Pirtobrutinib: A New and Distinctive Treatment Option for B-Cell Malignancies.

OBJECTIVE: The objective was to evaluate the efficacy/safety of pirtobrutinib in the treatment of B-cell malignancies and distinguish it from other available Bruton's tyrosine kinase (BTK) inhibitors. DATA SOURCES: A literature search of PubMed (January 2021 through November 2023) and Clinicaltrials.gov was conducted using terms pirtobrutinib, Jaypirca, and LOXO 305. Licensing trials of available BTK inhibitors were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language clinical trials were evaluated. DATA SYNTHESIS: Pirtobrutinib was approved by the US Food and Drug Administration for the treatment of relapsed/refractory mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) based largely on a phase 1/2 study in B-cell malignancies. Pirtobrutinib demonstrated a 73% overall response rate (ORR) in the CLL population and 58% in MCL. Pirtobrutinib has activity in patients resistant to earlier-generation, covalent BTK inhibitors. In fact, the ORRs were similar in BTK-pretreated and naïve patients. Adverse effects include fatigue, diarrhea, bleeding, and infection. Atrial fibrillation, a class effect of BTK inhibitors, may be less common with pirtobrutinib. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Compared with earlier-generation BTK inhibitors, pirtobrutinib is more selective for BTK and binds noncovalently to the receptor. Ongoing studies are evaluating pirtobrutinib's use in multiple B-cell malignancies and comparing it with other BTK inhibitors. CONCLUSION: The characteristics of pirtobrutinib render it useful in the treatment of B-cell malignancies no longer responding to a previous BTK inhibitor, and results from ongoing clinical trials may support future expanded use.

Prevalence of post-traumatic stress and tests of metacognition as a PTSD risk marker in patients with coronary heart disease and elevated HADS scores: analysis of data from the PATHWAY RCT's in UK cardiac rehabilitation.

Introduction: Anxiety and depression in coronary heart disease (CHD) are associated with poorer health outcomes, greater healthcare use and reduced quality of life. Post-traumatic stress symptoms may be a particular concern as they are associated with increased mortality at follow-up. We examined prevalence of PTSD in patients with elevated anxiety/depression scores referred for cardiac rehabilitation (CR) across seven NHS sites in North-West England. We tested a possible mechanism (metacognition) linking CHD to PTSD symptom severity as implicated in the metacognitive model. Methods: Data was collected at baseline as part of the NIHR funded PATHWAY trial of metacognitive therapy for anxiety and depression in CHD. Patients (n = 572) with at least mild symptoms of anxiety and depression under routine screening (assessed with the Hospital Anxiety and Depression Scale) and attending CR were eligible for the study. A battery of questionnaires, including assessment of demographic variables, PTSD symptoms (using the IES-R) and metacognitive beliefs was administered prior to random allocation and intervention delivery. Results: Rates of PTSD were high, with 48% of patients meeting threshold for PTSD and a further 15% partial PTSD. All five metacognition subscales were positively associated with PTSD vs. no PTSD, with beliefs about the uncontrollability and danger of worry and beliefs about need to control thoughts being most strongly related. For every unit increase in uncontrollability and danger metacognitions the odds of being in the PTSD group increased 30%, whilst the odds of partial PTSD increased 16%. Stepwise regression analysis using the metacognitive subscales along with demographic and health-related covariates found that uncontrollability/danger and need for control metacognitions explained unique variation in PTSD symptom severity, with unique contributions also for age, sex, and number of comorbidities. Conclusion: PTSD symptoms appeared highly prevalent in the current CR sample. Metacognitive beliefs were individually associated with symptom severity with the strongest positive relationship observed for beliefs about uncontrollability and dangerousness of worry, followed by need to control thoughts. The results highlight the importance in assessing PTSD in CR patients and add support to implementing metacognitive therapy in CHD to target particular metacognition risk factors in anxiety, depression and PTSD.

The influence of demographic, health and psychosocial factors on patient uptake of the English NHS diabetes prevention programme.

