Optimal vaccination strategy for dengue transmission in Kupang city, Indonesia.
Dengue is a public health problem with around 390 million cases annually and is caused by four distinct serotypes. Infection by one of the serotypes provides lifelong immunity to that serotype but have a higher chance of attracting the more dangerous forms of dengue in subsequent infections. Therefore, a perfect strategy against dengue is required. Dengue vaccine with 42-80% efficacy level has been licensed for the use in reducing disease transmission. However, this may increase the likelihood of obtaining the dangerous forms of dengue. In this paper, we have developed single and two-serotype dengue mathematical models to investigate the effects of vaccination on dengue transmission dynamics. The model is validated against dengue data from Kupang city, Indonesia. We investigate the effects of vaccination on seronegative and seropositive individuals and perform a global sensitivity analysis to determine the most influential parameters of the model. A sensitivity analysis suggests that the vaccination rate, the transmission probability and the biting rate have greater effects on the reduction of the proportion of dengue cases. Interestingly, with vaccine implementation, the mosquito-related parameters do not have significant impact on the reduction in the proportion of dengue cases. If the vaccination is implemented on seronegative individuals only, it may increase the likelihood of obtaining the severe dengue. To reduce the proportion of severe dengue cases, it is better to vaccinate seropositive individuals. In the context of Kupang City where the majority of individuals have been infected by at least one dengue serotype, the implementation of vaccination strategy is possible. However, understanding the serotype-specific differences is required to optimise the delivery of the intervention.


Innervation modulates the functional connectivity between pancreatic endocrine cells.
The importance of pancreatic endocrine cell activity modulation by autonomic innervation has been debated. To investigate this question, we established an in vivo imaging model that also allows chronic and acute neuromodulation with genetic and optogenetic tools. Using the GCaMP6s biosensor together with endocrine cell fluorescent reporters, we imaged calcium dynamics simultaneously in multiple pancreatic islet cell types in live animals in control states and upon changes in innervation. We find that by 4 days post fertilization in zebrafish, a stage when islet architecture is reminiscent of that in adult rodents, prominent activity coupling between beta cells is present in basal glucose conditions. Furthermore, we show that both chronic and acute loss of nerve activity result in diminished beta-beta and alpha-beta activity coupling. Pancreatic nerves are in contact with all islet cell types, but predominantly with beta and delta cells. Surprisingly, a subset of delta cells with detectable peri-islet neural activity coupling had significantly higher homotypic coupling with other delta cells suggesting that some delta cells receive innervation that coordinates their output. Overall, these data show that innervation plays a vital role in the maintenance of homotypic and heterotypic cellular connectivity in pancreatic islets, a process critical for islet function.


Population structure and survival in a solitary wasp (Microbembex cubana: Hymenoptera, Sphecidae, Nyssoninae).
This paper documents population structure in a solitary wasp, Microbembex cubana (Hymenoptera, Sphecidae, Nyssoninae), on a small (15 km2) Bahamian island. A relatively isolated portion of this population was studied April-June 1985. The population comprised small aggregations of territorial males and nesting females. Individuals of both sexes were with rare exceptions faithful to a "home" aggregation during their one- to two-month adult lifespans, conducting all reproductive activities there. Individuals from different aggregations, however, mixed daily during these activities: feeding on nectar, hunting for provisions and retiring to clustered sleeping burrows. Significant variation occurred among the nine breeding aggregations in size, density, sex-ratio (which was on average 2:1 in favor of males) and survival (which was 0.93-0.99 per individual/per day and which was not higher for females than for males). Aggregations retained the same characteristics for longer than the life expectancies of individuals in them.Factors affecting reproductive success and survivorship in M. cubana are complex: they are apparently only partially overlapping between males and females and subject to spatial variation. Patterns in the data suggest several hypotheses about how behavior, morphology and habitat interact to shape population processes. I propose that aggregations arise and are characterized by considerable behavioral inertia because individual M. cubana use conspecifics as sources of information on resource quality. Because M. cubana occurs in secondary habitats, individuals retain flexibility in responding to better opportunities for reproduction, but this population exhibits more viscosity than reported for other ground-nesting solitary Hymenoptera.


Screening of inbred rat strains for electrophoretic protein polymorphisms.
Nineteen inbred strains of the laboratory rat (Rattus norvegicus) were investigated for genetic differences by starch and agarose gel electrophoretic techniques. For six out of 21 loci, interstrain differences were observed: Tf, 6PGD, Es-1, Es-4, Es-5, and Svp. The variants are briefly described and the allelic distributions are tabulated. The 6GPD locus was found to be linked neither to the major histocompatibility gene region nor to the coat color genes c, a, h.


Deciphering the maturation of tertiary lymphoid structures in cancer and inflammatory diseases of the digestive tract using imaging mass cytometry.
Persistent inflammation can promote the development of tertiary lymphoid structures (TLS) within tissues resembling secondary lymphoid organs (SLO) such as lymph nodes (LN). The composition of TLS across different organs and diseases could be of pathophysiological and medical interest. In this work, we compared TLS to SLO in cancers of the digestive tract and in inflammatory bowel diseases. Colorectal and gastric tissues with different inflammatory diseases and cancers from the department of pathology of CHU Brest were analyzed based on 39 markers using imaging mass cytometry (IMC). Unsupervised and supervised clustering analyses of IMC images were used to compare SLO and TLS. Unsupervised analyses tended to group TLS per patient but not per disease. Supervised analyses of IMC images revealed that LN had a more organized structure than TLS and non-encapsulated SLO Peyer's patches. TLS followed a maturation spectrum with close correlations between germinal center (GC) markers' evolution. The correlations between organizational and functional markers made relevant the previously proposed TLS division into three stages: lymphoid-aggregates (LA) (CD20+CD21-CD23-) had neither organization nor GC functionality, non-GC TLS (CD20+CD21+CD23-) were organized but lacked GC's functionality and GC-like TLS (CD20+CD21+CD23+) had GC's organization and functionality. This architectural and functional maturation grading of TLS pointed to differences across diseases. TLS architectural and functional maturation grading is accessible with few markers allowing future diagnostic, prognostic, and predictive studies on the value of TLS grading, quantification and location within pathological tissues in cancers and inflammatory diseases.


Anterior chamber infiltrates associated with systemic lymphoma: report of two cases and review of the literature.
To describe the clinicopathologic features of two patients with systemic lymphoma who developed anterior chamber (AC) infiltrates of lymphoma cells. Two case reports and literature review. The clinical and pathologic findings in two patients with AC infiltrates secondary to systemic B-cell lymphoma are reviewed. Clinical observation and cytologic/flow cytometric examination of the infiltrate after AC aspiration. One patient presented with uveal infiltration, an exudative retinal detachment and an AC infiltrate. Systemic evaluation revealed a follicular lymphoma involving several groups of lymph nodes. The second patient with a known history of abdominal lymphoma was found to have blurred vision, photophobia and an AC infiltrate. Flow cytometric analysis of the AC infiltrate in both patients showed phenotypes consistent with the patients' systemic lymphomas. A pseudohypopyon in an adult may represent either the initial manifestation or a later complication of systemic lymphoma, similar to what has been reported in acute leukemia.


Ant removal distance, but not seed manipulation and deposition site increases the establishment of a myrmecochorous plant.
Myrmecochory (seed dispersal by ants) is a unique seed dispersal syndrome among invertebrates. It comprises three main phases: seed removal, seed manipulation, and seed deposition. However, the contribution of each phase to seed and seedling fate remains unclear. Here, we experimentally quantified the effects of each phase of myrmecochory on seed germination and seedling establishment, the two most critical life history stages involved in plant recruitment. We established 30 sample points, and each included an adult Mabea fistulifera tree, an Atta sexdens nest entrance, and six seed depots. We monitored the germination of M. fistulifera seeds for 3 months and subsequently followed the growth and mortality of the resulting seedlings for 12 months. Only the dispersal distance influenced plant establishment, reducing seed germination and increasing seedling growth, but with no effect of seed manipulation and deposition site. Despite the contrasting effects of distance on seed germination and seedling growth, the positive effect of dispersal distance on seedling growth was ten times greater than the negative effect on seed germination. Moreover, A. sexdens behaved neither as granivore nor as herbivore of M. fistulifera seeds or seedlings, which suggests that seed dispersal by A. sexdens is advantageous to M. fistulifera. Thus, the joint occurrence of these two species in disturbed areas could have a positive effect on this pioneer plant population, which might promote forest regeneration.


[The use of modern information technologies in the work of clinical-diagnostic laboratory in the surgical hospital].
Using the personal experience of exploitation of complex informative system, which automatises the work of diagnostic laboratory, authors propose some ideas. The original ways of improving the quality of laboratory diagnostics, decreasing time of diagnostics and easing the interpretation of results were suggested. The problem of results' interpretation considering different reference values is highlighted.


Novel quinazolinone inhibitors of the Pseudomonas aeruginosa quorum sensing transcriptional regulator PqsR.
Rising numbers of cases of multidrug- and extensively drug-resistant Pseudomonas aeruginosa over recent years have created an urgent need for novel therapeutic approaches to cure potentially fatal infections. One such approach is virulence attenuation where anti-virulence compounds, designed to reduce pathogenicity without affording bactericidal effects, are employed to treat infections. P. aeruginosa uses the pqs quorum sensing (QS) system, to coordinate the expression of a large number of virulence determinants as well as bacterial-host interactions and hence represents an excellent anti-virulence target. We report the synthesis and identification of a new series of thiazole-containing quinazolinones capable of inhibiting PqsR, the transcriptional regulator of the pqs QS system. The compounds demonstrated high potency (IC50 < 300 nM) in a whole-cell assay, using a mCTX:PpqsA-lux-based bioreporter for the P. aeruginosa PAO1-L and PA14 strains. Structural evaluation defined the binding modes of four analogues in the ligand-binding domain of PqsR through X-ray crystallography. Further work showed the ability of 6-chloro-3((2-pentylthiazol-4-yl)methyl)quinazolin-4(3H)-one (18) and 6-chloro-3((2-hexylthiazol-4-yl)methyl)quinazolin-4(3H)-one (19) to attenuate production of the PqsR-regulated virulence factor pyocyanin. Compounds 18 and 19 showed a low cytotoxic profile in the A549 human epithelial lung cell line making them suitable candidates for further pre-clinical evaluation.


