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PURPOSE: Exertional heat stress can induce systemic endotoxin exposure and a pro-inflammatory cascade, likely impairing thermoregulation. Cannabidiol (CBD) is protective in pre-clinical models of tissue ischaemia and inflammation. Therefore, this study examined the effects of CBD ingestion on exercise-induced thermoregulatory and inflammatory responses. METHODS: In a randomised, double-blinded study, thirteen active males (age 25 ± 5 y; peak oxygen uptake [V̇O2peak] 50.4 ± 3.2 mL/kg/min) ingested 298 mg CBD or placebo 105 minutes before 1 h treadmill exercise (60-65% V̇O2peak) in 32 °C and 50% relative humidity. Core temperature, skin temperature, heart rate, subjective outcomes and sweat loss were assessed during/after exercise. Plasma osmolality, plasma volume changes and plasma markers of intestinal damage (I-FABP), monocyte activation (CD14) and inflammatory cytokine responses (IL-6, IL-8 and TNF-α) were assessed at baseline, pre-exercise, 20- and 90-min post-exercise. RESULTS: Core temperature (∆ 1.69 ± 0.48 °C [CBD] and 1.79 ± 0.53 °C [Placebo]) and I-FABP increased during exercise, with no differences between conditions (p > 0.050). Mean (95% CI) CD14 was 1776 (463 to 3090) pg/mL greater 90 min post-exercise in placebo (p = 0.049). Median (interquartile range) peak IL-6 concentration was -0.8 (-1.1, -0.3) pg/mL less in CBD (p = 0.050), whilst the between-conditions difference in IL-6 area under curve was -113 (-172, 27) pg/mL·270 min (p = 0.054). CONCLUSIONS: CBD did not affect thermoregulation during exertional heat stress but appeared to elicit minor immunosuppressive effects, reducing CD14 and IL-6 responses, warranting investigation in humans under more severe heat strain and other pro-inflammatory scenarios.

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Importance: Since 2014, Medicaid expansion has been implemented in many states across the US, increasing health care access among vulnerable populations, including formerly incarcerated people who experience higher mortality rates than the general population. Objective: To examine population-level association of Medicaid expansion with postrelease mortality from all causes, unintentional drug overdoses, opioid overdoses, polydrug overdoses, suicides, and homicides among formerly incarcerated people in Rhode Island (RI), which expanded Medicaid, compared with North Carolina (NC), which did not expand Medicaid during the study period. Design, Setting, and Participants: A cohort study was conducted using incarceration release data from January 1, 2009, to December 31, 2018, linked to death records from January 1, 2009, to December 31, 2019, on individuals released from incarceration in RI and NC. Data analysis was performed from August 20, 2022, to February 15, 2024. Participants included those aged 18 years or older who were released from incarceration. Individuals who were temporarily held during ongoing judicial proceedings, died during incarceration, or not released from incarceration during the study period were excluded. Exposure: Full Medicaid expansion in RI effective January 1, 2014. Main Outcomes and Measures: Mortality from all causes, unintentional drug overdoses, unintentional opioid and polydrug overdoses, suicides, and homicides. Results: Between 2009 and 2018, 17 824 individuals were released from RI prisons (mean [SD] age, 38.39 [10.85] years; 31 512 [89.1%] male) and 160 861 were released from NC prisons (mean [SD] age, 38.28 [10.84] years; 209 021 [87.5%] male). Compared with NC, people who were formerly incarcerated in RI experienced a sustained decrease of 72 per 100 000 person-years (95% CI, -108 to -36 per 100 000 person-years) in all-cause mortality per quarter after Medicaid expansion. Similar decreases were observed in RI in drug overdose deaths (-172 per 100 000 person-years per 6 months; 95% CI, -226 to -117 per 100 000 person-years), including opioid and polydrug overdoses, and homicide deaths (-23 per 100 000 person-years per year; 95% CI, -50 to 4 per 100 000 person-years) after Medicaid expansion. Suicide mortality did not change after Medicaid expansion. After Medicaid expansion in RI, non-Hispanic White individuals experienced 3 times greater sustained decreases in all-cause mortality than all racially minoritized individuals combined, while non-Hispanic Black individuals did not experience any substantial benefits. There was no modification by sex. Individuals aged 30 years or older experienced greater all-cause mortality reduction after Medicaid expansion than those younger than 30 years. Conclusions and Relevance: Medicaid expansion in RI was associated with a decrease in all-cause, overdose, and homicide mortality among formerly incarcerated people. However, these decreases were most observed among White individuals, while racially minoritized individuals received little to no benefits in the studied outcomes.

