inclusion criteria. All published studies were case reports or case series. Chronic osteomyelitis had been present for a mean of 31 years (range 3-67) prior to SCC diagnosis. SCC was most commonly treated by amputation (81%). A poorer outcome occurred in those with metastatic disease (p = 0.006 at one year; p = 0.032 at five years), an incidental diagnosis at surgery for osteomyelitis (p = 0.052; p = 0.021) and SCC after pelvic osteomyelitis (p < 0.001; p = 0.002). SCC should be suspected in all cases of chronic osteomyelitis with skin changes, particularly if the duration of sinus drainage exceeds 3 years. Histological biopsy for malignancy should be taken in all suspected cases, as well as routinely during excision of osteomyelitis when chronic skin changes are present. Staging computed tomography (CT) scanning is recommended to guide adjunctive therapy. Amputation, where possible, may be considered as the definitive surgical management, after discussion with the patient.


High-Resolution 3D Printing of Mechanically Tough Hydrogels Prepared by Thermo-Responsive Poloxamer Ink Platform.
High-resolution 3D-printable hydrogels with high mechanical strength and biocompatibility are in great demand because of their potential applications in numerous fields. In this study, a material system comprising Pluronic F-127 dimethacrylate (FDMA) is developed to function as a direct ink writing (DIW) hydrogel for 3D printing. FDMA is a triblock copolymer that transforms into micelles at elevated temperatures. The transformation increases the viscosity of FDMA and preserves its structure during DIW 3D printing, whereupon the printed structure is solidified through photopolymerization. Because of this viscosity shift, various functionalities can be incorporated through the addition of other materials in the solution state. Acrylic acid is incorporated into the pregel solution to enhance the mechanical strength, because the carboxylate group of poly(acrylic acid) ionically crosslinks with Fe3+ , increasing the toughness of the DIW hydrogel 37 times to 2.46 MJ m-3 . Tough conductive hydrogels are also 3D printed by homogenizing poly(3,4-ethylenedioxythiophene) polystyrene sulfonate into the pregel solution. Furthermore, the FDMA platform developed herein uses DIW, which facilitates multicartridges 3D printing, and because all the materials included are biocompatible, the platform may be used to fabricate complex structures for biological applications.


A comparative analysis of microglial inducible Cre lines.
Cre/loxP technology has revolutionized genetic studies and allowed for spatial and temporal control of gene expression in specific cell types. Microglial biology has particularly benefited because microglia historically have been difficult to transduce with virus or electroporation methods for gene delivery. Here, we investigate five of the most widely available microglial inducible Cre lines. We demonstrate varying degrees of recombination efficiency, cell-type specificity, and spontaneous recombination, depending on the Cre line and inter-loxP distance. We also establish best practice guidelines and protocols to measure recombination efficiency, particularly in microglia. There is increasing evidence that microglia are key regulators of neural circuits and major drivers of a broad range of neurological diseases. Reliable manipulation of their function in vivo is of utmost importance. Identifying caveats and benefits of all tools and implementing the most rigorous protocols are crucial to the growth of the field and the development of microglia-based therapeutics.


Measurement of resonant bend loss in anti-resonant hollow core optical fiber: erratum.
An error on the part of the authors in drafting resulted in Eq. (3) being incorrect in the published paper [Opt. Express25, 20612 (2017)10.1364/OE.25.020612]. We present a corrected version of the equation. It should be noted that this does not affect the presented results or conclusions of the paper.


Associations of CB1 cannabinoid receptor (CNR1) gene polymorphisms with risk for alcohol dependence: Evidence from meta-analyses of genetic and genome-wide association studies.
Reported associations of the cannabinoid receptor 1 (CNR1) single nucleotide polymorphisms (SNPs) with alcohol dependence (AD) have been inconsistent, prompting a meta-analysis to obtain more precise estimates. A Boolean search of 4 databases (PubMed, Scopus, Google Scholar, and Mednar) sought articles that evaluated the association between CNR1 polymorphisms and risk of AD. We selected the articles with sufficient genotype frequency data to enable calculation of odds ratios (ORs) and 95% confidence intervals (CIs). Using the Population Intervention Comparators Outcome elements, AD patients (P) were compared by genotype data between AD-participants (I) and non-AD-participants (C) in order to determine the risk of AD (O) attributed to the CNR1 SNPs. Analyzing 4 SNPs (rs1049353, rs1535255, rs2023239, and rs806379) using standard genetic models, we examined associations where multiple comparisons were Holm-Bonferroni corrected. The pooled ORs were assessed for aggregate statistical power and robustness (sensitivity analysis). Subgroups were Caucasians and African-Americans. From 32 comparisons, 14 were significant indicating increased risk, from which 5 outcomes (P-value for association [Pa] = .003 to <.001) survived the Holm-Bonferroni-correction, which were deemed robust. In the rs1535255 outcomes, the codominant effect (OR = 1.43, 95% CIs = 1.24-1.65, Pa < .001) had greater statistical power than the dominant effect (OR = 1.30, 95% CI = 1.08-1.57, Pa = .006). In contrast, the rs2023239 codominant outcome was underpowered. Significance of both rs806379 Caucasian outcomes (ORs = 1.20-1.43, 95% CIs = 1.07-1.57, Pa = .003) contrasted with the null effects in African-Americans (ORs = 0.98-1.08, 95% CIs = 0.70-1.53). Three CNR1 SNPs (rs1535255, rs2023239, and rs806379) were implicated in their associations with development of AD: based on aggregate statistical power, rs1535255 presented greater evidence for associations than rs2023239; rs806379 implicated the Caucasian subgroup. Multiple statistical and meta-analytical features (consistency, robustness, and high significance) underpinned the strengths of these outcomes. Our findings could render the CNR1 polymorphisms useful in the clinical genetics of AD.


