Search

The increasing prevalence of neurological disorders such as Alzheimer's, Parkinson's, and multiple sclerosis presents a significant global health challenge. Despite extensive research, the precise mechanisms underlying these conditions remain elusive, with current treatments primarily addressing symptoms rather than root causes. Emerging evidence suggests that gut permeability and the kynurenine pathway are involved in the pathogenesis of these neurological conditions, offering promising targets for novel therapeutic and preventive strategies. Gut permeability refers to the intestinal lining's ability to selectively allow essential nutrients into the bloodstream while blocking harmful substances. Various factors, including poor diet, stress, infections, and genetic predispositions, can compromise gut integrity, leading to increased permeability. This condition facilitates the translocation of toxins and bacteria into systemic circulation, triggering widespread inflammation that impacts neurological health via the gut–brain axis. The gut–brain axis (GBA) is a complex communication network between the gut and the central nervous system. Dysbiosis, an imbalance in the gut microbiota, can increase gut permeability and systemic inflammation, exacerbating neuroinflammation—a key factor in neurological disorders. The kynurenine pathway, the primary route for tryptophan metabolism, is significantly implicated in this process. Dysregulation of the kynurenine pathway in the context of inflammation leads to the production of neurotoxic metabolites, such as quinolinic acid, which contribute to neuronal damage and the progression of neurological disorders. This narrative review highlights the potential and progress in understanding these mechanisms. Interventions targeting the kynurenine pathway and maintaining a balanced gut microbiota through diet, probiotics, and lifestyle modifications show promise in reducing neuroinflammation and supporting brain health. In addition, pharmacological approaches aimed at modulating the kynurenine pathway directly, such as inhibitors of indoleamine 2,3-dioxygenase, offer potential avenues for new treatments. Understanding and targeting these interconnected pathways are crucial for developing effective strategies to prevent and manage neurological disorders. [ABSTRACT FROM AUTHOR]

Quantitative Systems Pharmacology (QSP) modeling is increasingly applied in the pharmaceutical industry to influence decision making across a wide range of stages from early discovery to clinical development to post-marketing activities. Development of standards for how these models are constructed, assessed, and communicated is of active interest to the modeling community and regulators but is complicated by the wide variability in the structures and intended uses of the underlying models and the diverse expertise of QSP modelers. With this in mind, the IQ Consortium conducted a survey across the pharmaceutical/biotech industry to understand current practices for QSP modeling. This article presents the survey results and provides insights into current practices and methods used by QSP practitioners based on model type and the intended use at various stages of drug development. The survey also highlights key areas for future development including better integration with statistical methods, standardization of approaches towards virtual populations, and increased use of QSP models for late-stage clinical development and regulatory submissions. [ABSTRACT FROM AUTHOR]

As the age profile of our population expands, we can expect subsequent increase in patients presenting with intracapsular fracture. The onus remains on the surgeon to make all reasonable efforts to find new and innovative means of reducing associated morbidity and mortality of the treatment of these injuries. This challenge is particularly relevant in the elderly and in patients with multiple co-morbidities. In this study, 100 patients were randomly allocated into two groups. One group had dissection to the level of the hip joint under direct diathermy control; the other group had dissection using a scalpel with supplementary electrocautery. Intraoperative total blood loss prior to dissection of the abductors was measured by collecting blood using wound swabs using a local protocol and results were statistically analysed using PROC GLM SAS. We demonstrate a clear advantage in the use of diathermy to create a hip incision showing a significant reduction in wound-related blood loss and a reduction, whilst not statistically significant, in total operative blood loss using diathermy incision. Larger randomised prospective trials are necessary to study the effects of this intervention in a larger patient population so that these end-points can be adequately assessed. [ABSTRACT FROM AUTHOR]

The full-length prefusion-stabilized SARS-CoV-2 spike (S) is the principal antigen of COVID-19 vaccines. Vaccine efficacy has been impacted by emerging variants of concern that accumulate most of the sequence modifications in the immunodominant S1 subunit. S2, in contrast, is the most evolutionarily conserved region of the spike and can elicit broadly neutralizing and protective antibodies. Yet, S2’s usage as an alternative vaccine strategy is hampered by its general instability. Here, we use a simulation-driven approach to design S2-only immunogens stabilized in a closed prefusion conformation. Molecular simulations provide a mechanistic characterization of the S2 trimer’s opening, informing the design of tryptophan substitutions that impart kinetic and thermodynamic stabilization. Structural characterization via cryo-EM shows the molecular basis of S2 stabilization in the closed prefusion conformation. Informed by molecular simulations and corroborated by experiments, we report an engineered S2 immunogen that exhibits increased protein expression, superior thermostability, and preserved immunogenicity against sarbecoviruses.The evolutionarily conserved SARS-CoV-2 spike’s S2 subunit provides the foundation for its usage as an immunogen in vaccines. Here, the authors use a simulation-driven approach to design S2-only immunogens stabilized in the closed prefusion conformation. [ABSTRACT FROM AUTHOR]

Presented here is a systematic literature review of what the academic literature asserts about: (1) the stages of the ethical decision-making process (i.e. awareness, reasoning, motivation, and action) that are claimed to be improved or not improved by RI teaching and whether these claims are supported by evidence; (2) the measurements used to determine the effectiveness of RI teaching; and (3) the stage/s of the ethical decision-making process that are difficult to assess. Regarding (1), awareness was the stage most claimed to be amenable to improvement following RI teaching, and with motivation being the stage that is rarely addressed in the academic literature. While few, some sources claimed RI teaching cannot improve specific stages. With behaviour (action) being the stage referenced most, albeit in only 9% of the total sources, for not being amenable to improvement following RI teaching. Finally, most claims were supported by empirical evidence. Regarding (2), measures most frequently used are custom in-house surveys and some validated measures. Additionally, there is much debate in the literature regarding the adequacy of current assessment measures in RI teaching, and even their absence. Such debate warrants caution when we are considering the empirical evidence supplied to support that RI teaching does or does not improve a specific stage of the decision-making process. Regarding (3), only behaviour was discussed as being difficult to assess, if not impossible. In our discussion section we contextualise these results, and following this we derive some recommendations for relevant stakeholders in RI teaching. [ABSTRACT FROM AUTHOR]

