Traumatic brain injury is associated with the subsequent risk of atrial fibrillation or atrial flutter.

BACKGROUND: Traumatic brain injury (TBI) is associated with a variety of adverse long-term outcomes and increases sympathetic nervous system activation, which could increase the risk of arrhythmias including atrial fibrillation or atrial flutter (AF/AFL). OBJECTIVE: We examined episodes of TBI and subsequent AF/AFL in a large cohort of post-9/11 servicemembers and veterans. METHODS: The variable of interest was TBI, stratified by severity (mild, moderate/severe, and penetrating). The outcome was a subsequent diagnosis of AF/AFL. We used Fine-Gray competing risks models to evaluate the potential risk imparted by TBI on subsequent AF/AFL. RESULTS: Of the 1,924,900 participants included in the analysis, 369,891 (19.2%) experienced an episode of documented TBI. Most were young (63% <35 years), male (81.7%), and non-Hispanic White (62.7%). AF/AFL was diagnosed in 22,087 patients. On univariate analysis, only penetrating TBI (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.84-2.23; P < .001) was associated with AF/AFL compared with veterans without TBI. After adjustment in the full multivariable model (adjusted for age, sex, race and ethnicity, service branch, rank, component, and comorbidities), mild (HR 1.27, 95% CI 1.22-1.32; P < .001), moderate/severe (HR, 1.34; 95% CI, 1.24-1.44; P < .001), and penetrating TBI (HR, 1.82; 95% CI, 1.65-2.02; P < .001) were significantly associated with AF/AFL compared with no TBI. Post hoc analyses demonstrated that the risk of AF/AFL was concentrated in female and younger patients. CONCLUSION: We found that an episode of TBI, particularly penetrating TBI, significantly increased the risk for AF/AFL. Further work is needed to delineate the long-term risk of arrhythmias after TBI.

Antipsychotic management in general practice: serial cross-sectional study (2011-2020).

BACKGROUND: Long-term use of antipsychotics confers increased risk of cardiometabolic disease. Ongoing need should be reviewed regularly by psychiatrists. AIM: To explore trends in antipsychotic management in general practice, and proportions of patients prescribed antipsychotics receiving psychiatrist review. DESIGN AND SETTING: A serial cross-sectional study using linked general practice and hospital data in Wales (2011-2020). METHOD: Participants were adults (≥18 years) registered with general practices in Wales. Outcome measures were prevalence of patients receiving ≥6 antipsychotic prescriptions annually, proportion of patients prescribed antipsychotics receiving annual psychiatrist review, and proportion of patients prescribed antipsychotics registered on UK Serious Mental Illness, Depression and/or Dementia registers, or not on any of these registers. RESULTS: Prevalence of adults prescribed long-term antipsychotics increased from 1.06% (95%CI 1.04 to 1.07%) in 2011 to 1.45% (95%CI 1.43 to 1.46%) in 2020. The proportion receiving annual psychiatrist review decreased from 59.6% (95%CI 58.9 to 60.4%) in 2011 to 52.0% (95C%CI 51.4 to 52.7%) in 2020. The proportion of antipsychotics prescribed to patients not on the Serious Mental Illness register increased from 50% (95%CI 49 to 51%) in 2011 to 56% (95%CI 56 to 57%) by 2020. CONCLUSIONS: Prevalence of long-term antipsychotic use is increasing. More patients are managed by general practitioners without psychiatrist review and are not on monitored disease registers; they thus may be less likely to undergo cardiometabolic monitoring and miss opportunities to optimise or deprescribe antipsychotics. These trends pose risks for patients and need to be addressed urgently.

A qualitative exploration of barriers to efficient and effective structured medication reviews in primary care: Findings from the DynAIRx study.

