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Abstract Background Childhood cancer survivors face high risks of adverse late health effects. Long‐term follow‐up care for childhood cancer survivors is crucial to improve their health and quality of life. However, implementation remains a challenge. To support implementation of high‐quality long‐term follow‐up care, we explored expected barriers and facilitators for establishing this follow‐up care among healthcare providers from four European clinics. Methods A qualitative study was conducted using four focus groups comprising 30 healthcare providers in total. The semi‐structured interview guide was developed based on the Grol and Wensing framework. Data was analyzed following a thematic analysis, combining both inductive and deductive approaches to identify barriers and facilitators across the six levels of Grol and Wensing: innovation, professional, patient, social, organizational and economic and political. Results Most barriers were identified on the organizational level, including insufficient staff, time, capacity and psychosocial support. Other main barriers included limited knowledge of late effects among healthcare providers outside the long‐term follow‐up care team, inability of some survivors to complete the survivor questionnaire and financial resources. Main facilitators included motivated healthcare providers and survivors, a skilled hospital team, collaborations with important stakeholders like general practitioners, and psychosocial care facilities, utilization of the international collaboration and reporting long‐term follow‐up care results to convince hospital managers. Conclusion This study identified several factors for successful implementation of long‐term follow‐up care for childhood cancer survivors. Our findings showed that specific attention should be given to knowledge, capacity, and financial issues, along with addressing psychosocial issues of survivors.

Abstract Background Healthy behaviors are paramount in preventing long‐term adverse health outcomes in childhood, adolescent, and young adult (CAYA) cancer survivors. We systematically reviewed and synthesized existing literature on barriers, facilitators, and other factors associated with health behaviors in this population. Methods MEDLINE and PsycInfo were searched for qualitative and quantitative studies including survivors aged 16–50 years at study, a cancer diagnosis ≤25 years and ≥2 years post diagnosis. Health behaviors included physical activity, smoking, diet, alcohol consumption, sun exposure, and a combination of these behaviors (defined as health behaviors in general). Results Barriers, facilitators, and other factors reported in ≥2 two studies were considered relevant. Out of 4529 studies, 27 were included (n = 31,905 participants). Physical activity was the most frequently examined behavior (n = 12 studies), followed by smoking (n = 7), diet (n = 7), alcohol (n = 4), sun exposure (n = 4), and health behavior in general (n = 4). Relevant barriers to physical activity were fatigue, lack of motivation, time constraints, and current smoking. Relevant facilitators were perceived health benefits and motivation. Influence of the social environment and poor mental health were associated with more smoking, while increased energy was associated with less smoking. No relevant barriers and facilitators were identified for diet, alcohol consumption, and sun exposure. Barriers to healthy behavior in general were unmet information needs and time constraints whereas lifestyle advice, information, and discussions with a healthcare professional facilitated healthy behavior in general. Concerning other factors, women were more likely to be physically inactive, but less likely to drink alcohol and more likely to comply with sun protection recommendations than men. Higher education was associated with more physical activity, and lower education with more smoking. Conclusion This knowledge can be used as a starting point to develop health behavior interventions, inform lifestyle coaches, and increase awareness among healthcare providers regarding which survivors are most at risk of unhealthy behaviors.

Abstract Two ∼2‐week Ultra‐Fast Kelvin Wave (UFKW) events centered on days 158(203) during 2021 are investigated using winds, temperatures, plasma drifts and electron densities (Ne) measured by the Ionospheric CONnections (ICON) mission. Eastward‐propagating longitudinal wave‐1 (s = −1) structures with periods 2.5–4.0d, thought to mainly reflect Ultra‐Fast Kelvin waves (UFKWs), reveal ±45 ms−1 zonal winds (U) at 100 km for both events. Height‐latitude structures of the 3.0(3.5)d‐period UFKWs are obtained for the first time for both temperature (T, 94–120 km) and U (94–280 km) between 12°S and 39°N latitude. Maximum values of 36(29) ms−1 for U and 12(15)K for T occur at 102(106) km altitude and within ±3° latitude. The U‐T peak height displacement remains unexplained. Vertical wavelengths are in the range 36–43 km for both U and T during both events. Concurrent with the E‐region dynamo winds, topside (580 km) F‐region field‐aligned (±20–40 ms−1), meridional (±5–10 ms−1) and vertical (±5–10 ms−1) drift and Ne (±20–40%) 2.5–4.0d s = −1 variations are also measured. These key elements of atmosphere‐ionosphere (A‐I) coupling, contemporaneously measured for the first time, are relevant to testing the internal consistency of A‐I models. The mean wind propagation environment of the UFKWs is also quantified, showing no appreciable effects on the UFKW structures, consistent with modeling and theory.

Abstract First results are presented from the conjugate maneuvers performed by NASA's Ionospheric Connection Explorer (ICON) spacecraft. During each several‐minute maneuver, ICON crosses the magnetic equator, measuring the plasma drift at the ∼600‐km apex of a magnetic field line and the neutral wind profiles (∼90–300 km altitude) along both ends of that field line. The analysis utilizes 149 pairs of maneuvers separated by ∼24 hr but at nearly the same location and local time. Principal component regression reveals that 39 ± 7% and 24 ± 9% of the day‐to‐day variance in the daytime vertical and zonal drift, respectively, is attributable to conjugate neutral winds. The remaining variance is likely driven by external potentials from non‐conjugate winds and geomagnetic activity (median Kp 2−). Zonal winds at 100–113 km and >120 km altitude are the primary drivers of conjugate vertical and zonal drift variance, respectively. These observations can test vertical‐coupling mechanisms in whole‐atmosphere models.

