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.

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.

A European cross-sectional survey to investigate how involved doctors training in clinical pharmacology are in drug concentration monitoring.

PURPOSE: Therapeutic drug monitoring (TDM) is widely recognised as a key attribute of clinical pharmacologists; yet, the extent to which physicians undertaking postgraduate training in clinical pharmacology (hereafter trainees) are involved in TDM is poorly characterised. Our own experience suggests wide variation in trainee exposure to TDM. METHOD: We performed a Europe-wide cross-sectional internet-based survey of trainees to determine the nature and extent of trainee involvement in TDM. RESULTS: There were 43 responses from eight countries analysed. Of the 21 respondents from the UK, all were also training in general internal medicine (GIM), while all of the respondents who were solely training in clinical pharmacology were from outside the UK. Overall, 86.0% of respondents reported access to drug monitoring for clinical care at their affiliated institution, of which 81.0% were personally involved in TDM in some capacity. On average, trainees reported that drug monitoring was available for 16 of the 33 (48%) of the drug/drug classes surveyed. UK-based respondents were involved in requesting drug-level investigations and interpreting the results for patients under their care in 76.2% and 85.7% of cases, respectively, while non-UK respondents supported other healthcare professionals to interpret results in 45.4% of cases. Trainees felt TDM training was generally either insufficient or very inadequate. CONCLUSION: While access to TDM is relatively available at institutions where trainees are based, the role of trainees is variable and affected by a variety of factors including country and training programme. Universally, trainees feel they need more education in TDM.

Prevalence and correlates of self-reported cognitive difficulties in deployment-injured U.S. military personnel.

Cognitive difficulties typically resolve within days to weeks following mild traumatic brain injury (mTBI); however, a sizable proportion of individuals continue to report cognitive symptoms months to years later that are often associated with posttraumatic stress disorder (PTSD) and depression to a greater degree than a history of mTBI. The current study sought to evaluate the prevalence of self-reported cognitive difficulties as well as the relative contributions of demographic, injury-related, and mental health variables in a large study of U.S. military personnel injured during deployment since 2001. Slightly fewer than half (42.0%) of participants reported elevated cognitive difficulties compared with a normative population; however, this was driven primarily by those who screened positive for PTSD or depression. Hierarchical linear regression revealed that various demographic and injury factors, including lower educational attainment, retired or separated military status, enlisted rank, and a history of deployment-related mTBI, were associated with more self-reported cognitive difficulties, f2 = 0.07. Screening positive for PTSD or depression accounted for 32.1% of the variance in self-reported cognitive symptoms, f2 = 0.63, whereas injury variables, including a history of deployment-related mTBI, albeit significant in the model, accounted for 1.6%. The current findings add to the growing body of literature underscoring the importance of screening for and treating mental health conditions in injured military personnel.

Persistent Opioid Use After Combat Injury and Subsequent Long-term Risk of Abuse: A Retrospective Cohort Study.

OBJECTIVE: To determine whether persistent opioid use after injury is associated with subsequent long-term development of clinically recognized opioid abuse. SUMMARY BACKGROUND DATA: Opioid abuse is an epidemic in the United States and trauma can initiate persistent use; however, it remains unclear whether persistent opioid use contributes to the subsequent development of opioid abuse. The care of combat casualties by the Departments of Defense and Veterans Affairs uniquely allows investigation of this long-term outcome. METHODS: This retrospective cohort study randomly selected 10,000 battle-injured United States military personnel. We excluded patients who died during initial hospitalization or within 180 days of discharge, had a preinjury opioid abuse diagnosis, or had missing data in a preselected variable. We defined persistent opioid use as filling an opioid prescription 3 to 6 months after discharge and recorded clinically recognized opioid abuse using relevant diagnosis codes. RESULTS: After exclusion, 9284 subjects were analyzed, 2167 (23.3%) of whom developed persistent opioid use. During a median follow-up time of 8 years, 631 (6.8%) patients developed clinically recognized opioid abuse with a median time to diagnosis of 3 years. Injury severity and discharge opioid prescription amount were associated with persistent opioid use after trauma. After adjusting for patient and injury-specific factors, persistent opioid use was associated with the long-term development of clinically recognized opioid abuse (adjusted hazard ratio, 2.39; 95% confidence interval, 1.99-2.86). CONCLUSIONS: Nearly a quarter of patients filled an opioid prescription 3 to 6 months after discharge, and this persistent use was associated with long-term development of opioid abuse.

Traumatic injury and atrial fibrillation among deployed service members.

INTRODUCTION: Atrial fibrillation and atrial flutter (AF/AFL), the most common atrial arrhythmias, have never been examined in combat casualties. In this study, we investigated the impact of traumatic injury on AF/AFL among service members with deployment history. METHODS: Sampled from the Department of Defense (DoD) Trauma Registry (n = 10,000), each injured patient in this retrospective cohort study was matched with a non-injured service member drawn from the Veterans Affairs/DoD Identity Repository. The primary outcome was AF/AFL diagnosis identified using ICD-9-CM and ICD-10-CM codes. Competing risk regressions based on Fine and Gray subdistribution hazards model with were utilized to assess the association between injury and AF/AFL. RESULTS: There were 130 reported AF/AFL cases, 90 of whom were injured and 40 were non-injured. The estimated cumulative incidence rates of AF/AFL for injured was higher compared to non-injured patients (hazards ratio [HR] = 2.04; 95% confidence interval [CI] = 1.44, 2.87). After adjustment demographics and tobacco use, the association did not appreciably decrease (HR = 1.90; 95% CI = 1.23, 2.93). Additional adjustment for obesity, hypertension, diabetes, and vascular disorders, the association between injury and AF/AFL was no longer statistically significant (HR = 1.51; 95% CI = 0.99, 2.52). CONCLUSION: Higher AF/AFL incidence rate was observed among deployed service members with combat injury compared to servicemembers without injury. The association did not remain significant after adjustment for cardiovascular-related covariates. These findings highlight the need for combat casualty surveillance to further understand the AF/AFL risk within the military population and to elucidate the potential underlying pathophysiologic mechanisms.