Purpose of Review: To evaluate the adverse effects of common antihypertensive agents utilized or encountered in the Emergency Department. Recent Findings: All categories of antihypertensive agents may manifest adverse effects, inclusive of adverse drug reactions (ADRs), drug-to-drug interactions, or accidental overdose. Adverse effects, and specifically ADRs, may be stratified into the organ systems affected, might require specific time-sensitive interventions, could pose particular risks to vulnerable populations, and may result in significant morbidity, and potential mortality. Summary: Adverse effects of common antihypertensive agents may be encountered in the ED, necessitating that ED systems of care are poised to prevent, recognize, and intervene when adverse effects arise. [ABSTRACT FROM AUTHOR]

Nanomedicine has the potential to increase the biostability of drugs to treat retinal diseases, improving their performance and decreasing the required number of intravitreal injections. However, accurate pharmacokinetic studies of these nanoparticle-drug conjugates, nanoparticle motion across the vitreous humour and interaction with the retinal cell layers still need to be investigated. Existing nanoparticle tracking techniques require fluorescent labels, which can impact cytotoxicity, nanoparticles' motion, protein interactions, and cell internalization. In this study, a real-time label-free tracking technology, for single nanoparticles in an optical microscope based on the optical phenomena of caustics, was used to characterise the diffusion of nanoparticles in agar-hyaluronic acid hydrogels, previously validated as vitreous humour substitutes for in vitro models. The results demonstrated that the diffusion of nanoparticles through these hydrogels was heterogeneous, and that nanoparticle size had an important role in nanoparticle distribution across and within in vitro vitreous substitutes. These findings suggest that nanoparticle diameter is a critical parameter for designing novel therapeutics for retinal diseases. Moreover, nanoparticle charge did not affect nanoparticle diffusion or distribution in these synthetic hydrogels. The use of caustics in optical microscopy has been demonstrated to be a reproducible, inexpensive technique for screening novel therapeutics in eye in vitro models. [ABSTRACT FROM AUTHOR]

Museum genomics provide an opportunity to investigate population demographics of extinct species, especially valuable when research prior to extinction was minimal. The Bachman’s warbler (Vermivora bachmanii) is hypothesized to have gone extinct due to loss of its specialized habitat. However, little is known about other potential contributing factors such as natural rarity or changes to connectivity following habitat fragmentation. We examined mitochondrial DNA (mtDNA) and genome-wide SNPs using specimens collected from breeding and migration sites across the range of the Bachman’s warbler. We found no signals of strong population structuring across the breeding range of Bachman’s warblers in both mtDNA and genome-wide SNPs. Thus, long-term population isolation did not appear to be a significant contributor to the extinction of the Bachman’s warbler. Instead, our findings support the theory that Bachman’s warblers underwent a rapid decline likely driven by habitat destruction, which may have been exacerbated by the natural rarity, habitat specificity and low genetic diversity of the species. [ABSTRACT FROM AUTHOR]

Background and Objective: Pediatric dosing of enoxaparin was derived based on extrapolation of the adult therapeutic range to children. However, a large fraction of children do not achieve therapeutic anticoagulation with initial dosing. We aim to use real-world anti-Xa data obtained from children receiving enoxaparin per standard of care to characterize the population pharmacokinetics (PopPK).Author names: Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct.The author names are accurately presented and the metadata are correct. Methods: A PopPK analysis was performed using NONMEM, and a stepwise covariate modeling approach was applied for the covariate selection. The final PopPK model, developed with data from 1293 patients ranging in age from 1 day to 18 years, was used to simulate enoxaparin subcutaneous dosing for prophylaxis and treatment based on total body weight (0–18 years, TBW) or fat-free mass (2–18 years, FFM). Simulated exposures in children with obesity (body mass index percentile ≥95th percentile) were compared with those without obesity. Results: A linear, one-compartment PopPK model that included allometric scaling using TBW (<2 years) or FFM (≥2 years) characterized the enoxaparin pharmacokinetic data. In addition, serum creatinine was identified as a significant covariate influencing clearance. Simulations indicated that in patients aged <2 years, the recommended 1.5 mg/kg TBW-based dosing achieves therapeutic simulated concentrations. In pediatric patients aged ≥2 years, the recommended 1.0 mg/kg dose resulted in exposures more comparable in children with and without obesity when FFM weight-based dosing was applied. Conclusion: Using real-world data and PopPK modeling, enoxaparin's pharmacokinetics were characterized in pediatric patients. Using FFM and twice-daily dosing might reduce the risk of overdosing, especially in children with obesity. [ABSTRACT FROM AUTHOR]

Objectives: To quantify brain microstructural changes in recently diagnosed relapsing-remitting multiple sclerosis (RRMS) using longitudinal T1 measures, and determine their associations with clinical disability. Methods: Seventy-nine people with recently diagnosed (< 6 months) RRMS were recruited from a single-centre cohort sub-study, and underwent baseline and 1-year brain MRI, including variable flip angle T1 mapping. Median T1 was measured in white matter lesions (WML), normal-appearing white matter (NAWM), cortical/deep grey matter (GM), thalami, basal ganglia and medial temporal regions. Prolonged T1 (≥ 2.00 s) and supramedian T1 (relative to cohort WML values) WML voxel counts were also measured. Longitudinal change was assessed with paired t-tests and compared with Bland-Altman limits of agreement from healthy control test-retest data. Regression analyses determined relationships with Expanded Disability Status Scale (EDSS) score and dichotomised EDSS outcomes (worsening or stable/improving). Results: Sixty-two people with RRMS (mean age 37.2 ± 10.9 [standard deviation], 48 female) and 11 healthy controls (age 44 ± 11, 7 female) contributed data. Prolonged and supramedian T1 WML components increased longitudinally (176 and 463 voxels, respectively; p <.001), and were associated with EDSS score at baseline (p <.05) and follow-up (supramedian: p <.01; prolonged: p <.05). No cohort-wide median T1 changes were found; however, increasing T1 in WML, NAWM, cortical/deep GM, basal ganglia and thalami was positively associated with EDSS worsening (p <.05). Conclusion: T1 is sensitive to brain microstructure changes in early RRMS. Prolonged WML T1 components and subtle changes in NAWM and GM structures are associated with disability. Clinical relevance statement: MRI T1 brain mapping quantifies disability-associated white matter lesion heterogeneity and subtle microstructural damage in normal-appearing brain parenchyma in recently diagnosed RRMS, and shows promise for early objective disease characterisation and stratification. Key Points: • Quantitative T1 mapping detects brain microstructural damage and lesion heterogeneity in recently diagnosed relapsing-remitting multiple sclerosis. • T1 increases in lesions and normal-appearing parenchyma, indicating microstructural damage, are associated with worsening disability. • Brain T1 measures are objective markers of disability-relevant pathology in early multiple sclerosis. [ABSTRACT FROM AUTHOR]

