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.

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients.

BACKGROUND: New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. RESULTS: A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, -6.8 percentage points; 95% confidence interval [CI], -11.3 to -2.4; P = 0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, -3.0 percentage points; 95% CI, -5.9 to -0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. CONCLUSIONS: Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.).

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.

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.

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.

Impact of Molnupiravir Treatment on Patient-Reported COVID-19 Symptoms in the Phase 3 MOVe-OUT Trial: A Randomized, Placebo-Controlled Trial.

BACKGROUND: Molnupiravir is an orally administered antiviral authorized for COVID-19 treatment in adults at high risk of progression to severe disease. Here, we report secondary and post hoc analyses of participants' self-reported symptoms in the MOVe-OUT trial, which evaluated molnupiravir initiated within 5 days of symptom onset in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed COVID-19. METHODS: Eligible participants completed a 15-item symptom diary daily from day 1 (randomization) through day 29, rating symptom severity as "none," "mild," "moderate," or "severe"; loss of smell and loss of taste were rated as "yes" or "no." Time to sustained symptom resolution/improvement was defined as the number of days from randomization to the first of 3 consecutive days of reduced severity, without subsequent relapse. Time to symptom progression was defined as the number of days from randomization to the first of 2 consecutive days of worsening severity. The Kaplan-Meier method was used to estimate event rates at various time points. The Cox proportional hazards model was used to estimate the hazard ratio between molnupiravir and placebo. RESULTS: For most targeted COVID-19 symptoms, sustained resolution/improvement was more likely, and progression was less likely, in the molnupiravir versus placebo group through day 29. When evaluating 5 distinctive symptoms of COVID-19, molnupiravir participants had a shorter median time to first resolution (18 vs 20 d) and first alleviation (13 vs 15 d) of symptoms compared with placebo. CONCLUSIONS: Molnupiravir treatment in at-risk, unvaccinated patients resulted in improved clinical outcomes for most participant-reported COVID-19 symptoms compared with placebo. Clinical Trials Registration. ClinicalTrials.gov: NCT04575597.

Molnupiravir for the treatment of COVID-19 in immunocompromised participants: efficacy, safety, and virology results from the phase 3 randomized, placebo-controlled MOVe-OUT trial.

PURPOSE: Immunocompromised patients have a potentially increased risk for progression to severe COVID-19 and prolonged replication of SARS-CoV-2. This post hoc analysis examined outcomes among immunocompromised participants in the MOVe-OUT trial. METHODS: In phase 3 of MOVe-OUT, non-hospitalized at-risk adults with mild-to-moderate COVID-19 were randomized to receive molnupiravir 800 mg or placebo twice daily for 5 days. Immunocompromised participants were identified based on prior/concomitant medications and/or medical history. All-cause hospitalization/death, adverse events, SARS-CoV-2 titers, infectivity, and RNA sequences were compared between immunocompromised participants who received molnupiravir or placebo and with non-immunocompromised participants. RESULTS: Fifty-five of 1408 participants were considered immunocompromised. Compared to placebo, fewer molnupiravir-treated immunocompromised participants were hospitalized/died through Day 29 (22.6% [7/31] vs. 8.3% [2/24]), with fewer adverse events (45.2% [14/31] vs. 25.0% [6/24]). A larger mean change from baseline in SARS-CoV-2 RNA was observed with molnupiravir compared to placebo in non-immunocompromised participants (least squares mean [LSM] difference Day 5: - 0.31, 95% confidence interval [CI] - 0.47 to - 0.15), while the mean change was comparable between treatment groups in immunocompromised participants (LSM difference Day 5: 0.23, 95% CI - 0.71 to 1.17). Molnupiravir treatment was associated with increased clearance of infectious virus. Increased errors in viral nucleotide sequences in post-baseline samples compared to placebo support molnupiravir's mechanism of action and were not associated with observation of novel treatment-emergent amino acid substitutions in immunocompromised participants. CONCLUSION: Although the study population was small, these data suggest that molnupiravir treatment for mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults is efficacious and safe and quickly reduces infectious SARS-CoV-2. GOV REGISTRATION NUMBER: NCT04575597.

