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The High-Altitude Water Cherenkov (HAWC) observatory is a second-generation continuously operated, wide field-of-view, TeV gamma-ray observatory. The HAWC observatory and its analysis techniques build on experience of the Milagro experiment in using ground-based water Cherenkov detectors for gamma-ray astronomy. HAWC is located on the Sierra Negra volcano in M\'exico at an elevation of 4100 meters above sea level. The completed HAWC observatory principal detector (HAWC) consists of 300 closely spaced water Cherenkov detectors, each equipped with four photomultiplier tubes to provide timing and charge information to reconstruct the extensive air shower energy and arrival direction. The HAWC observatory has been optimized to observe transient and steady emission from sources of gamma rays within an energy range from several hundred GeV to several hundred TeV. However, most of the air showers detected are initiated by cosmic rays, allowing studies of cosmic rays also to be performed. This paper describes the characteristics of the HAWC main array and its hardware., Comment: Accepted for publications in Nuclear Inst. and Methods in Physics Research, A (2023) 168253 ( https://www.sciencedirect.com/science/article/abs/pii/S0168900223002437 ); 39 pages, 14 Figures

The human microbiome is an integral component of the human body and a co-determinant of several health conditions1,2. However, the extent to which interpersonal relations shape the individual genetic makeup of the microbiome and its transmission within and across populations remains largely unknown3,4. Here, capitalizing on more than 9,700 human metagenomes and computational strain-level profiling, we detected extensive bacterial strain sharing across individuals (more than 10 million instances) with distinct mother-to-infant, intra-household and intra-population transmission patterns. Mother-to-infant gut microbiome transmission was considerable and stable during infancy (around 50% of the same strains among shared species (strain-sharing rate)) and remained detectable at older ages. By contrast, the transmission of the oral microbiome occurred largely horizontally and was enhanced by the duration of cohabitation. There was substantial strain sharing among cohabiting individuals, with 12% and 32% median strain-sharing rates for the gut and oral microbiomes, and time since cohabitation affected strain sharing more than age or genetics did. Bacterial strain sharing additionally recapitulated host population structures better than species-level profiles did. Finally, distinct taxa appeared as efficient spreaders across transmission modes and were associated with different predicted bacterial phenotypes linked with out-of-host survival capabilities. The extent of microorganism transmission that we describe underscores its relevance in human microbiome studies5, especially those on non-infectious, microbiome-associated diseases., This work was supported by the European Research Council (ERC-STG project MetaPG-716575 and ERC-CoG microTOUCH-101045015) to N.S. and by EMBO ALTF 593–2020 to M.V.-C. The work was also partially supported by MIUR ‘Futuro in Ricerca’ (grant no. RBFR13EWWI_001) to N.S., by the European H2020 programme (ONCOBIOME-825410 project, MASTER-818368 project, and IHMCSA-964590) to N.S., by the National Cancer Institute of the National Institutes of Health (1U01CA230551) to N.S., by the Premio Internazionale Lombardia e Ricerca 2019 to N.S., by the Simons Foundation (award ID 648614) to E.D. and N.S., and by the European Research Council (ERC-STG project Mami-639226) to M.C.C

Metagenomic assembly enables new organism discovery from microbial communities, but it can only capture few abundant organisms from most metagenomes. Here we present MetaPhlAn 4, which integrates information from metagenome assemblies and microbial isolate genomes for more comprehensive metagenomic taxonomic profiling. From a curated collection of 1.01 M prokaryotic reference and metagenome-assembled genomes, we define unique marker genes for 26,970 species-level genome bins, 4,992 of them taxonomically unidentified at the species level. MetaPhlAn 4 explains ~20% more reads in most international human gut microbiomes and >40% in less-characterized environments such as the rumen microbiome and proves more accurate than available alternatives on synthetic evaluations while also reliably quantifying organisms with no cultured isolates. Application of the method to >24,500 metagenomes highlights previously undetected species to be strong biomarkers for host conditions and lifestyles in human and mouse microbiomes and shows that even previously uncharacterized species can be genetically profiled at the resolution of single microbial strains.