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With the increased attention focused on active learning, educators strive to find better and more innovative ways to engage students in the classroom. One of the hurtles that educators are presented with is that the classroom is no longer limited to a physical location but rather students and professor can meet via the internet, Before COVID-19, distance or remote learning was something that students, by and large, had the option of choosing in which whether to engage. Students had the option to take "online courses," whether those be synchronous remote learning or asynchronous online courses. Indeed, numerous studies have focused on investigating the efficacy of many different approaches to distance and online learning. Unfortunately, COVID 19 mandated a rapid transition to remote learning, and with this forced change has come what some students describe as "Zoom fatigue" (Wolf CR. Psychology Today, May 2020). Many students reported feeling exhausted, overwhelmed, and disengaged by the dramatic increase in mandated distance education required by the COVID pandemic. Video conferencing has become the "go-to" panacea for education during this time, and students are spending unprecedented amounts of time in front of a screen when normally they would be in a classroom. This heretofore singular and unique approach to education coupled with decreased peer-to-peer interaction has caused a problem with student engagement (Goodman BE, Barker MK, Cooke JE. Adv Physiol Educ 42: 417-423, 2018). Students' engagement and performance have decreased during COVID-19 because of forced online learning and lack of peer interaction. We hypothesize that creating a nongraded, fun, and relaxing physiology-focused "Trivia Night" will increase student engagement and performance on summative assessments. Using a master's level class progressing through the respiratory physiology module utilizing remote, synchronous lectures to deliver content, we introduced a voluntary Trivia Night review session with teams randomly assigned to increase interaction among peers and review respiratory physiology material.NEW & NOTEWORTHY This article presents the effectiveness of the use of the "pub Trivia Night" to facilitate learning, deconstruct misconceptions, and increase engagement during remote teaching due to the COVID-19 pandemic.

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Since 2014, the stony coral tissue loss disease (SCTLD) has been decimating corals in the Caribbean. Although the trigger of this outbreak remains elusive, evidence suggests waterborne sediment-mediated disease transmission. The outbreak reportedly initiated in September 2014 at a reef site off Virginia Key (VKR), during extensive dredging operations at the Port of Miami. Here we use a high-resolution ocean model to identify the potential driver of the outbreak by simulating the dispersal of dredged sediments, wastewater plumes and disease agents. Our results suggest that VKR could have been impacted by fine sediments produced by dredging operations, especially those involving non-conventional rock-chopping techniques. Wastewater contamination was unlikely. Additionally, our connectivity analysis indicates potential disease transmission from other affected reefs to VKR. Our results therefore suggest that dredging operations might be responsible for the onset of the epidemics. This underscores the need for stricter operational guidelines in future dredging projects.

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Risk stratification has gained an increasing role in predicting outcomes and guiding the treatment of patients with pulmonary arterial hypertension (PAH). The most predictive prognostic factors are three noninvasive parameters (World Health Organization functional class, 6-min walk distance and natriuretic peptides) that are included in all currently validated risk stratification tools. However, suffering from limitations mainly related to reduced specificity of PAH severity, these variables may not always be adequate in isolation for guiding individualised treatment decisions. Moreover, with effective combination treatment regimens and emerging PAH therapies, markers associated with pulmonary vascular remodelling are expected to become of increasing relevance in guiding the treatment of patients with PAH. While reaching a low mortality risk, assessed with a validated risk tool, remains an important treatment goal, preliminary data suggest that invasive haemodynamics and cardiac imaging may add incremental value in guiding treatment decisions.