Modulation of operational lung volumes with the use of salbutamol in COPD patients accomplishing upper limbs exercise tests.
Pulmonary dynamic hyperinflation (DH) is an important factor limiting the physical capacity of patients with COPD. Inhaled bronchodilator should be able to reduce DH. To measure DH in COPD patients during upper limbs exercise tests with previous use of bronchodilator or placebo, and to evaluate the respiratory pattern to justify the dynamics of hyperinflation. Inspiratory capacity (IC) of 16 patients with COPD (age: 63+/- 13 years; FEV(1) of 1.5+/-0.7 L-41+/-11% predicted) was measured before and after an incremental arm exercise test (diagonal technique) with randomly and double-blinded inhaled placebo or salbutamol. Rest IC increased from 2.32+/-0.44 L to 2.54+/-0.39 L after inhalation of 400 mcg of salbutamol (p=0.0012). There was a decrease in the IC after a maximal incremental arm exercise test, 222+/-158 ml (p=0.001) with placebo use, but no change was seen after the salbutamol use: 104+/-205 ml (p=0.41); 62% of the patients presented a 10% or more reduction in the IC after the exercise with placebo. There was a correlation between DH and lower FEV(1)/FVC (p=0.0067), FEV(1) predicted (p=0.0091) and IC% predicted (p=0.043) and higher VO(2)ml/Kg/min % predicted (p=0.05). Minute ventilation and respiratory rate were higher during the exercise with placebo (p=0.002) whereas VE/MVV ratio was lower in the exercise after salbutamol (p>0.05). We conclude that the use of bronchodilator increases the IC of patient with COPD and may help not to increase the DH during a maximal exercise with the arms.


[A case of sterility treated with sulpiride (author's transl)].
Oligospermia associated with asthenia is a frequent cause of sterility. Sulpiride, which is a regulator of autonomic nervous system function, was prescribed alone in such a case and pregnancy resulted on two occasions. The relationship between the normal duration of spermatogenesis and the periods during which sulpiride was prescribed was such that the hypothesis of a hormonal effect could be rejected and strongly suggests the existence of psychological factors in some patients with oligospermia.


Discovery of 2-aryloxy-4-amino-quinazoline derivatives as novel protease-activated receptor 2 (PAR2) antagonists.
Protease-activated receptor 2 (PAR2) is a member of G protein-coupled receptor and its activation initiates diverse inflammatory responses. Recent studies suggest that antagonists of PAR2 may provide a novel therapeutic strategy for inflammatory diseases. In this study, we have developed a series of 2-aryloxy-4-amino-quinazoline derivatives as PAR2 antagonists and examined their effects against LPS-induced inflammatory responses in RAW 264.7 macrophages. Among these derivatives, compound 2f displayed the greatest antagonistic activity with the IC50 value of 2.8μM. Binding modes of the newly identified PAR2 antagonists were analyzed by molecular docking using IFD/MM-GBSA methods in the putative binding site of PAR2 homology model. Moreover, 2f demonstrated significant inhibitory effects on the LPS-activated pro-inflammatory mediators including nitric oxide (NO), prostaglandin E2 (PGE2), interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) through the regulation of various intracellular signaling pathways involving nuclear factor-κB (NF-κB), activator protein 1 (AP-1) and the mitogen-activated protein kinases (MAPK). Furthermore, administration of 2f significantly reduced the mortality of LPS-induced sepsis in mice. These results provide useful insights into the development of novel PAR2 antagonists with anti-inflammatory activity in vitro and in vivo.


Employment of substandard antiemetic prophylaxis in recent trials of chemotherapy-induced nausea and vomiting.
To determine the prevalence of substandard antiemetic therapy among recently published trials conducted in patients with cancer who received emetogenic chemotherapy. A MEDLINE search was conducted (2000-July 2004) using the key words 5-HT(3) antagonists, ondansetron, granisetron, dolasetron, tropisetron, ramosetron, palonosetron, NK-1 antagonists, and aprepitant. All antiemetic trials in patients receiving chemotherapy that were published from January 2000 to July 2004 were evaluated. Standard prophylactic antiemetic therapy was derived from contemporary antiemetic guidelines published by oncology professional organizations and expert panels. The number of patients and studies in which patients received standard and substandard antiemetic therapy was determined for both the acute and delayed phases of chemotherapy-induced nausea and vomiting (CINV). Separate determinations were made for severely and moderately emetogenic chemotherapy. The annual percentage of studies in which substandard antiemetic prophylaxis was given and the percentage of patients who received substandard prophylaxis also were determined. Fifty-six studies were reviewed, which included a total of 10 274 patients and 125 study arms. The percentage of patients who received substandard antiemetic prophylaxis was 30% (n = 3063) for acute CINV and 33% (n = 3413) for delayed CINV. The average annual percentage of studies that employed substandard prophylaxis during this time period was 54%. In recent antiemetic trials for CINV, the employment of substandard antiemetic therapy is common. These results raise important ethical questions regarding contemporary antiemetic trial design.


Arthroscopic Repair for the Anterior Horn of the Lateral Meniscus With Suture Anchor.
The anterior horn tear of the lateral meniscus, often accompanied with local parameniscal cysts, is usually managed by cysts debridement and meniscus repair with the outside-in technique (OIT). However, a big gap between the meniscus and anterior capsule would be produced after cysts debridement and be difficult to be closed by the OIT. Or, the OIT would result in knee pain because of the overly tight knots. Therefore, we devised an anchor repair technique. Following the cysts resection, the anterior horn of the lateral meniscus (AHLM) is fixed at the anterolateral edge of the tibial plateau with 1 suture anchor, and then followed by suturing the AHLM with the surrounding synovium to promote healing. We recommend this technique as an alternative method for repairing an AHLM tear accompanied with local parameniscal cysts.


Prevention of focal intimal hyperplasia in rat vein grafts by using a tissue engineering approach.
The present study focused on the role of blood flow in the formation of focal intimal hyperplasia in vein grafts, as well as the development of an engineering approach that can be used to eliminate disturbed blood flow and prevent blood flow-related focal intimal hyperplasia. A rat vein graft model was constructed by interposing a jugular vein into the abdominal aorta with end-to-end anastomoses. Locally disturbed flow was identified by analyzing particle streak-lines in methyl salicylate-cleared and perfused vein grafts in vitro with a physiological Reynolds number. At day 10, 20, and 30 after surgery, focal intimal hyperplasia of the vein grafts was examined using a histological approach and the density of alpha-actin positive cells was determined using immunohistological and fluorescent approaches. Results showed that apparent eddy blood flow formed at the proximal, but not at the distal, end of the vein grafts due to graft-host diameter mismatch and local geometric distortions, and was associated with apparent focal intimal hyperplasia. The thickness of the alpha-actin positive layers of the proximal vein grafts was significantly higher than that of the distal grafts (192 +/- 27 vs. 94 +/- 18 microm, 278 +/- 55 vs. 124 +/- 20 microm, and 288 +/- 24 vs. 131 +/- 23 microm for day 10, 20. and 30, respectively). The density of the alpha-actin positive cells, however, was similar between the proximal and the distal regions (3569 +/- 361 vs. 3285 +/- 343 cells/mm2, 5540 +/- 650 vs. 5376 + 887 cells/mm2, and 5465 +/- 791 vs. 5278 +/- 524 cells/mm2 for day 10, 20, and 30, respectively). When eddy blood flow was eliminated by matching the graft-host diameters using a tissue engineering approach, the average thickness of the alpha-actin positive layers of the proximal (71 +/- 15, 86 +/- 16, and 85 +/- 14 microm for day 10, 20, and 30, respectively) and the distal vein grafts (68 +/- 13, 80 +/- 14, and 79 +/- 13 microm for day 10, 20, and 30, respectively) was reduced significantly. The density of the alpha-actin positive cells was also reduced significantly in the proximal (2946 +/- 359, 3261 +/- 295, 3472 +/- 599 cells/mm2 for day 10, 20, and 30, respectively) and in the distal regions (3151 +/- 511, 3466 +/- 687, 3593 +/- 688 cells/mm2 for day 10, 20, and 30, respectively). The thickness of the alpha-actin positive layers and the density of the alpha-actin positive cells were not significantly different between the proximal and distal regions of the engineered vein grafts at each observation time. These results suggest that eddy flow may develop in vein grafts and may facilitate the formation of focal intimal hyperplasia, and the vascular tissue engineering approach developed in this study may be used to prevent blood flow-related focal intimal hyperplasia in vein grafts.


Individualized busulfan dosing improves outcomes compared to fixed-dose administration in pre-transplant minimal residual disease-positive acute myeloid leukemia patients with intermediate-risk undergoing allogeneic stem cell transplantation in CR.
Pre-transplant minimal residual disease (MRD) impacts negatively on post-transplant relapse risk in acute myeloid leukemia (AML). Therapeutic drug monitoring by calculating area under the curve (AUC) was developed to optimize busulfan (Bu) exposure. Here, we compared post-transplant outcomes after individualized versus fixed busulfan dosage in intermediate-risk AML who achieved CR prior to allograft focusing on pre-transplant flow-MRD. Eighty-seven patients (median, 56 years) with intermediate-risk AML and pre-transplant flow-MRD ("different from normal") were included. Thirty-two patients received individualized busulfan; 54 fixed dosages. Individualized dosage was adjusted in 25/32 patients: increased, n = 18/25 (72%); decreased: n = 7/25 (28%). After median follow-up of 27 months, we observed lower 3-year relapses (6%, 2%-19% vs. 35%, 23%-49% p = 0.02), improved 3-year leukemia-free survival (LFS) (78%, 54%-91% vs. 55%, 40%-70% p = 0.009) and - overall survival (OS) (82%, 60%-93% vs. 69%, 54%-81% p = 0.05) after individualized compared to fixed Bu. Non-relapsed mortality (NRM) and acute graft versus host disease (GvHD) were not different. In multivariate analysis, fixed Bu showed unfavorable impact on OS (hazard ratio [HR] 4.6, p = 0.044), LFS (HR 3.6, p = 0.018) and relapses (HR 3.6, p = 0.033). Fixed Bu also had unfavorable impact on LFS (3.6, 1.1-12.6, p = 0.041) in pre-transplant MRD-positive patients. Individualized, AUC-based, busulfan is associated with lower relapses in intermediate-risk AML patients allografted in CR and may overcome pre-transplant MRD-positivity.


