title: [Mechanism of Xuanfei Baidu Tang in treatment of COVID-19 based on network pharmacology].

text: The study aimed to investigate the multi-constituent, multi-target mechanism of Xuanfei Baidu Tang(XFBD) in the treatment of coronavirus disease 2019(COVID-19), through exploring the main ingredients and effective targets of XFBD, as well as analyzing the correlation between XFBD targets and COVID-19. The compounds of each herb in XFBD were collected from TCM-PTD, ETCM, TCMSP and SymMap database. Next, the information of meridian tropisms was collected from Chinese Pharmacopoeia(2015 edition), and the target information of the major constituents of XFBD were obtained from TCM-PTD, ETCM, TCMSP and TargetNet database. Subsequently, the target network model and the major modules were generated by Cytoscape, and the functional enrichment analysis of XFBD targets were completed by DAVID and STRING. As a result, ten of the 13 herbs in XFBD belonged to the lung meridian, and 326 of the 1 224 putative XFBD targets were associated with the disease target of COVID-19, among which 109 targets were enriched in the disease pathways of viral infection and lung injury. The main biological pathways regulated by the key XFBD targets included viral infection, energy metabolism, immunity and inflammation, parasites and bacterial infections. In conclusion, the therapeutic mechanism of XFBD in COVID-19 showed a multi-herb, multi-constituent, multi-target pattern, with lung as the chief targeted organ. By regulating a series of biological pathways closely related to the occurrence and development of diseases, XFBD plays a role in balancing immunity, eliminating inflammation, regulating hepatic and biliary metabolism and recovering energy metabolism balance.


title: The Effect of Specimen Preparation on Post-Excision and Post-Fixation Dimensions, Translation, and Distortion of Canine Cadaver Skin-Muscle-Fascia Specimens.

text: OBJECTIVE To assess the effect of various tissue apposition techniques on specimens after formalin fixation, and to assess canine cadaveric composite skin-muscle-fascia specimen changes after excision without and with addition of a tumor model. STUDY DESIGN Canine cadaveric study; unbalanced paired design. ANIMALS Fresh canine cadavers (n = 30) METHODS: Experiment 1: Paired 7 cm diameter, circular skin-muscle-fascia specimens were harvested bilaterally from three sites (thorax, abdomen, and thigh) on 10 cadavers. For each pair, the skin-to-fascia was sutured with a circumferential continuous pattern in one specimen and left unsutured in the other during excision. Specimen length and width were measured post-excision and post-fixation. Specimen rotation, translation, and distortion was measured post-fixation. Experiment 2: A subcutaneous tumor model was implanted at 2 sites (neck, thorax) on 20 cadavers and specimens were then excised with 2 cm lateral margins and a deep fascial plane. Three suturing techniques of the skin-to-fascia at both sites were performed during excision: unsutured versus circumferential continuous suture (10 pairs) or circumferential versus 4 interrupted quadrant sutures (10 pairs). Lateral margins were compared post-excision and post-fixation. RESULTS Experiment 1: There was significant reduction in the length and width of the fascia and skin post-excision, but no further reduction after fixation. The circumferential suture decreased rotation and translation of the tissue layers but did not significantly affect specimen shrinkage or distortion compared with the unsutured specimen. Experiment 2: All 4 lateral margins decreased significantly post-excision and post-fixation compared with the planned pre-excision margins. No difference was found between any of the 4 lateral margins for any skin-to-fascia suture technique. CONCLUSION Canine skin-muscle-fascia specimens significantly decrease in size from gross pre-excision dimensions after removal. Suturing the specimen during surgery before excision will significantly improve alignment of tissue planes without creating distortion of the sample, but may alter the length, width, and lateral margins of the specimen.


Reply to Radermacher et al on "Serum Hydrogen Sulfide and Outcome Association in Pneumonia by the Sars-cov-2 Coronavirus".


Asymptomatic COVID-19 positive patient suspected on FDG-PET/CT.


title: Persistent equine arteritis virus infection in HeLa cells.

text: The horse-adapted virulent Bucyrus (VB) strain of equine arteritis virus (EAV) established persistent infection in high-passage-number human cervix cells (HeLa-H cells; passages 170 to 221) but not in low-passage-number human cervix cells (HeLa-L cells; passages 95 to 115) or in several other cell lines that were evaluated. However, virus recovered from the 80th passage of the persistently infected HeLa-H cells (HeLa-H-EAVP80) readily established persistent infection in HeLa-L cells. Comparative sequence analysis of the entire genomes of the VB and HeLa-H-EAVP80 viruses identified 16 amino acid substitutions, including 4 in the replicase (nsp1, nsp2, nsp7, and nsp9) and 12 in the structural proteins (E, GP2, GP3, GP4, and GP5). Reverse genetic studies clearly showed that substitutions in the structural proteins but not the replicase were responsible for the establishment of persistent infection in HeLa-L cells by the HeLa-H-EAVP80 virus. It was further demonstrated that recombinant viruses with substitutions in the minor structural proteins E and GP2 or GP3 and GP4 were unable to establish persistent infection in HeLa-L cells but that recombinant viruses with combined substitutions in the E (Ser53-->Cys and Val55-->Ala), GP2 (Leu15-->Ser, Trp31-->Arg, Val87-->Leu, and Ala112-->Thr), GP3 (Ser115-->Gly and Leu135-->Pro), and GP4 (Tyr4-->His and Ile109-->Phe) proteins or with a single point mutation in the GP5 protein (Pro98-->Leu) were able to establish persistent infection in HeLa-L cells. In summary, an in vitro model of EAV persistence in cell culture was established for the first time. This system can provide a valuable model for studying virus-host cell interactions, especially virus-receptor interactions.


title: Fibrin sheath formation and intimal thickening after catheter placement in dog model: role of hemodynamic wall shear stress.

text: PURPOSE To investigate the role of wall shear stress in aspects of the formation of fibrin sheath and intimal thickening in a dog model. METHODS Tunneled silicone 14.5-F catheters were inserted into the left internal jugular vein in eight dogs. The dogs were separated into two groups according to catheter indwelling time of 14 and 28 days. All dogs underwent extracorporeal circulation three times a week. Multidetector computed tomography venography (MDCTV) examination was used to examine the catheter tip thrombus. After the animals were sacrificed, histological and immunohistochemistry evaluations were performed to confirm specific cell populations. We used computer modeling to generate wall shear stress profiles for the blood flow through the catheter. RESULTS Catheter-related sheaths were identified in all catheter specimens, but there was no fibrin sheath around the catheter tip. There were also differences in wall shear stress between the different venous wall sites. Differences in vein wall thickening at different sites have been found at both 14 days (intima to media (I/M) ratio S1 vs S2: p = 0.01, S3 vs S4: p<0.01) and 28 days (I/M ratio S1 vs S2: p<0.01, S3 vs S4: p<0.05). CONCLUSIONS After catheter placement, fibrin sheath formation partially covered the catheter. Meanwhile, focal areas of intimal thickening were also seen in the venous wall adjacent to the sites of high wall shear stress. These findings indicate an important role of wall shear stress profiles in fibrin sheath formation and intimal thickening.


title: Prevalence, profile and predictors of malnutrition in children with congenital heart defects: a case-control observational study.

text: OBJECTIVE To investigate the prevalence, profile and predictors of severe malnutrition in children with congenital heart defects (CHDs). DESIGN Case-control, observational study. SETTING Tertiary teaching hospital in Lagos, Nigeria (March 2006 to March 2008). PARTICIPANTS Children aged 3-192 months with uncorrected symptomatic CHD and healthy controls, frequency matched for age and sex. MAIN OUTCOME MEASURES Prevalence of malnutrition based on WHO/National Center for Health Statistics/Centers for Disease Control and Prevention z score ≤-2; weight for age, weight for height/length and height for age; proportions of underweight, wasting and stunting in cases and controls, and in acyanotic and cyanotic CHD; and predictors of malnutrition using multivariate logistic analysis. RESULTS 90.4% of cases and 21.1% of controls had malnutrition (p=0.0001), and 61.2% and 2.6%, respectively, had severe malnutrition (p=0.0001). Wasting, stunting and underweight were identified in 41.1%, 28.8% and 20.5%, and 2.6%, 3.9% and 14.5% of cases and controls, respectively. Wasting was significantly higher (58.3%) in acyanotic CHD (p=0.0001), and stunting (68.0%) in cyanotic CHD (p=0.0001). Age at weaning was significantly lower in cases than controls (3.24±0.88 and 7.04±3.04 months, respectively; p=0.0001) and in acyanotic than cyanotic CHD (2.14±0.33 and 5.33±1.22 months, respectively; p=0.004). Predictors of malnutrition in CHD were anaemia, moderate to severe congestive heart failure (CHF), poor dietary intake of fat and prolonged unoperated disease. CONCLUSION Severe malnutrition in association with anaemia and moderate to severe CHF is highly prevalent in CHD preoperatively in these children. Early weaning may be a marker of feeding difficulties in heart failure.


Observation scales to suspect dyspnea in non-communicative intensive care unit patients.