The long-term prognostic and predictive capacity of cyclin D1 gene amplification in 2305 breast tumours.
Use of cyclin D1 (CCND1) gene amplification as a breast cancer biomarker has been hampered by conflicting assessments of the relationship between cyclin D1 protein levels and patient survival. Here, we aimed to clarify its prognostic and treatment predictive potential through comprehensive long-term survival analyses. CCND1 amplification was assessed using SNP arrays from two cohorts of 1965 and 340 patients with matching gene expression array and clinical follow-up data of over 15 years. Kaplan-Meier and multivariable Cox regression analyses were used to determine survival differences between CCND1 amplified vs. non-amplified tumours in clinically relevant patient sets, within PAM50 subtypes and within treatment-specific subgroups. Boxplots and differential gene expression analyses were performed to assess differences between amplified vs. non-amplified tumours within PAM50 subtypes. When combining both cohorts, worse survival was found for patients with CCND1-amplified tumours in luminal A (HR = 1.68; 95% CI, 1.15-2.46), luminal B (1.37; 1.01-1.86) and ER+/LN-/HER2- (1.66; 1.14-2.41) subgroups. In gene expression analysis, CCND1-amplified luminal A tumours showed increased proliferation (P < 0.001) and decreased progesterone (P = 0.002) levels along with a large overlap in differentially expressed genes when comparing luminal A and B-amplified vs. non-amplified tumours. Our results indicate that CCND1 amplification is associated with worse 15-year survival in ER+/LN-/HER2-, luminal A and luminal B patients. Moreover, luminal A CCND1-amplified tumours display gene expression changes consistent with a more aggressive phenotype. These novel findings highlight the potential of CCND1 to identify patients that could benefit from long-term treatment strategies.


Cis-platinum and 5-fluorouracil as induction therapy for advanced head and neck cancer.
Sixty-one patients were treated with a three course induction regimen of 5-fluorouracil and cis-platinum for advanced squamous cell carcinoma of the head and neck area. Thirty-three patients (54 percent) had complete clinical remission with the administration of these drugs. Twenty-four patients (39 percent) showed a 50 percent or greater reduction in tumor size, for a significant response rate of 93 percent. The toxicities were within acceptable limits, and only three patients did not complete all three courses. Surgery and radiation therapy were supposed to follow the chemotherapy but several patients refused surgery after the disappearance of their lesion. This has created a problem in patient management.


Activation of persulfate with natural organic acids (ascorbic acid/catechin hydrate) for naproxen degradation in water and soil: Mechanism, pathway, and toxicity assessment.
In this study, we investigated the effects of different natural organic acids (NOAs), L-ascorbic acid (AA) and (+)-catechin hydrate (CAT), on the activation of persulfate (PDS) for the oxidation of naproxen (NAP) in water and soil. We found that only AA-activated PDS process had a significant degradation efficiency of NAP in water. High AA concentration (500 μM) inhibited the degradation of NAP, whereas high levels of PDS (7.5 mM) and acidic conditions (pH=3-7) were beneficial for NAP degradation. In soil, both CAT and AA promoted PDS activation and NAP degradation. Low soil organic matter and high Fe/Mn-mineral contents were favorable for NAP degradation by AA-activated PDS. Column experiments confirmed that NAP was readily transported and degraded under porous medium conditions using AA-activated PDS. Moreover, we revealed that SO4•- and HO• were the dominant reactive species for NAP degradation by AA-activated PDS. Intermediate products of NAP in the AA-activated PDS process were analyzed and the reactive sites of NAP were predicted. E. coli growth tests verified that the intermediate products in the AA-activated PDS process were less toxic than NAP. Our results highlight the high potential of NOAs-activated PDS process for the remediation of NAP-contaminated water and soil.


Towards feedback-controlled nanomedicines for smart, adaptive delivery.
The timing and rate of release of pharmaceuticals from advanced drug delivery systems is an important property that has received considerable attention in the scientific literature. Broadly, these mostly fall into two classes: controlled release with a prolonged release rate or triggered release where the drug is rapidly released in response to an environmental stimulus. This review aims to highlight the potential for developing adaptive release systems that more subtlety modulate the drug release profile through continuous communication with its environment facilitated through feedback control. By reviewing the key elements of this approach in one place (fundamental principles of nanomedicine, enzymatic nanoreactors for medical therapies and feedback-controlled chemical systems) and providing additional motivating case studies in the context of chronobiology, we hope to inspire innovative development of novel "chrononanomedicines."