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An organism's genomic DNA must be accurately duplicated during each cell cycle. DNA synthesis is catalysed by DNA polymerase enzymes, which extend nucleotide polymers in a 5' to 3' direction. This inherent directionality necessitates that one strand is synthesised forwards (leading), while the other is synthesised backwards discontinuously (lagging) to couple synthesis to the unwinding of duplex DNA. Eukaryotic cells possess many diverse polymerases that coordinate to replicate DNA, with the three main replicative polymerases being Pol α, Pol δ and Pol ε. Studies conducted in yeasts and human cells utilising mutant polymerases that incorporate molecular signatures into nascent DNA implicate Pol ε in leading strand synthesis and Pol α and Pol δ in lagging strand replication. Recent structural insights have revealed how the spatial organization of these enzymes around the core helicase facilitates their strand-specific roles. However, various challenging situations during replication require flexibility in the usage of these enzymes, such as during replication initiation or encounters with replication-blocking adducts. This review summarises the roles of the replicative polymerases in bulk DNA replication and explores their flexible and dynamic deployment to complete genome replication. We also examine how polymerase usage patterns can inform our understanding of global replication dynamics by revealing replication fork directionality to identify regions of replication initiation and termination.

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BACKGROUND: Self-directed violence (SDV) comprises both suicide and self-injury and represents a pressing problem among incarcerated persons. Negative impacts of SDV in correctional settings also extend to behavioral health clinicians (BHCs) (e.g., job turnover). Correctional SDV risk assessment and management standards include staff training as part of the comprehensive approach. The Core Competency Model for Corrections (CCM-C) is a novel, evidence-informed training program for BHCs covering both clinician self-management and clinical care skills. METHODS: This pilot trial is a type 3 hybrid implementation-effectiveness approach. It will employ a wait-list control sequential cross-over design. Participants (N = 50-100) will be BHCs employed by the North Carolina Department of Adult Corrections. Following stratification for years of clinical experience, BHCs will be randomly assigned to (1) a training group that receives CCM-C immediately and (2) a wait-list control receiving CCM-C approximately 6 weeks later. Electronically administrated survey evaluation will occur across baseline and two follow-up (i.e., 2 weeks after each training session) time points. DISCUSSION: The primary outcome is feasibility assessed through collaboration with a Corrections Advisory Panel and feedback from BHCs. Secondary effectiveness outcomes that will be evaluated over time include SDV-related knowledge, attitudes, stigma, and intent to use training content. We will examine a tertiary outcome, namely compassion fatigue. Clinical trial limitations and impacts are discussed. TRIAL REGISTRATION: Clinicaltrials.gov, NCT06359574. This study was registered on 04/05/2024.

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INTRODUCTION: Solid metals may create a variety of injuries. White phosphorous (WP) is a metal that causes both caustic and thermal injuries. Because of its broad use in munitions and smoke screens during conflicts and wars, all military clinicians should be competent at WP injury identification and acute therapy, as well as long-term consequence recognition. MATERIALS AND METHODS: English-language manuscripts addressing WP injuries were curated from PubMed and Medline from inception to January 31, 2024. Data regarding WP injury identification, management, and sequelae were abstracted to construct a Scale for the Assessment of Narrative Review Articles guideline-consistent narrative review. RESULTS: White phosphorous appears to be ubiquitous in military conflicts. White phosphorous creates a characteristic wound appearance accompanied by smoke, a garlic aroma, and spontaneous combustion on contact with air. Decontamination and burning prevention or cessation are key and may rely on aqueous irrigation and submersion or immersion in substances that prevent air contact. Topical cooling is a key aspect of preventing spontaneous ignition as well. Disposal of all contaminated clothing and gear is essential to prevent additional injury, especially to rescuers. Long-term sequelae relate to phosphorous absorption and may lead to death. Chronic or repeated exposure may induce jaw osteonecrosis. Tactical Combat Casualty Care recommendations do not currently address WP injury management. CONCLUSIONS: Education and management regarding WP acute injury and late sequelae is essential for acute battlefield and definitive facility care. Resource-replete and resource-limited settings may use related approaches for acute management and ignition prevention. Current burn wound management recommendations should incorporate specific WP management principles and actions for military clinicians at every level of skill and environment.