BACKGROUND: The prevention of type 2 diabetes (T2DM) is a major concern for health services around the world. The English NHS Diabetes Prevention Programme (NHS-DPP) offers a group face-to-face behaviour change intervention, based around exercise and diet, to adults with non-diabetic hyperglycaemia (NDH), referred from primary care. Previous analysis of the first 100,000 referrals revealed just over half of those referred to the NHS-DPP took up a place. This study aimed to identify the demographic, health and psychosocial factors associated with NHS-DPP uptake to help inform the development of interventions to improve uptake and address inequities between population groups. METHODS: Drawing on the Behavioral Model of Health Services Utilization we developed a survey questionnaire to collect data on a wide range of demographic, health and psychosocial factors that might influence uptake of the NHS-DPP. We distributed this questionnaire to a cross-sectional random sample of 597 patients referred to the NHS-DPP across 17 general practices, chosen for variation. Multivariable regression analysis was used to identify factors associated with NHS-DPP uptake. RESULTS: 325 out of 597 questionnaires were completed (54%). Only a third of responders took up the offer of a place. The best performing model for uptake (AUC = 0.78) consisted of four factors: older age; beliefs concerning personal vulnerability to T2DM; self-efficacy for reducing T2DM risk; and the efficacy of the NHS-DPP. After accounting for these, demographic and health-related factors played only a minor role. CONCLUSION: Unlike fixed demographic characteristics, psychosocial perceptions may be amenable to change. NHS-DPP uptake rates may be improved by targeting the beliefs of patients about their risk of developing T2DM, their ability to carry out and sustain behaviours to reduce this risk, and the efficacy of the NHS-DPP in providing the necessary understanding and skills required. The recently introduced digital version of the NHS DPP could help address the even lower uptake amongst younger adults. Such changes could facilitate proportional access from across different demographic strata.

QTc prolongation risk among patients receiving oral targeted antineoplastic medications: A real-world community-based oncology analysis.

Introduction: Thirty oral targeted antineoplastic agents are associated with prolongation of the QT interval. However, limited data exists regarding QTc prolongation and associated risk factors in the ambulatory oncology setting. Methods: This retrospective study was completed to describe QTc prolongation incidence among patients receiving oral targeted tyrosine kinase inhibitors (TKI) and identify potential risk factors in the ambulatory community-based oncology clinic. Results: Of the 341 patients identified as receiving oral TKI, 49 with a baseline and follow-up ECG were included. The incidence of QTc prolongation (QTc > 470 ms in males, QTc > 480 ms in females, or >20 ms increase in QTc from baseline) was 24%. Three patients developed significant QTc prolongation (QTc >500 ms or >60 ms increase in QTc from baseline). No patients discontinued therapy primarily due to QTc prolongation or experienced symptomatic torsades de pointes. Analysis of risk factors demonstrated that patients with QTc prolongation were more likely to receive concomitant therapy with a loop diuretic (41% vs 11%, respectively, p=0.029). Discussion: The frequency of QTc prolongation may be higher in the real-world setting than that observed in clinical trials; however, continuation of therapy may be possible. Patients receiving concomitant loop diuretics should be monitored more closely for QTc prolongation and electrolyte abnormalities.

Retrospective study of more than 5 million emergency admissions to hospitals in England: Epidemiology and outcomes for people with dementia.

INTRODUCTION: People living with dementia (PwD) admitted in emergency to an acute hospital may be at higher risk of inappropriate care and poorer outcomes including longer hospitalisations and higher risk of emergency re-admission or death. Since 2009 numerous national and local initiatives in England have sought to improve hospital care for PwD. We compared outcomes of emergency admissions for cohorts of patients aged 65+ with and without dementia at three points in time. METHODS: We analysed emergency admissions (EAs) from the Hospital Episodes Statistics datasets for England 2010/11, 2012/13 and 2016/17. Dementia upon admission was based on a diagnosis in the patient's hospital records within the last five years. Outcomes were length of hospital stays (LoS), long stays (> = 15 days), emergency re-admissions (ERAs) and death in hospital or within 30 days post-discharge. A wide range of covariates were taken into account, including patient demographics, pre-existing health and reasons for admission. Hierarchical multivariable regression analysis, applied separately for males and females, estimated group differences adjusted for covariates. RESULTS: We included 178 acute hospitals and 5,580,106 EAs, of which 356,992 (13.9%) were male PwD and 561,349 (18.6%) female PwD. Uncontrolled differences in outcomes between the patient groups were substantial but were considerably reduced after control for covariates. Covariate-adjusted differences in LoS were similar at all time-points and in 2016/17 were 17% (95%CI 15%-18%) and 12% (10%-14%) longer for male and female PwD respectively compared to patients without dementia. Adjusted excess risk of an ERA for PwD reduced over time to 17% (15%-18%) for males and 17% (16%-19%) for females, but principally due to increased ERA rates amongst patients without dementia. Adjusted overall mortality was 30% to 40% higher for PwD of both sexes throughout the time-period; however, adjusted in-hospital rates of mortality differed only slightly between the patient groups, whereas PwD had around double the risk of dying within 30 days of being discharged. CONCLUSION: Over the six-year period, covariate-adjusted hospital LoS, ERA rates and in-hospital mortality rates for PwD were only slightly elevated compared to similar patients without dementia and remaining differences potentially reflect uncontrolled confounding. PwD however, were around twice as likely to die shortly after discharge, the reasons for which require further investigation. Despite being widely used for service evaluation, LoS, ERA and mortality may lack sensitivity to changes in hospital care and support to PwD.