Fasting blood glucose level is a predictor of mortality in patients with COVID-19 independent of diabetes history.
No study elucidated the role of fasting blood glucose (FBG) level in the prognosis of coronavirus disease 2019 (COVID-19). This cohort study was conducted in a single center at Renmin Hospital of Wuhan University, Wuhan, China. Clinical laboratory, and treatment data of inpatients with laboratory-confirmed COVID-19 were collected and analyzed. Outcomes of patients with and without pre-existing diabetes were compared. The associations of diabetes history and/or FBG levels with mortality were analyzed. Multivariate cox regression analysis on the risk factors associated with mortality in patients with COVID-19 was performed. A total of 941 hospitalized patients with COVID-19 were enrolled in the study. There was a positive relationship between pre-existing diabetes and the mortality of patients who developed COVID-19 (21 of 123 [17.1%] vs 76 of 818 [9.3%]; P = 0.012). FBG ≥7.0 mmol/L was an independent risk factor for the mortality of COVID-19 regardless of the presence or not of a history of diabetes (hazard ratio, 2.20 [95% CI, 1.21-4.03]; P = 0.010). We firstly showed FBG ≥7.0 mmol/L predicted worse outcome in hospitalized patients with COVID-19 independent of diabetes history. Our findings indicated screening FBG level is an effective method to evaluate the prognosis of patients with COVID-19.


Indentation properties of young and old osteons.
The purpose of this study was to quantify differences in indentation modulus and microhardness between labeled osteons identified by epifluorescent microscopy and neighboring unlabeled osteons. In microradiographs and backscattered images, newly formed osteons appear more radiolucent (darker) than older osteons. This is ascribed to incomplete mineralization of the osteon. However, the mechanical properties of these young osteons are unknown. Nine femoral cross-sectional specimens were obtained from five skeletally mature dogs. Prior to death, the dogs received a pair of calcein bone labels. Labeled osteons were identified under an epiflourescent microscope. Bone specimens were transferred to a nanoindenter specimen holder, and the previous identified labeled osteons were located. Labeled (n = 102) and unlabeled (n = 101) osteons were examined by instrumented indentation testing. Indents were made to a depth of 500 nm at a loading rate of 10 nm/second. There were significant differences in the indentation modulus (P < 0.001) of labeled (10.02 +/- 3.61 gigapascal (GPa), mean +/- standard deviation) and unlabeled (15.11 +/- 3.72 GPa) osteons. Similar differences existed in microhardness measurements. Newly formed osteons had lower modulus (34%) and hardness (41%) than older osteons found in femoral cross sections. These data provide information on the indentation moduli of osteons during an early phase of mineralization compared to osteons that have completed mineralization.


Ultrasonographic elastography of thyroid nodules: is adding strain ratio to colour mapping better?
To determine the diagnostic performance of colour mapping and strain ratio for characterizing malignant thyroid nodules on ultrasonographic (US) elastography. The study was approved by the institutional review board and written informed consent was obtained. One hundred and thirty-one patients with 142 thyroid nodules >0.5 cm were prospectively enrolled between July 2010 and January 2011. Seven radiologists performed US elastography (iU22 Vision 2010; Philips, Seattle, WA, USA) using colour mapping and strain ratio for thyroid nodules blinded to the cytopathological results. Diagnostic performances of colour mapping alone, strain ratio alone, colour mapping and strain ratio, and colour mapping or strain ratio were compared using receiver operating characteristic (ROC) curve analysis. Of the 142 nodules, 69 (48.6%) were benign and 73 (51.4%) were malignant. Colour mapping of elastography showed a more frequent blue colour in malignant nodules than in benign nodules (65.8% versus 24.6%, p < 0.0001). A higher ratio than 1.21 as the best cut-off value was found in 65.8% of malignant nodules and 46.4% of benign nodules (p = 0.030). Area under the ROC curve (AUC) of colour mapping alone was significantly greater than that of colour mapping or strain ratio (AUC = 0.706 versus AUC = 0.63, p = 0.0195) and similar to that of colour mapping and strain ratio (AUC = 0.673, p = 0.1364). US elastography is helpful to predict malignant thyroid nodules. However, adding strain ratio to colour mapping does not improve performance compared to colour mapping alone.


Multi-targeted therapy of cancer by omega-3 fatty acids.
Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) are essential fatty acids necessary for human health. Currently, the Western diet contains a disproportionally high amount of n-6 PUFAs and low amount of n-3 PUFAs, and the resulting high n-6/n-3 ratio is thought to contribute to cardiovascular disease, inflammation, and cancer. Studies in human populations have linked high consumption of fish or fish oil to reduced risk of colon, prostate, and breast cancer, although other studies failed to find a significant association. Nonetheless, the available epidemiological evidence, combined with the demonstrated effects of n-3 PUFAs on cancer in animal and cell culture models, has motivated the development of clinical interventions using n-3 PUFAs in the prevention and treatment of cancer, as well as for nutritional support of cancer patients to reduce weight loss and modulate the immune system. In this review, we discuss the rationale for using long-chain n-3 PUFAs in cancer prevention and treatment and the challenges that such approaches pose in the design of clinical trials.


Nicotinamide mononucleotide, a potential future treatment in ocular diseases.
The burden of ocular diseases has been gradually increasing worldwide. Various factors are suggested for the development and progression of ocular diseases, such as ocular inflammation, oxidative stress, and complex metabolic dysregulation. Thus, managing ocular diseases requires the modulation of pathologic signaling pathways through many mechanisms. Nicotinamide mononucleotide (NMN) is a bioactive molecule naturally found in life forms. NMN is a direct precursor of the important molecule nicotinamide adenine dinucleotide (NAD+), an essential co-enzyme required for enormous cellular functions in most life forms. While the recent experimental evidence of NMN treatment in various metabolic diseases has been well-reviewed, NMN treatment in ocular diseases has not been comprehensively summarized yet. In this regard, we aimed to focus on the therapeutic roles of NMN treatment in various ocular diseases with recent advances. How we came to our current opinion with a recent summary was described based on our own recent reports as well as a search of the related literature. We found that NMN treatment might be available for the prevention of and protection from various experimental ocular diseases, as NMN treatment modulated ocular inflammation, oxidative stress, and complex metabolic dysregulation in murine models for eye diseases such as ischemic retinopathy, corneal defect, glaucoma, and age-related macular degeneration. Our current review suggests and discusses new modes of actions of NMN for the prevention of and protection from various ocular diseases and can urge future research to obtain more solid evidence on a potential future NMN treatment in ocular diseases at the preclinical stages.


Stable Nuclear Transformation System for the Coccolithophorid Alga Pleurochrysis carterae.
Of the three dominant marine microalgal groups, dinoflagellates and diatoms can undergo genetic transformation; however, no transformation method has been established for haptophytes to date. Here, we report the first stable genetic transformation of a coccolithophore, Pleurochrysis carterae, by means of polyethylene glycol (PEG)-mediated transfer of a bacterial hygromycin B-resistance gene. Together with the novel transient green fluorescent protein (GFP) expression system, this approach should facilitate further molecular-based research in this phylum.


A hospital-based study on ischaemic stroke characteristics, management, and outcomes in Sarawak: Where do we stand?
Located on the Borneo Island, Sarawak is the largest state of Malaysia and has a population distinctive from Peninsular Malaysia. The ischaemic stroke data in Sarawak had not been reported despite the growing number of patients annually. We aimed to investigate patient characteristics, management, and outcomes of ischaemic stroke in Sarawak and benchmark the results with national and international published data. We included ischaemic stroke cases admitted to Sarawak General Hospital between June 2013 and August 2018 from Malaysia National Stroke Registry. We performed descriptive analyses on patient demographics, cardiovascular risk factors, prior medications, smoking status, arrival time, thrombolysis rate, Get With The Guidelines (GWTG)-Stroke measures, and outcomes at discharge. We also numerically compared the results from Sarawak with the published data from selected national and international cohorts. We analysed 1435 ischaemic stroke cases. The mean age was 60.1±13.2 years old; 64.9% were male; median baseline National Institute of Health Stroke Scale was seven points. Hypertension was the most prevalent risk factor of ischaemic stroke; 12.7% had recurrent stroke; 13.7% were active smokers. The intravenous thrombolysis rate was 18.8%. We achieved 80-90% in three GWTG-Stroke performance measures and 90-98% in four additional quality measures in our ischaemic stroke management. At discharge, 57% had modified Rankin Scale of 0-2; 6.7% died during hospitalisation. When compared with selected national and international data, patients in Sarawak were the youngest; Sarawak had more male and more first-ever stroke. Thrombolysis rate in Sarawak was higher compared with most studies in the comparison. Functional outcome at discharge in Sarawak was better than national cohort but still lagging behind when compared with the developed countries. In-hospital mortality rate in Sarawak was slightly lower than the national data but higher when compared with other countries. Our study described characteristics, management, and outcomes of ischaemic stroke in Sarawak. We achieved high compliance with most of GTWG-Stroke performance and quality indicators. Sarawak had better outcomes than the national results on ischaemic stroke. However, there is still room for improvement when compared with other countries. Actions are needed to reduce the cardiovascular burdens for stroke prevention, enhance healthcare resources for stroke care, and improve intravenous thrombolysis treatment in Sarawak.


Precision in the measurement of lexical expertise: the selection of optimal items for a spelling assessment.
Skilled adult readers vary in many skills related to visual word form processing such as phonological processing, vocabulary size, comprehension skill, and spelling skill (Kuperman & Van Dyke, 2011). Spelling skill in particular has received much attention because low- and high-skill spellers show different patterns of lexical processing as measured through eye movement behavior, reaction times, and word learning (Eskenazi et al., 2018; Veldre & Andrews, 2014). Researchers commonly use a spelling dictation task to measure lexical expertise; however, there is limited evidence for its psychometric properties and room for improvement in item selection (Andrews et al., 2020). The purpose of this study was to assess the precision of 110 words as measures of lexical expertise, to compare various subsets of words in a spelling dictation task, and to provide a set of words that more precisely measure lexical expertise. In Study 1, a spelling dictation task with 110 words was administered to 682 participants. In Study 2, that same task and measures of vocabulary and comprehension were administered to 786 participants. Results indicated that the set of 110 words contains many words that are imprecise measures of spelling skill. Through an iterative process of removing words with high error variance, a set of 20 words was selected that minimizes measurement error and demonstrates discriminant validity from vocabulary and comprehension ability. We recommend this set of words as a more precise measure of spelling skill, which will provide more power to detect moderating effects of lexical expertise on reading processes.


