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Background: Frailty is generally a marker of worse prognosis. The impact of frailty on both in-hospital and long-term outcomes in ST-segment-elevation myocardial infarction (STEMI) patients has not been well described. Given this context, we aimed to determine the prevalence and impact of frailty on in-hospital and 1-year outcomes in STEMI patients undergoing primary percutaneous coronary intervention (pPCI). Methods: This retrospective study reviewed STEMI patients aged ≥ 65 years who underwent pPCI at 1 of the 2 pPCI-capable hospitals at Vancouver Coastal Health. A frailty index (FI) was determined using a deficit-accumulation model, with those with an FI > 0.25 being defined as frail. The primary outcome was 1-year all-cause mortality. The secondary outcomes included in-hospital all-cause mortality, a composite of adverse in-hospital outcomes (all-cause mortality, cardiogenic shock, heart failure, reinfarction, major bleeding, or stroke), and the individual components of the composite. Results: A total of 1579 patients were reviewed, of which 228 (14.4%) were determined to be frail. After multivariable adjustment, greater frailty (ie, increasing FI) was associated with increased in-hospital all-cause mortality (odds ratio [OR], 1.88; 95% confidence interval [CI], 1.50-2.35, P < 0.001), the composite adverse in-hospital outcome (OR, 1.46; 95% CI, 1.27-1.68, P < 0.001), and 1-year all-cause mortality (OR, 1.48; 95% CI, 1.10-2.00, P = 0.011). Conclusions: In a contemporary STEMI cohort of older patients receiving pPCI, 1 in 7 patients were frail, with greater frailty being independently associated with increased in-hospital and long-term adverse outcomes. These findings highlight the need for the early recognition of frailty and implementation of an interdisciplinary approach toward the management of frail STEMI patients. Résumé: Contexte: La fragilité est généralement un marqueur de mauvais pronostic. Les conséquences de la fragilité sur l’état de santé des patients hospitalisés et sur l’évolution de l’état de santé à long terme après un infarctus du myocarde avec élévation du segment ST (STEMI) ne sont pas bien établies. Nous avons donc cherché à déterminer la prévalence et les conséquences de la fragilité durant une hospitalisation et après un an chez des patients ayant eu un STEMI et devant subir une première intervention coronarienne percutanée (ICP). Méthodologie: Cette étude rétrospective visait à évaluer les patients de ≥ 65 ans ayant présenté un STEMI et ayant subi une première ICP dans l’un des deux hôpitaux de Vancouver Coastal Health capables d’effectuer une telle intervention. Un indice de fragilité a été établi à l’aide d’un modèle d’accumulation de déficit, les patients ayant un indice > 0,25 étant définis comme fragiles. Le critère d’évaluation principal était la mortalité toutes causes confondues après un an. Les critères d’évaluation secondaires comprenaient la mortalité toutes causes confondues à l’hôpital, un critère composé regroupant les résultats défavorables obtenus à l’hôpital (mortalité toutes causes confondues, choc cardiogénique, insuffisance cardiaque, nouvel infarctus, hémorragie majeure ou accident vasculaire cérébral) et les composants individuels du critère composé. Résultats: Au total, 1579 patients ont été évalués, dont 228 (14,4 %) ont été jugés fragiles. Après un ajustement à variables multiples, une plus grande fragilité (c.-à-d. une augmentation de l’indice de fragilité) était associée à une augmentation de la mortalité toutes causes confondues à l’hôpital (rapport de cote [RC] : 1,88; intervalle de confiance [IC] à 95 % : 1,50 à 2,35; p < 0,001), à des résultats défavorables obtenus à l’hôpital selon le critère composé (RC : 1,46; IC à 95 % : 1,27 à 1,68; p < 0,001) et à la mortalité toutes causes confondues après un an (RC : 1,48; IC à 95 % : 1,10 à 2,00; p = 0,011). Conclusions: Dans une cohorte contemporaine de patients âgés ayant présenté un STEMI et ayant subi une première ICP, un patient sur sept était fragile, une plus grande fragilité étant associée de manière indépendante à une augmentation des résultats défavorables à l’hôpital et à long terme. Ces résultats soulignent la nécessité de reconnaître rapidement la fragilité et de mettre en œuvre une approche interdisciplinaire pour prendre en charge les patients fragiles présentant un STEMI.

Abstract Accurate forecasts can enable more effective public health responses during seasonal influenza epidemics. For the 2021–22 and 2022–23 influenza seasons, 26 forecasting teams provided national and jurisdiction-specific probabilistic predictions of weekly confirmed influenza hospital admissions for one-to-four weeks ahead. Forecast skill is evaluated using the Weighted Interval Score (WIS), relative WIS, and coverage. Six out of 23 models outperform the baseline model across forecast weeks and locations in 2021–22 and 12 out of 18 models in 2022–23. Averaging across all forecast targets, the FluSight ensemble is the 2nd most accurate model measured by WIS in 2021–22 and the 5th most accurate in the 2022–23 season. Forecast skill and 95% coverage for the FluSight ensemble and most component models degrade over longer forecast horizons. In this work we demonstrate that while the FluSight ensemble was a robust predictor, even ensembles face challenges during periods of rapid change.

Abstract Objectives We evaluated a novel leave‐behind naloxone (LBN) program that allows Emergency Medical Services (EMS) personnel to distribute naloxone after an opioid overdose. Our objective was to explore EMS engagement and experiences with the program, as well as interest in education on addiction and harm reduction. We also assessed the acceptability of LBN programs among people who use drugs (PWUD). Methods We conducted telephone interviews with EMS personnel and residents of substance use recovery housing between February and September 2023. EMS personnel described their direct experiences with the LBN program and perceived facilitating factors and barriers to naloxone distribution. First responder interactions and support for LBN were explored with PWUD. A rapid assessment method was used to analyze the interview data. Results Eighteen of the 23 EMS participants had distributed LBN; most agreed EMS agencies should have an LBN program. Barriers included forgetting, patient acuity, patients declining, and perceived liability. Facilitators included having a clear protocol, accessible kits, and minimal documentation burden. The majority expressed interest in harm reduction education. Eight of the 11 PWUD participants reported recent involvement in an opioid overdose. The majority supported LBN and felt comfortable receiving naloxone training from EMS. Conclusion In this qualitative evaluation, we found broad support for EMS‐based naloxone distribution among EMS personnel and PWUD. We identified several modifiable barriers to the success of such programs, which should be the subject of future investigation. EMS and harm reduction communities should support the expansion of LBN programs across the United States.

Forecasts of infectious agents provide public health officials advanced warning about the intensity and timing of the spread of disease. Past work has found that accuracy and calibration of forecasts is weakest when attempting to predict an epidemic peak. Forecasts from a mechanistic model would be improved if there existed accurate information about the timing and intensity of an epidemic. We presented 3000 humans with simulated surveillance data about the number of incident hospitalizations from a current and two past seasons, and asked that they predict the peak time and intensity of the underlying epidemic. We found that in comparison to two control models, a model including human judgment produced more accurate forecasts of peak time and intensity of hospitalizations during an epidemic. Chimeric models have the potential to improve our ability to predict targets of public health interest which may in turn reduce infectious disease burden.

Abstract In this study, three generations of polymerase chain reaction (PCR) assays: (i) conventional PCR, (ii) qPCR and (iii) droplet digital PCR (ddPCR), were systematically tested for their abilities to detect non-pathogenic and pathogenic populations of Vibrio parahaemolyticus. The limit of detection (LOD) for the ddPCR was 1.1 pg/µL of purified DNA, followed by the qPCR (5.6 pg/µL) and the conventional PCR (8.8 pg/µL). Regarding the LOD for V. parahaemolyticus cells, the ddPCR assay was able to detect 29 cells, followed by the conventional PCR assay (58 cells) and the qPCR assay (115 cells). Regarding the sensitivities to detect this pathogen from PCR inhibition prone samples (naturally contaminated mussels), the ddPCR assay significantly outperformed the conventional PCR and qPCR. The ddPCR assay was able to consistently detect non-pathogenic and pathogenic populations of V. parahaemolyticus from naturally contaminated mussels, indicating its tolerance to various PCR inhibitors. This study also revealed the significant difference between conventional PCR and qPCR. The conventional PCR assay showed significantly greater sensitivity than that of the qPCR assay in detecting V. parahaemolyticus in crude samples, whereas the qPCR assay showed better sensitivity in detecting the presence of V. parahaemolyticus in purified DNA samples.

We devised a model to interpret discordant SARS-CoV-2 test results. We estimate that, during March 2020–May 2022, a patient in the United States who received a positive rapid antigen test result followed by a negative nucleic acid test result had only a 15.4% (95% CI 0.6%–56.7%) chance of being infected.

Abstract Communities worldwide have used vaccines and facemasks to mitigate the COVID-19 pandemic. When an individual opts to vaccinate or wear a mask, they may lower their own risk of becoming infected as well as the risk that they pose to others while infected. The first benefit–reducing susceptibility–has been established across multiple studies, while the second–reducing infectivity–is less well understood. Using a new statistical method, we estimate the efficacy of vaccines and facemasks at reducing both types of risks from contact tracing data collected in an urban setting. We find that vaccination reduced the risk of onward transmission by 40.7% [95% CI 25.8–53.2%] during the Delta wave and 31.0% [95% CI 19.4–40.9%] during the Omicron wave and that mask wearing reduced the risk of infection by 64.2% [95% CI 5.8–77.3%] during the Omicron wave. By harnessing commonly-collected contact tracing data, the approach can broadly provide timely and actionable estimates of intervention efficacy against a rapidly evolving pathogen.

