Implementation of a Pharmacist-Driven Contraception Service at a Safety-Net Health-System.

Background: Access to safe, effective, and appropriate contraception significantly reduces the rates of unintended pregnancies; however, this preventative care is not always easily accessible. There is a high patient demand for contraception visits that is often delayed or unmet due to lack of access to traditional providers. Pharmacists are highly accessible and can help manage this high demand, yet clinical pharmacists as providers of contraception services remains a gap in published literature. Objective: Develop and implement a pharmacist-led contraception service at a safety-net health-system. Methods: A comprehensive pharmacist-led clinical contraception service was created to improve patient access. To support this project, a collaborative practice agreement (CPA) was developed and enhancements were built into an electronic medical record. The CPA allowed the pharmacist to complete contraception-related interventions such as ordering urine pregnancy tests, prescribing hormonal and emergency contraceptives, and manage adverse effects. The piloting pharmacist was available at the Narcotics Treatment Program (NTP) clinic one half-day each week for scheduled and same-day visits. Results: Within the initial five half-day clinic sessions at NTP, the pharmacist had written seven prescriptions, including three for emergency contraceptives. Of all patients seen for this service at NTP, only one had been using a method of contraception consistently prior to their visit. Conclusion: The interventions that were able to be made by the pharmacist highlighted the need for improved access to contraceptives. Pharmacist-managed services in sexual and reproductive health can help fill this gap. Patients also self-reported ease of access as a benefit to this service.

The influence of pretreatment respiratory sinus arrhythmia dimensions on trauma-focused cognitive behavioral therapy outcomes: Findings from a randomized controlled feasibility trial.

Child maltreatment is associated with respiratory sinus arrhythmia (RSA) dysregulation, a physiological indicator of emotion regulation that predicts elevated posttraumatic stress disorder (PTSD) symptoms and may be a mechanism of action for exposure-based therapies, such as trauma-focused cognitive behavioral therapy (TF-CBT). Animal-assisted therapy (AAT) has been proposed as an adjunct to TF-CBT for improving emotion regulation following maltreatment. The current study reports findings from a randomized controlled feasibility trial (N = 33; Mage = 11.79 years, SD = 3.08; 63.6% White; 66.7% female) that measured youths' resting RSA, RSA reactivity, and RSA recovery in response to a pretreatment laboratory challenge. We tested whether (a) lower pretreatment resting RSA was associated with blunted RSA during the challenge; (b) either of the pretreatment RSA dimensions predicted more severe pretreatment PTSD symptoms; and (c) either of the pretreatment RSA dimensions predicted less severe posttreatment PTSD symptoms and, as an exploratory aim, whether this was moderated by treatment group (i.e., TF-CBT vs. TF-CBT + AAT). Results from multiple linear regression indicated that, after controlling for pretreatment symptom severity, there was a large effect size for higher resting RSA predicting less severe caregiver-reported posttreatment PTSD symptoms, ß = -.52, p = .058, and higher RSA during recovery predicting less severe child-reported posttreatment PTSD symptoms, ß = -.70, p = .056, although these findings were not significant. These preliminary results offer important insights for future studies to investigate how the ability to regulate RSA informs which children need additional support to benefit from psychotherapeutic treatment.

The future of childhood maltreatment research: Diversity and equity-informed perspectives for inclusive methodology and social justice.

A long-standing practice in clinical and developmental psychology research on childhood maltreatment has been to consider prospective, official court records to be the gold standard measure of childhood maltreatment and to give less weight to adults' retrospective self-reports of childhood maltreatment, sometimes even treating this data source as invalid. We argue that both formats of assessment - prospective and retrospective - provide important information on childhood maltreatment. Prospective data drawn from court records should not necessarily be considered the superior format, especially considering evidence of structural racism in child welfare. Part I overviews current maltreatment definitions in the context of the developmental psychopathology (DP) framework that has guided maltreatment research for over 40 years. Part II describes the ongoing debate about the disproportionalities of minoritized children at multiple decision-making stages of the child welfare system and the role that racism plays in many minoritized families' experience of this system. Part III offers alternative interpretations for the lack of concordance between prospective, official records of childhood maltreatment and retrospective self-reports, and for the differential associations between each format of data with health outcomes. Moving forward, we recommend that future DP research on childhood maltreatment apply more inclusive, diversity and equity-informed approaches when assessing and interpreting the effects of childhood maltreatment on lifespan and intergenerational outcomes. We encourage future generations of DP scholars to use assessment methods that affirm the lived experiences of individuals and families who have directly experienced maltreatment and the child welfare system.