Simple enzyme immunoassay methods for recombinant human tumor necrosis factor alpha and its antibodies using a bacterial cell wall carrier.
We have developed simple methods for measuring recombinant human tumor necrosis factor alpha (rHu-TNF alpha) and antibodies to rHu-TNF alpha in the sera of animals intravenously injected with rHu-TNF alpha. rHu-TNF alpha was measured by a competitive binding enzyme immunoassay (C-EIA) using standard rHu-TNF alpha, beta-galactosidase labeled rHu-TNF alpha as enzyme-labeled antigen (E-Ag) and anti-rabbit IgG goat immunoglobulins coupled to bacterial cell walls (insolubilized second antibody). In contrast, anti-rHu-TNF alpha antibodies were measured by a sandwich EIA (S-EIA) using purified anti-rHu-TNF alpha rabbit IgG as standard, beta-galactosidase labeled rHu-TNF alpha as E-Ag, and rHu-TNF alpha coupled to bacterial cell walls as insolubilized antigen. C-EIA permits the determination of serum rHu-TNF alpha within the range of 2-150 U/ml (about 0.7-52 ng/ml) with a CV of below 7.6% and 99% recovery. S-EIA permits the determination of anti-rHu-TNF alpha antibodies within the range of 70-1000 ng/ml with a CV of less than 4% and 94.8-106.9% recovery.


A Surgical Integration Technique for Right-Sided and Left-Sided Superior Venae Cavae.
The treatment of some subsets of patients having both right-sided superior vena cava (SVC) and left-sided SVC may be very challenging. We performed the SVC integration (SVCI) technique with end-to-side anastomoses between the two SVCs on 4 such patients (age, 5 to 11 months; body weight, 5.4 to 10.2 kg) with excellent outcomes. In 2 patients, we performed intrapulmonary artery septation with SVCI; in 1 patient, pulmonary artery sling repair with SVCI; and in 1 patient with supramitral stenosis related to persistent left-sided SVC, repeated Blalock-Taussig shunt (BTS) with SVCI. Our SVCI technique is very useful in specific cases (eg, in candidates for the Fontan procedure.


Development and Physical Characterization of α-Glucan Nanoparticles.
α-Glucans that were enzymatically synthesized from sucrose using glucansucrase cloned from Leuconostoc mesenteroides NRRL B-1118 were found to have a glass transition temperature of approximately 80 °C. Using high-pressure homogenization (~70 MPa), the α-glucans were converted into nanoparticles of ~120 nm in diameter with a surface potential of ~-3 mV. Fluorescence measurements using 1,6-diphenyl-1,3,5-hexatriene (DPH) indicate that the α-glucan nanoparticles have a hydrophobic core that remains intact from 10 to 85 °C. α-Glucan nanoparticles were found to be stable for over 220 days and able to form at three pH levels. Accelerated exposure measurements demonstrated that the α-glucan nanoparticles can endure exposure to elevated temperatures up to 60 °C for 6 h intervals.


Oral Health Status and Treatment Needs of Gunj Marketing Yard Laborers of Raichur City, Karnataka.
Oral health is a vital part of general health and is a valuable asset of every individual. The working population in India usually belong to the lower socioeconomic group. This study was conducted to assess the oral health status and treatment needs of Gunj marketing yard laborers. A descriptive study was conducted among 550 laborers of Gunj marketing yard of Raichur city. A specially designed questionnaire was used to assess the demographic variables and oral hygiene practices. Oral health status was assessed using the WHO assessment form 1997. Simplified oral hygiene index (1964) was used to assess the oral hygiene status. The mean age of the study participants was 35.1 (± 8.02) years and the mean decayed teeth, missing teeth, filled teeth, and decayed, missing, filled teeth was 2.06 (± 1.49), 0.76 (± 2.53), 0.13 (± 0.39), and 2.95 (± 3.02), respectively. The prevalence of dental caries and periodontal disease was 85.7% and 93.5%, respectively. The oral hygiene status was poor in 45.9% of the study participants. This study demonstrates poor oral hygiene and high prevalence of periodontal diseases and dental caries as well as a large proportion of unmet dental needs among these laborers.


Regulation of the immunoglobulin gene transcription.
The transcription of the immunoglobulin heavy (IGH), kappa (IGK) and lambda (IGL) chain genes is coordinate and B lymphocyte specific. This expression of the immunoglobulin genes is under the control of regulatory elements: the promoters located 5' of each variable (V) gene and the enhancers located between the joining and constant genes in the IGH and IGK locus and downstream on the C kappa gene. These sequences represent sites for the binding of transcription factors. A 90-100 kDa ubiquitous proteins (NF-A1) as well as two specific B cell proteins (NF-A2, OTF-2B) bind to the octamer site of the V promoter and IGH enhancer. The NF-kB protein binds to the kB site in the intron kappa enhancer, but also to kB-like sites found in the promoter regions of other genes. This paper reviews the recent data on these factors and other transcription factors which bind to the promoters and enhancers of the immunoglobulin genes and control their expression.


[Two anomalous muscles of a forearm revealed by ulnar nerve compressions, a Double Crush syndrome].
This article describes the concomitant presence of two anomalous muscles on a left forearm in a 40-year-old man. The anconeus epitrochlearis muscle was responsible for a cubital tunnel syndrome and the unusual origin of the flexor digiti minimi brevis muscle was responsible for a compartment syndrome with ulnar nerve compression at the level of Guyon's canal during effort diagnosed by MRI. Resection of these muscles relieved the symptoms and allowed the patient to return to work.


Prophylactic ureteral stent placement for the prevention of genitourinary tract injury during hysterectomy for placenta accreta spectrum: systematic review and meta-analysis.
This study aimed to assess the effectiveness of prophylactic ureteral stent placement for the prevention of genitourinary tract injury at the time of cesarean hysterectomy for placenta accreta spectrum. The secondary objectives were to assess mean blood loss, operative time, number of packed red blood cells transfused, and rates of urinary tract infection among patients undergoing cesarean hysterectomy for placenta accreta spectrum with and without prophylactic ureteral stent placement. The search was performed using PubMed, Cochrane Library, and ClinicalTrials.gov from inception to February 2022 to December 2022. The protocol for this review was registered with the International Prospective Register of Systematic Reviews before data collection (registration number: CRD42022372817). All studies that examined differences in the rate of genitourinary tract injury among women undergoing cesarean hysterectomy for prenatally suspected placenta accreta spectrum with and without placement of prophylactic ureteral stents were included. Genitourinary injury was defined as cystotomy, ureteral injury, and/or bladder fistula. Cases of both intentional and unintentional genitourinary injuries were included in the analysis. For all studies meeting the inclusion criteria, the following data were extracted: number of included patients, maternal demographic information, obstetrical history, type of invasive placentation, placement of stents (yes or no), type of stent placed, blood loss, operative time, genitourinary tract injury, and urinary tract infection. Pooled data analysis was completed using the Review Manager (version 5.3; Nordic Cochrane Centre, Copenhagen, Denmark; Cochrane Collaboration, 2014). The summary measures were reported as summary relative risk or as summary mean difference. The quality and risk of biases of the included studies were assessed according to the Newcastle-Ottawa Scale. Overall, 9 studies, including 848 patients, fulfilled our inclusion criteria and were included in our analysis. Moreover, 523 patients (61.7%) had prophylactic ureteral stents placed, and 325 patients (38.3%) did not. Genitourinary injury occurred in 138 of 523 patients (26.4%) in the ureteral stent group vs 83 of 325 patients (25.5%) in the no ureteral stent group (relative risk, 0.94; 95% confidence interval, 0.74-1.20). The mean number of packed red blood cells transfused did not differ between the 2 groups. The pooled analysis demonstrated decreased blood loss among patients who received prophylactic ureteral stents, with a mean difference of 392 mL (95% confidence interval, 52.74-738.13). Our systematic review and meta-analysis demonstrated no difference in the rates of genitourinary tract injury with the use of prophylactic ureteral stent placement among cases of prenatally suspected placenta accreta spectrum undergoing cesarean hysterectomy.


Neural Stem Cells Derived from Human-Induced Pluripotent Stem Cells and Their Use in Models of CNS Injury.
Induced pluripotent stem (iPS) cells are derived from differentiated cells by different reprogramming techniques, by introducing specific transcription factors responsible for pluripotency. Induced pluripotent stem cells can serve as an excellent source for differentiated neural stem/progenitor cells (NSCs/NPs). Several methods and protocols are utilized to create a robust number of NSCs/NPs without jeopardizing the safety issues required for in vivo applications. A variety of disease-specific iPS cells have been used to study nervous system diseases. In this chapter, we will focus on some of the derivation and differentiation approaches and the application of iPS-NPs in the treatment of spinal cord injury and stroke.


Tracing the origin of a singular HIV-1 CRF45_cpx clade identified in Brazil.
The HIV-1 epidemiology has changed over the past decade toward a marked increase in the circulation of strains previously restricted to local epidemics. Recent molecular epidemiological surveys identified some HIV-1 strains of probable African origin circulating in Brazil, including the Circulating Recombinant Form (CRF) 45_cpx, a complex A1/K/U recombinant that circulates in Central Africa. Here, we characterize partial genomic sequences and reconstruct the evolutionary history of HIV-1 CRF45_cpx-related recombinant samples identified in independent studies carried out with HIV+ individuals in Brazil. The sequences were obtained by overlapping PCR amplifications followed by direct sequencing. Recombination profiles were determined by phylogenetic and bootscaning analyses. The evolutionary history was estimated by a Bayesian coalescent-based method using datasets representing the gag, pol and env gene fragments. Six of the 10 samples isolated in Rio de Janeiro showed a CRF45_cpx-like pattern throughout the sequenced genome. The remaining were classified as second-generation recombinants, showing the mosaic patterns: CRF45_cpx/B/D/F1/U, CRF45_cpx/B/F1/U, CRF45_cpx/B/U and CRF45_cpx/F1. All Brazilian CRF45_cpx sequences, except one, formed a monophyletic clade (CRF45-BR), which seems to be the result of a single introduction event that has spread to the Rio de Janeiro, São Paulo and Minas Gerais states and is related to sequences from Argentina, Italy and Belgium. The Bayesian analyses pointed out quite consistent onset dates for CRF45-BR clade (~1984: 1976-1996) in the three gene datasets. These results indicate that the CRF45-BR clade has been circulating in the Southeastern Brazilian region for about 30years, although its presence was not detected until recently due to its very low prevalence. This reinforces the relevance of large-scale molecular surveillance data to identify the emergence of new HIV variants and their impact on local epidemics.


Polarization of pulsar radiation.
The polarization of radiation from four pulsars has been measured and interpretations of the results are suggested.