Referral to the NHS Diabetes Prevention Programme and conversion from nondiabetic hyperglycaemia to type 2 diabetes mellitus in England: A matched cohort analysis.

BACKGROUND: The NHS Diabetes Prevention Programme (NDPP) is a behaviour change programme for adults who are at risk of developing type 2 diabetes mellitus (T2DM): people with raised blood glucose levels, but not in the diabetic range, diagnosed with nondiabetic hyperglycaemia (NDH). We examined the association between referral to the programme and reducing conversion of NDH to T2DM. METHODS AND FINDINGS: Cohort study of patients attending primary care in England using clinical Practice Research Datalink data from 1 April 2016 (NDPP introduction) to 31 March 2020 was used. To minimise confounding, we matched patients referred to the programme in referring practices to patients in nonreferring practices. Patients were matched based on age (≥3 years), sex, and ≥365 days of NDH diagnosis. Random-effects parametric survival models evaluated the intervention, controlling for numerous covariates. Our primary analysis was selected a priori: complete case analysis, 1-to-1 practice matching, up to 5 controls sampled with replacement. Various sensitivity analyses were conducted, including multiple imputation approaches. Analysis was adjusted for age (at index date), sex, time from NDH diagnosis to index date, BMI, HbA1c, total serum cholesterol, systolic blood pressure, diastolic blood pressure, prescription of metformin, smoking status, socioeconomic status, a diagnosis of depression, and comorbidities. A total of 18,470 patients referred to NDPP were matched to 51,331 patients not referred to NDPP in the main analysis. Mean follow-up from referral was 482.0 (SD = 317.3) and 472.4 (SD = 309.1) days, for referred to NDPP and not referred to NDPP, respectively. Baseline characteristics in the 2 groups were similar, except referred to NDPP were more likely to have higher BMI and be ever-smokers. The adjusted HR for referred to NDPP, compared to not referred to NDPP, was 0.80 (95% CI: 0.73 to 0.87) (p < 0.001). The probability of not converting to T2DM at 36 months since referral was 87.3% (95% CI: 86.5% to 88.2%) for referred to NDPP and 84.6% (95% CI: 83.9% to 85.4%) for not referred to NDPP. Associations were broadly consistent in the sensitivity analyses, but often smaller in magnitude. As this is an observational study, we cannot conclusively address causality. Other limitations include the inclusion of controls from the other 3 UK countries, data not allowing the evaluation of the association between attendance (rather than referral) and conversion. CONCLUSIONS: The NDPP was associated with reduced conversion rates from NDH to T2DM. Although we observed smaller associations with risk reduction, compared to what has been observed in RCTs, this is unsurprising since we examined the impact of referral, rather than attendance or completion of the intervention.

Development and validation of the Montreal cognitive assessment for people with hearing impairment (MoCA-H).

BACKGROUND: Hearing impairment is common among older adults and affects cognitive assessments for identification of dementia which rely on good hearing function. We developed and validated a version of the Montreal Cognitive Assessment (MoCA) for people with hearing impairment. METHODS: We adapted existing MoCA 8.1 items for people with hearing impairment by presenting instructions and stimuli in written rather than spoken format. One Attention domain and two Language domain items required substitution by alternative items. Three and four candidate items respectively were constructed and field-tested along with the items adapted to written form. We used a combination of individual item analysis and item substitution to select the set of alternative items to be included in the final form of the MoCA-H in place of the excluded original items. We then evaluated the performance and reliability of the final tool, including making any required adjustments for demographic factors. RESULTS: One hundred and fifty-nine hearing-impaired participants, including 76 with normal cognition and 83 with dementia, completed the adapted version of the MoCA. A further 97 participants with normal hearing completed the standard MoCA as well as the novel items developed for the MoCA-H to assess score equivalence between the existing and alternative MoCA items and for independence from hearing impairment. Twenty-eight participants were retested between 2-4 weeks after initial testing. After the selection of optimal item set, the final MoCA-H had an area under the curve of 0.973 (95% CI 0.952-0.994). At a cut-point of 24 points or less sensitivity and specificity for dementia was 92.8% and 90.8%, respectively. The intraclass correlation for test-retest reliability was 0.92 (95%CI 0.78-0.97). CONCLUSION: The MoCA-H is a sensitive and reliable means of identifying dementia among adults with acquired hearing impairment.