Abstract Objective Intranasal medications have been proposed as adjuncts to out‐of‐hospital cardiac arrest (OHCA) care. We sought to quantify the effects of intranasal medication administration (INMA) in OHCA workflows. Methods We conducted separate randomized OHCA simulation trials with lay rescuers (LRs) and first responders (FRs). Participants were randomized to groups performing hands‐only cardiopulmonary resuscitation (CPR)/automated external defibrillator with or without INMA during the second analysis phase. Time to compression following the second shock (CPR2) was the primary outcome and compression quality (chest compression rate (CCR) and fraction (CCF)) was the secondary outcome. We fit linear regression models adjusted for CPR training in the LR group and service years in the FR group. Results Among LRs, INMA was associated with a significant increase in CPR2 (mean diff. 44.1 s, 95% CI: 14.9, 73.3), which persisted after adjustment (p = 0.005). We observed a significant decrease in CCR (INMA 95.1 compressions per min (cpm) vs control 104.2 cpm, mean diff. −9.1 cpm, 95% CI −16.6, −1.6) and CCF (INMA 62.4% vs control 69.8%, mean diff. −7.5%, 95% CI −12.0, −2.9). Among FRs, we found no significant CPR2 delays (mean diff. −2.1 s, 95% CI −15.9, 11.7), which persisted after adjustment (p = 0.704), or difference in quality (CCR INMA 115.5 cpm vs control 120.8 cpm, mean diff. −5.3 cpm, 95% CI −12.6, 2.0; CCF INMA 79.6% vs control 81.2% mean diff. −1.6%, 95% CI −7.4, 4.3%) Conclusions INMA in LR resuscitation was associated with diminished resuscitation performance. INMA by FR did not impede key times or quality.

Background: The Vancouver Coastal Health (VCH) ST-elevation myocardial infarction (STEMI) program aimed to increase access to primary percutaneous coronary intervention (PPCI) and reduce first-medical-contact-to-device times (FMC-DTs). We evaluated the long-term program impact on PPCI access and FMC-DT, and overall and reperfusion-specific in-hospital mortality. Methods: We analyzed all VCH STEMI patients between June 2007 and November 2019. The primary outcome was the proportion of patients receiving PPCI over 4 program implementation phases over 12 years. We also evaluated overall changes in median FMC-DT and the proportion of patients achieving guideline-mandated FMC-DT, in addition to overall and reperfusion-specific in-hospital mortality. Results: A total of 3138 of 4305 VCH STEMI patients were treated with PPCI. PPCI rates increased from 40.2% to 78.7% from 2007 to 2019 (P < 0.001). From phase 1 to 4, median FMC-DT improved from 118 to 93 minutes (percutaneous coronary intervention [PCI]-capable hospitals, P < 0.001) and from 174 to 118 minutes (non-PCI-capable hospitals, P < 0.001), with a concomitant increase in those achieving guideline-mandated FMC-DT (35.5% to 66.1%, P < 0.001). Overall in-hospital mortality was 9.0% (P = 0.20 across phases), with mortality differing significantly by reperfusion strategy (4.0% fibrinolysis, 5.7% PPCI, 30.6% no reperfusion therapy, P < 0.001). Mortality significantly decreased from phase 1 to phase 4 at non-PCI-capable centres (9.6% to 3.9%, P = 0.022) but not at PCI-capable centres (8.7% vs 9.9%, P = 0.27). Conclusions: A regional STEMI program increased the proportion of patients who received PPCI and improved reperfusion times over 12 years. Although no statistically significant decrease occurred in overall regional mortality incidence, mortality incidence was decreased for patients presenting to non-PCI-capable centres. Résumé: Contexte: Le programme sur l’infarctus du myocarde avec élévation du segment ST (STEMI) de la régie régionale de santé Vancouver Coastal Health (VCH) visait à améliorer l’accès à des interventions coronariennes percutanées primaires (ICPP) et à réduire le temps entre le premier contact médical et l’intervention. Nous avons évalué les effets à long terme du programme sur l’accès aux ICPP, sur le temps entre le premier contact médical et l’intervention, ainsi que sur le taux global de mortalité hospitalière et le taux de mortalité hospitalière lié à la reperfusion. Méthodologie: Nous avons analysé les cas de tous les patients admis au programme STEMI de la VCH entre juin 2007 et novembre 2019. Le critère d’évaluation principal était la proportion de patients recevant une ICPP pendant les 4 phases du programme, qui se sont étalées sur 12 ans. Nous avons aussi évalué la variation totale du temps médian entre le premier contact médical et l’intervention, et de la proportion de patients chez qui le temps recommandé entre le premier contact médical et l’intervention a été respecté ainsi que la variation du taux global de mortalité hospitalière et du taux de mortalité hospitalière lié à la reperfusion. Résultats: Au total, 3138 des 4305 patients du programme STEMI de la VCH ont été traités par une ICPP. Les taux d’ICPP sont passés de 40,2 % à 78,7 % entre 2007 et 2019 (p < 0,001). De la phase 1 à la phase 4 du programme, le temps médian entre le premier contact médical et l’intervention s’est amélioré, passant de 118 minutes à 93 minutes (hôpitaux en mesure d’effectuer une intervention coronarienne percutanée [ICP]; p < 0,001) et de 174 à 118 minutes (hôpitaux n’étant pas en mesure d’effectuer une ICP; p < 0,001), avec une augmentation du nombre de personnes pour qui le temps recommandé entre le premier contact médical et l’intervention a été respecté (35,5 % à 66,1 %; p < 0,001). Le taux global de mortalité hospitalière était de 9,0 % (p = 0,20 pour toutes les phases), et le taux de mortalité hospitalière lié à la reperfusion différait de manière significative selon la stratégie adoptée (fibrinolyse : 4,0 %; ICPP : 5,7 %; aucune reperfusion : 30,6 %; p < 0,001). Le taux de mortalité a diminué de manière significative entre la phase 1 et la phase 4 dans les centres qui n’étaient pas en mesure d’effectuer une ICP (9,6 % à 3,9 %; p = 0,022), mais pas dans les centres en mesure d’effectuer une ICP (8,7 % c. 9,9 %; p = 0,27). Conclusions: Le programme STEMI régional a permis d’augmenter la proportion de patients qui ont reçu une ICPP et d'améliorer les temps de reperfusion sur 12 ans. Bien qu’aucune diminution statistiquement significative n’ait été observée quant au taux global de mortalité dans la région, le taux de mortalité a diminué chez les patients se présentant dans un centre qui n’était pas en mesure d’effectuer une ICP.

We present a review of frontier research advances in the investigation of cryptic structures that transect the South American Andes at oblique strike directions. The intersections between these cryptic structures and the superimposed Andean belt correlate with the spatial distribution of gold-rich mineral deposit clusters. The deposit clusters can be described as superclusters, as they comprise various gold deposit types that formed at multiple times throughout the Phanerozoic, impinging repeatedly on the structural intersections. However, the cryptic inherited fault structures are difficult to detect, because their deeper-seated roots are often overlain by younger supracrustal successions, and/or their exposed surface manifestations are structurally obscured by subsequent tectonic-magmatic activity. Thus, it also remains a challenge to constrain the nature and timing of formation, and the respective subsequent evolutionary path, of these proposed pre-Andean structures. Based on various case studies, we demonstrate that the localization of identified Phanerozoic gold deposit superclusters along the western South American margin is fundamentally controlled by structural inheritance often dating back to at least the Mesoproterozoic. Integration of multi-approach observations and datasets allows insights into a larger-scale tectonic history that showcases the successive inheritance of major structures originating from the Amazonian Craton, over the Paleozoic Gondwana margin, into the Cenozoic magmatic belts of the Andes, and even into recent fractures within the subducting oceanic Nazca plate, recording >1.2-billion-years of progressive structural inheritance and growth at one of the longest-lived tectonic margins in Earth history. In contrast to previous models of the spatial distribution of gold deposits, based on statistical approaches and spatial periodicity in self-organized systems focusing on single subduction and/or accretion episodes and belts, we propose that the structural inheritance and intersections are key to the localization of gold deposits in the Andes. In combination with bulk-geochemical data from magmatic rocks, we suggest that inherited structures maintained a trans-lithospheric connectivity to pre-fertilized gold enriched upper mantle reservoirs, which were tapped during multiple tectono-magmatic reactivation episodes.

