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Background Individuals with a prior diagnosis of chronic lymphocytic leukaemia (CLL) have a higher risk of developing melanoma and exhibit poorer outcomes than patients without CLL. However, there are limited data reporting the clinicopathological features of melanoma diagnosed in patients with CLL. Aims To review clinicopathological characteristics of patients with coexisting diagnoses of melanoma and CLL. Methods A retrospective review was undertaken for patients with coexisting diagnoses of melanoma and CLL between 2005 and 2015 in 11 centres in the UK and Ireland. Results Overall, 46 cutaneous melanomas identified in 45 patients were included. In 28 (62.2%) patients, melanoma was diagnosed after an existing diagnosis of CLL. In this group, mean Breslow thickness was 2.7 mm (range 0.2–25 mm). Ten patients (35.7%) developed locoregional recurrence and 8 (28.6%) developed distant metastases. Melanoma-specific mortality was 5 of 28 (17.9%) and all-cause mortality was 13 of 28 (46.4%). In 17 patients, melanoma was diagnosed before CLL. In this group, mean BT was 2.9 mm (range 0.4–14 mm); five patients (29.4%) developed locoregional recurrence and three (17.6%) developed distant metastases. Melanoma-specific mortality was 1 of 17 (5.8%) and all-cause mortality was 5 of 17 (29.4%) in this group. Conclusions To our knowledge, this is the first and largest cohort study to report clinicopathological data of coexisting melanoma and CLL in the UK and Ireland. Although the thickness of primary melanoma was not different before or after a CLL diagnosis, melanoma recurrence and melanoma-specific mortality appear to be more common in patients with a prior diagnosis of CLL.

Despite ongoing efforts to decrease ionizing radiation exposure from computed tomography (CT) use in pediatric appendicitis, high CT utilization rates are still observed across many hospitals. This study aims to identify factors influencing CT use and facilitators and barriers to quality improvement efforts.The Pediatric Surgery Quality Collaborative is a voluntary consortium of 42 children's hospitals participating in the National Surgical Quality Improvement Project - Pediatric. Hospitals were compared based on CT utilization from January 1, 2019, to December 31, 2019. Semi-structured interviews were conducted with surgeons, radiologists, emergency medicine physicians, and clinical data abstractors from 7 hospitals with low CT use rates (high performers) and 6 hospitals with high CT use rates (low performers). A mixed deductive and inductive coding approach for analysis of the interview transcripts was used to develop a codebook based on the Theoretical Domains Framework and subsequently identify prominent barriers and facilitators to CT reduction.Thematic saturation was achieved after 13 interviews. We identified four factors that distinguish high-performing from low-performing hospitals: (1) consistent availability of resources such as ultrasound technicians, pediatric radiologists, and magnetic resonance imaging (MRI); (2) presence of and adherence to protocols guiding imaging modality decision making and imaging execution; (3) culture of inter-departmental collaboration; and (4) presence of a radiation reduction champion.Significant barriers to reducing the use of CT in pediatric appendicitis exist. Our findings highlight that future quality improvement efforts should target resource availability, protocol adherence, collaborative culture, and radiation reduction champions.Level III.

Background: This study aims to address the potential of ex vivo diffusion tensor imaging to provide insight into the microstructural composition and morphological arrangement of aged human atherosclerotic carotid arteries. Methods: In this study, whole human carotid arteries were investigated both anatomically and by comparing healthy and diseased regions. Nonrigid image registration was used with unsupervised segmentation to investigate the influence of elastin, collagen, cell density, glycosaminoglycans, and calcium on diffusion tensor imaging derived metrics (fractional anisotropy and mean diffusivity). Early stage atherosclerotic features were also investigated in terms of microstructural components and diffusion tensor imaging metrics. Results: All vessels displayed a dramatic decrease in fractional anisotropy compared with healthy animal arterial tissue, while the mean diffusivity was sensitive to regions of advanced disease. Elastin content strongly correlated with both fractional anisotropy (r>0.7, P −0.79, P Conclusions: These different investigations point to the potential of diffusion tensor imaging to identify characteristics of arterial disease progression, at early and late-stage lesion development.

Objective This study aimed to qualitatively explore how partner support for health behaviours is perceived, received, and utilised in people living with and beyond cancer (LWBC). Methods Semi-structured audio interviews were conducted with 24 participants, 15 men and nine women, living with and beyond breast, prostate, and colorectal cancer. Inductive and deductive Thematic Analysis was used to analyse the data. Results Three key themes with six subthemes were identified relating to partner support for health behaviours: (1) Interdependence (Reciprocity, Overt Control, Influence & Motivation) (2) Concordance (Shared Attitudes & Health Beliefs, Shared Health Behaviour) and (3) Communal Coping (Communal Orientation towards Health and Decision Making, Co-operative Action in Health Behaviour). Conclusions Partner support plays a unique and significant role in the health behaviours of people LWBC. Partners play a collaborative role in managing health and facilitating health behaviours, while the high level of concordance in couples may represent a potential barrier to change via the reinforcement of maladaptive health beliefs and behaviours. Implications for Cancer Survivors Overall, findings demonstrate that partners should be considered and included where possible when designing future behaviour change interventions for people LWBC.

Purpose Individual Placement and Support (IPS) is a recovery-based approach to support people with mental health difficulties back into employment. Embedding of IPS within the mental health Multi-Disciplinary Team (MDT) is a key component of IPS fidelity; however, few studies have examined how those involved with IPS implementation navigate this process. This article explores how IPS Employment Specialists (ES) and Occupational Therapist (OT) Managers integrated and embedded IPS within traditionally-oriented MDTs as part of a national reform program in the Republic of Ireland. Methods The study design was qualitative, descriptive with data collected through three focus groups with 17 IPS ESs and 11 OT Managers. Data were analyzed using thematic synthesis. Results Three key themes emerged from analysis. The first characterizes the context into which IPS landed, described as one marked by clinical resistance, doubt, and fear of risk. The second explores the strategies and factors that helped with the introduction of IPS into Irish mental health services. These included strategies, such as providing education and information about IPS and reassuring the MDT about IPS governance and IPS ES’ competencies. The evidenced-based nature of IPS and its attached accountabilities through IPS fidelity measures were perceived to be an important factor in its acceptance. The final theme encapsulates perceptions of how IPS impacted on the MDTs’ views of people with mental health difficulties. Findings suggest a shift in the ways in which MDTs view their clients. Initial fears about work capacity and risk shifted towards seeing people beyond the label of ‘service user’ and their diagnosis. Conclusions It is contended that IPS is an approach that allows practitioners to engage with real recovery-practice and may be one key to unlocking how a recovery approach can truly trickle down and embed itself within mental health service provision and support mental health system reform.