Impact of diabetes (type 2) and glycemic control on health-related outcomes of patients receiving chemotherapy for non-metastatic breast cancer: a retrospective analysis.

PURPOSE: To examine the impact of diabetes (type 2) and glycemic control on healthcare-related outcomes (healthcare utilization, adverse effects, and treatment modifications) in non-metastatic breast cancer (NMBC) patients during chemotherapy treatment. METHODS: This was a retrospective study of 243 NMBC patients (stages 1-3) with/without diabetes receiving neoadjuvant or adjuvant cytotoxic chemotherapy. The primary study endpoint was to compare healthcare utilization between NMBC patients with and without diabetes. Secondary study endpoints included adverse events and chemotherapy treatment modifications. Additional analyses were conducted to compare these health-related outcomes by glycemic control status. RESULTS: NMBC patients with diabetes had higher utilization of emergency department (ED) services (52% vs. 33%, p = 0.013) and a higher frequency of unplanned inpatient admissions (35% vs. 19%, p = 0.014). Additionally, NMBC patients with diabetes had a higher incidence of infection and treatment modifications. NMBC patients, regardless of diabetes diagnosis, who had poor glycemic control, specifically hyperglycemia (per random blood glucose), during the study period also had increased healthcare utilization, adverse effects, and treatment modifications. Patients with a baseline HbA1c ≥ 7 had a greater number of ED visits and a higher incidence of infection than those without diabetes. CONCLUSION: Diabetes and glycemic control may impact the health-related outcomes of NMBC patients. Additional studies are needed to confirm these findings and determine optimal monitoring and management strategies for NMBC patients with diabetes and/or poor glycemic control during cytotoxic chemotherapy.

Metacognitive therapy home-based self-help for anxiety and depression in cardiovascular disease patients in the UK: A single-blind randomised controlled trial.

BACKGROUND: Anxiety and depression in cardiac rehabilitation (CR) are associated with greater morbidity, mortality, and increased healthcare costs. Current psychological interventions within CR have small effects based on low-quality studies of clinic-based interventions with limited access to home-based psychological support. We tested the effectiveness of adding self-help metacognitive therapy (Home-MCT) to CR in reducing anxiety and depression in a randomised controlled trial (RCT). METHODS AND FINDINGS: We ran a single-blind, multi-centre, two-arm RCT. A total of 240 CR patients were recruited from 5 NHS-Trusts across North West England between April 20, 2017 and April 6, 2020. Patients were randomly allocated to Home-MCT+CR (n = 118, 49.2%) or usual CR alone (n = 122, 50.8%). Randomisation was 1:1 via randomised blocks within hospital site, balancing arms on sex and baseline Hospital Anxiety and Depression Scale (HADS) scores. The primary outcome was the HADS total score at posttreatment (4-month follow-up). Follow-up data collection occurred between August 7, 2017 and July 20, 2020. Analysis was by intention to treat. The 4-month outcome favoured the MCT intervention group demonstrating significantly lower end of treatment scores (HADS total: adjusted mean difference = -2.64 [-4.49 to -0.78], p = 0.005, standardised mean difference (SMD) = 0.38). Sensitivity analysis using multiple imputation (MI) of missing values supported these findings. Most secondary outcomes also favoured Home-MCT+CR, especially in reduction of post-traumatic stress symptoms (SMD = 0.51). There were 23 participants (19%) lost to follow-up in Home-MCT+CR and 4 participants (3%) lost to follow-up in CR alone. No serious adverse events were reported. The main limitation is the absence of longer term (e.g., 12-month) follow-up data. CONCLUSION: Self-help home-based MCT was effective in reducing total anxiety/depression in patients undergoing CR. Improvement occurred across most psychological measures. Home-MCT was a promising addition to cardiac rehabilitation and may offer improved access to effective psychological treatment in cardiovascular disease (CVD) patients. TRIAL REGISTRATION: NCT03999359.

