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Are atypical antipsychotics effective as monotherapies or as adjunctive therapy for bipolar mania?METHODSDesign: Systematic review and meta-ono isData sources: MEDLINE and PubMed (search date 2004); abstracts from the 2003 meetings of the American College of Neurapsychatry, American Psychiatric Association, and International Conference on Bipolar Disorder; and contact with investigators and drug manufacturers.Study selection and analysis: Placebo controlled, randomised controlled trials (Ras) of atypical antipsychotics (aripiprazole, clozapine, quetiapine, risperidone, ziprasidone, olanzapine) as monotherapy or adjunctive therapy (in addition to lithium, valproate, or carbamazepine) for acute bipolar mania. Meta analysis was conducted using a random-effects model.Outcomes: Manic symptoms (change in Young Mania Rating Scale (YMRS) or Mania Rating Scale (MRS) from baseline to endpoint using last observation carried forward analysis).MAIN RESULTSEighteen RCTs met inclusion criteria. Atypical antipsychotic monotherapy significantly improved mania symptoms compared with placebo at 3-4 weeks (12 RCTs, 13 atypical antipsychotic arms, 3114 people; pooled mean difference in mania rating scale score change from baseline: -5.5, 95% CI -4.0 to -7.1). When analysed individually, olanzapine (two RCTs), risperidone (three RCTs), quetiapine (two RCTs), aripiprazole (four RCTs), and ziprasidone (two RCTs) monotherapy each improved mania symptoms compared with placebo (results displayed graphically). When used as an adjunctive therapy, atypical antipsychotics also significantly improved mania symptoms compared with placebo at 3-6 weeks (six RCTs, seven atypical antipsychotic arms, 1190 people; pooled mean difference in mania rating scale score change from baseline: -4.1, 95% CI -1.7 to -6.6). Olanzapine, risperidone, and quetiapine were more effective than placebo for treating mania when used as adjunctive therapy, but there was no significant difference between ziprasidone and placebo (results displayed graphically).CONCLUSIONSAtypical antipsychotics are more effective than placebo for treating bipolar mania, both as monotherapies and as adjunctive treatments.NOTESThe included studies were heterogeneous with respect to inclusion of people with rapid-cycling bipolar disorder or those in mixed states, the proportion of people with psychosis, severity of mania, rates of study completion, and, for combination therapies, mean levels of primary mood stabiliser, mean time period before commencing adjunctive therapy, and proportion of people starting primary mood stabiliser treatment for the first time. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Obesity has become a public health epidemic in adults and children. Clinician practices need new models to effectively address overweight in patients, yet, practices lack time and resources. We tested a clinician-delivered intervention that utilized community resources for in-depth counseling for unhealthy behaviors including overweight. METHODS: Eligible patients in nine primary care practices were identified using an electronic linkage system (eLinkS) which also automated patient referrals to group (Weight Watcher's), telephone counseling (TC), or usual care. Pre/post-survey data were used to assess factors related to counseling choices as well as changes in BMI (kg/m(2)) and weight-related behaviors using descriptive statistics, unadjusted, and adjusted statistical analyses. RESULTS: Study sample (n=146) was 70% female with a mean age of 57 years. More patients (57%) selected WW, followed by usual care (27%) or TC (16%). Age, gender, clinician recommendation, and counseling program characteristics were influential in counseling selections. Weight Watcher's participants and those in TC, reported statistically significant weight loss, WW participants also reported significant increases in fruit/vegetable intake; after 4 months compared with usual care. CONCLUSIONS: This practice-based intervention utilizing community counseling referrals was associated with positive health behavior change. PRACTICE IMPLICATIONS: Identifying influential factors related to patient weight counseling choices may help guide referrals to community programs. [ABSTRACT FROM AUTHOR]

Metalated intact and deprotonated histidyl glycine and glycyl histidine dipeptides were investigated in the gas phase by using infrared multiple photon dissociation (IRMPD) spectroscopy with light from a free-electron laser (FEL). The dipeptides M 2+ (GlyHis), M 2+ (HisGly), [M(GlyHis-H)] + , and [M(HisGly-H)] + , where M = Zn and Cd, were probed to elucidate how the His position along the peptide chain and ligand charge state might influence the structures observed in the gas phase. Simulated annealing calculations were performed to determine energetically low-lying conformers and isomers of these structures. Quantum chemical calculations were used to optimize the structures at the B3LYP level of theory using the 6-311+G(d,p) and def2-TZVP basis sets for zinc and cadmium complexes, respectively. IRMPD and calculated linear absorption spectra were compared to evaluate which structures are present. Relative energies of the various species were evaluated using single-point energy calculations for low-lying structures at the B3LYP, B3LYP-GD3BJ, ωB97XD, and MP2(full) levels using the 6-311+G(2d,2p) and def2-TZVPP basis sets. For all species, structures for both metals mirror each other, and those that reproduce the experimental spectrum were determined to be iminol structures for the intact ligands or iminol-like structures for the deprotonated ligands. Additionally, when the spectra of the deprotonated dipeptides are compared to the intact dipeptides, the change in the spectra is correlated to the group that is deprotonated.