INTRODUCTION: Structured medication reviews (SMRs), introduced in the United Kingdom (UK) in 2020, aim to enhance shared decision-making in medication optimisation, particularly for patients with multimorbidity and polypharmacy. Despite its potential, there is limited empirical evidence on the implementation of SMRs, and the challenges faced in the process. This study is part of a larger DynAIRx (Artificial Intelligence for dynamic prescribing optimisation and care integration in multimorbidity) project which aims to introduce Artificial Intelligence (AI) to SMRs and develop machine learning models and visualisation tools for patients with multimorbidity. Here, we explore how SMRs are currently undertaken and what barriers are experienced by those involved in them. METHODS: Qualitative focus groups and semi-structured interviews took place between 2022-2023. Six focus groups were conducted with doctors, pharmacists and clinical pharmacologists (n = 21), and three patient focus groups with patients with multimorbidity (n = 13). Five semi-structured interviews were held with 2 pharmacists, 1 trainee doctor, 1 policy-maker and 1 psychiatrist. Transcripts were analysed using thematic analysis. RESULTS: Two key themes limiting the effectiveness of SMRs in clinical practice were identified: 'Medication Reviews in Practice' and 'Medication-related Challenges'. Participants noted limitations to the efficient and effectiveness of SMRs in practice including the scarcity of digital tools for identifying and prioritising patients for SMRs; organisational and patient-related challenges in inviting patients for SMRs and ensuring they attend; the time-intensive nature of SMRs, the need for multiple appointments and shared decision-making; the impact of the healthcare context on SMR delivery; poor communication and data sharing issues between primary and secondary care; difficulties in managing mental health medications and specific challenges associated with anticholinergic medication. CONCLUSION: SMRs are complex, time consuming and medication optimisation may require multiple follow-up appointments to enable a comprehensive review. There is a need for a prescribing support system to identify, prioritise and reduce the time needed to understand the patient journey when dealing with large volumes of disparate clinical information in electronic health records. However, monitoring the effects of medication optimisation changes with a feedback loop can be challenging to establish and maintain using current electronic health record systems.

Oligomer Formation Effects on the Separation of Trivalent Lanthanide Fission Products.

The assessment of trivalent lanthanide yields from the fission of uranium-235 is currently achieved using LN (LaNthanide) resin, di(2-ethylhexyl)orthophosphoric acid immobilized on a solid support. However, coelution of lighter lanthanides into terbium (Tb3+) fractions remains a significant problem in recovery of analytically pure fractions. In order to understand how the separation of trivalent lanthanides and yttrium (Ln3+) with LN resin proceeds and how to improve it, their speciation with the organic extractant HDEHP must be fully understood under aqueous conditions. A comprehensive luminescence analysis of aqueous solutions of Ln3+ in contact with HDEHP, along with infrared spectroscopy, elemental combustion analysis, inductively coupled plasma atomic emission spectroscopy (ICP-AES), and mass spectrometry, was used to indicate that an intermediate species is responsible for the coelution; where similar Ln3+ centers (e.g., Eu3+ and Tb3+) are bridged by the O-P-O moiety of deprotonated HDEHP to form large heteronuclear oligomeric structures with the general formula [Ln2(DEHP)6]n. Energy transfer from Tb3+ to Eu3+ in this structure confirms that lanthanide centers are within 10 Å and was used to propose that the oligomeric [Ln2(DEHP)6]n structure is formed rather than a dimeric Ln2(DEHP)6 structure. The effect of this speciation on LN resin column elution is investigated using luminescence spectroscopy, confirming that the oligomeric [Ln2(DEHP)6]n species could disrupt regular elution behavior and cause the problematic bleeding of lighter lanthanides (Sm3+ and Eu3+) into Tb3+ fractions. Resin luminescence measurements were used to propose that the bleeding of the organic extractant HDEHP from its solid support causes the formation of the disruptive oligometallic species.

Incorporating transgender and nonbinary participants in phase 1 clinical drug trials: Current knowledge gaps and considerations.

Phase 1 clinical drug trials critically depend on the participation of healthy volunteers to evaluate the safety and pharmacokinetics of new medicinal products. Current selection criteria and health definitions often overlook the unique health profiles of transgender and nonbinary individuals, potentially excluding them from participating in these essential early-stage studies. This review aims to identify and discuss current knowledge gaps and considerations regarding the inclusion of transgender and nonbinary participants in phase 1 clinical drug trials. We highlight the need for research on how gender-affirming hormone therapy may affect drug pharmacokinetics and call for the development of inclusive biological reference ranges that account for the physiological effects of hormone therapies.