Nivolumab/Relatlimab: A Novel Addition to Immune Checkpoint Inhibitor Therapy in Unresectable or Metastatic Melanoma.

OBJECTIVE: The aim of this article is to assess available data regarding use of nivolumab/relatlimab for adult and pediatric patients 12 years of age and older with unresectable or metastatic melanoma. DATA SOURCES: A search of PubMed conducted from August 2019 to August 2022 with the search terms Opdualag, nivolumab AND relatlimab, and BMS-986016 resulted in 14 publications. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials written in English language were analyzed. DATA SYNTHESIS: Nivolumab/relatlimab was approved by the Food and Drug Administration following results of a phase 1/2 trial and phase 2/3 RELATIVITY-047 trial. Nivolumab/relatlimab demonstrated a median progression free survival (PFS) of 10.1 months in the first-line setting without new safety signals. The PFS benefits appear greatest in those with programmed cell death-ligand 1 (PD-L1) <1% and lymphocyte activation gene-3 (LAG-3) ≥1%. Adverse effects commonly experienced were immune related in nature and require early identification and prompt management. Grade 3 or 4 adverse effects occurred in 18.9% of patients. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: For patients 12 years of age and older with unresectable or metastatic melanoma, nivolumab/relatlimab offers a new first-line treatment option. Evaluation of PD-L1 expression along with concomitant use of medications with potential interactions should be evaluated when deciding if nivolumab/relatlimab is the most appropriate treatment option. CONCLUSIONS: Nivolumab/relatlimab adds an additional first-line treatment option demonstrating promising improved PFS for patients with unresectable or metastatic melanoma, particularly those with PD-L1 <1% and/or LAG 3 ≥1%. Additional uses of nivolumab/relatlimab may be on the horizon as further clinical trials are ongoing.

Targeting EGFR Exon 20 Insertion Mutation in Non-small cell Lung Cancer: Amivantamab and Mobocertinib.

OBJECTIVE: To evaluate clinical data regarding the use of amivantamab and mobocertinib for epidermal growth factor receptor (EGFR) exon 20 insertion mutation non-small cell lung cancer (NSCLC) and assess their potential impact on the care of patients. DATA SOURCES: A comprehensive literature search of PubMed and Clinicaltrials.gov was conducted using the terms amivantamab, Rybrevant, JNJ-61186372, mobocertinib, Exkivity, TAK-788. STUDY SELECTION AND DATA EXTRACTION: Relevant English-language clinical trials were evaluated. DATA SYNTHESIS: Amivantamab and mobocertinib were Food and Drug Administration (FDA) approved based on phases 1 and 2 studies. Amivantamab demonstrated an overall response rate (ORR) of 40% and median progression-free survival (PFS) of 8.3 months. Patients commonly experienced rash (86%), paronychia (45%), and stomatitis (21%). Mobocertinib demonstrated an ORR of 28% and median PFS of 7.3 months in phase 1/2 study. Patients frequently experienced diarrhea (91%), rash (45%), and paronychia (38%). Cardiac monitoring is recommended with mobocertinib due to risk of QTc prolongation and cardiac failure. RELEVANCE TO PATIENT CARE: For NSCLC patients who possess an EGFR exon 20 insertion mutation, amivantamab and mobocertinib are indicated as second-line therapy. Ongoing studies are evaluating these therapies as first-line monotherapy and as part of combination regimens in multiple cancer types. Dosage forms, drug interactions, and patient comorbidities should be considered when deciding which of the 2 agents may be most appropriate. CONCLUSION: Amivantamab and mobocertinib target an uncommon NSCLC mutation that has historically marked a poor prognosis because of innate resistance to previously approved EGFR tyrosine kinase inhibitors. Promising results from early phase trials supported accelerated FDA approval.

Clinical code usage in UK general practice: a cohort study exploring 18 conditions over 14 years.