Management of Short Bowel Syndrome (SBS) and Intestinal Failure.

Short bowel syndrome (SBS) is a chronic disease whose natural history requires a changing array of management strategies over time. Chief amongst these is the chronic use of parenteral nutrition (PN) to ensure adequate nutritional intake. With time and appropriate management, approximately half of all SBS patients will successfully regain a functional, baseline level of intrinsic bowel function that will allow for them to achieve PN independence. However, the other half of SBS patients will progress into chronic intestinal failure which warrants a change in therapy to include more aggressive medical and potentially surgical measures. This review examines the evolving treatment strategies involved in the management of SBS as well as intestinal failure.

Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19 : A Randomized, Placebo-Controlled Trial.

BACKGROUND: In the MOVe-OUT trial, molnupiravir showed a clinically meaningful reduction in the risk for hospitalization or death in adults with mild to moderate COVID-19 and risk factors for progression to severe disease. OBJECTIVE: To identify other potential clinical benefits of molnupiravir versus placebo. DESIGN: Secondary analysis of the randomized, double-blind, placebo-controlled phase 3 component of MOVe-OUT. (ClinicalTrials.gov: NCT04575597). SETTING: 107 sites globally. PARTICIPANTS: 1433 nonhospitalized adults aged 18 years or older with mild to moderate COVID-19. INTERVENTION: Molnupiravir, 800 mg, or placebo every 12 hours for 5 days. MEASUREMENTS: Changes from baseline in C-reactive protein (CRP) concentration and oxygen saturation (Spo 2), need for respiratory interventions (including invasive mechanical ventilation), and need for medical services in all randomly assigned participants through day 29, and need for respiratory interventions and time to discharge in the subgroup of participants who were hospitalized after randomization. RESULTS: Participants receiving molnupiravir showed faster normalization of CRP and Spo 2, with improvements observed on day 3 of therapy, compared with placebo. Molnupiravir-treated participants had a decreased need for respiratory interventions versus placebo-treated participants (relative risk reduction [RRR], 34.3% [95% CI, 4.3% to 54.9%]), with similar findings in participants who were hospitalized after randomization (RRR, 21.3% [CI, 0.2% to 38.0%]). Hospitalized participants who received molnupiravir were discharged a median of 3 days before those who received placebo. Acute care visits (7.2% vs. 10.6%; RRR, 32.1% [CI, 4.4% to 51.7%]) and COVID-19-related acute care visits (6.6% vs. 10.0%; RRR, 33.8% [CI, 5.6% to 53.6%]) were less frequent in molnupiravir- versus placebo-treated participants. LIMITATIONS: Some analyses were performed post hoc. Longer-term benefits of molnupiravir therapy were not evaluated. Participants were not immunized against SARS-CoV-2. CONCLUSION: The findings suggest there are additional important clinical benefits of molnupiravir beyond reduction in hospitalization or death. PRIMARY FUNDING SOURCE: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc.

Why We Want Our Students to Learn about Poverty and Health Care: Sharing Our Own Experiences from Poverty Simulations.

Poverty is a leading cause of numerous health and social inequities in the United States. Educators are increasingly searching for ways to create meaningful learning opportunities about poverty and its profound effect on individuals and communities. In this narrative, we explore our own perspectives as faculty who guide students through a simulated poverty experience. This essay unfolds primarily as a dialogue among us as we make sense of and clarify why we participate in the coordination and facilitation of poverty simulations on our campus and their anticipated benefits for future health care professionals and social service providers.

Why We Want Our Students to Learn about Poverty and Healthcare: Sharing Our Students' Experiences from Poverty Simulations.