Synthesis and cytotoxic analysis of thiolated xylose derivatives decorated on gold nanoparticles.
The rapid development of metal nanoparticles capped by an organic monolayer offers the possibility to create a whole new variety of products with novel characteristic, functions and applications. Among these, nanoparticles covered with carbohydrates (glyconanoparticles) constitute a good bio-mimetic model of carbohydrate presentation at the cell surface and are currently centered on many glycobiological and biomedical applications. In this study, a series of novel D-xylose gold nanoparticles (AuNPs) with linkages of alkyl or polyethylene glycol have been synthesized via D-xylosethiols, forming self-assembled monolayers on gold nanoparticles. The nano-gold solution, two carbohydrate derivatives and modified nano-gold solution were tested for cytotoxicity to check the biocompatibility. The MTT assay on NIH 3T3 cell lines confirmed that all the test materials showed no toxicity with the more than 90 % of cell viability in both low concentration (1 μM) and high concentration (100 μM), compared with the control.


Low-temperature-resistance granulation of activated sludge and the microbial responses to the granular structural stabilization.
Completely loss of granular structural stability and reliable start-up of aerobic granular sludge (AGS) system are considered as the biggest challenges for its engineering application under seasonal temperature variation, especially extremely low temperatures. In this study, two identical sequencing batch reactors (SBR) were successfully start-up at 10 °C (R1) and 25 °C (R2), respectively, and then operated under a strategy of stepwise change of temperatures to investigate the stability of the granular sludge by examining its microbial characteristics, bis (3'-5')-cyclic dimeric guanosine monophosphate (c-di-GMP), extracellular polymeric substance (EPS) and sludge physiochemical properties. The results showed that AGS formed under the low temperature preferentially secrete EPS and c-di-GMP for stable granulation and improvement of its resistance to temperature changes. Meanwhile, R1 successfully obtained aerobic granulation with high biomass concentration and superior settleability, as well as high pollutant removal performance. In comparison, R2 took a longer time for granulation and was subjected to serious disintegration of AGS. The matrix structure partially formed by filamentous bacteria during the start-up stage in R1 was one of major reasons for its own superiority beyond R2 in granulation. Slow-growing organisms such as autotrophic nitrifying and Anammox bacteria, phosphorus accumulation organisms, EPS-producing genera, and c-di-GMP pathway-dependent genera, were exclusively enriched in the R1 and resulted in higher pollutants removal efficiencies and stable structure, whereas Sphaerotilus dominated in R2 that related closely with its unstable performance. Therefore, the strategy based on the stepwise change of temperatures from extremely low temperatures may be one feasible way for the sustainable application of AGS system, which is of significance to address the challenging problems of AGS applications.


Antacid effects of Chinese herbal prescriptions assessed by a modified artificial stomach model.
To assess the antacid effects of the tonic Chinese herbal prescriptions, si-jun-zi-tang (SJZT) and shen-ling-bai-zhu-san (SLBZS). Decoctions of the tonic Chinese herbal prescriptions, SJZT and SLBZS, were prepared according to Chinese original documents. The pH of the prescription decoctions and their neutralizing effects on artificial gastric acids were determined and compared with water and the active controls, sodium bicarbonate and colloidal aluminum phosphate. A modified model of Vatier's artificial stomach was used to determine the duration of consistent neutralization effect on artificial gastric acids. The neutralization capacity in vitro was determined with the titration method of Fordtran's model. The results showed that both SJZT and SLBZS have antacid effects in vitro. Compared with the water group, SJZT and SLBZS were found to possess significant gastric acid neutralizing effects. The duration for consistent neutralization of SLBZS was significantly longer than that of water. Also, SLBZS and SJZT exhibited significant antacid capacities compared to water. SJZT and SLBZS were consistently active in the artificial stomach model and are suggested to have antacid effects similar to the active control drugs.


The impact of blastocyst freezing and biopsy on the association of blastocyst morphological parameters with live birth and singleton birthweight.
To explore whether the associations of 3 blastocyst morphological parameters, namely, degree of blastocyst expansion (expansion), appearance of trophectoderm (TE) and inner cell mass, with live birth and singleton birth weight are influenced by blastocyst freezing and biopsy. A retrospective study. An assisted reproductive technology center. 28,515 single blastocyst transfer cycles between January 2014 and August 2019. Not applicable. Live birth and singleton birth weight. Blastocyst transfer cycles were divided into 4 groups: biopsied blastocyst cycles (biopsied-blast), thawed blastocyst cycles (thawed-blast), blastocyst from thawed cleavage embryo cycles (blast-thawed-D3), and fresh blastocyst cycles (fresh-blast). Subgroup analyses by blastocyst stage (day 5 and day 6) were performed in thawed-blast and blast-thawed-D3. Because almost all blastocysts were biopsied on day 6 and fresh blastocysts were transferred on day 5, the biopsied-blast and fresh-blast were not divided into subgroups. First, the associations between blastocyst morphological parameters and live birth were analyzed. To explore the effect of freezing, we compared day-5 frozen cycles (thawed-blast) vs. day-5 fresh cycles (including fresh-blast and blast-thawed-D3) and day 6 frozen cycles (thawed-blast) vs. day-6 fresh cycles (blast-thawed-D3). Inner cell mass and TE were associated with live birth for day 5 embryos, and only TE affected live birth for day-6 embryos. The associations were the same in frozen cycles and fresh cycles. To explore the effect of biopsy, we compared day-6 biopsied cycles (biopsied-blast) vs. day-6 nonbiopsied cycles (including thawed-blast and blast-thawed-D3). All the 3 parameters were associated with live birth in biopsied-blast, whereas only TE was associated with live birth in nonbiopsied cycles. In addition, the associations between blastocyst morphological parameters and singleton birthweight were analyzed. In the 6 subgroups, expansion stage of day-6 embryos in biopsied-blast and TE grade of day-6 embryos in thawed-blast were associated with birth weight, and there are no associations in other subgroups. The association of blastocyst morphological parameters with live birth may be affected by blastocyst biopsy and/or genetic testing, and its association with birth weight may be affected by blastocyst freezing and biopsy and/or genetic testing.