Abstract Relocating levees further back from river channels to increase river–floodplain connection can reduce flood stages and provide a host of co‐benefits. Modeling case studies show the significant potential of large levee setbacks for reducing flood stages; however, the difficulty of comparing between these case studies limits our understanding of how the hydraulic effects of setbacks vary in different settings. We filled this research gap by systematically modeling the hydraulic effects of setbacks across a range of river and flood conditions. We used unsteady, 1D Hydrologic Engineering Center‐River Analysis System models to quantify changes in flood stage, channel velocity, and sediment transport capacity for various setback sizes with different river slopes, widths, floodplain roughness, and flood sizes (peak flows) and durations. Setbacks reduce flood stages within the setback, as well as up‐ and downstream. Channel velocity and sediment transport capacity both increased upstream and decreased within the setback. Channel slope, flood size, and flood duration had the largest influence on hydraulic changes. There are diminishing returns in hydraulic effects with increasing setback size. These results can help guide the design and prioritization of levee setback projects and help set reasonable expectations for the scale of changes to flood hydraulics relative to the size of the reconnected floodplain.

Abstract The role of NRF2 in kidney biology has received considerable interest over the past decade. NRF2 transcriptionally controls genes responsible for cellular protection against oxidative and electrophilic stress and has anti‐inflammatory functions. NRF2 is expressed throughout the kidney and plays a role in salt and water handling. In disease, animal studies show that NRF2 protects against tubulointerstitial damage and reduces interstitial fibrosis and tubular atrophy, and may slow progression of polycystic kidney disease. However, the role of NRF2 in proteinuric glomerular diseases is controversial. Although the NRF2 inducer, bardoxolone methyl (CDDO‐Me), increases glomerular filtration rate in humans, it has not been shown to slow disease progression in diabetic kidney disease and Alport syndrome. Furthermore, bardoxolone methyl was associated with negative effects on fluid retention, proteinuria, and blood pressure. Several animal studies replicate findings of worsened proteinuria and a more rapid progression of kidney disease, although considerable controversy exists. It is clear that further study is needed to better understand the effects of NRF2 in the kidney. This review summarizes the available data to clarify the promise and risks associated with targeting NRF2 activity in the kidney.

Liver cancer is the fourth most common cause of cancer‐related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTK) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTK can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTK, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTK upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co‐inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well‐tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.

Abstract Background The predictive value of left ventricular (LV) global longitudinal strain (GLS) to predict outcomes in different left ventricular ejection fraction (LVEF) cohorts is not well known. We aimed to assess the role of LV GLS predicting outcomes in HF patients by LVEF. Methods In the Multicenter Automatic Defibrillator Implantation Trial Cardiac Resynchronization Therapy (MADIT‐CRT), we studied 1077 patients (59%) with 2D speckle tracking data available, 437 patients with LVEF > 30% and 640 with LVEF ≤ 30%. Baseline LV GLS was stratified in tertiles in both LVEF subgroups. The primary endpoint was ventricular tachycardia/fibrillation (VT/VF) or death; the secondary endpoint was heart failure (HF) or death. Results In patients with LVEF ≤ 30%, a higher tertile GLS (T3, less contractility) was associated with a higher rate of VT/VF/death (P 30% (P = 0.057). In patients with LVEF ≤ 30%, a higher tertile GLS was also associated with a higher rate of HF/death. In multivariable models, LV GLS predicted VT/VF or death in the LVEF ≤ 30% subgroup [T1 vs. T2/3 HR = 1.67 (1.16–2.38), P = 0.005], but not in those with LVEF > 30% [T1 vs. T2.3 HR = 1.32 (0.86–2.04), P = 0.21]. LV GLS predicted HF/death in the LVEF ≤ 30% subgroup [T1 vs T2/3 HR = 2.00 (1.30–3.13), P = 0.002], but not in in those with LVEF > 30%. Conclusions In this MADIT‐CRT sub‐study, LV GLS identified patients at higher risk of VT/VF, HF/death risk independently of conventional clinical parameters in patients with LVEF ≤ 30%, but not in patients with LVEF > 30%.

As of 2020, maternal and infant health in the US has worsened. At the same time, the number of health professionals available to manage female health issues is changing; the number of physicians in obstetrics and gynecology (Ob-Gyn) and midwives is decreasing, whereas the number of Ob-Gyn physician associates (PAs) is growing. We analyzed PAs practicing in the Ob-Gyn discipline, drawing on the PA Professional Profile, a database maintained by the National Commission on Certification of PAs. In 2021, there were 1,322 Ob-Gyn PAs (1.2% of all clinically active PAs). This health profession has grown by 66.9% since 2013, when only 792 PAs practiced in this specialty. As of 2021, their median age was 38, and 98.0% were female (70.1% of all PAs were female). The practice setting was between office (54.7%) and hospital (34.0%) employment, with 11.3% described as “other.” In 2021, the median annual income of Ob-Gyn PAs was $105,000. With the reduction of obstetrician-gynecologists, the relative growth of PAs in this area of medicine and surgery is a natural part of the solution to the projected obstetrical physician deficit.