Acute myeloid leukaemia in Western Australia 1991-2005: a retrospective population-based study of 898 patients regarding epidemiology, cytogenetics, treatment and outcome.
Patient characteristics and cytogenetics of acute myeloid leukaemia (AML) in clinical trials do not reflect that of the general population. There has not been a large population-based study that has examined cytogenetic features and outcomes of AML in Australia. Investigation of epidemiological, prognostic, treatment and outcome data in adults diagnosed with AML in Western Australia between 1991 and 2005. Patients were identified utilising the Western Australia Cancer Registry, cytogenetic databases and hospital inpatient discharge diagnoses. Data were retrospectively collected from patients presenting to tertiary hospitals on patient characteristics, karyotype, induction therapy, remission, transplantation and survival. A total of 987 patients with AML was identified, of which 91% (898) attended a tertiary hospital. Median age was 67 years and 45% of cases represented secondary AML. Cytogenetic analysis was available in 81% of patients. Frequent karyotypes were normal (38.8%), complex (13.8%) and -7/add(7q)/del(7q) (12.1%). Aggressive therapy was initiated in 62.6%. Less than 15% were enrolled in clinical trials. Overall 16.5% received a stem cell transplant. Median overall survival for all patients was 5.6 months. In patients treated aggressively, complete remission was achieved in 56.9% and median overall survival was 12.2 months. Age, secondary disease and karyotype were significantly predictive of remission and overall survival. Age distribution, remission and survival rates were comparable with published population-based studies. High median age was reflected in the rate of secondary AML and trial eligibility. These findings highlight the need for prospective data collection.


p53-dependent G1 arrest and p53-independent apoptosis influence the radiobiologic response of glioblastoma.
Loss of the p53 tumor suppressor gene has been associated with tumor progression, disease relapse, poor response to antineoplastic therapy, and poor prognosis in many malignancies. We have investigated the contribution of p53-mediated radiation-induced apoptosis and G1 arrest to the well described radiation resistance of glioblastoma multiforme (GM) cells. Radiation survival in vitro was quantitated using linear quadratic and repair-saturation mathematical models. Isogenic derivatives of glioblastoma cells differing only in their p53 status were generated using a retroviral vector expressing a dominant negative mutant of p53. Radiation-induced apoptosis was assayed by Fluorescence-activated cell sorter (FACS) analysis, terminal deoxynucleotide transferase labeling technique, and chromatin morphology. Cells were synchronized in early G1 phase and mitotic and labeling indices were measured. Radiation-induced apoptosis of GM cells was independent of functional wild-type p53 (wt p53). Decreased susceptibility to radiation-induced apoptosis was associated with lower alpha values characterizing the shoulder of the clonogenic radiation survival curve. Using isogenic GM cells differing only in their p53 activity, we found that a p53-mediated function, radiation-induced G1 arrest, could also influence the value of alpha and clonogenic radiation resistance. Inactivation of wt p53 function by a dominant negative mutant of p53 resulted in a significantly diminished alpha value with no alteration in cellular susceptibility to radiation-induced apoptosis. The clonal derivative U87-LUX.8 expressing a functional wt p53 had an alpha (Gy-1) value of 0.609, whereas the isogenic clonal derivative U87-175.4 lacking wt p53 function had an alpha (Gy-1) value of 0.175. We conclude that two distinct cellular responses to radiation, p53-independent apoptosis and p53-dependent G1-arrest, influence radiobiological parameters that characterize the radiation response of glioblastoma cells. Further understanding of the molecular basis of GM radiation resistance will lead to improvement in existing therapeutic modalities and to the development of novel treatment approaches.


Fisheries as a large-scale experiment on life-history evolution: disentangling phenotypic and genetic effects in changes in maturation and reproduction of North Sea plaice, Pleuronectes platessa L.
This paper attempts to interpret the observed changes in reproductive strategy of female North Sea plaice since 1900 in the light of possible genetical selection exerted by the fisheries. Somatic growth of juvenile plaice increased between the 1950s and the 1980s, probably as a response to an increase in food availability. Adult growth rate was constant, except during a period of increased population abundance when somatic growth decreased. Both length (L mat) and age at first sexual maturity decreased since 1990. No firm evidence was obtained for a change in total reproductive investment, although size-specific fecundity was reduced in the period of increased population abundance, suggesting a trade-off between egg numbers and egg size. Analysis of the phenotypic response of maturation to an increase in juvenile growth suggested that only a part of the decrease in L mat could be ascribed to the observed increase in juvenile growth. The unexplained part of the change in L mat corresponded with the predicted change due to genetical selection by the fisheries. This supported the hypothesis that fishing caused a genetical change in L mat, although an unequivocal interpretation is not possible from a descriptive study.


Differences in mean arterial pressure of young and elderly people measured by oscilometry during inflation and deflation of the arm cuff.
Systemic arterial blood pressure (BP) is one of the most important parameters of the cardiovascular system. An oscillometric NIBP monitor was specifically designed to measure oscillometric pulsations and mean arterial pressure (MAP) during inflation and deflation of the cuff. Nineteen healthy young (age 23.1±1.7 years; mean±SD) and 35 elderly (83.9±7.9 years; mean±SD) subjects were studied. Differential analysis of MAP during inflation and deflation show mean |ΔMAP|=2.9±2.6 mm Hg in the young group (mean±SD) and |ΔMAP|=6.3±5.2 mm Hg for seniors (mean±SD). There was a significant difference (p<0.05) in means of |ΔMAP| measured during cuff inflation and cuff deflation between both groups. In about 50% of elderly subjects |ΔMAP| was higher than 5 mm Hg. Potential clinical relevance of the method needs to be further evaluated.


Evaluation of the first oral rabies vaccination campaign of the red foxes in Greece.
Following the late 2012 recurrence of rabies in wild foxes (Vulpes vulpes) in central and north-western Greece, the first oral fox vaccination campaign co-financed by the European Union (EU) and the Greek state budget, was implemented. Initially, it involved 24 regional units of the Greek territory during the period October-December 2013. Vaccine-baits were aerially distributed by fixed-wing aircrafts. Vaccines were scattered along parallel flight paths 500m apart in order to optimize aerial missions and achieve homogeneous distribution. A geographical information system was used to objectively evaluate bait distribution. This system identified areas of inadequate bait density that would require additional flights. A total number of 1,504,821 baits were distributed covering an area of 54,584.29km(2). To assess the effectiveness of oral vaccination campaign a monitoring program was introduced, which entailed examination of serum samples and canine teeth derived from red foxes collected in the field. The laboratory analysis revealed 60% seropositivity and detection of tetracycline biomarker in 70% of the foxes tested.


Kimura Disease: Rare Parotid Entity.
Kimura disease is a rare chronic inflammatory disorder of unknown cause, primarily seen in young Asian males. The disease is characterized by painless subcutaneous swelling, blood and tissue eosinophilia and raised IgE levels. Early diagnosis of Kimura's disease may spare the patient from unnecessary invasive diagnostic procedure. We describe a case of Kimura disease in a 17-year-old male presenting with left submandibular swelling.


Repeatability of edited lactate and other metabolites in astrocytoma at 3T.
To assess the repeatability of measurement of lactate and other metabolites in tumors using magnetic resonance spectroscopy (MRS). MRS with spectral editing for lactate was performed on 10 patients with astrocytoma (two Grade III, eight Grade IV) using an 8-channel receive coil at 3T. Lactate, lipid, choline, creatine, and N-acetyl aspartate (NAA) signals were measured in regions of tumor and contralateral white matter. Metabolites were quantified relative to unsuppressed water using LCModel fitting software. The within-patient coefficients of variation were ≈16% (tumor lactate), 6%-8% (tumor choline and contralateral choline, creatine, and NAA), and 22% (tumor lipid). As expected due to their low concentration in normal tissue, lactate and lipid were not reliably detected in white matter but were found at high levels in most tumors. NAA and creatine were lower in tumors than in normal white matter, and choline varied between above- and below-normal values. No consistent short-term variation in metabolite levels was observed, despite differences in the time elapsed since administration of contrast agent. MRS appears repeatable enough to provide longitudinal measures of metabolite content in tumors and contralateral tissue in the brain in vivo.


Innominate artery compression of the trachea: relationship to cervical herniation of the normal thymus.
To document the possible association of segmental tracheomalacia in the thoracic inlet with the combination of a large thymus and normal innominate artery. Eight infants with symptoms of innominate artery compression of the trachea were studied. The diagnostic approach included observation of posterior tracheal displacement and focal tracheal collapse at fluoroscopy, ablation of the right radial pulse by rigid endoscopic pressure, and compression of the anterior tracheal wall by the innominate artery at magnetic resonance imaging. Six patients had relief of symptoms with either thymectomy and innominate artery reimplantation (n = 4) or subtotal thymectomy and innominate artery suspension (n = 2). The ratio of the sagittal diameter of the thymus to the sagittal diameter of the thoracic inlet was significantly (P < .0009) higher in the symptomatic patients (0.58 +/- 0.03) than in age-matched control subjects (0.35 +/- 0.08). Crowding of the thoracic inlet by cervical herniation of an enlarged but normal thymus may contribute to the development of tracheomalacia and the symptoms of innominate artery compression.


Assessment of the vascularity of a left atrial mass using myocardial perfusion contrast echocardiography.
Emerging applications of myocardial contrast echocardiography (MCE) include the evaluation of myocardial perfusion, the improvement of the definition of intracavitary structures, and evaluation of the relative perfusion of a cardiac mass. We present a case of a patient that was found incidentally to have a cardiac mass on transthoracic echocardiography. MCE was used to evaluate the vascularity of the mass. This case is compared with another patient with a left atrial thrombus, which represents an "avascular" cardiac mass by MCE.


Hybrid III-V/IV Nanowires: High-Quality Ge Shell Epitaxy on GaAs Cores.
The integration of optically active III-V and electronic-suitable IV materials on the same nanowire could provide a great potential for the combination of photonics and electronics in the nanoscale. In this Letter, we demonstrate the growth of GaAs/Ge core-shell nanowires on Si substrates by molecular beam epitaxy and investigate the radial and axial Ge epitaxy on GaAs nanowires in detail. High-quality core-shell nanowires with smooth side facets and dislocation-free, sharp interfaces are achieved. It is found that the low shell growth temperature leads to smoother side facets, while higher shell growth temperatures lead to more relaxed structures with significantly faceted sidewalls. The possibility of forming a III-V/IV heterostructure nanowire with a Ge section development in the axial direction of a GaAs nanowire using a Ga droplet is also revealed. These nanowires provide an ideal platform for nanoscale III-V/IV combination, which is promising for highly integrated photonic and electronic hybrid devices on a single chip.


