Creeping Fat in Crohn's Disease: Innocuous or innocuum?

In Crohn's disease, the characteristic expansion of mesenteric tissue on sites of intestinal inflammation is known as creeping fat. In a recent issue of Cell, Ha et al. report that translocation of gut bacteria to the mesenteries is associated with the formation of creeping fat.

Stromal Cells Covering Omental Fat-Associated Lymphoid Clusters Trigger Formation of Neutrophil Aggregates to Capture Peritoneal Contaminants.

The omentum is a visceral adipose tissue rich in fat-associated lymphoid clusters (FALCs) that collects peritoneal contaminants and provides a first layer of immunological defense within the abdomen. Here, we investigated the mechanisms that mediate the capture of peritoneal contaminants during peritonitis. Single-cell RNA sequencing and spatial analysis of omental stromal cells revealed that the surface of FALCs were covered by CXCL1+ mesothelial cells, which we termed FALC cover cells. Blockade of CXCL1 inhibited the recruitment and aggregation of neutrophils at FALCs during zymosan-induced peritonitis. Inhibition of protein arginine deiminase 4, an enzyme important for the release of neutrophil extracellular traps, abolished neutrophil aggregation and the capture of peritoneal contaminants by omental FALCs. Analysis of omental samples from patients with acute appendicitis confirmed neutrophil recruitment and bacterial capture at FALCs. Thus, specialized omental mesothelial cells coordinate the recruitment and aggregation of neutrophils to capture peritoneal contaminants.

A solar C/O and sub-solar metallicity in a hot Jupiter atmosphere.

Measurements of the atmospheric carbon (C) and oxygen (O) relative to hydrogen (H) in hot Jupiters (relative to their host stars) provide insight into their formation location and subsequent orbital migration1,2. Hot Jupiters that form beyond the major volatile (H2O/CO/CO2) ice lines and subsequently migrate post disk-dissipation are predicted have atmospheric carbon-to-oxygen ratios (C/O) near 1 and subsolar metallicities2, whereas planets that migrate through the disk before dissipation are predicted to be heavily polluted by infalling O-rich icy planetesimals, resulting in C/O < 0.5 and super-solar metallicities1,2. Previous observations of hot Jupiters have been able to provide bounded constraints on either H2O (refs. 3-5) or CO (refs. 6,7), but not both for the same planet, leaving uncertain4 the true elemental C and O inventory and subsequent C/O and metallicity determinations. Here we report spectroscopic observations of a typical transiting hot Jupiter, WASP-77Ab. From these, we determine the atmospheric gas volume mixing ratio constraints on both H2O and CO (9.5 × 10-5-1.5 × 10-4 and 1.2 × 10-4-2.6 × 10-4, respectively). From these bounded constraints, we are able to derive the atmospheric C/H ([Formula: see text] × solar) and O/H ([Formula: see text] × solar) abundances and the corresponding atmospheric carbon-to-oxygen ratio (C/O = 0.59 ± 0.08; the solar value is 0.55). The sub-solar (C+O)/H ([Formula: see text] × solar) is suggestive of a metal-depleted atmosphere relative to what is expected for Jovian-like planets1 while the near solar value of C/O rules out the disk-free migration/C-rich2 atmosphere scenario.

Structural Basis of Splicing Modulation by Antitumor Macrolide Compounds.

SF3B is a multi-protein complex essential for branch site (BS) recognition and selection during pre-mRNA splicing. Several splicing modulators with antitumor activity bind SF3B and thereby modulate splicing. Here we report the crystal structure of a human SF3B core in complex with pladienolide B (PB), a macrocyclic splicing modulator and potent inhibitor of tumor cell proliferation. PB stalls SF3B in an open conformation by acting like a wedge within a hinge, modulating SF3B's transition to the closed conformation needed to form the BS adenosine-binding pocket and stably accommodate the BS/U2 duplex. This work explains the structural basis for the splicing modulation activity of PB and related compounds, and reveals key interactions between SF3B and a common pharmacophore, providing a framework for future structure-based drug design.

The cryo-EM structure of the SF3b spliceosome complex bound to a splicing modulator reveals a pre-mRNA substrate competitive mechanism of action.

