Role of RNA structural plasticity in modulating HIV-1 genome packaging and translation.

HIV-1 transcript function is controlled in part by twinned transcriptional start site usage, where 5' capped RNAs beginning with a single guanosine (1G) are preferentially packaged into progeny virions as genomic RNA (gRNA) whereas those beginning with three sequential guanosines (3G) are retained in cells as mRNAs. In 3G transcripts, one of the additional guanosines base pairs with a cytosine located within a conserved 5' polyA element, resulting in formation of an extended 5' polyA structure as opposed to the hairpin structure formed in 1G RNAs. To understand how this remodeling influences overall transcript function, we applied in vitro biophysical studies with in-cell genome packaging and competitive translation assays to native and 5' polyA mutant transcripts generated with promoters that differentially produce 1G or 3G RNAs. We identified mutations that stabilize the 5' polyA hairpin structure in 3G RNAs, which promote RNA dimerization and Gag binding without sequestering the 5' cap. None of these 3G transcripts were competitively packaged, confirming that cap exposure is a dominant negative determinant of viral genome packaging. For all RNAs examined, conformations that favored 5' cap exposure were both poorly packaged and more efficiently translated than those that favored 5' cap sequestration. We propose that structural plasticity of 5' polyA and other conserved RNA elements place the 5' leader on a thermodynamic tipping point for low-energetic (~3 kcal/mol) control of global transcript structure and function.

Neural evidence of switch processes during semantic and phonetic foraging in human memory.

Humans may retrieve words from memory by exploring and exploiting in "semantic space" similar to how nonhuman animals forage for resources in physical space. This has been studied using the verbal fluency test (VFT), in which participants generate words belonging to a semantic or phonetic category in a limited time. People produce bursts of related items during VFT, referred to as "clustering" and "switching." The strategic foraging model posits that cognitive search behavior is guided by a monitoring process which detects relevant declines in performance and then triggers the searcher to seek a new patch or cluster in memory after the current patch has been depleted. An alternative body of research proposes that this behavior can be explained by an undirected rather than strategic search process, such as random walks with or without random jumps to new parts of semantic space. This study contributes to this theoretical debate by testing for neural evidence of strategically timed switches during memory search. Thirty participants performed category and letter VFT during functional MRI. Responses were classified as cluster or switch events based on computational metrics of similarity and participant evaluations. Results showed greater hippocampal and posterior cerebellar activation during switching than clustering, even while controlling for interresponse times and linguistic distance. Furthermore, these regions exhibited ramping activity which increased during within-patch search leading up to switches. Findings support the strategic foraging model, clarifying how neural switch processes may guide memory search in a manner akin to foraging in patchy spatial environments.

Whole Blood and Blood Component Resuscitation in Trauma: Interaction and Association with Mortality.

OBJECTIVE: Evaluate the interaction between whole blood (WB) and blood component resuscitation in relation to mortality following trauma. SUMMARY BACKGROUND DATA: WB is increasingly available in civilian trauma resuscitation, and it is typically transfused concomitantly with blood components. The interaction between WB and blood component transfusions is unclear. METHODS: Adult trauma patients with a shock index >1 who received ≥4 combined units of red blood cells (RBC) or WB within 4 hours across 501 United States trauma centers were included using the American College of Surgeons Trauma Quality Improvement Program (ACS-TQIP) database. The associations between 1)WB resuscitation and mortality, 2)WB to total transfusion volume ratio (WB:TTV) and mortality, 3)balanced blood component transfusion in the setting of combined WB and component resuscitation and mortality were evaluated with multivariable analysis. RESULTS: A total of 12,275 patients were included (WB: 2,884 vs. component-only: 9,391). WB resuscitation was associated with lower odds of 4-hour (adjusted odds ratio [aOR]: 0.81 [0.68-0.97]), 24-hour, and 30-day mortality compared to component-only. Higher WB:TTV ratios were significantly associated with lower 4-hour, 24-hour, and 30-day mortality, with a 13% decrease in odds of 4-hour mortality for each 10% increase in the WB:TTV ratio (0.87 [95%CI:0.80 - 0.94]). Balanced blood component transfusion was associated with significantly lower odds of 4-hour (aOR: 0.45 [95%CI: 0.29 - 0.68]), 24-hour, and 30-day mortality in the setting of combined WB and blood component resuscitation. CONCLUSIONS: WB resuscitation, higher WB:TTV ratios, and balanced blood component transfusion in conjunction with WB were associated with lower mortality in trauma patients presenting in shock requiring 4 units of RBC and/or WB transfusion within 4 hours of arrival.

