Tirzepatide reduces the predicted risk of atherosclerotic cardiovascular disease and improves cardiometabolic risk factors in adults with obesity or overweight: SURMOUNT-1 post hoc analysis.

AIM: To assess the effect of tirzepatide on long-term risk of atherosclerotic cardiovascular disease (ASCVD) among people with obesity or overweight without diabetes from SURMOUNT-1. MATERIALS AND METHODS: SURMOUNT-1, a phase 3 trial, evaluated the efficacy and safety of tirzepatide in adults with body mass index ≥30 or ≥27 kg/m2 and at least one weight-related complication, excluding diabetes. Participants were randomly assigned to tirzepatide (5/10/15 mg) or placebo. Changes from baseline in cardiometabolic variables were assessed. The predicted 10-year ASCVD risk scores were calculated (American College of Cardiology/American Heart Association risk engine) at baseline, week 24, and week 72 in SURMOUNT-1 participants without a history of ASCVD. Percent change in risk scores from baseline to weeks 24 and 72 was compared between tirzepatide and placebo using mixed model for repeated measures analysis. Analyses were also conducted in participants with intermediate to high risk at baseline. RESULTS: Tirzepatide-treated groups demonstrated reductions in cardiometabolic variables over 72 weeks. In participants without a history of ASCVD (N = 2461), the baseline median risk score was low and did not differ across groups (1.5%-1.6%). Relative change in risk from baseline to week 72 was greater for tirzepatide (-23.5% to -16.4%) than placebo (12.7%; P < 0.001). Relative change among participants with intermediate-to-high baseline risk was significantly greater for tirzepatide (P < 0.05). Intermediate-to-high-risk participants demonstrated similar relative change but greater absolute risk reduction compared to the overall population. CONCLUSION: Tirzepatide treatment significantly reduced the 10-year predicted risk of ASCVD versus placebo in patients with obesity or overweight without diabetes.

Tools to measure barriers to medication management capacity in older adults: a scoping review.

BACKGROUND: Medication management capacity is a crucial component of medication adherence, particularly among older adults. Various factors, including physical abilities, cognitive functions, sensory capabilities, motivational, and environmental factors, influence older adults' ability to manage medications. It is, therefore, crucial to identify appropriate tools that allow clinicians to determine which factors may impact medication management capacity and, consequently, nonadherence to medications. PURPOSE: 1)To identify tools that measure physical, cognitive, sensory (vision, hearing, touch), motivational, and environmental barriers to medication self-management in older adults, and 2) to understand the extent to which these tools assess various barriers. METHODS: The scoping review was conducted using Arksey and O'Malley's scoping review framework and the PRISMA Extension for Scoping Reviews checklist. In June 2022, the relevant literature was identified by searching PubMed (MEDLINE), Ovid Embase, Ovid IPA, EBSCOhost CINAHL, APA PsycINFO, and Scopus. RESULTS AND DISCUSSION: In total, 7235 studies were identified. Following the removal of duplicates, 4607 articles were screened by title and abstract, of which 4253 did not meet the inclusion criteria. Three reviewers reviewed the full texts of the remaining 354 articles; among them, 41 articles, 4 theses and 1 conference abstract met the inclusion criteria. From the included studies, 44 tools were identified that measured a combination of physical, cognitive, sensory, motivational, and environmental barriers (n=19) or only cognition (n=13), vision (n=5), environmental factors (n=3), auditory (n=1), and motivational factors (n=1). The review also examined the psychometric properties of the identified tools and found that most of them had reported validity and reliability data. Several tools have demonstrated promise in assessing a combination of barriers with validity and reliability. These tools include the Self-Medication Assessment Tool (SMAT), ManageMed Screening (MMS), Self-Medication Risk Assessment Tool (RAT), HOME-Rx revised, and Medication Management Ability Assessment (MMAA). CONCLUSION: This scoping review identified 44 validated tools to measure various challenges that older adults encounter with medication management. However, no tool measures all five barriers (physical, cognitive, sensory, motivational, and environmental) to medication-taking at home. Therefore, utilizing a combination of tools would be most appropriate to measure these different aspects comprehensively. Further research is needed to develop a new comprehensive tool that simultaneously measures various barriers to medication self-management.

What is the role of chest X-ray imaging in the acute management of children with sickle cell disease?