Patterns of daily behaviour in two lizard species Lacerta agilis L. and Lacerta vivipara Jacquin.
During the period May to August 1978, individuals of both Lacerta agilis and Lacerta vivipara were observed in a specially constructed out-door vivarium. The daily patterns of behaviour of the two species were recorded along with surface and air temperatures. Daily activity of both species followed a similar basic pattern but was modified by variations in the local weather. Adults of L. vivipara reached a thermal preferendum more quickly and had a longer daily activity period than adults of L. agilis. The larger L. agilis can increase its period of activity by making use of different thermal conditions in a diverse habitat with varied vegetation structure under conditions of high solar radiation. The status of viable populations of L. agilis could be maintained or enhanced by management aimed at modifying the microenvironment of the lizard's habitat.


Evolution of polydom-like molecules: identification and characterization of cnidarian polydom (Cnpolydom) in the basal metazoan Hydractinia.
End sequencing of random BAC clones from a Hydractinia symbiolongicarpus (Cnidaria: Hydrozoa) genomic library revealed a gene across a approximately 37.5kb region of the H. symbiolongicarpus genome sharing highest sequence identity and domain architecture to mammalian polydom that we in turn named cnidarian polydom (CnPolydom). Sharing all eight domain types characteristic of polydom and organized in a similar 5'-3' manner, CnPolydom was predicted to contain three additional domain types: PAN, FA58C, and CUB that are characteristic of CnPolydom. Expression analysis of CnPolydom from H. symbiolongicarpus (Hysy-CnPolydom) showed upregulation in response to bacterial and primarily fungal challenges, with transcripts produced specifically by a subset of interstitial stem cells (i-cells) and/or neural cells throughout the ectodermal tissue layer of feeding polyps (gastrozooids). This is the first description of a polydom-like molecule outside of Mammalia and provides evolutionary perspective on the ancestral structure and role of this pentraxin family clade.


Endoscopic ultrasonography to evaluate pancreatitis.
Endoscopic ultrasonography (EUS) has become a well-accepted test in the workup of acute and chronic pancreatitis. However, further studies are needed to define its diagnostic role in patients with recurrent acute pancreatitis and minimal-change chronic pancreatitis.


Bile acids LVII. Analysis of bile acids by high pressure liquid chromatography and mass spectrometry.
Several high pressure liquid chromatographic methods for the separation of conjugated and free bile acids are presented. A mixture of synthetic conjugated bile acids has been separated by reverse-phase systems consisting of either a Waters Associated' "fatty-acid analysis" or a muBondapak/C18 column eluted with a mixture of 2-propanol/potassium phosphage buffer (pH 2.5 or 7.0). The major conjugated bile acids present in the gallbladder bile of obese subjects have been analyzed each in less than 30 min and quantitated with a U.V. detector set at 193 nm. Some of the 5 alpha- and 5 beta-isomers of conjugated bile salts could be resolved in straight-phase systems on Corasil II or muPorasil columns. Mass spectra of the conjugated bile acids obtained by electron impact were characteristics of the type of amino acid attached to the side chain, and the number of hydroxyl substituents on the nucleus. Most of the isomers could readily be differentiated by the relative intensities of the fragment ions.


Control of combustion-generated nitrogen oxides by selective non-catalytic reduction.
Controlling nitrogen oxides (NO(x)) emissions is becoming a daunting technical challenge as increasingly strict emission limits are being imposed. The stringent regulations have prompted the innovation and characterization of NO(x) control technologies suitable for various applications. This paper presents a review on NO(x) removal techniques with particular reference to selective non-catalytic reduction (SNCR) technology. This includes initially how SNCR emerged as a technology along with a comparison with other relevant technologies. A review of various features related to selective non-catalytic gas phase injection of ammonia and ammonium salts (as reducing agent) is presented. The use of urea solution as a reducing agent and its performance in laboratory and pilot scale tests as well as large-scale applications is also discussed. Use of cyanuric acid as a potential reducing agent is also presented. The underlying reaction mechanisms have been reviewed for ammonia, urea and cyanuric acid for the explanation of various observations. Computational fluid dynamics (CFD) modeling as applied to SNCR is also presented. Subsequently the use of SNCR coupled with other in-combustion and post-combustion NO(x) control techniques is elaborated. Additionally, a two-stage NO(x) removal strategy to control un-reacted ammonia slip and to improve overall efficiency is discussed. At the end a summary is given which highlights various areas needing further research.


Advances in understanding the interrelations between leptin resistance and obesity.
Obesity, which has developed into a global epidemic, is a risk factor in most chronic diseases and some forms of malignancy. The discovery of leptin in 1994 has opened a new field in obesity research. Currently, we know that leptin is the primary signal from energy stores and exerts negative feedback effects on energy intake. However, most individuals with diet-induced obesity (DIO) develop leptin resistance, which is characterized by elevated circulating leptin levels and decreased leptin sensitivity. To date, though various mechanisms have been proposed to explain leptin resistance, the exact mechanisms of leptin resistance in obesity are poorly understood. Consequently, it's an important issue worth discussing regarding what the exact interrelations between leptin resistance and obesity are. Here, we review the latest advancements in the molecular mechanisms of leptin resistance and the exact interrelations between leptin resistance, obesity, and obesity-related diseases, in order to supply new ideas for the study of obesity.


The thermal shrinkage force in perimysium from different beef muscles is not affected by post-mortem ageing.
Differences in the thermal shrinkage and collagen solubility between bovine Semitendinosus (ST) and Pectoralis profundus (PP) muscles and their interactions with ageing were evaluated by studying collagen solubility, hydrothermal isometric tension and thermal denaturation properties of intramuscular connective tissue after 5-20days post-mortem storage at 4°C. Collagen solubility was higher in ST than in PP muscle at 5-13days, but the differences between the two muscles decreased at longer ageing times. A small decrease in the peak denaturation temperature of perimysium occurred with increasing ageing times in both muscles. Maximum force in isometrically-heated perimysium was broadly equivalent in both muscles. Although the amount and solubility of collagen varies between muscles and ageing decreases the stability of some of the collagen, thermal shrinkage forces in heated perimysium are not significantly diminished by ageing. These findings support the idea of one collagen fraction easily degraded by ageing and heat, and another more resistant fraction that determines the physical properties of the tissue after ageing and cooking.


Age-Related Outcomes of the Ross Procedure Over 20 Years.
The Ross procedure is an alternative for patients with aortic valve disease not amenable to repair. Long-term follow-up after a Ross has demonstrated the need for autograft (left ventricular outflow tract [LVOT]) and homograft (right ventricular outflow tract [RVOT]) reinterventions. We assessed the age-stratified outcomes of the LVOT and RVOT after the Ross procedure performed by a single surgeon during a 20-year period. We retrospectively reviewed 305 consecutive patients aged 4 days to 70 years, stratified by age younger than than 1 (n = 41), 1 to 10 (n = 85), 10 to 20 (n = 84), 20 to 40 (n = 59), and older than 40 years (n = 36). Median follow-up was 8.2 years (interquartile range, 1 month to 19.2 years). Primary end points were survival and freedom from reintervention on the LVOT and RVOT. Outcomes were compared by Kaplan-Meier analysis. A total of 173 patients (57%) had prior intervention on their aortic valve, 95 (31%) had isolated regurgitation, 91 (30%) had stenosis, and 119 (39%) had mixed pathology. There were 92 concomitant procedures (43 congenital lesions, 18 aorta, 9 mitral valve). In-hospital morbidity was 11.5% (35 of 305); mortality was 3.6% (11 of 305) and highest in infants. Need for an emergency operation (p < 0.05) predicted mortality in infants. The LVOT reintervention rate was lowest in infants compared with older patients (p < 0.05); conversely, age was directly related to RVOT reintervention (p < 0.01). Autograft encasement in a Hemashield (Atrium, Hudson, NH) tube in patients aged older than 10 years improved 5-year freedom from reintervention on the LVOT from 81% to 91% (p < 0.001). At last follow-up, aortic insufficiency was mild or less in 290 (95%) patients, and heart function was normal in 285 (93%). The Ross procedure is a safe, effective, and anti-coagulation-free alternative for aortic valve replacement across all age groups. Long-term survival and preservation of heart function are highly favorable. Surgical mortality is related to salvage procedures in infants. When feasible, autograft durability can be improved by using a Hemashield graft for support.


Effects of PRRSV Infection on the Porcine Thymus.
Porcine reproductive and respiratory syndrome virus (PRRSV) dramatically affects the thymus and its ability to carry out its normal functions. In particular, infection incapacitates PRRSV-susceptible CD14pos antigen-presenting cells (APCs) in the thymus and throughout the body. PRRSV-induced autophagy in thymic epithelial cells modulates the development of T cells, and PRRSV-induced apoptosis in CD4posCD8pos thymocytes modulates cellular immunity against PRRSV and other pathogens. Pigs are less able to resist and/or eliminate secondary infectious agents due the effect of PRRSV on the thymus, and this susceptibility phenomenon is long recognized as a primary characteristic of PRRSV infection.


A Patient-Centered Environmental Scan of Inpatient Visitor Policies During the COVID-19 Pandemic.
Researchers and patients conducted an environmental scan of policy documents and public-facing websites and abstracted data to describe COVID-19 adult inpatient visitor restrictions at 70 academic medical centers. We identified variations in how centers described and operationalized visitor policies. Then, we used the nominal group technique process to identify patient-centered information gaps in visitor policies and provide key recommendations for improvement. Recommendations were categorized into the following domains: 1) provision of comprehensive, consistent, and clear information; 2) accessible information for patients with limited English proficiency and health literacy; 3) COVID-19 related considerations; and 4) care team member methods of communication.


Identification of human hnRNP C1/C2 as a dengue virus NS1-interacting protein.
Dengue virus nonstructural protein 1 (NS1) is a key glycoprotein involved in the production of infectious virus and the pathogenesis of dengue diseases. Very little is known how NS1 interacts with host cellular proteins and functions in dengue virus-infected cells. This study aimed at identifying NS1-interacting host cellular proteins in dengue virus-infected cells by employing co-immunoprecipitation, two-dimensional gel electrophoresis, and mass spectrometry. Using lysates of dengue virus-infected human embryonic kidney cells (HEK 293T), immunoprecipitation with an anti-NS1 monoclonal antibody revealed eight isoforms of dengue virus NS1 and a 40-kDa protein, which was subsequently identified by quadrupole time-of-flight tandem mass spectrometry (Q-TOF MS/MS) as human heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2. Further investigation by co-immunoprecipitation and co-localization confirmed the association of hnRNP C1/C2 and dengue virus NS1 proteins in dengue virus-infected cells. Their interaction may have implications in virus replication and/or cellular responses favorable to survival of the virus in host cells.