Myxomas are a heterogeneous group of mesenchymal tumors. Soft tissue myxomas are divided into myocardial, intramuscular, juxta-articular, superficial, aggressive, and nerve sheath myxomas. Although benign, myxomas have site-specific biologic behavior and syndromic associations, which can influence prognosis and management. In addition, myxomas need to be distinguished from malignant neoplasms, such as myxofibrosarcomas, low-grade fibromyxoid sarcomas, myxoid liposarcomas, and peripheral nerve sheath tumors. While myxomas can occur throughout the body, these tumors arise more commonly in the thigh, shoulder, buttocks, and upper extremity, and less often in the head and neck. Rarely, myxomas can arise in a periocular location, typically in the conjunctiva and eyelid skin. In this case report, we present a patient with recurrent intramuscular myxoma of the eyelid and discuss the differential diagnosis and syndromic associations of this neoplasm. To our knowledge, there have been no prior reports of intramuscular myxoma of the eyelid and orbit.

Takayasu arteritis is a rare inflammatory disease of large arteries. We performed a genetic study in Takayasu arteritis comprising 6,670 individuals (1,226 affected individuals) from five different populations. We discovered HLA risk factors and four non-HLA susceptibility loci in VPS8, SVEP1, CFL2, and chr13q21 and reinforced IL12B, PTK2B, and chr21q22 as robust susceptibility loci shared across ancestries. Functional analysis proposed plausible underlying disease mechanisms and pinpointed ETS2 as a potential causal gene for chr21q22 association. We also identified >60 candidate loci with suggestive association (p < 5 x 10(-s)) and devised a genetic risk score for Takayasu arteritis. Takayasu arteritis was compared to hundreds of other traits, revealing the closest genetic relatedness to inflammatory bowel disease. Epigenetic patterns within risk loci suggest roles for monocytes and B cells in Takayasu arteritis. This work enhances understanding of the genetic basis and pathophysiology of Takayasu arteritis and provides clues for potential new therapeutic targets., National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [R01 AR070148]; National Institute of Arthritis and Musculoskeletal and Skin DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Arthritis & Musculoskeletal & Skin Diseases (NIAMS) [U54 AR057319, U01 AR51874 04]; National Center for Research ResourcesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Center for Research Resources (NCRR) [U54 RR019497]; Office of Rare Diseases Research of the National Center for Advancing Translational Sciences; Imperial College, National Institute for Health Research, Biomedical Research Centre; Wellcome TrustWellcome TrustEuropean Commission [WT107881]; Medical Research CouncilUK Research & Innovation (UKRI)Medical Research Council UK (MRC)European Commission [MC_UU_00002/4], This work was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health grant R01 AR070148 to A.H.S. The Vasculitis Clinical Research Consortium has received support from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (U54 AR057319 and U01 AR51874 04), the National Center for Research Resources (U54 RR019497), and the Office of Rare Diseases Research of the National Center for Advancing Translational Sciences. J.C.M., A.P.K., and R.M.M. acknowledge support from the Imperial College, National Institute for Health Research, Biomedical Research Centre. C.W. and G.R. acknowledge support from The Wellcome Trust (WT107881) and the Medical Research Council (MC_UU_00002/4). This work was supported by the use of study data downloaded from the dbGaP website, under dbGaP: phs000272.v1.p1, phs000431.v2.p1, phs000583.v1.p1, and phs000444.v1.p1.

Introduction: Despite respiratory disease being a major cause of excess mortality in people with schizophrenia, the prevalence of respiratory conditions in this population is poorly defined. A systematic review and meta-analysis were conducted to establish the prevalence and association of respiratory diseases in people with schizophrenia. Material and methods: Major electronic databases were searched from inception to 27 April 2020 for articles reporting respiratory disease (asthma, chronic obstructive pulmonary disease [COPD], pneumonia, and tuberculosis) in people with schizophrenia and, where possible, a control group. A random-effects meta-analysis was conducted. The study was registered with PROSPERO (CRD42018115137). Results: Of 1569 citations, 21 studies consisting of 619,214 individuals with schizophrenia and 52,159,551 controls were included in the meta-analysis. Compared to the general population, people with schizophrenia had significantly higher rates of COPD (odds ratio [OR]: 1.82, 95% CI: 1.28–2.57), asthma (OR: 1.70, 95% CI: 1.02–2.83), and pneumonia (OR: 2.62, 95% CI: 1.10–6.23). In people with schizophrenia, the prevalence of COPD was 7.7% (95% CI: 4.0–14.4), asthma 7.5% (95% CI: 4.9–11.3), pneumonia 10.3% (95% CI 5.4–18.6), and tuberculosis 0.3% (95% CI 0.1 –0.8). After adjusting for publication bias, the prevalence of COPD increased to 19.9% (95% CI: 9.6–36.7). Discussion: All respiratory diseases examined were significantly more prevalent in people with schizophrenia compared with the general population. Future studies should focus on improving the prevention and management of respiratory disease in this group to reduce associated excess mortality. © 2021 Elsevier B.V.