OBJECTIVE: To assess the diagnostic Read code usage for 18 conditions by examining their frequency and diversity in UK primary care between 2000 and 2013. DESIGN: Population-based cohort study SETTING: 684 UK general practices contributing data to the Clinical Practice Research Datalink (CPRD) GOLD. PARTICIPANTS: Patients with clinical codes for at least one of asthma, chronic obstructive pulmonary disease, diabetes, hypertension (HT), coronary heart disease, atrial fibrillation (AF), heart failure, stroke, hypothyroidism, chronic kidney disease, learning disability (LD), depression, dementia, epilepsy, severe mental illness (SMI), osteoarthritis, osteoporosis and cancer. PRIMARY AND SECONDARY OUTCOME MEASURES: For the frequency ranking of clinical codes, canonical correlation analysis was applied to correlations of clinical code usage of 1, 3 and 5 years. Three measures of diversity (Shannon entropy index of diversity, richness and evenness) were used to quantify changes in incident and total clinical codes. RESULTS: Overall, all examined conditions, except LD, showed positive monotonic correlation. HT, hypothyroidism, osteoarthritis and SMI codes' usage had high 5-year correlation. The codes' usage diversity remained stable overall throughout the study period. Cancer, diabetes and SMI had the highest richness (code lists need time to define) unlike AF, hypothyroidism and LD. SMI (high richness) and hypothyroidism (low richness) can last for 5 years, whereas cancer and diabetes (high richness) and LD (low richness) only last for 2 years. CONCLUSIONS: This is an under-reported research area and the findings suggest the codes' usage diversity for most conditions remained overall stable throughout the study period. Generated mental health code lists can last for a long time unlike cardiometabolic conditions and cancer. Adopting more consistent and less diverse coding would help improve data quality in primary care. Future research is needed following the transfer to the Systematised Nomenclature of Medicine Clinical Terms (SNOMED CT) coding.

Evaluating Metacognitive Therapy to Improve Treatment of Anxiety and Depression in Cardiovascular Disease: The NIHR Funded PATHWAY Research Programme.

Background: Anxiety and depression contribute to poorer physical and mental health outcomes in cardiac patients. Psychological treatments are not routinely offered in cardiac care and have mixed and small effects. We conducted a series of studies under the PATHWAY research programme aimed at understanding and improving mental health outcomes for patients undergoing cardiac rehabilitation (CR) through provision of metacognitive therapy (MCT). Methods: PATHWAY was a series of feasibility trials, single-blind, multicenter, randomized controlled trials (RCTs), qualitative, stated preferences for therapy and health economics studies. Findings: Patients felt their psychological needs were not met in CR and their narratives of distress could be parsimoniously explained by the metacognitive model. Patients reported they would prefer therapy over no therapy as part of CR, which included delivery by a cardiac professional. Two feasibility studies demonstrated that RCTs of group-based and self-help MCT were acceptable, could be embedded in CR services, and that RCTs of these interventions were feasible. A definitive RCT of group-MCT within CR (n = 332) demonstrated significantly greater reductions in the severity of anxiety and depression, exceeding CR alone, with gains maintained at 12 month follow-up (SMD HADS total score = 0.52 at 4 months and 0.33 at 12 months). A definitive trial of self-help MCT is ongoing. Conclusion: There is a need to better meet the psychological needs of CR patients. Embedding MCT into CR demonstrated high acceptability and improved efficacy on psychological outcomes. Results support roll-out of MCT in CR with evaluation of national implementation. Registration: URL: NCT02420431; ISRCTN74643496; NCT03129282.

Invasiveness risks of naked goby, Gobiosoma bosc, to North Sea transitional waters.

In recent decades, gobies have dispersed or introduced from the Ponto-Caspian region of eastern Europe in a westerly direction to North American and western European waters. By contrast, the naked goby, Gobiosoma bosc, is the only known gobiid species to have been introduced in an easterly direction from North American to western Europe. The potential invasiveness of G. bosc was assessed using the Aquatic Species Invasiveness Screening Kit (AS-ISK) for rivers and transitional waters for the western and eastern sides of the North Sea. Using globally-derived thresholds, G. bosc was assessed as low-medium invasiveness risk for both sides of the North Sea under current climate conditions. Under future climate conditions, potential invasiveness will increase for both risk assessment areas. Environmental suitability assessment indicated an increase in environmental suitability for G. bosc on the eastern coastline of the North Sea under climate change scenarios and suitability remained unchanged on the western coastline, reflecting the authors' expectations of invasiveness risk.

Update on cancer therapy-induced atherosclerosis.