Abstract Accurate and precise density estimates are crucial for effective species management and conservation. However, efficient monitoring of mammal densities over large spatial and temporal scales is challenging. In the United Kingdom, published density estimates for many mammals, including species considered to be common, are imprecise. Camera trap distance sampling (CTDS) can estimate densities of multiple species at a time and has been used successfully in a small number of studies. However, CTDS has typically been used over relatively homogeneous landscapes, often over large time scales, making monitoring changes (by repeating surveys) difficult. In this study, we deployed camera traps at 109 sites across an area of 2725 km2 of varied habitat in North‐East England, United Kingdom. The 4‐month survey generated 51 447 photos of wild mammal species. Data were sufficient for us to use CTDS to estimate the densities of eight mammal species across the whole‐survey area and within four specific habitats. Both survey‐wide and habitat‐specific density estimates largely fell within previously published density ranges and our estimates were amongst the most precise produced for these species to date. Lower precision for some species was typically due to animals being missed by the camera at certain distances, highlighting the need for careful consideration of practical and methodological decisions, such as how high to set cameras and where to left‐truncate data. Although CTDS is a promising methodology for determining densities of multiple species from one survey, species‐specific decisions are still required and these cannot always be generalized across species types and locations. Taking the United Kingdom as a case study, our study highlights the potential for CTDS to be used on a national scale, although the scale of the task suggests that it would need to be integrated with a citizen science approach.

We conducted a retrospective cohort study that tested 2,000 US military personnel for Coccidioides antibodies in a disease-endemic region. The overall incidence of seroconversion was 0.5 cases/100 person-years; 12.5% of persons who seroconverted had illnesses requiring medical care. No significant association was found between demographic characteristics and seroconversion or disease.

Abstract Objective In the United States, police are often important co‐responders to 911 calls with emergency medical services for medical emergencies. To date, there remains a lack of a comprehensive understanding of the mechanisms by which police response modifies time to in‐hospital medical care for traumatically injured patients. Further, it remains unclear if differentials exist within or between communities. A scoping review was performed to identify studies evaluating prehospital transport of traumatically injured patients and the role or impact of police involvement. Methods PubMed, SCOPUS, and Criminal Justice Abstracts databases were utilized to identify articles. English‐language, US‐based, peer‐reviewed articles published on or prior to March 30, 2022 were eligible for inclusion. Results Of 19,437 articles initially identified, 70 articles were selected for full review and 17 for final inclusion. Key findings included (1) current law enforcement practices involving scene clearance introduce the potential for delayed patient transport but to date there is little research quantifying delays; (2) police transport protocols may decrease transport times; and (3) there are no studies examining the potential impact of scene clearance practices at the patient or community level. Conclusions Our results highlight that police are often the first on scene when responding to traumatic injuries and have an active role via scene clearance or, in some systems, patient transport. Despite the significant potential for impact on patient well‐being, there remains a paucity of data examining and driving current practices.

Immune function changes across the life stages; for example, senior adults exhibit a tendency towards a weaker cell-mediated immune response and a stronger inflammatory response than younger adults. This might be partly mediated by changes in oxylipin synthesis across the life course. Oxylipins are oxidation products of polyunsaturated fatty acids (PUFAs) that modulate immune function and inflammation. A number of PUFAs are precursors to oxylipins, including the essential fatty acids (EFAs) linoleic acid (LA) and α-linolenic acid (ALA). LA and ALA are also substrates for synthesis of longer chain PUFAs. Studies with stable isotopes have shown that the relative amounts of LA and ALA can influence their partitioning by T lymphocytes between conversion to longer chain PUFAs and to oxylipins. It is not known whether the relative availability of EFA substrates influences the overall pattern of oxylipin secretion by human T cells or if this changes across the life stages. To address this, the oxylipin profile was determined in supernatants from resting and mitogen activated human CD3+ T cell cultures incubated in medium containing an EFA ratio of either 5:1 or 8:1 (LA : ALA). Furthermore, oxylipin profiles in supernatants of T cells from three life stages, namely fetal (derived from umbilical cord blood), adults and seniors, treated with the 5:1 EFA ratio were determined. The extracellular oxylipin profiles were affected more by the EFA ratio than mitogen stimulation such that n-3 PUFA-derived oxylipin concentrations were higher with the 5:1 EFA ratio than the 8:1 ratio, possibly due to PUFA precursor competition for lipoxygenases. 47 oxylipin species were measured in all cell culture supernatants. Extracellular oxylipin concentrations were generally higher for fetal T cells than for T cells from adult and senior donors, although the composition of oxylipins was similar across the life stages. The contribution of oxylipins towards an immunological phenotype might be due to the capacity of T cells to synthesize oxylipins rather than the nature of the oxylipins produced.

COVID-19 has disproportionately impacted individuals depending on where they live and work, and based on their race, ethnicity, and socioeconomic status. Studies have documented catastrophic disparities at critical points throughout the pandemic, but have not yet systematically tracked their severity through time. Using anonymized hospitalization data from March 11, 2020 to June 1, 2021 and fine-grain infection hospitalization rates, we estimate the time-varying burden of COVID-19 by age group and ZIP code in Austin, Texas. During this 15-month period, we estimate an overall 23.7% (95% CrI: 22.5-24.8%) infection rate and 29.4% (95% CrI: 28.0-31.0%) case reporting rate. Individuals over 65 were less likely to be infected than younger age groups (11.2% [95% CrI: 10.3-12.0%] vs 25.1% [95% CrI: 23.7-26.4%]), but more likely to be hospitalized (1,965 per 100,000 vs 376 per 100,000) and have their infections reported (53% [95% CrI: 49-57%] vs 28% [95% CrI: 27-30%]). We used a mixed effect poisson regression model to estimate disparities in infection and reporting rates as a function of social vulnerability. We compared ZIP codes ranking in the 75th percentile of vulnerability to those in the 25th percentile, and found that the more vulnerable communities had 2.5 (95% CrI: 2.0-3.0) times the infection rate and only 70% (95% CrI: 60%-82%) the reporting rate compared to the less vulnerable communities. Inequality persisted but declined significantly over the 15-month study period. Our results suggest that further public health efforts are needed to mitigate local COVID-19 disparities and that the CDC's social vulnerability index may serve as a reliable predictor of risk on a local scale when surveillance data are limited.

In this paper, we report (η5-pentamethylcyclopentadienyl)iridium{1,3-bis(2,3,4,5,6-pentafluorobenzyl)imidazolin-2-ylidene}dichloride, 2, synthesized using a silver transfer agent generated from 1,3-bis(2,3,4,5,6-pentafluorobenzyl)imidazolium bromide. Compound 2 was characterized using 1H and 19F NMR spectroscopy and mass spectrometry, and its structure was determined in a single-crystal X-ray diffraction study.

Background: Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of ‘doctor-diagnosed asthma’, thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes. Methods: We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9568 individuals from five UK birth cohorts. Results: Forty-four independent SNPs were associated with early-onset persistent, 25 with pre-school remitting, 33 with mid-childhood remitting, and 32 with late-onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 [ANXA1], p

Rev7 is a regulatory protein with roles in translesion synthesis (TLS), double strand break (DSB) repair, replication fork protection, and cell cycle regulation. Rev7 forms a homodimer in vitro using its HORMA (Hop, Rev7, Mad2) domain; however, the functional importance of Rev7 dimerization has been incompletely understood. We analyzed the functional properties of cells expressing either wild-type mouse Rev7 or Rev7K44A/R124A/A135D, a mutant that cannot dimerize. The expression of wild-type Rev7, but not the mutant, rescued the sensitivity of Rev7−/− cells to X-rays and several alkylating agents and reversed the olaparib resistance phenotype of Rev7−/− cells. Using a novel fluorescent host-cell reactivation assay, we found that Rev7K44A/R124A/A135D is unable to promote gap-filling TLS opposite an abasic site analog. The Rev7 dimerization interface is also required for shieldin function, as both Rev7−/− cells and Rev7−/− cells expressing Rev7K44A/R124A/A135D exhibit decreased proficiency in rejoining some types of double strand breaks, as well as increased homologous recombination. Interestingly, Rev7K44A/R124A/A135D retains some function in cell cycle regulation, as it maintains an interaction with Ras-related nuclear protein (Ran) and partially rescues the formation of micronuclei. The mutant Rev7 also rescues the G2/M accumulation observed in Rev7−/− cells but does not affect progression through mitosis following nocodazole release. We conclude that while Rev7 dimerization is required for its roles in TLS, DSB repair, and regulation of the anaphase promoting complex, dimerization is at least partially dispensable for promoting mitotic spindle assembly through its interaction with Ran.

A microgrid is a proven effective way to integrate renewable resources. This study presents an innovative control concept for decentralized AC microgrids, which is based on the architectural advantage of a radial microgrid structure. Under the proposed concept, power sharing between the distributed sources is achieved without droop control. Thus the need for a secondary control level is eliminated. Moreover, the use of explicit communication is replaced in the paper by a novel coordination mechanism based on the locally measured currents. The paper shows that, with a special design of the current control of grid-feeding converters, the proposed microgrid automatically provides equitable sharing of the load demand amongst the distributed generators (DGs). Moreover, the dynamic responses of the DGs are identical and decoupled from one another. It is further shown that the proposed AC microgrid is stable in the presence of any type of load. The findings of the paper are validated by simulations and laboratory experiments.