Chest X-rays are the most commonly performed medical imaging exam, yet they are often misinterpreted by physicians. Here, we present an FDA-cleared, artificial intelligence (AI) system which uses a deep learning algorithm to assist physicians in the comprehensive detection and localization of abnormalities on chest X-rays. We trained and tested the AI system on a large dataset, assessed generalizability on publicly available data, and evaluated radiologist and non-radiologist physician accuracy when unaided and aided by the AI system. The AI system accurately detected chest X-ray abnormalities (AUC: 0.976, 95% bootstrap CI: 0.975, 0.976) and generalized to a publicly available dataset (AUC: 0.975, 95% bootstrap CI: 0.971, 0.978). Physicians showed significant improvements in detecting abnormalities on chest X-rays when aided by the AI system compared to when unaided (difference in AUC: 0.101, p < 0.001). Non-radiologist physicians detected abnormalities on chest X-ray exams as accurately as radiologists when aided by the AI system and were faster at evaluating chest X-rays when aided compared to unaided. Together, these results show that the AI system is accurate and reduces physician errors in chest X-ray evaluation, which highlights the potential of AI systems to improve access to fast, high-quality radiograph interpretation., (© 2024. The Author(s).)

Background: There are ongoing concerns regarding the impact of Canada's cannabis legalization and commercialization on vulnerable persons such as those with serious forms of mental illness, including persons with schizophrenia-spectrum disorders and users of forensic mental health services. The primary objective of this study was to investigate the potential harms and mental health-related impacts associated with cannabis legalization on a sample of forensic patients in Ontario (N = 187)., Methods: Using a pseudo-prospective design, we investigated the frequency of cannabis use over a four-year period encompassing two years preceding and two years following the legislative change. We recorded clinical and public safety outcomes (i.e., mental health deterioration, length of stay in the forensic system, rates of hospital readmission, victimization and violence) over the same period to test relationships between these variables and rates of cannabis use., Results: We found that one-third of patients either self-reported or were discovered, via urine testing, to have used cannabis over the study period. Frequency of use was lower in the pre-legalization period, and then gradually and significantly increased after legalization. Compared to patients with no cannabis use, those with one or more instances of use were more likely to be readmitted to hospital and had higher rated static risk factors for violence. However, there were no observed differences in the actual rate of violence between patients using and not using cannabis, nor differences in the rate of violence over time. Over half of the patients who used cannabis experienced a worsening of their mental health status in the week following use., Conclusions: Cannabis use among those with SMI is associated with adverse clinical outcomes. Results from this study suggest that the mental health burdens associated with cannabis use have risen in terms of delayed clinical recovery and progress through the forensic system since legalization., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

The permeability glycoprotein, encoded by the ABCB1 gene, is widely implicated in multidrug resistance (MDR), as it has been shown to reduce the intracellular concentration of most small molecule therapeutics, including the majority of the breakpoint cluster region Abelson proto-oncogene 1 (BCR-ABL1) kinase inhibitors used in the treatment of Philadelphia chromosome positive (Ph+) leukemias. With this in mind, we describe an integrated theoretical and experimental approach to shed light on substituent effects in the pendant anilino moiety of 4-anilinoquinazolines and 4-anilinoquinoline-3-carbonitrile-based kinase inhibitors and their influence on P-gp-mediated efflux. This analysis culminated in the identification of a hydroxylamine-bearing, dual cSRC/BCR-ABL1 kinase inhibitor 16a that exhibits a marked reduction in P-gp-mediated efflux ratio and potent activity in a Ph+ patient-derived cell line (K562) and an MDR-Ph+ patient-derived cell line (K562/Dox) overexpressing P-gp. Overall, we demonstrate that the P-gp-mediated efflux ratio can be minimized by computationally driven optimization of the molecular dipole and/or cp K a without recourse to intramolecular hydrogen bonds.