Spontaneous reports as evidence of adverse drug reactions.


title: In vivo imaging of abdominal aortic aneurysms: increased FDG uptake suggests inflammation in the aneurysm wall.

text: PURPOSE To study the potential of integrated positron emission tomography and computed tomography (PET/CT) to identify aneurysm wall inflammation. METHODS The level of F18-fluorodeoxyglucose (FDG) uptake was studied in aneurysmal and normal-sized aortas of 34 male patients [17 with abdominal aortic aneurysm (AAA) and 17 age-matched controls] identified in a database of 278 consecutive patients evaluated for staging of primary lung cancer. The maximal standardized uptake value (SUV) was calculated to quantify FDG uptake in the AAA wall. RESULTS AAAs showed significantly higher FDG uptake than the normal-sized aorta in age-matched controls (SUV 2.52+/-0.52 versus 1.78+/-0.45, respectively; p<0.001). The level of FDG uptake did not correlate with maximal aneurysm diameter (r=0.09; 95% CI -0.42 to 0.56; p=0.7). CONCLUSION FDG-PET/CT is a promising technique to identify inflammation of the aneurysm wall. Irrespective of aneurysm diameter, asymptomatic AAAs show more FDG uptake and more inflammatory activity in the wall than the non-dilated abdominal aorta of sex/age-matched controls. Future studies will be directed at the predictive value of increased FDG uptake for aneurysm wall strength, rupture risk, and the utility of FDG-PET/CT in assessing the effect of medical interventions.


title: Growth of linked hospital data use in Australia: a systematic review.

text: Objective The aim of the present study was to quantify and understand the utilisation of linked hospital data for research purposes across Australia over the past two decades. Methods A systematic review was undertaken guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2009 checklist. Medline OVID, PsycINFO, Embase, EconLit and Scopus were searched to identify articles published from 1946 to December 2014. Information on publication year, state(s) involved, type of data linkage, disease area and purpose was extracted. Results The search identified 3314 articles, of which 606 were included; these generated 629 records of hospital data linkage use across all Australian states and territories. The major contributions were from Western Australia (WA; 51%) and New South Wales (NSW; 32%) with the remaining states and territories having significantly fewer publications (total contribution only 17%). WA's contribution resulted from a steady increase from the late 1990s, whereas NSW's contribution is mostly from a rapid increase from 2010. Current data linkage is primarily used in epidemiological research (73%). Conclusion More than 80% of publications were from WA and NSW, whereas other states significantly lag behind. The observable growth in these two states clearly demonstrates the underutilised opportunities for data linkage to add value in health services research in the other states. What is known about the topic? Linking administrative hospital data to other data has the potential to be a cost-effective method to significantly improve health policy. Over the past two decades, Australia has made significant investments in improving its data linkage capabilities. However, several articles have highlighted the many barriers involved in using linked hospital data. What does this paper add? This paper quantitatively evaluates the performance across all Australian states in terms of the use of their administrative hospital data for research purposes. The performance of states varies considerably, with WA and NSW the clear stand-out performers and limited outputs currently seen for the other Australian states and territories. What are the implications for practitioners? Given the significant investments made into data linkage, it is important to continue to evaluate and monitor the performance of the states in terms of translating this investment into outputs. Where the outputs do not match the investment, it is important to identify and overcome those barriers limiting the gains from this investment. More generally, there is a need to think about how we improve the effective and efficient use of data linkage investments in Australia.


title: Thinking Outside the Triangle: Replication Fidelity of the Largest RNA Viruses.

text: When judged by ubiquity, adaptation, and emergence of new diseases, RNA viruses are arguably the most successful biological organisms. This success has been attributed to a defect of sorts: high mutation rates (low fidelity) resulting in mutant swarms that allow rapid selection for fitness in new environments. Studies of viruses with small RNA genomes have identified fidelity determinants in viral RNA-dependent RNA polymerases and have shown that RNA viruses likely replicate within a limited fidelity range to maintain fitness. In this review we compare the fidelity of small RNA viruses with that of the largest RNA viruses, the coronaviruses. Coronaviruses encode the first known viral RNA proofreading exoribonuclease, a function that likely allowed expansion of the coronavirus genome and that dramatically increases replication fidelity and the range of tolerated variation. We propose models for regulation of coronavirus fidelity and discuss the implications of altered fidelity for RNA virus replication, pathogenesis, and evolution.


Urgent Appeal from International Society for Aerosols in Medicine (ISAM) During COVID-19: Clinical Decision Makers and Governmental Agencies Should Consider the Inhaled Route of Administration: A Statement from the ISAM Regulatory and Standardization Issues Networking Group.


title: Partial splenectomy in the era of minimally invasive surgery: the current laparoscopic and robotic experiences.

text: BACKGROUND Partial splenectomy (PS) is a spleen-preserving technique that is applied as a result of trauma, focal lesions or hematological conditions. Despite the improvement of laparoscopic techniques within the past several decades, minimally invasive PS has remained a marginal technique that has not been well evaluated. Our objective was to provide an update on the indications and the feasibility of this procedure. METHODS The MEDLINE database (PubMed) was searched, and all relevant articles that involved a true minimally invasive PS (i.e., segmental or lobar devascularization of the spleen with parenchymal transection) were included. The search was conducted until the 31st of March 2014. Demographic data, operative indications, estimated blood losses, operative times, conversion rates and complications were extracted from the included articles and were summarized for discussion. RESULTS Out of the 195 publications that were retrieved, 33 were included, which were mainly case reports and case series that represented a total of 187 patients. There were 37 men, 33 women and 117 patients of unknown gender. The mean age of the patients was ranged from 6 to 58 years. The mean total operative time was between 70 and 216 min for conventional laparoscopy and between 108 and 120 min for the robotic approach. For most studies, the mean estimated blood loss was minimal. The complication rate was 5.36% for conventional laparoscopy and 5.56% for the robotic approach. CONCLUSION The outcomes of minimally invasive PS were favorable and comparable to those of the open technique according to the literature. This procedure may constitute an attractive alternative to the open technique for selected cases. Moreover, a robotic approach might be an interesting technical option, but additional research is needed before any definitive conclusions can be drawn.


title: Cuff pressure of endotracheal tubes after changes in body position in critically ill patients treated with mechanical ventilation.

text: BACKGROUND In order to avoid microaspiration and tracheal injury, the target for endotracheal tube cuff pressure is 20 to 30 cm H2O. OBJECTIVE To assess the effect of changes in body position on cuff pressure in adult patients. METHODS Twelve orally intubated and sedated patients received neuromuscular blockers and were positioned in a neutral starting position (backrest, head-of-bed elevation 30º, head in neutral position) with cuff pressure at 25 cm H2O. Then, 16 changes in position were performed: anteflexion head, hyperextension head, left and right lateral flexion of head, left and right rotation of the head, semirecumbent position (head-of-bed elevation 45°), recumbent position (head-of-bed elevation 10°), horizontal backrest, Trendelenburg position (10°), and left and right lateral positioning over 30°, 45°, and 90°. Once a patient was correctly positioned, cuff pressure was recorded during an end-expiratory ventilatory hold. The pressure observed was compared with the cuff pressure at the starting position. Values outside the target range (20-30 cm H2O) were considered clinically relevant. RESULTS A total of 192 measurements were performed (12 subjects × 16 positions). A significant deviation in cuff pressure occurred with all 16 changes (P < .05). No pressures were less than the lower limit (20 cm H2O). Pressures were greater than the upper limit (30 cm H2O) in 40.6% of the measurements. In each position, the upper target limit was exceeded at least once. Within-patient variability was substantial (P = .02). CONCLUSION Simple changes in patients' positioning can result in potentially harmful cuff pressures.


title: Global surge in measles and major international survey reinforce the need for greater awareness and uptake of all vaccinations.

text: Infectious diseases have posed significant challenges for the worldwide medical community since records began. COVID-19, which originated in China, has provided yet another timely reminder of how vulnerable we can be, despite considerable medical advances. But another worrying trend has been emerging in recent years and that is the resurgence of deaths from infectious disease that can be prevented by effective vaccination programmes. The global increase in measles is a classic example.


title: Interobserver agreement after pipeline embolization device implantation.

text: BACKGROUND AND PURPOSE Although flow diversion devices are popular in treatment of aneurysms, angiographic assessment with these devices has rarely been verified by interobserver variability study. The purpose of this study was to determine the interobserver agreement of a 3-point grading system for assessing the angiographic outcome after flow diversion therapy of intracranial, saccular aneurysms and to determine factors affecting such agreement. MATERIALS AND METHODS After approval by the institutional review board, 5 independent readers assessed pretreatment and follow-up digital subtraction angiograms from 96 patients treated with the Pipeline embolization device by using a 3-point grading system (complete, near-complete, and incomplete occlusion). "Minor discrepancy" was defined as a difference between any 2 readers of 1 grade, that is, complete vs near-complete or near-complete vs incomplete. "Major discrepancy" was defined as a difference between any 2 readers in which 1 reader noted complete occlusion and the other reader noted incomplete occlusion. We performed statistical analysis for the interobserver agreement by using the intraclass correlation coefficient. Subgroup analyses for discrepancy rate and ICC were performed for previously coiled aneurysms. RESULTS The interobserver agreement was excellent (ICC, 0.76; 95% CI, 0.69-0.92). Among 96 cases, there was absolute agreement in 74 (77%), of which 67 had unanimous consensus of "complete" occlusion, 2 "near-complete" occlusion, and 5 "incomplete" occlusion. Discordance between any 2 readers was noted in 22 cases (23%), of which 7 (7.3%) revealed a major discrepancy. Subgroup analysis showed that minor discrepancies were more common among patients previously treated with coils vs those not previously treated with coils (37.5% vs 11.2%; P < .05). CONCLUSIONS The observer agreement regarding occlusion after PED therapy is excellent. Only a minority of cases demonstrated discrepancy considered as major in this study.


title: Evaluation of a monoclonal antibody-based rapid immunochromatographic test for direct detection of rabies virus in the brain of humans and animals.

text: Rabies diagnosis uses a direct fluorescent antibody test (FAT) that is difficult, costly, and time-consuming, and requires trained personnel. We developed a rapid immunochromatographic test (RICT) for the diagnosis of rabies. The efficacy of the RICT was compared with that of the FAT. Brain samples were collected from humans, dogs, cats, and other animals in Sri Lanka (n = 248), Bhutan (n = 27), and Thailand (n = 228). The sensitivity (0.74-0.95), specificity (0.98-1.0), positive predictive value (0.98-1.0), negative predictive value (0.75-0.97), accuracy (0.91-0.98), and kappa measure of agreement (0.79-0.93) were all satisfactory for animal samples and samples preserved in 50% glycerol saline solution. Because the RICT showed high sensitivity but low specificity with human brain samples, it is unsuitable for confirming rabies in humans. No amino acid substitutions were found in the antibody attachment sites of the nucleoprotein gene with FAT-positive, RICT-negative samples. The RICT is reliable, user friendly, rapid, robust, and can be used in laboratories with a modest infrastructure.


title: Effects of ventilator settings, nebulizer and exhalation port position on albuterol delivery during non-invasive ventilation: an in-vitro study.

