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SARS-CoV-2 antibody seroprevalence among health-care workers (HCW) can assess past exposure and possible immunity, which varies across different regions, populations and times. We investigated the seroprevalence among HCW in Massachusetts (a region suffering high COVID-19 mortality) at the end of first wave of the SARS-CoV-2 pandemic. All HCW at Cambridge Health Alliance were invited to participate in this cross-sectional survey in June 2020. Those who volunteered, consented and provided a blood sample were included. Dried blood specimens from finger-prick sampling collected either at home by each HCW or onsite by the study team were analyzed for anti-SARS-CoV-2 IgM and IgG to the virus’ receptor binding domain, using an enzyme-linked immunosorbent assay. IgM and IgG antibody abundance were categorized based on the number of standard deviations above the cross-reacting levels found in existing, pre-pandemic blood samples previously obtained by the Ragon Institute and analyzed by the Broad Institute (Cambridge, MA). Seroprevalence estimates were made based on ‘positive’ IgM or IgG using ‘low’ (>6 SD), ‘medium’ (>4.5 SD), and ‘high’ prevalence cutoffs (>3 SD). A total of 433 out of 5,204 eligible HCWs consented and provided samples. Participating HCWs had a lower cumulative incidence (from the start of the pandemic up to the bloodspot collections) of SARS-CoV-2 RT-PCR positivity (1.85%) compared to non-participants (3.29%). The low, medium, and high seroprevalence estimates were 8.1%, 11.3%, and 14.5%, respectively. The weighted estimates based on past PCR positivity were 13.9%, 19.4%, and 24.9%, respectively, for the entire healthcare system population after accounting for participation bias.

This project asks whether existing patterns of lobbying are replicated online. We theorize that business and professional groups will be less likely to engage in social media use and will be more likely to use social media platforms as a form of inside lobbying, building and reinforcing relationships with policymakers. In contrast, we expect that citizens’ advocacy groups will be most likely to engage in an online form of outside lobbying, using social media to inform the public and build grassroots support for their policy agendas. Using an original dataset of Twitter and Facebook posts from interest groups, we find that outside lobbying messages are more frequent than inside lobbying messages on social media across all groups. Citizens’ groups are significantly more likely to engage in social media use overall, and they are more likely to use it for both inside and outside lobbying messages than other types of groups.

This study aims to describe infectious complications in both out-of-hospital cardiac arrest (OHCA) and in-hospital cardiac arrest (IHCA) patients with sustained return of spontaneous circulation (ROSC) and to compare differences in antimicrobial treatment and outcomes between the two groups. This was a retrospective, single-center, observational study. Adult patients (≥ 18 years) with OHCA or IHCA who had sustained ROSC between December 2007 to March 2015 were included. Blood, urine, sputum, and other fluid cultures, as well as radiologic imaging, were obtained at the discretion of the treating clinical teams. 275 IHCA and 318 OHCA patients were included in the analysis. We found evidence of infection in 181 IHCA and 168 OHCA patients. Significant differences were found between the IHCA and OHCA group in terms of initial rhythm, duration of arrest (10 min vs. 20, p =

The long circulating half-life and inherently bivalent architecture of IgGs provide an ideal vehicle for presenting otherwise short-lived G-protein-coupled receptor agonists in a format that enables avidity-driven enhancement of potency. Here, we describe the site-specific conjugation of a dual agonist peptide (an oxyntomodulin variant engineered for potency and in vivo stability) to the complementarity-determining regions (CDRs) of an immunologically silent IgG4. A cysteine-containing heavy chain CDR3 variant was identified that provided clean conjugation to a bromoacetylated peptide without interference from any of the endogenous mAb cysteine residues. The resulting mAb-peptide homodimer has high potency at both target receptors (glucagon receptor, GCGR, and glucagon-like peptide 1 receptor, GLP-1R) driven by an increase in receptor avidity provided by the spatially defined presentation of the peptides. Interestingly, the avidity effects are different at the two target receptors. A single dose of the long-acting peptide conjugate robustly inhibited food intake and decreased body weight in insulin resistant diet-induced obese mice, in addition to ameliorating glucose intolerance. Inhibition of food intake and decrease in body weight was also seen in overweight cynomolgus monkeys. The weight loss resulting from dosing with the bivalently conjugated dual agonist was significantly greater than for the monomeric analog, clearly demonstrating translation of the measured in vitro avidity to in vivo pharmacology.