Comparison of Racial and Ethnic Mortality Disparities among Post-9/11 Veterans with and without Traumatic Brain Injury to the Total U.S. Adult Population.

INTRODUCTION: The extent of racial/ethnic disparities and whether they are attenuated in the Veteran population compared to the total US population is not well understood. We aimed to assess racial/ethnic mortality disparities from all-cause, cardiovascular (CVD) and cancer among post-9/11 military Veterans with and without exposure to TBI, compared to the total US population. METHODS: This cohort study included 2,502,101 US military Veterans (18,932,083 person-years) who served after 09/11/2001 with 3 or more years of care in the Military Health System (MHS); or had 3 or more years of care in the MHS and 2 or more years of care in the Veterans Health Administration. Mortality follow-up occurred from 01/01/2002 to 12/31/2020. Mortality rate ratios (MRR) from negative binomial regression models were reported for racial/ethnic groups compared to White non-Hispanic Veterans for all-cause, CVD and cancer mortality. Veteran MRR were compared to the total US population. RESULTS: Mortality rates for Black Non-Hispanic Veterans were higher for all-cause (MRR = 1.21;95%CI: 1.13-1.29; p < 0.001), CVD (MRR = 1.78;95%CI: 1.62-1.96; p < 0.001) and cancer (MRR = 1.17;95%CI: 1.10-1.25; p < 0.001) than in White Non-Hispanic Veterans. Among Veterans with TBI, only Black Non-Hispanics had higher mortality than White Non-Hispanics and only for CVD (MRR = 1.32;95%CI: 1.12-1.54; p < 0.001), while CVD mortality was higher among Veterans without TBI (MRR = 1.77;95%CI: 1.63-1.93;p < 0.001). MRR for Black Non-Hispanics in the total US population, were consistently higher than those in the Veteran population for all-cause (MRR = 1.52;95%CI: 1.46-1.58; p < 0.001), CVD (MRR = 2.03;95%CI: 1.95-2.13; p < 0.001) and cancer (MRR = 1.26;95%CI: 1.22-1.30; p < 0.001). CONCLUSION: This Veteran cohort experienced less racial/ethnic disparity in mortality than the total US population, especially among Veterans with TBI.

Addressing the gaps in evaluation of new drugs for older adults: Strategies from the International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee.

The International Union of Basic and Clinical Pharmacology (IUPHAR) Geriatric Committee aims to improve the use of drugs in older adults and develop new therapeutic approaches for the syndromes and diseases of old age through advocacy, education, and research. In the present paper, we propose strategies relevant to drug development and evaluation, spanning preclinical and the full range of clinical studies. Drugs for older adults need to consider not only age, but also other characteristics common in geriatric patients, such as multimorbidity, polypharmacy, falls, cognitive impairment, and frailty. The IUPHAR Geriatric Committee's position statement on 'Measurement of Frailty in Drug Development and Evaluation' is included, highlighting 12 key principles that cover the spectrum of translational research. We propose that where older adults are likely to be major users of a drug, that frailty is measured at baseline and as an outcome. Preclinical models that replicate the age, frailty, duration of exposure, comorbidities, and co-medications of the proposed patients may improve translation. We highlight the potential application of recent technologies, such as physiologically based pharmacokinetic-pharmacodynamic modeling informed by frailty biology, and Artificial Intelligence, to inform personalized medicine for older patients. Considerations for the rapidly aging populations in low- and middle-income countries related to health-care and clinical trials are outlined. Involving older adults, their caregivers and health-care providers in all phases of research should improve drug development, evaluation, and outcomes for older adults internationally.

What is the association of polypharmacy with frailty in heart failure? A systematic review and meta-analysis.