Background/Objectives: Focused ultrasound (FUS) and microbubble (MB) exposure is a promising technique for targeted drug delivery to the brain; however, refinement of protocols suitable for large-volume treatments in a clinical setting remains underexplored. Methods: Here, the impacts of various sonication parameters on blood-brain barrier (BBB) permeability enhancement and tissue damage were explored in rabbits using a clinical-prototype hemispherical phased array developed in-house, with real-time 3D MB cavitation imaging for exposure calibration. Initial experiments revealed that continuous manual agitation of MBs during infusion resulted in greater gadolinium (Gd) extravasation compared to gravity drip infusion. Subsequent experiments used low-dose MB infusion with continuous agitation and a low burst repetition frequency (0.2 Hz) to mimic conditions amenable to long-duration clinical treatments. Results: Key sonication parameters-target level (proportional to peak negative pressure), number of bursts, and burst length-significantly affected BBB permeability enhancement, with all parameters displaying a positive relationship with relative Gd contrast enhancement ( p < 0.01). Even at high levels of BBB permeability enhancement, tissue damage was minimal, with low occurrences of hypointensities on T2*-weighted MRI. When accounting for relative Gd contrast enhancement, burst length had a significant impact on red blood cell extravasation detected in histological sections, with 1 ms bursts producing significantly greater levels compared to 10 ms bursts ( p = 0.03), potentially due to the higher pressure levels required to generate equal levels of BBB permeability enhancement. Additionally, albumin and IgG extravasation correlated strongly with relative Gd contrast enhancement across sonication parameters, suggesting that protein extravasation can be predicted from non-invasive imaging. Conclusions: These findings contribute to the development of safer and more effective clinical protocols for FUS + MB exposure, potentially improving the efficacy of the approach.

Focused ultrasound (FUS) combined with circulating microbubbles (MBs) can be employed for non-invasive, localized agent delivery across the blood-brain barrier (BBB). Previous work has demonstrated the feasibility of clinical-scale transmit-receive phased arrays for performing transcranial therapies under MB imaging feedback., Objective: This study aimed to design, construct, and evaluate a dual-mode phased array for MB-mediated FUS brain therapy in small animals., Methods: A 256-element sparse hemispherical array (100 mm diameter) was fabricated by installing 128 PZT cylinder transmitters (f0 = 1.16 MHz) and 128 broadband PVDF receivers within a 3D-printed scaffold., Results: The transmit array's focal size at the geometric focus was 0.8 mm × 0.8 mm × 1.7 mm, with a 31 mm/27 mm (lateral/axial) steering range. The receive array's point spread function was 0.6 mm × 0.6 mm × 1.5 mm (1.16 MHz source) at the geometric focus, and sources were localized up to 30 mm/16 mm (lateral/axial) from geometric focus. The array was able to spatially map MB cloud activity in 3D throughout a vessel-mimicking phantom at sub-, ultra-, and second-harmonic frequencies. Preliminary in-vivo work demonstrated its ability to induce localized BBB permeability changes under 3D sub-harmonic MB imaging feedback in a mouse model., Conclusion: Small form factor transmit-receive phased arrays enable acoustic imaging-controlled FUS and MB-mediated brain therapies with high targeting precision required for rodent studies., Significance: Dual-mode phased arrays dedicated for small animal use will facilitate high-throughput studies of FUS-mediated BBB permeability enhancement to explore novel therapeutic strategies for future clinical application.