This paper proposes a novel and robust version of Model Predictive Control scheme for AC drives based on Voltage Source Inverter (VSI) with Active Front End (AFE). The main feature of the proposed MPC is elimination of Common Mode Voltage (CMV) without imposing a penalty on the corresponding term in the cost function, but rather by a smart utilisation of the restricted set of switching states in a computationally efficient algorithm. Furthermore, the paper proposes to split the conventional MPC scheme into separate Control and Modulation stages, and to enhance the Control stage by integral action, and the Modulation stage - by a Feedback Quantizer. The resulting AC drive scheme provides high tracking accuracy over the full speed range, robustness to disturbances and parameters error, coupled with practically zero CMV and consequently - very low levels of conducted and radiated electromagnetic interference (EMI). This makes the proposed scheme a competitive alternative to the existing AC drive solutions in the most challenging industrial applications. The benefits of the proposed scheme are validated by simulation and experiment.

In this paper, we report on the crystal structure of salt 1-(4-bromo-2,3,5,6-tetrafluorophenyl)-3-(3-phenylbenzyl)-4-methylimidazolium bromide, 3, synthesized by the sequential nucleophilic attack of 4-methylimidazole on bromopentafluorobenzene and then 3-phenylbenzyl bromide. The salt was characterized by 1H, 13C, and 19F NMR spectroscopy and mass spectrometry.

Vaccinating children against COVID-19 is critical as a public health strategy in order to reach herd immunity and prevent illness among children and adults. The aim of the study was to identify correlation between willingness to vaccinate children under 12 years old, and vaccination rate for adult population in Canada, the United States, and Israel. This was a secondary analysis of a cross-sectional survey study (COVID-19 Parental Attitude Study) of parents of children 12 years and younger presenting to 12 pediatric emergency departments (EDs). Parental reports of willingness to vaccinate against COVID-19 when vaccines for children will be approved was correlated to country-specific rate of vaccination during December 2020–March 2021, obtained from ourworldindata.org. Logistic regression models were fit with covariates for week and the corresponding vaccine rate. A total of 720 surveys were analyzed. In Canada, administering mostly first dose to the adult population, willingness to vaccinate children was trending downward (correlation = −0.28), in the United States, it was trending upwards (correlation = 0.21) and in Israel, initially significant increase with decline shortly thereafter (correlation = 0.06). Odds of willingness to vaccinate in Canada, the United States, and Israel was OR = 0.82, 95% CI = 0.63–1.07, OR = 1.24, 95% CI = 0.99–1.56, and OR = 1.03, 95% CI = 0.95–1.12, respectively. A robust population-based vaccination program as in Israel, and to a lesser degree the United States, led to increasing willingness by parents to vaccinate their children younger than 12 years against COVID-19. In Canada, slow rate of vaccination of the adult population was associated with lower willingness to vaccinate children.

IntroductionImmune function changes across the life course; the fetal immune system is characterised by tolerance while that of seniors is less able to respond effectively to antigens and is more pro-inflammatory than in younger adults. Lipids are involved centrally in immune function but there is limited information about how T cell lipid metabolism changes during the life course.Methods and ResultsWe investigated whether life stage alters fatty acid composition, lipid droplet content and α-linolenic acid (18:3ω-3) metabolism in human fetal CD3+ T lymphocytes and in CD3+ T lymphocytes from adults (median 41 years) and seniors (median 70 years). Quiescent fetal T cells had higher saturated (SFA), monounsaturated fatty acid (MUFA), and ω-6 polyunsaturated fatty acid (PUFA) contents than adults or seniors. Activation-induced changes in fatty acid composition differed between life stages. The principal metabolic fates of [13C]18:3ω-3 were constitutive hydroxyoctadecatrienoic acid synthesis and β-oxidation and carbon recycling into SFA and MUFA. These processes declined progressively across the life course. Longer chain ω-3 PUFA synthesis was a relatively minor metabolic fate of 18:3ω-3 at all life stages. Fetal and adult T lymphocytes had similar lipid droplet contents, which were lower than in T cells from seniors. Variation in the lipid droplet content of adult T cells accounted for 62% of the variation in mitogen-induced CD69 expression, but there was no significant relationship in fetal cells or lymphocytes from seniors.DiscussionTogether these findings show that fatty acid metabolism in human T lymphocytes changes across the life course in a manner that may facilitate the adaptation of immune function to different life stages.

Abstract Background/aims Despite evidence that preferential use of balanced/buffered fluids may improve outcomes compared with chloride-rich 0.9% saline, saline remains the most commonly used fluid for children with septic shock. We aim to determine if resuscitation with balanced/buffered fluids as part of usual care will improve outcomes, in part through reduced kidney injury and without an increase in adverse effects, compared to 0.9% saline for children with septic shock. Methods The Pragmatic Pediatric Trial of Balanced versus Normal Saline Fluid in Sepsis (PRoMPT BOLUS) study is an international, open-label pragmatic interventional trial being conducted at > 40 sites in the USA, Canada, and Australia/New Zealand starting on August 25, 2020, and continuing for 5 years. Children > 6 months to

Abstract The roles of endothelial nitric oxide synthase (eNOS) in the ventilatory responses during and after a hypercapnic gas challenge (HCC, 5% CO2, 21% O2, 74% N2) were assessed in freely-moving female and male wild-type (WT) C57BL6 mice and eNOS knock-out (eNOS-/-) mice of C57BL6 background using whole body plethysmography. HCC elicited an array of ventilatory responses that were similar in male and female WT mice, such as increases in breathing frequency (with falls in inspiratory and expiratory times), and increases in tidal volume, minute ventilation, peak inspiratory and expiratory flows, and inspiratory and expiratory drives. eNOS-/- male mice had smaller increases in minute ventilation, peak inspiratory flow and inspiratory drive, and smaller decreases in inspiratory time than WT males. Ventilatory responses in female eNOS-/- mice were similar to those in female WT mice. The ventilatory excitatory phase upon return to room-air was similar in both male and female WT mice. However, the post-HCC increases in frequency of breathing (with decreases in inspiratory times), and increases in tidal volume, minute ventilation, inspiratory drive (i.e., tidal volume/inspiratory time) and expiratory drive (i.e., tidal volume/expiratory time), and peak inspiratory and expiratory flows in male eNOS-/- mice were smaller than in male WT mice. In contrast, the post-HCC responses in female eNOS-/- mice were equal to those of the female WT mice. These findings provide the first evidence that the loss of eNOS affects the ventilatory responses during and after HCC in male C57BL6 mice, whereas female C57BL6 mice can compensate for the loss of eNOS, at least in respect to triggering ventilatory responses to HCC.

Leslie Citrome,1 Christine Graham,2 Adam Simmons,2 Ying Jiang,2 Mark S Todtenkopf,2 Bernard Silverman,2 Lauren DiPetrillo,2 Hannah Cummings,2 Lei Sun,2 David McDonnell3 1Department of Psychiatry and Behavioral Sciences, New York Medical College, Valhalla, NY, USA; 2Alkermes, Inc., Waltham, MA, USA; 3Alkermes Pharma Ireland Limited, Dublin, IrelandCorrespondence: Leslie Citrome 11 Medical Park Drive, Suite 102, Pomona, NY, 10970, USATel +1-845-362-2081Email citrome@cnsconsultant.comAbstract: Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is limited by the risk of significant weight gain and metabolic effects. OLZ/SAM, a combination of olanzapine and samidorphan, was recently approved in the United States for the treatment of adults with schizophrenia or BD-I. OLZ/SAM provides the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data characterizing pharmacokinetics, antipsychotic efficacy, weight mitigation efficacy, safety, and long-term treatment effects. In an acute exacerbation of schizophrenia, OLZ/SAM and olanzapine provided similar symptom improvements versus placebo at week 4. In stable outpatients with schizophrenia, OLZ/SAM treatment resulted in significantly less weight gain, reducing the risk for clinically significant weight gain and waist circumference increases of ≥ 5 cm by half, compared with olanzapine at week 24. Based on open-label extension studies, OLZ/SAM is safe and well tolerated for up to 3.5 years of treatment, while maintaining schizophrenia symptom control and stabilizing weight. The olanzapine component of OLZ/SAM was bioequivalent to branded olanzapine (Zyprexa); adjunctive OLZ/SAM had no clinically significant effects on lithium or valproate pharmacokinetics. Additionally, OLZ/SAM had no clinically relevant effect on electrocardiogram parameters in a dedicated thorough QT study. Overall, safety and tolerability findings from clinical studies with OLZ/SAM indicate a similar safety profile to that of olanzapine, with the exception of less weight gain. As OLZ/SAM contains the opioid antagonist samidorphan, it is contraindicated in patients using opioids and in those undergoing acute opioid withdrawal. Clinical trial results from more than 1600 subjects support the use of OLZ/SAM as a new treatment option for patients with schizophrenia or BD-I.Keywords: antipsychotic agents, clinical efficacy, olanzapine, opioid antagonists, safety, weight gain

Abstract Decreases in arterial blood oxygen stimulate increases in minute ventilation via activation of peripheral and central respiratory structures. This study evaluates the role of endothelial nitric oxide synthase (eNOS) in the expression of the ventilatory responses during and following a hypoxic gas challenge (HXC, 10% O2, 90% N2) in freely moving male and female wild-type (WT) C57BL6 and eNOS knock-out (eNOS–/–) mice. Exposure to HXC caused an array of responses (of similar magnitude and duration) in both male and female WT mice such as, rapid increases in frequency of breathing, tidal volume, minute ventilation and peak inspiratory and expiratory flows, that were subject to pronounced roll-off. The responses to HXC in male eNOS–/– mice were similar to male WT mice. In contrast, several of the ventilatory responses in female eNOS–/– mice (e.g., frequency of breathing, and expiratory drive) were greater compared to female WT mice. Upon return to room-air, male and female WT mice showed similar excitatory ventilatory responses (i.e., short-term potentiation phase). These responses were markedly reduced in male eNOS–/– mice, whereas female eNOS–/– mice displayed robust post-HXC responses that were similar to those in female WT mice. Our data demonstrates that eNOS plays important roles in (1) ventilatory responses to HXC in female compared to male C57BL6 mice; and (2) expression of post-HXC responses in male, but not female C57BL6 mice. These data support existing evidence that sex, and the functional roles of specific proteins (e.g., eNOS) have profound influences on ventilatory processes, including the responses to HXC.