This systematic review and meta-analysis aimed to explore the differences in the number of prescribed medications and polypharmacy risk between patients with heart failure (HF) and frailty vs. those with HF but without frailty. Eligible studies included observational or experimental studies in patients aged ≥50 years. Thirteen studies met the criteria and were included in the final analysis. Patients with frailty and HF exhibited a higher risk of polypharmacy (OR: 1.87, 95% CI 1.72 - 2.04, I2 = 0%, P < 0.01) compared to those without frailty. Results remained significant after adjusting for comorbidity status. Additionally, patients with frailty and HF were prescribed more medications compared to those without (k = 6; MD: 1.43, 95% CI 0.31 - 2.55, I2 = 94%, P = 0.01), with a high degree of heterogeneity. However, results were non-significant after adjustment for comorbidity status. Patients with HF and frailty have a higher need of polypharmacy compared to those without frailty, which may increase the risk of potentially inappropriate medications (PIM). Investigating the real-world prevalence of PIM may support clinicians in their routine assessment as part of a comprehensive management strategy in patients with HF and frailty.

Management of antipsychotics in primary care: Insights from healthcare professionals and policy makers in the United Kingdom.

INTRODUCTION: Antipsychotic medication is increasingly prescribed to patients with serious mental illness. Patients with serious mental illness often have cardiovascular and metabolic comorbidities, and antipsychotics independently increase the risk of cardiometabolic disease. Despite this, many patients prescribed antipsychotics are discharged to primary care without planned psychiatric review. We explore perceptions of healthcare professionals and managers/directors of policy regarding reasons for increasing prevalence and management of antipsychotics in primary care. METHODS: Qualitative study using semi-structured interviews with 11 general practitioners (GPs), 8 psychiatrists, and 11 managers/directors of policy in the United Kingdom. Data was analysed using thematic analysis. RESULTS: Respondents reported competency gaps that impaired ability to manage patients prescribed antipsychotic medications, arising from inadequate postgraduate training and professional development. GPs lacked confidence to manage antipsychotic medications alone; psychiatrists lacked skills to address cardiometabolic risks and did not perceive this as their role. Communication barriers, lack of integrated care records, limited psychology provision, lowered expectation towards patients with serious mental illness by professionals, and pressure to discharge from hospital resulted in patients in primary care becoming 'trapped' on antipsychotics, inhibiting opportunities to deprescribe. Organisational and contractual barriers between services exacerbate this risk, with socioeconomic deprivation and lack of access to non-pharmacological interventions driving overprescribing. Professionals voiced fears of censure if a catastrophic event occurred after stopping an antipsychotic. Facilitators to overcome these barriers were suggested. CONCLUSIONS: People prescribed antipsychotics experience a fragmented health system and suboptimal care. Several interventions could be taken to improve care for this population, but inadequate availability of non-pharmacological interventions and socioeconomic factors increasing mental distress need policy change to improve outcomes. The role of professionals' fear of medicolegal or regulatory censure inhibiting antipsychotic deprescribing was a new finding in this study.

The status of drug evaluation in older adults in the United Kingdom: Bridging the representation gap.

Older adults are persistently underrepresented in clinical drug trials worldwide, despite increasing multiple long-term conditions and significant prescribing in this demographic. We discuss systemic challenges such as the exclusion of people with comorbid conditions and the lack of assessment for comorbidities as modifiers of treatment effects and highlight the rising trend of polypharmacy, especially among the oldest age groups, which is linked to a significant percentage of unplanned hospitalizations and medication errors. The consequences of these trends prompted the United Kingdom National Overprescribing review, culminating in a set of recommendations for drug development tailored to older adults. Building on this, two critical reports released in April 2023 by the International Longevity Centre (ILC) and the Nuffield Council on Bioethics (NCOB) are discussed. These reports emphasize the importance of diversity and inclusion in clinical trials, advocating for ethical frameworks and methodologies that cater to the complex needs of older adults. The development of inclusive criteria, innovative statistical methodologies, and the integration of patient-reported outcomes are needed to address the persistent barriers to older adult participation in research, suggesting that pragmatic trials, exemplified by the UK's RECOVERY trial during the COVID-19 pandemic, could pave the way for more inclusive research practices.