Molnupiravir: Mechanism of action, clinical, and translational science.

Molnupiravir is an oral prodrug of the broadly active, antiviral ribonucleoside analog N-hydroxycytidine (NHC). The primary circulating metabolite NHC is taken up into cells and phosphorylated to NHC-triphosphate (NHC-TP). NHC-TP serves as a competitive substrate for viral RNA-dependent RNA polymerase (RdRp), which results in an accumulation of errors in the viral genome, rendering virus replication incompetent. Molnupiravir has demonstrated activity against SARS-CoV-2 both clinically and preclinically and has a high barrier to development of viral resistance. Little to no molnupiravir is observed in plasma due to rapid hydrolysis to NHC. Maximum concentrations of NHC are reached at 1.5 h following administration in a fasted state. The effective half-life of NHC is 3.3 h, reflecting minimal accumulation in the plasma following twice-daily (Q12H) dosing. The terminal half-life of NHC is 20.6 h. NHC-TP exhibits a flatter profile with a lower peak-to-trough ratio compared with NHC, which supports Q12H dosing. Renal and hepatic pathways are not major routes of elimination, as NHC is primarily cleared by metabolism to uridine and cytidine, which then mix with the endogenous nucleotide pools. In a phase III study of nonhospitalized patients with COVID-19 (MOVe-OUT), 5 days of treatment with 800 mg molnupiravir Q12H significantly reduced the incidence of hospitalization or death compared with placebo. Patients treated with molnupiravir also had a greater reduction in SARS-CoV-2 viral load and improved clinical outcomes, compared with those receiving placebo. The clinical effectiveness of molnupiravir has been further demonstrated in several real-world evidence studies. Molnupiravir is currently authorized or approved in more than 25 countries.

Fusobacterium nucleatum: An Overview of Evidence, Demi-Decadal Trends, and Its Role in Adverse Pregnancy Outcomes and Various Gynecological Diseases, including Cancers.

Gynecological and obstetric infectious diseases are crucial to women's health. There is growing evidence that links the presence of Fusobacterium nucleatum (F. nucleatum), an anaerobic oral commensal and potential periodontal pathogen, to the development and progression of various human diseases, including cancers. While the role of this opportunistic oral pathogen has been extensively studied in colorectal cancer in recent years, research on its epidemiological evidence and mechanistic link to gynecological diseases (GDs) is still ongoing. Thus, the present review, which is the first of its kind, aims to undertake a comprehensive and critical reappraisal of F. nucleatum, including the genetics and mechanistic role in promoting adverse pregnancy outcomes (APOs) and various GDs, including cancers. Additionally, this review discusses new conceptual advances that link the immunomodulatory role of F. nucleatum to the development and progression of breast, ovarian, endometrial, and cervical carcinomas through the activation of various direct and indirect signaling pathways. However, further studies are needed to explore and elucidate the highly dynamic process of host-F. nucleatum interactions and discover new pathways, which will pave the way for the development of better preventive and therapeutic strategies against this pathobiont.

Randomized self-controlled study comparing open-face vs. closed immobilization masks in fractionated cranial radiotherapy.

PURPOSE: To compare patient discomfort and immobilisation performance of open-face and closed immobilization masks in cranial radiotherapy. MATERIAL AND METHODS: This was a single-center randomized self-controlled clinical trial. At CT simulation, an open-face and closed mask was made for each patient and treatment plans with identical dose prescription were generated for each mask. Patients were randomised to start treatment with an open-face or closed mask. Masks were switched halfway through the treatment course; every patient was their own control. Patients self-reported discomfort, anxiety and pain using the visual analogue scale (VAS). Inter- and intrafraction set-up variability was measured with planar kV imaging and a surface guided radiotherapy (SGRT) system for the open-face masks. RESULTS: 30 patients with primary or metastatic brain tumors were randomized - 29 completed radiotherapy to a median total dose of 54 Gy (range 30-60 Gy). Mean discomfort VAS score was significantly lower with open-face masks (0.5, standard deviation 1.0) vs. closed masks (3.3, standard deviation 2.9), P < 0.0001. Anxiety and pain VAS scores were significantly lower with open-face masks (P < 0.0001). Closed masks caused more discomfort in infraorbital (P < 0.001) and maxillary (P = 0.02) areas. Two patients and 27 patients preferred closed or open-face masks, respectively. Interfraction longitudinal shifts and roll and yaw rotations were significantly smaller and lateral shifts were significantly larger with closed masks in combination with the laser system (P < 0.05) compared to open masks in combination with a SGRT system. Intrafraction variability did not differ between the masks. CONCLUSIONS: Open-face masks are associated with decreased patient discomfort without compromising patient positioning and immobilisation accuracy.