Abstract In light of global biodiversity loss, there is an increasing need for large‐scale wildlife monitoring. This is difficult for mammals, since they can be elusive and nocturnal. In the United Kingdom, there is a lack of systematic, widespread mammal monitoring, and a recognized deficiency of data. Innovative new approaches are required. We developed MammalWeb, a portal to enable UK‐wide camera trapping by a network of citizen scientists and partner organizations. MammalWeb citizen scientists contribute to both the collection and classification of camera trap data. Following trials in 2013–2017, MammalWeb has grown organically to increase its geographic reach (e.g. ∼2000 sites in Britain). It has so far provided the equivalent of over 340 camera trap‐years of wild mammal monitoring, and produced nearly 440,000 classified image sequences and videos, of which, over 180,000 are mammal detections. We describe MammalWeb, its background, its development and the novel approaches we have for participation. We consider the data collected by MammalWeb participants, especially in light of their relevance to the main goals of wildlife monitoring: to provide spatial data, abundance data and temporal behavioural data. MammalWeb can complement existing approaches to mammal monitoring. Explicit accounting for spatial and temporal patterns in animal activity enables accounting of bias relative to ad hoc observational data. Estimating abundance presents challenges, as for many camera‐trapping studies, but we discuss the potential of the data as they stand, and opportunities to advance their value for abundance estimation. Challenges remain to MammalWeb's central missions of enhancing engagement with and connection to nature, and delivering policy‐relevant data on Britain's wild mammals. We discuss these challenges and the opportunities they provide for advances in respect of engagement, science and financial security. Our approach reduces administrative burden and increases spatial coverage and, as such, MammalWeb provides a useful addition to existing case studies of citizen science camera‐trapping program design. We believe MammalWeb is an important step towards fulfilling calls for UK‐wide mammal monitoring and our description of challenges identifies an agenda for fulfilling that purpose.

Abstract Outbreaks of disease at the wildlife–livestock interface may require management interventions. Where they involve exotic/non‐endemic pathogens in wildlife, then such plans may need to be rapidly conceived and implemented to prevent further disease spread. However, detailed information on the distribution of infection is likely to be absent, whilst limited resources and tools, and ethical considerations impose constraints on what is possible and proportionate. We describe four considerations to inform decision‐making on whether to intervene. With reference to two recent examples (bovine tuberculosis in badgers in an otherwise disease‐free area, and African swine fever in wild boar in central Europe), we outline six steps to guide implementation. In both examples, a Disease Control Area was defined by determining a minimum infected area (MIA) and a buffer zone based on wildlife ecology and the potential for unrecorded spread of infection. The total area was the subject of management intervention, with the level of infection used to inform adaptive management. The MIA is defined as the minimum area that could contain all infected wildlife, given our current level of information, with a surrounding buffer zone to account for the possibility of further onward spread. In our examples, the zones were defined using a combination of field data and existing knowledge of host spatial organization and movement. The MIA (plus buffer zone) approach provides a framework for optimizing the targeting of resources in a proportionate response to a disease outbreak. Where infected animals occur outside the MIA, our examples show how wildlife management has been adapted. In principle, this approach is suitable for the delivery of disease outbreak control in wildlife, whether through culling, vaccination or other forms of control.

Background Cardiac intensive care units were originally created in the prerevascularization era for the early recognition of ventricular arrhythmias following a myocardial infarction. Many patients with stable ST‐segment–elevation myocardial infarction (STEMI) are still routinely triaged to cardiac intensive care units after a primary percutaneous coronary intervention (pPCI), independent of clinical risk or the provision of critical care therapies. The aim of this study was to determine factors associated with in‐hospital adverse events in a hemodynamically stable, postreperfusion population of patients with STEMI. Methods and Results Between April 2012 and November 2019, 2101 consecutive patients with STEMI who received pPCI in the Vancouver Coastal Health Authority were evaluated. Patients were stratified into those with and without subsequent adverse events, which were defined as cardiogenic shock, in‐hospital cardiac arrest, stroke, re‐infarction, and death. Multivariable logistic regression models were used to determine predictors of adverse events. After excluding patients presenting with cardiac arrest, cardiogenic shock, or heart failure, the final analysis cohort comprised 1770 stable patients with STEMI who had received pPCI. A total of 94 (5.3%) patients developed at least one adverse event: cardiogenic shock 55 (3.1%), in‐hospital cardiac arrest 42 (2.4%), death 28 (1.6%), stroke 21 (1.2%), and re‐infarction 5 (0.3%). Univariable predictors of adverse events were older age, female sex, prior stroke, chronic kidney disease, and atrial fibrillation. There was no significant difference in reperfusion times between those with and without adverse events. Following multivariable adjustment, moderate to severe chronic kidney disease (creatinine clearance

Background: Major bleeding (MB) is an independent predictor of mortality among ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI). Prevention of access-site MB has received significant attention. However, limited data have been obtained on the influence of access-site MB vs non-access-site MB and association with subsequent adverse in-hospital outcomes in the STEMI population undergoing pPCI. Methods: We identified 1494 STEMI patients who underwent pPCI between 2012 and 2018. Unadjusted and adjusted differences among patients with no MB, access-site MB, non-access-site MB, and in-hospital clinical outcomes were assessed. The use of bleeding-avoidance strategies and their effects on MB were also evaluated. Results: MB occurred in 121 (8.1%) patients. Access-site MB occurred in 34 (2.3%) patients, and non-access-site MB occurred in 87 (5.8%). The median reduction in hemoglobin was 31 g/L (interquartile range: 19-43) with access-site MB, and 44 g/L (interquartile range: 29-62) with non-access-site MB. After multivariable adjustment, non-access-site MB was independently associated with in-hospital death (adjusted odds ratio [aOR] 4.21; 95% confidence interval [CI] 2.04-8.68), cardiogenic shock (aOR 10.91; 95% CI 5.67-20.98), and cardiac arrest (aOR 5.63; 95% CI 2.88-11.01). Conversely, access-site MB was not associated with adverse in-hospital outcomes. Bleeding-avoidance strategies were used frequently; however, after multivariable adjustment, no single bleeding-avoidance strategy was significantly associated with reduced MB. Conclusions: In STEMI patients undergoing pPCI, non-access-site MB was independently associated with adverse in-hospital outcomes, whereas access-site MB was not. Additional study of strategies to reduce the incidence and impact of non-access-site MB appears to be warranted. Résumé: Contexte: Le saignement majeur (SM) est un facteur prédictif indépendant de la mortalité chez les patients ayant eu un infarctus du myocarde avec élévation du segment ST (STEMI) qui subissent une intervention coronarienne percutanée primaire (ICPp). La prévention du SM lié à l'accès vasculaire a fait l'objet de nombreuses études. Toutefois, rares sont les données sur l'influence du SM lié à l'accès vasculaire par rapport au SM non lié à cet élément et sur son association avec des résultats indésirables intrahospitaliers subséquents chez des patients ayant subi une ICPp après un STEMI. Méthodologie: Nous avons répertorié 1 494 patients ayant subi une ICPp après un STEMI entre 2012 et 2018. Nous avons évalué les différences non ajustées et ajustées entre les cas sans SM, les cas de SM liés à l'accès vasculaire et les cas de SM non liés à l'accès vasculaire, et les résultats cliniques intrahospitaliers. L'utilisation de stratégies d'évitement des saignements et leurs effets sur le SM ont également été évalués. Résultats: Un SM a été observé chez 121 (8,1 %) patients. Le SM lié à l'accès vasculaire touchait 34 (2,3 %) patients, et le SM non lié à l'accès vasculaire 87 (5,8 %) patients. La réduction médiane du taux d'hémoglobine était de 31 g/L (intervalle interquartile : 19 à 43) dans le cas du SM lié à l'accès vasculaire, et de 44 g/L (intervalle interquartile : 29 à 62) pour le SM non lié à l'accès vasculaire. Après ajustement multivarié, une association indépendante a été observée entre le SM non lié à l'accès vasculaire et le décès (rapport de cotes ajusté [RRa] 4,21; intervalle de confiance [IC] à 95 % : de 2,04 à 8,68), le choc cardiogénique (RRa 10,91; IC à 95 % : de 5,67 à 20,98), et l'arrêt cardiaque (RRa 5,63; IC à 95 % : de 2,88 à 11,01) intrahospitaliers. Inversement, le SM lié à l'accès vasculaire n'était associé à aucun résultat indésirable intrahospitalier. Les stratégies d'évitement des saignements avaient été utilisées fréquemment; toutefois, après ajustement multivarié, aucune stratégie particulière d'évitement des saignements n'était associée de façon significative à une réduction du SM. Conclusions: Chez les patients subissant une ICPp après un STEMI, le SM non lié à l'accès vasculaire était associé de façon indépendante aux résultats indésirables intrahospitaliers, alors que le SM lié à l'accès vasculaire ne l'était pas. La poursuite des recherches sur les stratégies permettant de réduire l'incidence et les conséquences du SM non lié à l'accès vasculaire semble donc justifiée.