On the historical and conceptual background of the Wisconsin Card Sorting Test.
In this paper, we describe the development of the Wisconsin Card Sorting Test (WCST). We trace the history of sorting tasks from the studies of Narziss Ach on the psychology of thinking, via the work of Kurt Goldstein and Adhémar Gelb on brain lesioned patients around 1920 and subsequent developments, up to the actual design of the WCST by Harry Harlow, David Grant, and their student Esther Berg. The WCST thus seems to originate from the psychology of thinking ('Denkpsychologie'), but the test, as it is used in clinical neuropsychological practice, was designed by experimenters working within the behaviorist tradition. We also note recent developments suggesting that, contrary to the general impression, implicit learning may play a role in WCST-like discrimination learning tasks.


[Titanium implants of Brånemark type for oral rehabilitation of partially edentulous patients].
This paper describes the principles for different types of partial reconstructions using tissue integrated titanium fixtures, according to the Brånemark technique, as abutments for fixed bridges. The implant-supported bridges can be designed either in separate units (Type I) or integrated into tooth-supported reconstructions (Type IIA and Type IIB). The different designs of the fixed bridge-work are illustrated by a number of patient presentations.


Exploring everyday work as a dynamic non-event and adaptations to manage safety in intraoperative anaesthesia care: an interview study.
Safety has been described as a dynamic non-event and as constantly present in professionals' work processes. Investigating management of complex everyday situations may create an opportunity to elucidate safety management. Anaesthesia has been at the frontline of enhancing patient safety - testing and implementing knowledge from other high-reliability industries, such as aviation, in the complex, adaptive system of an operating room. The aim of this study was to explore factors supporting anaesthesia nurses and anaesthesiologists in managing complex everyday situations during intraoperative anaesthesia care processes. Individual interviews with anaesthesia nurses (n = 9) and anaesthesiologists (n = 6) using cognitive task analysis (CTA) on case scenarios from previous prospective, structured observations. The interviews were analysed using the framework method. During intraoperative anaesthesia care, management of everyday complex situations is sustained through preparedness, support for mindful practices, and monitoring and noticing complex situations and managing them. The prerequisites are created at the organization level. Managers should ensure adequate resources in the form of trained personnel, equipment and time, team and personnel sustainability and early planning of work. Management of complex situations benefits from high-quality teamwork and non-technical skills (NTS), such as communication, leadership and shared situational awareness. Adequate resources, stability in team compositions and safe boundaries for practice with shared baselines for reoccurring tasks where all viewed as important prerequisites for managing complex everyday work. When and how NTS are used in a specific clinical context depends on having the right organizational prerequisites and a deep expertise of the relevant clinical processes. Methods like CTA can reveal the tacit competence of experienced staff, guide contextualized training in specific contexts and inform the design of safe perioperative work practices, ensuring adequate capacity for adaptation.


Dying to Learn: A Scoping Review of Breast and Cervical Cancer Studies Focusing on Black Canadian Women.
In Canada, data on race/ethnicity are not routinely collected. Black Canadian women may be under-screened for cervical/breast cancer and may be predisposed to worse outcomes, however data are difficult to find. A scoping review was conducted to identify common themes and gaps in the literature regarding cervical/breast cancer prevention and management in Black Canadian women. Medline, Embase, the Cochrane Library, CINAHL, PsycINFO, and Scopus databases (2003-2018) and grey literature were searched. Relevant studies were selected, data were charted, and themes were extracted. Twenty-three studies met inclusion criteria. Women from sub-Saharan Africa appear to have lower cervical and breast cancer screening rates; those of Caribbean/Latin American origin appear to have screening rates comparable to the general population; no studies reported prevalence or mortality rates for Black Canadian women. There is a paucity of health research on breast and cervical cancer specific to Black Canadian women.