Somatic mutations in spliceosome proteins lead to dysregulated RNA splicing and are observed in a variety of cancers. These genetic aberrations may offer a potential intervention point for targeted therapeutics. SF3B1, part of the U2 small nuclear RNP (snRNP), is targeted by splicing modulators, including E7107, the first to enter clinical trials, and, more recently, H3B-8800. Modulating splicing represents a first-in-class opportunity in drug discovery, and elucidating the structural basis for the mode of action opens up new possibilities for structure-based drug design. Here, we present the cryogenic electron microscopy (cryo-EM) structure of the SF3b subcomplex (SF3B1, SF3B3, PHF5A, and SF3B5) bound to E7107 at 3.95 Å. This structure shows that E7107 binds in the branch point adenosine-binding pocket, forming close contacts with key residues that confer resistance upon mutation: SF3B1R1074H and PHF5AY36C The structure suggests a model in which splicing modulators interfere with branch point adenosine recognition and supports a substrate competitive mechanism of action (MOA). Using several related chemical probes, we validate the pose of the compound and support their substrate competitive MOA by comparing their activity against both strong and weak pre-mRNA substrates. Finally, we present functional data and structure-activity relationship (SAR) on the PHF5AR38C mutation that sensitizes cells to some chemical probes but not others. Developing small molecule splicing modulators represents a promising therapeutic approach for a variety of diseases, and this work provides a significant step in enabling structure-based drug design for these elaborate natural products. Importantly, this work also demonstrates that the utilization of cryo-EM in drug discovery is coming of age.

Percutaneous Coronary Intervention Versus Coronary Artery Bypass Grafting in Patients With Left Main Disease With and Without Diabetes: Findings From a Pooled Analysis of 4 Randomized Clinical Trials.

BACKGROUND: Diabetes may be associated with differential outcomes in patients undergoing left main coronary revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). The aim of this study was to investigate outcomes in patients with left main disease with and without diabetes randomized to PCI versus CABG. METHODS: Individual patient data were pooled from 4 trials (SYNTAX [Synergy Between PCI With Taxus and Cardiac Surgery], PRECOMBAT [Premier of Randomized Comparison of Bypass Surgery Versus Angioplasty Using Sirolimus-Eluting Stent in Patients With Left Main Coronary Artery Disease], NOBLE [Nordic-Baltic-British Left Main Revascularisation Study], and EXCEL [Evaluation of XIENCE Versus Coronary Artery Bypass Surgery for Effectiveness of Left Main Revascularization]) that randomized patients with left main disease to PCI or CABG. Patients were considered suitable for either approach. Patients were categorized by diabetes status. Kaplan-Meier event rates, Cox model hazard ratios, and interactions were assessed. RESULTS: Among 4393 patients, 1104 (25.1%) had diabetes. Patients with diabetes experienced higher rates of 5-year death (158/1104 [Kaplan-Meier rate, 14.7%] versus 297/3289 [9.3%]; P<0.001), spontaneous myocardial infarction (MI; 67/1104 [6.7%] versus 114/3289 [3.7%]; P<0.001), and repeat revascularization (189/1104 [18.5%] versus 410/3289 [13.2%]; P<0.001). Rates of all-cause mortality did not differ after PCI versus CABG in those with (84/563 [15.3%] versus 74/541 [14.1%]; hazard ratio, 1.11 [95% CI, 0.82-1.52]) or without (155/1634 [9.7%] versus 142/1655 [8.9%]; hazard ratio, 1.08 [95% CI, 0.86-1.36; PintHR=0.87) diabetes. Rates of stroke within 1 year were lower with PCI versus CABG in the entire population, with no heterogeneity based on diabetes status (PintHR=0.51). The 5-year rates of spontaneous MI and repeat coronary revascularization were higher after PCI regardless of diabetes status (spontaneous MI: 45/563 [8.9%] versus 22/541 [4.4%] in diabetes and 82/1634 [5.3%] versus 32/1655 [2.1%] in no diabetes, PintHR=0.47; repeat revascularization: 127/563 [24.5%] versus 62/541 [12.4%] in diabetes and 254/1634 [16.3%] versus 156/1655 [10.1%] in no diabetes, PintHR=0.18). For spontaneous MI and repeat revascularization, there were greater absolute risk differences beyond 1 year in patients with diabetes (4.9% and 9.9%) compared with those without (2.1% and 4.3%; PintARD=0.047 and 0.016). CONCLUSIONS: In patients with left main disease considered equally suitable for PCI or CABG and with largely low to intermediate SYNTAX scores, diabetes was associated with higher rates of death and cardiovascular events through 5 years. Compared with CABG, PCI resulted in no difference in the risk of death and a lower risk of early stroke regardless of diabetes status, and a higher risk of spontaneous MI and repeat coronary revascularization, with larger late absolute excess risks in patients with diabetes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01205776, NCT0146651, NCT00422968, and NCT00114972.