The coronavirus disease 2019 (COVID-19) pandemic has taken an unprecedented global toll and vaccination is needed to restore healthy living. Timely inclusion of children in vaccination trials is critical. We surveyed caregivers of children seeking care in 17 Emergency Departments (ED) across 6 countries during the peak of the pandemic to identify factors associated with intent to participate in COVID-19 vaccine trials. Questions about child and parent characteristics, COVID-19 expressed concerns and parental attitudes toward participation in a trial were asked. Of 2768 completed surveys, 18.4% parents stated they would enroll their child in a clinical trial for a COVID-19 vaccine and 14.4% would agree to a randomized placebo-controlled study. Factors associated with willingness to participate were parents agreeing to enroll in a COVID-19 vaccine trial themselves (Odds Ratio (OR) 32.9, 95% Confidence Interval (CI) (21.9–51.2)) having an older child (OR 1.0 (1.0–1.01)), having children who received all vaccinations based on their country schedule (OR 2.67 (1.35–5.71)) and parents with high school education or lower (OR 1.79 (1.18–2.74)). Mothers were less likely to enroll their child in a trial (OR 0.68 (0.47–0.97)). Only one fifth of families surveyed will consider enrolling their child in a vaccine trial. Parental interest in participation, history of vaccinating their child, and the child being older all are associated with parents allowing their child to participate in a COVID vaccine trial. This information may help decision-makers and researchers shape their strategies for trial design and participation engagement in upcoming COVID19 vaccination trials.

Despite numerous applications of physically-based models for incised landscapes, their applicability for overland flow on unchanneled surfaces is not known. This work challenges a widely used landscape evolution model for the case of non-uniform rainfall and absence of rills using laboratory flume experiment. Rainfall with an average intensity of 85 mm h−1 was applied for 16 h during which high resolution laser scans of the morphology were captured. The overland flow was modeled as a network that preserves the water flux for each cell in the discretized domain. This network represented the gravity-driven surface flow and determined the evolution direction. The model was calibrated using the first 8 h of the experiment and was then used to predict the second 8 h. The calibrated model predicted, as expected, a smoother surface morphology (and less detailed overland flow network) than that measured. This difference resulted from quenched randomness (e.g., small pebbles) within the experimental soil that emerged during erosion and that were captured by the laser scans. To investigate the quality of the prediction, a low-pass filter was applied to remove the small-scale variability of the surface morphology. This step confirmed that the model simulations captured the main characteristics of the measured morphology. The experimental results were found to satisfy a scaling relation for the exceedance probability of discharge even in absence of rills. However, the model did not reproduce the experimental scaling relation as the detailed surface micro-roughness was not accounted for by the model. A lower cutoff on the scale of applicability of the general landscape evolution equation is thus suggested, complementing other work on the upper cutoff underpinned by runoff-producing areas.

Abstract Study Objectives Timely coronary reperfusion is critical for favorable outcomes after ST‐elevation myocardial infarction (STEMI). A substantial proportion of the total ischemic time is patient related, occurring before first medical contact (FMC). We aimed to expand the limited current understanding of the associations between prehospital intervals and clinical outcomes. Methods We conducted a retrospective analysis of consecutive STEMI patients who underwent primary percutaneous coronary intervention (pPCI) (January 2009–March 2016) and assessed the associations between prehospital intervals and the incidence of new heart failure, cardiogenic shock, and hospital length of stay (LOS), adjusting for important clinical variables. Results A total of 773 patients (77% men, median age 65 years) met eligibility criteria. The median pre‐911 activation interval was 29 minutes (interquartile range: 11, 89); the median 911 call to FMC interval was 12 minutes (interquartile range: 9, 15). In multivariable analysis, there was a V‐shaped relationship between the pre‐911 activation interval and outcomes: a lower likelihood of new heart failure (odds ratio [OR] 0.51; 95% confidence interval [CI]: 0.30, 0.87), cardiogenic shock (OR 0.40; 95% CI: 0.21, 0.75) and prolonged LOS (OR 0.24; 95% CI: 0.14, 0.42) for midrange intervals (11–88 minutes) when compared to the early (

In the search for efficient non-permanent magnet variable-speed wind generator solutions, this paper proposes a maximum power point tracking (MPPT) current-control method for a wound rotor synchronous wind generator. The focus is on direct-drive, medium-speed wind generators. In the proposed method, the currents of the wound rotor synchronous generator (WRSG) are optimally adjusted according to the generator speed to ensure maximum power generation from the wind turbine without needing information on wind speed. The design, modeling, and simulation of the MPPT current controllers are done in Matlab/Simulink with the WRSG in the synchronous reference frame. The controller is put to the test using different wind speed profiles between cut-in and rated speeds. The simulation results indicate that the proposed current control method is simple, effective, and robust, suggesting its practical implementation. To validate the simulation results, experimental work on a 4.2 kW WRSG prototype system is presented to demonstrate the stability and robustness of the MPPT current control method in operating the turbine at or near the maximum power point.

Ribosome assembly is a complex fundamental cellular process that involves assembling multiple ribosomal proteins and several ribosomal RNA species in a highly coordinated yet flexible and resilient manner. The highly conserved YbeY protein is a single-strand specific endoribonuclease, important for ribosome assembly, 16S rRNA processing, and ribosome quality control. In Escherichia coli, ybeY deletion results in pleiotropic phenotypes including slow growth, temperature sensitivity, accumulation of precursors of 16S rRNA, and impaired formation of fully assembled 70S subunits. Era, an essential highly conserved GTPase protein, interacts with many ribosomal proteins, and its depletion results in ribosome assembly defects. YbeY has been shown to interact with Era together with ribosomal protein S11. In this study, we have analyzed a suppressor mutation, era(T99I), that can partially suppress a subset of the multiple phenotypes of ybeY deletion. The era(T99I) allele was able to improve 16S rRNA processing and ribosome assembly at 37°C. However, it failed to suppress the temperature sensitivity and did not improve 16S rRNA stability. The era(T99I) allele was also unable to improve the 16S rRNA processing defects caused by the loss of ribosome maturation factors. We also show that era(T99I) increases the GroEL levels in the 30S ribosome fractions independent of YbeY. We propose that the mechanism of suppression is that the changes in Era’s structure caused by the era(T99I) mutation affect its GTP/GDP cycle in a way that increases the half-life of RNA binding to Era, thereby facilitating alternative processing of the 16S RNA precursor. Taken together, this study offers insights into the role of Era and YbeY in ribosome assembly and 16S rRNA processing events.

Emerging microparasite (e.g. viruses, bacteria, protozoa and fungi) epidemics and the introduction of non-native pests and weeds are major biosecurity threats worldwide. The likelihood of these threats is often estimated from probabilities of their entry, establishment, spread and ease of prevention. If ecosystems are considered equivalent to hosts, then compartment disease models should provide a useful framework for understanding the processes that underpin non-native species invasions. To enable greater cross-fertilisation between these two disciplines, the Epidemiological Framework for Biological Invasions (EFBI) is developed that classifies ecosystems in relation to their invasion status: Susceptible, Exposed, Infectious and Resistant. These states are linked by transitions relating to transmission, latency and recovery. This viewpoint differs markedly from the species-centric approaches often applied to non-native species. It allows generalisations from epidemiology, such as the force of infection, the basic reproductive ratio R0, super-spreaders, herd immunity, cordon sanitaire and ring vaccination, to be discussed in the novel context of non-native species and helps identify important gaps in the study of biological invasions. The EFBI approach highlights several limitations inherent in current approaches to the study of biological invasions including: (i) the variance in non-native abundance across ecosystems is rarely reported; (ii) field data rarely (if ever) distinguish source from sink ecosystems; (iii) estimates of the susceptibility of ecosystems to invasion seldom account for differences in exposure to non-native species; and (iv) assessments of ecosystem susceptibility often confuse the processes that underpin patterns of spread within -and between- ecosystems. Using the invasion of lakes as a model, the EFBI approach is shown to present a new biosecurity perspective that takes account of ecosystem status and complements demographic models to deliver clearer insights into the dynamics of biological invasions at the landscape scale. It will help to identify whether management of the susceptibility of ecosystems, of the number of vectors, or of the diversity of pathways (for movement between ecosystems) is the best way of limiting or reversing the population growth of a non-native species. The framework can be adapted to incorporate increasing levels of complexity and realism and to provide insights into how to monitor, map and manage biological invasions more effectively.