The Enduring Health Consequences of Combat Trauma: a Legacy of Chronic Disease.

BACKGROUND: A better understanding of the long-term health effects of combat injury is important for the management of veterans' health in the Department of Defense (DoD) and Veterans Affairs (VA) health care systems and may have implications for primary care management of civilian trauma patients. OBJECTIVE: To determine the impact of traumatic injury on the subsequent development of hypertension (HTN), diabetes mellitus (DM), and coronary artery disease (CAD) after adjustment for sociodemographic, health behavior, and mental health factors. DESIGN: Retrospective cohort study of current and former US military personnel with data obtained from both the DoD and VA health care systems. PARTICIPANTS: Combat injured (n = 8727) service members between 1 February 2002 and 14 June 2016 randomly selected from the DoD Trauma Registry matched 1:1 based on year of birth, sex, and branch of service to subjects that deployed to a combat zone but were not injured. MAIN MEASURES: Traumatic injury, stratified by severity, compared with no documented injury. Diagnoses of HTN, DM, and CAD defined by International Classification of Diseases 9th or 10th Revision Clinical Modification codes. KEY RESULTS: After adjustment, severe traumatic injury was significantly associated with HTN (HR 2.78, 95% CI 2.18-3.55), DM (HR 4.45, 95% CI 2.15-9.18), and CAD (HR 4.87, 95% CI 2.11-11.25), compared with no injury. Less severe injury was associated with HTN (HR 1.14, 95% CI 1.05-1.24) and CAD (HR 1.62, 95% CI 1.11-2.37). CONCLUSIONS: Severe traumatic injury is associated with the subsequent development of HTN, DM, and CAD. These findings have profound implications for the primary care of injured service members in both the DoD/VA health systems and may be applicable to civilian trauma patients as well. Further exploration of pathophysiologic, health behavior, and mental health changes after trauma is warranted to guide future intervention strategies.

Long-term bisphosphonate therapy and atypical femoral fracture: Can you have too much of a good thing?

The long-term, continuous use of bisphosphonates (beyond 5 years) is not wholly without risk. Atypical femoral fracture is an uncommon but potentially very serious adverse event associated with the long-term use of bisphosphonates. Here we consider the complexities of long-term bisphosphonate prescribing, particularly in those that are low risk of osteoporotic fracture, wherein the duration of therapy should be reviewed regularly with individualised risk assessment to ensure the duration of treatment is appropriate.

TEMPORARY REMOVAL: Reference intervals for putative biomarkers of drug-induced liver injury and liver regeneration in healthy human volunteers.

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Rhabdomyolysis among Critically Ill Combat Casualties: Long-Term Outcomes.

BACKGROUND: Although rhabdomyolysis has been associated with acute kidney injury and mortality in the short term, the long-term consequences of an episode of rhabdomyolysis remain unknown. We sought to identify the long-term outcomes of rhabdomyolysis, including mortality, renal function, and incidence of hypertension (HTN), among service members initially admitted to the intensive care unit after sustaining a combat injury in Iraq or Afghanistan between February 1, 2002 and February 1, 2011. METHODS: Information on age, sex, injury severity score, mechanism of injury, serum creatinine, burn injury, presenting mean arterial pressure, and creatine kinase were retrospectively collected and analyzed for 2,208 patients. Standard descriptive tests were used to compare characteristics of patients with and without rhabdomyolysis. Competing risk Cox proportional hazards models were performed to assess the associated risk of rhabdomyolysis with both HTN and poor renal function. RESULTS: While rhabdomyolysis was associated with HTN on univariate analysis (hazard ratio [HR] 1.30, 95% CI 1.03-1.64; p = 0.029), this difference did not persist on multivariable analysis (HR 1.27, 95% CI 0.99-1.62; p = 0.058). The median estimated glomerular filtration rate (eGFR) was 119 (interquartile range [IQR] 103-128) among those with rhabdomyolysis, compared with 108 (IQR 94-121) in the group without rhabdomyolysis (p < 0.001). CONCLUSION: After adjustment, patients with rhabdomyolysis were not at an increased risk of HTN compared to patients without rhabdomyolysis. eGFR was paradoxically higher in patients with rhabdomyolysis. There was no association found between rhabdomyolysis and mortality.

WONOEP appraisal: Molecular and cellular biomarkers for epilepsy.

Peripheral biomarkers have myriad potential uses for treatment, prediction, prognostication, and pharmacovigilance in epilepsy. To date, no single peripheral biomarker has demonstrated proven effectiveness, although multiple candidates are in development. In this review, we discuss the major areas of focus including inflammation, blood-brain barrier dysfunction, redox alterations, metabolism, hormones and growth factors.

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.

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.

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.

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.

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.

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.