Background: Determining the prevalence of doping within an elite athlete population is challenging due to the extreme sensitivity of the topic; however, understanding true doping prevalence is important when designing anti-doping programs and measuring their effectiveness. The objective of this study was to estimate the prevalence of doping among Olympic, Paralympic, World, and National-level competitive athletes in the United States subject to the World Anti-Doping Code. All athletes who were subject to the U.S. Anti-Doping Agency's Protocol for Olympic and Paralympic Movement Testing, a World Anti-Doping Code ("Code")-compliant anti-doping program, were invited to complete a web-delivered survey. Using a direct questioning approach, the survey items asked athletes whether they had used each specific category of banned substance / method on the World Anti-Doping Agency's Prohibited List. Multiple strategies to encourage honest reporting (e.g., protecting anonymity by collecting minimal demographic information; using an outside organization to administer the survey) and to detect inconsistent responses were used. Results: Depending on the method of calculation, 6.5–9.2% of the 1,398 respondents reported using one or more prohibited substances or methods in the 12 months prior to survey administration. Specific doping prevalence rates for each individual substance / method categories ranged from 0.1% (for both diuretics / masking agents and stem cell / gene editing) to 4.2% for in-competition use of cannabinoids. Conclusion: Determining the prevalence of doping within different athlete populations is critical so that sport governing bodies can evaluate their anti-doping efforts and better tailor their programming. By measuring doping prevalence of specific categories of substances and methods, rather than just the overall prevalence of doping, this study also highlights where sport governing bodies should focus their future educational and detection efforts. Key Points: Estimated doping prevalence among U.S. elite athletes ranged from 6.5 to 9.2%. The most prevalent category of doping was in-competition use of cannabinoids (at 4.2%), whereas the least prevalent categories of doping were diuretics or masking agents (0.1%), stem cell or gene editing (0.1%), narcotics (0.2%), and hormone and metabolic modulators (0.2%). Of the athletes who reported doping, most reported using only one substance or method. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, with up to 32% of patients with NSCLC harboring an epidermal growth factor receptor (EGFR) mutation. NSCLC harboring an EGFR mutation has a dedicated treatment pathway, with EGFR tyrosine kinase inhibitors and platinum-based chemotherapy often being the therapy of choice. Objective: The aim of this study was to systemically review and summarize economic models of first-line treatments used for locally advanced or metastatic NSCLC harboring EGFR mutations, as well as to identify areas for improvement for future models. Methods: Literature searches were conducted via Ovid in PubMed, MEDLINE, MEDLINE In-Process, Embase, Evidence-Based Medicine Reviews: Health Technology Assessment, Evidence-Based Medicine Reviews: National Health Service Economic Evaluation Database, and EconLit. An initial search was conducted on 19 December 2022 and updated on 11 April 2023. Studies were selected according to predefined criteria using the Population, Intervention, Comparator, Outcome and Study design (PICOS) framework. Results: Sixty-seven articles were included in the review, representing 59 unique studies. The majority of included models were cost-utility analyses (n = 52), with the remaining studies being cost-effectiveness analyses (n = 4) and a cost-minimization analysis (n = 1). Two studies incorporated both a cost-utility and cost-minimization analysis. Although the model structure across studies was consistently reported, justification for this choice was often lacking. Conclusions: Although the reporting of economic models in NSCLC harboring EGFR mutations is generally good, many of these studies lacked sufficient reporting of justification for structural choices, performing extensive sensitivity analyses and validation in economic evaluations. In resolving such gaps, the validity of future models can be increased to guide healthcare decision making in rare indications. [ABSTRACT FROM AUTHOR]

Mosquitoes are a complex nuisance around the world and tropical countries bear the brunt of the burden of mosquito-borne diseases. Rwanda has had success in reducing malaria and some arboviral diseases over the last few years, but still faces challenges to elimination. By building our understanding of in situ mosquito communities in Rwanda at a disturbed, human-occupied site and at a natural, preserved site, we can build our understanding of natural mosquito microbiomes toward the goal of implementing novel microbial control methods. Here, we examined the composition of collected mosquitoes and their microbiomes at two diverse sites using Cytochrome c Oxidase I sequencing and 16S V4 high-throughput sequencing. The majority (36 of 40 species) of mosquitoes captured and characterized in this study are the first-known record of their species for Rwanda but have been characterized in other nations in East Africa. We found significant differences among mosquito genera and among species, but not between mosquito sexes or catch method. Bacteria of interest for arbovirus control, Asaia, Serratia, and Wolbachia, were found in abundance at both sites and varied greatly by species. [ABSTRACT FROM AUTHOR]

Despite considerable legacy issues, Girdlestone's resection arthroplasty (GRA) remains a valuable tool in the armoury of the arthroplasty surgeon. When reserved for massive lysis in the context of extensive medical co-morbidities which preclude staged or significant surgical interventions, and/or the presence of pelvic discontinuity, GRA as a salvage procedure can have satisfactory outcomes. These outcomes include infection control, pain control and post-op function. We describe a case series of 13 cases of GRA and comment of the indications, peri, and post-operative outcomes. [ABSTRACT FROM AUTHOR]

This study evaluated patient experiences with genetic testing for inherited retinal diseases (IRDs) and the association between underlying knowledge, testing outcomes, and the perceived value of the results. An online survey was distributed to adults with IRDs and parents/guardians of dependents with IRDs who had had genetic testing. Data included details of genetic testing, pre- and post- test perceptions, Decision Regret Scale, perceived value of results, and knowledge of gene therapy. Of 135 responses (85% from adults with IRDs), genetic testing was primarily conducted at no charge through public hospitals (49%) or in a research setting (30%). Key motivations for genetic testing were to confirm IRD diagnosis and to contribute towards research. Those who had received a genetic diagnosis (odds ratio: 6.71; p < 0.001) and those self-reported to have good knowledge of gene therapy (odds ratio: 2.69; p = 0.018) were more likely to have gained confidence in managing their clinical care. For over 80% of respondents, knowing the causative gene empowered them to learn more about their IRD and explore opportunities regarding clinical trials. Key genetic counselling information needs include resources for family communications, structured information provision, and ongoing genetic support, particularly in the context of emerging ocular therapies, to enhance consistency in information uptake. [ABSTRACT FROM AUTHOR]