text: BACKGROUND Few studies have investigated the factors affecting aerosol delivery during non-invasive ventilation (NIV). Our aim was to investigate, using a bench-top model, the effect of different ventilator settings and positions of the exhalation port and nebulizer on the amount of albuterol delivered to a lung simulator. METHODS A lung model simulating spontaneous breathing was connected to a single-limb NIV ventilator, set in bi-level positive airway pressure (BIPAP) with inspiratory/expiratory pressures of 10/5, 15/10, 15/5, and 20/10 cmH2O, or continuous positive airway pressure (CPAP) of 5 and 10 cmH2O. Three delivery circuits were tested: a vented mask with the nebulizer directly connected to the mask, and an unvented mask with a leak port placed before and after the nebulizer. Albuterol was collected on a filter placed after the mask and then the delivered amount was measured with infrared spectrophotometry. RESULTS Albuterol delivery during NIV varied between 6.7 ± 0.4% to 37.0 ± 4.3% of the nominal dose. The amount delivered in CPAP and BIPAP modes was similar (22.1 ± 10.1 vs. 24.0 ± 10.0%, p = 0.070). CPAP level did not affect delivery (p = 0.056); in BIPAP with 15/5 cmH2O pressure the delivery was higher compared to 10/5 cmH2O (p = 0.033) and 20/10 cmH2O (p = 0.014). Leak port position had a major effect on delivery in both CPAP and BIPAP, the best performances were obtained with the unvented mask, and the nebulizer placed between the leak port and the mask (p < 0.001). CONCLUSIONS In this model, albuterol delivery was marginally affected by ventilatory settings in NIV, while position of the leak port had a major effect. Nebulizers should be placed between an unvented mask and the leak port in order to maximize aerosol delivery.


title: Clinical epidemiology and outcomes of community acquired infection and sepsis among hospitalized patients in a resource limited setting in Northeast Thailand: A prospective observational study (Ubon-sepsis).

text: Infection and sepsis are leading causes of death worldwide but the epidemiology and outcomes are not well understood in resource-limited settings. We conducted a four-year prospective observational study from March 2013 to February 2017 to examine the clinical epidemiology and outcomes of adults admitted with community-acquired infection in a resource-limited tertiary-care hospital in Ubon Ratchathani province, Northeast Thailand. Hospitalized patients with infection and accompanying systemic manifestations of infection within 24 hours of admission were enrolled. Subjects were classified as having sepsis if they had a modified sequential organ failure assessment (SOFA) score ≥2 at enrollment. This study was registered with ClinicalTrials.gov, number NCT02217592. A total of 4,989 patients were analyzed. Of the cohort, 2,659 (53%) were male and the median age was 57 years (range 18-101). Of these, 1,173 (24%) patients presented primarily to the study hospital, 3,524 (71%) were transferred from 25 district hospitals or 8 smaller hospitals in the province, and 292 (6%) were transferred from one of 30 hospitals in other provinces. Three thousand seven hundred and sixteen (74%) patients were classified as having sepsis. Patients with sepsis had an older age distribution and a greater prevalence of comorbidities compared to patients without sepsis. Twenty eight-day mortality was 21% (765/3,716) in sepsis and 4% (54/1,273) in non-sepsis patients (p<0.001). After adjusting for gender, age, and comorbidities, sepsis on admission (adjusted hazard ratio [HR] 3.30; 95% confidence interval [CI] 2.48-4.41, p<0.001), blood culture positive for pathogenic organisms (adjusted HR 2.21; 95% CI 1.89-2.58, p<0.001) and transfer from other hospitals (adjusted HR 2.18; 95% CI 1.69-2.81, p<0.001) were independently associated with mortality. In conclusion, mortality of community-acquired sepsis in Northeast Thailand is considerable and transferred patients with infection are at increased risk of death. To reduce mortality of sepsis in this and other resource-limited setting, facilitating rapid detection of sepsis in all levels of healthcare facilities, establishing guidelines for transfer of sepsis patients, and initiating sepsis care prior to and during transfer may be beneficial.


title: Cholesterol effectively blocks entry of flavivirus.

text: Japanese encephalitis virus (JEV) and dengue virus serotype 2 (DEN-2) are enveloped flaviviruses that enter cells through receptor-mediated endocytosis and low pH-triggered membrane fusion and then replicate in intracellular membrane structures. Lipid rafts, cholesterol-enriched lipid-ordered membrane domains, are platforms for a variety of cellular functions. In this study, we found that disruption of lipid raft formation by cholesterol depletion with methyl-beta-cyclodextrin or cholesterol chelation with filipin III reduces JEV and DEN-2 infection, mainly at the intracellular replication steps and, to a lesser extent, at viral entry. Using a membrane flotation assay, we found that several flaviviral nonstructural proteins are associated with detergent-resistant membrane structures, indicating that the replication complex of JEV and DEN-2 localizes to the membranes that possess the lipid raft property. Interestingly, we also found that addition of cholesterol readily blocks flaviviral infection, a result that contrasts with previous reports of other viruses, such as Sindbis virus, whose infectivity is enhanced by cholesterol. Cholesterol mainly affected the early step of the flavivirus life cycle, because the presence of cholesterol during viral adsorption greatly blocked JEV and DEN-2 infectivity. Flavirial entry, probably at fusion and RNA uncoating steps, was hindered by cholesterol. Our results thus suggest a stringent requirement for membrane components, especially with respect to the amount of cholesterol, in various steps of the flavivirus life cycle.


title: Metformin Treatment Was Associated with Decreased Mortality in COVID-19 Patients with Diabetes in a Retrospective Analysis.

text: Metformin was proposed to be a candidate for host-directed therapy for COVID-19. However, its efficacy remains to be validated. In this study, we compared the outcome of metformin users and nonusers in hospitalized COVID-19 patients with diabetes. Hospitalized diabetic patients with confirmed COVID-19 in the Tongji Hospital of Wuhan, China, from January 27, 2020 to March 24, 2020, were grouped into metformin and no-metformin groups according to the diabetic medications used. The demographics, characteristics, laboratory parameters, treatments, and clinical outcome in these patients were retrospectively assessed. A total of 283 patients (104 in the metformin and 179 in the no-metformin group) were included in this study. There were no significant differences between the two groups in gender, age, underlying diseases, clinical severity, and oxygen-support category at admission. The fasting blood glucose level of the metformin group was higher than that of the no-metformin group at admission and was under effective control in both groups after admission. Other laboratory parameters at admission and treatments after admission were not different between the two groups. The length of hospital stay did not differ between the two groups (21.0 days for metformin versus 19.5 days for no metformin, P = 0.74). However, in-hospital mortality was significantly lower in the metformin group (3/104 (2.9%) versus 22/179 (12.3%), P = 0.01). Antidiabetic treatment with metformin was associated with decreased mortality compared with diabetics not receiving metformin. This retrospective analysis suggests that metformin may offer benefits in patients with COVID-19 and that further study is indicated.


title: Structural Equation Modeling of Social Networks: Specification, Estimation, and Application.

text: Psychologists are interested in whether friends and couples share similar personalities or not. However, no statistical models are readily available to test the association between personalities and social relations in the literature. In this study, we develop a statistical model for analyzing social network data with the latent personality traits as covariates. Because the model contains a measurement model for the latent traits and a structural model for the relationship between the network and latent traits, we discuss it under the general framework of structural equation modeling (SEM). In our model, the structural relation between the latent variable(s) and the outcome variable is no longer linear or generalized linear. To obtain model parameter estimates, we propose to use a two-stage maximum likelihood (ML) procedure. This modeling framework is evaluated through a simulation study under representative conditions that would be found in social network data. Its usefulness is then demonstrated through an empirical application to a college friendship network.


title: Trigeminal postherpetic neuralgia responsive to treatment with capsaicin 8 % topical patch: a case report.

text: Postherpetic neuralgia has been variably defined but is generally understood to be pain that persists for longer than a few months after an attack of herpes zoster. Pain persists for years in approximately 10 % of those afflicted with acute herpes zoster. The likelihood of postherpetic neuralgia increases with older age, severity of the zoster, trigeminal location, and other factors. Postherpetic neuralgia is a neuropathic pain and treatment usually involves sequential trials of topical and systemic drugs; a variety of other therapies may be considered in refractory cases. A new topical capsaicin 8 % patch has been approved for this indication based on the positive studies in patients with non-trigeminal postherpetic neuralgia. Experience with the use of the capsaicin 8 % patch for trigeminal distribution neuralgia is lacking. We report a case of trigeminal postherpetic neuralgia which was safely and effectively treated with capsaicin 8 % patch.


title: JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction.

text: The Activation-Induced Cell Death (AICD) is a stimulation-dependent form of apoptosis used by the organism to shutdown T-cell response once the source of inflammation has been eliminated, while allowing the generation of immune memory. AICD is thought to progress through the activation of the extrinsic Fas/FasL pathway of cell death, leading to cytochrome-C release through caspase-8 and Bid activation. We recently described that, early upon AICD induction, mitochondria undergo structural alterations, which are required to promote cytochrome-C release and execute cell death. Here, we found that such alterations do not depend on the Fas/FasL pathway, which is instead only lately activated to amplify the cell death cascade. Instead, such alterations are primarily dependent on the MAPK proteins JNK1 and ERK1/2, which, in turn, regulate the activity of the pro-fission protein Drp1 and the pro-apoptotic factor Bim. The latter regulates cristae disassembly and cooperate with Drp1 to mediate the Mitochondrial Outer Membrane Permeabilization (MOMP), leading to cytochrome-C release. Interestingly, we found that Bim is also downregulated in T-cell Acute Lymphoblastic Leukemia (T-ALL) cells, this alteration favouring their escape from AICD-mediated control.


title: Efficacy of Instant Hand Sanitizers against Foodborne Pathogens Compared with Hand Washing with Soap and Water in Food Preparation Settings: A Systematic Review.

text: Hands can be a vector for transmitting pathogenic microorganisms to foodstuffs and drinks, and to the mouths of susceptible hosts. Hand washing is the primary barrier to prevent transmission of enteric pathogens via cross-contamination from infected persons. Conventional hand washing involves the use of water, soap, and friction to remove dirt and microorganisms. The availability of hand sanitizing products for use when water and soap are unavailable has increased in recent years. The aim of this systematic review was to collate scientific information on the efficacy of hand sanitizers compared with washing hands with soap and water for the removal of foodborne pathogens from the hands of food handlers. An extensive literature search was carried out using three electronic databases: Web of Science, Scopus, and PubMed. Twenty-eight scientific publications were ultimately included in the review. Analysis of this literature revealed various limitations in the scientific information owing to the absence of a standardized protocol for evaluating the efficacy of hand products and variation in experimental conditions. However, despite conflicting results, scientific evidence seems to support the historical skepticism about the use of waterless hand sanitizers in food preparation settings. Water and soap appear to be more effective than waterless products for removal of soil and microorganisms from hands. Alcohol-based products achieve rapid and effective inactivation of various bacteria, but their efficacy is generally lower against nonenveloped viruses. The presence of food debris significantly affects the microbial inactivation rate of hand sanitizers.


title: Equid herpesvirus type 1 activates platelets.