The human microbiome seeding starts at birth, when pioneer microbes are acquired mainly from the mother. Mode of delivery, antibiotic prophylaxis, and feeding method have been studied as modulators of mother-to-infant microbiome transmission, but other key influencing factors like modern westernized lifestyles with high hygienization, high-calorie diets, and urban settings, compared with non-westernized lifestyles have not been investigated yet. In this study, we explored the mother-infant sharing of characterized and uncharacterized microbiome members via strain-resolved metagenomics in a cohort of Ethiopian mothers and infants, and we compared them with four other cohorts with different lifestyles. The westernized and non-westernized newborns' microbiomes composition overlapped during the first months of life more than later in life, likely reflecting similar initial breast-milk-based diets. Ethiopian and other non-westernized infants shared a smaller fraction of the microbiome with their mothers than did most westernized populations, despite showing a higher microbiome diversity, and uncharacterized species represented a substantial fraction of those shared in the Ethiopian cohort. Moreover, we identified uncharacterized species belonging to the Selenomonadaceae and Prevotellaceae families specifically present and shared only in the Ethiopian cohort, and we showed that a locally produced fermented food, injera, can contribute to the higher diversity observed in the Ethiopian infants' gut with bacteria that are not part of the human microbiome but are acquired through fermented food consumption. Taken together, these findings highlight the fact that lifestyle can impact the gut microbiome composition not only through differences in diet, drug consumption, and environmental factors but also through its effect on mother-infant strain-sharing patterns., This work was supported by the European Research Council (ERC-STG project MetaPG-716575) to N.S., by MIUR “Futuro in Ricerca” (grant no. RBFR13EWWI_001) to N.S., by the European H2020 program (ONCOBIOME-825410 project and MASTER-818368 project) to N.S., by the National Cancer Institute of the National Institutes of Health (1U01CA230551) to N.S., by the Premio Internazionale Lombardia e Ricerca 2019 to N.S., by the Italian Ministry of Health with Ricerca Corrente and 5x1000 funds, and by the EMBO ALTF 593-2020 to M.V.-C. The authors would like to acknowledge support from the European Research Council (ERC-STG project MAMI, ref. 639226) and PROMETEO GVA (ref. 012/2020) to M.C.C. and M.S.-R., respectively, and from Plan GenT project (CDEIGENT 2020) to R.C.-R. Finally, M.C.C., R.C.-R., and M.S.-R. acknowledge the award of the Spanish government MCIN/AEI to the IATA-CSIC as Center of Excellence Accreditation Severo Ochoa (CEX2021-001189-S/MCIN/AEI/10.13039/501100011033).This article is part of a project that has received funding from the European Union’s Horizon 2020 Research and Innovation Programme (GA no. 949742 ERC-HealthXCross) to R.R.

Catheter ablation for atrial fibrillation (AF) in comparison to medical therapy alone is known to improve freedom from arrhythmia and quality of life, but the benefit regarding mortality is unclear. The publication of several recent large randomized controlled trials (RCT) comparing ablation with medical therapy has warranted an updated meta-analysis.We sought to compare the effectiveness of catheter ablation versus medical therapy only in patients with AF. MEDLINE, Cochrane, and ClinicalTrials.gov databases were searched from inception until 04/30/2021. Relevant RCTs comparing catheter ablation versus medical therapy in patients with AF were selected.A total of 24 RCTs involving 5730 adult patients were included (2992 in catheter ablation and 2738 in medical therapy). There was a reduction in all-cause mortality with catheter ablation compared with medical therapy only (risk ratio (RR) 0.70 [95% confidence interval (CI) 0.55-0.89]; p = .003). Catheter ablation also demonstrated a reduction in hospitalizations (RR 0.50 [95% CI 0.36-0.70]; p .001), improvement in left ventricular ejection fraction (LVEF) (mean difference [MD] + 5.94% [95% CI 0.40-11.48] p = .04), greater freedom from atrial arrhythmia (RR 2.23 [95% CI 1.79-2.76]; p .001), and AF (RR 1.95 [95% CI 1.44-2.66]; p .001). In subgroup analysis, catheter ablation demonstrated a significant reduction in mortality and hospitalizations among patients with reduced LVEF, and when ablation was compared with antiarrhythmic drug use.In comparison to medical therapy only, catheter ablation for atrial fibrillation reduces mortality, hospitalizations, and increases freedom from arrhythmia.

The dense uniformed joints between molybdenum disilicides (MoSi2) and stainless steel powders were prepared using the spark plasma sintering (SPS) technique with nine graded materials and their welding behavior was investigated. The results showed that such joints can be achieved using graded interlayers because the coefficient of thermal expansion (CTE) of each interlayer closely matched over a wide temperature range. Furthermore, the compatibility between the graded interlayers prevented MoSi2 with low toughness from the occurrence of microcracks resulted from the residual stresses formed during cooling of the joint. Moreover, the 9-layer joint with a thickness of 1.0 mm for each layer exhibited the minimum residual stress if the compositional exponent was 0.8.

Whether chlorthalidone is superior to hydrochlorothiazide for preventing major adverse cardiovascular events in patients with hypertension is unclear.In a pragmatic trial, we randomly assigned adults 65 years of age or older who were patients in the Department of Veterans Affairs health system and had been receiving hydrochlorothiazide at a daily dose of 25 or 50 mg to continue therapy with hydrochlorothiazide or to switch to chlorthalidone at a daily dose of 12.5 or 25 mg. The primary outcome was a composite of nonfatal myocardial infarction, stroke, heart failure resulting in hospitalization, urgent coronary revascularization for unstable angina, and non-cancer-related death. Safety was also assessed.A total of 13,523 patients underwent randomization. The mean age was 72 years. At baseline, hydrochlorothiazide at a dose of 25 mg per day had been prescribed in 12,781 patients (94.5%). The mean baseline systolic blood pressure in each group was 139 mm Hg. At a median follow-up of 2.4 years, there was little difference in the occurrence of primary-outcome events between the chlorthalidone group (702 patients [10.4%]) and the hydrochlorothiazide group (675 patients [10.0%]) (hazard ratio, 1.04; 95% confidence interval, 0.94 to 1.16; P = 0.45). There were no between-group differences in the occurrence of any of the components of the primary outcome. The incidence of hypokalemia was higher in the chlorthalidone group than in the hydrochlorothiazide group (6.0% vs. 4.4%, P0.001).In this large pragmatic trial of thiazide diuretics at doses commonly used in clinical practice, patients who received chlorthalidone did not have a lower occurrence of major cardiovascular outcome events or non-cancer-related deaths than patients who received hydrochlorothiazide. (Funded by the Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT02185417.).