PURPOSE OF REVIEW: Recent advances in oncologic therapies have significantly improved overall survival for patients with malignancy. However, cardiovascular complications have not only increased in this population due to shared risk factors and pathophysiology, but also due to the therapies themselves. One key mechanism that warrants further attention is accelerated atherosclerosis due to these agents. RECENT FINDINGS: Here we review recent studies focusing on four classes of anticancer agents with the potential to accelerate atherosclerosis, including breakpoint cluster region-Ableson (BCR-ABL) tyrosine kinase inhibitors, immunotherapies, androgen deprivation therapies, and vascular endothelial growth factor inhibitors. In addition to drug therapy, radiation therapy may also accelerate atherosclerosis. SUMMARY: In order to optimize outcomes for patients with malignancy, enhanced efforts need to focus on mitigating common risk factors, but also recognizing enhanced atherosclerotic risk with certain oncologic therapies. For patients exposed to these agents, risk reduction with agents such as aspirin and/or statins prior to, during, and after cancer treatment may provide opportunities to improve overall outcomes.

Drowsy driving and teen motor vehicle crashes: Impact of changing school start times.

INTRODUCTION: Motor vehicle crashes (MVC) are the second leading cause of death for adolescents in the United States, with drowsy driving a major contributing factor. Early school start times have been identified as a significant factor that reduces adolescent sleep duration, which in turn contributes to drowsy driving and MVC. This paper examined the longitudinal impact of delaying secondary school start times on self-reported student drowsy driving and teen MVC. METHODS: Secondary school students (10th and 11th grade, 51.7% female, 67.8% White) in the United States completed annual surveys 1 year before and 2 years after implementation of later school start times (70-min delay, n range 1642-2452 per year), reporting frequency of drowsy driving (less than once/week vs. at least once/week). Teen (16-18 years) MVC data from the Colorado Department of Transportation for the 2 years before and 2 years after later start time implementation were compared for Arapahoe County (where start times changed) and neighboring Adams County and Douglas County (where start times did not change). RESULTS: With later start times, there was a significant drop in the percent of students who reported frequent drowsy driving (pre-change: 32.6%, post-change: 21.9%, follow-up: 22.8%). Weekday teen MVC rates went down in Arapahoe County (p = .04) during the school year, while no change or increases in MVC rates were seen in neighboring counties. CONCLUSIONS: Healthy school start times are important for adolescent health and safety, with study findings highlighting the downstream effects of increased sleep duration following a 70-min delay in secondary school start times on adolescent drowsy driving and teen MVC rates.

Understanding the implementation of interventions to improve the management of frailty in primary care: a rapid realist review.

OBJECTIVE: Identifying and managing the needs of frail people in the community is an increasing priority for policy makers. We sought to identify factors that enable or constrain the implementation of interventions for frail older persons in primary care. DESIGN: A rapid realist review. DATA SOURCES: Cochrane Library, SCOPUS and EMBASE, and grey literature. The search was conducted in September 2019 and rerun on 8 January 2022. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We considered all types of empirical studies describing interventions targeting frailty in primary care. ANALYSIS: We followed the Realist and Meta-narrative Evidence Syntheses: Evolving Standards quality and publication criteria for our synthesis to systematically analyse and synthesise the existing literature and to identify (intervention-context-mechanism-outcome) configurations. We used normalisation processes theory to illuminate mechanisms surrounding implementation. RESULTS: Our primary research returned 1755 articles, narrowed down to 29 relevant frailty intervention studies conducted in primary care. Our review identified two families of interventions. They comprised: (1) interventions aimed at the comprehensive assessment and management of frailty needs; and (2) interventions targeting specific frailty needs. Key factors that facilitate or inhibit the translation of frailty interventions into practice related to the distribution of resources; patient engagement and professional skill sets to address identified need. CONCLUSION: There remain challenges to achieving successful implementation of frailty interventions in primary care. There were a key learning points under each family. First, targeted allocation of resources to address specific needs allows a greater alignment of skill sets and reduces overassessment of frail individuals. Second, earlier patient involvement may also improve intervention implementation and adherence. PROSPERO REGISTRATION NUMBER: The published protocol for the review is registered with PROSPERO (CRD42019161193).

Metacognitive therapy self-help for anxiety-depression: Single-blind randomized feasibility trial in cardiovascular disease.