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Transition metal dichalcogenides have been extensively studied in recent years because of their fascinating optical, electrical, and catalytic properties. However, low-cost, scalable production remains a challenge. Aerosol-assisted chemical vapor deposition (AACVD) provides a new method for scalable thin film growth. In this study, we demonstrate the growth of molybdenum disulfide (MoS2) thin films using AACVD method. This method proves its suitability for low-temperature growth of MoS2thin films on various substrates, such as glass, silicon dioxide, quartz, silicon, hexagonal boron nitride, and highly ordered pyrolytic graphite. The as-grown MoS2shows evidence of substrate-induced strain. The type of strain and the morphology of the as-grown MoS2highly depend on the growth substrate's surface roughness, crystallinity, and chemical reactivity. Moreover, the as-grown MoS2shows the presence of both direct and indirect band gaps, suitable for exploitation in future electronics and optoelectronics.

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Solid nitrogen exhibits a panoply of phenomena ranging from complex molecular crystalline configurations to polymerization and closing band gap at higher densities. Among the elemental molecular solids, nitrogen stands apart for having phases, which can only be stabilized following particular pressure-temperature pathways, indicative of metastability and kinetic barriers. Here, through the combination of Raman spectroscopy and dynamic compression techniques, we find that the appearance of the whole nitrogen phase diagram is determined by the P-T paths taken below 2 GPa. We reveal the existence of the path- and phase-dependent triple point between the ß - N 2 , δ loc - N 2 and γ - or ϵ - N 2 . We further show that the ß - N 2 towards γ - N 2 path below the triple point, that evades δ ( δ loc )- N 2 , results in the formation of γ - N 2 , which in turn becomes a dominant phase. We then demonstrate, that the ß - N 2 through δ ( δ loc )- N 2 above the triple point path leads to the formation of ϵ - N 2 and the "well-established" phase diagram. An additional pathway, which by-passes the rotationally inhibited modifications δ ( δ loc )- N 2 , via rapid compression is found to produce γ - N 2 at higher temperatures. We argue that the pathway and phase sensitive triple point and the compression rate dependent phase formation challenge our understanding of this archetypal dense molecular solid.

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The upcoming Paris 2024 Olympic and Paralympic Games could face environmental challenges related to heat, air quality and water quality. These challenges will pose potential threats to athletes and impact thousands of stakeholders and millions of spectators. Recognising the multifaceted nature of these challenges, a range of strategies will be essential for mitigating adverse effects on participants, stakeholders and spectators alike. From personalised interventions for athletes and attendees to comprehensive measures implemented by organisers, a holistic approach is crucial to address these challenges and the possible interplay of heat, air and water quality factors during the event. This evidence-based review highlights various environmental challenges anticipated at Paris 2024, offering strategies applicable to athletes, stakeholders and spectators. Additionally, it provides recommendations for Local Organising Committees and the International Olympic Committee that may be applicable to future Games. In summary, the review offers solutions for consideration by the stakeholders responsible for and affected by the anticipated environmental challenges at Paris 2024.