Formation of ER-lumenal intermediates during export of Plasmodium proteins containing transmembrane-like hydrophobic sequences.

During the blood stage of a malaria infection, malaria parasites export both soluble and membrane proteins into the erythrocytes in which they reside. Exported proteins are trafficked via the parasite endoplasmic reticulum and secretory pathway, before being exported across the parasitophorous vacuole membrane into the erythrocyte. Transport across the parasitophorous vacuole membrane requires protein unfolding, and in the case of membrane proteins, extraction from the parasite plasma membrane. We show that trafficking of the exported Plasmodium protein, Pf332, differs from that of canonical eukaryotic soluble-secreted and transmembrane proteins. Pf332 is initially ER-targeted by an internal hydrophobic sequence that unlike a signal peptide, is not proteolytically removed, and unlike a transmembrane segment, does not span the ER membrane. Rather, both termini of the hydrophobic sequence enter the ER lumen and the ER-lumenal species is a productive intermediate for protein export. Furthermore, we show in intact cells, that two other exported membrane proteins, SBP1 and MAHRP2, assume a lumenal topology within the parasite secretory pathway. Although the addition of a C-terminal ER-retention sequence, recognised by the lumenal domain of the KDEL receptor, does not completely block export of SBP1 and MAHRP2, it does enhance their retention in the parasite ER. This indicates that a sub-population of each protein adopts an ER-lumenal state that is an intermediate in the export process. Overall, this suggests that although many exported proteins traverse the parasite secretory pathway as typical soluble or membrane proteins, some exported proteins that are ER-targeted by a transmembrane segment-like, internal, non-cleaved hydrophobic segment, do not integrate into the ER membrane, and form an ER-lumenal species that is a productive export intermediate. This represents a novel means, not seen in typical membrane proteins found in model systems, by which exported transmembrane-like proteins can be targeted and trafficked within the lumen of the secretory pathway.

Inferring Consciousness in Phylogenetically Distant Organisms.

The neural dynamics of subjectivity (NDS) approach to the biological explanation of consciousness is outlined and applied to the problem of inferring consciousness in animals phylogenetically distant from ourselves. The NDS approach holds that consciousness or felt experience is characteristic of systems whose nervous systems have been shaped to realize subjectivity through a combination of network interactions and large-scale dynamic patterns. Features of the vertebrate brain architecture that figure in other accounts of the biology of consciousness are viewed as inessential. Deep phylogenetic branchings in the animal kingdom occurred before the evolution of complex behavior, cognition, and sensing. These capacities arose independently in brain architectures that differ widely across arthropods, vertebrates, and cephalopods, but with conservation of large-scale dynamic patterns of a kind that have an apparent link to felt experience in humans. An evolutionary perspective also motivates a strongly gradualist view of consciousness; a simple distinction between conscious and nonconscious animals will probably be replaced with a view that admits differences of degree, perhaps on many dimensions.

Using unsupervised clustering approaches to identify common mental health profiles and associated mental health-care service-use patterns in Ontario, Canada.

Mental health is a complex, multidimensional concept that goes beyond clinical diagnoses, including psychological distress, life stress, and well-being. In this study, we aimed to use unsupervised clustering approaches to identify multidimensional mental health profiles that exist in the population, and their associated service-use patterns. The data source was the 2012 Canadian Community Health Survey-Mental Health, linked to administrative health-care data; all Ontario, Canada, adult respondents were included. We used a partitioning around medoids clustering algorithm with Gower's proximity to identify groups with distinct combinations of mental health indicators and described them according to their sociodemographic and service-use characteristics. We identified 4 groups with distinct mental health profiles, including 1 group that met the clinical threshold for a depressive diagnosis, with the remaining 3 groups expressing differences in positive mental health, life stress, and self-rated mental health. The 4 groups had different age, employment, and income profiles and exhibited differential access to mental health-care services. This study represents the first step in identifying complex profiles of mental health at the population level in Ontario. Further research is required to better understand the potential causes and consequences of belonging to each of the mental health profiles identified. This article is part of a Special Collection on Mental Health.