Children with sickle cell disease (SCD) frequently present to hospital acutely unwell and are often exposed to diagnostic chest X-rays (CXRs). Little evidence exists to determine when CXRs are clinically useful. Using electronic hospital records, we audited CXR use in children aged 0-18 who presented to hospital over the past 10 years in both an inpatient and emergency department setting. From a total of 915 first CXRs, only 28·2% of CXRs (n = 258) had clinically significant findings that altered management or final diagnosis. Of these abnormalities, consolidation represented 52·3%, effusion 8·9%, cardiomegaly 8·4% and sickle cell-related bone changes 6·3%. Indications for CXR of respiratory distress (OR = 3·74, 95% CI 2·28-6·13), hypoxia (OR = 1·86, 95% CI 1·50-2·31) and cough (OR = 1·64, 95% CI 1·33-2·02), were more likely to have significant CXR findings. Patients who had higher peak fever (38·4°C vs. 37·4°C, P = 0·001), higher peak CRP (156·4 vs. 46·1, P < 0·001) and higher WCC (20·2 vs. 13·6, P < 0·001) were more likely to have clinically significant abnormalities on CXR. We found a decision tool using either hypoxia, cough, respiratory distress, T > 38°C, CRP > 50 or WCC > 15 × 109 /l as indications for CXR, to have a sensitivity of 88% (with 95% CI 0·78-0·95) and specificity of 46% (95% CI 0·43-0·50) for clinically significant findings.

Snacktivity™ to promote physical activity and reduce future risk of disease in the population: protocol for a feasibility randomised controlled trial and nested qualitative study.

BACKGROUND: Many people do not regularly participate in physical activity, which may negatively impact their health. Current physical activity guidelines are focused on promoting weekly accumulation of at least 150 min of moderate to vigorous intensity physical activity (MVPA). Whilst revised guidance now recognises the importance of making small changes to physical activity behaviour, guidance still focuses on adults needing to achieve at least 150 min of MVPA per week. An alternative 'whole day' approach that could motivate the public to be more physically active, is a concept called Snacktivity™. Instead of focusing on achieving 150 min per week of physical activity, for example 30 min of MVPA over 5 days, Snacktivity™ encourages the public to achieve this through small, but frequent, 2-5 min 'snacks' of MVPA throughout the whole day. METHODS: The primary aim is to undertake a feasibility trial with nested qualitative interviews to assess the feasibility and acceptability of the Snacktivity™ intervention to inform the design of a subsequent phase III randomised trial. A two-arm randomised controlled feasibility trial aiming to recruit 80 inactive adults will be conducted. Recruitment will be from health and community settings and social media. Participants will be individually randomised (1:1 ratio) to receive either the Snacktivity™ intervention or usual care. The intervention will last 12 weeks with assessment of outcomes completed before and after the intervention in all participants. We are interested in whether the Snacktivity™ trial is appealing to participants (assessed by the recruitment rate) and if the Snacktivity™ intervention and trial methods are acceptable to participants (assessed by Snacktivity™/physical activity adherence and retention rates). The intervention will be delivered by health care providers within health care consultations or by researchers. Participants' experiences of the trial and intervention, and health care providers' views of delivering the intervention within health consultations will be explored. DISCUSSION: The development of physical activity interventions that can be delivered at scale are needed. The findings from this study will inform the viability and design of a phase III trial to assess the effectiveness and cost-effectiveness of Snacktivity™ to increase physical activity. TRIAL REGISTRATION: ISRCTN: 64851242.

Impact of enteral methadone on the ability to wean off continuously infused opioids in critically ill, mechanically ventilated adults: a case-control study.

BACKGROUND: Continuously infused opioids are frequently used to optimize patient comfort in the intensive care unit (ICU). However, concerns about rebound pain and opioid withdrawal may delay efforts to discontinue this therapy. OBJECTIVE: To measure the association between use of scheduled enteral methadone according to a protocol in mechanically ventilated, medical critically ill adults receiving prolonged continuously infused fentanyl and the time to discontinue continuously infused fentanyl therapy. METHODS: This case-control study included 20 consecutive mechanically ventilated adults in a medical ICU, without a history of chronic opioid use, who received 72 or more hours of continuously infused fentanyl and were prescribed scheduled enteral methadone as part of a protocol medical ICU strategy to wean off continuously infused fentanyl. Patients were matched in a 1:2 fashion, by duration of mechanical ventilation, to 40 consecutive preprotocol medical ICU patients meeting the same criteria but who were never given methadone. Duration of continuously infused fentanyl was compared between the 2 groups by constructing Kaplan-Meier plots and estimating the likelihood that methadone use was associated with a decrease in continuously infused fentanyl requirements over time, using a Cox proportional hazards model. RESULTS: The groups were well matched except the methadone patients were older (p = 0.04). Time (median [interquartile range]) to continuously infused fentanyl discontinuation was shorter in the methadone group (4.5 [3.9-5.8] vs 7.0 [4.9-11.5] days; p = 0.002). Continuously infused fentanyl was more likely to be discontinued 2 days after methadone was first initiated (hazard ratio 9.1; p = 0.0004). The proportion of patients who experienced 1 or more episodes of either QTc interval prolongation (p = 0.79) or unarousability (p = 0.47) was similar between the groups. CONCLUSIONS: Enterally administered methadone is associated with earlier cessation of continuously infused fentanyl in mechanically ventilated adults without a history of opioid dependence admitted to a medical ICU. Prospective, controlled studies are needed to further evaluate the safety and efficacy of methadone as a strategy to wean off continuously infused fentanyl in different ICU populations.