The impact of dietary fiber on intestinal T cell development is poorly understood. Here we show that a low fiber diet reduces MHC-II antigen presentation by small intestinal epithelial cells (IECs) and consequently impairs development of CD4 + CD8αα + intraepithelial lymphocytes (DP IELs) through changes to the microbiota. Dietary fiber supports colonization by Segmented Filamentous Bacteria (SFB), which induces the secretion of IFNγ by type 1 innate lymphoid cells (ILC1s) that lead to MHC-II upregulation on IECs. IEC MHC-II expression caused either by SFB colonization or exogenous IFNγ administration induced differentiation of DP IELs. Finally, we show that a low fiber diet promotes overgrowth of Bifidobacterium pseudolongum, and that oral administration of B. pseudolongum reduces SFB abundance in the small intestine. Collectively we highlight the importance of dietary fiber in maintaining the balance among microbiota members that allow IEC MHC-II antigen presentation and define a mechanism of microbiota-ILC-IEC interactions participating in the development of intestinal intraepithelial T cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Cutaneous mycobacterial infections cause substantial morbidity and are challenging to diagnose and treat. An improved understanding of the dermal immune response to mycobacteria may inspire new therapeutic approaches. We conducted a controlled human infection study with 10 participants who received 2 × 106 CFUs of Mycobacterium bovis bacillus Calmette-Guérin (Tice strain) intradermally and were randomized to receive isoniazid or no treatment. Peripheral blood was collected at multiple time points for flow cytometry, bulk RNA sequencing (RNA-seq), and serum Ab assessments. Systemic immune responses were detected as early as 8 d postchallenge in this M. bovis bacillus Calmette-Guérin-naive population. Injection-site skin biopsies were performed at days 3 and 15 postchallenge and underwent immune profiling using mass cytometry and single-cell RNA-seq, as well as quantitative assessments of bacterial viability and burden. Molecular viability testing and standard culture results correlated well, although no differences were observed between treatment arms. Single-cell RNA-seq revealed various immune and nonimmune cell types in the skin, and communication between them was inferred by ligand-receptor gene expression. Day 3 communication was predominantly directed toward monocytes from keratinocyte, muscle, epithelial, and endothelial cells, largely via the migration inhibitory factor pathway and HLA-E-KLRK1 interaction. At day 15, communication was more balanced between cell types. These data reveal the potential role of nonimmune cells in the dermal immune response to mycobacteria and the utility of human challenge studies to augment our understanding of mycobacterial infections., (Copyright © 2024 The Authors.)

Abstract: Synovial cell sarcoma is a rare mesenchymal tumor that typically originates from the soft tissues of the extremities of young adults. Only 3 cases of primary diaphragmatic synovial cell sarcoma have been described in the literature: 2 in adult males and 1 in a 12-year-old pediatric patient. 1-3 When this tumor is found in the mediastinum or pericardial region, prognosis is historically poor because of the advanced disease stage at time of diagnosis. The surgical course and pathology have been described in this 12-year-old boy. 3 This is the first case, to our knowledge, of the use of cardiac point-of-care ultrasound in the early identification and diagnosis of a primary diaphragmatic synovial sarcoma in a pediatric patient., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Track PCC includes five geographic surveillance sites to conduct standardized population-based surveillance to estimate and track Post-COVID Conditions (PCC) by age, sex, race/ethnicity, geographic area, severity of initial infection, and risk factors among persons with evidence of SARS-CoV-2 infection (based on the Council of State and Territorial Epidemiologist [CSTE] case definitions for confirmed cases or laboratory-confirmed evidence of infection)., Methods: The study will estimate the incidence, prevalence, including temporal trends, and duration and severity of PCC symptoms, among children, adolescents, and adults. PCCs include a broad range of symptoms and conditions that continue or develop after acute SARS-CoV-2 infection or COVID-19 illness. Surveillance includes both passive and active components for diverse populations in Arizona, Indiana, and Utah as well as the Bronx Borough, NY, and part of Philadelphia County, PA. Passive surveillance will utilize electronic health records and health information exchanges within each site catchment area to longitudinally follow persons with COVID-19 to estimate PCC occurring at least 30 days after acute COVID-19 illness. Active surveillance will utilize self-report of PCCs from detailed surveys of persons ages 7 years and older with evidence of SARS-CoV-2 infection in the past 3 months. Respondents will complete follow-up surveys at 6-, 12- and 18-months post-infection., Discussion: These data can help identify which groups are most affected by PCC, and what health differences among demographic groups exist, as well as indicate potential barriers to care. These additional levels of granularity can inform public health action and help direct needed clinical care for patients., (© 2024. The Author(s).)