Improving prevalence estimates of mental health and well-being indicators among Sexual Minority Men: A Propensity Weighting Approach.

The prevalence and relative disparities of mental health outcomes and well-being indicators are often inconsistent across studies of Sexual Minority Men (SMM) due to selection biases in community-based surveys (non-probability sample), as well as misclassification biases in population-based surveys where some SMM often conceal their sexual orientation identities. The current paper estimated the prevalence of mental health related outcomes (depressive symptoms, mental health service use [MHSU], anxiety) and well-being indicators (loneliness and self-rated mental health) among SMM, broken down by sexual orientation using the Adjusted Logistic Propensity score (ALP) weighting. We applied the ALP to correct for selection biases in the 2019 Sex Now data (a community-based survey of SMMs in Canada) by reweighting it to the 2015-2018 Canadian Community Health Survey (a population survey from Statistics Canada). For all SMMs, the ALP-weighted prevalence of depressive symptoms is 15.96% (95% CI: 11.36%, 23.83%), while for MHSU, it is 32.13% (95% CI: 26.09, 41.20). The ALP estimates lie in between the crude estimates from the two surveys. This method was successful in providing a more accurate estimate than relying on results from one survey alone. We recommend to the use of ALP on other minority populations under certain assumptions.

Work as a social determinant of health in high-income countries: past, present, and future.

This paper, the first in a three-part Series on work and health, provides a narrative review of research into work as a social determinant of health over the past 25 years, the key emerging challenges in this field, and the implications of these challenges for future research. By use of a conceptual framework for work as a social determinant of health, we identified six emerging challenges: (1) the influence of technology on the nature of work in high-income countries, culminating in the sudden shift to telework during the COVID-19 pandemic; (2) the intersectionality of work with gender, sexual orientation, age, race, ethnicity, migrant status, and socioeconomic status as codeterminants of health disparities; (3) the arrival in many Organisation for Economic Co-operation and Development countries of large migrant labour workforces, who are often subject to adverse working conditions and social exclusion; (4) the development of precarious employment as a feature of many national labour markets; (5) the phenomenon of working long and irregular hours with potential health consequences; and (6) the looming threat of climate change's effects on work. We conclude that profound changes in the nature and availability of work over the past few decades have led to widespread new psychosocial and physical exposures that are associated with adverse health outcomes and contribute to increasing disparities in health. These new exposures at work will require novel and creative methods of data collection for monitoring of their potential health impacts to protect the workforce, and for new research into better means of occupational health promotion and protection. There is also an urgent need for a better integration of occupational health within public health, medicine, the life sciences, and the social sciences, with the work environment explicitly conceptualised as a major social determinant of health.

Integrated management of HIV, diabetes, and hypertension in sub-Saharan Africa (INTE-AFRICA): a pragmatic cluster-randomised, controlled trial.