Close link between reduction of c-myc expression by interferon and, G0/G1 arrest.
It has recently been reported that c-myc is an inducible gene, regulated directly by growth signals which promote proliferation and expressed in a cell-cycle dependent manner. Because various leukaemic cell lines express high levels of c-myc messenger RNA, it was of interest to discover whether the gene could be down-regulated in these cells by a growth inhibitor such as interferon (IFN). We show here that in Daudi Burkitt's lymphoma cells, IFN-alpha produces a five- to sevenfold reduction in c-myc mRNA through a decreased rate of c-myc gene transcription. By isolating a growth-resistant Daudi cell variant that had escaped from this down-regulation, we provide the first clear link between reduction of c-myc mRNA and the IFN-mediated G0/G1 arrest characteristic of Daudi cells. Furthermore, by screening other cell lines, we demonstrate the heterogeneity of human leukaemic cells with respect to these criteria. Thus, IFN-alpha fails to reduce the c-myc mRNA and to change the cell-cycle distribution in HL-60 and U937 cells, although normal induction of other IFN-regulated activities takes place. The latter group of cells shows a decline in c-myc gene expression when they become arrested in the G0/G1 phase as part of their terminal differentiation.


Dystroglycan: emerging roles in mammary gland function.
Dystroglycan (DG) is a single receptor that binds to multiple basement membrane proteins and forms a transmembrane link to the actin cytoskeleton. It was first isolated as a component of the dystrophin-glycoprotein complex, which plays a role in the maintenance of muscle cell integrity and is defective in many muscular dystrophies. Although studied most extensively in muscle tissues, DG is present at most cell-basement membrane interfaces, and only recently has investigation of DG functions in nonmuscle cells gained momentum. Information emerging from recent studies in epithelial cells is implicating DG in a wide range of critical cell responses to the basement membrane, ranging from organization of tissue architecture to cell survival. Moreover, DG functions appear to be frequently absent in carcinoma cells, implicating its loss in cancer progression. Although many questions remain as to its precise role in mammary tissue, DG is emerging as a potentially important player in mammary gland function.


Pulmonary infections associated with non-tuberculous mycobacteria in immunocompetent patients.
A decline in the prevalence of tuberculosis in the developed world over the past several years has been accompanied by an increase in the rate of mycobacterial disease caused by non-tuberculous mycobacteria. However, it is still unclear whether there is a real increase in prevalence or whether non-tuberculous mycobacterial disease is being recognised more frequently by clinicians in a variety of clinical settings, thus enhancing the competence of microbiologists to detect the more unusual and fastidious mycobacteria. The introduction of liquid media for isolation of mycobacteria coupled with more accurate methods for identification have allowed several new species associated with human disease to be recognised. Despite this progress, several issues related to non-tuberculous mycobacterial infections need to be addressed, including the timely and reliable identification of isolates, standardisation and clinical evaluation of susceptibility testing, and capability to distinguish disease-causing isolates from contaminant or saprophytic species. Treatment regimens for non-tuberculous mycobacterial disease are still largely undefined and outcome remains disappointing despite substantial upgrading in laboratory diagnosis and the availability of new antimicrobials. Treatment success is impaired by the long duration of regimens, side-effects, and drug interactions, which prevent patients from full compliance. We discuss the epidemiological features, clinical syndromes, and developments in the investigation, prevention, and treatment of pulmonary non-tuberculous mycobacterial infections.


Erratum: Author Correction: Humoral immune response to tick-borne encephalitis vaccination in allogeneic blood and marrow graft recipients.
[This corrects the article DOI: 10.1038/s41541-020-00215-1.].


Statistical evaluation for detection of peptide specific interferon-gamma secreting T-cells induced by HIV vaccine determined by ELISPOT assay.
Interferon-gamma (IFN-gamma) secreting T-cells play an important role in immunodeficiency virus (HIV) disease pathogenesis. A common technique to determine the efficacy of the HIV vaccines in murine models is to compare the number of IFN-gamma secreting T-cells induced by HIV vaccine to a control group. The measurement of IFN-gamma secreting T-cells relies on an ELISPOT assay. This assay is carried out in triplicate wells from the same mouse on the same ELISPOT plate. The numbers of spot forming cells (SFC) from these wells are correlated counts. Traditionally, simple statistical methods, such as ANOVA or Kruskall-Wallis tests, are performed on means by mouse. These approaches ignore the fact that the data are correlated counts. Count data are usually assumed to follow the Poisson distribution. However, some count data exhibit overdispersion that can affect the test statistics. The negative binomial distribution is an alternative to the Poisson distribution in the presence of overdispersion. Hence, negative binomial regression is a more suitable approach for overdispersed count data. In this study, we used a negative binomial regression to determine that IL-12 was a good adjuvant. The results of the study using a negative binomial regression are discussed.


TPMT genotype and the use of thiopurines in paediatric inflammatory bowel disease.
Thiopurines are used in the treatment of inflammatory bowel disease. They are metabolised via methylation by thiopurine-S-methyltransferase (TPMT), which displays a genetically determined polymorphic activity. Subjects with reduced TPMT activity have a higher concentration of active thiopurine metabolites and may be at increased risk of bone-marrow suppression. To evaluate the relevance of TPMT genotyping in the management of thiopurines therapy in inflammatory bowel disease patients. Adverse effects and clinical response were determined retrospectively and correlated with TPMT genotype in 70 paediatric inflammatory bowel disease patients. Nineteen patients (27.1%) developed adverse effects; of the 51 who did not, 34 (66.7%) responded to treatment. Five patients (7.1%) were heterozygous for a variant TPMT allele; two of these (40%) were intolerant to thiopurines, compared to 17 of the 65 patients (26.2%) with a wild type gene (O.R. 1.88, 95% CI 0.29-12.2, p=0.61); among the 34 responders, the median dosage of the drug required to obtain remission was lower for mutated than for wild type patients (1.6mgkg(-1)day(-1) versus 2.0mgkg(-1)day(-1), p=0.043). There was no significant association between adverse effects of thiopurines and TPMT heterozygous genotype, but TPMT genotyping could be useful in establishing the most appropriate dose of thiopurines to start treatment.


Investigation of Coordinational Properties of Europium(III) Complexes with Picolinic Acid Using Eu(III) Excitation Spectroscopy.
The 7F0 --> 5D0 excitation spectra of Eu(III) complexed with picolinic acid were investigated using Eu(III) excitation spectroscopy. Six overlapping peaks are seen in the excitation spectra, indicating the formation of six species. The structures of the six species are proposed here and described in terms of both coordination by carboxylate and N-chelation. Copyright 1999 Academic Press.


Fetal malformations associated with breech delivery. Implications for obstetric management.
Among 1,411 breech deliveries at the Soroka Medical Center, Beer-Sheva, Israel, there were 116 cases of congenital anomalies (8.2 %). Forty-nine fetuses (3.47%) exhibited major congenital anomalies and 67 (4.7%), minor ones. The incidence of chromosomal anomalies was 0.63% (1 per 159 births) as compared with 0.25% in the general population. The frequency distribution indicated that most of the fetuses with congenital abnormalities weighed 2,000 gm or more. In view of the high incidence of chromosomal aberrations and major congenital anomalies among fetuses with breech presentation, it seems desirable to consider ultrasonographic assessment and chromosomal analysis during the last trimester of pregnancy.


A polymorphism of the interleukin-1 receptor antagonist plays a prominent role within the interleukin-1 gene cluster in vulvar carcinogenesis.
The interleukin-1 (IL-1) family, that is, IL-1alpha and beta and the IL-1 receptor antagonist (IL-1RA), is known to modulate various tumorigenic and tumoricidal effects in humans. Its biological function in squamous cell carcinogenesis of various anatomical sites has been stressed. Although various studies showed a certain association between genes encoding the IL-1 family and human malignancies, no data with respect to vulvar cancer have been published to date. We ascertained four polymorphisms of the IL-1alpha gene (IL1A C[-889]T), the IL-1beta gene (IL1B promoter C[-511]T and IL1B exon 5 position +3953), and the IL-1RA gene (IL1RN intron 2) in 68 patients with surgically treated squamous cell vulvar cancer and 228 healthy Caucasian controls. Presence of the minor allele of the IL1RN polymorphism was found to be protective for vulvar cancer [odds ratio (OR)=0.5, P=0.03], the other investigated polymorphisms showed no association with the disease and the investigated clinicopathological parameters. In a multivariate analysis, only the established prognosticators were associated with patients' survival. We are the first to report on polymorphisms in genes encoding cytokines in patients with vulvar cancer. Reflecting its biological role, the common IL1RN intron 2 polymorphism seems to play a prominent role within the IL-1 gene cluster with respect to vulvar carcinogenesis.


Comprehensive platelet phenotyping supports the role of platelets in the pathogenesis of acute venous thromboembolism - results from clinical observation studies.
The pathogenesis of arterial and venous thrombosis is in large part interlaced. How much platelet phenotype relates to acute venous thromboembolism (VTE) independent of the underlying cardiovascular profile is presently poorly investigated. Platelet count and mean platelet volume (MPV), platelet aggregation in whole blood and platelet rich plasma (PRP), platelet-dependent thrombin generation (TG) and platelet surface activation markers were measured under standardized conditions. Machine learning was applied to identify the most relevant characteristics associated with VTE from a large array (N = 58) of clinical and platelet-related variables. VTE cases (N = 159) presented with lower platelet count and MPV vs controls (N = 140). Whole blood aggregation showed shorter collagen/Epinephrine closure times in cases, particularly within acetylsalicylic acid (ASA) users. Within ASA users, higher PRP aggregation after adenosine diphosphate (ADP), epinephrine, collagen and arachidonic acid was observed in cases vs controls. Within non-ASA and/or subjects on anticoagulants, cases presented with lower aggregation after ADP and collagen vs controls. Lower platelet-dependent TG, higher CD63 on resting and lower PAC-1 expression after collagen/ADP in-vitro stimulated platelets further characterized VTE cases vs controls, independent of therapy. Lasso regression analysis identified 26 variables associated with VTE of which 69% were platelet-related. Comprehensive phenotyping of platelet function identified a large proportion of low responders to ASA in VTE cases. Lower platelet-dependent TG and lower platelet reactivity after ex-vivo stimulation characterized the "platelet exhausted syndrome" in cases. Finally, from a large array of covariates including clinical risk factors, platelet biomarkers comprised 69% of all selected variables differentiating VTE cases vs controls. German Federal Ministry of Education and Research, CTH-Mainz and Bayer AG.