This paper outlines the current state of learning, the problems arising and research needed by developers and educators using Virtual Worlds as an intelligent learning environment. Artificially intelligent avatars are required for virtual on-line problem and case based learning. However, the use of AI requires supportive frameworks, models and both staff and student goals. Natural simulations and avatar interactions are all part of the learning environment but realism, student paced learning, adaptive goals, natural language interaction, feedback and assessment are active goals for the next decade of virtual education research. Postprint

Background Thiamine is a vitamin that is essential for adequate aerobic metabolism. The objective of this study was to determine if thiamine administration prior to coronary artery bypass grafting would decrease post-operative lactate levels as a measure of increased aerobic metabolism. Methods We performed a randomized, double-blind, placebo-controlled trial of patients undergoing coronary artery bypass grafting. Patients were randomized to receive either intravenous thiamine (200 mg) or placebo both immediately before and again after the surgery. Our primary endpoint was post-operative lactate levels. Additional endpoints included pyruvate dehydrogenase activity, global and cellular oxygen consumption, post-operative complications, and hospital and intensive care unit length of stay. Results Sixty-four patients were included. Thiamine levels were significantly higher in the thiamine group as compared to the placebo group immediately after surgery (1200 [683, 1200] nmol/L vs. 9 [8, 13] nmol/L, p

High-throughput screening of 66,000 compounds using competitive binding of peptides comprising the BH3 domain to anti-apoptotic Bfl-1 led to the identification of 14 validated ‘hits’ as inhibitors of Bfl-1. N-Aryl maleimide 1 was among the validated ‘hits’. A chemical library encompassing over 280 analogs of 1 was prepared following a two-step synthesis. Structure–activity studies for inhibition of Bfl-1 by analogs of N-aryl maleimide 1 revealed a preference for electron-withdrawing substituents in the N-aryl ring and hydrophilic amines appended to the maleimide core. Inhibitors of Bfl-1 are potential development candidates for anti-cancer therapeutics.

We report the solid-phase syntheses of two series of phosphonylated peptides using Fmoc-protected amino acids. The peptides corresponded to regions containing phosphonylated Ser195 in the active site of butyrylcholinesterase and Tyr411 of human serum albumin. The phosphonylated Fmoc-protected amino acids were used in solid-phase peptide synthesis to prepare the peptides. Fmoc-serine and Fmoc-tyrosine with benzyl ester protection were treated with alkyl methylphosphonic monochloridates to phosphonylate the side-chain hydroxy groups. The phosphonylated peptides were designed to mimic the protein region after exposure of the proteins to organophosphorus agents.

Dysregulated antigen receptor-mediated NF-kappaB activation can contribute to development of autoimmunity, chronic inflammation, and malignancy. A chemical biology screening strategy has identified a substituted benzimidazole that selectively inhibits antigen receptor-mediated NF-kappaB activation without blocking other NF-kappaB activation pathways. A library of analogs was synthesized and the structure-activity relationship and metabolic stability for the series is presented.

Study Objectives: Sleep disordered breathing (SDB), a cause of clinically important cardiovascular comorbidity, is often not recognized and diagnosed. An automated system that detects SDB using signals from a standard hospital monitor might provide useful information about the presence and severity of SDB without the need to evaluate the patient in a sleep laboratory and without additional hardware. The aim of this study was to examine the feasibility and accuracy of routine overnight sleep testing for SDB detection by an automated analysis system that operates by analyzing signals derived from standard hospital monitors.

Organophosphorus (OP) nerve agents are potent toxins that inhibit cholinesterases and produce a rapid and lethal cholinergic crisis. Development of protein-based therapeutics is being pursued with the goal of preventing nerve agent toxicity and protecting against the long-term side effects of these agents. The drug-metabolizing enzyme human carboxylesterase 1 (hCE1) is a candidate protein-based therapeutic because of its similarity in structure and function to the cholinesterase targets of nerve agent poisoning. However, the ability of wild-type hCE1 to process the G-type nerve agents sarin and cyclosarin has not been determined. We report the crystal structure of hCE1 in complex with the nerve agent cyclosarin. We further use stereoselective nerve agent analogs to establish that hCE1 exhibits a 1700- and 2900-fold preference for the P R enantiomers of analogs of soman and cyclosarin, respectively, and a 5-fold preference for the P S isomer of a sarin analog. Finally, we show that for enzyme inhibited by racemic mixtures of bona fide nerve agents, hCE1 spontaneously reactivates in the presence of sarin but not soman or cyclosarin. The addition of the neutral oxime 2,3-butanedione monoxime increases the rate of reactivation of hCE1 from sarin inhibition by more than 60-fold but has no effect on reactivation with the other agents examined. Taken together, these data demonstrate that hCE1 is only reactivated after inhibition with the more toxic P S isomer of sarin. These results provide important insights toward the long-term goal of designing novel forms of hCE1 to act as protein-based therapeutics for nerve agent detoxification.

Both G and V type nerve agents possess a center of chirality about phosphorus. The S(p) enantiomers are generally more potent inhibitors than their R(p) counterparts toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To develop model compounds with defined centers of chirality that mimic the target nerve agent structures, we synthesized both the S(p) and the R(p) stereoisomers of two series of G type nerve agent model compounds in enantiomerically enriched form. The two series of model compounds contained identical substituents on the phosphorus as the G type agents, except that thiomethyl (CH(3)-S-) and thiocholine [(CH(3))(3)NCH(2)CH(2)-S-] groups were used to replace the traditional nerve agent leaving groups (i.e., fluoro for GB, GF, and GD and cyano for GA). Inhibition kinetic studies of the thiomethyl- and thiocholine-substituted series of nerve agent model compounds revealed that the S(p) enantiomers of both series of compounds showed greater inhibition potency toward AChE and BChE. The level of stereoselectivity, as indicated by the ratio of the bimolecular inhibition rate constants between S(p) and R(p) enantiomers, was greatest for the GF model compounds in both series. The thiocholine analogues were much more potent than the corresponding thiomethyl analogues. With the exception of the GA model compounds, both series showed greater potency against AChE than BChE. The stereoselectivity (i.e., S(p) > R(p)), enzyme selectivity, and dynamic range of inhibition potency contributed from these two series of compounds suggest that the combined application of these model compounds will provide useful research tools for understanding interactions of nerve agents with cholinesterase and other enzymes involved in nerve agent and organophosphate pharmacology. The potential of and limitations for using these model compounds in the development of biological therapeutics against nerve agent toxicity are also discussed.

Study Objectives : Although sleep disordered breathing is thought to be common in patients with systolic heart failure, prior studies are diffi - cult to interpret due to a variety of factors including small sample sizes, referral bias to sleep laboratories among participants, lack of modern medical therapy for congestive heart failure, and the failure to use modern techniques to assess breathing such as nasal pressure. Our objective was to determine the current prevalence of sleep disordered breathing in a state-of-the-art congestive heart failure clinic. Methods : We conducted a prospective study of consecutive patients who visited our heart failure clinic to assess the prevalence of sleep apnea in all eligible patients on maximal medical therapy. We used 4-channel recording equipment and modified Chicago criteria for scor - ing respiratory events (using heart rate response as a surrogate for arousal from sleep). Results : We observed that among the 108 participants, 61% had some form of sleep disordered breathing (31% central apnea with Cheyne Stokes respiration and 30% obstructive sleep apnea). Sleep disordered breathing was significantly associated with atrial fibrillation (OR = 11.56, p = 0.02) and worse functional heart failure class (OR = 2.77, p = 0.02), after adjusting for male sex, age over 60 years, body mass index, and left ventricular ejection fraction. conclusions : We conclude that both obstructive and central sleep apnea remain common in congestive heart failure patients despite advances in medical therapy, and that the previously reported high prevalence values are unlikely to be explained by referral bias or par- ticipation bias in prior studies. These data have important clinical im- plications for practitioners providing CHF therapy.

Design patterns are supposed to be the well documented, tried and tested solutions to recurrent problems. Current evaluation techniques do not provide a demonstrable and holistic means to evaluate pattern quality. This paper introduces Pattern Report Cards an evaluation process for software design patterns that is demonstrable, measurable, and reproducible. A set of quality indicators for determining pattern quality has been identified, and a set of qualitative and quantitative evaluation techniques assembled to determine the quality of adherence to these indicators. Further, management and execution of the evaluation process is controlled by the PREMES framework. This framework describes a management cycle that facilitates the construction of bespoke evaluation systems for design patterns. Process tailoring is achieved by providing guidance over the selection and construction of the techniques used to assess pattern quality. Use of these techniques will help bolster existing evaluation processes, and lead to the improvement of design pattern evaluation techniques. Postprint

The Virtual St Andrews (ViStA) project aims to embed students within a Virtual Environment which duplicates, as near as possible, the real University’s centre, functions and social areas. The main project objectives are to allow Postgraduate Taught students, especially international students who only have one year to acculturate, work, socialize and graduate, to experience a pre-arrival orientation, meeting current and prospective students online as well as learning where designated staff and buildings are. The hypothesis that drives the research and virtual world development, is that online activities reduce acclimatisation stress and improve socialization, well being and study readiness. The project aim is to develop a Virtual World through which prospective or incoming students can learn about the University, talk to current students, seek advice and complete tasks that lead them through the orientation process. The world is growing organically through student projects and staff additions. Postprint

This study aimed to assess the accuracy of a wrist-worn device based on peripheral arterial tonometry (Watch_PAT 100) to detect residual episodes of respiratory disturbance during continuous positive airway pressure (CPAP) therapy. Concurrent polysomnography was used as the reference standard to identify sleep disordered breathing (SDB) events. The study was conducted in three sleep laboratories affiliated with tertiary care academic medical centers. Seventy patients using CPAP to treat obstructive sleep apnea for at least 3 months, following an in-laboratory titration to determine the optimal therapeutic positive airway pressure, participated in this study. Symptoms indicating suboptimal therapy were not required for participation, but self-reported adherence to CPAP therapy was necessary for inclusion. Interventions are not applicable in this study. The accuracy of the PAT-derived respiratory disturbance index (PAT RDI scored by automated algorithm) to detect residual SDB on CPAP was assessed against polysomnography (PSG) using Bland-Altman analysis, receiver-operator characteristic (ROC) curves, and likelihood ratios for increasing (LR+) and decreasing (LR-) the probability of moderate-severe SDB in the study population. Respiratory events on the PSG were quantified using standard criteria for research investigations ("Chicago criteria") to yield a PSG RDI.C. Based on the PSG results, 19% of the participants had moderate-severe SDB (PSG RDI.C>15 events per hour) on their prescribed pressure. For PAT RDI >15 events per hour, the area under the ROC curve was 0.95 (SE 0.03, p < 0.0001, 95% CI 0.89 to 1.00), the LR+ was 8.04 (95% CI 3.64-17.7), and the LR- was 0.17 (95% CI 0.05-0.62). The mean difference between the PAT RDI and PSG RDI.C was three (2SD 14.5) events per hour. Therefore, residual moderate-severe SDB on CPAP was not uncommon in a multicenter population self-reporting adherence to CPAP therapy to treat obstructive sleep apnea. The Watch_PAT device accurately identified participants with moderate-severe SDB while using CPAP in the attended setting of a sleep laboratory.