Traumatic Brain Injury and Subsequent Risk of Brain Cancer in US Veterans of the Iraq and Afghanistan Wars.

Importance: While brain cancer is rare, it has a very poor prognosis and few established risk factors. To date, epidemiologic work examining the potential association of traumatic brain injury (TBI) with the subsequent risk of brain cancer is conflicting. Further data may be useful. Objective: To examine whether a history of TBI exposure is associated with the subsequent development of brain cancer. Design, Setting, and Participants: A retrospective cohort study was conducted from October 1, 2004, to September 20, 2019, and data analysis was performed between January 1 and June 26, 2023. The median follow-up for the cohort was 7.2 (IQR, 4.1-10.1) years. Veterans Affairs (VA) and Department of Defense (DoD) administrative data on 1 919 740 veterans from the Long-Term Impact of Military-Relevant Brain Injury Consortium-Chronic Effects of Neurotrauma Consortium were included. Exposure: The main exposure of interest was TBI severity (categorized as mild, moderate or severe [moderate/severe], and penetrating). Main Outcomes and Measures: The outcome of interest was the development of brain cancer based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) diagnostic codes in either the DoD/VA medical records or from the National Death Index. Results: After 611 107 exclusions (predominately for no encounter during the study period), a cohort including 1 919 740 veterans was included, most of whom were male (80.25%) and non-Hispanic White (63.11%). Median age at index date was 31 (IQR, 25-42) years. The cohort included 449 880 individuals with TBI (mild, 385 848; moderate/severe, 46 859; and penetrating, 17 173). Brain cancer occurred in 318 individuals without TBI (0.02%), 80 with mild TBI (0.02%), 17 with moderate/severe TBI (0.04%), and 10 or fewer with penetrating TBI (≤0.06%). After adjustment, moderate/severe TBI (adjusted hazard ratio [AHR], 1.90; 95% CI, 1.16-3.12) and penetrating TBI (AHR, 3.33; 95% CI, 1.71-6.49), but not mild TBI (AHR, 1.14; 95% CI, 0.88-1.47), were associated with the subsequent development of brain cancer. Conclusions and Relevance: In this cohort study of veterans of the Iraq and Afghanistan wars, moderate/severe TBI and penetrating TBI, but not mild TBI, were associated with the subsequent development of brain cancer.

Public Attitudes Towards Access to Health Data for Research Purposes Through Citizens' Jury in Uganda.

Citizens juries (CJ) are a method of deliberative action research that have been utilized in countries with well-funded health care systems to address questions about access to health data. Uganda is classified as a low-income country and utilizes a predominantly paper-based health record system. The burgeoning electronic health record in the central area represents an opportunity to collect and analyze longitudinal data on patients living with long term HIV infection and multiple diseases, a hitherto unexplored disease mapping exercise We set out to understand the public perception towards the use of data for research purposes such as this among Ugandans utilizing an adapted strategy sensitive to the local culture. The jury were unanimous that electronic data should be used for research provided certain safeguards are adhered to and most importantly, that consent to do so is obtained on the basis of a clear rationale for the project.

Clark's nutcracker forest community visitation: Whitebark pine maintains a keystone seed disperser.

Clark's nutcrackers (Nucifraga columbiana) are obligate seed dispersers for whitebark pine (Pinus albicaulis), but they frequently use other conifer seed resources because of annual variability in cone production or geographic variation in whitebark pine availability. Whitebark pine is declining from several threats including white pine blister rust, leading to potential population declines in the nutcracker and the pine. We hypothesize that where there are few additional seed resources, whitebark pine becomes the key and limiting resource supporting nutcracker populations. We investigated how nutcrackers use coniferous forest community types within Yellowstone National Park to determine potential seed resources and the importance of whitebark pine. We established sites representing five forest community types, including whitebark pine, lodgepole pine (P. contorta), Engelmann spruce (Picea engelmannii), limber pine (P. flexilis), and Douglas-fir (Pseudotsuga menziesii). Each transect annually generated nutcracker point counts, conifer cone production indices, community composition data, and seed resource use observations. We compared hierarchical distance sampling models, estimating nutcracker density and its relationship to forest community type, seed harvesting time-period, year, study site, and cone seed energy. We found cone production varied across years indicating annual variability in energy availability. Nutcracker density was best predicted by forest community type and survey time-period and was highest in whitebark pine stands during the mid-harvesting season. Nutcracker density was comparatively low for all other forest community types. This finding underscores the importance of whitebark pine as a key seed resource for Clark's nutcracker in Yellowstone National Park. The decline of whitebark pine potentially leads to a downward spiral in nutcrackers and whitebark pine, arguing for continued monitoring of nutcrackers and implementation of restoration treatments for whitebark pine.