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use's (ICH) renovation of Good Clinical Practice (GCP) represents a philosophical shift in the conduct of clinical research away from a one-size-fits-all application to promoting a proactive, risk-based approach. The aim of this paper is to enhance the understanding of specific topics detailed in ICH E8 based on direct feedback from TransCelerate member companies who identified Quality by Design (QbD), Critical to Quality (CtQ), Fit for Purpose, and Stakeholder Engagement, as most changed and open to interpretation. The TransCelerate framework seeks to highlight and expand each of these central topics to support utilization and implementation of a strong foundation for quality in clinical development. [ABSTRACT FROM AUTHOR]

Background: Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment. Methods: A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed. Results: Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported. Conclusions: This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT. Systematic review registration. PROSPERO-CRD42016036802. [ABSTRACT FROM AUTHOR]

Purpose: Residual or undertreated inflow disease is a major cause of stent occlusion following endovascular thrombectomy for iliofemoral deep venous thrombosis (DVT). The profunda femoral vein (PFV) is an important inflow vessel alongside the femoral vein but is traditionally challenging to treat via an antegrade popliteal approach. This technical note describes a novel approach for PFV clearance in iliofemoral thrombectomy via the popliteal vein. Materials and Methods: Eight patients underwent PFV clearance as part of iliofemoral DVT thrombectomy via an antegrade popliteal approach. In seven patients, a popliteal-profunda communicating vessel was identified permitting PFV access and thrombectomy. In one patient, a popliteal-profunda communicator was not identified and an 'up and over' approach via the femoral bifurcation from the same popliteal access was utilised. Thrombectomy was performed using the Inari ClotTriever device or Penumbra's Indigo system. Results: Technical success in PFV thrombectomy was 100%. Six patients (75%) underwent stenting for an iliac stenotic lesion or May Thurner compression point. At the four-week ultrasound follow-up, the pelvic iliofemoral segment was patent in 7 patients (87.5%). The PFV was patent in 7 patients (87.5%) whereas the FV was only patent in 4 patients (50%). One patient underwent reintervention for iliofemoral stent occlusion. No PFV injury occurred and no post-procedure profunda reflux was identified. Conclusion: PFV clearance can be achieved via an antegrade popliteal approach in iliofemoral thrombectomy to optimise inflow, negating the need for alternative or additional venous access. PFV may maintain upstream iliofemoral vein patency even with an occluded femoral vein. Level of Evidence: Level 4, Case Series. [ABSTRACT FROM AUTHOR]

Background: Mandibular angle fractures (MAF) have a recognized complexity of treatment and an increased risk of incurring complications. Methods: This retrospective study included 45 consecutive patients who were diagnosed with an isolated MAF and no other facial fractures. The average age was 27.3 (SD = 7.7). Results: A comparatively low rate of complications (11.1%) and a low rate of reoperation (1.8%) are reported, along with a significant role of smoking in complications (p = 0.022). A non-significant association was noted between complications, male gender and assault as an aetiological factor. Conclusions: Review of the data from this study confirms that complication rates for patients attending the National Maxillofacial Unit are similar to or better than that of international studies. An overview of the aetiology of fracture complications is included. [ABSTRACT FROM AUTHOR]

Beer is made via the fermentation of an aqueous extract predominantly composed of malted barley flavoured with hops. The transforming microorganism is typically a single strain of Saccharomyces cerevisiae, and for the majority of major beer brands the yeast strain is a unique component. The present yeast used to make Guinness stout brewed in Dublin, Ireland, can be traced back to 1903, but its origins are unknown. To that end, we used Illumina and Nanopore sequencing to generate whole-genome sequencing data for a total of 22 S. cerevisiae yeast strains: 16 from the Guinness collection and 6 other historical Irish brewing. The origins of the Guinness yeast were determined with a SNP-based analysis, demonstrating that the Guinness strains occupy a distinct group separate from other historical Irish brewing yeasts. Assessment of chromosome number, copy number variation and phenotypic evaluation of key brewing attributes established Guinness yeast-specific SNPs but no specific chromosomal amplifications. Our analysis also demonstrated the effects of yeast storage on phylogeny. Altogether, our results suggest that the Guinness yeast used today is related to the first deposited Guinness yeast; the 1903 Watling Laboratory Guinness yeast. A genomic analysis of 22 S. cereviseae yeast strains used in beer brewing suggest that yeast used to brew Guinness form a distinct evolutionary sub-clade, and that the modern-day Guinness yeast is closely related to the 1903 Watling Laboratory Guinness yeast. [ABSTRACT FROM AUTHOR]

Introduction: Gas leaks polluting the operating room are common in laparoscopy. Studies defining methods for sensitive leak characterisation and mechanical mitigation in real world settings are, however, lacking. Methods: Mobile optical gas imagers (both a miniaturised Schlieren system and sensitive tripod-mounted near-infrared carbon dioxide camera (GF343, FLIR)) prospectively defined trocar-related gas leaks occurring either spontaneously or with instrumentation during planned laparoscopic surgery at three hospitals. A boutique Matlab-based analyser using sequential frame subtraction categorised leaks (class 0—no observable leak; class 1—marginally detectable leak; class 2—short-lived plume; class 3—energetic, turbulent jet). Concurrently, the usefulness of a novel vacuum—ring device (LeakTrap™, Palliare, Ireland) designed as a universal adjunct for existing standard laparoscopic ports at both abdominal wall and port valve level was determined similarly in a phase I/11 clinical trial along with the device's useability through procedural observation and surgeon questionnaire. Results: With ethical and regulatory approval, 40 typical patients (mean age 58.6 years, 20 males) undergoing planned laparoscopic cholecystectomy (n = 36) and hernia repair (n = 4) were studied comprising both control (n = 20) and intervention (n = 20) cohorts. Dual optical gas imaging was successfully performed across all procedures with minimal impact on procedural flow. In total, 1643 trocar instrumentations were examined, 819 in the control group (mean 41 trocar instrumentations/procedure) and 824 in the intervention group (mean 41.2 trocar instrumentations/procedure). Gas leaks were detected during 948(62.6%) visualised trocar instrumentations (in 129–7.8%—the imaging was obscured). 14.8% (110/742) and 60% (445/742) of leaks in control patients were class 0 and 3, respectively, versus 59.1% (456/770) and 8.7% (67/772) in the interventional group (class 3 v non-class 3, p < 0.0001, χ2). The Leaktrap proved surgically acceptable without significant workflow disruption. Conclusion: Laparoscopic gas leaks can be sensitively detected and consistently, effectively mitigated using straightforward available-now technology with most impact on the commonest, highest energy instrument exchange leaks. [ABSTRACT FROM AUTHOR]