Background: Direct-acting antiviral (DAA) therapy among hepatitis C virus (HCV)-infected kidney transplant recipients is associated with short-term improvement in protein/creatinine (P/C) ratios, but how HCV cure affects long-term graft outcomes remains unknown. Methods: This is a retrospective follow-up study of 59 HCV-infected patients who underwent kidney transplant at the University of Alabama at Birmingham between 2007-2015 who were followed until the end of 2017. We examined the association of DAA-induced HCV cure with graft failure or death by survival analyses (Kaplan-Meier, Cox regression). Redsults: Mean age was 55 years, 73% were African American, and 68% were male. Median baseline creatinine was 1.4 mg/dL, P/C ratio was 0.5, and estimated glomerular filtration rate (eGFR) was 59 mL/min. Of those who received DAA, 24 (83%) achieved cure. The remaining 5 DAA patients (17%) did not have documented evidence of sustained virologic response (SVR). Overall, 19 (32%) patients experienced graft failure or death; with lower incidence in treated patients than untreated (4 vs 15 events; 2.6 vs 10.3 per 100 person-years [cHR 0.19, 95% CI: 0.06–0.66]). When adjusted for age, sex, race, and proteinuria, the association remained strong and invariant across time-varying (aHR 0.30, 95% CI: 0.08–1.10), time-averaged (aHR 0.28, 95% CI: 0.07–1.07), and time-varying-cumulative (aHR 0.32, 95% CI: 0.08–1.21) proteinuria metrics. Conclusions: DAAs therapy was associated with improved graft survival and reduced mortality. While not statistically significant, the association was strong, and these single-center findings warrant larger studies to demonstrate the benefits of HCV treatment in this population.

Background: Patients with ST-elevation myocardial infarction (STEMI) presenting to percutaneous coronary intervention (PCI)-capable hospitals often experience delays for primary PCI (pPCI). We sought to describe the effect of specific delay intervals and patient/system-level factors on STEMI reperfusion times. Methods: We analyzed all consecutive patients with STEMI who presented to 2 PCI-capable hospital emergency departments (EDs) between June 2007 and March 2016 who received successful pPCI. We excluded patients with prehospital cardiac arrest. We compared specific system delay intervals, patient characteristics, and in-hospital outcomes among patients who received timely (first medical contact-device ≤90/≤120 minutes) vs delayed >90/>120 minutes) pPCI. Results: Of 1936 patients with STEMI, 1127 (58%) presented directly to a PCI-capable hospital via emergency health services (EHS), 499 (26%) were transferred from the ED of a non-PCI hospital, and 310 (16%) self-presented to the ED of a pPCI-capable hospital. Guideline-recommended reperfusion times were met in 47% of direct-EHS, 42% of transfers, and 33% of self-presenters. Each time interval from first medical contact to device deployment was significantly prolonged in the delayed vs timely reperfusion cohorts across all 3 groups, excepting vascular access time. ED dwell time contributed the most to the difference in median reperfusion time within each group. Time of presentation, comorbidities, and sex were each significantly associated with delayed reperfusion. Within the EHS-direct group, prolonged reperfusion and ED dwell times were significantly associated with increased mortality, major bleeding, and cardiogenic shock. Conclusion: Ongoing efforts to identify and reduce ED dwell time and other systemic pPCI delays may improve STEMI outcomes, including mortality. Résumé: Contexte: Les patients en infarctus du myocarde avec élévation du segment ST (STEMI) qui se présentent dans un hôpital en mesure d’effectuer une intervention coronarienne percutanée (ICP) doivent souvent attendre pour subir une ICP primaire (ICPP). Nous avons tenté de décrire les effets de différents temps d’attente et facteurs relevant des patients ou du système de santé sur le délai avant la reperfusion lors d’un STEMI. Méthodologie: Nous avons analysé tous les cas consécutifs de patients en STEMI admis entre juin 2007 et mars 2016 au service des urgences de deux hôpitaux en mesure d’effectuer une ICP, et qui ont effectivement subi une ICPP. Les patients qui avaient subi un arrêt cardiaque avant leur arrivée à l’hôpital ont été exclus. Nous avons comparé les temps d’attente à des étapes particulières relevant du système de santé, les caractéristiques des patients et les issues de l’hospitalisation chez les patients qui ont subi une ICPP rapidement (intervalle entre la première prise de contact avec les services médicaux et la pose d’un dispositif ≤ 90/≤ 120 minutes) ou tardivement (intervalle > 90/> 120 minutes). Résultats: Sur les 1 936 patients ayant subi un STEMI, 1 127 (58 %) ont été conduits par l’entremise des services d’urgences de santé (SUS) directement dans un hôpital en mesure d’effectuer une ICP, 499 (26 %) ont été transférés depuis le service des urgences d’un hôpital n’étant pas en mesure d’effectuer une ICP et 310 (16 %) se sont présentés eux-mêmes au service des urgences d’un hôpital en mesure d’effectuer une ICPP. Les délais avant la reperfusion recommandés dans les lignes directrices ont été respectés dans 47 % des cas où le patient a été conduit par l’entremise des SUS, dans 42 % des cas de transfert et dans 33 % des cas où le patient s’est présenté lui-même. À l’exception du temps écoulé entre l’arrivée au laboratoire de cathétérisme et la création d’un accès vasculaire, les temps d’attente à chacune des étapes entre la première prise de contact avec les services médicaux et la pose d’un dispositif étaient significativement plus longs chez les patients ayant subi une reperfusion tardive que chez ceux ayant subi rapidement une ICPP, et ce, dans les trois groupes de patients. C’est le temps d’attente au service des urgences qui a le plus contribué à la différence entre les groupes en ce qui concerne le délai médian avant la reperfusion. L’heure de l’arrivée au service des urgences, la présence d’affections concomitantes et le sexe étaient tous des facteurs associés de manière significative à une reperfusion tardive. Chez les patients conduits par l’entremise des SUS directement dans un hôpital en mesure d’effectuer une ICP, un délai avant la perfusion et un temps d’attente au service des urgences plus longs étaient associés de manière significative à une hausse de la mortalité, des hémorragies majeures et des chocs cardiogéniques. Conclusion: Les efforts actuellement déployés pour reconnaître les sources de retard et réduire les temps d’attente au service des urgences et aux autres étapes avant la réalisation de l’ICPP pourraient permettre d’améliorer l’issue d’un STEMI, y compris la mortalité.

ABSTRACT Various lethal stresses, including bactericidal antibiotics, can trigger the production of reactive oxygen species (ROS) that contribute to killing. Incomplete base excision repair (BER) of oxidized nucleotides, especially 8-oxo-dG, has been identified as a major component of ROS-induced lethality. However, the relative contributions of this pathway to death vary widely between stresses, due in part to poorly understood complex differences in the physiological changes caused by these stresses. To identify new lethal stresses that kill cells through this pathway, we screened an essential protein degradation library and found that depletion of either DapB or Dxr leads to cell death through incomplete BER; the contribution of this pathway to overall cell death is greater for DapB than for Dxr. Depletion of either protein generates oxidative stress, which increases incorporation of 8-oxo-dG into the genome. This oxidative stress is causally related to cell death, as plating on an antioxidant provided a protective effect. Moreover, incomplete BER was central to this cell death, as mutants lacking the key BER DNA glycosylases MutM and MutY were less susceptible, while overexpression of the nucleotide sanitizer MutT, which degrades 8-oxo-dGTP to prevent its incorporation, was protective. RNA sequencing of cells depleted of these proteins revealed widely different transcriptional responses to these stresses. Our discovery that oxidative stress-induced incomplete BER is highly dependent on the exact physiological changes that the cell experiences helps explain the past confusion that arose concerning the role of ROS in antibiotic lethality. IMPORTANCE Bacterial cell death is a poorly understood process. The generation of reactive oxygen species (ROS) is an apparently common response to challenges by a wide variety of lethal stresses, including bactericidal antibiotics. Incomplete BER of nucleotides damaged by these ROS, especially 8-oxo-dG, is a significant contributing factor to this lethality, but the levels of its contribution vary widely between different lethal stresses. A better understanding of the conditions that cause cells to die because of incomplete BER may lead to improved strategies for targeting this mode of death as an adjunct to antimicrobial therapy.

Longer-chain polyunsaturated fatty acids (LCPUFAs) ≥20 carbons long are required for leukocyte function. These can be obtained from the diet, but there is some evidence that leukocytes can convert essential fatty acids (EFAs) into LCPUFAs. We used stable isotope tracers to investigate LCPUFA biosynthesis and the effect of different EFA substrate ratios in human T lymphocytes. CD3+ T cells were incubated for up to 48 h with or without concanavalin A in media containing a 18:2n-6:18:3n-3 (EFA) ratio of either 5:1 or 8:1 and [13C]18:3n-3 plus [d5]18:2n-6. Mitogen stimulation increased the amounts of 16:1n-7, 18:1n-9, 18:2n-6, 20:3n-6, 20:4n-6, 18:3n-3, and 20:5n-3 in T cells. Expression of the activation marker CD69 preceded increased FADS2 and FADS1 mRNA expression and increased amounts of [d5]20:2n-6 and [13C]20:3n-3 at 48 h. In addition, 22-carbon n-6 or n-3 LCPUFA synthesis was not detected, consistent with the absence of ELOVL2 expression. An EFA ratio of 8:1 reduced 18:3n-3 conversion and enhanced 20:2n-6 synthesis compared to a 5:1 ratio. Here, [d5]9- and [d5]-13-hydroxyoctadecadienoic (HODE) and [13C]9- and [13C]13-hydroxyoctadecatrienoic acids (HOTrE) were the major labelled oxylipins in culture supernatants; labelled oxylipins ≥20 carbons were not detected. An EFA ratio of 8:1 suppressed 9- and 13-HOTrE synthesis, but there was no significant effect on 9- and 13-HODE synthesis. These findings suggest that partitioning of newly assimilated EFA between LCPUFA synthesis and hydroxyoctadecaenoic acid may be a metabolic branch point in T-cell EFA metabolism that has implications for understanding the effects of dietary fats on T lymphocyte function.