text: Equid herpesvirus type 1 (EHV-1) causes outbreaks of abortion and neurological disease in horses. One of the main causes of these clinical syndromes is thrombosis in placental and spinal cord vessels, however the mechanism for thrombus formation is unknown. Platelets form part of the thrombus and amplify and propagate thrombin generation. Here, we tested the hypothesis that EHV-1 activates platelets. We found that two EHV-1 strains, RacL11 and Ab4 at 0.5 or higher plaque forming unit/cell, activate platelets within 10 minutes, causing α-granule secretion (surface P-selectin expression) and platelet microvesiculation (increased small events double positive for CD41 and Annexin V). Microvesiculation was more pronounced with the RacL11 strain. Virus-induced P-selectin expression required plasma and 1.0 mM exogenous calcium. P-selectin expression was abolished and microvesiculation was significantly reduced in factor VII- or X-deficient human plasma. Both P-selectin expression and microvesiculation were re-established in factor VII-deficient human plasma with added purified human factor VIIa (1 nM). A glycoprotein C-deficient mutant of the Ab4 strain activated platelets as effectively as non-mutated Ab4. P-selectin expression was abolished and microvesiculation was significantly reduced by preincubation of virus with a goat polyclonal anti-rabbit tissue factor antibody. Infectious virus could be retrieved from washed EHV-1-exposed platelets, suggesting a direct platelet-virus interaction. Our results indicate that EHV-1 activates equine platelets and that α-granule secretion is a consequence of virus-associated tissue factor triggering factor X activation and thrombin generation. Microvesiculation was only partly tissue factor and thrombin-dependent, suggesting the virus causes microvesiculation through other mechanisms, potentially through direct binding. These findings suggest that EHV-1-induced platelet activation could contribute to the thrombosis that occurs in clinically infected horses and provides a new mechanism by which viruses activate hemostasis.


title: U.S. medical countermeasure development since 2001: a long way yet to go.

text: The U.S. government has taken significant steps toward developing and acquiring vaccines, drugs, and other medical countermeasures (MCMs) to protect and treat the population after a biological attack. In contrast to 2001, there is now a procedure for the Department of Health and Human Services (HHS) to develop, license, and stockpile MCMs for civilian use. Another major accomplishment is smallpox preparedness: There is now an adequate supply of vaccine for every person in the U.S., and there is an alternative vaccine meant for immunocompromised people and those with close contact with them. In spite of these and other accomplishments, the U.S. government MCM effort has been criticized by federal advisory committees, National Academy of Sciences reports, a congressional commission, and outside analysts who state that the efforts lack central leadership and accountability and that the pace of progress has been slow. A clear operational strategy for using MCMs, which would guide their development and acquisition, is also lacking. In this article, we review key areas of progress made since 2001 to develop and acquire MCMs, and we summarize what we judge to be the most critical and often mentioned areas where improvements are needed.


title: Racial and Socioeconomic Disparities in Hysterectomy Route for Benign Conditions.

text: BACKGROUND The aim of this paper was to explore disparities associated with the route of hysterectomy in the University of Pittsburgh Medical Center (UPMC) health system and to evaluate whether the hysterectomy clinical pathway implementation impacted disparities in the utilization of minimally invasive hysterectomy (MIH). METHODS We performed a retrospective medical record review of all the patients who have undergone hysterectomy for benign indications at UPMC-affiliated hospitals between fiscal years (FY) 2012 and 2014. RESULTS A total number of 6373 hysterectomy patient cases were included in this study: 88.7% (5653) were European American (EA), 11.02% (702) were African American (AA), and the remaining 0.28% (18) were of other ethnicities. We found that non-EA, women aged 45-60, traditional Medicaid, and traditional Medicare enrollees were more likely to have a total abdominal hysterectomy (TAH). Residence in higher median income zip code (> $61,000) was associated with 60% lower odds of undergoing TAH. Both FY 2013 and 2014 were associated with significantly lower odds of TAH. Logistic regression results from the model for non-EA patients for FY 2012 and FY 2014 demonstrated that FY and zip code income group were not significant predictors of surgery type in this subgroup. Pathway implementation did not reduce racial disparity in MIH utilization. CONCLUSION This study demonstrated that there is a significant disparity in MIH utilization, where non-EA and Medicaid/Medicare recipients had higher odds of undergoing TAH. Further research is needed to investigate how care standardization may alleviate healthcare disparities.


title: Involvement of gadolinium chelates in the mechanism of nephrogenic systemic fibrosis: an update.

text: Nephrogenic systemic fibrosis (NSF) is a highly debilitating scleroderma-like disease occurring exclusively in patients with severe or end-stage renal failure. Since the recognition of a link between gadolinium chelates (GCs) used as contrast agents for MR imaging and NSF by two independent European teams in 2006, numerous studies have described the clinical issues and investigated the mechanism of this disease. So far the most commonly reported hypothesis is based on the in vivo dechelation of GCs. The physicochemical properties of GCs, especially their thermodynamic and kinetic stabilities, are described in the present article. High kinetic stability provided by the macrocyclic structure, combined with high thermodynamic stability, minimizes the amount of free gadolinium released in the body. The current hypotheses regarding the pathophysiologic mechanism are critically discussed.


title: Duodenal Rupture after Blunt Abdominal Trauma by Bicycle Handlebar: Case Report and Literature Review.

text: Blunt abdominal trauma is most frequent in the pediatric population. Duodenal lesions after abdominal trauma in children are infrequent and tend to be secondary to traffic accidents. It is up to five times more frequent in males, with an average age between 16 and 30 years. Bicycle accidents continue to lead to morbidity and mortality in children, representing between 5% and 14% of total blunt abdominal injuries. The diagnosis of duodenal injuries after trauma is difficult and requires a high index of clinical suspicion. We present the case of a 17-year-old patient seen in the emergency room after falling off his bicycle and presented a blunt trauma in the epigastric region. On physical examination, there was a swelling in the upper right abdominal quadrant and epigastrium with tenderness on deep palpation. He presented with hematemesis without hemodynamic repercussion. A contrast abdominal computed tomography was performed and he was diagnosed with third-part duodenal rupture. A resection of the perforated third-part duodenal rupture was performed, and the transit was reconstructed using a Roux-Y duodenojejunostomy. The postoperative period was uneventful and the patient was discharged after 16 days of stay. Duodenal injury is very rare, produced by high-energy trauma. They rarely present as single lesions as other visceral lesions are usually associated. The early diagnosis is important to reduce the morbidity and mortality.


title: COVID19 in South Asians/Asian Indians: Heterogeneity of Data and Implications for Pathophysiology and Research.

text: Despite a large population and limited health infrastructure, the incidence and mortality of Coronavirus Disease 2019 (COVID-19) has been lower in South Asia than many regions. The underlying reasons and mechanisms for this relative protection are not established. However both genetic and environmental factors might play a role. Polymorphisms in ACE2 gene, ACE gene and in genes for some of the host cell proteases could affect the viral entry and replication. There is some evidence that HLA polymorphisms and several pathways involved in immune and inflammatory response could contribute to ethnic variation. Cross immunity because of past exposure to viral infections as well as malaria is likely to protect from the severe manifestations of disease. Role of BCG vaccination in trained innate immunity is recognised and could be a protective factor against COVID-19. There is limited evidence of the possibility of a less virulent viral strain circulating in South Asia. There is evidence from different parts of the world that temperature and humidity can influence viral survival as well as the host immune response. Finally implementation of early containment measures by some South Asian countries has also contributed to a less disease burden.


title: Human T-cells directed to seasonal influenza A virus cross-react with 2009 pandemic influenza A (H1N1) and swine-origin triple-reassortant H3N2 influenza viruses.

text: Virus-specific CD8(+) T-cells contribute to protective immunity against influenza A virus (IAV) infections. As the majority of these cells are directed to conserved viral proteins, they may afford protection against IAVs of various subtypes. The present study assessed the cross-reactivity of human CD8(+) T-lymphocytes, induced by infection with seasonal A (H1N1) or A (H3N2) influenza virus, with 2009 pandemic influenza A (H1N1) virus [A(H1N1)pdm09] and swine-origin triple-reassortant A (H3N2) [A(H3N2)v] viruses that are currently causing an increasing number of human cases in the USA. It was demonstrated that CD8(+) T-cells induced after seasonal IAV infections exerted lytic activity and produced gamma interferon upon in vitro restimulation with A(H1N1)pdm09 and A(H3N2)v influenza A viruses. Furthermore, CD8(+) T-cells directed to A(H1N1)pdm09 virus displayed a high degree of cross-reactivity with A(H3N2)v viruses. It was concluded that cross-reacting T-cells had the potential to afford protective immunity against A(H1N1)pdm09 viruses during the pandemic and offer some degree of protection against infection with A(H3N2)v viruses.


title: Systematic review of the design, implementation and effectiveness of mass media and nutrition education interventions for infant and young child feeding.

text: OBJECTIVE To systematically review the design, implementation and effectiveness of mass media and nutrition education interventions for improving infant and young child feeding (IYCF) practices and related psychosocial factors. DESIGN A search of PubMed, Embase and PsycINFO databases, a Google search, and a consultation with experts in the field of IYCF performed in July 2016. SETTING Low- and middle-income countries, as defined by the World Bank Group. SUBJECTS Eligible studies: included a mass media component (with or without nutrition education); conducted a pre-post evaluation (with or without a control group); assessed IYCF knowledge, attitudes, beliefs and/or practices; and were published in English between 2000 and present. RESULTS Eighteen unique studies were identified that examined the effect of mass media (types included: television; print; voice and/or SMS (text) messages; radio; megaphones/loudspeakers; videos; social media; songs/dramas) and nutrition education interventions on IYCF practices within thirteen countries. Of these, fifteen studies reported improvements in breast- and/or complementary feeding practices, using indicators recommended by the WHO, and six studies reported improvements in related psychosocial factors. However, little detail was provided on the use of formative research, a formal behaviour change theory and behaviour change techniques. Few studies reported both dose delivered and participants' exposure to the intervention. CONCLUSIONS Despite evidence of effectiveness, few common elements in the design of interventions were identified. Future research should consistently report these details to open the 'black box' of IYCF interventions, identify effective design components and ensure replicability.


title: Detection and significance of serum protein markers of small-cell lung cancer.

text: Currently, no satisfactory biomarkers are available to screen for small-cell lung cancer (SCLC). We applied a surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) ProteinChip system to detect 150 serum samples (including 54 SCLC patients, 24 non-small cell lung cancer [NSCLC] patients, 32 pneumonia patients, and 40 healthy individuals). The spectra data were analyzed by support vector machine (SVM) and potential biomarkers were chosen for the system training and used to construct diagnostic model. Pattern 1, constructed of four protein peaks with mass/charge (m/z) of 4,293 Da, 4,612 Da, 6,455 Da, and 7,582 Da, separated SCLC patients from the healthy individuals with a sensitivity of 88.9% and a specificity of 85.7%. This pattern performed significantly better than the current marker, neuron-specific enolase (NSE) (P<0.05). Pattern 2, constructed of protein peaks with mass/charge (m/z) of 2,764 Da and 1,7368 Da, separated SCLC from pneumonia with a sensitivity of 88.9% and a specificity of 91.7%. Pattern 3, constructed of another three protein peaks with m/z of 3,912 Da, 7,562 Da, and 13,777 Da, separated SCLC from NSCLC. The sensitivity and specificity were 83.3% and 75.0%, respectively. These results suggested that SELDI-TOF MS combined with support vector machine yields significantly higher sensitivity and specificity for the detection of serum protein of SCLC.