Association Between Emergency Medical Service Agency Volume and Mortality in Trauma Patients.

OBJECTIVE: The aim of this study was to evaluate the association of annual trauma patient volume on outcomes for emergency medical services (EMS) agencies. BACKGROUND: Regionalization of trauma care saves lives. The underlying concept driving this is a volume-outcome relationship. EMS are the entry point to the trauma system, yet it is unknown if a volume-outcome relationship exists for EMS. METHODS: A retrospective analysis of prospective cohort including 8 trauma centers and 20 EMS air medical and metropolitan ground transport agencies. Patients 18 to 90 years old with injury severity scores ≥9 transported from the scene were included. Patient and agency-level risk-adjusted regression determined the association between EMS agency trauma patient volume and early mortality. RESULTS: A total of 33,511 were included with a median EMS agency volume of 374 patients annually (interquartile range: 90-580). Each 50-patient increase in EMS agency volume was associated with 5% decreased odds of 6-hour mortality (adjusted odds ratio=0.95; 95% CI: 0.92-0.99, P =0.03) and 3% decreased odds of 24-hour mortality (adjusted odds ratio=0.97; 95% CI: 0.95-0.99, P =0.04). Prespecified subgroup analysis showed EMS agency volume was associated with reduced odds of mortality for patients with prehospital shock, requiring prehospital airway placement, undergoing air medical transport, and those with traumatic brain injury. Agency-level analysis demonstrated that high-volume (>374 patients/year) EMS agencies had a significantly lower risk-standardized 6-hour mortality rate than low-volume (<374 patients/year) EMS agencies (1.9% vs 4.8%, P <0.01). CONCLUSIONS: A higher volume of trauma patients transported at the EMS agency level is associated with improved early mortality. Further investigation of this volume-outcome relationship is necessary to leverage quality improvement, benchmarking, and educational initiatives.

Determining evolutionary origin and phylogenetic relationships of mallard-like ducks of Oceania, greater Indonesia, and the Philippines with ddRAD-seq data.

AIM: We aim to determine the evolutionary origins and population genetics of mallard-like ducks of Oceania, greater Indonesia, and the Philippines. LOCATION: Oceania, greater Indonesia, and the Philippines. TAXON: Mallard (Anas platyrhynchos), Pacific black duck (A. superciliosa spp.), and Philippine duck (A. luzonica) METHODS: Thousands of nuclear ddRAD-seq loci and the mitochondrial DNA control region were assayed across individuals representative of each species' range. We assessed population structure and phylogenetic relationships, as well as estimated demographic histories to reconstruct the biogeographical history of each species. RESULTS: Philippine and Pacific black ducks represent unique genetic lineages that diverged from the mallard 1-2 million years ago. We find no support for the Philippine duck representing a hybrid species as once posited; however, their low levels of genetic diversity requires further attention. We find a lack of substructure among Philippine ducks. However, we found pronounced differentiation between subspecies of Pacific black ducks, especially between A. s. superciliosa from New Zealand and A. s. rogersi from Australia, Papua New Guinea, and Timor-Leste, Indonesia. Anas superciliosa pelewensis gave mixed results; individuals from the Solomon Islands were differentiated from the other subspecies, but those from the island of Aunu'u, American Samoa, were genetically more similar to A. s. rogersi than A. s. pelewensis samples from the Solomon Islands. Finally, we find limited evidence of interspecific gene flow at evolutionary scales, and mallard introgression among contemporary samples. MAIN CONCLUSIONS: Mallard-like ducks radiated across Oceania, greater Indonesia, and the Philippines within the last 2 million years. Only the Pacific black duck showed unique sub-structuring that largely followed known sub-species ranges, except for A. s. pelewensis. We posit that the high interrelatedness among Solomon Island samples suggests that their genetic distinctiveness may simply be the result of high levels of genetic drift. In contrast, we conclude that mainland Australian Pacific black ducks were the most likely source for the recent colonization of American Samoa. As a result, our findings suggest that either the A. s. pelewensis subspecies designations and/or its geographical range may require re-evaluation. Continued re-evaluation of evolutionary and taxonomic relationships is necessary when attempting to reconstruct and understand biogeographical histories, with important implications towards any attempts to implement conservation strategies.

Hypertension during transfer is associated with poor outcomes in unstable patients with ruptured abdominal aortic aneurysm.