The crystal structures of 1-(2,3,5,6-tetrafluoro-4-pyridyl)-3-benzylimidazolium chloride (1) and iodide (3) have been determined by single crystal X-ray diffraction. The crystal structure of 1 is similar to that of the bromide salt (2), possessing anion···C5F5N···C6H5 motifs, whilst that of 3 contains columns of alternating iodide anions and parallel tetrafluoropyridyl rings. All three crystal structures possess C(1)–H∙∙∙X− and C(2)–H∙∙∙X− hydrogen bonding. DFT calculations reveal that the strengths of the hydrogen bonding interactions lie in the order C(1)–H···X− > C(3)–H···X− > C(2)–H···X− for the same halide (X−) and Cl− > Br− > I− for each position. It is suggested that salt 3 adopts a different structure to salts 1 and 2 because of the larger size of iodide.

We have developed photochromic probes for the nicotinic acetylcholine receptor that exploit the unique chemical properties of the tetrafluoroazobenzene (4FAB) scaffold. Ultraviolet light switching and rapid thermal relaxation of the metastable cis configuration are the main drawbacks associated with standard AB-based switches. We designed our photoprobes to take advantage of the excellent thermodynamic stability of the cis-4FAB configuration (thermal half-life > 12 days at 37 °C in physiological buffer) and cis–trans photostationary states above 84%. Furthermore, the well-separated n–π* absorption bands of trans- and cis-4FAB allow facile photoswitching with visible light in two optical channels. A convergent 11-step synthetic approach allowed the installation of a trimethylammonium (TA) head onto the 4FAB scaffold, by means of an alkyl spacer, to afford a free diffusible 4FABTA probe. TAs are known to agonize nicotinic receptors, so 4FABTA was tested on mouse brain slices and enabled reversible receptor activation with cycles of violet and green light. Due to the very long-lived metastable cis configuration, 4FAB in vivo use could be of great promise for long term biological studies. Further chemical functionalization of this 4FAB probe with a maleimide functionality allowed clean cross-linking with glutathione. However, attempts to conjugate with a cysteine on a genetically modified nicotinic acetylcholine receptor did not afford the expected light-responsive channel. Our data indicate that the 4FAB photoswitch can be derivatized bifunctionally for genetically-targeted photopharmacology whilst preserving all the favorable photophysical properties of the parent 4FAB scaffold, however, the tetrafluoro motif can significantly perturb pharmacophore–protein interactions. In contrast, we found that the freely diffusible 4FABTA probe could be pre-set with green light into an OFF state that was biologically inert, irradiation with violet light effectively "uncaged" agonist activity, but in a photoreversible manner. Since the neurotransmitter acetylcholine has fully saturated heteroatom valences, our photoswitchable 4FABTA probe could be useful for physiological studies of this neurotransmitter.

Silver nanoparticles (AgNPs) are an emerging class of contaminants with the potential to impact ecosystem structure and function. AgNPs are antimicrobial, suggesting that microbe-driven ecosystem functions may be particularly vulnerable to AgNP exposure. Predicting the environmental impacts of AgNPs requires in situ investigation of environmentally relevant dosing regimens over time scales that allow for ecosystem-level responses. We used 3000 L enclosures installed in a boreal lake to expose plankton communities to chronic and pulse AgNP dosing regimens with concentrations mimicking those recorded in natural waters. We compared temporal patterns of plankton responses, Ag accumulation, and ecosystem metabolism (i.e., daily ecosystem respiration, gross primary production, and net ecosystem production) for 6 weeks of chronic dosing and 3 weeks following a pulsed dose. Ag accumulated in microplankton and zooplankton, but carbon-specific Ag was nonlinear over time and generally did not predict plankton response. Ecosystem metabolism did not respond to either AgNP exposure type. This lack of response corresponded with weak microplankton responses in the chronic treatments but did not reflect the stronger microplankton response in the pulse treatment. Our results suggest that lake ecosystem metabolism is somewhat resistant to environmentally relevant concentrations of AgNPs and that organismal responses do not necessarily predict ecosystem-level responses.

Abstract Aim Decisions on wildlife conservation, management, and epidemiological risk are best based on robust evidence. The continual improvement of species distributions, such that they can be relied upon in decision‐making, is important. Here we seek to refine aspects of a generic modelling approach and improve the utility of species distribution maps. Location Great Britain (GB). Methods We applied a modeling framework based on hierarchical Bayesian species distribution models exploiting opportunistic occurrence records from citizen science datasets to predict both current and potential distributions for each of the six deer species known to be present in GB. Using the resulting maps, we performed a simple analysis of the overlap between species to illustrate possible contact, which we interpret as the relative risk of potential disease spread given an introduction. Results Predicted distribution maps showed good agreement with the broader scale occurrence reported by a recent national deer survey with an average True Skill Statistics and AUC of 0.69 and 0.89, respectively. Aggregation of the maps for all species highlighted regions of central and eastern England as well as parts of Scotland where extensive areas of range overlap could result in interspecific contact with consequences for risk assessments for diseases of deer. However, if populations are allowed to expand to their predicted potential, then areas of overlap, and therefore disease interspecific transmission risk, will become extensive and widespread across all of mainland Britain. Main conclusions The generic modeling approach outlined performed well across all of the deer species tested, offering a robust and reliable tool through which current and potential animal distributions can be estimated and presented. Our application, intended to inform quantitative risk assessments, demonstrates the practical use of such outputs to generate the valuable evidence required to inform policy decisions on issues such as management strategy.

A 45-year-old female presents with suspected acute myocardial infarction with cardiogenic shock requiring mechanical circulatory support. Pheochromocytoma-induced atypical Takotsubo syndrome is diagnosed. Clinicians should suspect high catecholamine states as a cause of the basal subtype of atypical Takotsubo syndrome. (Level of Difficulty: Beginner.)

Citizen science schemes enable ecological data collection over very large spatial and temporal scales, producing datasets of high value for both pure and applied research. However, the accuracy of citizen science data is often questioned, owing to issues surrounding data quality and verification, the process by which records are checked after submission for correctness. Verification is a critical process for ensuring data quality and for increasing trust in such datasets, but verification approaches vary considerably between schemes. Here, we systematically review approaches to verification across ecological citizen science schemes that feature in published research, aiming to identify the options available for verification, and to examine factors that influence the approaches used. We reviewed 259 schemes and were able to locate verification information for 142 of those. Expert verification was most widely used, especially among longer-running schemes, followed by community consensus and automated approaches. Expert verification has been the default approach for schemes in the past, but as the volume of data collected through citizen science schemes grows and the potential of automated approaches develops, many schemes might be able to implement approaches that verify data more efficiently. We present an idealised system for data verification, identifying schemes where this system could be applied and the requirements for implementation. We propose a hierarchical approach in which the bulk of records are verified by automation or community consensus, and any flagged records can then undergo additional levels of verification by experts.

Isolation of the pathogens Yersinia enterocolitica and Yersinia pseudotuberculosis from foods typically rely on slow (10–21 day) “cold enrichment” protocols before confirmed results are obtained. We describe an approach that yields results in 39 h that combines an alternative enrichment method with culture on a non-selective medium, and subsequent identification of suspect colonies using elastic light scatter (ELS) analysis. A prototype database of ELS profiles from five Yersinia species and six other bacterial genera found in pork mince was established, and used to compare similar profiles of colonies obtained from enrichment cultures from pork mince samples seeded with representative strains of Y. enterocolitica and Y. pseudotuberculosis. The presumptive identification by ELS using computerised or visual analyses of 83/90 colonies in these experiments as the target species was confirmed by partial 16S rDNA sequencing. In addition to seeded cultures, our method recovered two naturally occurring Yersinia strains. Our results indicate that modified enrichment combined with ELS is a promising new approach for expedited detection of foodborne pathogenic yersiniae.

Industry-led culling of badgers has occurred in England to reduce the incidence of bovine tuberculosis in cattle for a number of years. Badger vaccination is also possible, and a move away from culling was "highly desirable" in a recent report to the UK government. Here we used an established simulation model to examine badger control option in a post-cull environment in England. These options included no control, various intermittent culling, badger vaccination and use of a vaccine combined with fertility control. The initial simulated cull led to a dramatic reduction in the number of infected badgers present, which increased slowly if there was no further badger management. All three approaches led to a further reduction in the number of infected badgers, with little to choose between the strategies. We do note that of the management strategies only vaccination on its own leads to a recovery of the badger population, but also an increase in the number of badgers that need to be vaccinated. We conclude that vaccination post-cull, appears to be particularly effective, compared to vaccination when the host population is at carrying capacity.