Fever in a traveler returning from Ethiopia.


title: Fistula-in-ano: when to cut, tie, plug, or sew.

text: INTRODUCTION Management of fistula-in-ano requires understanding of both perianal and rectal anatomy, as well as the surgical approaches available to ensure the highest possible postoperative continence and wound healing. Further, high rates of recurrence with medical management commonly bring these patients under the care of the colorectal surgeon after variable periods of failed conservative management. Novel techniques provide surgeons with tools to treat increasingly complex fistulas with a focus on maintaining sphincteric functionality and limiting recurrence. METHOD This manuscript presents our practice, including perioperative decision making regarding surgical approach, in managing patients with fistula-in-ano. CONCLUSION Familiarity with these techniques prepares the general surgeon and colorectal surgeon to improve wound healing and functional outcomes in these patients, especially with complex disease involving the external and internal anal sphincters.


title: Status of endoscopes and instruments used during NOTES.

text: Natural orifice translumenal endoscopic surgery (NOTES) requires an intentional perforation of a hollow lumen to pass an endoscope into an otherwise inaccessible body cavity with diagnostic or therapeutic intent. The limitations of current flexible instruments for this purpose are outlined, including the unsuitability for NOTES of current flexible needle knives, guidewires, balloons, overtubes, grasping forceps, and scissors. The development of novel suturing instruments, trocars, articulating instruments, flexible bipolar forceps, flexible clips, magnetic devices, and staplers as well as the advent of manual mechanical manipulators for flexible accessories is outlined. New instrument solutions for endosurgery are described, such as articulating flexible accessories for gastroscopes, novel "platforms" that can be rigidized, and unconventional scope arrangements. Debatably, the greatest current benefit of NOTES is that it may lead to further development of better instrumentation for endosurgery.


title: Predicting transient particle transport in enclosed environments with the combined computational fluid dynamics and Markov chain method.

text: To quickly obtain information about airborne infectious disease transmission in enclosed environments is critical in reducing the infection risk to the occupants. This study developed a combined computational fluid dynamics (CFD) and Markov chain method for quickly predicting transient particle transport in enclosed environments. The method first calculated a transition probability matrix using CFD simulations. Next, the Markov chain technique was applied to calculate the transient particle concentration distributions. This investigation used three cases, particle transport in an isothermal clean room, an office with an underfloor air distribution system, and the first-class cabin of an MD-82 airliner, to validate the combined CFD and Markov chain method. The general trends of the particle concentrations vs. time predicted by the Markov chain method agreed with the CFD simulations for these cases. The proposed Markov chain method can provide faster-than-real-time information about particle transport in enclosed environments. Furthermore, for a fixed airflow field, when the source location is changed, the Markov chain method can be used to avoid recalculation of the particle transport equation and thus reduce computing costs.


title: Health economic evaluations of sepsis interventions in critically ill adult patients: a systematic review.

text: Background Sepsis is a global health priority. Interventions to reduce the burden of sepsis need to be both effective and cost-effective. We performed a systematic review of the literature on health economic evaluations of sepsis treatments in critically ill adult patients and summarised the evidence for cost-effectiveness. Methods We systematically searched MEDLINE, Embase, and the Cochrane Library using thesaurus (e.g. MeSH) and free-text terms related to sepsis and economic evaluations. We included all articles that reported, in any language, an economic evaluation of an intervention for the management of sepsis in critically ill adult patients. Data extracted included study details, intervention details, economic evaluation methodology, and outcomes. Included studies were appraised for reporting quality using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results We identified 50 records representing 46 economic evaluations for a variety of interventions including antibiotics (n = 5), fluid therapy (n = 2), early goal-directed therapy and other resuscitation protocols (n = 8), immunoglobulins (n = 2), and interventions no longer in clinical use such as monoclonal antibodies (n = 7) and drotrecogin alfa (n = 13). Twelve (26%) evaluations were of excellent reporting quality. Incremental cost-effectiveness ratios (ICERs) ranged from dominant (lower costs and higher effectiveness) for early goal-directed therapy, albumin, and a multifaceted sepsis education program to dominated (higher costs and lower effectiveness) for polymerase chain reaction assays (LightCycler SeptiFast testing MGRADE®, SepsiTest™, and IRIDICA BAC BSI assay). ICERs varied widely across evaluations, particularly in subgroup analyses. Conclusions There is wide variation in the cost-effectiveness of sepsis interventions. There remain important gaps in the literature, with no economic evaluations identified for several interventions routinely used in sepsis. Given the high economic and social burden of sepsis, high-quality economic evaluations are needed to increase our understanding of the cost-effectiveness of these interventions in routine clinical practice and to inform decision makers. Trial registration PROSPERO CRD42018095980.


title: Single versus multimodality training basic laparoscopic skills.

text: INTRODUCTION Even though literature provides compelling evidence of the value of simulators for training of basic laparoscopic skills, the best way to incorporate them into a surgical curriculum is unclear. This study compares the training outcome of single modality training with multimodality training of basic laparoscopic skills. METHODS Thirty-six medical students without laparoscopic experience performed six training sessions of 45 min each, one per day, in which four different basic tasks were trained. Participants in the single-modality group (S) (n = 18) practiced solely on a virtual reality (VR) simulator. Participants in the multimodality group (M) (n = 18) practiced on the same VR simulator (2x), a box trainer (2x), and an augmented reality simulator (2x). All participants performed a pre-test and post-test on the VR simulator (the four basic tasks + one additional basic task). Halfway through the training protocol, both groups performed a salpingectomy on the VR simulator as interim test. RESULTS Both groups improved their performance significantly (Wilcoxon signed-rank, P < 0.05). The performances of group S and group M in the additional basic task and the salpingectomy did not differ significantly (Mann-Whitney U test, P > 0.05). Group S performed the four basic tasks in the post-test on the VR faster than group M (P ≤ 0.05), which can be explained by the fact that they were much more familiar with these tasks. CONCLUSIONS Training of basic laparoscopic tasks on single or multiple modalities does not result in different training outcome. Both training methods seem appropriate for the attainment of basic laparoscopic skills in future curricula.


title: Is VLSM a valid tool for determining the functional anatomy of the brain? Usefulness of additional Bayesian network analysis.

text: OBJECTIVES The ability of voxel-based lesion-symptom mapping (VLSM) to define the functional anatomy of the human brain has not been fully assessed. With a view to assessing VLSM's validity, the present study analyzed the technique's ability to determine the known clinical-anatomic correlates of hemiparesis in stroke patients. DESIGN Lesions (damaged in at least 5 patients) associated with transformed limb motor score (after adjustment on lesion volume) at 6 months were examined in 272 patients using VLSM. The value of additional multivariable linear, logistic and Bayesian analyses was examined. RESULTS We first checked that motor hemiparesis was fully accounted for by corticospinal tract (CST) lesions (sensitivity = 100%; p = 0.0001). Conventional VLSM analysis flagged up 2 regions corresponding to the CST, but also 8 regions located outside the CST. All 10 brain regions achieving statistical significance in the VLSM analysis were submitted to 3 additional analyses. The backward linear regression analysis selected 5 regions, one only corresponding to the CST (R2: 0.03, p = 0.0008). The logistic regression analysis selected correctly the CST (OR: 2.39, 95%CI: 1.44-3.96; 0.001). The Bayesian network analysis selected regions including the CST (in 92% of 3000 bootstrap replications) and identified the source of multicollinearity. These lesions evaluated by structural equation modeling resulted in an excellent fit (p-value = 0.228, chi/df = 1.19, RMSEA = 0.032, CFI = 0.999). Analyses of confusion factors showed that conventional VLSM analyses were strongly influenced by lesion frequency (R2 = 0.377; p = 0.0001) and multicollinearity. CONCLUSIONS Conventional VLSM analyses are sensitive but weakened by a type I error due to the combined effects of multicollinearity and lesion frequency. We demonstrate that the addition of a Bayesian network analysis, and to a lesser extent of logistic regression, controlled for this type I error and constituted a reliable means of defining the functional anatomy of the motor system in stroke patients.