Poverty contributes to acute illness, chronic disease and health inequity among millions of Americans, yet health care providers often do not understand the daily experiences of those who live below the poverty line and how it affects their interactions with the health care system. In this narrative, we share healthcare students' stories and reflect on how they account for their experiences of participating in a poverty simulation. Their words come from reflection assignments, and when we read their words, that for a moment, many of our students understand that as a healthcare practitioner, they can make a difference in the life of someone living in poverty. We believe that this experience will inspire our students to make meaningful change as future healthcare professionals. We also believe that the impact on these students goes toward our collective goal as teachers of future healthcare providers to make a difference in our world.

Improving nurses' blood transfusion knowledge and skills.

The World Health Organization (2019) has determined that patient safety is a global public health challenge. In UK clinical areas, policies and procedures are in place for the safe prescribing and delivery of blood and blood product transfusions, yet patient safety incidences continue. Undergraduate nurse education and training may provide the underlying knowledge to practitioners, while postgraduate standalone training sessions support skill development. However, over time, without regular experience, competence will diminish. Nursing students may have little exposure to transfusion practice and COVID-19 may have exacerbated this challenge with a reduction in placement availability. The use of simulation to support theory with follow-up and ongoing drop-in training sessions may help to inform practitioners and improve patient safety in the management and delivery of blood and blood product transfusion.

Blood and blood products transfusion errors: what can we do to improve patient safety?

Evidence suggests that blood transfusion errors tend to occur because of an external stimulus, limiting control for the professional administering it. Whether it be cognitive bias, human traits, organisational or human factors, errors should be prevented because they put the safety of the patient at risk from major morbidity and mortality. The authors explored the literature that looked at the blood transfusion errors that occur, suggesting interventions that may have a positive impact on patient safety. A review of the literature was undertaken using key words and limiters to focus the search. The review found that, when practitioners do not perform skills or interventions regularly, competence diminishes. Training and rolling refresher programmes appeared to improve retention and knowledge, therefore enhancing patient safety. Consequently, the impact of human factors in the healthcare setting requires more comprehensive investigation. Nurses may have the knowledge and understanding regarding blood transfusions; however, the environment in which they work could contribute to the likelihood of errors.

Evaluation of at-home serum anti-Müllerian hormone testing: a head-to-head comparison study.

BACKGROUND: For optimal fertility testing, serum anti-Müllerian hormone levels are used in combination with other testing to provide reliable ovarian reserve evaluations. The use of the ADx 100 card is widely commercially available for at-home reproductive hormone testing, but data demonstrating that its results are reproducible outside of a clinical setting are limited, as well as comparisons of its performance with other newer blood collection techniques. This study aimed to evaluate the concordance of serum AMH levels found via standard venipuncture and self-administered blood collection using the TAP II device (TAP) and ADx card in women of reproductive age. METHODS: This was a prospective, head-to-head-to-head within-person crossover comparison trial that included 41 women of reproductive age (20-39 years). It was hypothesized that the TAP device would be superior to the ADx card both in terms of agreement with venipuncture reference standard and patient experience. Each subject had their blood drawn using the three modalities (TAP, ADx, and venipuncture). We evaluated the concordance of AMH assays from samples obtained via the TAP device and ADx card with the gold standard being venipuncture. Two-sided 95% CIs were generated for each method to compare relative performance across all three modes. Patient preference for the TAP device versus the ADx card was based on self-reported pain and Net Promoter Score (NPS). RESULTS: The TAP device was superior to the ADx card on all outcome measures. TAP R-squared with venipuncture was 0.99 (95% CI 0.99, > 0.99), significantly higher than the ADx card, which had an R-squared of 0.87 (95% CI 0.80, 0.94) under most favorable treatment. TAP sensitivity and specificity were both 100% (no clinical disagreement with venipuncture), versus 100 and 88%, respectively, for the ADx card. Average pain reported by users of the TAP device was significantly lower than the ADx card (0.75 versus 2.73, p < 0.01) and the NPS was significantly higher than the ADx card (+ 72 versus - 48, p < 0.01). CONCLUSIONS: The TAP was non-inferior to venipuncture and superior to the ADx card with respect to correlation and false positives. Moreover, the TAP was superior to both alternatives on patient experience. TRIAL REGISTRATION: NCT04784325 (Mar 5, 2021).