Flood exposure has been linked to shifts in population sizes and composition. Traditionally, these changes have been observed at a local level providing insight to local dynamics but not general trends, or at a coarse resolution that does not capture localized shifts. Using historic flood data between 2000-2023 across the Contiguous United States (CONUS), we identify the relationships between flood exposure and population change. We demonstrate that observed declines in population are statistically associated with higher levels of historic flood exposure, which may be subsequently coupled with future population projections. Several locations have already begun to see population responses to observed flood exposure and are forecasted to have decreased future growth rates as a result. Finally, we find that exposure to high frequency flooding (5 and 20-year return periods) results in 2-7% lower growth rates than baseline projections. This is exacerbated in areas with relatively high exposure to frequent flooding where growth is expected to decline over the next 30 years. Using historical data across the U.S., the authors find that population declines are associated with flood exposure. Projecting this relationship to 2053, the authors find that flood risk may result in 7% lower growth than otherwise expected. [ABSTRACT FROM AUTHOR]

Before the colonial period, California harboured more language variation than all of Europe, and linguistic and archaeological analyses have led to many hypotheses to explain this diversity1. We report genome-wide data from 79 ancient individuals from California and 40 ancient individuals from Northern Mexico dating to 7,400–200 years before present (bp). Our analyses document long-term genetic continuity between people living on the Northern Channel Islands of California and the adjacent Santa Barbara mainland coast from 7,400 years bp to modern Chumash groups represented by individuals who lived around 200 years bp. The distinctive genetic lineages that characterize present-day and ancient people from Northwest Mexico increased in frequency in Southern and Central California by 5,200 years bp, providing evidence for northward migrations that are candidates for spreading Uto-Aztecan languages before the dispersal of maize agriculture from Mexico2–4. Individuals from Baja California share more alleles with the earliest individual from Central California in the dataset than with later individuals from Central California, potentially reflecting an earlier linguistic substrate, whose impact on local ancestry was diluted by later migrations from inland regions1,5. After 1,600 years bp, ancient individuals from the Channel Islands lived in communities with effective sizes similar to those in pre-agricultural Caribbean and Patagonia, and smaller than those on the California mainland and in sampled regions of Mexico.Genome-wide analyses of ancient DNA from individuals from California and Mexico shed light on the spread of Mexican ancestry to California and how it correlates with linguistic flow. [ABSTRACT FROM AUTHOR]

Though urban-associated shifts in behavior of adult animals are well documented in the literature, few studies have investigated how urbanization shapes juvenile behavior. For birds, the transition from nestling to fledgling (i.e., leaving the nest or fledging) marks a critical transition that profoundly affects survival. Though species often fledge at different times during the day, young birds are thought to time their fledging relative to civil dawn—which may mark when habitats are first visible for birds. Because sensory pollution within cities can affect the timing of daily activities, we hypothesized that urbanization and light pollution (artificial light at night (ALAN), in particular) would promote earlier fledging times. To test this hypothesis, we examined whether urbanization and light pollution were associated with shifts in diel patterns of fledging in Northern Cardinals (Cardinalis cardinalis) breeding across a rural-to-urban gradient in central-Ohio, USA. From 2007 to 2010, we deployed nest cameras across 227 nests and documented 72 fledging events, from which we characterized and compared diel patterns of fledging between urban and rural cardinals. Consistent with our hypothesis, fledging times were ~ 23% earlier in urban cardinals (5.49 ± 0.63 SE h after civil dawn) compared to their rural counterparts (7.13 ± 0.62 SE h), and cardinals fledged progressively earlier as the landscape became more urbanized and light-polluted. Our findings suggest that ALAN is among many urban-associated factors (e.g., changes in predator communities, predation risk) that may shape juvenile behavior, but future studies are required to identify the mechanisms underlying this shift in fledging behavior. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "The effectiveness and safety of proton beam radiation therapy in children and young adults with Central Nervous System (CNS) tumours: a systematic review." The correction addresses incorrect reference numbers and citations in the original article, as well as missing references. The corrected text and references are provided. The document also mentions the debate surrounding the necessity and ethical justification of conducting randomized controlled trials (RCTs) to evaluate proton beam therapy in children. The rarity of pediatric CNS tumors and the challenges in evaluating clinical effectiveness are discussed. [Extracted from the article]

Background: There has been growing interest in the UK and internationally of risk-stratified breast screening whereby individualised risk assessment may inform screening frequency, starting age, screening instrument used, or even decisions not to screen. This study evaluates the cost-effectiveness of eight proposals for risk-stratified screening regimens compared to both the current UK screening programme and no national screening. Methods: A person-level microsimulation model was developed to estimate health-related quality of life, cancer survival and NHS costs over the lifetime of the female population eligible for screening in the UK. Results: Compared with both the current screening programme and no screening, risk-stratified regimens generated additional costs and QALYs, and had a larger net health benefit. The likelihood of the current screening programme being the optimal scenario was less than 1%. No screening amongst the lowest risk group, and triannual, biennial and annual screening amongst the three higher risk groups was the optimal screening strategy from those evaluated. Conclusions: We found that risk-stratified breast cancer screening has the potential to be beneficial for women at the population level, but the net health benefit will depend on the particular risk-based strategy. [ABSTRACT FROM AUTHOR]