Respiratory health and disease in Europe: the new European Lung White Book.


title: Complications of bronchial stapling in thoracic surgery.

text: OBJECTIVE The use of staplers for thoracic surgery has been widely accepted and regarded as a safe procedure. However, complications of stapling are occasionally experienced. The aim of this retrospective study was to analyze complications of bronchial stapling. METHODS A retrospective multi-institutional review was conducted by the Central Japan Lung Cancer Surgery Study Group, comprising 29 institutions. All instances of bronchial stapling in thoracic surgery were reviewed during the research period. RESULTS Bronchial stapling was performed 2,030 times, using 36 kinds of staplers. The total number of complications related to stapling was 36 (1.8 %); 31 events occurred intraoperatively and five events occurred postoperatively. The intraoperative complications were air leakage (N = 20) and stapling failure (N = 11), which were caused by stapler-tissue thickness mismatch (N = 17), stapler defect (N = 3), tissue fragility (N = 2), and unknown reasons (N = 9). In all 31 cases, intraoperative complications were recovered intraoperatively with additional suturing, and no further complications were observed postoperatively. The postoperative complications were bronchopleural fistula (BPF) (N = 4) and bleeding from the chest wall (intercostal artery) (N = 1). The rate of BPF was 0.2 % (4 of 2,030). Two of four BPFs induced critical conditions. Postoperative bleeding was caused by the use of Duet TRS(TM). Both total complications and BPF occurred more frequently in the main bronchus than in the lobar or segmental bronchus. No relationship was seen between the incidence of complications and cartridge colors in lobar bronchial stapling. The compression types of staplers were associated with the incidence of complication. CONCLUSIONS Intraoperative and postoperative complications of bronchial stapling were studied. Generally, bronchial stapling in recent thoracic surgery was safe, but rare postoperative complications may induce critical conditions. Knowledge of potential complications and causes of bronchial stapling may decrease the incidence of stapling complications.


title: Structure-activity relationship study of the tumour-targeting peptide A20FMDV2 via modification of Lys16, Leu13, and N- and/or C-terminal functionality.

text: The 20-residue linear peptide A20FMDV2 has been shown to exhibit high selectivity and affinity for the tumour-related αvβ6 integrin and has potential as a vector for therapeutic drugs. However, it exhibits poor half-life in plasma in part due to its high susceptibility to serum proteases. In this study fourteen A20FMDV2 analogues incorporating non-proteinogenic substitutes of the native Lys16 and Leu13 residues and six A20FMDV2 analogues containing modified N- and C-termini were synthesised to increase the half-life and activity of A20FMDV2. The analogues incorporating modified terminal motifs of A20FMDV2 were found to strongly bind to the αvβ6 integrin and were subsequently functionalized with the diethylenetriaminepentaacetic acid chelating agent to facilitate coupling with radioactive indium-111 for human plasma stability and in vivo biodistribution studies. A20FMDV2 peptide variants incorporating an N-terminal d-Asn and C-terminal d-Thr exhibited improved relative activity in vitro and were less susceptible to plasma degradation.


title: Clampless laparoendoscopic single-site partial nephrectomy for renal cancer with low PADUA score: technique and surgical outcomes.

text: UNLABELLED WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Laparoendoscopic single-site (LESS) surgery has proved to be immediately applicable in the clinical field, being safe and feasible in the hands of experienced laparoscopic surgeons in well-selected patients. All extirpative and reconstructive urological procedures have been described in the literature, but LESS partial nephrectomy (PN) is one of the most complex procedures and few studies have been published on this subject. The study describes a clampless technique for LESS PN, by reducing the blood pressure and increasing the intra-abdominal pressure of the pneumoperitoneum to 20 mmHg, timed to precisely coincide with excision of the tumour. This technique was found to be safe and feasible in the treatment of low-risk T1a RCC. OBJECTIVE To describe the technique and report the surgical outcomes of clampless laparoendoscopic single-site (LESS) partial nephrectomy (PN) in the treatment of renal cell carcinoma (RCC) with low PADUA score. PATIENTS AND METHODS Clampless LESS PN was performed in 14 patients with cT1a renal tumours. Indications to perform a clampless LESS PN were low-risk, laterally based renal tumours, located away from the renal hilum, with a PADUA score ≤7. Demographic data and peri-operative and postoperative variables were recorded and analysed. Kidney function was evaluated by measuring serum creatinine concentration and estimated glomerular filtration rate (eGFR) pre- and postoperatively and at 6-month follow-up. RESULTS The median operating time was 120 min and warm ischaemia time was zero in all cases. Only one early complication (Clavien grade 1) was recorded: one patient developed a flank haematoma which it was possible to treat by conservative therapy. Serum creatinine and modification of diet renal disease eGFR were not found to be significantly different pre- and postoperatively and at 6-month follow-up. Definitive pathological results showed 12 pT1a RCCs and two pT1a-chromophobe RCCs. All tumours were removed with negative surgical margins. All patients were satisfied with the cosmetic results. At a median (range) follow-up period of 12 (8-15) months, all patients were alive without evidence of tumour recurrence or port-site metastasis. CONCLUSION Clampless LESS PN is a safe and feasible surgical procedure in the treatment of low-risk T1a RCC, with excellent cosmetic results.


title: Structure of coronavirus hemagglutinin-esterase offers insight into corona and influenza virus evolution.

text: The hemagglutinin-esterases (HEs) are a family of viral envelope glycoproteins that mediate reversible attachment to O-acetylated sialic acids by acting both as lectins and as receptor-destroying enzymes (RDEs). Related HEs occur in influenza C, toro-, and coronaviruses, apparently as a result of relatively recent lateral gene transfer events. Here, we report the crystal structure of a coronavirus (CoV) HE in complex with its receptor. We show that CoV HE arose from an influenza C-like HE fusion protein (HEF). In the process, HE was transformed from a trimer into a dimer, whereas remnants of the fusion domain were adapted to establish novel monomer-monomer contacts. Whereas the structural design of the RDE-acetylesterase domain remained unaltered, the HE receptor-binding domain underwent remodeling to such extent that the ligand is now bound in opposite orientation. This is surprising, because the architecture of the HEF site was preserved in influenza A HA over a much larger evolutionary distance, a switch in receptor specificity and extensive antigenic variation notwithstanding. Apparently, HA and HEF are under more stringent selective constraints than HE, limiting their exploration of alternative binding-site topologies. We attribute the plasticity of the CoV HE receptor-binding site to evolutionary flexibility conferred by functional redundancy between HE and its companion spike protein S. Our findings offer unique insights into the structural and functional consequences of independent protein evolution after interviral gene exchange and open potential avenues to broad-spectrum antiviral drug design.


title: Implementing wildlife disease surveillance in the Netherlands, a One Health approach.

text: The surveillance of (emerging) wildlife diseases can provide important, objective evidence of the circulation of pathogens of interest for veterinary and/or public health. The involvement of multiple research institutions in wildlife disease surveillance can ensure the best use of existing knowledge and expertise, but can also complicate or add challenges to the integration of wildlife disease surveillance components into a national programme. Documenting the existing efforts in a country's surveillance of wildlife diseases, including the institutes in which it takes place, provides a basis for policy-makers and authorities to identify gaps and priorities in their current surveillance programmes. This paper describes the wildlife disease surveillance activities taking place in the Netherlands. The authors recommend that, in addition to funding these current activities, surveillance resources should be allocated with the flexibility to allow for additional targeted surveillance, to detect and adequately respond to newly introduced or emerging pathogens. Similar structured overviews of wildlife disease surveillance in other countries would be very useful to facilitate international collaboration.


title: Avian coronaviruses.

text: Coronaviruses (CoVs) mainly cause enteric and / or respiratory signs. Mammalian CoVs including COVID-19 (now officially named SARS-CoV-2) belong to either the Alphacoronavirus or Betacoronavirus genera. In birds the majority of the known CoVs belong to the Gammacoronavirus genus, whilst a small number are classified as Deltacoronaviruses. Gammacoronaviruses continue to be reported in an increasing number of avian species, generally by detection of viral RNA. Apart from infectious bronchitis virus in chickens, the only avian species in which CoV has been definitively associated with disease are the turkey, pheasant and guinea fowl. Whilst there is strong evidence for recombination between gammacoronaviruses of different avian species, and between betacoronaviruses in different mammals, evidence of recombination between coronaviruses of different genera is lacking. Furthermore, recombination of an apha or betacoronavirus with a gammacoronavirus is extremely unlikely. For recombination to happen, the 2 viruses would need to be present in the same cell of the same animal at the same time; a highly unlikely scenario as they cannot replicate in the same host!


title: Influence of Molecular Design on the Targeting Properties of ABD-Fused Mono- and Bi-Valent Anti-HER3 Affibody Therapeutic Constructs.

text: Overexpression of human epidermal growth factor receptor type 3 (HER3) is associated with tumour cell resistance to HER-targeted therapies. Monoclonal antibodies (mAbs) targeting HER3 are currently being investigated for treatment of various types of cancers. Cumulative evidence suggests that affibody molecules may be appropriate alternatives to mAbs. We previously reported a fusion construct (3A3) containing two HER3-targeting affibody molecules flanking an engineered albumin-binding domain (ABD035) included for the extension of half-life in circulation. The 3A3 fusion protein (19.7 kDa) was shown to delay tumour growth in mice bearing HER3-expressing xenografts and was equipotent to the mAb seribantumab. Here, we have designed and explored a series of novel formats of anti-HER3 affibody molecules fused to the ABD in different orientations. All constructs inhibited heregulin-induced phosphorylation in HER3-expressing BxPC-3 and DU-145 cell lines. Biodistribution studies demonstrated extended the half-life of all ABD-fused constructs, although at different levels. The capacity of our ABD-fused proteins to accumulate in HER3-expressing tumours was demonstrated in nude mice bearing BxPC-3 xenografts. Formats where the ABD was located on the C-terminus of affibody binding domains (3A, 33A, and 3A3) provided the best tumour targeting properties in vivo. Further development of these promising candidates for treatment of HER3-overexpressing tumours is therefore justified.


Universal Testing-Based Response to COVID-19 Outbreak by a Long-Term Care and Post-Acute Care Facility.


World leaders in covid-19 control.


title: Securitization of infectious diseases in Vietnam: the cases of HIV and avian influenza.

text: The frequent and swift emergence of new and devastating infectious diseases has brought renewed attention to health as an issue of international importance. Some states and regional organizations, including in Asia, have begun to regard infectious disease as a national and international security issue. This article seeks to examine the Vietnamese government's response to the epidemics of avian influenza and Human immunodeficiency virus. Both diseases have been recognized at different times as threats to international security and both are serious infectious disease problems in Vietnam. Yet, the character of the central government's response to these two epidemics has been starkly different. How and why this disparity in policy approaches occurs depends largely on the epidemiological, economic and political context in which they occur. Although epidemiological factors are frequently explored when discussing disease as a security issue, seldom are the political, social and economic characteristics of the state invoked. These dimensions, and their interaction with the epidemiology of the disease, are central to understanding which diseases are ultimately treated by states as security issues. In particular, the role of economic security as a powerful motivator for resistance to control measures and the role that local implementation of policies can have in disrupting the effect of central government policy are explored. In exploring both the outcomes of securitization, and its facilitating conditions, I suggest some preliminary observations on the potential costs and benefits of securitizing infectious disease and its utility as a mechanism for protecting health in Asia.