Variants in the leucine-rich repeat kinase 2 gene (LRRK2) are risk factors for Parkinson's disease (PD), but their prevalence varies geographically, reflecting the locations of founder events and dispersion of founders' descendants.A comprehensive literature review was conducted to identify studies providing prevalence estimates for any of ten variants in LRRK2 (G2019S, R1441C, R1441G, R1441H, I2020T, N1437H, Y1699C, S1761R, G2385R, R1628P) among individuals with PD globally. We calculated crude country-specific variant prevalence estimates and, when possible, adjusted estimates for ethno-racial composition. For clinic-based studies, probands were used over other familial cases, whereas for population-based studies, all PD cases were used.The analysis included 161 articles from 52 countries yielding 581 prevalence estimates across the ten variants. G2019S was the most common variant, exceeding 1.0% in 26 of 51 countries with estimates. The other variants were far less common. G2385R and R1628P were observed almost exclusively in East Asian countries, where they were found in ∼5-10% of cases. All prevalence estimates adjusted for ethno-racial composition were lower than their unadjusted counterparts, although data permitting this adjustment was only available for six countries.Except for G2019S, the LRRK2 variants covered in this review were uncommon in most countries studied. However, there were countries with higher prevalence for some variants, reflecting the uneven geographic distribution of LRRK2 variants. The fact that ethno-racial group‒adjusted estimates were lower than crude estimates suggests that estimates derived largely from clinic-based studies may overstate the true prevalence of some LRRK2 variants in PD.

Background/Purpose Comprehensive opioid stewardship programs require collective stakeholder alignment and proficiency. We aimed to determine opioid-related prescribing practices, knowledge, and beliefs among providers who care for pediatric surgical patients. Methods A single-center, cross-sectional survey was conducted of attending physicians, residents, and advanced practice providers (APPs), who managed pediatric surgical patients. Results Of 110 providers surveyed, 75% completed the survey. Over half of respondents (n = 43, 52%) reported always/very often prescribing opioids at discharge, with residents reporting the highest rate (66%). Provider types had varying prescribing patterns, including what types of opioids and non-opioids they prescribed. There was a lack of formal training, particularly among residents, of which only 42% reported receiving formal opioid prescribing education. Finally, although only 28% of providers felt that the opioid epidemic affects children, 48% believed pediatric providers’ prescribing patterns contributed to the opioid epidemic as a whole, and 80% reported changing their prescribing practices in response. Conclusions Significant variability exists in opioid prescribing practices, knowledge, and beliefs among providers who care for pediatric surgical patients. Effective opioid stewardship requires comprehensive policies, pediatric specific guidelines, and education for all providers caring for children to align provider proficiency and optimize prescribing patterns.

Cardiac dysfunction is a key determinant of outcome in congenital diaphragmatic hernia (CDH). Pro-b-type natriuretic peptide (proBNP) is used as a prognosticator in heart failure and cardiomyopathy. We hypothesized that proBNP levels would be associated with ventricular dysfunction and high-risk disease in CDH.Patients in the CDH Study Group (CDHSG) from 2015-2019 with at least one proBNP value were included. Ventricular function was determined using echocardiograms from the first 48 h of life.A total of 2,337 patients were identified, and 212 (9%) had at least one proBNP value. Of those, 3 (1.5%) patients had CDHSG stage A defects, 58 (29.6%) B, 111 (56.6%) C, and 24 (12.2%) D. Patients with high-risk defects (Stage C/D) had higher proBNP compared with low-risk defects (Stage A/B) (14,281 vs. 5,025, p = 0.007). ProBNP was significantly elevated in patients who died (median 14,100, IQR 4,377-22,900 vs 4,911, IQR 1,883-9,810) (p0.001). Ventricular dysfunction was associated with higher proBNP than normal ventricular function (8,379 vs. 4,778, p = 0.005). No proBNP value was both sensitive and specific for ventricular dysfunction (AUC=0.61).Among CDH patients, elevated proBNP was associated with high-risk defects, ventricular dysfunction, and mortality. ProBNP shows promise as a biomarker in CDH-associated cardiac dysfunction.

There is profound and long-standing debate over the role of explicit instruction in reading acquisition. In this research, we investigated the impact of teaching regularities in the writing system explicitly rather than relying on learners to discover these regularities through text experience alone. Over 10 days, 48 adults learned to read novel words printed in two artificial writing systems. One group learned spelling-to-sound and spelling-to-meaning regularities solely through experience with the novel words, whereas the other group received a brief session of explicit instruction on these regularities before training commenced. Results showed that virtually all participants who received instruction performed at ceiling on tests that probed generalization of underlying regularities. In contrast, despite up to 18 hr of training on the novel words, less than 25% of discovery learners performed on par with those who received instruction. These findings illustrate the dramatic impact of teaching method on outcomes during reading acquisition.

Objective To describe the prevalence of frailty in a single-centre cohort of patients with PMR and describe its association with health-related quality of life (HRQoL), cognition and sarcopenia. Methods This was a cross-sectional study of patients with PMR, according to 2012 EULAR/ACR Classification Criteria, presenting within 12 months of diagnosis and on treatment with glucocorticoids. Frailty was defined according to the Fried frailty criteria. HRQoL was assessed using Patient-Reported Outcomes Measurement Information System Computerized Adaptive Test (PROMIS-CAT) and cognition was assessed using the Mini-Mental State Examination. Sarcopenia was measured by DXA. Results Forty-one patients were enrolled. Prevalence of frailty and pre-frailty was 17% and 59%, respectively. Frail patients had higher inflammatory markers at diagnosis compared with pre-frail and robust patients. Of 27 patients with DXA results, 26% were sarcopenic. Frail patients had worse physical function, and more pain behaviour and interference compared with pre-frail and robust patients. In univariable analyses, frail patients were more likely to have worse physical function, and more pain behaviour and pain interference, which remained significant after adjusting for age. There were no significant associations between cognition or sarcopenia and frailty. Conclusions In this cohort of PMR patients, there was a higher prevalence of frailty and pre-frailty compared with that reported in community-dwelling elderly. Frailty was associated with worse physical function, and increased pain behaviour and pain interference, differences that were also clinically meaningful. Larger prospective studies are needed to confirm these findings and analyse the association of frailty with other PMR disease outcomes.