Induction of labour for predicted macrosomia: study protocol for the 'Big Baby' randomised controlled trial.

INTRODUCTION: Large-for-gestational age (LGA) fetuses have an increased risk of shoulder dystocia. This can lead to adverse neonatal outcomes and death. Early induction of labour in women with a fetus suspected to be macrosomic may mitigate the risk of shoulder dystocia. The Big Baby Trial aims to find if induction of labour at 38+0-38+4 weeks' gestation, in pregnancies with suspected LGA fetuses, reduces the incidence of shoulder dystocia. METHODS AND ANALYSIS: The Big Baby Trial is a multicentre, prospective, individually randomised controlled trial of induction of labour at 38+0 to 38+4 weeks' gestation vs standard care as per each hospital trust (median gestation of delivery 39+4) among women whose fetuses have an estimated fetal weight >90th customised centile according to ultrasound scan at 35+0 to 38+0 weeks' gestation. There is a parallel cohort study for women who decline randomisation because they opt for induction, expectant management or caesarean section. Up to 4000 women will be recruited and randomised to induction of labour or to standard care. The primary outcome is the incidence of shoulder dystocia; assessed by an independent expert group, blind to treatment allocation, from delivery records. Secondary outcomes include birth trauma, fractures, haemorrhage, caesarean section rate and length of inpatient stay. The main trial is ongoing, following an internal pilot study. A qualitative reporting, health economic evaluation and parallel process evaluation are included. ETHICS AND DISSEMINATION: The study received a favourable opinion from the South West-Cornwall and Plymouth Health Research Authority on 23/03/2018 (IRAS project ID 229163). Study results will be reported in the National Institute for Health Research journal library and published in an open access peer-reviewed journal. We will plan dissemination events for key stakeholders. TRIAL REGISTRATION NUMBER: ISRCTN18229892.

CD2 Regulates Pathogenesis of Asthma Induced by House Dust Mice Extract.

Characteristic of allergic asthma, CD4+Th2 lymphocytes secrete Th2 cytokines, interleukin (IL)-4, IL-13, and IL-5 that mediate the inflammatory immune response. Surface expression of CD2 and its ligand, CD58, is increased on the monocytes and eosinophils of asthma patients, which correlate with elevated serum IgE levels, suggesting that CD2 may contribute to allergic airway inflammation. Using a murine model of asthma, we observed that house dust mice extract (HDME)-exposed Balb/c mice have increased airway hyperresponsiveness (AHR), lung inflammation, goblet cell hyperplasia, and elevated levels of Th2 cytokines in the lungs, as well as increased serum IgE levels as compared to the control mice. In contrast, with the exception of serum IgE levels, all the other parameters were significantly reduced in HDME-treated Cd2-/- mice. Interestingly, Il13 but not Il4 or Il5 gene expression in the lungs was dramatically decreased in HDME-exposed Cd2-/- mice. Of note, the gene expression of IL-13 downstream targets (Muc5b and Muc5ac) and high affinity IL-13Rα2 were upregulated in the lungs of HDME-exposed Balb/c mice but were significantly reduced in HDME-exposed Cd2-/- mice. Consistently, gene expression of microRNAs regulating mucin production, inflammation, airway smooth muscle cell proliferation and IL-13 transcripts were increased in the lungs of HDME-exposed Cd2-/- mice. Given the established role of IL-13 in promoting goblet cell hyperplasia, lung inflammation and AHR in allergic asthma, our studies reveal a unique role for CD2 in the regulation of Th2-associated allergic asthma.

Outcomes of Capecitabine and Temozolomide (CAPTEM) in Advanced Neuroendocrine Neoplasms (NENs).

Capecitabine and temozolomide (CAPTEM) have shown promising results in the treatment of neuroendocrine neoplasms (NEN). The aim of this study was to evaluate the outcome and role for CAPTEM in malignant neuroendocrine neoplasms. Data were obtained from NEN patients who received at least one cycle of CAPTEM between November 2010 and June 2018. The average number of cycles was 9.5. For analysis, 116 patients were included, of which 105 patients (91%) underwent prior treatment. Median progression free survival (PFS) and overall survival (OS) were 13 and 38 months, respectively. Overall response rate (ORR) was 21%. Disease control rate (DCR) was 73% in all patients. PFS, median OS, ORR, and DCR for pancreatic NENs (pNEN) vs. non-pNEN was 29 vs. 11 months, 35 vs. 38 months, 38% vs. 9%, and 77% vs. 71%, respectively. Patients with pNEN had a 50% lower hazard of disease progression compared to those with non-pNEN (adjusted Hazard Ratio: 0.498, p = 0.0100). A significant difference in PFS was found between Ki-67 < 3%, Ki-67 3-20%, Ki-67 > 20-54%, and Ki-67 ≥ 55% (29 vs. 12 vs. 7 vs. 5 months; p = 0.0287). Adverse events occurred in 74 patients (64%). Our results indicate that CAPTEM is associated with encouraging PFS, OS, and ORR data in patients with NENs.