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) trials targeting the anterior limb of the internal capsule have shown promising results. We evaluated the long-term safety and efficacy of MRgFUS capsulotomy in patients with obsessive-compulsive disorder (OCD) and major depressive disorder (MDD)., Methods: This phase 1, single-center, open-label study recruited patients with treatment-resistant OCD and MDD. Outcomes were measured 6 months, 12 months, and 18 to 24 months (long term) after MRgFUS capsulotomy. Neuropsychological testing and neuroimaging were conducted at baseline and 12 months postoperatively. The primary outcome was safety. The secondary outcome was clinical response, defined for OCD as a ≥35% improvement in Yale-Brown Obsessive Compulsive Scale scores and for MDD as a ≥50% reduction in Hamilton Depression Rating Scale scores compared with baseline., Results: No serious adverse effects were registered. In patients with OCD (n= 15), baseline Yale-Brown Obsessive Compulsive Scale scores (31.9 ± 1.2) were significantly reduced by 23% (p = .01) at 6 months and 35% (p < .0001) at 12 months. In patients with MDD (n = 12), a 26% and 25% nonsignificant reduction in Hamilton Depression Rating Scale scores (baseline 24.3 ± 1.2) was observed at 6 months and 12 months, respectively. Neuropsychological testing revealed no negative effects of capsulotomy. In the OCD and MDD cohorts, we found a correlation between clinical outcome and lesion laterality, with more medial left-placed lesions (OCD, p = .08) and more lateral right-placed lesions (MDD, p < .05) being respectively associated with a stronger response. In the MDD cohort, more ventral tracts appeared to be associated with a poorer response., Conclusions: MRgFUS capsulotomy is safe in patients with OCD and MDD and particularly effective in the former population., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: Neither the United States nor the European oncology guidelines include details for appropriate management of hyperglycemia in cancer patients. The aim was to identify fasting and random blood glucose thresholds, and hemoglobin A1c (HbA1c) targets used by oncologists in clinical practice when managing hyperglycemia in patients with cancer undergoing chemotherapy., Methods: This national, cross sectional study utilized a questionnaire to collect oncologists' perceptions about optimal blood glucose thresholds and HbA1c targets in patients with cancer undergoing chemotherapy. Descriptive statistics were calculated to summarize glucose thresholds, HbA1c targets, and sample characteristics. Responses to an open-ended question about oncologists' approach to hyperglycemia management were analyzed via thematic analysis using an inductive approach., Results: Respondents (n = 229) were on average 52.1 years of age, 67.7% men, and 91.3% White. For patients without diabetes but experiencing hyperglycemia, oncologists targeted lower and upper fasting blood glucose levels between 75-121 mg/dL and 105-135 mg/dL, respectively. For patients with diabetes, the targets for lower and upper fasting blood glucose levels ranged between 100-130 mg/dL and 128-150 mg/dL, respectively. Fasting blood glucose (95.6%) and HbA1c (78.6%) were the most commonly used clinical indicators to consider chemotherapy dose reduction, delay, or discontinuation due to hyperglycemia in patients receiving chemotherapy with curative intent. Among those receiving palliative intent chemotherapy, the preferred clinical parameters were random blood glucose (90.0%), patient-reported blood glucose readings (70.7%), continuous glucose monitoring readings (65.1%), and patient-reported symptoms of hyperglycemia (65.1%). Three main themes emerged about oncologists' approach to hyperglycemia management: 1) identification of high-risk patients; 2) need for early identification, screening, and diagnosis of hyperglycemia; and 3) multiple hyperglycemia management strategies., Conclusion: Oncologists reported a wide variation of target blood glucose ranges considered appropriate in patients undergoing chemotherapy. Lack of clear guidance for hyperglycemia management during chemotherapy in the United States may be contributing to a lack of consistency in clinical practice., (© 2024. The Author(s).)

Ultra-high dose rate (UHDR) irradiation has been shown to have a sparing effect on healthy tissue, an effect known as 'FLASH'. This effect has been studied across several radiation modalities, including photons, protons and clinical energy electrons, however, very little data is available for the effect of FLASH with Very High Energy Electrons (VHEE). pBR322 plasmid DNA was used as a biological model to measure DNA damage in response to Very High Energy Electron (VHEE) irradiation at conventional (0.08 Gy/s), intermediate (96 Gy/s) and ultra-high dose rates (UHDR, (2 × 10 9  Gy/s) at the CERN Linear Electron Accelerator (CLEAR) user facility. UHDRs were used to determine if the biological FLASH effect could be measured in the plasmid model, within a hydroxyl scavenging environment. Two different concentrations of the hydroxyl radical scavenger Tris were used in the plasmid environment to alter the proportions of indirect damage, and to replicate a cellular scavenging capacity. Indirect damage refers to the interaction of ionising radiation with molecules and species to generate reactive species which can then attack DNA. UHDR irradiated plasmid was shown to have significantly reduced amounts of damage in comparison to conventionally irradiated, where single strand breaks (SSBs) was used as the biological endpoint. This was the case for both hydroxyl scavenging capacities. A reduced electron energy within the VHEE range was also determined to increase the DNA damage to pBR322 plasmid. Results indicate that the pBR322 plasmid model can be successfully used to explore and test the effect of UHDR regimes on DNA damage. This is the first study to report FLASH sparing with VHEE, with induced damage to pBR322 plasmid DNA as the biological endpoint. UHDR irradiated plasmid had reduced amounts of DNA single-strand breaks (SSBs) in comparison with conventional dose rates. The magnitude of the FLASH sparing was a 27% reduction in SSB frequency in a 10 mM Tris environment and a 16% reduction in a 100 mM Tris environment., (© 2024. The Author(s).)