Sequential azacitidine and carboplatin induces immune activation in platinum-resistant high-grade serous ovarian cancer cell lines and primes for checkpoint inhibitor immunotherapy.

BACKGROUND: Platinum chemoresistance results in high-grade serous ovarian cancer (HGSOC) disease recurrence. Recent treatment advances using checkpoint inhibitor immunotherapy has not benefited platinum-resistant HGSOC. In ovarian cancer, DNA methyltransferase inhibitors (DNMTi) block methylation and allow expression of silenced genes, primarily affecting immune reactivation pathways. We aimed to determine the epigenome and transcriptome response to sequential treatment with DNMTi and carboplatin in HGSOC. METHODS: In vitro studies with azacitidine or carboplatin alone and in sequential combination. Response was determined by cell growth, death and apoptosis. Genome-wide DNA methylation levels and transcript expression were compared between untreated and azacitidine and carboplatin sequential treatment. RESULTS: Sequential azacitidine and carboplatin significantly slowed cell growth in 50% of cell lines compared to carboplatin alone. The combination resulted in significantly higher cell death in 25% of cell lines, and significantly higher cell apoptosis in 37.5% of cell lines, than carboplatin alone. Pathway analysis of upregulated transcripts showed that the majority of changes were in immune-related pathways, including those regulating response to checkpoint inhibitors. CONCLUSIONS: Sequential azacitidine and carboplatin treatment slows cell growth, and demethylate and upregulate pathways involved in immune response, suggesting that this combination may be used to increase HGSOC response to immune checkpoint inhibitors in platinum-resistant patients who have exhausted all currently-approved avenues of treatment.

Bereaved Caregiver Perspectives on the End of Life in Pediatric Patients With Ventricular Assist Devices.

OBJECTIVES: Ventricular assist devices (VADs) are increasingly used in pediatric heart failure as bridges to heart transplantation, although 25% will die with VADs. Family experiences in this population are not well-described. The objective is to understand bereaved families' perspectives on VAD and end-of-life decision-making. DESIGN: Semistructured interviews with bereaved caregivers of pediatric VAD patients. SETTING: Tertiary children's hospital. PATIENTS: Families of six pediatric VAD patients who died from 2014 to 2020. INTERVENTIONS: Not available. MEASUREMENTS AND MAIN RESULTS: Applying a grounded theory framework, interviews were coded by two independent readers using qualitative software. Themes were discussed in iterative multidisciplinary meetings. Participants were interviewed at a median 2.4 years after their child died. Three major themes emerged: 1) "lack of regret" for VAD implantation despite the outcome; 2) "caregiver-child accord" (via patient's verbal assent or physical cues) at implantation and end-of-life was important in family decision-making; and 3) development of a "local surrogate family" (medical team and peer families) provided powerful support. CONCLUSIONS: Bereaved families' perspectives provide insight into quality decision-making for major interventions and end-of-life care in pediatric patients with chronic illness who face decisions regarding technology dependence.

Exploring the Discursive Emphasis on Patients and Coaches Who Participated in Technology-Assisted Diabetes Self-management Education: Clinical Implementation Study of Health360x.