The influence of friendships on the mental health of maltreated youth: A pre-registered systematic review using a developmental psychopathology perspective.

Friendships are a potential factor that influence maltreated children's risk for psychopathology. This systematic review examined (1) how friendships influence the association between child maltreatment and psychopathology and (2) developmental differences in how friendships influence this association. Four databases were searched. Inclusion criteria were primary study, quantitative, measures of maltreatment and friendship up to the age of 18 years, measures of psychopathology up to the age of 24 years, and a non-maltreated sample. Exclusion criteria were qualitative, reviews or meta-analyses, no distinction between maltreatment and other trauma, and no differentiation between friendships and other support. Risk of bias was assessed. Data were narratively synthesized. Two hundred thirty-five articles were retrieved for full review. Fourteen met inclusion criteria (N = 98,676 participants). Eleven of the fourteen studies found that some aspect of friendships influenced the association between maltreatment and psychopathology, with positive qualities generally decreasing risk and negative qualities increasing risk for psychopathology. However, peer support exacerbated maltreated children's risk for psychopathology in two studies. Only three studies assessed friendship prior to adolescence, which precluded conclusions regarding developmental differences. Future research should consider developmental differences and use findings and validated measures from the peer relations literature to better understand how friendships influence maltreated youth's vulnerability to psychopathology.

Exploring Endoscopic Competence in Gastroenterology Training: A Simulation-Based Comparative Analysis of GAGES, DOPS, and ACE Assessment Tools.

Purpose: Accurate and convenient evaluation tools are essential to document endoscopic competence in Gastroenterology training programs. The Direct Observation of Procedural Skills (DOPS), Global Assessment of Gastrointestinal Endoscopic Skills (GAGES), and Assessment of Endoscopic Competency (ACE) are widely used validated competency assessment tools for gastrointestinal endoscopy. However, studies comparing these 3 tools are lacking, leading to lack of standardization in this assessment. Through simulation, this study seeks to determine the most reliable, comprehensive, and user-friendly tool for standardizing endoscopy competency assessment. Methods: A mixed-methods quantitative-qualitative approach was utilized with sequential deductive design. All nine trainees in a gastroenterology training program were assessed on endoscopic procedural competence using the Simbionix Gi-bronch-mentor high-fidelity simulator, with 2 faculty raters independently completing the 3 assessment forms of DOPS, GAGES, and ACE. Psychometric analysis was used to evaluate the tools' reliability. Additionally, faculty trainers participated in a focused group discussion (FGD) to investigate their experience in using the tools. Results: For upper GI endoscopy, Cronbach's alpha values for internal consistency were 0.53, 0.8, and 0.87 for ACE, DOPS, and GAGES, respectively. Inter-rater reliability (IRR) scores were 0.79 (0.43-0.92) for ACE, 0.75 (-0.13-0.82) for DOPS, and 0.59 (-0.90-0.84) for GAGES. For colonoscopy, Cronbach's alpha values for internal consistency were 0.53, 0.82, and 0.85 for ACE, DOPS, and GAGES, respectively. IRR scores were 0.72 (0.39-0.96) for ACE, 0.78 (-0.12-0.86) for DOPS, and 0.53 (-0.91-0.78) for GAGES. The FGD yielded three key themes: the ideal tool should be scientifically sound, comprehensive, and user-friendly. Conclusion: The DOPS tool performed favourably in both the qualitative assessment and psychometric evaluation to be considered the most balanced amongst the three assessment tools. We propose that the DOPS tool be used for endoscopic skill assessment in gastroenterology training programs. However, gastroenterology training programs need to match their learning outcomes with the available assessment tools to determine the most appropriate one in their context.

Respiratory virus coinfections during the COVID-19 pandemic: epidemiologic analysis and clinical outcomes from the Phase 2/3 molnupiravir trial (MOVe-OUT).