To ensure timely duplication of the entire eukaryotic genome, thousands of replication machineries (replisomes) act on genomic DNA at any time during S phase. In the final stages of this process, replisomes are unloaded from chromatin. Unloading is driven by polyubiquitylation of MCM7, a subunit of the terminated replicative helicase, and processed by p97/VCP segregase. Most of our knowledge of replication termination comes from model organisms, and little is known about how this process is executed and regulated in human somatic cells. Here we show that replisome disassembly in this system requires CUL2 LRR1 -driven MCM7 ubiquitylation, p97, and UBXN7 for unloading and provide evidence for "backup" mitotic replisome disassembly, demonstrating conservation of such mechanisms. Finally, we find that small-molecule inhibitors against Cullin ubiquitin ligases (CULi) and p97 (p97i) affect replisome unloading but also lead to induction of replication stress in cells, which limits their usefulness to specifically target replisome disassembly processes., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Purpose: One manifestation of systemic inequities in communication sciences and disorders (CSD) is the chronic underreporting and underrepresentation of sex, gender, race, and ethnicity in research. The present study characterized recent demographic reporting practices and representation of participants across CSD research., Methods: We systematically reviewed and extracted key reporting and participant data from empirical studies conducted in the United States (US) with human participants published in the year 2020 in journals by the American Speech-Language-Hearing Association (ASHA; k = 407 articles comprising a total n = 80,058 research participants, search completed November 2021). Sex, gender, race, and ethnicity were operationalized per National Institutes of Health guidelines (National Institutes of Health, 2015a, 2015b)., Results: Sex or gender was reported in 85.5% of included studies; race was reported in 33.7%; and ethnicity was reported in 13.8%. Sex and gender were clearly differentiated in 3.4% of relevant studies. Where reported, median proportions for race and ethnicity were significantly different from the US population, with underrepresentation noted for all non-White racial groups and Hispanic participants. Moreover, 64.7% of studies that reported sex or gender and 67.2% of studies that reported race or ethnicity did not consider these respective variables in analyses or discussion., Conclusion: At present, research published in ASHA journals frequently fails to report key demographic data summarizing the characteristics of participants. Moreover, apparent gaps in representation of minoritized racial and ethnic groups threaten the external validity of CSD research and broader health care equity endeavors in the US. Although our study is limited to a single year and publisher, our results point to several steps for readers that may bring greater accountability, consistency, and diversity to the discipline.

The coronavirus disease 2019 pandemic highlighted the need for more rapid and routine application of modeling approaches such as quantitative microbial risk assessment (QMRA) for protecting public health. QMRA is a transdisciplinary science dedicated to understanding, predicting, and mitigating infectious disease risks. To better equip QMRA researchers to inform policy and public health management, an Advances in Research for QMRA workshop was held to synthesize a path forward for QMRA research. We summarize insights from 41 QMRA researchers and experts to clarify the role of QMRA in risk analysis by (1) identifying key research needs, (2) highlighting emerging applications of QMRA; and (3) describing data needs and key scientific efforts to improve the science of QMRA. Key identified research priorities included using molecular tools in QMRA, advancing dose-response methodology, addressing needed exposure assessments, harmonizing environmental monitoring for QMRA, unifying a divide between disease transmission and QMRA models, calibrating and/or validating QMRA models, modeling co-exposures and mixtures, and standardizing practices for incorporating variability and uncertainty throughout the source-to-outcome continuum. Cross-cutting needs identified were to: develop a community of research and practice, integrate QMRA with other scientific approaches, increase QMRA translation and impacts, build communication strategies, and encourage sustainable funding mechanisms. Ultimately, a vision for advancing the science of QMRA is outlined for informing national to global health assessments, controls, and policies., (© 2024 The Author(s). Risk Analysis published by Wiley Periodicals LLC on behalf of Society for Risk Analysis.)