Spiritual care in critically ill patients during COVID-19 pandemic.
Spiritual care has a positive influence when patients are subjected to serious illnesses, and critically ill situations such as the case of the COVID-19 pandemic. The purpose of this study was to investigate the perceptions and attitudes of nurses working at critical care units and emergency services in Spain concerning the spiritual care providing to patients and families during the COVID-19 pandemic. A qualitative investigation was carried out using in-depth interviews with 19 ICU nursing professionals. During the pandemic, nurses provided spiritual care for their patients. Although they believed that spirituality was important to help patients to cope with the disease, they do not had a consensual definition of spirituality. Work overload, insufficient time and lack of training were perceived as barriers for providing spiritual healthcare. These results support the role of spirituality in moments of crisis and should be considered by health professionals working in critical care settings.


Competitive advantage of rare behaviours induces adaptive diversity rather than social conformity in skill learning.
Recent studies have emphasized the role of social learning and cultural transmission in promoting conformity and uniformity in animal groups, but little attention has been given to the role of negative frequency-dependent learning in impeding conformity and promoting diversity instead. Here, we show experimentally that under competitive conditions that are common in nature, social foragers (although capable of social learning) are likely to develop diversity in foraging specialization rather than uniformity. Naive house sparrows that were introduced into groups of foraging specialists did not conform to the behaviour of the specialists, but rather learned to use the alternative food-related cues, thus forming groups of complementary specialists. We further show that individuals in such groups may forage more effectively in diverse environments. Our results suggest that when the benefit from socially acquired skills diminishes through competition in a negative frequency-dependent manner, animal societies will become behaviourally diverse rather than uniform.


Analysis of expressed sequence tags from the anamorphic basidiomycetous yeast, Pseudozyma antarctica, which produces glycolipid biosurfactants, mannosylerythritol lipids.
Pseudozyma antarctica T-34 secretes a large amount of biosurfactants (BS), mannosylerythritol lipids (MEL), from different carbon sources such as hydrocarbons and vegetable oils. The detailed biosynthetic pathway of MEL remained unknown due to lack of genetic information on the anamorphic basidiomycetous yeasts, including the genus Pseudozyma. Here, in order to obtain genetic information on P. antarctica T-34, we constructed a cDNA library from yeast cells producing MEL from soybean oil and identified the genes expressed through the creation of an expressed sequence tags (EST) library. We generated 398 ESTs, assembled into 146 contiguous sequences. Based upon a BLAST search similarity cut-off of E<or=10(-5), 21.4% of all contigs were orphan, while 78.6% showed similarity to sequences in the protein database; 60.3% of all contiguous sequences shared significant identities to hypothetical protein of Ustilago maydis, which is a smut fungus and BS producer. Based on the gene expression study using real-time reverse transcriptase-PCR, the predicted genes, such as mannosyltranferase and acyltransferase, were demonstrated to be highly involved in MEL biosynthesis in soybean oil-grown cells.


Cognitive outcome of surgery.
Epilepsy surgery is now widely accepted as an effective therapeutic option for carefully selected children with medically refractory epilepsy. The surgical procedure may cause cognitive deficits or exacerbate existing impairments, but it may also improve cognitive abilities by the restoration of functions located in adjacent or contralateral areas that had been secondarily affected by the epilepsy or the underlying pathology. Compared to adults, better cognitive outcome has been reported in children, a finding probably due to the developing state of the brain, which possesses considerable structural and functional plasticity. More extensive and effective surgery such as hemispherectomy is more commonly used in the pediatric population, and this must also influence surgical outcome. However, studies related to cognitive outcome of epilepsy surgery in children are limited, and controversial results are often reported. In this chapter, we provide a current overview of the literature on cognitive outcomes in children who undergo different types of epilepsy surgery, including focal resections as well as corpus callosotomy and hemispherectomy. Early surgical intervention appears to be a rational option for the treatment of childhood epilepsy since many cognitive deficits are linked to the epileptic process and may disappear when seizures are controlled.


Human upper extremity motor cortex activity shows distinct oscillatory signatures for stereotyped arm and leg movements.
Stepping and arm swing are stereotyped movements that require coordination across multiple muscle groups. It is not known whether the encoding of these stereotyped movements in the human primary motor cortex is confined to the limbs' respective somatotopy. We recorded subdural electrocorticography activities from the hand/arm area in the primary motor cortex of 6 subjects undergoing deep brain stimulation surgery for essential tremor and Parkinson's disease who performed stepping (all patients) and arm swing (n = 3 patients) tasks. We show stepping-related low frequency oscillations over the arm area. Furthermore, we show that this oscillatory activity is separable, both in frequency and spatial domains, from gamma band activity changes that occur during arm swing. Our study contributes to the growing body of evidence that lower extremity movement may be more broadly represented in the motor cortex, and suggest that it may represent a way to coordinate stereotyped movements across the upper and lower extremities.