This exploratory post hoc analysis assessed the incidence of respiratory viral coinfections and their impact on clinical outcomes in non-hospitalized adults with mild-to-moderate coronavirus disease-2019 (COVID-19) treated with molnupiravir versus placebo for 5 days in the Phase 2/3 MOVe-OUT trial (NCT04575597), which took place in October 2020 to January 2021 (Phase 2, n = 302) and May 2021 to October 2021 (Phase 3, n = 1,433). Among 1,735 total randomized participants, 1,674 had a baseline respiratory pathogen panel (NxTAG Respiratory Pathogen Panel for the Luminex MAGPIX instrument) performed and 69 (4.1%) were coinfected with at least one additional respiratory viral pathogen. Human rhinovirus/enterovirus (39/69, 56.5%) was the most common coinfection detected at baseline. In the modified intention-to-treat population, two participants with coinfecting respiratory RNA viruses were hospitalized and received respiratory interventions through Day 29, and none died; one participant in the molnupiravir group was coinfected with human rhinovirus/enterovirus, and one participant in the placebo group was coinfected with human metapneumovirus. Hospitalization or death occurred in 6.2% and 9.0% of non-coinfected participants in the molnupiravir versus placebo group, respectively, and over 90% did not require respiratory interventions. Most coinfecting respiratory RNA viruses detected at baseline were not detected at the end of therapy in both the molnupiravir and placebo groups. In summary, participants coinfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and another respiratory RNA virus were not more likely to be hospitalized or die, or require respiratory interventions, compared to participants who were not coinfected with another respiratory RNA virus at baseline in both groups. IMPORTANCE: Respiratory viral coinfections are known to occur with coronavirus disease-2019 (COVID-19). In a cohort of non-hospitalized adults with mild-to-moderate COVID-19 treated with molnupiravir versus placebo in the MOVe-OUT trial during October 2020 to October 2021, 4.1% of participants had a documented viral coinfection; human rhinovirus/enterovirus was the most common pathogen detected with the NxTAG Respiratory Pathogen Panel assay. Participants who had a coinfection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and another respiratory RNA virus were not more likely to have worse clinical outcomes compared to those participants without a viral coinfection, and many coinfecting respiratory RNA viruses were no longer detected at the end of the 5-day treatment period in both groups.

The bii4africa dataset of faunal and floral population intactness estimates across Africa's major land uses.

Sub-Saharan Africa is under-represented in global biodiversity datasets, particularly regarding the impact of land use on species' population abundances. Drawing on recent advances in expert elicitation to ensure data consistency, 200 experts were convened using a modified-Delphi process to estimate 'intactness scores': the remaining proportion of an 'intact' reference population of a species group in a particular land use, on a scale from 0 (no remaining individuals) to 1 (same abundance as the reference) and, in rare cases, to 2 (populations that thrive in human-modified landscapes). The resulting bii4africa dataset contains intactness scores representing terrestrial vertebrates (tetrapods: ±5,400 amphibians, reptiles, birds, mammals) and vascular plants (±45,000 forbs, graminoids, trees, shrubs) in sub-Saharan Africa across the region's major land uses (urban, cropland, rangeland, plantation, protected, etc.) and intensities (e.g., large-scale vs smallholder cropland). This dataset was co-produced as part of the Biodiversity Intactness Index for Africa Project. Additional uses include assessing ecosystem condition; rectifying geographic/taxonomic biases in global biodiversity indicators and maps; and informing the Red List of Ecosystems.

Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study.

BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.

Beliefs and Intentions of Anesthesia Physicians Toward Providing Culturally Competent Care to Transgender Patients.

Purpose: Anesthesiologists have limited relationships with their patients before delivering care and have little time for patient interactions. Yet, they should possess the knowledge and skills to treat all patients in an equitable, culturally competent manner, including transgender patients. The study's purpose was to determine behavioral factors influencing culturally competent care by anesthesia physicians with transgender patients. Methods: A two-phase design was utilized in 2020 to examine the attitudes, subjective norms, and perceived behavioral control of anesthesia physicians, both in training and practicing independently. Phase 1 allowed exploration of themes related to facilitators and barriers of the provision of culturally competent care to transgender patients. Phase 2 involved the creation and deployment of a 51-question survey informed by phase 1 to 100 anesthesia physicians at a single academic medical center in the southeastern United States. Results: Thematic analysis was performed on results from the phase 1 elicitation survey, which informed the creation of the survey for phase 2. One hundred phase 2 surveys were distributed, with a 70% response rate. Analyses were conducted to determine the largest influence of intent to interact with transgender patients in a culturally competent manner, as well as to establish the reliability of the tool. Conclusion: Attitude followed by subjective norms were positive influencers of intent, while lack of knowledge was a negative influencer. Strengthening attitudes and subjective norms, while implementing programs to increase knowledge, competence, and humility, would be goals for future studies and actions toward improving healthcare of transgender individuals.