Emerging evidence shows that the meninges conduct essential immune surveillance and immune defense at the brain border, and the dysfunction of meningeal immunity contributes to aging and neurodegeneration. However, no study exists on the molecular properties of cell types within human leptomeninges. Here, we provide single nuclei profiling of dissected postmortem leptomeninges from aged individuals. We detect diverse cell types, including unique meningeal endothelial, mural, and fibroblast subtypes. For immune cells, we show that most T cells express CD8 and bear characteristics of tissue-resident memory T cells. We also identify distinct subtypes of border-associated macrophages (BAMs) that display differential gene expressions from microglia and express risk genes for Alzheimer's Disease (AD), as nominated by genome-wide association studies (GWAS). We discover cell-type-specific differentially expressed genes in individuals with Alzheimer's dementia, particularly in fibroblasts and BAMs. Indeed, when cultured, leptomeningeal cells display the signature of ex vivo AD fibroblasts upon amyloid-β treatment. We further explore ligand-receptor interactions within the leptomeningeal niche and computationally infer intercellular communications in AD. Thus, our study establishes a molecular map of human leptomeningeal cell types, providing significant insight into the border immune and fibrotic responses in AD. The meninges protect the central nervous system at the brain border, and its dysfunction can lead to neural inflammation and cell damage. Here, the authors uncover the gene signatures of diverse cell types in the aged human leptomeninges and highlight their changes in Alzheimer's Disease. [ABSTRACT FROM AUTHOR]

Canadian beekeepers have faced high colony mortality each winter over the last decade. Frequently citing "poor queen quality" as a top contributing factor to colony loss, Canadian beekeepers report needing to replace half their queens each year. Domestic queen production exists throughout Canada but is limited due to the short season and can be further limited when colony mortality is high. Consequently, Canadian beekeepers import over 260,000 queens annually, primarily from locations with warmer climates. In this study, newly mated imported queens from Hawaii (USA) and New Zealand were compared to domestic Canadian queens produced in British Columbia; these stocks were evaluated on their morphological and sperm storage characteristics. Stock quality was also evaluated in the field at two locations in Alberta, Canada over two production seasons. Our results show initial variation in queen morphology and fertility among imported and domestic queen stocks. Most striking, the New Zealand queens weighed 10–13% less than the Hawaii and British Columbia queens, respectively upon arrival. Colony performance over a two-year field study suggests: (1) brood pattern solidness has a positive nonlinear correlation with honey production regardless of queen stock and environment; (2) environment (i.e., apiary location) and queen stock variably predict colony health and productivity depending on year; specifically, apiary site appears to be a stronger predictor of colony health and productivity than queen stock in year one, but in year two, queen stock appears to be a stronger predictor than apiary site; (3) high clinical symptoms of chalkbrood may explain the prevalence of poor brood patterns in colonies headed by queens from New Zealand; (4) domestic queens are 25% more likely to survive winter in Alberta than imported queens. Therefore, it is important to consider possible mismatches in disease immunity and climate conditioning of imported queen stocks heading colonies in temperate regions that face drastically different seasonal climates and disease ecology dynamics. [ABSTRACT FROM AUTHOR]

Bats are widespread mammals that play key roles in ecosystems as pollinators and insectivores. However, there is a paucity of information about bat-associated microbes, in particular their fungal communities, despite the important role microbes play in host health and overall host function. The emerging fungal disease, white-nose syndrome, presents a potential challenge to the bat microbiome and understanding healthy bat-associated taxa will provide valuable information about potential microbiome-pathogen interactions. To address this knowledge gap, we collected 174 bat fur/skin swabs from 14 species of bats captured in five locations in New Mexico and Arizona and used high-throughput sequencing of the fungal internal transcribed (ITS) region to characterize bat-associated fungal communities. Our results revealed a highly heterogeneous bat mycobiome that was structured by geography and bat species. Furthermore, our data suggest that bat-associated fungal communities are affected by bat foraging, indicating the bat skin microbiota is dynamic on short time scales. Finally, despite the strong effects of site and species, we found widespread and abundant taxa from several taxonomic groups including the genera Alternaria and Metschnikowia that have the potential to be inhibitory towards fungal and bacterial pathogens. [ABSTRACT FROM AUTHOR]

Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, -3, -4) decorate immune cells and act as key regulators in cellular immunity. However, their dense O-glycosylation remains enigmatic, primarily due to the challenges associated with studying mucin domains. Here, we demonstrate that the mucinase SmE has a unique ability to cleave at residues bearing very complex glycans. SmE enables improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we perform molecular dynamics (MD) simulations of TIM-3 and -4 to understand how glycosylation affects structural features of these proteins. Finally, we use these models to investigate the functional relevance of glycosylation for TIM-3 function and ligand binding. Overall, we present a powerful workflow to better understand the detailed molecular structures and functions of the mucinome. Mucin glycoproteins are biologically relevant but are challenging to study. Here, the authors characterized the SmE enzyme and used it to glycoproteomic ally map immune checkpoint proteins. This information then drove MD simulations and binding assays to understand how glycosylation controls structure and function. [ABSTRACT FROM AUTHOR]

Purpose of Review: Many prostate cancer active surveillance protocols mandate serial monitoring at defined intervals, including but certainly not limited to serum PSA (often every 6 months), clinic visits, prostate multiparametric MRI, and repeat prostate biopsies. The purpose of this article is to evaluate whether current protocols result in excessive testing of patients on active surveillance. Recent Findings: Multiple studies have been published in the past several years evaluating the utility of multiparametric MRI, serum biomarkers, and serial prostate biopsy for men on active surveillance. While MRI and serum biomarkers have promise with risk stratification, no studies have demonstrated that periodic prostate biopsy can be safely omitted in active surveillance. Summary: Active surveillance for prostate cancer is too active for some men with seemingly low-risk cancer. The use of multiple prostate MRIs or additional biomarkers do not always add to the prediction of higher-grade disease on surveillance biopsy. [ABSTRACT FROM AUTHOR]

Structure determination of amorphous materials remains challenging, owing to the disorder inherent to these materials. Nuclear magnetic resonance (NMR) powder crystallography is a powerful method to determine the structure of molecular solids, but disorder leads to a high degree of overlap between measured signals, and prevents the unambiguous identification of a single modeled periodic structure as representative of the whole material. Here, we determine the atomic-level ensemble structure of the amorphous form of the drug AZD4625 by combining solid-state NMR experiments with molecular dynamics (MD) simulations and machine-learned chemical shifts. By considering the combined shifts of all 1H and 13C atomic sites in the molecule, we determine the structure of the amorphous form by identifying an ensemble of local molecular environments that are in agreement with experiment. We then extract and analyze preferred conformations and intermolecular interactions in the amorphous sample in terms of the stabilization of the amorphous form of the drug. The atomic-level ensemble structure of an amorphous form of a drug is determined by combining NMR experiments with molecular dynamics simulations and machine-learned chemical shifts. The structure explains the stabilization of the amorphous form. [ABSTRACT FROM AUTHOR]