This paper conducts a cost–benefit analysis of Australia’s Covid-19 lockdown strategy relative to pursuit of a mitigation strategy in March 2020. The estimated additional deaths from a mitigation strategy are 11,500 to 40,000, implying a Cost per Quality Adjusted Life Year saved by locking down of at least 11 times the generally employed figure of $100,000 for health interventions in Australia. The lockdowns do not then seem to have been justified by reference to the standard benchmark. Consideration of the information available to the Australian government in March 2020 yields a similar ratio and therefore the same conclusion that lockdown was not warranted. If Australia experiences a new outbreak, and cannot contain it without resort to a nationwide lockdown, the death toll from adopting a mitigation strategy at this point would be even less than had it done so in March 2020, due to the vaccination campaign, lessons learned since March 2020, and because the period over which the virus would then inflict casualties would now be much less than the period from March 2020. This would favour a mitigation policy even more strongly than in March 2020. This approach of assessing the savings in quality adjusted life years and comparing them to a standard benchmark figure ensures that all quality adjusted life years saved by various health interventions are treated equally, which accords with the ethical principle of equity across people.

The purpose of this study was to analyze the clinical characteristics and outcomes of low birthweight (LBW) infants with congenital diaphragmatic hernia (CDH) compared to normal birthweight (NBW) infants with CDH. We hypothesized that LBW was associated with increased mortality, decreased extracorporeal life support (ECLS) utilization, and increased pulmonary morbidity in CDH patients. Patients in the CDH Study Group from 2007 to 2018 were included. LBW was defined as p = .03). LBW infants had longer durations of mechanical ventilation and were more likely to require supplemental oxygen at 30 days and at the time of discharge. LBW is a risk factor for mortality and pulmonary morbidity in CDH. Prolonged oxygen requirement and increased length of stay are important considerations when managing this population.

Peripherin-2 (PRPH2) gene variants are a well-established cause of multiple inherited maculopathies including central areolar choroidal dystrophy (CACD) and pattern dystrophy. In this familial case study, we present a 63-year-old proband who presented with visual acuity of 20/63 right eye and 20/100 left eye with a complaint of lowered visual acuity in the left eye for unknown duration. Fundus examination presented with unifocal atrophic lesions bilaterally. Multi-modal imaging was obtained and genetic testing (My Retina Tracker; Blueprint Genetics) was performed. The proband was monoallelic for a novel missense mutation within the PRPH2 gene (Arg203Pro) not previously found in the literature or large databases (gnomAD, ClinVar, and HGMD). Subsequent examination of the proband's mother, older sister (65 years old), younger sister (53), and daughter (35) found the novel mutation to segregate with maculopathy ranging from speckled fundus autofluorescence with EZ disruption and RPE attenuation on spectral domain optical coherence tomography to large unifocal atrophic lesions throughout the macula bilaterally. The purpose of this case report is to add to the literature of PRPH2-associated disease by providing a comprehensive fundus examination of a family with autosomal dominant PRPH2-associated maculopathy diagnosed as central areolar choroidal dystrophy and pattern dystrophy.

Congenital diaphragmatic hernia (CDH) patients often have suspected isolated aortic arch anomalies (IAAA) on imaging. The purpose of this work was to describe the incidence and outcomes of CDH + IAAA patients.Cardiovascular data were collected for infants from the CDH Study Group born between 2007 and 2019. IAAA were defined as coarctation of aorta, hypoplastic aortic arch, interrupted aortic arch, and aortic aneurysmal disease on early, postnatal echocardiography. Patients with major cardiac malformations and/or chromosomal abnormalities were excluded. Primary outcomes included the rate of aortic intervention, rates of extracorporeal life support (ECLS) utilization, and mortality.Of 6357 CDH infants, 432 (7%) were diagnosed with a thoracic aortic anomaly. Of these, 165 were diagnosed with IAAA, most commonly coarctation of the aorta (n = 106; 64%) or hypoplastic aortic arch (n = 58; 35%). CDH + IAAA patients had lower birthweights (3 kg vs. 2.9 kg) and Apgar scores (7 vs. 6) than patients without IAAA (both χIAAA in CDH are associated with increased mortality. This often simply reflects severity of the defect and thoracic anatomic derangement, as opposed to unique aortic pathology, given few CDH + IAAA patients undergo aortic intervention.

Purpose The Oncology Nursing Society (ONS) tasked a rapid response research team (RRRT) to develop priorities to increase diversity, equity, and inclusivity in oncology clinical care and workforce development. Methods An RRRT of experts in health disparities conducted a rapid review of the literature, consulted with oncology nurse leaders and disparities researchers, and reviewed priorities from funding agencies. Results Significant gaps in the current oncology disparities literature were identified and used to inform priority areas for future research practice and workforce development in oncology nursing. Synthesis This is the second article in a two-part series that presents findings on structural racism and health inequities in oncology nursing. In the first article, three priority areas for oncology nursing research were presented. In this article, strategies to improve diversity, equity, and inclusivity in clinical practice and the oncology workforce are described. Implications for research Recommendations are presented to inform research, clinical, administrative, and academic oncology nursing settings on increasing diversity, equity, and inclusivity and deconstructing structural racism.

Introduction This open-label, phase 1–2 study evaluated the safety and efficacy of rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate targeting DLL3, plus immune checkpoint inhibitors nivolumab plus or minus ipilimumab in previously treated extensive-stage SCLC (ES SCLC). Methods Patients with histologically or cytologically confirmed, previously treated (two or more lines of therapy) ES SCLC were enrolled into two cohorts. Cohort 1 received 0.3 mg/kg Rova-T (once every 6 wk for two cycles) plus 360 mg nivolumab (two 3-wk cycles beginning on week 4). Cohort 2 received the same dosage of Rova-T as cohort 1 plus 1 mg/kg nivolumab (four 3-wk cycles) and 1 mg/kg ipilimumab (beginning week 4). Both cohorts received 480 mg nivolumab every 4 weeks starting at week 10. Key objectives were to evaluate safety and tolerability and efficacy (per Response Evaluation Criteria in Solid Tumors version 1.1). The response-related results are based on centrally read data. Results A total of 42 patients received therapy: cohort 1, n = 30; cohort 2, n = 12. Overall, 43% received two or more previous lines of therapy. All patients experienced one or more treatment-emergent adverse event (TEAE); 41 patients reported AEs considered related to the study drug by the investigator. The most frequent TEAE was pleural effusion (n = 20, 48%); most common grade greater than or equal to 3 was anemia (n = 9, 21%). Three grade 5 TEAEs considered related to the study drug were reported (cohort 1): pneumonitis (n = 2), acute kidney injury (n = 1). The objective response rate was 30% (12 of 40): cohort 1, 27.6% (8 of 29); cohort 2, 36.4% (4 of 11); all partial responses. Conclusions Despite encouraging antitumor activity in previously treated ES SCLC, combination therapy with Rova-T and nivolumab plus or minus ipilimumab was not well tolerated at the dose levels and administration schedules evaluated.