Outcome Analysis of Treatment Modalities for Thoracic Sarcomas.

BACKGROUND: Primary chest wall sarcomas are a rare and heterogeneous group of chest wall tumors that require multimodal oncologic and surgical therapy. The aim of this study was to review our experience regarding the surgical treatment of chest wall sarcomas, evaluating the short- and long-term results. METHODS: In this retrospective single-center study, patients who underwent surgery for soft tissue and bone sarcoma of the chest wall between 1999 and 2018 were included. We analyzed the oncologic and surgical outcomes of chest wall resections and reconstructions, assessing overall and recurrence-free survival and the associated clinical factors. RESULTS: In total, 44 patients underwent chest wall resection for primary chest wall sarcoma, of which 18 (41%) received surgery only, 10 (23%) received additional chemoradiotherapy, 7% (3) received surgery with chemotherapy, and 30% (13) received radiotherapy in addition to surgery. No perioperative mortality occurred. Five-year overall survival was 51.5% (CI 95%: 36.1-73.4%), and median overall survival was 1973 days (CI 95% 1461; -). As determined in the univariate analysis, the presence of metastasis upon admission and tumor grade were significantly associated with shorter survival (p = 0.037 and p < 0.01, respectively). Five-year recurrence-free survival was 71.5% (95% CI 57.6%; 88.7%). Tumor resection margins and metastatic disease upon diagnosis were significantly associated with recurrence-free survival (p < 0.01 and p < 0.01, respectively). CONCLUSION: Surgical therapy is the cornerstone of the treatment of chest wall sarcomas and can be performed safely. Metastasis and high tumor grade have a negative influence on overall survival, while tumor margins and metastasis have a negative influence on local recurrence.

Virologic Outcomes with Molnupiravir in Non-hospitalized Adult Patients with COVID-19 from the Randomized, Placebo-Controlled MOVe-OUT Trial.

INTRODUCTION: The randomized, placebo-controlled, double-blind MOVe-OUT trial demonstrated molnupiravir (800 mg every 12 h for 5 days) as safe and effective for outpatient treatment of mild-to-moderate COVID-19, significantly reducing the risk of hospitalization/death in high-risk adults. At the time of that report, virologic assessments from the trial were partially incomplete as a result of their time-intensive nature. Here we present final results from all prespecified virology endpoints in MOVe-OUT based on the full trial dataset. METHODS: Nasopharyngeal swabs were collected at baseline (day 1, prior to first dose) and days 3, 5 (end-of-treatment visit), 10, 15, and 29. From these samples, change from baseline in SARS-CoV-2 RNA titers (determined by quantitative PCR), detection of infectious SARS-CoV-2 (by plaque assay), and SARS-CoV-2 viral error induction (determined by whole genome next-generation sequencing) were assessed as exploratory endpoints. RESULTS: Molnupiravir was associated with greater mean reductions from baseline in SARS-CoV-2 RNA than placebo (including 50% relative reduction at end-of-treatment) through day 10. Among participants with infectious virus detected at baseline (n = 96 molnupiravir, n = 97 placebo) and evaluable post-baseline samples, no molnupiravir-treated participant had infectious SARS-CoV-2 by day 3, whereas infectious virus was recovered from 21% of placebo-arm participants on day 3 and 2% at end-of-treatment. Consistent with molnupiravir's mechanism of action, sequence analysis demonstrated that molnupiravir was associated with an increased number of low-frequency transition errors randomly distributed across the SARS-CoV-2 RNA genome compared with placebo (median 143.5 molnupiravir, 15 placebo), while transversion errors were infrequent overall (median 2 in both arms). Outcomes were consistent regardless of baseline SARS-CoV-2 clade, presence of SARS-CoV-2-specific immune response, or viral load. CONCLUSIONS: A 5-day course of orally administered molnupiravir demonstrated a consistently greater virologic effect than placebo, including rapidly eliminating infectious SARS-CoV-2, in high-risk outpatients with mild-to-moderate COVID-19. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04575597.