BackgroundInformation about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes during the Omicron surge is limited. We sought to determine the effectiveness of nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of COVID-19.MethodsWe conducted three retrospective target trial emulation studies comparing matched patient cohorts who received nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir in the Veterans Health Administration (VHA). Participants were Veterans in VHA care at risk for severe COVID-19 who tested positive for SARS-CoV-2 in the outpatient setting during January and February 2022. Primary outcomes included all-cause 30-day hospitalization or death and 31-180-day incidence of acute or long-term care admission, death, or post-COVID-19 conditions. For 30-day outcomes, we calculated unadjusted risk rates, risk differences, and risk ratios. For 31-180-day outcomes, we used unadjusted time-to-event analyses.ResultsParticipants were 90% male with median age 67 years and 26% unvaccinated. Compared to matched untreated controls, nirmatrelvir-ritonavir-treated participants (N=1,587) had a lower 30-day risk of hospitalization (27.10/1000 versus 41.06/1000, risk difference [RD] - 13.97, 95% CI -23.85 to -4.09) and death (3.15/1000 versus 14.86/1000, RD -11.71, 95% CI - 16.07 to -7.35). Among persons who were alive at day 31, further significant reductions in 31-180-day incidence of hospitalization (sub-hazard ratio 1.07, 95% CI 0.83 to 1.37) or death (hazard ratio 0.61, 95% CI 0.35 to 1.08) were not observed. Molnupiravir-treated participants aged ≥65 years (n=543) had a lower combined 30-day risk of hospitalization or death (55.25/1000 versus 82.35/1000, RD -27.10, 95% CI -50.63 to -3.58). A statistically significant difference in 30-day or 31-180-day risk of hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. Incidence of most post-COVID conditions was similar across comparison groups.ConclusionsNirmatrelvir-ritonavir was highly effective in preventing 30-day hospitalization and death. Short-term benefit from molnupiravir was observed in older groups. Significant reductions in adverse outcomes from 31-180 days were not observed with either antiviral.

All-metal 3D printing fabrication technologies provide an attractive alternative for direct manufacturing of waveguide components due to fast and cost-effective prototyping and the possibility to fabricate geometries which cannot be fabricated with traditional machining techniques. In radio astronomy, waveguide components in radio receivers are operated at cryogenic temperatures and inside a cryostat under vacuum conditions. In this paper, we report on the design, fabrication by 3D printing and testing at room and cryogenic temperatures of a corrugated horn to be used in astronomical receivers operating in the 35–50-GHz band.

在欧美国家左心室辅助装置（LVAD）已成为终末期心力衰竭非药物治疗的主要手段，国内亦有数十家医院正在临床开展应用。但LVAD术后患者面临的主要问题仍然是右心室功能衰竭，亦是引起LVAD术后死亡的主要原因。该文围绕LVAD植入术后右心功能障碍的发生机制、右心功能衰竭预测模型以及超声心动图在LVAD植入前后对右心功能的评估要点进行综述。.

ImportanceOlder adults and individuals with medical comorbidities are at increased risk for severe COVID-19. Several pharmacotherapies demonstrated to reduce the risk of COVID-19–related hospitalization and death have been authorized for use.ObjectiveTo describe factors associated with receipt of outpatient COVID-19 pharmacotherapies in the Veterans Affairs (VA) health care system.Design, Settings, and ParticipantsThis cohort study assessed outpatient veterans with risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022. The setting was the VA health care system, the largest integrated health care system in the US.ExposuresDemographic characteristics, place of residence, underlying medical conditions, and COVID-19 vaccination.Main Outcomes and MeasuresThe odds of receipt of any COVID-19 pharmacotherapy, including sotrovimab, nirmatrelvir boosted with ritonavir, molnupiravir, or remdesivir were estimated using multivariable logistic regression.ResultsAmong 111 717 veterans included in this study (median [IQR] age, 60 [46-72] years; 96 482 [86.4%] male, 23 362 [20.9%] Black, 10 740 [9.6%] Hispanic, 75 973 [68.0%] White) who tested positive for SARS-CoV-2 during January to February 2022, 4233 (3.8%) received any COVID-19 pharmacotherapy, including 2870 of 92 396 (3.1%) in January and 1363 of 19 321 (7.1%) in February. Among a subset of 56 285 veterans with documented COVID-19–related symptoms in the 30 days preceding a positive SARS-CoV-2 test, 3079 (5.5%) received any COVID-19 pharmacotherapy. Untreated veterans had a median (IQR) age of 60 (46-71) years and a median (IQR) of 3 (2-5) underlying medical conditions. Veterans receiving any treatment were more likely to be older (aged 65 to 74 years vs 50 to 64 years: adjusted odds ratio [aOR], 1.66 [95% CI, 1.52-1.80]; aged at least 75 years vs 50 to 64 years: aOR, 1.67 [95% CI, 1.53-1.84]) and have a higher number of underlying conditions (at least 5 conditions vs 1 to 2 conditions: aOR, 2.17 [95% CI, 1.98-2.39]). Compared with White veterans, Black veterans (aOR, 0.65 [95% CI, 0.60-0.72]) were less likely to receive treatment; and compared with non-Hispanic veterans, Hispanic veterans (aOR, 0.88 [95% CI, 0.77-0.99]) were less likely to receive treatment. There were 16 546 courses of sotrovimab, nirmatrelvir, and molnupiravir allocated across the VA during this period.Conclusions and RelevanceIn this cohort study of veterans who tested positive for SARS-CoV-2 during January and February when supply of outpatient COVID-19 pharmacotherapies was limited, prescription of these pharmacotherapies was underused, and many veterans with risk factors for severe COVID-19 did not receive treatment. Veterans from minority racial and ethnic groups were less likely to receive any pharmacotherapy.