Simulation, stories, and fictional worlds.
The authors explain our attraction to strange, literary places as resulting from our attraction to strange places in real life. I believe this is correct and important. The aim of the following commentary is to show that their main conclusion is closely related to - even (retrospectively) predictable from - the operation of simulation and the consequences of that operation for storytelling.


Negative emotions and quality of life of parents with children diagnosed with anorectal malformations.
To investigate the anxiety, depression, stress, and quality of life of parents with children diagnosed with anorectal malformations. 68 parents participated in the study and completed the unified Self-Rating Anxiety Scale, Self-Rating Depression Scale, Perceived Stress Scale, and the World Health Organization Quality of Life-BREF. Compared with the Chinese reference values, parents in our study had higher scores on anxiety and depression and lower scores on the psychological and environmental domain of the World Health Organization Quality of Life-BREF. Parents who live in rural areas, pay for medical treatment out of pocket, and have multiple children are prone to feel anxious. Parents with multiple children also scored worse in the domains of physiology, psychology, social relationships, and general quality of life assessment. They scored significantly lower in the domains of psychology and social relationships when parents had a low education level. Parents of children who had undergone staged operations got lower scores on the general quality of life assessment. Parents of children with anorectal malformations have varying degrees of psychological and emotional problems that require attention in the clinic.


The Association of Valsalva Status With Smoking and Its Impact on Ossiculoplasty Outcomes and Complications.
To assess the association of a patient's ability to perform a clinically observed Valsalva maneuver with tobacco smoking and post-ossiculoplasty outcomes. Case series with chart review. Tertiary referral, university-based otology practice. Adult patients (16-88 years of age) undergoing ossiculoplasty with tympanoplasty or tympanomastoidectomy using cartilage tympanic membrane grafts, retrograde mastoidectomy with canal wall reconstruction, or mastoid obliteration techniques. Patients were classified as Valsalva negative (Val) or positive (Val). Comparisons were then made between these two groups for smoking status, final audiometric outcomes, rate of cure of conductive hearing loss, anatomic outcomes, and incidence of significant complications after otologic surgery involving ossiculoplasty. Tobacco smoking is not significantly correlated with the inability to insufflate the middle ear with the Valsalva maneuver (p = 0.557). An insignificant difference in final pure-tone average air-bone gap (PTA-ABG) was observed between the Val and Val groups (20.2 dB HL versus 18.2 dB HL, respectively; p = 0.152). Similarly, the rate of successful PTA-ABG closure to ≤20 dB HL was not significantly different between the groups (62.5% [80 of 128] of Val patients and 56.8% [54 of 95] of Val patients [p = 0.394]). Postoperative complications were seen with a higher frequency in the Val patients (16.8% [16 of 95] versus 7.0% [9 of 128]; p = 0.022). A patient's inability to perform the Valsalva maneuver is not significantly associated with smoking; however, negative Valsalva status is associated with an increased incidence of significant complications after ossiculoplasty.


Comparison of the five-electrode-derived EASI electrocardiogram to the Mason Likar electrocardiogram in the prehospital setting.
This study compared the 5-electrode-derived EASI electrocardiogram (ECG) with the conventional Mason-Likar ECG in 200 consecutive patients with chest pain transported to 3 hospitals by 2 different emergency medical services. No significant differences were observed between the 2 systems for the detection of relevant electrocardiographic abnormalities. A questionnaire administered to participating emergency medical personnel revealed a high degree of acceptability of the EASI ECG, with some participants commenting that the sternal and mid-axillary locations of the EASI electrodes made them easier to apply, especially to women, than conventional precordial electrodes.


A rare case of Kearns-Sayre syndrome in a 17-year-old Venezuelan male with bilateral ptosis as the initial presentation.
Kearns-Sayre syndrome (KSS) was first described in 1958 as 'a rare neuromuscular disorder defined by a characteristic triad of progressive external ophthalmoplegia, pigmentary retinopathy, atrioventricular block and cerebellar ataxia'. The prevalence rate of KSS is ∼1-3 per 100 000 individuals. Here, we report a rare case of a 17-year-old Venezuelan male with KSS.


Long-term morbidity after fetal endoscopic surgery for severe twin-to-twin transfusion syndrome.
Severe twin-to-twin transfusion syndrome (TTTS) leads to 80% to 100% dual mortality. Endoscopic laser coagulation of connecting vessels improves outcome to 80% survival of at least 1 twin. There is limited long-term follow-up of surviving TTTS patients. The aim of this study was to analyze gestational age-stratified, long-term morbidity in these patients. A retrospective case-control study of TTTS surviving patients (38 patients, 72% follow-up rate) from one center. Perinatal and pediatric records were reviewed, and outcomes were compared with published reports and gestational age-matched controls. Forty percent (15/38) had at least 1 major sequela, all but 6 of which were fully resolved at a median follow-up of 4.4 years. There were no permanent cardiac, genitourinary, renal, or respiratory sequelae. All major complications were in patients born <29 weeks. There were no significant differences in complications between this cohort of patients and gestational age (GA)-matched control patients. The long-term morbidity of monochorionic twins after fetal laser surgery for severe TTTS is 13%. At a median follow-up of more than 4 years, these children fare no worse than gestational age-matched, non-operated twins and singletons. The degree of prematurity at birth is the best predictor of temporary or permanent sequela in this group of patients.


Effects of cardiopulmonary bypass on glucose homeostasis after coronary artery bypass surgery.
Hyperglycaemia is associated with increased mortality and morbidity after cardiac surgery. While surgical stress results in hyperglycaemia after all operations, it has been suggested that cardiopulmonary bypass is the dominating contributor after cardiac surgery. This study aimed to determine the contribution of cardiopulmonary bypass to hyperglycaemia after coronary artery bypass. Patients scheduled for primary coronary artery bypass grafting were randomised to surgery with or without cardiopulmonary bypass. All patients received continuous insulin infusions during the initial 24-h period. Glucose was infused (100mg/kg per h) postoperatively in the intensive care unit but not during surgery. Blood glucose was measured 4 times daily until the third postoperative day. Serum insulin, insulin-like growth factor-1 and its binding protein were determined. Average blood glucose during the day of surgery did not differ between groups, but 30% more insulin (P=0.003) was required when cardiopulmonary bypass was used. Blood glucose 2-3h after meals was higher in patients using cardiopulmonary bypass during the first 3 postoperative days. Fasting blood glucose was still equally elevated 20-30% in both groups on the third postoperative day. Insulin-like growth factor-1 decreased more (P=0.01) and insulin-like growth factor binding protein-1 increased more (P<0.001) with cardiopulmonary bypass than without. The ratio of insulin-like growth factor-1 concentration to the concentration of its binding protein-1 was more negative (indicating greater catabolism) with cardiopulmonary bypass than without both postoperatively (P=0.002) and on the third postoperative day (P=0.02). Insulin-like growth factor-1 standard deviation score, also a measure of catabolism, was greater after surgery with cardiopulmonary bypass than without (P=0.02). Glucose homeostasis is disturbed preoperatively for many non-diabetic patients undergoing coronary bypass surgery. Cardiopulmonary bypass exacerbates the catabolism and disturbed glucose homeostasis that is induced also to a lesser degree by surgery without cardiopulmonary bypass.


Exposure-response analysis of Camidanlumab tesirine in patients with relapsed or refractory classical Hodgkin lymphoma and non-Hodgkin lymphoma.
To investigate camidanlumab tesirine (Cami) exposure-response (E-R) relationships, using an integrated population pharmacokinetic model, for patients with classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma enrolled in an open-label, phase 1 study (NCT02432235). Exploratory analyses investigated relationships between exposure measures (Cmaxss, Cminss, and Cavgss) and the occurrence of binary variables (overall response rate [ORR] and selected adverse events [AEs]) and nonbinary variables (overall survival [OS]). Exploratory analyses showed a significant, positive relationship between exposure and ORR/OS. The final model showed this effect was non-significant due to the covariate effects. Cami exposures were higher in patients with selected grade ≥ 2 AEs at cycle 6 (the anticipated steady-state exposure level), confirmed in the final E-R models. Based on univariate results, Cmaxss was used as the exposure measure in all models, except for the autoimmune AE full E-R model in which Cavgss was used. The positive relationship between exposure and ORR/OS (higher exposure significantly associated with higher probabilities of ORR/OS) was not statistically significant in the final models. The final safety E-R models demonstrated a significant positive association between Cami exposure and selected grade ≥ 2 AEs, with higher exposures associated with higher probabilities of experiencing the grade ≥ 2 AEs at cycle 6. The results identify preliminary predictors of efficacy and safety and provide a basis for a dosing rationale and benefit-risk profile of Cami in patients with relapsed/refractory cHL.


A comparative analysis of cell surface targeting aptamers.
Aptamers represent a potentially important class of ligands for the development of diagnostics and therapeutics. However, it is often difficult to compare the function and specificity of many of these molecules as assay formats and conditions vary greatly. Here, with an interest in developing aptamer targeted therapeutics that could effectively deliver cargoes to cells, we chemically synthesize 15 aptamers that have been reported to target cell surface receptors or cells. Using standardized assay conditions, we assess each aptamer's binding properties on a panel of 11 different cancer cell lines, correlate aptamer binding to antibody controls and use siRNA transfection to validate each aptamer's binding to reported target receptors. Using a subset of these molecules known to be expressed on prostate cancers, we use near-infrared in vivo imaging to assess the tumor localization following intravenous injection. Our data demonstrate some surprising differences in the reported specificity and function for many of these molecules and raise concerns regarding their cell targeting capabilities. They also identify an anti-human transferrin aptamer, Waz, as a robust candidate for targeting prostate cancers and for future development of aptamer-based therapeutics.


An Executed Plan to Combat COVID-19 in the United States.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019. To date, this coronavirus is responsible for greater than 90 million cases in the United States and more than 1 million confirmed deaths. When this virus came to the United States, testing was unorganized, no effective treatments were known, and no vaccines had been discovered. A plan to correct these deficiencies through cooperative science and efficient clinical trials was implemented to combat this novel virus. This plan developed efficient and inexpensive tests, highly effective medicines to treat and prevent disease progression, and vaccines to immunize the population.