Objectives Given significant focus on improving survival for "high-risk" congenital diaphragmatic hernia, there is the potential to overlook the need to identify risk factors for suboptimal outcomes in "low-risk" congenital diaphragmatic hernia cases. We hypothesized that early cardiac dysfunction or severe pulmonary hypertension were predictors of adverse outcomes in this "low-risk" congenital diaphragmatic hernia population. Design This is a retrospective cohort study using data from the Congenital Diaphragmatic Hernia Study Group registry. "Low-risk" congenital diaphragmatic hernia was defined as Congenital Diaphragmatic Hernia Study Group defect size A/B without structural cardiac and chromosomal anomalies. Examined risk factors included left ventricular dysfunction, right ventricular dysfunction, and severe pulmonary hypertension on the first postnatal echocardiogram. The primary outcome was composite adverse events, defined as either death, extracorporeal membrane oxygenation utilization, oxygen requirement on day 30 of life, or hospitalization greater than or equal to 8 weeks. Multivariable adjustment was performed with logistic regression and inverse probability weighting. Setting Neonatal index hospitalization for congenital diaphragmatic hernia. Patients "Low-risk" congenital diaphragmatic hernia infants born between January 2015 and December 2018. Interventions First postnatal echocardiogram performed within 24 hours from birth. Measurements and main results Seven-hundred seventy-eight patients were identified as "low-risk" congenital diaphragmatic hernia. Left ventricular dysfunction, right ventricular dysfunction, and severe pulmonary hypertension were present in 10.8%, 20.5%, and 57.5%, respectively. The primary outcome occurred in 21.3%. Death occurred in 3.0% and 9.1% used extracorporeal membrane oxygenation. On unadjusted analysis, all three risk factors were associated with the primary outcome. On all multivariable adjustment methods, left ventricular dysfunction and severe pulmonary hypertension remained significant predictors of adverse outcomes while right ventricular dysfunction no longer demonstrated any effect. Conclusions Early left ventricular dysfunction and severe pulmonary hypertension are independent predictors of adverse outcomes among "low-risk" congenital diaphragmatic hernia infants. Early recognition may lead to interventions that can improve outcome in this at-risk cohort.

In cases of aortic stenosis, bioprosthetic heart valves (BHVs), with glutaraldehyde-fixed bovine pericardium leaflets (GLBP), are often implanted to replace the native diseased valve. Widespread use of BHVs, however, is restricted due to inadequate long-term durability, owing specifically to premature leaflet failure. Mechanical fatigue damage and calcification remain the primary leaflet failure modes, where glutaraldehyde treatment is known to accelerate calcification. The literature in this area is limited, with some studies suggesting mechanical damage increases calcification and others that they are independent degenerative mechanisms. In this study, specimens which were non-destructively pre-sorted according to collagen fibre architecture and uniaxially cyclically loaded until failure or 1 million cycles, were placed in an in vitro calcification solution. The weakest specimen group (those with fibres aligned perpendicular to the load) had statistically significantly higher volumes of calcification when compared to those with a high fatigue life. Moreover, SEM imaging revealed that ruptured and damaged fibres presented calcium binding sites; resulting in 4 times more calcification in fractured samples in comparison to those which did not fail by fatigue. To the authors’ knowledge, this study quantifies for the first time, that mechanical damage drives calcification in commercial-grade GLBP and that calcification varies spatially according to localised damage levels. These findings illustrate that not only is calcification of GLBP exacerbated by fatigue damage, but that both failure phenomena are underpinned by the collagen fibre organisation. Consequently, controlling for GLBP collagen fibre architecture in leaflets could minimise the progression of these primary failure modes in patient BHVs. Statement of significance Mechanical damage and calcification are the primary premature failure modes of glutaraldehyde-fixed bovine pericardial (GLBP) leaflets in bioprosthetic heart valves. In this study, commercial-grade GLBP specimens which were uniaxially cyclically loaded to failure or 1 million cycles, were placed in an in vitro calcification solution. MicroCT and SEM analysis showed that localised calcification levels varied spatially according to damage, where ruptured fibres offered additional calcium binding sites. Furthermore, specimens with a statistically significant lower fatigue life were associated with statistically significant higher calcification. This study revealed that mechanical damage drives calcification of GLBP. Non-destructive pre-screening of collagen fibres demonstrated that both the fatigue life and calcification potential of commercial-grade GLBP, are underpinned by the collagen fibre architecture.