Epidemiology of Trauma-Related Hemorrhage and Time to Definitive Care Across North America: Making the Case for Bleeding Control Education.

INTRODUCTION: Uncontrolled trauma-related hemorrhage remains the primary preventable cause of death among those with critical injury. STUDY OBJECTIVE: The purpose of this investigation was to evaluate the types of trauma associated with critical injury and trauma-related hemorrhage, and to determine the time to definitive care among patients treated at major trauma centers who were predicted to require massive transfusion. METHODS: A secondary analysis was performed of the Pragmatic, Randomized, Optimal Platelet and Plasma Ratios (PROPPR) trial data (N = 680). All patients included were predicted to require massive transfusion and admitted to one of 12 North American trauma centers. Descriptive statistics were used to characterize patients, including demographics, type and mechanism of injury, source of bleeding, and receipt of prehospital interventions. Patient time to definitive care was determined using the time from activation of emergency services to responder arrival on scene, and time from scene departure to emergency department (ED) arrival. Each interval was calculated and then summed for a total time to definitive care. RESULTS: Patients were primarily white (63.8%), male (80.3%), with a median age of 34 (IQR 24-51) years. Roughly one-half of patients experienced blunt (49.0%) versus penetrating (48.2%) injury. The most common types of blunt trauma were motor vehicle injuries (83.5%), followed by falls (9.3%), other (3.6%), assaults (1.8%), and incidents due to machinery (1.8%). The most common types of penetrating injuries were gunshot wounds (72.3%), stabbings (24.1%), other (2.1%), and impalements (1.5%). One-third of patients (34.5%) required some prehospital intervention, including intubation (77.4%), chest or needle decompression (18.8%), tourniquet (18.4%), and cardiopulmonary resuscitation (CPR; 5.6%). Sources of bleeding included the abdomen (44.3%), chest (20.4%), limb/extremity (18.2%), pelvis (11.4%), and other (5.7%). Patients waited for a median of six (IQR4-10) minutes for emergency responders to arrive at the scene of injury and traveled a median of 27 (IQR 19-42) minutes to an ED. Time to definitive care was a median of 57 (IQR 44-77) minutes, with a range of 12-232 minutes. Twenty-four-hour mortality was 15% (n = 100) with 81 patients dying due to exsanguination or hemorrhage. CONCLUSION: Patients who experience critical injury may experience lengthy times to receipt of definitive care and may benefit from bystander action for hemorrhage control to improve patient outcomes.

Population pharmacokinetics of molnupiravir in adults with COVID-19: Lack of clinically important exposure variation across individuals.

Effective antiviral treatments for coronavirus disease 2019 (COVID-19) are needed to reduce the morbidity and mortality associated with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, particularly in patients with risk factors for severe disease. Molnupiravir (MK-4482, EIDD-2801) is an orally administered, ribonucleoside prodrug of ß-D-N4-hydroxycytidine (NHC) with submicromolar potency against SARS-CoV-2. A population pharmacokinetic (PopPK) analysis for molnupiravir exposure was conducted using 4202 NHC plasma concentrations collected in 1207 individuals from a phase I trial in healthy participants, a phase IIa trial in non-hospitalized participants with COVID-19, a phase II trial in hospitalized participants with COVID-19, and a phase II/III trial in non-hospitalized participants with COVID-19. Molnupiravir pharmacokinetics (PK) was best described by a two-compartment model with a transit-compartment absorption model and linear elimination. Molnupiravir apparent elimination clearance increased with body weight less-than-proportionally (power 0.412) and was estimated as 70.6 L/h in 80-kg individuals with a moderate interindividual variability (43.4% coefficient of variation). Additionally, effects of sex and body mass index on apparent central volume and food status and formulation on the absorption mean transit time were identified as statistically significant descriptors of variability in these PK parameters. However, none of the identified covariate effects caused clinically relevant changes in the area under the NHC concentration versus time curve between doses, the exposure metric most closely related to clinical response. Overall, the PopPK model indicates that molnupiravir can be administered in adults without dose adjustment based on age, sex, body size, food, and mild-to-moderate renal or mild hepatic impairment.

The role of child maltreatment and adolescent victimization in predicting adolescent psychopathology and problematic substance use.