OBJECTIVE: To analyze the feasibility of using vascular plaque quantification (VPQ) to evaluate carotid atherosclerotic plaques and to observe the effect of statins on carotid atherosclerotic plaques. METHODS: Patients with carotid plaques from January 2016 to September 2018 in Peking University First Hospital Neurology Department were recruited and underwent three-dimonsional ultrasound (3DUS). Their gray scale median (GSM) and other parameters of carotid plaques were measured with VPQ. The patients were divided into low GSM group (GSM < 40) and high GSM group (GSM≥40). The clinical characteristics and plaque characteristics of the patients in the two groups were compared to analyze the stability of plaques. According to whether taking statins or not, the patients were further divided into statin group and non-statin group, plaque GSM and other parameters of their carotid plaques were measured and the changes of carotid plaques at the end of 3 months and 2 years were observed. RESULTS: A total of 120 patients were enrolled, including 79 males and 41 females, with an average age of (65.39±9.11) years. The patients were divided into low GSM group (31 cases) (GSM < 40) and high GSM group (89 cases) (GSM≥40). The stenosis of the lumen in the low GSM group was more severe (the area stenosis rate was 41.32%±21.37% vs. 29.79%±17.16%, P < 0.05). The nor-malized wall index (NWI) of plaque in low GSM group was significantly higher than that in high GSM group (0.61 ±0.14 vs. 0.52±0.12, P < 0.01). A total of 77 patients, including 51 males and 26 females, aged (64.96±9.58) years, were enrolled to observe the statin effects on carotid plaque. They were divided into statin group (n=56) and non-statin group (n=21) according to whether taking statins or not. At the baseline and 3-month follow-up, there were no significant differences in carotid plaque volume, area, degree of luminal stenosis and GSM between the two groups (P>0.05). At the end of the 2-year follow-up, GSM increased in the statin group [median 10.00 (2.00, 28.00)] but decreased in the non-statin group [median －7.00 (－11.00, 5.50)], with a statistically significant difference between the two groups (P < 0.01). There was no significant increase in carotid plaque volume in the statin group, while there was a slight increase in the non-statin group, but there was no significant difference between the two groups [median increase in plaque volume was 0.00 (－30.00, 40.00) mm(3) in the statin group and 30.00 (10.00, 70.00) mm(3) in the non-statin group, P>0.05]. CONCLUSION: The VPQ technology of 3DUS can be used to evaluate carotid atherosclerotic plaques. Patients with low GSM (GSM < 40) have more severe vascular stenosis and higher normalized wall index. VPQ technology can also be used to observe the effect of statins on carotid plaque, the GSM of plaques increase in patients who are taking moderate-intensity statin treatment for two years.

Background Nearly 30% of ischemic strokes are attributed to atrial fibrillation (AF) related cardiac thromboembolism. This subset of strokes are associated with higher recurrence rate, morbidity and mortality. As a result, current recommendation suggests a cardiac monitoring of variable intensity and duration to search for unknown AF after a stroke so that optimal secondary prevention could be administered. Unfortunately, it is reported that 24h Holter ECG monitoring for underlying AF is completed routinely in only a minority of stroke centers, making a huge gap between AF detection rate in clinical practice and estimated actual data (2–3% vs 23–30%). So, it is obvious that paroxysmal AF remains undetected in a significant proportion of patients after a stroke and an early and effective identification approach of cardiac disturbances is needed. Purpose We aim to develop an innovative end-to-end artificial intelligence model to rapidly search for atrial fibrillation in post ischemic stroke patients using MRI imaging data. Methods 489 patients diagnosed with ischemic stroke, 174 of which had a prior known history of AF or new AF detected by intensive ECG monitoring poststroke, from January 2018 to October 2021 were enrolled in this study. The MRI images obtained after their admission in the stroke unit were meticulously evaluated and acute ischemic stroke lesions on DWI sequences were segmented and confirmed by two senior neuroradiologists independently. These processed images were randomly split into training (n=315) and testing set (n=174) for the implementation and validation of our AI screening model. And the algorithm was based on the combination of radiomic features and semantic features extracted from convolutional neural network (CNN). The model performance was evaluated by accuracy, recall, precision, F-Measure and AUC. Also, heatmaps which indicate the attention mechanism of the model were generated for interpreting underlying patterns. Results The AUC of our model (COM) reached 0.8 (Figure 1A). Also, the algorithm yielded values for the accuracy, recall, precision and F-Measure of 70%, 92.5%, 63.8% and 75.5%, respectively, which showed satisfactory classification results. As to the interpretability of the AI model, we found that more “attention” was paid to the main lesions (Figure 1B) and radiomic features which indicated the minimum gray level intensity and the sphericity of the lesions (Figure 1C, D) were crucial to the classifier. Conclusions Our work revealed a potential correlation between brain ischemic lesion pattern on DWI images and underlying etiology of AF. Moreover, the AI model we developed may serve as a rapid screening tool for AF in clinical practice of stroke units. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Natural Science Foundation of China

As the most common cause of syncope, vasovagal syncope (VVS) is mediated by parasympathetic overactivity and/or sympathetic withdrawal. Although catheter ablation of ganglionated plexi or cardioneuroablation has been used to treat VVS, its role in quality of life (QoL) has not been formally evaluated. The aim of this study was to demonstrate if this novel treatment results in improvement QoL of patients with VVS.Twenty-seven consecutive patients (age: 34 ± 14 years, 51.8% male) with dominant cardioinhibitory type VVS were prospectively enrolled in the study. After confirmation of 3 s asystole on head-up tilt testing (HUT), all patients underwent cardioneuroablation. ECGs were obtained prior to procedure and at 12-month follow-up visit. HUTs were repeated 1 month after cardioneuroablation procedures. QoL was assessed with the use of SF-36, EQ-5D, and EQ VAS questionnaires.ECG, HUT, and QoL data were available in all patients. At 12-month follow-up, heart rate on rest ECG significantly increased (from 74 ± 15 to 84 ± 14 bpm, p = 0.003). Repeated HUTs were negative in 23 (85.1%) patients. All of 27 patients remained free of syncope. QoL assessed by SF-36 score significantly improved in postprocedural follow-up (92 ± 9 and 96 ± 11, p = 0.016). Similarly, significant improvements in mobility, self-care, and usual activity domains of EQ-5D were observed (mean scores of 3.0 ± 1.5 and 2.1 ± 1.3, p 0.001; 1.3 ± 0.9 and 1.2 ± 0.6, p = 0.041; 1.7 ± 1.0 and 1.4 ± 0.8 respectively). EQ-VAS score also improved significantly (39 ± 24 to 77 ± 18, p 0.001).Our findings suggest that cardioneuroablation may be associated with intermediate term improvement in QoL in patients with VVS.

Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide.To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies.Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022.Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression.Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P 10-257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems.Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.

Caloric restriction (CR) and Roux-en-Y Gastric Bypass (RYGB) are considered effective means of body weight control, but the mechanism by which CR and RYGB protect against high-fat diet (HFD)-induced obesity remains elusive. The browning of white adipose tissue (WAT) is a potential approach to combat obesity. Here we assess whether browning of WAT is involved in CR- and RYGB-treatment. The average size of adipocytes was determined by histological analysis. Expression of thermogenic genes in both human subjects and mice were measured by quantitative real-time PCR and immunohistochemical staining. The average size of adipocytes was bigger, while the expression of thermogenic genes such as uncoupling protein 1 (UCP1), nuclear factor erythroid-2 like 1 (NRF1) and PPARγ coactivator-1 α (PGC1α) were lower in the WAT of obese subjects when compared to lean controls. Both CR and RYGB promoted weight and fat loss. Increment of the average adipocytes size and down-regulation of thermogenic genes were significantly reversed by both CR and RYGB in the WAT of obese mice. Our findings showed that CR and RYGB significantly improved high-fat diet-induced lipid accumulation by promoting the browning of WAT.

Antibiotic resistance (AR) necessitates the discovery of new antimicrobials with alternative mechanisms of action to those employed by conventional antibiotics. One such strategy utilizes Ga3+ to target iron metabolism, a critical process for survival. Still, Ga-based therapies are generally ineffective against Gram-positive bacteria and promote Ga resistance. In response to these drawbacks, we report a lipophilic Ga complex, [Ga2L3(bpy)2] (L = 2,2'-bis(3-hydroxy-1,4-naphthoquinone; bpy = 2,2'-bipyridine)), effective against drug-resistant Pseudomonas aeruginosa (DRPA; minimum inhibitory concentration, MIC = 10 μM = 14.8 μg/mL) and methicillin-resistant Staphylococcus aureus (MRSA, MIC = 100 μM = 148 μg/mL) without iron-limited conditions. Importantly, [Ga2L3(bpy)2] shows noticeably delayed and decreased resistance in both MRSA and DRPA, with only 8× MIC in DRPA and none in MRSA after 30 passages. This is likely due to the dual mode of action afforded by Ga (disruption of iron metabolism) and the ligand (reactive oxygen species production). Overall, [Ga2L3(bpy)2] demonstrates the utility of lipophilic metal complexes with multiple modes of action in combatting AR in Gram-positive and Gram-negative bacteria.

Empirical evidence suggests that both leisure time and medical care are important for maintaining health. We develop a general equilibrium macroeconomic model in which taxation is a key determinant of the composition of these two inputs in the endogenous accumulation of health capital. In our model, higher taxes lead to using relatively more leisure time and less medical care in maintaining health. We find that difference in taxation between the US and Europe can account for a large fraction of their difference in health expenditure-GDP ratio and almost all of their difference in time input for health production.