OBJECTIVE: Limited data exist for optimal blood pressure (BP) management during transfer of patients with ruptured abdominal aortic aneurysm (rAAA). This study evaluates the effects of hypertension and severe hypotension during interhospital transfers in a cohort of patients with rAAA in hemorrhagic shock. METHODS: We performed a retrospective, single-institution review of patients with rAAA transferred via air ambulance to a quaternary referral center for repair (2003-2019). Vitals were recorded every 5 minutes in transit. Hypertension was defined as a systolic BP of ≥140 mm Hg. The primary cohort included patients with rAAA with hemorrhagic shock (≥1 episode of a systolic BP of <90 mm Hg) during transfer. The primary analysis compared those who experienced any hypertensive episode to those who did not. A secondary analysis evaluated those with either hypertension or severe hypotension <70 mm Hg. The primary outcome was 30-day mortality. RESULTS: Detailed BP data were available for 271 patients, of which 125 (46.1%) had evidence of hemorrhagic shock. The mean age was 74.2 ± 9.1 years, 93 (74.4%) were male, and the median total transport time from helicopter dispatch to arrival at the treatment facility was 65 minutes (interquartile range, 46-79 minutes). Among the cohort with shock, 26.4% (n = 33) had at least one episode of hypertension. There were no significant differences in age, sex, comorbidities, AAA repair type, AAA anatomic location, fluid resuscitation volume, blood transfusion volume, or vasopressor administration between the hypertensive and nonhypertensive groups. Patients with hypertension more frequently received prehospital antihypertensives (15% vs 2%; P = .01) and pain medication (64% vs 24%; P < .001), and had longer transit times (36.3 minutes vs 26.0 minutes; P = .006). Episodes of hypertension were associated with significantly increased 30-day mortality on multivariable logistic regression (adjusted odds ratio [aOR], 4.71; 95% confidence interval [CI], 1.54-14.39; P = .007; 59.4% [n = 19] vs 40.2% [n = 37]; P = .01). Severe hypotension (46%; n = 57) was also associated with higher 30-day mortality (aOR, 2.82; 95% CI, 1.27-6.28; P = .01; 60% [n = 34] vs 32% [n = 22]; P = .01). Those with either hypertension or severe hypotension (54%; n = 66) also had an increased odds of mortality (aOR, 2.95; 95% CI, 1.08-8.11; P = .04; 58% [n = 38] vs 31% [n = 18]; P < .01). Level of hypertension, BP fluctuation, and timing of hypertension were not significantly associated with mortality. CONCLUSIONS: Hypertensive and severely hypotensive episodes during interhospital transfer were independently associated with increased 30-day mortality in patients with rAAA with shock. Hypertension should be avoided in these patients, but permissive hypotension approaches should also maintain systolic BPs above 70 mm Hg whenever possible.

Patient sex and outcomes in children with life-threatening hemorrhage.

BACKGROUND: Recent data suggest female sex imparts a survival benefit after trauma in adults. The independent associations between patient sex and age with outcomes have not been examined in children with life-threatening hemorrhage (LTH) from all etiologies. STUDY DESIGN AND METHODS: In a secondary analysis of a multicenter prospective observational study of children with LTH, Massive Transfusion in Children (MATIC), we analyzed if patient sex and age were associated with differences in severity of illness, therapies, and outcomes. Primary outcomes were 24 hour mortality and weight-adjusted transfusion volume during LTH. Kruskal-Wallis, chi-square testing, and multivariable linear regression were used for adjusted analyses. RESULTS: Of 449 children, 45% were females and 55% were males. Females were more commonly younger, white, and with less trauma as the etiology of LTH compared to males. Markers of clinical severity were similar between groups, except injury severity score (ISS) was higher in females in the trauma subgroup. In terms of resuscitative practices, females received greater weight-adjusted total transfusion volumes compared to males (76 (40-150) mL/kg vs. 53 (24-100) mL/kg), as well as increased red blood cells (RBCs), plasma, and platelets compared to males. After adjustment for confounders, female sex and age 0-11 years were independently associated with increased transfusion volume during LTH. There were no differences in mortality or adverse outcomes according to patient sex. CONCLUSION: Patient sex and age may impact factors associated with LTH and therapies received. Studies in developmental hemostasis are needed to determine the optimal transfusion strategy for LTH according to patient sex and age.

Increased platelet to red blood cell transfusion ratio associated with acute kidney injury in children with life-threatening bleeding.