BACKGROUND: Maltreated children are more likely to experience adolescent victimization, which may underlie the association between maltreatment and adolescent psychopathology and substance use. OBJECTIVE: To determine whether number of adolescent victimization types predicts adolescent psychopathology and problematic substance use over and above number of child maltreatment subtypes; whether adolescent victimization mediates the relations between maltreatment and change in adolescent psychopathology and problematic substance use; and whether maltreatment moderates the relation between adolescent victimization and changes in these outcomes. PARTICIPANTS AND SETTING: Participants were 545 (295 maltreated, 250 non-maltreated; 328 males, 217 females) racially and ethnically diverse (52.8 % Black, 27.5 % White, 12.8 % Bi-racial; 13.4 % Latino/a) children and families from the Rochester, New York, USA area assessed across three waves of data (Wave 1, Mage = 7.6 years; Wave 2, Mage = 13.8 years; Wave 3, Mage = 16.2 years). METHODS: Maltreatment was coded at Wave 1 using Department of Human Services records. Adolescents self-reported psychopathology, problematic substance use, and victimization at Waves 2 and 3. RESULTS: Structural equation modeling revealed that adolescent victimization predicted adolescent psychopathology (ß = 0.24, p < .001) and problematic substance use (ß = 0.27, p < .001) over and above child maltreatment. Adolescent victimization did not mediate the association between child maltreatment change in psychopathology and problematic substance use and child maltreatment did not moderate the association between adolescent victimization and these outcomes. CONCLUSIONS: We discuss the importance of future research utilizing multi-wave designs to examine relations between these constructs and of assessing for more proximal victimization.

Characterization of Resting-State Functional Connectivity Changes in Hypertension by a Modified Difference Degree Test.

Introduction: Hypertension affects over a billion people worldwide, and the application of neuroimaging may elucidate changes brought about by the disease. We have applied a graph theory approach to examine the organizational differences in resting-state functional magnetic resonance imaging (rs-fMRI) data between hypertensive and normotensive participants. To detect these groupwise differences, we performed statistical testing using a modified difference degree test (DDT). Methods: Structural and rs-fMRI data were collected from a cohort of 52 total (29 hypertensive and 23 normotensive) participants. Functional connectivity maps were obtained by partial correlation analysis of participant rs-fMRI data. We modified the DDT null generation algorithm and validated the change through different simulation schemes and then applied this modified DDT to our experimental data. Results: Through a comparative analysis, the modified DDT showed higher true positivity rates (TPR) when compared with the base DDT while also maintaining false positivity rates below the nominal value of 5% in nearly all analytically thresholded trials. Applying the modified DDT to our rs-fMRI data showed differential organization in the hypertension group in the regions throughout the brain including the default mode network. These experimental findings agree with previous studies. Conclusions: While our findings agree with previous studies, the experimental results presented require more investigation to prove their link to hypertension. Meanwhile, our modification to the DDT results in higher accuracy and an increased ability to discern groupwise differences in rs-fMRI data. We expect this to be useful in studying groupwise organizational differences in future studies.

A Meta-Ethnographic Review of Paid Staff and Volunteers Working together in Palliative Care.

CONTEXT: Volunteers in palliative care settings are an essential part of care provision for patients and those important to them. Effective collaboration between volunteers and paid staff has been regarded as an important element of successful working, however, at times failures in coordination, information sharing and tensions within teams have been highlighted. OBJECTIVES: To explore the views expressed by volunteers and paid staff about their experiences of working together in palliative care settings. METHODS: A systematic exploration of qualitative research using a meta-ethnographic approach. PsycINFO, CINAHL, Medline Complete, and AMED databases were searched from inception to December 2021 for the concepts "volunteers" and "palliative care." Repeated in-depth reading and appraisal of papers identified metaphors and concepts, providing new interpretations. RESULTS: Included papers (n = 14) enabled the construction of five storylines: 1) "we are the cake, and they are the cream": understanding the volunteer role-separate, but part of a whole. 2) "…we don't know what's wrong with people but sometimes we need to know": access to information and importance of trust. 3) "everybody looks out for each other": access to paid staff and their support. 4) "...we don't meddle in the medical": boundaries. 5) "it's the small things that the staff does for me that makes me feel good about my work": sense of value and significance. CONCLUSIONS: For effective working relationships between paid staff and volunteers, proactive engagement, recognition of each other's role and contribution, mutual sharing of information, and intentional interaction between both groups is needed.