BACKGROUND: In sub-Saharan Africa, health-care provision for chronic conditions is fragmented. The aim of this study was to determine whether integrated management of HIV, diabetes, and hypertension led to improved rates of retention in care for people with diabetes or hypertension without adversely affecting rates of HIV viral suppression among people with HIV when compared to standard vertical care in medium and large health facilities in Uganda and Tanzania. METHODS: In INTE-AFRICA, a pragmatic cluster-randomised, controlled trial, we randomly allocated primary health-care facilities in Uganda and Tanzania to provide either integrated care or standard care for HIV, diabetes, and hypertension. Random allocation (1:1) was stratified by location, infrastructure level, and by country, with a permuted block randomisation method. In the integrated care group, participants with HIV, diabetes, or hypertension were managed by the same health-care workers, used the same pharmacy, had similarly designed medical records, shared the same registration and waiting areas, and had an integrated laboratory service. In the standard care group, these services were delivered vertically for each condition. Patients were eligible to join the trial if they were living with confirmed HIV, diabetes, or hypertension, were aged 18 years or older, were living within the catchment population area of the health facility, and were likely to remain in the catchment population for 6 months. The coprimary outcomes, retention in care (attending a clinic within the last 6 months of study follow-up) for participants with either diabetes or hypertension (tested for superiority) and plasma viral load suppression for those with HIV (>1000 copies per mL; tested for non-inferiority, 10% margin), were analysed using generalised estimating equations in the intention-to-treat population. This trial is registered with ISCRTN 43896688. FINDINGS: Between June 30, 2020, and April 1, 2021 we randomly allocated 32 health facilities (17 in Uganda and 15 in Tanzania) with 7028 eligible participants to the integrated care or the standard care groups. Among participants with diabetes, hypertension, or both, 2298 (75·8%) of 3032 were female and 734 (24·2%) of 3032 were male. Of participants with HIV alone, 2365 (70·3%) of 3365 were female and 1000 (29·7%) of 3365 were male. Follow-up lasted for 12 months. Among participants with diabetes, hypertension, or both, the proportion alive and retained in care at study end was 1254 (89·0%) of 1409 in integrated care and 1457 (89·8%) of 1623 in standard care. The risk differences were -0·65% (95% CI -5·76 to 4·46; p=0·80) unadjusted and -0·60% (-5·46 to 4·26; p=0·81) adjusted. Among participants with HIV, the proportion who had a plasma viral load of less than 1000 copies per mL was 1412 (97·0%) of 1456 in integrated care and 1451 (97·3%) of 1491 in standard care. The differences were -0·37% (one-sided 95% CI -1·99 to 1·26; pnon-inferiority<0·0001 unadjusted) and -0·36% (-1·99 to 1·28; pnon-inferiority<0·0001 adjusted). INTERPRETATION: In sub-Saharan Africa, integrated chronic care services could achieve a high standard of care for people with diabetes or hypertension without adversely affecting outcomes for people with HIV. FUNDING: European Union Horizon 2020 and Global Alliance for Chronic Diseases.

Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease.

BACKGROUND: No therapies are currently approved for the treatment of pulmonary hypertension in patients with interstitial lung disease. The safety and efficacy of inhaled treprostinil for patients with this condition are unclear. METHODS: We enrolled patients with interstitial lung disease and pulmonary hypertension (documented by right heart catheterization) in a multicenter, randomized, double-blind, placebo-controlled, 16-week trial. Patients were assigned in a 1:1 ratio to receive inhaled treprostinil, administered by means of an ultrasonic, pulsed-delivery nebulizer in up to 12 breaths (total, 72 µg) four times daily, or placebo. The primary efficacy end point was the difference between the two groups in the change in peak 6-minute walk distance from baseline to week 16. Secondary end points included the change in N-terminal pro-B-type natriuretic peptide (NT-proBNP) level at week 16 and the time to clinical worsening. RESULTS: A total of 326 patients underwent randomization, with 163 assigned to inhaled treprostinil and 163 to placebo. Baseline characteristics were similar in the two groups. At week 16, the least-squares mean difference between the treprostinil group and the placebo group in the change from baseline in the 6-minute walk distance was 31.12 m (95% confidence interval [CI], 16.85 to 45.39; P<0.001). There was a reduction of 15% in NT-proBNP levels from baseline with inhaled treprostinil as compared with an increase of 46% with placebo (treatment ratio, 0.58; 95% CI, 0.47 to 0.72; P<0.001). Clinical worsening occurred in 37 patients (22.7%) in the treprostinil group as compared with 54 patients (33.1%) in the placebo group (hazard ratio, 0.61; 95% CI, 0.40 to 0.92; P = 0.04 by the log-rank test). The most frequently reported adverse events were cough, headache, dyspnea, dizziness, nausea, fatigue, and diarrhea. CONCLUSIONS: In patients with pulmonary hypertension due to interstitial lung disease, inhaled treprostinil improved exercise capacity from baseline, assessed with the use of a 6-minute walk test, as compared with placebo. (Funded by United Therapeutics; INCREASE ClinicalTrials.gov number, NCT02630316.).

Survival analysis from the INCREASE study in PH-ILD: evaluating the impact of treatment crossover on overall mortality.