Purpose Repetitive painful stimuli and early exposure to opioids places neonates at risk for neurocognitive delays. We aimed to understand opioid utilization for neonates with gastroschisis. Methods We performed a retrospective review of infants with gastroschisis at a tertiary children's hospital (2017–2019). Multivariate linear regression was performed to analyze variations in opioid use. Results Among 30 patients with gastroschisis, 33% were managed by primary suture-less closure, 7% by primary sutured closure, 40% by spring silo, and 20% by handsewn silo. The proportion of pain medication used was: morphine (89%), acetaminophen (8%), and fentanyl (3%). Opioids were used for a median of 6.5 days (range 0–20) per patient. Median total opioid administered across all patients was 2.2 morphine milligram equivalents (MME)/kg (IQR 0.7–3.3). Following definitive closure, median opioid use was 0.2 MME/kg (IQR 0.1–0.8). With multivariate regression, 45% of the variation in MME use was associated with the type of surgery after adjusting for weight, gestational age, and gender, p = 0.02. After definitive fascial closure, there was no significant variations in opioid use. Conclusion There is a significant variation in the utilization of opioid, primarily prior to fascial closure. Understanding pain needs and standardization may improve opioid stewardship in infants with gastroschisis. 197/200 Level of Evidence Level III

To determine the association between prenatal ultrasound (US) and magnetic resonance imaging (MRI) characteristics in right congenital diaphragmatic hernia (RCDH) with postnatal outcome.CDH Study Group data were reviewed for all RCDH infants (n = 156) born between 2015 and 2019. Prenatal US and MRI lung size measurements were correlated with survival, extracorporeal life support (ECLS), and defect size.Overall survival was 64.1%. ECLS was required in 40.4%. US and MRI-based prenatal assessment of pulmonary hypoplasia does not predict survival. Prenatal measurement of lung size using either US or MRI correlates with ECLS use. Only MRI-based measures of lung size are associated with defect size.Image-based prenatal predictors of survival, ECLS, and defect size are of limited value in RCDH. Extrapolation of prenatal survival and morbidity indicators from left to right-sided CDH is not appropriate. There is an urgent need to develop RCDH prenatal prediction models.

To evaluate the association between prenatal imaging predictors of patients with left-sided congenital diaphragmatic hernia (LCDH) and postnatal outcomes.CDH study group data were reviewed for LCDH infants born 2015-2019. Prenatal ultrasound (US) and magnetic resonance imaging (MRI) data were collected and correlated with postnatal information including CDHSG defect size (A through D or non-repair (NR)).In total, 929 LCDH patients were included. Both US and MRI imaging predictors correlated with postnatal survival (72.2%) and ECLS use (29.6%). Logistic regression models confirmed increased survival and decreased ECLS use with larger values for all predictors. Importantly, all prenatal values evaluated showed no significant difference between defect size D and NR patients.This is the largest cohort of LCDH patients and demonstrates that prenatal imaging factors correlate with postnatal outcomes and confirms that patients in the non-repair group are prenatally similar to type D defects.

There is a known association between Cornelia de Lange syndrome (CdLS) and congenital diaphragmatic hernia (CDH), with CDH being the cause of death in 5%-20% of CdLS cases. We aimed to identify and describe patients with CDLS and CDH. We hypothesized that CdLS would be associated with high-risk CDH and poor outcomes.CDH Study Group patients from 1995 to 2019 were included. Those with CdLS were reviewed retrospectively. Rates of repair and outcomes were compared between patients with and without CdLS.We identified 9,251 CDH patients. Of those, 21 had confirmed CdLS. CdLS patients had a lower birth weight (2.2±0.57 kg) than non-CdLS patients (2.9±0.64 kg) (p0.001). 5-min Apgar scores were lower in CdLS patients (6, 4-7) than non-CdLS patients (7, 5-8) (p=0.014). Only 33% of CdLS patients underwent diaphragmatic repair compared to 84.2% of non-CdLS patients (p0.001). Mortality was 76% for CdLS patients compared with 29% for non-CdLS patients (p0.001). Of the 7 CdLS patients who underwent repair, 5 survived to hospital discharge.Infants with CdLS and CDH have a poor prognosis. However, CdLS patients who undergo repair can survive to discharge; therefore, the concomitant diagnosis of CdLS and CDH is not necessarily a contraindication to repair. Early recognition of these anomalies can assist with counseling and prognostication.Retrospective comparative study LEVEL OF EVIDENCE: III.

X-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease predominantly affecting males.A comprehensive literature review was conducted to determine the prevalence of retinitis pigmentosa GTPase regulatorThe prevalence of XLRP was estimated to be between 2.7-3.5 per 100,000 males in the US, Europe, and Australia. After correction for misclassification, the prevalence increased to 4.0-5.2 per 100,000 males. Finally, the proportion of XLRP cases due toThese findings address an important gap in the understanding of

Purpose To compare identification rates of retinal fluid of the Notal Vision Home Optical Coherence Tomography (OCT) device (NVHO) when used by people with age-related macular degeneration (AMD) to those captured by a commercial OCT. Methods Prospective, cross-sectional study where patients underwent commercial OCT imaging followed by self-imaging with either the NVHO 2.5 or the NVHO 3 in clinic setting. Outcomes included patients’ ability to acquire analyzable OCT images with the NVHO and to compare those with commercial images. Results Successful images were acquired with the NVHO 2.5 in 469/531 eyes (88%) in 264/290 subjects (91%) with the mean (SD) age of 78.8 (8.8); 153 (58%) were female with median visual acuity (VA) of 20/40. In the NVHO 3 cohort, 69 eyes of 45 subjects (93%) completed the self-imaging. Higher rates of successful imaging were found in eyes with VA ≥ 20/320. Positive percent agreement/negative percent agreement for detecting the presence of subretinal and/or intraretinal fluid when reviewing for fluid in three repeated volume scans were 97%/95%, respectively for the NVHO v3. Conclusion Self-testing with the NVHO can produce high quality images suitable for fluid identification by human graders, suggesting the device may be able to complement standard-of-care clinical assessments and treatments.

Background In 2014, a systematic review found large gaps in the quality of reporting of measures used in 86 published trials evaluating the effectiveness of patient decision aids (PtDAs). The purpose of this study was to update that review. Methods We examined measures of decision making used in 49 randomized controlled trials included in the 2014 and 2017 Cochrane Collaboration systematic review of PtDAs. Data on development of the measures, reliability, validity, responsiveness, precision, interpretability, feasibility, and acceptability were independently abstracted by 2 paired reviewers. Results Information from 273 measures was abstracted, and 109 of these covered the core domains of decision processes ( n = 55) and decision quality including informed choice/knowledge ( n = 48) and values-choice concordance ( n = 12). Very few studies reported data on the performance and clinical sensibility of measures, with reliability (23%) and validity (6%) being the most common. Studies using new measures were less likely to include information about their psychometric performance compared with previously published measures. Limitations The review was limited to reporting of measures in studies included in the Cochrane review and did not consult prior publications. Conclusion There continues to be very little reported about the development or performance of measures used to evaluate the effectiveness of PtDAs in published trials. Minimum reporting standards have been published, and efforts to require investigators to use them are needed.