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AIMS: WHO Grade 3 (G3) meningiomas are rare tumours with limited data to guide management. This retrospective study documents UK management approaches across 14 centres over 11 years. MATERIALS AND METHODS: Patients with WHO G3 meningioma between 01/01/2008 and 31/12/2018 were identified. Data were collected on demographics, management strategy, adjuvant radiotherapy, approach in recurrence setting and survival. RESULTS: 84 patients were identified. 21.4% transformed from lower-grade disease. 96.4% underwent primary surgical resection, with 20.8% having evidence of residual disease on their post-op MRI. 59.3% of patients underwent adjuvant radiotherapy (RT) following surgical resection. Overall median PFS and OS were 12.6 months and 28.2 months, respectively. Median OS in the group who underwent complete surgical resection was 34.9 months, compared to 27.5 months for those who had incomplete resection (HR 0.58, 95% CI 0.27-1.23, p = 0.15). Median OS was 33.1 months for those who underwent adjuvant RT and 14.0 months for those who did not (HR 0.48, 95% CI 0.27-0.84, p = 0.004). Median adjuvant RT dose delivered was 60Gy (range 12Gy-60Gy), 45.8% of adjuvant RT was delivered using IMRT. At disease relapse, 31% underwent salvage surgery and 29.3% underwent salvage RT. Of those treated with salvage RT, 64.7% were re-treats and all were treated with hypofractionated RT. CONCLUSION: Surgery continues to be the preferred primary management strategy. Post-operative MRI within 48 hours is indicated to assess presence of residual disease and guide further surgical options. Adjuvant radiotherapy plays an important part of the management paradigm in these patients with the data supporting an attached survival advantage. Further surgery and re-irradiation is an option in the disease recurrence setting with radiosurgery frequently utilised in this context.

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Sulawesi crested macaques (Macaca nigra) (SCMs) are critically endangered and frequently suffer from chronic intestinal disease in captivity. Often, despite routine diagnostic investigations and confirmation of intestinal inflammation, an aetiology cannot be identified, leading to a non-specific categorization as chronic enterocolitis rather than an aetiological diagnosis. This study evaluates the histological features of gastrointestinal tissues from 23 SCMs, comparing animals with a clinical history suggestive of chronic enterocolitis (n = 14) with those without gastrointestinal clinical signs (n = 9). Tissues were graded according to the Nancy index (NI), a scoring system used in human medicine to evaluate disease activity in ulcerative colitis, a common form of human inflammatory bowel disease (IBD). Additionally, inflammatory cells in the colonic lamina propria were visually identified by type, counted and subsequently compared between diseased and control animals. Moderate to severe lymphoplasmacytic inflammation and structural changes were most common in the colons of affected SCMs, whereas histopathological changes were absent or mild in all examined small intestine (n = 17) and stomach (n = 11) tissues. The colonic NI had a significant positive correlation with clinical disease severity and 57% (n = 8) of animals with clinical signs had a NI grade of ≥2, consistent with moderate to severe, active IBD. Half of SCMs with recurrent rectal prolapse (n = 6) had a NI grade of 0, suggesting that intestinal inflammation is not always part of this condition's pathogenesis. The numbers of colonic lymphocytes, plasma cells, neutrophils, macrophages and total leucocytes were significantly higher in diseased animals. This study validated the use of the NI in SCMs, enabling a more standardized histopathological evaluation of the colon in this species.

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Nonribosomal cyclic peptides (NRcPs) are structurally complex natural products and a vital pool of therapeutics, particularly antibiotics. Their structural diversity arises from the ability of the multidomain enzyme assembly lines, nonribosomal peptide synthetases (NRPSs), to utilize bespoke nonproteinogenic amino acids, modify the linear peptide during elongation, and catalyze an array of cyclization modes, e.g., head to tail, side chain to tail. The study and drug development of NRcPs are often limited by a lack of easy synthetic access to NRcPs and their analogues, with selective macrolactamization being a major bottleneck. Herein, we report a generally applicable chemical macrocyclization method of unprecedented speed and selectivity. Inspired by biosynthetic cyclization, it combines the deprotected linear biosynthetic precursor peptide sequence with a highly reactive C-terminus to produce NRcPs and analogues in minutes. The method was applied to several NRcPs of varying sequences, ring sizes, and cyclization modes including rufomycin, colistin, and gramicidin S with comparable success. We thus demonstrate that the linear order of modules in NRPS enzymes that determines peptide sequence encodes the key structural information to produce peptides conformationally biased toward macrocyclization. To fully exploit this conformational bias synthetically, a highly reactive C-terminal acyl azide is also required, alongside carefully balanced pH and solvent conditions. This allows for consistent, facile cyclization of exceptional speed, selectivity, and atom efficiency. This exciting macrolactamization method represents a new enabling technology for the biosynthetic study of NRcPs and their development as therapeutics.