BACKGROUND: A critical unmet need for underserved patients with diabetes is regular access to sufficient support for diabetes self-management. Although advances in digital technologies have made way for eHealth applications that provide a scalable path for tailored interventions for self-management of chronic conditions, health and digital literacy has remained an obstacle to leveraging these technologies for effective diabetes self-management education. Studies have shown that the availability of coaches helps to maintain engagement in internet-based studies and improves self-efficacy for behavior change. However, little is known about the substances involved in these interactions. OBJECTIVE: This study aims to compare the content of conversations between patient-coach pairs that achieved their self-management goals and those that did not. The context is a clinical implementation study of diabetes self-management behavior change using Health360x within the practices of the Morehouse Choice Accountable Care Organization in the Atlanta metro area. Health360x is a coach-assisted consumer health information technology designed to support self-management skills acquisition and behavior among underserved, high-risk patients with diabetes. METHODS: We provide a novel analysis of the discursive emphasis on patients and coaches. We examined transcripts of visits using a structural topic model to estimate topic content and prevalence as a function of patient and coach characteristics. We compared topics between patient-coach pairs that achieved diabetes-related self-management goals and those who did not. We also estimated a regression in which utterances are the units, the dependent variable is the proportion of an utterance that is about a given topic, and the independent variables are speaker types and explored other themes. RESULTS: Transcripts from 50 patients who were recruited and consented, starting in February 2015, were analyzed. A total of 44 topics were estimated for patient-coach pairs that achieved their intended health goals and 50 topics for those who did not. Analysis of the structural topic model results indicated that coaches in patient-coach pairs that were able to achieve self-management goals provided more contextual feedback and probed into patients' experience with technology and trust in consumer information technologies. We also found that discussions around problem areas and stress, support (ßCoach=.015; P<.001), initial visits (ßCoach=.02; P<.001), problems with technology (ßCoach=.01; P<.001), health eating goals (ßCoach=.01; P=.04), diabetes knowledge (ßCoach=.02; P<.001), managing blood sugar (ßCoach=.03; P<.001), and using Health360x (ßCoach=.003; P=.03) were dominated by coaches. CONCLUSIONS: Coach-facilitated, technology-based diabetes self-management education can help underserved patients with diabetes. Our use of topic modeling in this application sheds light on the actual dynamics in conversations between patients and coaches. Knowledge of the key elements for successful coach-patient interactions based on the analysis of transcripts could be applied to understanding everyday patient-provider encounters, given the recent paradigm shift around the use of telehealth.

A validated triplex RT-qPCR protocol to simultaneously detect chikungunya, dengue and Zika viruses in mosquitoes.

BACKGROUND & OBJECTIVES: Recently, the incidences of chikungunya, dengue and Zika infections have increased due to globalization and urbanization. It is vital that reliable detection tools become available to assess the viral prevalence within mosquito populations. METHODS: Based on the previous publications on clinical diagnosis in human infections, for the first time, we described a customized triplex RT-qPCR protocol for simultaneous detection of chikungunya virus (CHIKV), dengue virus serotypes 1-4 (DENV1-4) and Zika virus (ZIKV) in mosquitoes. RESULTS: In preliminary assessment to determine the specificity and sensitivity of primers and probes, all six targets were detected individually with the following thresholds as indicated by calculated pfu equivalents: 3.96x100 for CHIKV, 3.80x101 for DENV1, 3.20x101 for DENV2, 8.00x104 for DENV3, 1.58x100 for DENV4, and 6.20x100 for ZIKV When tested in a full combination of six targets (CDZ mix), CHIKV, DENV1-4 mix or ZIKV were all detected with the thresholds of 1.32x100 for CHIKV, 3.79x100 for DENV1-4 and 2.06x100 for ZIKV All targets, individually or in full combination were detected in the mixtures of Aedes aegypti (L.) homogenate and viral lysates. A robust evaluation with three replicates in each of three plates for CHIKV, DENV1-4 and ZIKV individually or in full combination was conducted. In individual assays, CHIKV was detected to 3.96x10-1, DENV1-4 to 1.14x100 and ZIKV to 3.20x100. In full combination assays, CHIKV was detected to 1.32x104, DENV1-4 to 3.79x101 and ZIKV to 1.07x100. INTERPRETATION & CONCLUSION: This triplex RT-qPCR assay appears to consistently detect all six targets and does not cross react with Ae. aegypti homogenate, making it a feasible, practical, and immediately adoptable protocol for use among vector control and other entities, particularly in the endemic areas of CHIKV, DENVs and ZIKV.