Reduction of resistance artery stiffness by treatment with the AT(1)-receptor antagonist losartan in essential hypertension.
In spontaneously hypertensive rats resistance artery structure, endothelial dysfunction and geometry-independent wall stiffness were reduced by an angiotensin AT(1)-receptor antagonist. In previous studies of human hypertension, interruption of the renin-angiotensin system corrected small artery structure and endothelial dysfunction, whereas the beta-blocker atenolol did not. We hypothesized that the AT(1)R antagonist losartan, but not the beta-blocker atenolol, would reduce stiffness of gluteal subcutaneous small arteries in essential hypertensive patients. Seventeen untreated mild essential hypertensive patients (47+/-2 years; 75% male) were randomly assigned in double-blind fashion to losartan or atenolol treatment for one year. Small, resistance size arteries were studied on pressurized myographs. Blood pressure (mmHg) was reduced (p<0.01) from 145 +/- 4/101 +/- 2 and 147 +/- 6/98 +/- 2 to 128 +/- 4/86 +/- 2 and 131 +/- 3/84 +/- 1 by losartan and atenolol, respectively. The media/lumen ratio of small arteries was unaffected by atenolol (8.3+/-0.3% before and 8.8+/-0.5% after treatment). In contrast, losartan reduced media/lumen ratio from 8.4+/-0.4% to 6.7+/-0.3% (p<0.01). Whereas isobaric elastic modulus was unaffected by either treatment, geometry-independent stiffness (slope of elastic modulus vs. stress) was reduced from 9.7+/-1.2 to 6.1+/-0.9 (P<0.05) under losartan treatment, but was unchanged by atenolol (8.2+/-1.3 to 7.8+/-0.6). In conclusion, treatment with losartan reduced stiffness and structural alterations of subcutaneous resistance arteries of previously untreated essential hypertensive patients, whereas atenolol failed to do so.


Expression of the alpha subunit of PABA peptide hydrolase (EC 126.96.36.199) in MDCK cells. Synthesis and secretion of an enzymatically inactive homodimer.
In this paper, we report the expression of PPH alpha in the polarized cell line MDCK (Madin Darby canine kidney). In these cells, the enzyme was synthesized in an inactive proform, which upon treatment with trypsin was activated. The enzyme isolated from cell extracts was core-glycosylated and appeared to be retained in the ER as a homodimer. No PPH alpha was detectable on the surface of intact cells by immunofluorescence. However, a complex glycosylated soluble but inactive form was present in the culture medium, suggesting that proteolytic removal of the C-terminal membrane anchoring peptide leads to the secretion of PPH alpha.


2001 Census output areas: from concept to prototype.
This article describes the development of a prototype output area production system for the 2001 Census. A number of outstanding design issues concerning 2001 output areas are explained, and the implications of using a geographical information system for the management of census geography are explored.


Exploring the modeling and site-ranking performance of Bayesian spatiotemporal crash frequency models with mixture components.
The current study introduces the flexible approach of mixture components to model the spatiotemporal interaction for ranking of hazardous sites and compares the model performance with the conventional methods. In case of predictive accuracy based on in-sample errors (posterior deviance), the Mixture-5 demonstrated superior performance in majority of the cases, indicating the advantage of mixture approach to accurately predict crash counts. LPML (log pseudo marginal likelihood) was also calculated as a cross-validation measure based on out-of-sample errors and this criterion also established the dominance of Mixture-5, further reinforcing the superiority of the mixture approach from different perspectives. The site ranking evaluation results demonstrated the advantages of adopting the mixture approach. In terms of total rank difference (TRD) results, there were several discrepancies between the two approaches, suggesting that two approaches designate unsafe sites differently. Another site ranking criterion, site consistency test (SCT), was employed to explore the difference in identification of unsafe sites based on two datasets: estimated crash count (traditional) and the spatial variability across time. The advantage of mixture models to act as a complimentary approach for site ranking was revealed by the spatial variability SCT results. The method consistency test (MCT) results also indicate the advantages of mixture models over the Base one. These findings suggested that mixture approach may prove helpful in the network screening step of safety management process to identify sites which may turn unsafe in the future and escape the detection from traditional methods.


Predictors of marital adjustment among child brides.
The researchers aim was to examine the predictors of marital adjustment among child brides in Turkey. The sample included 246 women who were between 18 and 49 years of age, got married while under the age of 18, not divorced, who spoke Turkish or Kurdish, by using convenience sampling method. We used a marital adjustment scale and a survey form to collect data. Our findings indicated that marital adjustment was low among child brides. The factors affecting women's marital adjustment were duration and types of the marriage, number of pregnancies and physical violence. The incidence of physical violence was inversely correlated with the scores of marital adjustment of women, while the women's age, education, income level, number of living children, age, and the education level of their partner was not correlated. The results of this study would be useful for nurses, midwives, social workers, and counselors who assist women who are facing domestic violence.


Anaerobic degradation of p-Xylene by a sulfate-reducing enrichment culture.
A strictly anaerobic enrichment culture was obtained with p-xylene as organic substrate and sulfate as electron acceptor from an aquifer at a former gasworks plant contaminated with aromatic hydrocarbons. p-Xylene was completely oxidized to CO(2). The enrichment culture depended on Fe(II) in the medium as a scavenger of the produced sulfide. 4-Methylbenzylsuccinic acid and 4-methylphenylitaconic acid were identified in supernatants of cultures indicating that degradation of p-xylene was initiated by fumarate addition to one of the methyl groups. Therefore, p-xylene degradation probably proceeds analogously to toluene degradation by Thauera aromatica or anaerobic degradation pathways for o- and m-xylene.