Background: Lifelong reduction of growth hormone (GH) action extends lifespan and improves healthspan in mice. Moreover, congenital inactivating mutations of GH receptor (GHR) in mice and humans impart resistance to age-associated cancer, diabetes, and cognitive decline. To investigate the consequences of GHR disruption at an adult age, we recently ablated the GHR at 6-months of age in mature adult (6mGHRKO) mice. We found that both, male and female 6mGHRKO mice have reduced oxidative damage, with males 6mGHRKO showing improved insulin sensitivity and cancer resistance. Importantly, 6mGHRKO females have an extended lifespan compared to controls. Objective and Methods: To investigate the possible mechanisms leading to health improvements, we performed RNA sequencing using livers from male and female 6mGHRKO mice and controls. Results: We found that disrupting GH action at an adult age reduced the gap in liver gene expression between males and females, making gene expression between sexes more similar. However, there was still a 6-fold increase in the number of differentially expressed genes when comparing male 6mGHRKO mice vs controls than in 6mGHRKO female vs controls, suggesting that GHR ablation affects liver gene expression more in males than in females. Finally, we found that lipid metabolism and xenobiotic metabolism pathways are activated in the liver of 6mGHRKO mice. Conclusion: The present study shows for the first time the specific hepatic gene expression profile, cellular pathways, biological processes and molecular mechanisms that are driven by ablating GH action at a mature adult age in males and females. Importantly, these results and future studies on xenobiotic metabolism may help explain the lifespan extension seen in 6mGHRKO mice. [ABSTRACT FROM AUTHOR]

Background: Over the last 6 years, there has been a change in the demographics of people presenting to gender services in Ireland. This is in line with international trends describing a higher number of transgender men (Female-Male, FTM, AFAB) presenting to gender services as compared to transgender women (Male–Female, MTF, AMAB), and lower ages at referral. Given the changes in demographics, it would be anticipated that clinical needs may have changed. This study describes the demographics of a young Irish sample (participants aged 18–30 years old) and explores the referral pathways and clinical needs of this cohort. Methods: The study was performed as a retrospective chart review of 167 charts at The National Gender Service in Ireland over a five-month period. Results: Transgender men represented 62.3% of the sample, transgender women 35.3%, and transmasculine/non-binary individuals represented 2.4%. Over two-thirds of participants were on gender affirming hormone therapy or GnRH antagonists and 16.1% had undergone surgical interventions. The median time from referral received to being seen at the clinic was 450 days (481 mean). Mental health comorbidities remain high with 49.1% of youth experiencing depression, a further 15.6% low mood and 26.3% anxiety. Conclusion: This is the first study to show increasing referrals of people who were assigned female at birth (AFAB) over assigned male at birth (AMAB) individuals in Ireland, and to document the clinical needs of this cohort. By understanding the changing demographics and clinical needs, we can better plan for care and service improvements. [ABSTRACT FROM AUTHOR]

Objective: Adverse childhood experiences (ACEs) are common and robustly predict drug misuse. Dispositional mindfulness inversely associates with both childhood adversity and drug use severity. However, mindfulness is a multi-faceted construct, and emerging findings suggest that facets may differentially link to favorable outcomes. The present study tested the hypothesis that mindfulness facets would differentially mediate the relationship between ACEs and cannabis misuse. Method: A college student sample (n = 354) completed the Adverse Childhood Experiences Questionnaire (ACE), Five Facet Mindfulness Questionnaire (FFMQ), and Cannabis Use Disorders Identification Test-Revised (CUDIT-R). Individual mediation models tested whether FFMQ total score and facets (Awareness, Nonjudge, Observe) differentially mediated the relationship between ACEs and CUDIT-R scores. Results: Significant associations were observed between the number of ACE exposures, CUDIT-R severity, and the three FFMQ facets. The FFMQ Awareness (unstandardized indirect effect (IE) = 0.12, SE = 0.05, 95% CI [0.03, 0.22]), Nonjudge (IE = 0.24, SE = 0.07, 95% CI [0.11, 0.39]), and Observe (IE = 0.11, SE = 0.05, 95% CI [0.03, 0.22]) facets each partially mediated the relationship between ACE exposures and CUDIT-R severity in their individual models and accounted for 20%, 41%, and 19% of the variance in this relationship, respectively. Conclusions: Findings highlight the differential importance of mindfulness facets and the need to consider the unique contributions of these facets in understanding the relationship on ACE-related consequences and drug misuse. Preregistration: This study is not pre-registered. [ABSTRACT FROM AUTHOR]

Accountability, human rights and social justice are inextricably linked. Rights cannot be defended and upheld, and inequalities cannot be highlighted and challenged in the absence of accountability. In recent decades, recordkeepers have increasingly emphasised the role of archives and records in facilitating accountability, upholding rights and exposing instances of social injustice. This paper assesses the twenty-first-century recordkeeping literature as it relates to the ethical issues of accountability, human rights and social justice in public sector recordkeeping. While there is some consensus on the role of recordkeeping with regard to accountability and human rights, there is less agreement regarding social justice, which remains a contested and poorly defined concept in the literature. The debates around accountability, human rights and social justice impact on perceptions of the role of the archivist and have led to a strong trend towards more activist interpretations, with increasing calls for greater inclusion and the development of participatory recordkeeping models. Despite this trend, implementation remains a challenge, and the gap between theory and practice needs to be continually addressed. [ABSTRACT FROM AUTHOR]

Abstract Cellular signal transduction pathways are usually studied following administration of an external stimulus. However, disease‐associated aberrant activity of the pathway is often due to misregulation of the equilibrium state. The transcription factor NF‐κB is typically described as being held inactive in the cytoplasm by binding its inhibitor, IκB, until an external stimulus triggers IκB degradation through an IκB kinase‐dependent degradation pathway. Combining genetic, biochemical, and computational tools, we investigate steady‐state regulation of the NF‐κB signaling module and its impact on stimulus responsiveness. We present newly measured in vivo degradation rate constants for NF‐κB‐bound and ‐unbound IκB proteins that are critical for accurate computational predictions of steady‐state IκB protein levels and basal NF‐κB activity. Simulations reveal a homeostatic NF‐κB signaling module in which differential degradation rates of free and bound pools of IκB represent a novel cross‐regulation mechanism that imparts functional robustness to the signaling module.