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A common evolutionary mechanism in biology to drive function is protein oligomerization. In prokaryotes, the symmetrical assembly of repeating protein units to form homomers is widespread, yet consideration in vitro of whether such assemblies have functional or mechanistic consequences is often overlooked. Dye-decolorizing peroxidases (DyPs) are one such example, where their dimeric α + ß barrel units can form various oligomeric states, but the oligomer influence, if any, on mechanism and function has received little attention. In this work, we have explored the oligomeric state of three DyPs found in Streptomyces lividans, each with very different mechanistic behaviors in their reactions with hydrogen peroxide and organic substrates. Using analytical ultracentrifugation, we reveal that except for one of the A-type DyPs where only a single sedimenting species is detected, oligomer states ranging from homodimers to dodecamers are prevalent in solution. Using cryo-EM on preparations of the B-type DyP, we determined a 3.02 Å resolution structure of a hexamer assembly that corresponds to the dominant oligomeric state in solution as determined by analytical ultracentrifugation. Furthermore, cryo-EM data detected sub-populations of higher-order oligomers, with one of these formed by an arrangement of two B-type DyP hexamers to give a dodecamer assembly. Our solution and structural insights of these oligomer states provide a new framework to consider previous mechanistic studies of these DyP members and are discussed in terms of long-range electron transfer for substrate oxidation and in the "storage" of oxidizable equivalents on the heme until a two-electron donor is available.

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The premise of research in human physiology is to explore a multifaceted system whilst identifying one or a few outcomes of interest. Therefore, the control of potentially confounding variables requires careful thought regarding the extent of control and complexity of standardisation. One common factor to control prior to testing is diet, as food and fluid provision may deviate from participants' habitual diets, yet a self-report and replication method can be flawed by under-reporting. Researchers may also need to consider standardisation of physical activity, whether it be through familiarisation trials, wash-out periods, or guidance on levels of physical activity to be achieved before trials. In terms of pharmacological agents, the ethical implications of standardisation require researchers to carefully consider how medications, caffeine consumption and oral contraceptive prescriptions may affect the study. For research in females, it should be considered whether standardisation between- or within-participants in regards to menstrual cycle phase is most relevant. The timing of measurements relative to various other daily events is relevant to all physiological research and so it can be important to standardise when measurements are made. This review summarises the areas of standardisation which we hope will be considered useful to anyone involved in human physiology research, including when and how one can apply standardisation to various contexts.

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The premise of research in human physiology is to explore a multifaceted system whilst identifying one or a few outcomes of interest. Therefore, the control of potentially confounding variables requires careful thought regarding the extent of control and complexity of standardisation. One common factor to control prior to testing is diet, as food and fluid provision may deviate from participants' habitual diets, yet a self-report and replication method can be flawed by under-reporting. Researchers may also need to consider standardisation of physical activity, whether it be through familiarisation trials, wash-out periods, or guidance on levels of physical activity to be achieved before trials. In terms of pharmacological agents, the ethical implications of standardisation require researchers to carefully consider how medications, caffeine consumption and oral contraceptive prescriptions may affect the study. For research in females, it should be considered whether standardisation between- or within-participants in regards to menstrual cycle phase is most relevant. The timing of measurements relative to various other daily events is relevant to all physiological research and so it can be important to standardise when measurements are made. This review summarises the areas of standardisation which we hope will be considered useful to anyone involved in human physiology research, including when and how one can apply standardisation to various contexts.

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