INTRODUCTION: Transfusion may increase the risk of organ failure through immunomodulatory effects. The primary objective of this study was to assess for patient or transfusion-related factors that are independently associated with the risk of acute kidney injury (AKI) and acute respiratory distress syndrome (ARDS) in a cohort of children with life-threatening bleeding from all etiologies. METHODS: In a secondary analysis of the prospective observational massive transfusion in children (MATIC) study, multivariable logistic regression was performed in an adjusted analysis to determine if blood product ratios or deficits were independently associated with AKI or ARDS in children with life-threatening bleeding. RESULTS: There were 449 children included with a median (interquartile range, IQR) age of 7.3 years (1.7-14.7). Within 5 days of the life-threatening bleeding event, AKI occurred in 18.5% and ARDS occurred in 20.3% of the subjects. Every 10% increase in the platelet to red blood cell transfusion ratio is independently associated with a 12.7% increase in the odds of AKI (adjusted odds ratio 1.127; 95% confidence interval 1.025-1.239; p-value .013). Subjects with operative or medical etiologies were independently associated with an increased risk of AKI compared to those with traumatic injury. No transfusion-related variables were independently associated with the risk of developing ARDS. CONCLUSION: The use of increased platelet to red blood cell transfusion ratios in children with life-threatening bleeding of any etiology may increase the risk of AKI but not ARDS. Prospective trials are needed to determine if increased platelet use in this cohort increases the risk of AKI to examine possible mechanisms.

Pharmacological adjuncts and transcranial magnetic stimulation-induced synaptic plasticity: a systematic review.

BACKGROUND: Transcranial magnetic stimulation (TMS) is a noninvasive neurostimulation modality that has been used to study human synaptic plasticity. Leveraging work in ex vivo preparations, mechanistically informed pharmacological adjuncts to TMS have been used to improve our fundamental understanding of TMS-induced synaptic plasticity. METHODS: We systematically reviewed the literature pairing pharmacological adjuncts with TMS plasticity-induction protocols in humans. We searched MEDLINE, PsycINFO, and Embase from 2013 to Mar. 10, 2023. Studies published before 2013 were extracted from a previous systematic review. We included studies using repetitive TMS, theta-burst stimulation, paired associative stimulation, and quadripulse stimulation paradigms in healthy and clinical populations. RESULTS: Thirty-six studies met our inclusion criteria (28 in healthy and 8 in clinical populations). Most pharmacological agents have targeted the glutamatergic N-methyl-d-aspartate (NMDA; 15 studies) or dopamine receptors (13 studies). The NMDA receptor is necessary for TMS-induced plasticity; however, sufficiency has not been shown across protocols. Dopaminergic modulation of TMS-induced plasticity appears to be dose-dependent. The GABAergic, cholinergic, noradrenergic, and serotonergic neurotransmitter systems have small evidence bases supporting modulation of TMS-induced plasticity, as do voltage-gated calcium and sodium channels. Studies in clinical populations suggest that pharmacological adjuncts to TMS may rescue motor cortex plasticity, with implications for therapeutic applications of TMS and a promising clinical trial in depression. LIMITATIONS: This review is limited by the predominance in the literature of studies with small sample sizes and crossover designs. CONCLUSION: Pharmacologically enhanced TMS largely parallels findings from ex vivo preparations. As this area expands and novel targets are tested, adequately powered samples in healthy and clinical populations will inform the mechanisms of TMS-induced plasticity in health and disease.

Incremental burden on health-related quality of life, health service utilization and direct medical expenditures associated with cognitive impairment among non-institutionalized people with diabetes aged 65 years and older.

AIMS: To quantify the incremental health and economic burden associated with cognitive impairment (CI) among non-institutionalized people with diabetes ≥65 years in the United States. MATERIALS AND METHODS: Using 2016-2019 Medical Expenditure Panel Surveys data, we identified participants ≥65 years with diabetes. We used propensity score weighting to quantify the CI-associated incremental burden on health-related quality of life measured by the 12-item Short Form Survey (SF-12), including the mental component summary score, physical component summary score and health utility. We also compared the annual health service utilization and expenditures on ambulatory visits, prescriptions, home care, emergency room (ER), hospitalizations and total annual direct medical expenditures. RESULTS: We included 5094 adults aged ≥65 with diabetes, of whom 804 had CI. After propensity score weighting, CI was associated with a lower mental component summary score (-8.4, p < .001), physical component summary score (-5.2, p < .001) and health utility (-0.12, p < .001). The CI group had more ambulatory visits (+4.4, p = .004) and prescriptions (+9.9, p < .001), with higher probabilities of having home care (+11.3%, p < .001) and ER visits (+8.2%, p = .001). People with CI spent $5441 (p < .001) more annually, $2039 (p = .002) more on prescriptions, $2695 (p < .001) more on home care and $118 (p < .001) more on ER visits. There is no statistically significant difference in the utilization and expenditure of hospitalizations. CONCLUSION: CI was associated with worse health-related quality of life, higher health service utilization and expenditures. Our findings can be used to monitor the health and economic burden of CI in non-institutionalized older persons with diabetes.

Association between low cognitive performance and diabetes-related health indicators across racial and ethnic groups in adults with diabetes.

AIM: To examine the associations between low cognitive performance (LCP) and diabetes-related health indicators (including body mass index [BMI], HbA1c, systolic blood pressure [SBP], low-density lipoprotein [LDL] and self-reported poor physical health) and whether these associations vary across racial/ethnic subgroups. METHODS: We identified adults aged 60 years or older with self-reported diabetes from the 2011-2014 National Health and Nutrition Examination Survey. Individuals with cognitive test scores in the lowest quartile were defined as having LCP. We used regression models to measure the associations of LCP with diabetes-related biometrics (BMI, HbA1c, SBP and LDL); and self-reported poor physical health. Moreover, we explored potential variations in these associations across racial/ethnic subgroups. RESULTS: Of 873 (261 with LCP) adults with diabetes, LCP was associated with higher HbA1c, SBP and LDL (adjusted difference: 0.41%, 5.01 mmHg and 5.08 mg/dL, respectively; P < .05), and greater odds of reporting poor physical health (adjusted odds ratio: 1.59, P < .05). The association between LCP and HbA1c was consistent across racial/ethnic groups, and notably pronounced in Hispanic and Other. BMI worsened with LCP, except for non-Hispanic Black. Excluding the Other group, elevated SBP was observed in people with LCP, with Hispanic showing the most significant association. LDL levels were elevated with LCP for Hispanic and Other. Physical health worsened with LCP for both non-Hispanic Black and Hispanic. CONCLUSIONS: We quantified the association between LCP and diabetes-related health indicators. These associations were more pronounced in Hispanic and Other racial/ethnic groups.

The Role of Integrated Air Transport System in Managing Patients with Abdominal Aortic Aneurysm Rupture.

OBJECTIVE: Ruptured abdominal aortic aneurysms (rAAAs) are highly morbid emergencies. Not all hospitals are equipped to repair them, and an air ambulance network may aid in regionalising specialty care to quaternary referral centres. The association between travel distance by air ambulance and rAAA mortality in patients transferred as an emergency for repair was examined. METHODS: A retrospective review of institutional data. Adults with rAAA (2002 - 2019) transferred from an outside hospital (OSH) to a single quaternary referral centre for repair via air ambulance were identified. Patients who arrived via ground transport or post-repair at an OSH for continued critical care were excluded. Patients were divided into near and far groups based on the 75th percentile of the straight line travel distance (> 72 miles) between hospitals. The primary outcome was 30 day mortality. Multivariable logistic regression was used to assess the association between distance and mortality after adjusting for age, sex, ethnicity, cardiovascular comorbidities, and repair type. RESULTS: A total of 290 patients with rAAA were transported a median distance of 40.4 miles (interquartile range 25.5, 72.7) with 215 (74.1%) near and 75 (25.9%) far patients. Both the near and far groups had similar ages, sex, and ethnicity. There was no difference in pre-operative loss of consciousness, intubation, or cardiac arrest between groups. Endovascular aneurysm repair utilisation and intra-operative aortic occlusion balloon use were also similar. Neither the observed (26.8% vs. 23.9%, p = .61) nor the adjusted odds ratio (0.70, 95% confidence interval 0.36 - 1.39, p = .32) 30 day mortality rate differed significantly between the near and far groups. CONCLUSION: Increasing distance travelled during transfer by air ambulance was not associated with worse outcomes in patients with rAAA. The findings support the regionalisation of rAAA repair to large quaternary centres via an integrated and robust air ambulance network.

Measuring neurobehavioral side effects of corticosteroids in pediatric acute lymphoblastic leukemia: A scoping review.

Corticosteroids are essential to curative acute lymphoblastic leukemia (ALL) treatment, yet have significant neuropsychiatric side effects that decrease quality of life for patients and families. We conducted a scoping review, following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, to describe the existing measurement tools used to evaluate neurobehavioral side effects of corticosteroids in pediatric ALL. From various databases and registers, 4047 studies were identified. Twenty-four articles met inclusion criteria. Clinical assessment was most used to evaluate these symptoms. Twelve validated measures were identified. Existing data about neuropsychiatric side effects of corticosteroids in pediatric ALL are extremely heterogeneous, creating challenges for standardized assessment and management.

A Review of Concordance and Quality in Clinical Guidelines for Hormonal Contraceptives to Mitigate Drug-Drug Interactions in Women With Epilepsy.

PURPOSE: Concomitant use of hormonal contraceptive agents (HCAs) and enzyme-inducting antiepileptic drugs (EIAEDs) may lead to contraceptive failure and unintended pregnancy. This review identified and evaluated concordance and quality of clinical treatment guidelines related to the use of HCAs in women with epilepsy (WWE) receiving EIAEDs. METHODS: Relevant clinical guidelines were identified across four databases and were independently evaluated for quality utilizing the AGREE-II protocol instrument. Quality in this context is defined as the rigor and transparency of the methodologies used to develop the guideline. Guidelines were further assessed in terms of concordance and discordance with the latest body of knowledge concerning the use of hormonal contraception in the presence of EIAEDs. RESULTS: A total of n = 5 guidelines were retrieved and evaluated. Overall guideline scores ranged from 17% to 92%, while individual domain scores ranged from 0% to 100%. Contraceptive guidelines consistently recommended the use of intrauterine systems and long-acting injectables in the presence of EIAEDs, recommended against the use of oral, transdermal, and vaginal ring contraceptives, and differed regarding recommendations related to implants. Guidelines agreed regarding recommendations that women treated with EIAEDs should receive intrauterine systems and long-acting injectables; however, the suggested frequency of administration of injectable contraceptives differed. The use of intrauterine systems in this population is supported by evidence, but there is uncertainty surrounding the use of long-acting injectables and contraceptive implants. CONCLUSIONS: To mitigate the risk of unintended pregnancy and its consequences, recommendations related to implants and long-acting injectable contraceptives should be evidence-based.

Risk of Suicidal Ideation and Behavior Following Early-Onset Idiopathic Restless Legs Syndrome Treatment.

PURPOSE: To estimate incidence rates of suicidal ideation and behavior following treatment initiation with gabapentinoids or dopamine agonists (DAs) in patients with newly diagnosed early-onset idiopathic restless legs syndrome (RLS) and to examine suicidal behavior risk, comparing between those receiving gabapentinoids and DAs. METHODS: A new user retrospective cohort study using MarketScan claims data from 2012 to 2019 was conducted. Exposures were monotherapy gabapentinoids or DAs initiated within 60 days of new RLS diagnosis. Three varying outcome measures of suicidality were examined and incidence rates were calculated for each. A log-binomial regression model the estimated relative risk (RR) of the outcomes with gabapentinoids. Propensity score weighting adjusted for baseline covariates, including age, substance use disorders, hyperlipidemia, antipsychotic use, hypnotic/sedative use, and mood stabilizer use, which were most imbalanced before weighting. RESULTS: The cohort included 6672 patients, with 4986 (74.7%) initiating a DA and 1686 (25.3%) initiating a gabapentinoid. Incidence rates for all outcome measures were higher in the gabapentinoid group (suicidality: 21.6 vs. 10.7 per 1000 person-years; suicidality with self-harm: 23.0 vs. 11.1 per 1000 person-years; overdose- and suicide-related events: 30.0 vs. 15.5 person-years). Associated risk of suicidality (adjusted RR, 1.27 [95% CI, 0.86-1.88]); suicidality with self-harm (adjusted RR, 1.30 [95% CI, 0.89-1.90]); or overdose- and suicide-related events (adjusted RR, 1.30 [95% CI, 0.93-1.80]) was not significant with gabapentinoids. CONCLUSIONS: Incidence rates for suicidal ideation and behavior were higher among the gabapentinoid group, although increased risk was not detected after adjustment. A possible signal cannot be ruled out given limitations of the data and rarity of the outcome.

Updated core competencies in pharmacoepidemiology to inform contemporary curricula and training for academia, government, and industry.

PURPOSE: The first paper to specify the core content of pharmacoepidemiology as a profession was published by an ISPE (International Society for Pharmacoepidemiology) workgroup in 2012 (Jones JK et al. PDS 2012; 21[7]:677-689). Due to the broader and evolving scope of pharmacoepidemiology, ISPE considers it important to proactively identify, update and expand the list of core competencies to inform curricula of education programs; thus, better positioning pharmacoepidemiologists across academic, government (including regulatory), and industry positions. The aim of this project was to update the list of core competencies in pharmacoepidemiology. METHODS: To ensure applicability of findings to multiple areas, a working group was established consisting of ISPE members with positions in academia, industry, government, and other settings. All competencies outlined by Jones et al. were extracted from the initial manuscript and presented to the working group for review. Expert-based judgments were collated and used to identify consensus. It was noted that some competencies could contribute to multiple groups and could be directly or indirectly related to a group. RESULTS: Five core domains were proposed: (1) Epidemiology, (2) Clinical Pharmacology, (3) Regulatory Science, (4) Statistics and data science, and (5) Communication and other professional skills. In total, 55 individual competencies were proposed, of which 25 were new competencies. No competencies from the original work were dropped but aggregation or amendments were made where considered necessary. CONCLUSIONS: While many core competencies in pharmacoepidemiology have remained the same over the past 10 years, there have also been several updates to reflect new and emerging concepts in the field.

Early Glasgow Coma Scale Score and Prediction of Traumatic Brain Injury: A Secondary Analysis of Three Harmonized Prehospital Randomized Clinical Trials.

OBJECTIVES: The prehospital prediction of the radiographic diagnosis of traumatic brain injury (TBI) in hemorrhagic shock patients has the potential to promote early therapeutic interventions. However, the identification of TBI is often challenging and prehospital tools remain limited. While the Glasgow Coma Scale (GCS) score is frequently used to assess the extent of impaired consciousness after injury, the utility of the GCS scores in the early prehospital phase of care to predict TBI in patients with severe injury and concomitant shock is poorly understood. METHODS: We performed a post-hoc, secondary analysis utilizing data derived from three randomized prehospital clinical trials: the Prehospital Air Medical Plasma trial (PAMPER), the Study of Tranexamic Acid During Air Medical and Ground Prehospital Transport trial (STAAMP), and the Pragmatic Prehospital Type O Whole Blood Early Resuscitation (PPOWER) trial. Patients were dichotomized into two cohorts based on the presence of TBI and then further stratified into three groups based on prehospital GCS score: GCS 3, GCS 4-12, and GCS 13-15. The association between prehospital GCS score and clinical documentation of TBI was assessed. RESULTS: A total of 1,490 enrolled patients were included in this analysis. The percentage of patients with documented TBI in those with a GCS 3 was 59.5, 42.4% in those with a GCS 4-12, and 11.8% in those with a GCS 13-15. The positive predictive value (PPV) of the prehospital GCS score for the diagnosis of TBI is low, with a GCS of 3 having only a 60% PPV. Hypotension and prehospital intubation are independent predictors of a low prehospital GCS. Decreasing prehospital GCS is strongly associated with higher incidence or mortality over time, irrespective of the diagnosis of TBI. CONCLUSIONS: The ability to accurately predict the presence of TBI in the prehospital phase of care is essential. The utility of the GCS scores in the early prehospital phase of care to predict TBI in patients with severe injury and concomitant shock is limited. The use of novel scoring systems and improved technology are needed to promote the accurate early diagnosis of TBI.

Assessment of the Risk Evaluation and Mitigation Strategy (REMS) for Phentermine-Topiramate to Prevent Exposure During Pregnancy.

BACKGROUND: The U.S. Food and Drug Administration approved phentermine-topiramate for obesity in 2012 and required a Risk Evaluation and Mitigation Strategy (REMS) to prevent prenatal exposure. No such requirement was introduced for topiramate. OBJECTIVE: To evaluate the rate of prenatal exposure, contraceptive use, and pregnancy testing among patients with phentermine-topiramate compared with topiramate or other antiobesity medications (AOMs). DESIGN: Retrospective cohort study. SETTING: Nationwide health insurance claims database. PARTICIPANTS: Females aged 12 to 55 years with no infertility diagnosis or sterilization procedure. Patients with other indications for topiramate were excluded to identify a cohort that was likely treated for obesity. MEASUREMENTS: Patients initiated use of phentermine-topiramate, topiramate, or an AOM (liraglutide, lorcaserin, or bupropion-naltrexone). Pregnancy at treatment initiation, conception during treatment, contraceptive use, and pregnancy testing outcomes were ascertained. Measurable confounders were adjusted for, and extensive sensitivity analyses were done. RESULTS: A total of 156 280 treatment episodes were observed. Adjusted prevalence of pregnancy at treatment initiation was 0.9 versus 1.6 per 1000 episodes (prevalence ratio, 0.54 [95% CI, 0.31 to 0.95]) for phentermine-topiramate versus topiramate. The incidence rate of conception during treatment was 9.1 versus 15.0 per 1000 person-years (rate ratio, 0.61 [CI, 0.40 to 0.91]) for phentermine-topiramate versus topiramate. Both outcomes were similarly lower for phentermine-topiramate compared with AOM. Prenatal exposure was marginally lower in topiramate users compared with AOM users. Approximately 20% of patients in all cohorts had at least 50% of treatment days covered by contraceptives. Few patients had pregnancy tests before treatment (≤5%), but this was more common among phentermine-topiramate users. LIMITATIONS: Outcome misclassification; unmeasured confounding due to lack of prescriber data to account for possible clustering and spillover effects. CONCLUSION: Prenatal exposure seemed to be significantly lower among phentermine-topiramate users under the REMS. Pregnancy testing and contraceptive use appeared to be inadequate for all groups, which deserves attention to prevent the remaining potential exposures. PRIMARY FUNDING SOURCE: None.