OBJECTIVE: A post-hoc analysis of the INCREASE trial and its open-label extension (OLE) was performed to evaluate whether inhaled treprostinil has a long-term survival benefit in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). METHODS: Two different models of survival were employed; the inverse probability of censoring weighting (IPCW) and the rank-preserving structural failure time (RPSFT) models both allow construction of a pseudo-placebo group, thereby allowing for long-term survival evaluation of patients with PH-ILD receiving inhaled treprostinil. Time-varying stabilised weights were calculated by fitting Cox proportional hazards models based on the baseline and time-varying prognostic factors to generate weighted Cox regression models with associated adjusted HRs. RESULTS: In the INCREASE trial, there were 10 and 12 deaths in the inhaled treprostinil and placebo arms, respectively, during the 16-week randomised trial. During the OLE, all patients received inhaled treprostinil and there were 29 and 33 deaths in the prior inhaled treprostinil arm and prior placebo arm, respectively. With a conventional analysis, the HR for death was 0.71 (95% CI 0.46 to 1.10; p=0.1227). Both models demonstrated significant reductions in death associated with inhaled treprostinil treatment with HRs of 0.62 (95% CI 0.39 to 0.99; p=0.0483) and 0.26 (95% CI 0.07 to 0.98; p=0.0473) for the IPCW and RPSFT methods, respectively. CONCLUSION: Two independent modelling techniques that have been employed in the oncology literature both suggest a long-term survival benefit associated with inhaled treprostinil treatment in patients with PH-ILD.

Immune Mechanisms Underpinning Long COVID: Collegium Internationale Allergologicum Update 2024.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can result in a prolonged multisystem disorder termed long COVID, which may affect up to 10% of people following coronavirus disease 2019 (COVID-19). It is currently unclear why certain individuals do not fully recover following SARS-CoV-2 infection. SUMMARY: In this review, we examine immunological mechanisms that may underpin the pathophysiology of long COVID. These mechanisms include an inappropriate immune response to acute SARS-CoV-2 infection, immune cell exhaustion, immune cell metabolic reprogramming, a persistent SARS-CoV-2 reservoir, reactivation of other viruses, inflammatory responses impacting the central nervous system, autoimmunity, microbiome dysbiosis, and dietary factors. KEY MESSAGES: Unfortunately, the currently available diagnostic and treatment options for long COVID are inadequate, and more clinical trials are needed that match experimental interventions to underlying immunological mechanisms.

Evaluation of the Ontario Mandatory Working-at-Heights Training Requirement in Construction, 2012‒2019.

The province of Ontario, Canada, implemented mandatory day-long training for construction workers required to use fall-protection equipment. More than 400 000 training sessions were completed by 2017 when the requirement took full effect. The lost-time workers' compensation claim incidence rate attributable to falls targeted by the training was 19% lower in 2017-2019 than in 2012-2014. Rates for two comparator injuries increased or stayed the same. The decline in targeted fall claim incidence rate of the other Canadian provinces was 6%. (Am J Public Health. 2024;114(1):38-41. https://doi.org/10.2105/AJPH.2023.307440).

Variation in occupational exposure risk for COVID-19 workers' compensation claims across pandemic waves in Ontario.

OBJECTIVES: To understand rates of work-related COVID-19 (WR-C19) infection by occupational exposures across waves of the COVID-19 pandemic in Ontario, Canada. METHODS: We combined workers' compensation claims for COVID-19 with data from Statistics Canada's Labour Force Survey, to estimate rates of WR-C19 among workers spending the majority of their working time at the workplace between 1 April 2020 and 30 April 2022. Occupational exposures, imputed using a job exposure matrix, were whether the occupation was public facing, proximity to others at work, location of work and a summary measure of low, medium and high occupational exposure. Negative binomial regression models examined the relationship between occupational exposures and risk of WR-C19, adjusting for covariates. RESULTS: Trends in rates of WR-C19 differed from overall COVID-19 cases among the working-aged population. All occupational exposures were associated with increased risk of WR-C19, with risk ratios for medium and high summary exposures being 1.30 (95% CI 1.09 to 1.55) and 2.46 (95% CI 2.10 to 2.88), respectively, in fully adjusted models. The magnitude of associations between occupational exposures and risk of WR-C19 differed across waves of the pandemic, being weakest for most exposures in period March 2021 to June 2021, and highest at the start of the pandemic and during the Omicron wave (December 2021 to April 2022). CONCLUSIONS: Occupational exposures were consistently associated with increased risk of WR-C19, although the magnitude of this relationship differed across pandemic waves in Ontario. Preparation for future pandemics should consider more accurate reporting of WR-C19 infections and the potential dynamic nature of occupational exposures.