BACKGROUND Radiofrequency (RF) ablation with half-normal saline (HNS) has shown promise as a bail-out strategy following failed ventricular tachycardia ablation using standard approaches. OBJECTIVE To use a novel infrared thermal imaging (ITI) model to evaluate biophysical and lesion characteristics during RF ablation using normal saline (NS) and HNS irrigation. METHODS Left ventricular strips of myocardium were excised from fresh porcine hearts. RF ablation was performed using an open-irrigated ablation catheter (Thermocool ST/SF) with NS (n = 75) and HNS (n = 75) irrigation using different power settings (40/50 W), RF durations (30/60 s), contact force of 10-15 g, and flow rate of 15 ml/min. RF lesions were recorded using an infrared thermal camera and border zone, lethal, 100° isotherms were matched with necrotic borders after 2% triphenyltetrazolium chloride staining. Lesion dimensions and isotherms (mm2 ) were measured. RESULTS In total, 150 lesions were delivered. HNS lesions were deeper (6.4 ± 1.1 vs. 5.7 ±0.8 mm; p = .03), and larger in volume (633 ± 153 vs. 468 ± 107 mm3 ; p = .007) than NS lesions. Steam pops (SPs) occurred during 19/75 lesions (25%) in the NS group and 32/75 lesions (43%) in the HNS group (p = .34). Lethal (57.8 ± 6.5 vs. 36.0 ± 3.9 mm2 ; p = .001) and 100°C isotherm areas (16.9 ± 6.9 vs. 3.8 ± 4.2 mm2 ; p = .003) areas were larger and were reached earlier in the HNS group. CONCLUSIONS RFA using HNS created larger lesions than NS irrigation but led to more frequent SPs. The presence of earlier lethal isotherms and temperature rises above 100°C on ITI suggest a potentially narrower therapeutic-safety window with HNS.

Analysis of earthquake locations and centroid moment tensors (CMTs) is critical in assessing seismogenic structures and connecting earthquakes to anthropogenic activities. The objective of this study was to gain insights into the seismotectonics of the Eagle Ford Shale play (EF), southern Texas, through relative relocation of earthquakes, assessment of CMT solutions, and investigation of the background stress field. Using Texas Seismological Network (TexNet) data from 2017 through 2019, we were able to relocate 326 earthquakes and obtain CMT solutions for 37 ML≥2.0 earthquakes. These earthquakes are located in the sedimentary basin and uppermost crust, with depths ranging from 2 to 10 km. The earthquake groups in the northeastern EF are linearly distributed along the Karnes fault zone, whereas the southern and western groups are spatially scattered around mapped or unmapped faults. CMT solutions identified 32 normal fault earthquakes and five strike-slip earthquakes. The orientation of the fault plane of most normal fault earthquakes is southwest–northeast, whereas the possible fault plane of the strike-slip fault is from north-northwest to south-southeast, which is roughly perpendicular to the normal faults. Normal and strike-slip faults in the EF are of high dip angles, with the dip angles of the most faults ranging from 60° to 80°. Stress inversion results show that the major orientation of maximum horizontal stress (SHmax) is southwest–northeast, with minor local stress-field rotations. We further estimated earthquake energy release in the EF region using moment magnitude from the CMT solutions, and the cumulative earthquake energy release curve reveals three notable increases in cumulative seismic moment, which occurred in January–July 2018 and January–March 2019, and May–August 2019. Whether these energy releases were caused by anthropogenic activities is a matter for further investigation.

Chronic low back pain (cLBP) is a common and highly disabling problem world-wide. Although many treatment options exist, it is unclear how to best sequence the multitude of care options to provide the greatest benefit to patients.The Sequential and Comparative Evaluation of Pain Treatment Effectiveness Response (SCEPTER) trial uses a pragmatic, randomized, stepped design. Enrollment targets 2529 participants from 20 Veterans Affairs (VA) medical centers. Participants with chronic low back pain will first be randomized to one of three options: 1) an internet-based self-management program (Pain EASE); 2) a tailored physical therapy program (Enhanced PT); or 3) continued care with active monitoring (CCAM), a form of usual care. Participants not achieving a 30% or 2-point reduction on the study's primary outcome (Brief Pain Inventory Pain Interference (BPI-PI) subscale), 3 months after beginning treatment may undergo re-randomization in a second step to cognitive behavioral therapy for chronic pain, spinal manipulation therapy, or yoga. Secondary outcomes include pain intensity, back pain-related disability, depression, and others. Participants will be assessed every three months until 12 months after initiating their final trial therapy. Companion economic and implementation analyses are also planned.The SCEPTER trial is currently recruiting and enrolling participants.Trial results will inform treatment decisions for the stepped management of chronic low back pain - a common and disabling condition. Additional analyses will help tailor treatment selection to individual patient characteristics, promote efficient resource use, and identify implementation barriers of interventions.clinicaltrials.gov Identifier: NCT04142177.