Very High Energy Electron (VHEE) beams are a promising alternative to conventional radiotherapy due to their highly penetrating nature and their applicability as a modality for FLASH (ultra-high dose-rate) radiotherapy. The dose distributions due to VHEE need to be optimised; one option is through the use of quadrupole magnets to focus the beam, reducing the dose to healthy tissue and allowing for targeted dose delivery at conventional or FLASH dose-rates. This paper presents an in depth exploration of the focusing achievable at the current CLEAR (CERN Linear Electron Accelerator for Research) facility, for beam energies >200 MeV. A shorter, more optimal quadrupole setup was also investigated using the TOPAS code in Monte Carlo simulations, with dimensions and beam parameters more appropriate to a clinical situation. This work provides insight into how a focused VHEE radiotherapy beam delivery system might be achieved., (© 2024. The Author(s).)

Very high energy electrons (VHEE) are a potential candidate for radiotherapy applications. This includes tumours in inhomogeneous regions such as lung and prostate cancers, due to the insensitivity of VHEE to inhomogeneities. This study explores how electrons in the VHEE range can be used to perform successful in vitro radiobiological studies. The ARES (accelerator research experiment at SINBAD) facility at DESY, Hamburg, Germany was used to deliver 154 MeV electrons to both prostate (PC3) and lung (A549) cancer cells in suspension. Dose was delivered to samples with repeatability and uniformity, quantified with Gafchromic film. Cell survival in response to VHEE was measured using the clonogenic assay to determine the biological effectiveness of VHEE in cancer cells for the first time using this method. Equivalent experiments were performed using 300 kVp X-rays, to enable VHEE irradiated cells to be compared with conventional photons. VHEE irradiated cancer cell survival was fitted to the linear quadratic (LQ) model (R 2  = 0.96-0.97). The damage from VHEE and X-ray irradiated cells at doses between 1.41 and 6.33 Gy are comparable, suggesting similar relative biological effectiveness (RBE) between the two modalities. This suggests VHEE is as damaging as photon radiotherapy and therefore could be used to successfully damage cancer cells during radiotherapy. The RBE of VHEE was quantified as the relative doses required for 50% (D 0.5 ) and 10% (D 0.1 ) cell survival. Using these values, VHEE RBE was measured as 0.93 (D 0.5 ) and 0.99 (D 0.1 ) for A549 and 0.74 (D 0.5 ) and 0.93 (D 0.1 ) for PC3 cell lines respectively. For the first time, this study has shown that 154 MeV electrons can be used to effectively kill lung and prostate cancer cells, suggesting that VHEE would be a viable radiotherapy modality. Several studies have shown that VHEE has characteristics that would offer significant improvements over conventional photon radiotherapy for example, electrons are relatively easy to steer and can be used to deliver dose rapidly and with high efficiency. Studies have shown improved dose distribution with VHEE in treatment plans, in comparison to VMAT, indicating that VHEE can offer improved and safer treatment plans with reduced side effects. The biological response of cancer cells to VHEE has not been sufficiently studied as of yet, however this initial study provides some initial insights into cell damage. VHEE offers significant benefits over photon radiotherapy and therefore more studies are required to fully understand the biological effectiveness of VHEE., (© 2024. The Author(s).)

Medical assistance in dying (MAiD) (which includes euthanasia and assisted suicide) is available in an increasing number of countries. In Belgium, The Netherlands and Switzerland (and was due to be implemented in Canada from 2024) eligibility includes mental suffering in the absence of any physical disorder. There are particular ethical and legal issues when considering MAiD for those involuntarily detained in prisons and hospitals. We describe four recent cases that illustrate these complexities, and highlight issues of equivalence of healthcare and self-determination against concerns about the criteria for determining eligibility of those with non-terminal conditions as well as the objections raised by victims and families and the demands for justice.

Exploring the relative importance of different routes in SARS-CoV-2 transmission is crucial in infection prevention. However, even in the same environmental setting, the relative importance of different routes has varied in different studies. We hypothesize that respiratory aerosol size and number distribution might play a key role. In this study, size and number distribution of respiratory droplets emitted from breathing, talking, and coughing were identified from PubMed and Web of Science. The infection risk of SARS-CoV-2 via airborne, droplet, and fomite transmission routes was modeled in a household and a healthcare setting. The relative importance of three routes varied with different size distributions in both settings. Generally, the contribution of the airborne route increased with the volume percentage of respirable droplets emitted. And the increase of the total number of emitted droplets leads to an increase in the contribution of tdroplet route. In the healthcare setting, as the total number of emitted droplets increased from 110 to 4,973, the contribution of droplet route increased from 62.24% to 98.11%. Next, by considering the combination of breathing, coughing, and talking when the infected person was asymptomatic, the airborne route predominated over the droplet and contact routes. When the infected person had developed symptoms, that is, cough, the droplet route played a dominant role in SARS-CoV-2 transmission. In conclusion, risk analyses will be improved with improved sampling methods that enable characterization of viruses within respiratory droplets of different sizes., (© 2023 Society for Risk Analysis.)