Optimized arylomycins are a new class of Gram-negative antibiotics.

Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins-a class of natural products with weak activity and limited spectrum-to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.

The Known Biology of Neuropathic Pain and Its Relevance to Pain Management.

Patients with neuropathic pain are heterogeneous in pathophysiology, etiology, and clinical presentation. Signs and symptoms are determined by the nature of the injury and factors such as genetics, sex, prior injury, age, culture, and environment. Basic science has provided general information about pain etiology by studying the consequences of peripheral injury in rodent models. This is associated with the release of inflammatory cytokines, chemokines, and growth factors that sensitize sensory nerve endings, alter gene expression, promote post-translational modification of proteins, and alter ion channel function. This leads to spontaneous activity in primary afferent neurons that is crucial for the onset and persistence of pain and the release of secondary mediators such as colony-stimulating factor 1 from primary afferent terminals. These promote the release of tertiary mediators such as brain-derived neurotrophic factor and interleukin-1ß from microglia and astrocytes. Tertiary mediators facilitate the transmission of nociceptive information at the spinal, thalamic, and cortical levels. For the most part, these findings have failed to identify new therapeutic approaches. More recent basic science has better mirrored the clinical situation by addressing the pathophysiology associated with specific types of injury, refinement of methodology, and attention to various contributory factors such as sex. Improved quantification of sensory profiles in each patient and their distribution into defined clusters may improve translation between basic science and clinical practice. If such quantification can be traced back to cellular and molecular aspects of pathophysiology, this may lead to personalized medicine approaches that dictate a rational therapeutic approach for each individual.

A Retrospective Cohort Analysis of Mental Health-Related Emergency Department Visits Among Veterans and Non-Veterans Residing in Ontario, Canada: Une analyse de cohorte rétrospective des visites au service d'urgence liées à la santé mentale parmi les vétérans et non-vétérans résidant en Ontario, Canada.

OBJECTIVES: Emergency departments (EDs) are a vital part of healthcare systems, at times acting as a gateway to community-based mental health (MH) services. This may be particularly true for veterans of the Royal Canadian Mounted Police who were released prior to 2013 and the Canadian Armed Forces, as these individuals transition from federal to provincial healthcare coverage on release and may use EDs because of delays in obtaining a primary care provider. We aimed to estimate the hazard ratio (HR) of MH-related ED visits between veterans and non-veterans residing in Ontario, Canada: (1) overall; and by (2) sex; and (3) length of service. METHODS: This retrospective cohort study used administrative healthcare data from 18,837 veterans and 75,348 age-, sex-, geography-, and income-matched non-veterans residing in Ontario, Canada between April 1, 2002, and March 31, 2020. Anderson-Gill regression models were used to estimate the HR of recurrent MH-related ED visits during the period of follow-up. Sex and length of service were used as stratification variables in the models. RESULTS: Veterans had a higher adjusted HR (aHR) of MH-related ED visits than non-veterans (aHR, 1.97, 95% CI, 1.70 to 2.29). A stronger effect was observed among females (aHR, 3.29; 95% CI, 1.96 to 5.53) than males (aHR, 1.78; 95% CI, 1.57 to 2.01). Veterans who served for 5-9 years had a higher rate of use than non-veterans (aHR, 3.76; 95% CI, 2.34 to 6.02) while veterans who served for 30+ years had a lower rate compared to non-veterans (aHR, 0.60; 95% CI, 0.42 à 0.84). CONCLUSIONS: Rates of MH-related ED visits are higher among veterans overall compared to members of the Ontario general population, but usage is influenced by sex and length of service. These findings indicate that certain subpopulations of veterans, including females and those with fewer years of service, may have greater acute mental healthcare needs and/or reduced access to primary mental healthcare.