Metagenomic assembly enables novel organism discovery from microbial communities, but from most metagenomes it can only capture few abundant organisms. Here, we present a method - MetaPhlAn 4 - to integrate information from both metagenome assemblies and microbial isolate genomes for improved and more comprehensive metagenomic taxonomic profiling. From a curated collection of 1.01M prokaryotic reference and metagenome-assembled genomes, we defined unique marker genes for 26,970 species-level genome bins, 4,992 of them taxonomically unidentified at the species level. MetaPhlAn 4 explains ∼20% more reads in most international human gut microbiomes and >40% in less-characterized environments such as the rumen microbiome, and proved more accurate than available alternatives on synthetic evaluations while also reliably quantifying organisms with no cultured isolates. Application of the method to >24,500 metagenomes highlighted previously undetected species to be strong biomarkers for host conditions and lifestyles in human and mice microbiomes, and showed that even previously uncharacterized species can be genetically profiled at the resolution of single microbial strains. MetaPhlAn 4 thus integrates the novelty of metagenomic assemblies with the sensitivity and fidelity of reference-based analyses, providing efficient metagenomic profiling of uncharacterized species and enabling deeper and more comprehensive microbiome biomarker detection.

Mycobacteria diverge in a basic way from other bacterial and eukaryotic cells based on their distinct membrane structures. Here we report genome-wide transposon sequencing to discover the controllers of membrane compartmentalization in Mycobacterium smegmatis. cfa, a gene that encodes a putative cyclopropane-fatty-acyl-phospholipid synthase, shows the most significant effect on recovery from a membrane destabilizer, dibucaine. Lipidomic analysis of cfa deletion mutants demonstrates an essential role of Cfa in the synthesis of specific membrane lipids containing a C19:0 monomethyl-branched stearic acid. This molecule, also known as tuberculostearic acid (TBSA), has been intensively studied for decades due to its high level and genus-specific expression in mycobacteria. The proposed Cfa-mediated conversion of an unsaturation to a methylation matched well with its proposed role in lateral membrane organization, so we used new tools to determine the non-redundant effects of Cfa and TBSA in mycobacterial cells. cfa expression regulated major classes of membrane lipids including phosphatidylinositols, phosphatidylethanolamines and phosphatidylinositol mannosides. Cfa localized within the intracellular membrane domain (IMD), where it controls both cellular growth and recovery from membrane fluidization by facilitating subpolar localization of the IMD. Overall, cfa controls lateral membrane partitioning but does not detectably alter orthogonal transmembrane permeability. More generally, these results support the proposed role of the subpolar IMD as a subcellular site of mycobacterial control of membrane function.SignificanceMycobacteria remain major causes of disease worldwide based in part on their unusual membrane structures, which interface with the host. Here we discover the long sought biosynthetic origin of tuberculostearic acid (TBSA), a major fatty acid found selectively in mycobacteria, as well as its role in mycobacterial cells. The lipid is produced by an enzyme called Cfa, whose loss causes a growth defect and slow reformation of a membrane domain near the pole of the rod-shaped cell. Thus, our study offers mechanistic insights to the intrinsic molecular factors critical for mycobacterial plasma membrane partitioning.

With the increasing adoption of left atrial appendage occlusion (LAAO) procedures and the eligibility of patients for pulmonary vein isolation (PVI) post device placement, we examined the feasibility and safety of laser balloon (LB) for PVI in patients with prior LAAO.We retrospectively examined consecutive patients with paroxysmal or persistent, drug-resistant atrial fibrillation (AF) who underwent LB PVI, after Watchman FLX device implantation at Rush University Medical Center between January 2020 and December 2021.Seven patients (four persistent and three paroxysmal) with a mean age of 64 ± 11 years, predominantly male sex (86%), were included in the study. Two (29%) patients had prior cryoablation PVI with recurrence of AF. The mean CHALB PVI was safe and effective with 100% acute isolation of left-sided veins in patients with prior LAAO device.

The radio galaxy M87 is the central dominant galaxy of the Virgo Cluster. Very high-energy (VHE, ≳0.1 TeV) emission from M87 has been detected by imaging air Cherenkov telescopes. Recently, marginal evidence for VHE long-term emission has also been observed by the High Altitude Water Cherenkov Observatory, a gamma-ray and cosmic-ray detector array located in Puebla, Mexico. The mechanism that produces VHE emission in M87 remains unclear. This emission originates in its prominent jet, which has been spatially resolved from radio to X-rays. In this paper, we construct a spectral energy distribution from radio to gamma rays that is representative of the nonflaring activity of the source, and in order to explain the observed emission, we fit it with a lepto-hadronic emission model. We found that this model is able to explain nonflaring VHE emission of M87 as well as an orphan flare reported in 2005.

PurposeSevere community-acquired pneumonia (CAP) requiring intensive care unit admission is associated with significant acute and long-term morbidity and mortality. We hypothesized that downregulation of systemic and pulmonary inflammation with prolonged low-dose methylprednisolone treatment would accelerate pneumonia resolution and improve clinical outcomes.MethodsThis double-blind, randomized, placebo-controlled clinical trial recruited adult patients within 72-96h of hospital presentation. Patients were randomized in 1:1 ratio; an intravenous 40mg loading bolus was followed by 40mg/day through day 7 and progressive tapering during the 20-day treatment course. Randomization was stratified by site and need for mechanical ventilation (MV) at the time of randomization. Outcomes included a primary endpoint of 60-day all-cause mortality and secondary endpoints of morbidity and mortality up to 1year of follow-up.ResultsBetween January 2012 and April 2016, 586 patients from 42 Veterans Affairs Medical Centers were randomized, short of the 1420 target sample size because of low recruitment. 584 patients were included in the analysis. There was no significant difference in 60-day mortality between the methylprednisolone and placebo arms (16% vs. 18%; adjusted odds ratio 0.90, 95% CI 0.57-1.40). There were no significant differences in secondary outcomes or complications.ConclusionsIn patients with severe CAP, prolonged low-dose methylprednisolone treatment did not significantly reduce 60-day mortality. Treatment was not associated with increased complications.