Secretion of Alpha-Hemolysin by Escherichia coli Disrupts Tight Junctions in Ulcerative Colitis Patients.
The potential of Escherichia coli (E. coli) isolated from inflammatory bowel disease (IBD) patients to damage the integrity of the intestinal epithelium was investigated. E. coli strains isolated from patients with ulcerative colitis (UC) and healthy controls were tested for virulence capacity by molecular techniques and cytotoxic assays and transepithelial electric resistance (TER). E. coli isolate p19A was selected, and deletion mutants were created for alpha-hemolysin (α-hemolysin) (hly) clusters and cytotoxic necrotizing factor type 1 (cnf1). Probiotic E. coli Nissle and pathogenic E. coli LF82 were used as controls. E. coli strains from patients with active UC completely disrupted epithelial cell tight junctions shortly after inoculation. These strains belong to phylogenetic group B2 and are all α-hemolysin positive. In contrast, probiotic E. coli Nissle, pathogenic E. coli LF82, four E. coli from patients with inactive UC and three E. coli strains from healthy controls did not disrupt tight junctions. E. coli p19A WT as well as cnf1, and single loci of hly mutants from cluster I and II were all able to damage Caco-2 (Heterogeneous human epithelial colorectal adenocarcinoma) cell tight junctions. However, this phenotype was lost in a mutant with knockout (Δ) of both hly loci (P<0.001). UC-associated E. coli producing α-hemolysin can cause rapid loss of tight junction integrity in differentiated Caco-2 cell monolayers. This effect was abolished in a mutant unable to express α-hemolysin. These results suggest that high Hly expression may be a mechanism by which specific strains of E. coli pathobionts can contribute to epithelial barrier dysfunction and pathophysiology of disease in IBD.


Resistance rates among antiretroviral regimens in pregnant people living with HIV.
To update nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI) resistance rates and describe the frequency of HIV subtypes in a cohort of pregnant people living with HIV (PPLH) at a national Prevention of Mother-To-Child HIV Transmission (PMTCT) centre. We evaluated genotypic resistance among PPLH during prenatal care who were antiretroviral therapy-naïve or experienced. We determined mutations by the Surveillance of Drug Resistance Mutations (SDRM) dataset and also focused on studying participants with intermediate or high resistance defined through the Stanford score. From 2018 to 2021, 1170 PPLH received prenatal care at the centre and 550 were genotyped. Among the 295 SDRMs, with respect to NRTI resistance mutations, there were 27/295 (9.2%) M184V/I, 14/295 (4.7%) T215Y/C/D/E/F/V/I/S and 12/295 (4.1%) M41L. For NNRTI, there were 75/295 (25.4%) K103N, 18/295 (6.1%) M230L and 14/295 (4.7%) G190A/E/S mutations. For PI, the most frequent mutations were 13/295 (4.4%) V82A/S/F/T, 12/295 (4.1%) M46I/L and 10/295 (3.4%) D30N. Based on the Stanford score, 36/224 (16%) naïve participants had one or more antiretroviral resistance mutations, 81% of whom had NNRTI resistance. In the treatment-experience group, 108/326 (33%) had one or more mutations, 91% of whom had NNRTI resistance. The most frequent HIV subtype was B (82.5%). Our findings suggest that continuous surveys of HIV genotype appear to be important tools to map the distribution and evolution of HIV subtypes and resistance to provide information to support treatment policies. Furthermore, concerns about the use of rilpivirine-containing regimens underscore the importance of resistance surveillance.


Levels of S100B protein drive the reparative process in acute muscle injury and muscular dystrophy.
Regeneration of injured skeletal muscles relies on a tightly controlled chain of cellular and molecular events. We show that appropriate levels of S100B protein are required for timely muscle regeneration after acute injury. S100B released from damaged myofibers and infiltrating macrophages expands the myoblast population, attracts macrophages and promotes their polarization into M2 (pro-regenerative) phenotype, and modulates collagen deposition, by interacting with RAGE (receptor for advanced glycation end-products) or FGFR1 (fibroblast growth factor receptor 1) depending on the muscle repair phase and local conditions. However, persistence of high S100B levels compromises the regeneration process prolonging myoblast proliferation and macrophage infiltration, delaying M1/M2 macrophage transition, and promoting deposition of fibrotic tissue via RAGE engagement. Interestingly, S100B is released in high abundance from degenerating muscles of mdx mice, an animal model of Duchenne muscular dystrophy (DMD), and blocking S100B ameliorates histopathology. Thus, levels of S100B differentially affect skeletal muscle repair upon acute injury and in the context of muscular dystrophy, and S100B might be regarded as a potential molecular target in DMD.