Objective Suicide is a serious public health concern, but little is known about the relationship between access to mental health care and suicide deaths, and whether suicide rates differ by mental health provider Health Professional Shortage Areas (HPSAs). This study investigated the associations between mental health HPSAs and suicide rates. Method We used generalized linear mixed models to test the associations between HPSAs and suicide rates from 2010 to 2018. For each county during a 3-year period, the total number of suicides was obtained from Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research (WONDER). Results Mental health HPSAs had higher suicide rates (adjusted incidence rate ratio (IRR), 1.06 [95% CI, 1.03–1.09]). The interaction terms of mental health HPSAs and time (adjusted IRR, 1.01 [95% CI, 1.00–1.01]) showed that the association between mental health shortage areas and suicide rates has increased over time. Conclusions Suicide rates are more common in mental health provider shortage areas, and this association has been growing over time. The study's findings suggest that many communities in the US are likely facing simultaneous challenges of limited access to mental health care, social and economic disadvantage, and high burden of suicide.

Treatment resistance (TR) in patients with first-episode psychosis (FEP) is a major cause of disability and functional impairment, yet mechanisms underlying this severe disorder are poorly understood. As one view is that TR has neurodevelopmental roots, we investigated whether its emergence relates to disruptions in synchronized cortical maturation quantified using gyrification-based connectomes. Seventy patients with FEP evaluated at their first presentation to psychiatric services were followed up using clinical records for 4 years; of these, 17 (24.3%) met the definition of TR and 53 (75.7%) remained non-TR at 4 years. Structural MRI images were obtained within 5 weeks from first exposure to antipsychotics. Local gyrification indices were computed for 148 contiguous cortical regions using FreeSurfer; each subject’s contribution to group-based structural covariance was quantified using a jack-knife procedure, providing a single deviation matrix for each subject. The latter was used to derive topological properties that were compared between TR and non-TR patients using a Functional Data Analysis approach. Compared to the non-TR patients, TR patients showed a significant reduction in small-worldness (Hedges’s g = 2.09, P < .001) and a reduced clustering coefficient (Hedges’s g = 1.07, P < .001) with increased length (Hedges’s g = −2.17, P < .001), indicating a disruption in the organizing principles of cortical folding. The positive symptom burden was higher in patients with more pronounced small-worldness (r = .41, P = .001) across the entire sample. The trajectory of synchronized cortical development inferred from baseline MRI-based structural covariance highlights the possibility of identifying patients at high-risk of TR prospectively, based on individualized gyrification-based connectomes.

Small cell lung cancer (SCLC) is a leading cause of cancer death worldwide, with few treatment options. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate that targets delta-like 3 on SCLC cells to deliver a cytotoxic payload directly to tumor cells. In this study, the cardiac safety profile of Rova-T was assessed by evaluating changes in QT interval, electrocardiogram (ECG) waveform, heart rate, and proarrhythmic adverse events (AEs) after treatment with Rova-T in patients with previously treated extensive-stage SCLC. Patients underwent ECG monitoring for 2 weeks after each of 2 i.v. infusions of 0.3 mg/kg Rova-T over 30 minutes, administered 6 weeks apart. Forty-six patients received at least one dose of Rova-T. At the geometric mean Rova-T maximum serum concentration of 7,940 ng/mL, ECG monitoring showed no significant changes in the Fridericia-corrected QT (QTcF) interval; the upper limit of the 2-sided 90% confidence interval did not exceed 10 msec for any time point. There were no clinically significant changes in QRS or PR intervals, ECG waveforms, or heart rate after Rova-T administration. All patients experienced a treatment-emergent AE (TEAE); 78% had a grade ≥ 3 TEAE, 59% had a serious TEAE, and 41% had a cardiac-related TEAE. The TEAEs that might signal proarrhythmia tendencies were uncommon. Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova-T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.

PURPOSE: As part of a larger effort to integrate palliative care into a cancer center, we identified barriers to palliative care referral for patients with breast or gynecologic cancer and developed a pilot program to improve access to palliative care services. METHODS: We developed a multidisciplinary steering committee to uncover barriers to palliative care referral and developed a pilot program, called the Warm Handoff. Through ongoing collaboration and midpilot feedback sessions, we identified several additional barriers and opportunities to increase access to palliative care. RESULTS: Clinicians used the initial Warm Handoff process only 20 times over a period of 7 months. Of those calls, 10 were for issues outside of those that the Warm Handoff pilot was intended to address. During the pilot, we identified lack of access to urgent visits and clinician telephone availability for clinical case discussion as additional barriers to access. Increased collaboration led to the creation of a clinical provider of the day (CPOD) care model, which allowed for a notable increase in the capacity to see urgent consults. After this intervention, we observed an average of 19 patients seen urgently per month. In addition, there was a trend toward increasing referrals from breast oncology after the initiation of the CPOD. CONCLUSION: A CPOD model, developed via close oncology/palliative care collaboration, resulted in increased utilization of palliative care services.