Molecular Targets in Non-Small Cell Lung Cancer.

BACKGROUND: Lung cancer is the second most common cancer in the United States among men and women, and it is the most common cause of cancer-related death. Non-small cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases. Historically, patients with metastatic NSCLC received similar cytotoxic chemotherapy regimens. Genotyping studies have revealed genetic/molecular abnormalities in lung cancer. These driver mutations render a cancer dependent on that specific mutation's biochemical pathway for its growth and survival. With the development of tyrosine kinase inhibitors and antibodies against specific driver mutations, the landscape of lung cancer treatment has changed from treatment based on histologic subtype to treatment based on molecularly defined subtypes. METHODS: In this article, we review the current molecular-targeted therapies in lung cancer. RESULTS: We review landmark trials that have led to approval of molecular-targeted therapies against epidermal growth factor receptor, anaplastic lymphoma kinase, and ROS1. We also explore less common mutations/molecular abnormalities and review data on the use of targeted therapies against them. Finally, we offer a treatment algorithm for patients with metastatic NSCLC that harbors actionable mutations. CONCLUSION: Patients with advanced NSCLC should undergo mutational testing to evaluate for actionable mutations. If such a mutation is discovered, targeted therapy should be considered for first-line treatment.

Long-term effects of a diabetes boot cAMP on measures of diabetic care.

BACKGROUND: Diabetic patients should receive self-management education to improve self-care and quality of life but are frequently unable to attend such programs because of the time commitment. We instituted an intensive 2-hour Diabetes Boot Camp to provide this education in a condensed time frame. The objective was to determine the long-term effect of the boot camp on mean hemoglobin A1c (HgA1c) levels in patients with diabetes compared to diabetic patients receiving the standard of care. METHODS: The Diabetes Boot Camp population was defined as all diabetic patients referred to the boot camp from the 10 highest utilizing physicians between August 2009 and August 2010. A control population was randomly selected from these same physicians' diabetic patients during the same period. Baseline and postintervention HgA1c measurements on the same patients in both groups were extracted from the electronic medical record. Subpopulations studied included those with HgA1c ≥9% and <9% at baseline. To evaluate long-term effects, we compared HgA1c levels 3 years later (between July 1, 2012 and December 31, 2012) for all groups. RESULTS: Using comparison-over-time analysis, the overall boot camp group (n=69) showed a mean decrease in HgA1c from 8.57% (SD ± 2.32%) to 7.76% (SD ± 1.85%) vs an increase from 7.92% (SD ± 1.58%) to 8.22% (SD ± 1.82%) in the control group (n=107, P<0.001). Mean length of follow-up was 3.2 (SD ± 0.54) years. CONCLUSION: An intensive 2-hour multidisciplinary diabetes clinic was associated with significant long-term improvements in glycemic control in diabetic participants of the clinic.

Recruiting primary care physicians to teach medical students in the ambulatory setting: a model of protected time, allocated money, and faculty development.

PROBLEM: Medical schools face barriers to recruiting physicians to teach in the ambulatory setting for many reasons, including time required to teach, loss of productivity when learners are present, and physicians' uncertainty about how to teach. APPROACH: In 2012, the primary care department of the University of Queensland-Ochsner Clinical School (UQ-OCS) implemented an innovative model for recruiting primary care physicians to teach students in their clinics. The model's three-pronged approach allows protected teaching time, allocates tuition money to reimburse physicians for teaching via educational value unit (EVU) tracking, and includes a faculty development program. OUTCOMES: In the first two years of EVU tracking (academic years 2012 and 2013), 5,530 EVUs were provided by 48 primary care faculty teaching 60 students at 11 sites. In academic year 2013, the first year in which tuition dollars were available to fund teaching by primary care faculty, over $120,000 in tuition money was transferred to the department to pay for EVUs. No faculty in 2012 or 2013 experienced a change in salary as a result of teaching activities. Faculty development workshops have been well attended. The general practice clerkship has been the top-rated third-year clerkship by students for the first three years of clinical rotations at the UQ-OCS. NEXT STEPS: A qualitative study to describe the barriers to and solutions for recruiting physicians to teach students in ambulatory settings is planned. Other studies will evaluate the effectiveness of faculty development efforts and the impact of students' presence on patients' access to clinic appointments.