Associations between health-related behaviors and self-reported cognitive symptoms in U.S. military personnel injured on deployment.

Health behaviors may be core contributors to cognition and mental health following mild traumatic brain injury (TBI). The aims of the present study examined: (1) whether health behaviors including sleep duration, alcohol use, and physical activity differed in injured military personnel with and without deployment-related mild TBI history and (2) the relative contributions of health behaviors and deployment-related mild TBI history to self-reported cognitive, posttraumatic stress disorder (PTSD), and depressive symptoms. Participants included 3076 military personnel injured on deployment participating in the Wounded Warrior Recovery Project, an ongoing web-based study. Military personnel with deployment-related mild TBI history reported similar rates of physical activity and levels of alcohol problems as those without, but were less likely to report receiving the recommended duration of sleep. When adjusting for demographic and injury variables, all three health behaviors were associated with cognitive, PTSD, and depressive symptoms. Alcohol problems demonstrated significant but small effects across all outcomes measures (ηp2=.01) whereas physical activity was associated with slightly larger effects albeit still within the small range (ηp2=.02-0.04). Duration of sleep bordered a medium effect for cognitive symptoms (ηp2=.05) and was in the medium range for PTSD and depressive symptoms (ηp2=.06). Although deployment-related mild TBI history was significant in all models, effect sizes were small (ηp2=.01). Findings from the present study provide support that health behaviors have stronger effects with regard to cognitive, PTSD, and depressive symptoms compared to deployment-related mild TBI history in military personnel and, given their modifiable nature, may represent treatment targets in this population.

Increasing trend in hospitalisation due to adverse drug reactions: can we stem the tide?

Living with multiple long-term health conditions (multimorbidity) is increasingly common in older age. The more long-term conditions that an individual has, the more medicines they are likely to take. Hospitalisation as a consequence of medication-related harm is increasing and a concerted effort is needed to reduce the burden of harm caused by medication. However, making decisions about the balance between benefit and harm for an older person with multimorbidity and polypharmacy is very complex. There are various clinical tools that can help to identify patients at higher risk of harm and numerous strategies, including medicines optimisation reviews that incorporate personalised health information, to try to reduce risk. Further education and training of the healthcare professionals is needed to equip the multidisciplinary workforce with the skills and knowledge to address these challenges. This article discusses some of the changes that can be implemented now and highlights areas that will require more research before they can be introduced, in order to help patients to get the best out of their medicines.

Long-Term Health Care Costs for Service Members Injured in Iraq and Afghanistan.