Silent casualty of COVID-19: Training and education.


title: As We Went to Press: The United States Responds to COVID-19.

text: Ventilators, masks, and tests are in short supply.


title: A prospective, multi-centre US clinical trial to determine accuracy of FebriDx point-of-care testing for acute upper respiratory infections with and without a confirmed fever.

text: BACKGROUND FebriDx is a 10-minute disposable point-of-care test designed to identify clinically significant systemic host immune responses and aid in the differentiation of bacterial and viral respiratory infection by simultaneously detecting C-reactive protein (CRP) and myxovirus resistance protein A (MxA) from a fingerstick blood sample. FebriDx diagnostic accuracy was evaluated in the emergency room and urgent care setting. METHODS A prospective, multicentre, observational cohort study of acute upper respiratory tract infections (URIs), with and without a confirmed fever at the time of enrolment, was performed to evaluate the diagnostic accuracy of FebriDx to identify clinically significant bacterial infection with host response and acute pathogenic viral infection. The reference method consisted of an algorithm with physician override that included bacterial cell culture, respiratory PCR panels for viral and atypical pathogens, procalcitonin, and white blood cell count. RESULTS Among 220 patients enrolled, 100% reported fever 100.5°F within the last 72 hours while 55% had a measured hyperthermia (T > 100.4) at the time of enrolment. FebriDx demonstrated a sensitivity of 95% (95% CI: 77-100%), specificity of 94% (88-98%), PPV of 76% (59-87%), and a NPV of 99% (93-100%). CONCLUSION FebriDx may identify clinically significant bacterial URI's and supports outpatient antibiotic decisions. Key messages FebriDx is an outpatient POC test designed to identify a clinically significant systemic host immune response and aid in the differentiation of viral and bacterial infection through rapid measurement of MxA and CRP from a fingerstick blood sample. FebriDx test was determined to be an accurate test, with a 85% sensitivity, 93% specificity and 97% NPV to rule out bacterial infection for any patient presenting with symptoms and reported fever within the prior 3 days, and when confirming fever (hyperthermia) at the time of testing, the test was even more sensitive (95%) and specific (94%) with a 99% NPV. FebriDx may support antibiotic stewardship by rapidly identifying clinically significant bacterial URIs.


title: Laparoscopic transperitoneal left adrenalectomy and wandering spleen risk.

text: BACKGROUND AND OBJECTIVES Laparoscopic transperitoneal left adrenalectomy (LTLA) has become the standard treatment for adrenal masses<6 cm. LTLA involves the dissection of splenic suspensory ligaments, which replicates their congenital absence or weakening, present in cases of wandering spleen (WS). WS is a rare condition in which the spleen migrates from the left upper quadrant to a more caudal location in the abdomen. A unique case of WS after LTLA was described by Corcione et al. In this prospective study, we investigated the possibility of WS as a consequence of LTLA. METHODS Twenty-four patients, 8 men and 16 women, who underwent LTLA with the dissection of splenoparietal and splenorenal ligaments were selected. RESULTS Clinical and ultrasonographic follow-up showed no evidence of postoperative WS. CONCLUSIONS In the literature, WS is not commonly reported as a postoperative complication of LTLA. In effect, especially in the case of small adrenal masses, the spleen's repositioning in its seat is autonomous. However, the alarming possibility of WS should not be ignored, especially in the case of extensive dissection of the left colic flexure. It would be useful for other authors to signal this complication, so that different approaches and consequent results may be compared.


title: Adolescent cohorts assessing growth, cardiovascular and cognitive outcomes in low and middle-income countries.

text: INTRODUCTION Life-course studies are needed to explore how exposures during adolescence, particularly puberty, contribute to later cardiovascular risk and cognitive health in low and middle-income countries (LMIC), where 90% of the world's young people live. The extent of any existing cohorts investigating these outcomes in LMIC has not previously been described. METHODS We performed a systematic literature review to identify population cohort studies of adolescents in LMIC that assessed anthropometry and any of cardiovascular risk (blood pressure, physical activity, plasma glucose/lipid profile and substance misuse), puberty (age at menarche, Tanner staging, or other form of pubertal staging) or cognitive outcomes. Studies that recruited participants on the basis of a pre-existing condition or involved less than 500 young people were excluded. FINDINGS 1829 studies were identified, and 24 cohorts fulfilled inclusion criteria based in Asia (10), Africa (6) and South / Central America (8). 14 (58%) of cohorts identified were based in one of four countries; India, Brazil, Vietnam or Ethiopia. Only 2 cohorts included a comprehensive cardiovascular assessment, tanner pubertal staging, and cognitive outcomes. CONCLUSION Improved utilisation of existing datasets and additional cohort studies of adolescents in LMIC that collect contemporaneous measures of growth, cognition, cardiovascular risk and pubertal development are needed to better understand how this period of the life course influences future non-communicable disease morbidity and cognitive outcomes.


title: Total inverse transgastric resection with transoral specimen removal.

text: BACKGROUND Laparoscopic local excision is accepted for gastrointestinal stromal tumors (GIST) and benign lesions of the stomach. Yet, tumors at the gastroesophageal junction, on the posterior wall, or in the distal antrum are difficult to approach. Such tumors often must be exposed via gastrotomy or using a rendezvous maneuver. Our method of total intragastric laparoscopic resection using 'pneumogastrum', rigid laparoscope, and conventional laparoscopic instruments is described in an intuitive video. METHODS Two cases of total inverse transgastric resection involved resection of a submucosal GIST, one at the front wall of the cardia and the other on the posterior wall of the antrum. The third case required excision of a large prepyloric cystic lesion leading to a gastric outlet stenosis. After insertion of three trocars under laparoscopic control, a further trocar was introduced into the stomach and 'pneumogastrum' was established. Two additional 5-mm trocars were intragastrally placed. Intragastric endoscopy with a rigid optic provided an excellent view. The tumor was exposed resected with a linear stapler. The specimen was inserted into an Endo Pouch™ which was sutured to an orally inserted gastric tube. The Endo Pouch™ was gently pulled transorally. After removal of the intragastric trocars, the entrance points were laparoscopically closed. RESULTS From the first and second cases, we retrieved GIST tumors. In the third case, we retrieved a gastritis cystica profunda. Postoperative course was uneventful. CONCLUSIONS Gastric GIST should be resected laparoscopically if negative margins are safely achieved regardless of its size. Tumors at the frontwall and exophytic backwall GIST are addressed by laparoscopic wedge resection. Tumors at the gastrojejunal junction, in the prepyloric region, and fundus as well as submucous GIST of the gastric backwall are best approached by intragastric laparoscopic resection. Transoral specimen retrieval is an interesting option in smaller tumors.


title: Censored Regression Modeling To Predict Virus Inactivation in Wastewaters.

text: Among the many uncertainties presented by poorly studied pathogens is possible transmission via human fecal material or wastewaters. Such worries were a documented concern during the 2013 Ebola outbreak in West Africa. Using published experimental data on virus inactivation rates in wastewater and similar matrices, we extracted data to construct a model predicting the T90 (1 × log10 inactivation measured in seconds) of a virus. Extracted data were as follows: RNA or DNA genome, enveloped or not, primary transmission pathway, temperature, pH, light levels, and matrix. From the primary details, we further determined matrix level of contamination, genus, and taxonomic family. Prior to model construction, three records were separated for verification. A censored normal regression model provided the best fit model, which predicted T90 from DNA or RNA structure, enveloped status, whether primary transmission pathway was fecal-oral, temperature, and whether contamination was low, medium, or high. Model residuals and predicted values were evaluated against observed values. Mean values of model predictions were compared to independent data and considering 95% confidence ranges (which could be quite large). A relatively simple model can predict virus inactivation rates from virus and matrix attributes, providing valuable input when formulating risk management strategies for little studied pathogens.


title: Factors in B cell competition and immunodominance.

text: The majority of all vaccines work by inducing protective antibody responses. The mechanisms by which the B cells responsible for producing protective antibodies are elicited to respond are not well understood. Interclonal B cell competition to complex antigens, particularly in germinal centers, has emerged as an important hurdle in designing effective vaccines. This review will focus on recent advances in understanding the roles of B cell precursor frequency, B cell receptor affinity for antigen, antigen avidity, and other factors that can substantially alter the outcomes of B cell responses to complex antigens. Understanding the interdependence of these fundamental factors that affect B cell responses can inform current vaccine design efforts for pathogens with complex proteins as candidate immunogens such as HIV, influenza, and coronaviruses.


title: A functional proteogenomic analysis of endometrioid and clear cell carcinomas using reverse phase protein array and mutation analysis: protein expression is histotype-specific and loss of ARID1A/BAF250a is associated with AKT phosphorylation.

text: BACKGROUND Ovarian cancer is now recognized as a number of distinct diseases primarily defined by histological subtype. Both clear cell ovarian carcinomas (CCC) and ovarian endometrioid carcinomas (EC) may arise from endometriosis and frequently harbor mutations in the ARID1A tumor suppressor gene. We studied the influence of histological subtype on protein expression with reverse phase protein array (RPPA) and assessed proteomic changes associated with ARID1A mutation/BAF250a expression in EC and CCC. METHODS Immunohistochemistry (IHC) for BAF250a expression was performed on 127 chemotherapy-naive ovarian carcinomas (33 CCC, 29 EC, and 65 high-grade serous ovarian carcinomas (HGSC)). Whole tumor lysates were prepared from frozen banked tumor samples and profiled by RPPA using 116 antibodies. ARID1A mutations were identified by exome sequencing, and PIK3CA mutations were characterized by MALDI-TOF mass spectrometry. SAM (Significance Analysis of Microarrays) was performed to determine differential protein expression by histological subtype and ARID1A mutation status. Multivariate logistic regression was used to assess the impact of ARID1A mutation status/BAF250a expression on AKT phosphorylation (pAKT). PIK3CA mutation type and PTEN expression were included in the model. BAF250a knockdown was performed in 3 clear cell lines using siRNA to ARID1A. RESULTS Marked differences in protein expression were observed that are driven by histotype. Compared to HGSC, SAM identified over 50 proteins that are differentially expressed in CCC and EC. These included PI3K/AKT pathway proteins, those regulating the cell cycle, apoptosis, transcription, and other signaling pathways including steroid hormone signaling. Multivariate models showed that tumors with loss of BAF250a expression showed significantly higher levels of AKT-Thr308 and AKT-Ser473 phosphorylation (p < 0.05). In 31 CCC cases, pAKT was similarly significantly increased in tumors with BAF250a loss on IHC. Knockdown of BAF250a by siRNA in three CCC cell lines wild type for ARID1A showed no increase in either pAKT-Thr308 or pAKT-S473 suggesting that pAKT in tumor tissues is indirectly regulated by BAF250a expression. CONCLUSIONS Proteomic assessment of CCC and EC demonstrates remarkable differences in protein expression that are dependent on histotype, thereby further characterizing these cancers. AKT phosphorylation is associated with ARID1A/BAF250a deficient tumors, however in ovarian cancers the mechanism remains to be elucidated.


European universities dismal at reporting results of clinical trials.


Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy.


title: Gastroscopic surveillance with targeted biopsies compared with random biopsies in CDH1 mutation carriers.

text: BACKGROUND : The International Gastric Cancer Linkage Consortium (IGCLC) consensus guideline advises prophylactic gastrectomy in early adulthood to prevent gastric cancer development in CDH1 germline mutation carriers; psychosocial reasons may postpone gastrectomy. We analyzed the yield of signet-ring cell carcinoma (SRCC) during surveillance gastroscopy in CDH1 mutation carriers. METHODS : A retrospective analysis on surveillance gastroscopies in CDH1 mutation carriers was performed. The yield of SRCC in both targeted and random biopsies was studied. Endoscopic (biopsy) results were compared with the histopathologic outcomes in gastrectomy specimens. RESULTS : 42 CDH1 mutation carriers (18 men; mean age 43, range 20-82 years) underwent 96 surveillance gastroscopies. SRCC lesions were identified on surveillance gastroscopy in 21 patients (50 %), by either targeted biopsies only (n = 11), random biopsies only (n = 3), or both random and targeted biopsies (n = 7). SRCC was detected in 41 /377 targeted biopsies (11 %), whereas random biopsies revealed SRCC in 14/1563 biopsies (0.9 %). At least one SRCC lesion was found in 26 of 30 gastrectomy specimens. In 18 of these 26 specimens (69 %), SRCC had been identified by endoscopic biopsies. Missed lesions were all small superficial SRCC foci, mainly in the body of the stomach. CONCLUSION : In our cohort of CDH1 mutation carriers, SRCC lesions were identified by an extensive endoscopic surveillance protocol in 69 % of SRCC-positive patients who underwent a gastric resection. The low number of SRCC detected through random sampling demands a critical reappraisal of random biopsy sampling in the IGCLC guideline.


Cells edited with CRISPR prove safe in humans.


Pandemic influenza viruses--hoping for the road not taken.


title: A Human Long Non-Coding RNA ALT1 Controls the Cell Cycle of Vascular Endothelial Cells Via ACE2 and Cyclin D1 Pathway.

text: BACKGROUND/AIMS ALT1 is a novel long non-coding RNA derived from the alternatively spliced transcript of the deleted in lymphocytic leukemia 2 (DLEU2). To date, ALT1 biological roles in human vascular endothelial cells have not been reported. METHODS ALT1 was knocked down by siRNAs. Cell proliferation was analyzed by cck-8. The existence and sequence of human ALT1 were identified by 3' rapid amplification of cDNA ends. The interaction between lncRNA and proteins was analyzed by RNA-Protein pull down assay, RNA immunoprecipitation, and mass spectrometry analysis. RESULTS ALT1 was expressed in human umbilical vein endothelial cells (HUVECs). The expression of ALT1 was significantly downregulated in contact-inhibited HUVECs and in hypoxia-induced, growth-arrested HUVECs. Knocking down of ALT1 inhibited the proliferation of HUVECs by G0/G1 cell cycle arrest. We observed that angiotensin converting enzyme Ⅱ(ACE2) was a direct target gene of ALT1. Knocking-down of ALT1 or its target gene ACE2 could efficiently decrease the expression of cyclin D1 via the enhanced ubiquitination and degradation, in which HIF-1α and protein von Hippel-Lindau (pVHL) might be involved. CONCLUSION The results suggested the human long non-coding RNA ALT1 is a novel regulator for cell cycle of HUVECs via ACE2 and cyclin D1 pathway.


title: Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture.

text: Coronaviruses can cause respiratory and enteric disease in a wide variety of human and animal hosts. The 2003 outbreak of severe acute respiratory syndrome (SARS) first demonstrated the potentially lethal consequences of zoonotic coronavirus infections in humans. In 2012, a similar previously unknown coronavirus emerged, Middle East respiratory syndrome coronavirus (MERS-CoV), thus far causing over 650 laboratory-confirmed infections, with an unexplained steep rise in the number of cases being recorded over recent months. The human MERS fatality rate of ∼ 30% is alarmingly high, even though many deaths were associated with underlying medical conditions. Registered therapeutics for the treatment of coronavirus infections are not available. Moreover, the pace of drug development and registration for human use is generally incompatible with strategies to combat emerging infectious diseases. Therefore, we have screened a library of 348 FDA-approved drugs for anti-MERS-CoV activity in cell culture. If such compounds proved sufficiently potent, their efficacy might be directly assessed in MERS patients. We identified four compounds (chloroquine, chlorpromazine, loperamide, and lopinavir) inhibiting MERS-CoV replication in the low-micromolar range (50% effective concentrations [EC(50)s], 3 to 8 μM). Moreover, these compounds also inhibit the replication of SARS coronavirus and human coronavirus 229E. Although their protective activity (alone or in combination) remains to be assessed in animal models, our findings may offer a starting point for treatment of patients infected with zoonotic coronaviruses like MERS-CoV. Although they may not necessarily reduce viral replication to very low levels, a moderate viral load reduction may create a window during which to mount a protective immune response.


title: Trach tubes designed to maximize safety may increase risk to ventilated patients.

text: Dual-cannulae tracheostomy tubes with low-pressure cuffs, such as the Shiley LPC, are widely regarded as inherently safer than single lumen tubes with low-volume cuffs. For the patient who undergoes tracheostomy for failure to wean from mechanical ventilation, however, the insertion of a tube that occupies a large amount of space within the trachea can delay subsequent efforts to liberate him from the ventilator. With an aim to promote more timely rehabilitation of ventilated patients, London Ontario's University Hospital has been inserting the Bivona TTS, a single lumen tube with an elastic cuff, during tracheostomy. This allows caregivers to better exploit the benefits of a functional upper airway early during the weaning process, which may reduce complications associated with prolonged mechanical ventilation. We urge clinical studies to determine how the choice of initial tracheostomy tube can affect rehabilitation strategies and important patient outcomes.


title: Multifaceted Pharmacist-led Interventions in the Hospital Setting: A Systematic Review.

text: Clinical pharmacy services often comprise complex interventions. In this MiniReview, we conducted a systematic review aiming to evaluate the impact of multifaceted pharmacist-led interventions in a hospital setting. We searched MEDLINE, Embase, Cochrane Library and CINAHL for peer-reviewed articles published from 2006 to 1 March 2018. Controlled trials concerning hospitalized patients in any setting receiving patient-related multifaceted pharmacist-led interventions were considered. All types of outcome were accepted. Inclusion and data extraction were performed. Study characteristics were collected, and risk of bias assessment was conducted utilizing the Cochrane Risk of Bias tools. All stages were conducted by at least two independent reviewers. The review was registered in PROSPERO (CRD42017075808). A total of 11,896 publications were identified, and 28 publications were included. Of these, 17 were conducted in Europe. Six of the included publications were multi-centre studies, and 16 were randomized trials. Usual care was the comparator. Significant results on quality of medication use were reported as positive in eleven studies (n = 18; 61%) and negative in one (n = 18, 6%). Hospital visits were reduced significantly in seven studies (n = 16; 44%). Four studies (n = 12; 33%) reported a positive significant effect on either length of stay or time to revisit, and one study reported a negative effect (n = 12; 6%). All studies investigating mortality (n = 6), patient-reported outcome (n = 7) and cost-effectiveness (n = 1) showed no significant results. This MiniReview indicates that multifaceted pharmacist-led interventions in a hospital setting may improve the quality of medication use and reduce hospital visits and length of stay, while no effect was seen on mortality, patient-reported outcome and cost-effectiveness.


Calling all coronavirus researchers: keep sharing, stay open.


title: Prevention and treatment of viral diarrhea in pediatrics.

text: Diarrhea is the second largest cause of mortality worldwide in children from the perinatal period to the age of 5 years. Rotavirus has been the most commonly identified viral cause of diarrhea in children. Norovirus is now recognized as the second most common viral pathogen. Adenovirus, astrovirus and sapovirus are the other major viral causes of pediatric gastroenteritis. Strategies for prevention include basic hygiene, optimization of nutrition and, ultimately, vaccination. Two new vaccines have recently been licensed for the prevention of rotavirus, the monovalent human rotavirus vaccine (Rotarix) and the pentavalent bovine-human reassortant vaccine (RotaTeq). These vaccines have already dramatically decreased the morbidity associated with rotavirus in countries where they are widely used. Efforts to develop a norovirus vaccine face substantial hurdles. Treatment of the viral pathogens is primarily limited to symptomatic measures.


title: Bispectral index detects intraoperative cerebral ischaemia during balloon assisted cerebral aneurysm coiling.

text: Bispectral index (BIS) is a monitoring modality designed and used for monitoring depth of anaesthesia. We wish to report a case where BIS monitoring may have alerted us to a potential adverse neurological event during angiographic coiling of a cerebral aneurysm.


Covid-19 Crisis Triage - Optimizing Health Outcomes and Disability Rights.


title: Nephrectomy via ventral median celiotomy in equids.

text: OBJECTIVE To report technique for, and outcome after, nephrectomy through a ventral median celiotomy in equids. STUDY DESIGN Case series. ANIMALS Equids with unilateral renal disease (n = 6), aged 2 months to 18 years, weighing 90-434 kg. METHODS A ventral median celiotomy was used to access the left or right kidney. To facilitate surgical exposure, the small intestine was reflected towards the diaphragm using laparotomy sponges and the ascending colon was exteriorized and in some cases evacuated. The peritoneum over the affected kidney was incised and blunt dissection used to free the kidney from the retroperitoneal fat, then the renal artery, vein, and ureter were isolated and ligated. Abdominal lavage with sterile saline solution was performed before abdominal closure. RESULTS Four horses, 1 donkey, and 1 mule had unilateral nephrectomy to treat verminous nephritis (1), idiopathic hematuria (1), and ectopic ureter (4). A ventral median approach provided adequate access to the kidney in all 6 cases. Two horses had postoperative complications (peritonitis, chylous abdominal effusion) that resolved with medical therapy. No complications attributable to nephrectomy were reported by the owners upon follow-up 1-8 years after surgery. CONCLUSIONS A ventral median approach for nephrectomy can be used for unilateral nephrectomy in equids weighing up to 434 kg.