OBJECTIVES: Habit formation has been identified as one of the key determinants of behaviour change. To initiate habit formation, self-regulation interventions can support individuals to form a cue-behaviour plan and to repeatedly enact the plan in the same context. This randomized controlled trial aimed to model habit formation of an everyday nutrition behaviour and examined whether habit formation and plan enactment differ when individuals plan to enact their behaviour in response to a routine-based versus time-based cue. DESIGN: Following a baseline assessment, N = 192 adults (aged 18-77 years) were randomly assigned to a routine-based cue or a time-based cue planning intervention, in which they selected an everyday nutrition behaviour and linked it to a daily routine or a time cue. METHODS: Participants responded to daily questionnaires over 84 days assessing plan enactment and the behaviour's automaticity (as an indicator of habit formation). Multilevel models with days nested in participants were fitted. RESULTS: As indicated by asymptotic curves, it took a median of 59 days for participants who successfully formed habits to reach peak automaticity. Group-level analyses revealed that both routine-based and time-based cue planning led to increases in automaticity and plan enactment, but no between-condition differences were found. Repeated plan enactment was a key predictor for automaticity. CONCLUSIONS: Linking one's nutrition behaviour to a daily routine or a specific time was similarly effective for habit formation. Interventions should encourage persons to repeatedly carry out their planned behaviour in response to the planned cue to facilitate habit formation.

Introduction: Amyotrophic lateral sclerosis (ALS) is a rare neurological disorder characterized by progressive deterioration of motor neurons. Assessment of the size/geographic distribution of the ALS population, including ALS with genetic origin, is needed to understand the burden of the disease and the need for clinical intervention and therapy. Objectives: The main objective of this study was to estimate the number of prevalent and incident ALS cases overall and superoxide dismutase 1 (SOD1) and chromosome 9 open reading frame 72 (C9orf72) ALS in 22 countries across Europe (Belgium, France, Germany, Ireland, Italy, Netherlands, Norway, Russia, Spain, Sweden, and UK), North America (USA and Canada), Latin America (Argentina, Brazil, Colombia, Mexico, and Uruguay), and Asia (China, Japan, South Korea, and Taiwan). Methods: A comprehensive literature search was conducted to identify population-based studies reporting ALS prevalence and/or incidence rates. Pooled prevalence and incidence rates were obtained using a meta-analysis approach at the country and regional geographic level. A country-level pooled estimate was used when ≥2 studies were available per country and geographic regional pooled estimates were used otherwise. The proportion of cases with a SOD1 or C9orf72 mutation among sporadic (sALS) and familial (fALS) cases were obtained from a previous systematic review and meta-analysis. Results: Pooled prevalence rates (per 100,000 persons) and incidence rates (per 100,000 person-years) were 6.22 and 2.31 for Europe, 5.20 and 2.35 for North America, 3.41 and 1.25 for Latin America, 3.01 and 0.93 for Asian countries excluding Japan, and 7.96 and 1.76 for Japan, respectively. Significant heterogeneity in reported incidence and prevalence was observed within and between countries/geographic regions. The estimated number of 2020 ALS cases across the 22 countries is 121,028 prevalent and 41,128 incident cases. The total estimated number of prevalent SOD1 cases is 2,876 cases, of which, 1,342 (47%) were fALS and 1,534 (53%) were sALS, and the number of incident SOD1 cases is 946 (434 [46%] fALS and 512 [54%] sALS). The total estimated number of prevalent C9orf72 cases is 4,545 (1,198 [26%] fALS, 3,347 [74%] sALS), and the number of incident C9orf72 cases is 1,706 (450 [26%] fALS and 1,256 [74%] sALS). Discussion: The estimated number of patients with SOD1 and C9orf72 ALS suggests that although the proportions of SOD1 and C9orf72 are higher among those with fALS, the majority of SOD1 and C9orf72 ALS cases may be found among those with sALS (about 53 and 74%, respectively). These results suggest that classification of fALS based on reported family history does not capture the full picture of ALS of genetic origin.

Purpose To explore clinical features and outcomes of ocular surface squamous neoplasia (OSSN) treated with primary interferon (IFN)-α2b, based on patient cigarette smoking status. Methods Retrospective nonrandomized, interventional cohort study on 212 consecutive tumors in 194 patients, all of whom were treated with topical and/or injection IFNα2b. Results There were 88 tumors in 76 patients with current or past smoking history (smokers) and 124 tumors in 118 nonsmoking patients (nonsmokers). A comparison (smokers vs. nonsmokers) revealed smokers with more frequent bilateral disease (16% vs. 3%, P = 0.003), more frequent involvement of inferior forniceal (34% vs. 21%, P = 0.03) and inferior tarsal conjunctiva (38% vs. 24%, P = 0.04), greater mean number of clock hour involvement (4.1 vs. 3.5 clock hours, P = 0.04), and greater dome growth pattern (30% vs. 15%, P = 0.01). There was no difference regarding method of IFNα2b administration as topical (61% vs. 71%, P = 0.14), injection (10% vs. 6%, P = 0.32), or combination topical/injection (28% vs. 23%, P = 0.33). A comparison revealed smokers with more frequent recurrence after initial response (23% vs. 13%, P = 0.04). There was no difference regarding initial tumor response or time to response, treatment side effects, or systemic outcomes. Conclusions Regarding ocular surface squamous neoplasia, smokers more often display bilateral, dome-shaped tumors with inferior forniceal or tarsal involvement, and greater extent than nonsmokers. After treatment with topical and/or injection IFNα2b, control is equivalent, but smokers show greater recurrence.

Online systems that allow employees to pre-order their lunch may help reduce energy intake. We investigated the acceptability of a pre-ordering website for a workplace canteen that prompts customers to swap to lower-energy swaps and the factors influencing swap acceptance. Employees (n = 30) placed a hypothetical lunch order through a pre-ordering website designed for their canteen while thinking aloud. Semi-structured interview questions supported data collection. Data were analysed using thematic analysis. Acceptability was generally high, but potentially context dependent. Practical considerations, such as reminders to pre-order, user-friendliness, provision of images of menu items and energy information while browsing, an ability to reserve pre-ordered meals, and a swift collection service facilitated acceptability. The restrictive timeframe within which orders could be placed, a lack of opportunity to see foods before ordering, and prompts to swap being perceived as threatening autonomy were barriers to acceptability. Swap acceptance was facilitated by the provision of physical activity calorie equivalents (PACE) information, and swap similarity in terms of taste, texture, and expected satiety as well as the perception that alternatives provided meaningful energy savings. Online canteen pre-ordering systems that prompt lower-energy swaps may be an acceptable approach to help reduce energy intake in the workplace.