INTRODUCTION: Over the last two decades, the conflicts in Iraq and Afghanistan have cost the United States significantly in terms of lives lost, disabling injuries, and budgetary expenditures. This manuscript calculates the differences in costs between veterans with combat injuries vs veterans without combat injuries. This work could be used to project future costs in subsequent studies. MATERIALS AND METHODS: In this retrospective cohort study, we randomly selected 7,984 combat-injured veterans between February 1, 2002, and June 14, 2016, from Veterans Affairs Health System administrative data. We matched injured veterans 1:1 to noninjured veterans on year of birth (± 1 year), sex, and first service branch. We observed patients for a maximum of 10 years. This research protocol was reviewed and approved by the David Grant USAF Medical Center institutional review board (IRB), the University of Utah IRB, and the Research Review Committee of the VA Salt Lake City Health Care System in accordance with all applicable Federal regulations. RESULTS: Patients were primarily male (98.1% in both groups) and White (76.4% for injured patients, 72.3% for noninjured patients), with a mean (SD) age of 26.8 (6.6) years for the injured group and 27.7 (7.0) years for noninjured subjects. Average total costs for combat-injured service members were higher for each year studied. The difference was highest in the first year ($16,050 compared to $4,135 for noninjured). These differences remained significant after adjustment. Although this difference was greatest in the first year (marginal effect $12,386, 95% confidence interval $9,736-$15,036; P < 0.001), total costs continued to be elevated in years 2-10, with marginal effects ranging from $1,766 to $2,597 (P < 0.001 for all years). More severe injuries tended to increase costs in all categories. CONCLUSIONS: Combat injured patients have significantly higher long-term health care costs compared to their noninjured counterparts. If this random sample is extrapolated to the 53,251 total of combat wounded service members, it implies a total excess cost of $1.6 billion to date after adjustment for covariates and a median follow-up time of 10 years. These costs are likely to increase as injured veterans age and develop additional chronic conditions.

Suicide attempts and mental health diagnoses in combat-injured service members: A retrospective cohort study.

INTRODUCTION: Examinations of risk factors for suicide attempt in United States service members at high risk of mental health diagnoses, such as those with combat injuries, are essential to guiding prevention and intervention efforts. METHODS: Retrospective cohort study of 8727 combat-injured patients matched to deployed, non-injured patients utilizing Department of Defense and Veterans Affairs administrative records. RESULTS: Combat injury was positively associated with suicide attempt in the univariate model (HR = 1.75, 95% CI 1.5-2.1), but lost significance after adjustment for mental health diagnoses. Utilizing Latent Transition Analysis in the combat-injured group, we identified five mental/behavioral health profiles: (1) Few mental health diagnoses, (2) PTSD and depressive disorders, (3) Adjustment disorder, (4) Multiple mental health comorbidities, and (5) Multiple mental health comorbidities with alcohol use disorder (AUD). Multiple mental health comorbidities with AUD had the highest suicide attempt rate throughout the study and more than four times that of Multiple mental health comorbidities in the first study year (23.4 vs. 5.1 per 1000 person years, respectively). CONCLUSION: Findings indicate that (1) combat injury's impact on suicide attempt is attenuated by mental health and (2) AUD with multiple mental health comorbidities confers heightened suicide attempt risk in combat-injured service members.

The DynAIRx Project Protocol: Artificial Intelligence for dynamic prescribing optimisation and care integration in multimorbidity.

Background: Structured Medication Reviews (SMRs) are intended to help deliver the NHS Long Term Plan for medicines optimisation in people living with multiple long-term conditions and polypharmacy. It is challenging to gather the information needed for these reviews due to poor integration of health records across providers and there is little guidance on how to identify those patients most urgently requiring review. Objective: To extract information from scattered clinical records on how health and medications change over time, apply interpretable artificial intelligence (AI) approaches to predict risks of poor outcomes and overlay this information on care records to inform SMRs. We will pilot this approach in primary care prescribing audit and feedback systems, and co-design future medicines optimisation decision support systems. Design: DynAIRx will target potentially problematic polypharmacy in three key multimorbidity groups, namely, people with (a) mental and physical health problems, (b) four or more long-term conditions taking ten or more drugs and (c) older age and frailty. Structured clinical data will be drawn from integrated care records (general practice, hospital, and social care) covering an ∼11m population supplemented with Natural Language Processing (NLP) of unstructured clinical text. AI systems will be trained to identify patterns of conditions, medications, tests, and clinical contacts preceding adverse events in order to identify individuals who might benefit most from an SMR. Discussion: By implementing and evaluating an AI-augmented visualisation of care records in an existing prescribing audit and feedback system we will create a learning system for medicines optimisation, co-designed throughout with end-users and patients.

Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)-2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria (n = 59 for molnupiravir and n = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations.