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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 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.

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

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.

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.

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.

Nerve agents are highly toxic organophosphorus compounds (OPs) that are used as chemical warfare agents. Developing a catalytic bioscavenger to efficiently detoxify nerve agents in the bloodstream of affected individuals has been recognized as an attractive approach to prevent nerve agent toxicity. However, the search for nerve agent catalysts has been hindered by the lack of efficient direct assays for nerve agent hydrolysis. In addition, authentic nerve agents are restricted and access to use for experiments by the general research community is prohibited. Herein we report development of a method that combines use of novel nerve agent model compounds possessing a thiocholine leaving group that reacts with the fluorescent thio-detection probe, BES-Thio, to afford detection of sub-micromolar amounts of nerve agent model compounds hydrolysis products. The detection sensitivity of BES-Thio assay was approximately 10 times better than the Ellman assay. This developed method is useful as a direct, sensitive screening method for evaluating OP hydrolysis efficiency from catalytic cholinesterases. When the assay was assembled in the presence of oxime, OP-inhibited cholinesterases that were able to be reactivated by specific oxime showed oxime-assisted enzyme-mediated OP hydrolysis. Therefore, this method is also useful to screen oxime analogs to identify novel agents that can reactivate OP-inhibited cholinesterases or to screen various enzymes to identify pseudo-catalytic bioscavengers that can be readily reactivated by clinically approved oximes.

The goal was to test 14 nerve agent model compounds of soman, sarin, tabun, and cyclohexyl methylphosphonofluoridate (GF) for their suitability as substitutes for true nerve agents. We wanted to know whether the model compounds would form the identical covalent adduct with human butyrylcholinesterase that is produced by reaction with true nerve agents. Nerve agent model compounds containing thiocholine or thiomethyl in place of fluorine or cyanide were synthesized as Sp and Rp stereoisomers. Purified human butyrylcholinesterase was treated with a 45-fold molar excess of nerve agent analogue at pH 7.4 for 17 h at 21 degrees C. The protein was denatured by boiling and was digested with trypsin. Aged and nonaged active site peptide adducts were quantified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry of the tryptic digest mixture. The active site peptides were isolated by HPLC and analyzed by MALDI-TOF-TOF mass spectrometry. Serine 198 of butyrylcholinesterase was covalently modified by all 14 compounds. Thiocholine was the leaving group in all compounds that had thiocholine in place of fluorine or cyanide. Thiomethyl was the leaving group in the GF thiomethyl compounds. However, sarin thiomethyl compounds released either thiomethyl or isopropyl, while soman thiomethyl compounds released either thiomethyl or pinacolyl. Thiocholine compounds reacted more rapidly with butyrylcholinesterase than thiomethyl compounds. Labeling with the model compounds resulted in aged adducts that had lost the O-alkyl group (O-ethyl for tabun, O-cyclohexyl for GF, isopropyl for sarin, and pinacolyl for soman) in addition to the thiocholine or thiomethyl group. The nerve agent model compounds containing thiocholine and the GF thiomethyl analogue were found to be suitable substitutes for true soman, sarin, tabun, and GF in terms of the adduct that they produced with human butyrylcholinesterase. However, the soman and sarin thiomethyl compounds yielded two types of adducts, one of which was thiomethyl phosphonate, a modification not found after treatment with authentic soman and sarin.

To assess the accuracy of a wrist-worn device (Watch_PAT 100) to diagnose obstructive sleep apnea in the home.Participants completed 2 overnight diagnostic studies with the test device: 1 night in the laboratory with concurrent polysomnography and 1 night in the home with only the Watch_PAT. The order of the laboratory and home study nights was random. The frequency of respiratory events on the PSG was quantified using indexes based on 2 definitions of hypopnea: the respiratory disturbance index (RDI) using American Academy of Sleep Medicine Task Force criteria for clinical research, also referred to as the Chicago criteria (RDI.C), and the Medicare guidelines (RDI.M). The Watch_PAT RDI (PAT RDI) and oxygen desaturation index (PAT ODI) were then evaluated against the polysomnography RDI.C and RDI.M, respectively, for both Watch_PAT diagnostic nights, yielding IN-LAB and HOME-LAB comparisons.Sleep laboratory affiliated with a tertiary-care academic medical center.30 patients referred with suspected OSA.N/A.The polysomnography and PAT measures were compared using the mean [2 SD] of the differences and the intra-class correlation coefficient (ICC). The receiver-operator characteristic curve was used to assess optimum sensitivity and specificity and calculate likelihood ratios. For the IN-LAB comparison, there was high concordance between RDI.C and PAT RDI (ICC = 0.88, mean difference 2.5 [18.9] events per hour); RDI.M and PAT ODI (ICC = 0.95, mean difference 1.4 [12.9] events per hour; and sleep time (ICC = 0.70, mean difference 7.0 [93.1] minutes) between the test device and PSG. For the HOME-LAB comparison, there was good concordance between RDI.C and PAT RDI (ICC = 0.72, mean difference 1.4 [30.1] events per hour) and RDI.M and PAT ODI (ICC = 0.80, mean difference 1.6 [26.4] events per hour) for the test device and PSG. Home studies were performed with no technical failures.In a population of patients suspected of having obstructive sleep apnea, the Watch_PAT can quantify an ODI that compares very well with Medicare criteria for defining respiratory events and an RDI that compares favorably with Chicago criteria for defining respiratory events. The device can be used with a low failure rate for single use in the lab and home for self-administered testing.

Objective: To assess the accuracy of a wrist-worn device (Watch_PAT100) to diagnose obstructive sleep apnea (OSA). Methods: Thirty adult subjects with and without suspected OSA simultaneously had a standard in-laboratory polysomnogram (PSG) and wore the Watch_PAT100 during a full-night recording. PSG sleep and respiratory events were scored according to standard criteria. Watch_PAT data were analyzed with an automated computerized algorithm which calculated the frequency of respiratory events per hour of actigraphy measured sleep using a combination of peripheral arterial tonometry (PAT) signal attenuation, desaturation on pulse oximetry, and changes in heart rate. This yielded a PAT apnea hypopnea index (AHI). Results: Mean age was 47.0 ^ 14.8 years, mean body mass index 31.0 ^ 7.6 kg/m 2 , mean PSG AHI 23 ^ 23.9 events per hour, and mean PAT AHI 23 ^ 15.9 events per hour. There was a significant correlation between PAT AHI and AHI by PSG (r ¼ 0:87, P , 0:001). To assess sensitivity and specificity of Watch_PAT, we constructed receiver operator characteristic curves using a variety of AHI threshold values (10, 15, 20, and 30 events per hour). Optimal combinations of sensitivity and specificity for the various thresholds were 82.6/71.4, 93.3/73.3, 90.9/84.2, and 83.3/91.7, respectively. Conclusions: The Watch_PAT is a device that can detect OSA with reasonable accuracy. Thus, the Watch_PAT may be a useful method to diagnose OSA. q 2003 Elsevier B.V. All rights reserved.

1Neisseria meningitidis carriage was compared in swab specimens of nasopharynx, tonsils, and saliva taken from 258 students. We found a higher yield in nasopharyngeal than in tonsillar swabs (32% vs. 19%, p