BACKGROUND: One in three cardiovascular disease (CVD) patients experience significant anxiety and depression. Current psychological interventions have limited efficacy in reducing such symptoms and are offered as a face-to-face intervention that may be a barrier to accessing treatment. We evaluated the feasibility and acceptability of delivering assisted home-based self-help metacognitive therapy (home-MCT) to cardiac rehabilitation (CR) patients experiencing anxiety and depression. METHOD: One hundred eight CR patients with elevated anxiety and/or depression were recruited to a single-blind randomized feasibility trial across two United Kingdom National Health Service Trusts and were randomized to usual CR or usual CR plus home-MCT. The feasibility and acceptability of adding home-MCT to CR was based on credibility or expectancy ratings, recruitment rate, drop-outs, number of CR and home-MCT modules completed, and ability of outcome measures to discriminate between patients. The study was used to refine the sample size estimate for a full-scale trial. The quality of telephone support calls delivered by CR staff trained in MCT was assessed. RESULTS: Home-MCT was found to be feasible and acceptable for the current CR patients with anxiety and depression. Recruitment and retention of participants was high, and attendance at CR was similar for both groups. Completion of home-MCT was high, but the quality of telephone support calls delivered was lower than expected. CONCLUSIONS: Home-MCT was acceptable and feasible to deliver to CR patients experiencing anxiety and depression, and the feasibility of conducting a full-scale trial of the intervention was established. Home-MCT may provide additional treatment options for cardiac patients experiencing psychological distress. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Influence of offshore oil and gas structures on seascape ecological connectivity.

Offshore platforms, subsea pipelines, wells and related fixed structures supporting the oil and gas (O&G) industry are prevalent in oceans across the globe, with many approaching the end of their operational life and requiring decommissioning. Although structures can possess high ecological diversity and productivity, information on how they interact with broader ecological processes remains unclear. Here, we review the current state of knowledge on the role of O&G infrastructure in maintaining, altering or enhancing ecological connectivity with natural marine habitats. There is a paucity of studies on the subject with only 33 papers specifically targeting connectivity and O&G structures, although other studies provide important related information. Evidence for O&G structures facilitating vertical and horizontal seascape connectivity exists for larvae and mobile adult invertebrates, fish and megafauna; including threatened and commercially important species. The degree to which these structures represent a beneficial or detrimental net impact remains unclear, is complex and ultimately needs more research to determine the extent to which natural connectivity networks are conserved, enhanced or disrupted. We discuss the potential impacts of different decommissioning approaches on seascape connectivity and identify, through expert elicitation, critical knowledge gaps that, if addressed, may further inform decision making for the life cycle of O&G infrastructure, with relevance for other industries (e.g. renewables). The most highly ranked critical knowledge gap was a need to understand how O&G structures modify and influence the movement patterns of mobile species and dispersal stages of sessile marine species. Understanding how different decommissioning options affect species survival and movement was also highly ranked, as was understanding the extent to which O&G structures contribute to extending species distributions by providing rest stops, foraging habitat, and stepping stones. These questions could be addressed with further dedicated studies of animal movement in relation to structures using telemetry, molecular techniques and movement models. Our review and these priority questions provide a roadmap for advancing research needed to support evidence-based decision making for decommissioning O&G infrastructure.

Outcomes and Management of Immune Checkpoint Inhibitor-Induced Hypothyroidism: A Retrospective Analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) used in cancer treatment cause immune-related adverse effects (irAEs), including thyroiditis leading to hypothyroidism. The management and outcomes of this irAE are not well established. OBJECTIVE: The purpose of this analysis is to describe the onset, management, and outcomes of patients experiencing hypothyroidism from ICI. METHODS: A retrospective study was conducted of adults receiving ICI therapy at a community cancer center between January 1, 2017, and February 1, 2020. The primary endpoint was to describe onset (timing) of hypothyroidism (thyroid-stimulating hormone [TSH] > 10 µIU/mL). Secondary outcomes included describing hypothyroidism symptoms and levothyroxine use, time to documented disease progression, and occurrence of additional adverse effects (AEs). RESULTS: Of the 200 patients included in the study, 19% developed clinical hypothyroidism (TSH > 10 µIU/mL, or required initiation of or dose increase in levothyroxine). Median time to TSH higher than 10 µIU/mL was 13.3 weeks and symptoms of hypothyroidism occurred in 34% of patients developing clinical hypothyroidism. The median final daily levothyroxine dose was 88 mcg (0.88 mcg/kg). Time to disease progression was longer in those with clinical hypothyroidism (27.4 months vs. 6.8 months, respectively, P = .015). Additional AEs occurred in 68% of those developing hypothyroidism versus 49% without hypothyroidism (P = .029). CONCLUSION AND RELEVANCE: Patients with clinical hypothyroidism during ICI treatment may have improved cancer outcomes, but they also are more likely to develop other AEs. Patients requiring thyroid replacement therapy with levothyroxine may benefit from a starting dose between 50 and 100 mcg/day, approximately 0.88 mcg/kg/day.