Disease-modifying drugs have transformed the treatment options for many systemic autoimmune diseases. However, an evolving understanding of disease mechanisms, which might vary between individuals, is paving the way for the development of novel agents that operate in a patient-tailored manner through immunophenotypic regulation of disease-relevant cells and the microenvironment of affected tissue domains. Immunoengineering is a field that is focused on the application of engineering principles to the modulation of the immune system, and it could enable future personalized and immunoregulatory therapies for rheumatic diseases. An important aspect of immunoengineering is the harnessing of material chemistries to design technologies that span immunologically relevant length scales, to enhance or suppress immune responses by re-balancing effector and regulatory mechanisms in innate or adaptive immunity and rescue abnormalities underlying pathogenic inflammation. These materials are endowed with physicochemical properties that enable features such as localization in immune cells and organs, sustained delivery of immunoregulatory agents, and mimicry of key functions of lymphoid tissue. Immunoengineering applications already exist for disease management, and there is potential for this new discipline to improve disease modification in rheumatology., (© 2024. Springer Nature Limited.)

The eukaryotic replicative helicase (CMG complex) is assembled during DNA replication initiation in a highly regulated manner, which is described in depth by other manuscripts in this Issue. During DNA replication, the replicative helicase moves through the chromatin, unwinding DNA and facilitating nascent DNA synthesis by polymerases. Once the duplication of a replicon is complete, the CMG helicase and the remaining components of the replisome need to be removed from the chromatin. Research carried out over the last ten years has produced a breakthrough in our understanding, revealing that replication termination, and more specifically replisome disassembly, is indeed a highly regulated process. This review brings together our current understanding of these processes and highlights elements of the mechanism that are conserved or have undergone divergence throughout evolution. Finally, we discuss events beyond the classic termination of DNA replication in S-phase and go over the known mechanisms of replicative helicase removal from chromatin in these particular situations.

Gender-affirming hormone therapy (GAHT) is often prescribed to transgender (TG) adolescents to alleviate gender dysphoria, but the effect of GAHT on the growing skeleton is unclear. We found GAHT to improve trabecular bone structure via increased bone formation in young male mice and not to affect trabecular structure in female mice. GAHT modified gut microbiome composition in both male and female mice. However, fecal microbiota transfers (FMTs) revealed that GAHT-shaped gut microbiome was a communicable regulator of bone structure and turnover in male, but not in female mice. Mediation analysis identified 2 species of Bacteroides as significant contributors to the skeletal effects of GAHT in male mice, with Bacteroides supplementation phenocopying the effects of GAHT on bone. Bacteroides have the capacity to expand Treg populations in the gut. Accordingly, GAHT expanded intestinal Tregs and stimulated their migration to the bone marrow (BM) in male but not in female mice. Attesting to the functional relevance of Tregs, pharmacological blockade of Treg expansion prevented GAHT-induced bone anabolism. In summary, in male mice GAHT stimulated bone formation and improved trabecular structure by promoting Treg expansion via a microbiome-mediated effect, while in female mice, GAHT neither improved nor impaired trabecular structure.

The experience of burnout in forensic psychiatrists has not been well studied, with most studies focusing on the experiences of forensic nurses, the impact of vicarious trauma and compassion fatigue in forensic mental health professionals, and the risk of posttraumatic stress disorder related to workplace exposures. This study reports on a national survey (34% response rate) conducted with forensic psychiatrists across Canada to understand the rate of, and contributors to, burnout and professional fulfillment. Just over half of the physician respondents reported experiencing burnout, which is in line with other recent surveys in Canada that have indicated elevated levels of burnout since the onset of the pandemic. The highest rates were found among early-career psychiatrists and those whose values did not align with their workplace. Intellectual stimulation, the interface with the legal system, and flexibility in one's job were all strongly linked with professional fulfillment. The goal of this survey was not only to identify rates and variables affecting burnout and wellness in this population but also to expand the dialogue on potential interventions at institutional and systems levels that can reduce burnout, promote professional fulfillment, and enhance recruitment and retention in the field of forensic psychiatry., (© 2024 American Academy of Psychiatry and the Law.)