What is the long term impact of voucher scheme on primary care? Findings from a repeated cross sectional study using propensity score matching.
Vouchers are increasingly used as a demand-side subsidy to reduce financial hardship and improve quality of services. Elderly Healthcare Voucher Scheme has been introduced by the Hong Kong Government since 2009 to provide subsidy to elderly aged 65 and above to visit ten different types of private primary care providers for curative, preventive and chronic disease management. Several enhancements have been made over the past few years. This paper (as part of an evaluation study of this unique healthcare voucher scheme) aims to assess the long term impact of the voucher scheme in encouraging the use of primary care services. Two rounds of cross-sectional survey among elderly in Hong Kong were conducted in 2010 and 2016. Propensity score matching and analysis were used to compare changes in perception and usage of vouchers over time. 61.5% of respondents in 2016 agreed "the scheme encourages me to use more private primary care services", a significant increase from 36.2% in 2010. Among those who agreed in 2016, the majority thought the voucher scheme would encourage them to use acute services (90.3%) in the private sector, rather than preventive care (40.3%) and chronic disease management (12.2%). Respondents also reported that their current usual choice of care was visiting "both public and private doctors" (61.9%), representing a significant increase (up from 48.4%) prior to their use of voucher. The voucher scheme has encouraged the use of more private care services, particularly acute services rather than disease prevention or management of chronic disease. However, there needs to be caution that the untargeted and open-ended nature of voucher scheme could result in supply-induced demand which would affect long term financial sustainability. The dual utilization of health services in both the public and private sector may also compromise continuity and quality of care. The design of the voucher needs to be more specific, targeting prevention and chronic disease management rather than unspecified care which is mainly acute and episodic in order to maximize service delivery capacity as a whole for equitable access in universal health coverage and to contribute to a sustainable financing system.


Histamine release by pharmacological agents in the absence of external free Ca2+.
The involvement of extracellular free Ca2+ in histamine release was investigated in rat peritoneal mast cells. Incubation of non-antigenized cells in a media with high extracellular potassium did not increase histamine release. Secretion induced by A23187 and compound 48/80 in the presence of Ca2+ requires metabolic energy. In the absence of external free Ca2+ (2.5 microM) histamine release induced by A23187 is reduced but not abolished. Secretion induced by compound 48/80 is independent of extracellular Ca2+. These results lead us to suggest that mast cell plasma membranes probably lack voltage-gated Ca2+ channels and that external Ca2+ may not be an absolute requisite for histamine secretion.


Multi-target combinatory strategy to overcome tumor immune escape.
Immune therapy has become the fourth approach after surgery, chemotherapy, and radiotherapy in cancer treatment. Many immune checkpoints were identified in the last decade since ipilimumab, which is the first immune checkpoint inhibitor to cytotoxic T-lymphocyte associated protein 4, had been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable or metastatic melanoma in 2011. The use of several antibody drugs that target PD1/PD-L1 for various cancer treatments has been approved by the FDA. However, fewer people are benefitting from immune checkpoint inhibitor treatment in solid cancers. Approximately 80% of patients do not respond appropriately because of primary or acquired therapeutic resistance. Along with the characterization of more immune checkpoints, the combinatory treatment of multiimmune checkpoint inhibitors becomes a new option when monotherapy could not receive a good response. In this work, the author focuses on the combination therapy of multiple immune checkpoints (does not include targeted therapy of oncogenes or chemotherapy), introduces the current progression of multiple immune checkpoints and their related inhibitors, and discusses the advantages of combination therapy, as well as the risk of immune-related adverse events.


Declining incidence of low-trauma knee fractures in elderly women: nationwide statistics in Finland between 1970 and 2006.
The study assessed the recent secular trend in the incidence of low-trauma knee fractures among older Finns in the years 1970-2006. The clear rise in women's fracture incidence from early 1970s until the late 1990s was followed by a declining fracture rate. Exact reasons for the decline are unknown, but a cohort effect toward a healthier female population with improved functionality and reduced risk of injurious slips, trips and falls could partly explain the phenomenon. Although low-trauma fractures of elderly adults have been recognized as a major public health concern in modern societies with aging populations, fresh nationwide information on their secular trends is sparse. We determined the current trend in the number and incidence (per 100,000 persons) of low-trauma knee fractures among elderly people in Finland, an EU country with a well-defined white population of 5.3 million, by taking into account all persons 60 years of age or older who were admitted to our hospitals for primary treatment of such fractures from 1970 to 2006. The number and incidence of low-trauma knee fractures among 60-year-old or older Finnish women sharply rose between 1970 and 1997, from 218 (number) and 55 (incidence) in 1970 to 733 and 124 in 1997. However, thereafter both the number and incidence of fractures have continuously declined so that there were only 626 fractures in these women in 2006 (incidence 94). In the age-adjusted fracture incidence, the findings were similar. During 1970-1997, the age-adjusted incidence of low-trauma knee fractures in our elderly women clearly rose (from 60 to 118), but thereafter, this incidence declined to 85 in 2006. In men, the fracture incidence did not show consistent trend changes over time (30 in 1970 and 36 in 2006). The sharp rise in the incidence of low-trauma knee fractures in Finnish elderly women from early 1970s until late 1990s has been followed by a declining fracture rate. Exact reasons for this are unknown, but a cohort effect toward a healthier aging female population with improved functional ability and reduced risk of injurious slips, trips and falls cannot be excluded.