Emergency ultrasound (EUS) is a critical component of emergency medicine (EM) resident education. Currently, there is no consensus list of competencies for EUS training, and graduating residents have varying levels of skill and comfort. The objective of this study was to define a widely accepted comprehensive list of EUS competencies for graduating EM residents through a modified Delphi method.We developed a list of EUS applications through a comprehensive literature search, the American College of Emergency Physicians list of core EUS benchmarks, and the Council of Emergency Medicine Residency-Academy of Emergency Ultrasound consensus document. We assembled a multi-institutional expert panel including 15 faculty members from diverse practice environments and geographical regions. The panel voted on the list of competencies through two rounds of a modified Delphi process using a modified Likert scale (1 = not at all important, 5 = very important) to determine levels of agreement for each application-with revisions occurring between the two rounds. High agreement for consensus was set at80%.Fifteen of 15 panelists completed the first-round survey (100%) that included 359 topics related to EUS. After the first round, 195 applications achieved high agreement, four applications achieved medium agreement, and 164 applications achieved low agreement. After the discussion, we removed three questions and added 13 questions. Fifteen of 15 panelists completed the second round of the survey (100%) with 209 of the 369 applications achieving consensus.Our final list represents expert opinion on EUS competencies for graduating EM residents. We hope to use this consensus list to implement a more consistent EUS curriculum for graduating EM residents and to standardize EUS training across EM residency programs.

BackgroundOlder adults and persons with medical co-morbidities are at increased risk for severe COVID-19. Several pharmacotherapies demonstrated to reduce the risk of COVID-19-related hospitalization and death have been authorized for use. We describe factors associated with receipt of outpatient COVID-19 pharmacotherapies in the Veterans Health Administration.MethodsWe conducted a retrospective cohort study among Veterans with risk factors for severe COVID-19 who tested positive for SARS-CoV-2 during January and February 2022. We compared receipt of any COVID-19 pharmacotherapy, including sotrovimab, nirmatrelvir plus ritonavir, molnupiravir, or remdesivir versus no antiviral or monoclonal antibody treatment according to demographic characteristics, place of residence, underlying medical conditions, and COVID-19 vaccination using multivariable logistic regression.ResultsDuring January and February 2022, 16,546 courses of sotrovimab, nirmatrelvir, and molnupiravir were allocated across the Veterans Health Administration. Among 111,717 Veterans testing positive for SARS-CoV-2, 4,233 (3.8%) received any COVID-19 pharmacotherapy, including 2,870 of 92,396 (3.1%) in January and 1,363 of 19,321 (7.1%) in February. Among a subset of 56,206 Veterans with documented COVID-19-related symptoms in the 30 days preceding positive SARS-CoV-2 test, 3,079 of 53,206 (5.5%) received any COVID-19 pharmacotherapy. Untreated Veterans had a median age of 60 years (interquartile range [IQR] 46-71 years) and median 3 underlying medical conditions (IQR 2-5). Veterans receiving any treatment were more likely to be older (adjusted odds ratio [aOR] 1.66, 95% confidence interval [CI] 1.52-1.80, 65-74 versus 50-64 years; aOR 1.67, 95% CI 1.53-1.84 ≥75 versus 50-64 years) and have a higher number of underlying conditions (aOR 1.63, 95% CI 1.48-1.79, 3-4 versus 1-2 conditions; aOR 2.17, 95% CI 1.98-2.39, ≥5 versus 1-2 conditions). Persons of Black versus White race (aOR 0.65, 95% CI 0.60-0.72) and well as persons of Hispanic ethnicity (aOR 0.88, 95% CI 0.77-0.99) were less likely to receive treatment.Conclusions and RelevanceAlthough supply of outpatient COVID-19 pharmacotherapies during January and February 2022 was limited, prescription of these pharmacotherapies was underutilized, consistent with early national patterns in dispensing. Racial and ethnic minorities were less likely to receive any pharmacotherapy.

Natural fragmentation of steel cylinders with different charge sizes is investigated, and the correlation of different cylinders is proposed. The Mott fragment distribution has some obvious shortcomings, including the difficulty of accurately determining the number of fragments. Besides, there is no unified and convenient method to describe the fragmentation behavior of shells with different structures. The results show that the fragmentation behavior of the cylinder is self-similar statistically and can be characterized by a new integrated linear formula $$C_L = a + b (C / M)$$ . Due to the existence of the end face and the charge clearance, the fragmentation performance of the cylinder is reduced to a constant value, and the effect of the wall thickness is small. The influence of the end face and charge clearance on fragmentation is investigated by 3D simulations, and the numerical results ensure good validation of the experimental data.