Precise knowledge of each patient's index cancer and surrounding anatomy is required for nerve-sparing robot-assisted radical prostatectomy (NS-RARP). Complementary to this, 3D printing has proven its utility in improving the visualisation of complex anatomy. This is the first systematic review to critically assess the potential of 3D printed patient-specific prostate cancer models in improving visualisation and the practice of NS-RARP. A literature search of PubMed and OVID Medline databases was performed using the terms "3D Printing", "Robot Assisted Radical Prostatectomy" and related index terms as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Eight articles were included; six were identified via database searches, to which a further two articles were located via a snowballing approach. Eight papers were identified for review. There were five prospective single centre studies, one case series, one technical report and one letter to the editor. Of these articles, five publications (62.5%) reported on the utility of 3D printed models for NS-RARP planning. Two publications (25%) utilised 3D printed prostate models for simulation and training, and two publications (25%) used the models for patient engagement. Despite the nascency of the field, 3D printed models are emerging in the uro-oncological literature as a useful tool in visualising complex anatomy. This has proven useful in NS-RARP for preoperative planning, simulation and patient engagement. However, best practice guidelines, the future regulatory landscape, and health economic considerations need to be addressed before this synergy of new technologies is ready for the mainstream. [ABSTRACT FROM AUTHOR]

In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation. [ABSTRACT FROM AUTHOR]

We report a self-induced spatially-coherent dot array consisting of fourteen units of vertical-cavity surface-emitting modes that exhibit spatially uniform spectra. A 47.5 µm total beam width and 0.5° narrow emission are achieved using an oblong cavity enclosed with a flat top mirror, cylindrically curved bottom mirror, and side facet. Notably, terminating the side of the cavity with a perpendicular facet enhances the horizontal propagation, which couples with the vertical resonance in each dot, similar to the case of master lasers in injection-locked lasers that delocalize the modes. Conventional semiconductor lasers, edge-emitting lasers, and vertical-cavity surface-emitting lasers have a Fabry–Pérot cavity; furthermore, emission and resonance are in identical directions, limiting the beam width to micrometers. Though the present structure has the same scheme of propagation, the right-angled facet synchronizes the modes and drastically expands the beam width. [ABSTRACT FROM AUTHOR]

The Posttrauma Risky Behaviors Questionnaire (PRBQ) was developed as a comprehensive, yet brief assessment of the extent of engaging in posttrauma reckless and self-destructive behaviors (RSDBs). Extending upon the initial psychometric investigation of the PRBQ, the current study details a preliminary investigation of measurement (non)-invariance across trauma types (i.e., interpersonal vs. non-interpersonal) and count (i.e., singular vs. multiple) in a sample of 1,174 trauma-exposed undergraduates. Confirmatory factor analysis supported the unidimensional measurement model in the overall sample and trauma subgroups. Further, the RSDB construct evaluated by the PRBQ demonstrated configural, metric (ΔCFI =.008), and scalar invariance (ΔCFI =.009) across subgroups indexing non-interpersonal versus interpersonal trauma, and configural, partial metric (ΔCFI =.009), and scalar invariance (ΔCFI =.009) across subgroups reporting singular versus multiple trauma types. Findings indicate equivalence of the PRBQ-assessed RSDB construct across subgroups differentiated by interpersonal vs. non-interpersonal trauma types, but not count of trauma types. [ABSTRACT FROM AUTHOR]

A strong association between sleep problems and suicidal thoughts and behaviors (STBs) has been demonstrated in high-income countries. The sleep-STB relationship, however, is minimally understood among youth in low and middle-incomes countries. There also is a limited understanding of how individual- (i.e., age, sex) and country-level (i.e., economic inequality, economic quality) factors may moderate the magnitude of the sleep-STB association among youth. Data were analyzed from the cross-national Global School-based Health Survey 2003–2017, which assessed a range of health behaviors among school-enrolled adolescents aged 11–18 years from 88 low-, lower-middle, upper-middle, and high-income countries. Multilevel models were used to examine the influence of individual- and country-level factors on the association between past-year worry-related sleep problems and past-year suicide ideation, suicide plans, and suicide attempts. Worry-related sleep problems were significantly associated with suicide ideation, plans, and attempts. Adolescent sex, country economic quality (income group designation), and country economic inequality moderated the sleep-STB association, but age did not. The sleep-STB relationship was stronger for males and across macroeconomic indices, the relationship was generally strongest among upper-middle income countries (economic quality) and countries with a big income gap (economic inequality). When examining how individual-level factors differentially affected the sleep-STB relationship within economic quality (income group designation), the effects were driven by older adolescents in high-income countries for suicide ideation and suicide plans. Study findings suggest an important role for global macroeconomic factors, for males, and older adolescents in high-income countries in the sleep-STB relationship. Future directions include expanding worldwide coverage of countries, assessing a wider range of sleep problems, and longitudinal work to understand potential mechanisms in the sleep-STB relationship. [ABSTRACT FROM AUTHOR]

It has recently been proposed that the intermittent access (IntA) drug self-administration procedure better produces behavioral changes relevant to addiction than the long access (LgA) procedure. In this version of the IntA procedure, the drug is made available for a 5-min period during each half hour of a 6-h session. In contrast, on the LgA procedure, the drug is available continuously for 6 h. Previous studies have found that IntA drug self-administration produces greater drug motivation, measured by increased progressive ratio breakpoints, than LgA self-administration. It has been hypothesized that this effect is due to the rapid, "spiking" brain levels of the drug, and consequent neuroadaptations, experienced by rats during IntA sessions. However, no study has compared the effects of IntA versus LgA training on reinforcer motivation when using a non-drug reinforcer. The present study compared motivation for a saccharin reinforcer after IntA or LgA training. In Experiment 1, separate groups of rats lever-pressed for saccharin on the IntA or LgA procedures. In Experiment 2, a within-subjects design was used where rats pressed one lever on the IntA procedure and another lever on the LgA procedure for saccharin. In both experiments, IntA training produced greater breakpoints than LgA training. As no drug was used here, spiking drug levels could not have been responsible for the increased saccharin motivation observed after IntA training. Instead, it is proposed that differences in stimulus-reinforcer associations learned during IntA versus LgA training may be responsible for the effect. Future research is needed to determine the extent to which such learning factors may contribute to the increased motivation observed after IntA training with drug reinforcers. [ABSTRACT FROM AUTHOR]