Evaluation of Stop the Bleed Training Among High School Personnel: A Qualitative Study.

BACKGROUND: Uncontrolled hemorrhage is the primary preventable cause of death following trauma. Stop the Bleed training exists to promote identification and basic treatment of life-threatening bleeding in the prehospital or community setting. Limited qualitative research is available on participant evaluation of hemorrhage control training for laypersons. OBJECTIVE: To evaluate the experience and satisfaction with Stop the Bleed training among lay community members in an urban public school setting. METHODS: Three group interviews were conducted with public high school personnel (faculty and staff) who received Stop the Bleed training. Personnel were asked to evaluate the training and provide suggestions for improvement. Responses were digitally recorded and transcribed verbatim. Content analysis for common themes was performed using NVivo. RESULTS: A total of eight participants were interviewed. Participants expressed satisfaction with hands-on training and dissatisfaction with crowded and rushed training conditions. Major themes included: (1) skill acquisition, retention, and decay, (2) training format and setting, and (3) use of simulation. CONCLUSIONS: Current Stop the Bleed training is considered satisfactory among public school educators. Suggestions for improvement include annual retraining programs and simulation-enhanced training opportunities.

A Randomized, Double-blind, Multicenter Trial Comparing Efficacy and Safety of Imipenem/Cilastatin/Relebactam Versus Piperacillin/Tazobactam in Adults With Hospital-acquired or Ventilator-associated Bacterial Pneumonia (RESTORE-IMI 2 Study).

BACKGROUND: Imipenem combined with the ß-lactamase inhibitor relebactam has broad antibacterial activity, including against carbapenem-resistant gram-negative pathogens. We evaluated efficacy and safety of imipenem/cilastatin/relebactam in treating hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP). METHODS: This was a randomized, controlled, double-blind phase 3 trial. Adults with HABP/VABP were randomized 1:1 to imipenem/cilastatin/relebactam 500 mg/500 mg/250 mg or piperacillin/tazobactam 4 g/500 mg, intravenously every 6 hours for 7-14 days. The primary endpoint was day 28 all-cause mortality in the modified intent-to-treat (MITT) population (patients who received study therapy, excluding those with only gram-positive cocci at baseline). The key secondary endpoint was clinical response 7-14 days after completing therapy in the MITT population. RESULTS: Of 537 randomized patients (from 113 hospitals in 27 countries), the MITT population comprised 264 imipenem/cilastatin/relebactam and 267 piperacillin/tazobactam patients; 48.6% had ventilated HABP/VABP, 47.5% APACHE II score ≥15, 24.7% moderate/severe renal impairment, 42.9% were ≥65 years old, and 66.1% were in the intensive care unit. The most common baseline pathogens were Klebsiella pneumoniae (25.6%) and Pseudomonas aeruginosa (18.9%). Imipenem/cilastatin/relebactam was noninferior (P < .001) to piperacillin/tazobactam for both endpoints: day 28 all-cause mortality was 15.9% with imipenem/cilastatin/relebactam and 21.3% with piperacillin/tazobactam (difference, -5.3% [95% confidence interval {CI}, -11.9% to 1.2%]), and favorable clinical response at early follow-up was 61.0% and 55.8%, respectively (difference, 5.0% [95% CI, -3.2% to 13.2%]). Serious adverse events (AEs) occurred in 26.7% of imipenem/cilastatin/relebactam and 32.0% of piperacillin/tazobactam patients; AEs leading to treatment discontinuation in 5.6% and 8.2%, respectively; and drug-related AEs (none fatal) in 11.7% and 9.7%, respectively. CONCLUSIONS: Imipenem/cilastatin/relebactam is an appropriate treatment option for gram-negative HABP/VABP, including in critically ill, high-risk patients. CLINICAL TRIALS REGISTRATION: NCT02493764.