Longitudinal Monitoring of Clinician-Patient Video Visits During the Peak of the COVID-19 Pandemic: Adoption and Sustained Challenges in an Integrated Health Care Delivery System.

BACKGROUND: Numerous prior opinion papers, administrative electronic health record data studies, and cross-sectional surveys of telehealth during the pandemic have been published, but none have combined assessments of video visit success monitoring with longitudinal assessments of perceived challenges to the rapid adoption of video visits during the pandemic. OBJECTIVE: This study aims to quantify (1) the use of video visits (compared with in-person and telephone visits) over time during the pandemic, (2) video visit successful connection rates, and (3) changes in perceived video visit challenges. METHODS: A web-based survey was developed for the dual purpose of monitoring and improving video visit implementation in our health care system during the COVID-19 pandemic. The survey included questions regarding rates of in-person, telephone, and video visits for clinician-patient encounters; the rate of successful connection for video visits; and perceived challenges to video visits (eg, software, hardware, bandwidth, and technology literacy). The survey was distributed via email to physicians, advanced practice professionals, and clinicians in May 2020. The survey was repeated in March 2021. Differences between the 2020 and 2021 responses were adjusted for within-respondent correlation across surveys and tested using generalized estimating equations. RESULTS: A total of 1126 surveys were completed (511 surveys in 2020 and 615 surveys in 2021). In 2020, only 21.7% (73/336) of clinicians reported no difficulty connecting with patients during video visits and 28.6% (93/325) of clinicians reported no difficulty in 2021. The distribution of the percentage of successfully connected video visits ("Over the past two weeks of scheduled visits, what percentage did you successfully connect with patients by video?") was not significantly different between 2020 and 2021 (P=.74). Challenges in conducting video visits persisted over time. Poor connectivity was the most common challenge reported by clinicians. This response increased over time, with 30.5% (156/511) selecting it as a challenge in 2020 and 37.1% (228/615) in 2021 (P=.01). Patients not having access to their electronic health record portals was also a commonly reported challenge (109/511, 21.3% in 2020 and 137/615, 22.3% in 2021, P=.73). CONCLUSIONS: During the pandemic, our health care delivery system rapidly adopted synchronous patient-clinician communication using video visits. As experience with video visits increased, the reported failure rate did not significantly decline, and clinicians continued to report challenges related to general network connectivity and patient access to technology.

Knockdown of Esr1 from DRD1-Rich Brain Regions Affects Adipose Tissue Metabolism: Potential Crosstalk between Nucleus Accumbens and Adipose Tissue.

Declining estrogen (E2) leads to physical inactivity and adipose tissue (AT) dysfunction. Mechanisms are not fully understood, but E2's effects on dopamine (DA) activity in the nucleus accumbens (NAc) brain region may mediate changes in mood and voluntary physical activity (PA). Our prior work revealed that loss of E2 robustly affected NAc DA-related gene expression, and the pattern correlated with sedentary behavior and visceral fat. The current study used a new transgenic mouse model (D1ERKO) to determine whether the abolishment of E2 receptor alpha (ERα) signaling within DA-rich brain regions affects PA and AT metabolism. Adult male and female wild-type (WT) and D1ERKO (KD) mice were assessed for body composition, energy intake (EE), spontaneous PA (SPA), and energy expenditure (EE); underwent glucose tolerance testing; and were assessed for blood biochemistry. Perigonadal white AT (PGAT), brown AT (BAT), and NAc brain regions were assessed for genes and proteins associated with DA, E2 signaling, and metabolism; AT sections were also assessed for uncoupling protein (UCP1). KD mice had greater lean mass and EE (genotype effects) and a visible change in BAT phenotype characterized by increased UCP1 staining and lipid depletion, an effect seen only among females. Female KD had higher NAc Oprm1 transcript levels and greater PGAT UCP1. This group tended to have improved glucose tolerance (p = 0.07). NAc suppression of Esr1 does not appear to affect PA, yet it may directly affect metabolism. This work may lead to novel targets to improve metabolic dysfunction following E2 loss, possibly by targeting the NAc.