Abstract Background Childhood cancer survivors (CCSs) have an increased risk of developing chronic health conditions. Evidence suggests that poor health behaviors further increase health risks. Healthcare professionals (HCPs) involved in survivorship care have a key role in providing health behavior support (HBS) but can feel limited in their ability to do so. This study aims to explore European HCPs perceived facilitators and barriers to providing HBS to CCSs. Methods Five focus groups with 30 HCPs from survivorship care clinics across Europe were conducted. Topic guides were informed by the Theoretical Domains Framework (TDF) to capture domains that may influence provision of HBS. Focus groups were analyzed with thematic analysis. Transcripts were inductively coded, after which axial coding was applied to organize codes into categories. Finally, categories were mapped onto the TDF domains. Results Nine TDF domains were identified in the data. The most commonly reported TDF domains were “Knowledge”, “Skills”, and “Environmental context and resources”. HCPs indicated that their lack of knowledge of the association between late effects and health behaviors, besides time restrictions, were barriers to HBS. Facilitators for HBS included possession of skills needed to pass on health behavior information, good clinic organization, and an established network of HCPs. Conclusions This study identified education and training of HCPs as key opportunities to improve HBS. Survivorship care clinics should work towards establishing well‐integrated structured care with internal and external networks including HBS being part of routine care. Proper understanding of facilitators and barriers should lead to better survivorship care for CCSs.

Abstract Background The use of a Left Ventricular Assist Device (LVAD) in patients with advanced heart failure refractory to optimal medical management has progressed steadily over the past two decades. Data have demonstrated reduced LVAD efficacy, worse clinical outcome, and higher mortality for patients who experience significant ventricular tachyarrhythmia (VTA). We hypothesize that a novel prophylactic intra‐operative VTA ablation protocol at the time of LVAD implantation may reduce the recurrent VTA and adverse events postimplant. Methods We designed a prospective, multicenter, open‐label, randomized‐controlled clinical trial enrolling 100 patients who are LVAD candidates with a history of VTA in the previous 5 years. Enrolled patients will be randomized in a 1:1 fashion to intra‐operative VTA ablation (n = 50) versus conventional medical management (n = 50) with LVAD implant. Arrhythmia outcomes data will be captured by an implantable cardioverter defibrillator (ICD) to monitor VTA events, with a uniform ICD programming protocol. Patients will be followed prospectively over a mean of 18 months (with a minimum of 9 months) after LVAD implantation to evaluate recurrent VTA, adverse events, and procedural outcomes. Secondary endpoints include right heart function/hemodynamics, healthcare utilization, and quality of life. Conclusion The primary aim of this first‐ever randomized trial is to assess the efficacy of intra‐operative ablation during LVAD surgery in reducing VTA recurrence and improving clinical outcomes for patients with a history of VTA.

Abstract Miscanthus, a C4 perennial rhizomatous grass, is capable of growing in varied climates and soil types in Europe, including on marginal lands. It can produce high yields with low nutrient inputs when harvested after complete senescence. Senescence induction and rate depend on complex genetic, environmental, and management interactions. To explore these interactions, we analysed four miscanthus hybrids (two novel seed‐based hybrids, GRC 3 [Miscanthus sinensis × sinensis] and GRC 14 [M. sacchariflorus × sinensis]; GRC 15, a novel M. sacchariflorus × sinensis clone; and GRC 9, a standard Miscanthus × giganteus clone) in Italy, Croatia, Germany and the UK. Over all trial locations and hybrids, the average aboveground biomass of the 3‐year‐old stands in August 2020 was 15 t DM ha−1 with nutrient contents of 7.6 mg N g−1 and 14.6 mg K g−1. As expected, delaying the harvest until spring reduced overall yield and nutrient contents (12 t DM ha−1, 3.3 mg N g−1, and 5.5 mg K g−1). At lower latitudes, the late‐ripening M. sacchariflorus × sinensis GRC 14 and GRC 15 combined high yields with low nutrient contents. At the most elevated latitude location (UK), the early‐ripening M. sinensis × sinensis combined high biomass yields with low nutrient offtakes. The clonal Miscanthus × giganteus with intermediate flowering and senescence attained similar low nutrient contents by spring harvest at all four locations. Seasonal changes in yield and nutrient levels analysed in this study provide: (1) a first step towards recommending hybrids for specific locations and end uses in Europe; (2) crucial data for determination of harvest time and practical steps in the valorization of biomass; and (3) key sustainability data for life cycle assessments. Identification of trade‐offs resulting from genetic × environment × management interactions is critical for increasing sustainable biomass supply from miscanthus grown on marginal lands.

Abstract Urbanization is decreasing wildlife habitat and connectivity worldwide, including for apex predators, such as the puma (Puma concolor). Puma populations along California's central and southern coastal habitats have experienced rapid fragmentation from development, leading to calls for demographic and genetic management. To address urgent conservation genomic concerns, we used double‐digest restriction‐site associated DNA (ddRAD) sequencing to analyze 16,285 genome‐wide single‐nucleotide polymorphisms (SNPs) from 401 pumas sampled broadly across the state. Our analyses indicated support for 4–10 geographically nested, broad‐ to fine‐scale genetic clusters. At the broadest scale, the four genetic clusters had high genetic diversity and exhibited low linkage disequilibrium, indicating that pumas have retained genomic diversity statewide. However, multiple lines of evidence indicated substructure, including 10 finer‐scale genetic clusters, some of which exhibited fixed alleles and linkage disequilibrium. Fragmented populations along the Southern Coast and Central Coast had particularly low genetic diversity and strong linkage disequilibrium, indicating genetic drift and close inbreeding. Our results demonstrate that genetically at risk populations are typically nested within a broader‐scale group of interconnected populations that collectively retain high genetic diversity and heterogenous fixations. Thus, extant variation at the broader scale has potential to restore diversity to local populations if management actions can enhance vital gene flow and recombine locally sequestered genetic diversity. These state‐ and genome‐wide results are critically important for science‐based conservation and management practices. Our nested population genomic analysis highlights the information that can be gained from population genomic studies aiming to provide guidance for the conservation of fragmented populations.

Abstract Context Robot‐assisted radical prostatectomy (RARP) has become the standard surgical procedure for localized prostate‐cancer (PCa). Nerve‐sparing surgery (NSS) during RARP has been associated with improved erectile function and continence rates after surgery. However, it remains unclear what are the most appropriate indications for NSS. Objective The objective of this study is to systematically review the available parameters for selection of patients for NSS. The weight of different clinical variables, multiparametric magnetic‐resonance‐imaging (mpMRI) findings, and the impact of multiparametric‐nomograms in the decision‐making process on (side‐specific) NSS were assessed. Evidence acquisition This systematic review searched relevant databases and included studies performed from January 2000 until December 2020 and recruited a total of 15 840 PCa patients. Studies were assessed that defined criteria for (side‐specific) NSS and associated them with oncological safety and/or functional outcomes. Risk of bias assessment was performed. Evidence synthesis Nineteen articles were eligible for full‐text review. NSS is primarily recommended in men with adequate erectile function, and with low‐risk of extracapsular extension (ECE) on the side‐of NSS. Separate clinical and radiological variables have low accuracy for predicting ECE, whereas nomograms optimize the risk‐stratification and decision‐making process to perform or to refrain from NSS when oncological safety (organ‐confined disease, PSM rates) and functional outcomes (erectile function and continence rates) were assessed. Conclusions Consensus exists that patients who are at high risk of ECE should refrain from NSS. Several multiparametric preoperative nomograms were developed to predict ECE with increased accuracy compared with single clinical, pathological, or radiological variables, but controversy exists on risk thresholds and decision rules on a conservative versus a less‐conservative surgical approach. An individual clinical judgment on the possibilities of NSS set against the risks of ECE is warranted. Patient summary NSS is aimed at sparing the nerves responsible for erection. NSS may lead to unfavorable tumor control if the risk of capsule penetration is high. Nomograms predicting extraprostatic tumor‐growth are probably most helpful.

Background Integrin α7β1 is a major laminin receptor in skeletal and cardiac muscle. In skeletal muscle, integrin α7β1 plays an important role during muscle development and has been described as an important modifier of skeletal muscle diseases. The integrin α7β1 is also highly expressed in the heart, but its precise role in cardiac function is unknown. Mutations in the integrin α7 gene (ITGA7) have been reported in children with congenital myopathy. Methods and Results In this study, we described skeletal and cardiac muscle pathology in Itga7−/− mice and 5 patients from 2 unrelated families with ITGA7 mutations. Proband in family 1 presented a homozygous c.806_818del [p.S269fs] variant, and proband in family 2 was identified with 2 intron variants in the ITGA7 gene. The complete absence of the integrin α7 protein in muscle supports the ITGA7 mutations are pathogenic. We performed electrocardiography, echocardiography, or cardiac magnetic resonance imaging, and histological biopsy analyses in patients with ITGA7 deficiency and Itga7−/− mice. The patients exhibited cardiac dysrhythmia and dysfunction from the third decade of life and late‐onset respiratory insufficiency, but with relatively mild limb muscle involvement. Mice demonstrated corresponding abnormalities in cardiac conduction and contraction as well as diaphragm muscle fibrosis. Conclusions Our data suggest that loss of integrin α7 causes a novel form of adult‐onset cardiac dysfunction indicating a critical role for the integrin α7β1 in normal cardiac function and highlights the need for long‐term cardiac monitoring in patients with ITGA7‐related congenital myopathy.

Abstract Background Docetaxel (D) or secondary hormonal therapy (SHT) each combined with androgen deprivation therapy (ADT) represent possible treatment options in males with metastasized hormone‐sensitive prostate cancer (mHSPC). Real‐world data comparing different protocols are lacking yet. Thus, our objective was to compare the efficacy and safety of abiraterone acetate (AA)+ADT versus D+ADT in mHSPC. Methods In a retrospective multicenter analysis including males with mHSPC treated with either of the aforementioned protocols, overall survival (OS), progression‐free survival 1 (PFS1), and progression‐free survival 2 (PFS2) were assessed for both cohorts. Median time to event was tested by Kaplan–Meier method and log‐rank test. The Cox‐proportional hazards model was used for univariate and multivariate regression analyses. Results Overall, 196 patients were included. The AA+ADT cohort had a longer PFS1 in the log‐rank testing (23 vs. 13 mos., p

Abstract Integration of orthogonal data could provide new opportunities to pinpoint the underlying molecular mechanisms of hematologic disorders. Using a novel gene network approach, we integrated DNA methylation data from The Cancer Genome Atlas (n = 194 cases) with the corresponding gene expression profile. Our integrated gene network analysis classified AML patients into low‐, intermediate‐, and high‐risk groups. The identified high‐risk group had significantly shorter overall survival compared to the low‐risk group (p‐value ≤10−11). Specifically, our approach identified a particular subgroup of nine high‐risk AML cases that died within 2 years after diagnosis. These high‐risk cases otherwise would be incorrectly classified as intermediate‐risk solely based on cytogenetics, mutation profiles, and common molecular characteristics of AML. We confirmed the prognostic value of our integrative gene network approach using two independent datasets, as well as through comparison with European LeukemiaNet and LSC17 criteria. Our approach could be useful in the prognostication of a subset of borderline AML cases. These cases would not be classified into appropriate risk groups by other approaches that use gene expression, but not DNA methylation data. Our findings highlight the significance of epigenomic data, and they indicate integrating DNA methylation data with gene coexpression networks can have a synergistic effect.

Abstract Aims The implantable cardiac defibrillator/cardiac resynchronization therapy with defibrillator‐based HeartLogic™ algorithm has recently been developed for early detection of impending decompensation in heart failure (HF) patients; but whether this novel algorithm can reduce HF hospitalizations has not been evaluated. We investigated if activation of the HeartLogic algorithm reduces the number of hospital admissions for decompensated HF in a 1 year post‐activation period as compared with a 1 year pre‐activation period. Methods and results Heart failure patients with an implantable cardiac defibrillator/cardiac resynchronization therapy with defibrillator with the ability to activate HeartLogic and willingness to have remote device monitoring were included in this multicentre non‐blinded single‐arm trial with historical comparison. After a HeartLogic alert, the presence of HF symptoms and signs was evaluated. If there were two or more symptoms and signs apart from the HeartLogic alert, lifestyle advices were given and/or medication was adjusted. After activation of the algorithm, patients were followed for 1 year. HF events occurring in the 1 year prior to activation and in the 1 year after activation were compared. Of the 74 eligible patients (67.2 ± 10.3 years, 84% male), 68 patients completed the 1 year follow‐up period. The total number of HF hospitalizations reduced from 27 in the pre‐activation period to 7 in the post‐activation period (P = 0.003). The number of patients hospitalized for HF declined from 21 to 7 (P = 0.005), and the hospitalization length of stay diminished from average 16 to 7 days (P = 0.079). Subgroup analysis showed similar results (P = 0.888) for patients receiving cardiac resynchronization therapy during the pre‐activation period or not receiving cardiac resynchronization therapy, meaning that the effect of hospitalizations cannot solely be attributed to reverse remodelling. Subanalysis of a single‐centre Belgian subpopulation showed important reductions in overall health economic costs (P = 0.025). Conclusion Activation of the HeartLogic algorithm enables remote monitoring of HF patients, coincides with a significant reduction in hospitalizations for decompensated HF, and results in health economic benefits.

Abstract Background Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by inherited defects in the ATP7B gene and results in toxic accumulation of copper in various organs. We previously reported a family with three consecutive generations affected by WD that carries the variant, p.P1379S, which was classified at the time as likely pathogenic. However, recent investigations of the p.P1379S variant indicate a possible conflict of interpretations regarding its pathogenicity. This led us to explore the quantification of ATP7B in dried blood spots (DBS) using a surrogate peptide to study the effects of the p.P1379S variant on ATP7B concentrations in two unrelated families with the common p.P1379S variant. Methods and results ATP7B was quantified using the peptide immunoaffinity enrichment coupled with selected reaction monitoring mass spectrometry (immuno‐SRM) method which utilizes antibody‐mediated peptide capture from DBS. Two patients affected with WD had undetectable ATP7B level while four compound heterozygous children with one known pathogenic variant and the p.P1379S had significantly reduced ATP7B levels. Of note, all four children remain asymptomatic without abnormal laboratory consequences despite being untreated for WD. Conclusion These two families demonstrated that p.P1379S, when compounded with two known pathogenic variants, resulted in significantly reduced protein levels but retained enough function to maintain normal copper homeostasis. This implies that p.P1379S is benign in nature. A better understanding of the nature and consequences of variants in WD will help in informing patient care and avoiding unnecessary treatments.

Abstract Background Cancer cachexia is a condition often seen at diagnosis, throughout anti‐cancer treatments and in end‐stage non‐small‐cell lung cancer patients. Methods and results Participants with late‐stage non‐small‐cell lung cancer and cachexia (defined as ≥5% weight loss within 12 months) were randomly assigned 1:2 to 2.09 g of eicosapentaenoic acid (EPA) and 300 mg of cyclo‐oxygenase‐2 inhibitor celecoxib orally once daily vs. same dosing of EPA, celecoxib, plus two sessions per week of progressive resistance training and 20 g of oral essential amino acids high in leucine in a split dose over 3 days, after each session. Primary endpoint was the acceptability of the earlier multi‐targeted approach. Main secondary endpoints included change in body weight and fat‐free mass, by bioelectric impedance analysis and total quadriceps muscle volume by magnetic resonance imaging over 20 weeks. Sixty‐nine patients were screened resulting in 20 patients being enrolled. Acceptability scored high, with 4.5/5 (Arm A) and 5/5 (Arm B) for EPA and 5/5 for celecoxib within both arms and 4.8/5 for progressive resistance training sessions and 4.5/5 for essential amino acids within Arm B, all at Week 20. Results showed a net gain in bioelectric impedance analysis fat‐free mass of +1.3 kg, n = 2 (Arm A), compared with +0.7 kg, n = 7 (Arm B) at Week 12, and —1.5 kg, n = 2 (Arm A), compared with —1.7 kg, n = 4 (Arm B) at Week 20. Trends in efficacy in terms of improvement and/or stability in cachexia markers were seen within magnetic resonance imaging muscle volume, albumin, and C‐reactive protein levels within both arms. There were no exercise‐related adverse events, with one possible related adverse event of asymptomatic atrial fibrillation in one participant within Arm A. Conclusions Non‐small‐cell lung cancer cachectic patients are willing to be enrolled onto a multi‐targeted treatment regimen and may benefit from cachexia symptom management even during the late/refractory stage.

Physical interactions with the real world have many degrees of freedom, which has led to the development of novel input devices with a multitude of sensors to capture increasingly high‐dimensional data. This high dimensionality makes the design of interactive systems more complex. Herein, the use of autoencoder‐based dimensionality reduction is explored to simplify the design process. For this purpose, a data glove equipped with accelerometers is used to record high‐dimensional hand movement data that are thereafter reduced to 2D embeddings using autoencoders. The exploration and evaluation of the resulting embeddings suggest that autoencoders can be used to create meaningful low‐dimensional representations of complex human movement. The characteristics generality, variability, connectivity, and distinguishability are established and a guideline is provided for assessing low‐dimensional embeddings. Referring to these characteristics, system engineers can evaluate different input modalities and gestures for their specific interaction task. Further, a framework is outlined for designing and evaluating gesture interaction in the low‐dimensional space. By demonstrating the exemplary design of the interaction with a virtual lever, this research gives system engineers a template for interaction design in the low‐dimensional space.

Abstract Introduction Mexican Americans remain severely underrepresented in Alzheimer's disease (AD) research. The Health & Aging Brain among Latino Elders (HABLE) study was created to fill important gaps in the existing literature. Methods Community‐dwelling Mexican Americans and non‐Hispanic White adults and elders (age 50 and above) were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T magnetic resonance imaging (MRI) of the brain. Amyloid and tau positron emission tomography (PET) scans were added at visit 2. Blood samples were stored in the Biorepository. Results Data was examined from n = 1705 participants. Significant group differences were found in medical, demographic, and sociocultural factors. Cerebral amyloid and neurodegeneration imaging markers were significantly different between Mexican Americans and non‐Hispanic Whites. Discussion The current data provide strong support for continued investigations that examine the risk factors for and biomarkers of AD among diverse populations.

The study aimed to deepen our understanding of the menstrual hygiene management (MHM) of adolescents and the influence of menstruation on school absenteeism. We employed a school-based cross-sectional design in five Junior High Schools combining both quantitative and qualitative data collection methods. A questionnaire was used to collect quantitative data from 250 schoolgirls, and key informant interviews were conducted with a teacher in each of the five schools. We performed logistic regression analysis to provide crude and adjusted effect estimates and 95% confidence intervals. About fifty percent of the girls were engaged in good MHM, and approximately forty percent of them reported menstrual-related school absenteeism. We did not find evidence (p=0.858) of association between MHM and menstrual-related school absenteeism. However, after controlling for the effect of other factors, we found evidence that the age of the schoolgirls, their father’s occupation, and the receipt of allowance for menstrual care products were associated with MHM. When compared to those aged 17 to 19, those aged 10 to 13 years had 0.72 (95% CI 0.21, 2.44) decreased odds of poor MHM while those aged 14 to 16 had almost 3-fold increased odds (95% CI 1.49, 4.55) of poor MHM. The adolescents whose fathers were farmers had 0.42 (95% CI 0.21, 0.82) decreased odds of poor MHM while those whose fathers were unemployed had 0.24 (95% CI 0.10, 0.61) decreased odds of poor MHM. We found that girls who did not receive regular allowance for menstrual care products had nearly 2-fold increased odds (95% CI 1.06, 3.09) of poor MHM compared to those who received allowance for menstrual care products. Menstrual pain (82.2%), fear of staining clothing (70.3%), fear of being teased (70.3%), nonavailability of sanitary pad (63.4%), and lack of private place to manage period at school (60.4%) were the common reasons cited for menstrual-related school absenteeism.

Abstract Anthropogenic disturbances may alter a population's conservation status if the ability of individuals to survive and breed is affected. We used an adaptation of the Heligman‐Pollard model to estimate survival at age of Cook Inlet belugas (CIB; Delphinapterus leucas), an endangered population in south‐central Alaska. We developed an age‐structured Leslie matrix model, based on the life history parameters survival and fecundity probability, to evaluate the sensitivity of population size and growth of CIB, to variation in estimate values of Chinook and coho salmon abundance in the Deshka River, a major tributary of the Susitna River. Birth effect (eb) was regressed against Chinook and coho salmon levels for the year of, the year before, and two years before a beluga calf birth. The effect of a range of modifications of salmon availability was illustrated in CIB with a series of simulations. The maximum annual population growths (λ) were set at 1.036 (3.6%). Ranges of CIB survival and fecundity probabilities indicated small changes in survival probabilities have a greater impact on population growth than similar changes in birth probability. As either survival (es) or fecundity (eb) was reduced, the annual growth declined, with either es = 0.961 or eb = 0.388, causing a decreased annual growth of −0.4%. Regressions of Chinook salmon for the year of, the year before, and two years before a birth were all significant at the 5% level as was coho in the year of and year prior to birth. The mechanism model with the best fit was the sum of Chinook and coho in the year of birth and year prior to birth. Simulations showed that if salmon runs remained at their current levels, the CIB population would likely continue its current slow decline and per capita births would continue to be low. The results from this study suggest reproductive success in CIB is tied to salmon abundance in the Deshka River. Current management practices should consider this when setting research priorities, designing new studies, and developing management actions to achieve CIB population recovery targets.

Abstract The PREDICTS project—Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (https://www.nhm.ac.uk/our-science/our-work/biodiversity/predicts.html)—has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.

Background Adults with a systemic right ventricle (sRV) have a high risk of cardiac complications. This study aimed to identify prognostic markers in adults with sRV based on clinical evaluation, echocardiography, and blood biomarkers. Methods and Results In this prospective cohort study, consecutive clinically stable adults with sRV caused by Mustard‐ or congenitally corrected transposition of the great arteries were included (2011–2013). Eighty‐six patients were included (age 37±9 years, 65% male, 83% New York Heart Association functional class I, 76% Mustard transposition of the great arteries, 24% congenitally corrected transposition of the great arteries). Venous blood sampling was performed including N‐terminal pro B‐type natriuretic peptide, high‐sensitive‐troponin‐T, high‐sensitivity C‐reactive protein, growth differentiation factor‐15, galectin‐3, red cell distribution width, estimated glomerular filtration rate, and hemoglobin. Besides conventional echocardiographic measurements, longitudinal, circumferential, and radial strain were assessed using strain analysis. During a median follow‐up of 5.9 (interquartile range 5.3–6.3) years, 19 (22%) patients died or had heart failure (primary end point) and 29 (34%) patients died or had arrhythmia (secondary end point). Univariable Cox regression analysis was performed using dichotomous or standardized continuous variables. New York Heart Association functional class >I, systolic blood pressure, and most blood biomarkers were associated with the primary and secondary end point (galectin‐3 not for primary, N‐terminal pro B‐type natriuretic peptide and high‐sensitivity C‐reactive protein not for secondary end point). Growth differentiation factor‐15 showed the strongest association with both end points (hazard ratios; 2.44 [95% CI 1.67–3.57, P

Abstract This paper describes the development, conceptualization, and implementation of a transdisciplinary research pilot, the aim of which is to understand how human and planetary health could become a priority for those who control the urban development process. Key challenges include a significant dislocation between academia and the real world, alongside systemic failures in valuation and assessment mechanisms. The National Institutes of Health four‐phase model of transdisciplinary team‐based research is drawn on and adapted to reflect on what has worked well and what has not operationally. Results underscore the need for experienced academics open to new collaborations and ways of working; clarity of leadership without compromising exploration; clarification of the poorly understood “impacts interface” and navigation toward effective real world impact; acknowledgement of the additional time and resource required for transdisciplinary research and “nonacademic” researchers. Having practitioner‐researchers as part of the research leadership team requires rigourous reflective practice and effective management, but it can also ensure breadth in transdisciplinary outlook as well as constant course correction toward real‐world impact. It is important for the research community to understand better the opportunities and limitations provided by knowledge intermediaries in terms of function, specialism, and experience.

Abstract While studying ecological patterns at large scales, ecologists are often unable to identify all collections, forcing them to either omit these unidentified records entirely, without knowing the effect of this, or pursue very costly and time‐consuming efforts for identifying them. These “indets” may be of critical importance, but as yet, their impact on the reliability of ecological analyses is poorly known. We investigated the consequence of omitting the unidentified records and provide an explanation for the results. We used three large‐scale independent datasets, (Guyana/ Suriname, French Guiana, Ecuador) each consisting of records having been identified to a valid species name (identified morpho‐species – IMS) and a number of unidentified records (unidentified morpho‐species – UMS). A subset was created for each dataset containing only the IMS, which was compared with the complete dataset containing all morpho‐species (AMS: = IMS + UMS) for the following analyses: species diversity (Fisher's alpha), similarity of species composition, Mantel test and ordination (NMDS). In addition, we also simulated an even larger number of unidentified records for all three datasets and analyzed the agreement between similarities again with these simulated datasets. For all analyses, results were extremely similar when using the complete datasets or the truncated subsets. IMS predicted ≥91% of the variation in AMS in all tests/analyses. Even when simulating a larger fraction of UMS, IMS predicted the results for AMS rather well. Using only IMS also out‐performed using higher taxon data (genus‐level identification) for similarity analyses. Finding a high congruence for all analyses when using IMS rather than AMS suggests that patterns of similarity and composition are very robust. In other words, having a large number of unidentified species in a dataset may not affect our conclusions as much as is often thought.

BackgroundObesity may increase heart failure risk through cardiac remodeling. Cross‐sectional associations between adiposity and cardiac structure and function have been elucidated, but the impact of longitudinal changes in adiposity on cardiac remodeling is less well understood. Methods and ResultsParticipants in the Dallas Heart Study without cardiovascular disease or left ventricular dysfunction underwent assessment of body weight, anthropometrics, and cardiac magnetic resonance imaging at baseline and 7 years later. Associations between changes in indices of generalized and central adiposity with changes in left ventricular mass, volume, mass/volume ratio (concentricity), wall thickness, and ejection fraction were assessed using multivariable linear regression. The study cohort (n=1262) mean age was 44 years with 57% women, 44% black, and 36% obese participants. At follow‐up, 41% had ≥5% weight gain, and 15% had ≥5% weight loss. Greater weight gain was associated with younger age, lower risk factor burden, and lower body mass index at baseline. In multivariable models adjusting for age, sex, race, comorbid conditions at baseline and follow‐up, baseline adiposity, and cardiac measurement, increasing weight was associated with increases in left ventricular mass (β=0.10, P

Abstract Biological control using natural antagonists has been a most successful management tool against alien invasive plants that threaten biodiversity. The selection of candidate agents remains a critical step in a biocontrol program before more elaborate and time‐consuming experiments are conducted. Here, we propose a biogeographic approach to identify candidates and combinations of candidates to potentially cover a large range of the invader. We studied Ambrosia artemisiifolia (common ragweed), native to North America (NA) and invasive worldwide, and six NA biocontrol candidates for the introduced Europe (EU) range of ragweed, both under current and future bioclimatic conditions. For the first time, we constructed species distribution models based on worldwide occurrences and important bioclimatic variables simultaneously for a plant invader and its biocontrol candidates in view of selecting candidates that potentially cover a large range of the target invader. Ordination techniques were used to explore climatic constraints of each species and to perform niche overlap tests with ragweed. We show a large overlap in climatic space between candidates and ragweed, but a considerable discrepancy in geographic range overlap between EU (31.4%) and NA (83.3%). This might be due to niche unfilling and expansion of ragweed in EU and the fact that habitats with high ragweed occurrences in EU are rare in NA and predicted to be unsuitable for the candidates. Total geographic range of all candidates combined is expected to decrease under climate change in both ranges, but they will respond differently. The relative geographic coverage of a plant invader by biocontrol candidates at home is largely transferable to the introduced range, even when the invader shifts its niche. Our analyses also identified which combination of candidates is expected to cover the most area and for which abiotic conditions to select in order to develop climatically adapted strains for particular regions, where ragweed is currently unlikely to be controlled.

Background The incidence, predictors, and impact of atrial arrhythmias along with left atrial structural changes in patients with left ventricular assist devices (LVADs) remain undetermined. Methods and Results All patients who underwent LVAD implantation from 2008 to 2015 at the University of Chicago Medical Center were included. Electronic medical records, electrocardiograms, echocardiograms, and cardiac electrical device interrogations were reviewed. The association of arrhythmias and clinical covariates with survival was evaluated by Kaplan–Meier and Cox proportional hazards analyses. A total of 331 patients were followed for a median of 330 days (range 0–2306 days). Mean age was 57.8±12.8 years, 256 participants (77.3%) were male, mean left ventricular ejection fraction was 20±6.6%, and 124 (37.5%) had ischemic cardiomyopathy. Atrial arrhythmias (53.8%) were highly prevalent and frequently coexisted before LVAD implantation: atrial fibrillation (AF) in 45.9%, atrial flutter in 13.9%, atrial tachycardia in 6.9%, and atrioventricular nodal reentrant tachycardia in 1.2%. New‐onset AF was documented in 14 patients (7.8% of patients without prior AF) after the first 30 days with an LVAD. Increasing age, renal insufficiency, and lung disease were predictors of new‐onset AF after LVAD implantation. Of patients with paroxysmal AF, 43% had no further AF after LVAD. Left atrial size and volume index improved with LVAD (P

The field of catheter ablation of VT has evolved conceptually and technologically over the past three decades. From the fundamental understanding of the reentrant mechanism in scar-mediated VT to the advent and routine implementation of electroanatomic mapping, catheter ablation has emerged from a palliative last-resort therapy to a more preemptive strategy for patients at risk for arrhythmia recurrence. An increasing utilization of pre-procedural imaging, high-density mapping, epicardial access, and more extensive ablation strategies have all contributed to improved clinical success. Advances in ablation technology and randomized trials are needed to build upon the progress in this growing field as sudden cardiac death from ventricular tachyarrhythmia continues to be the one of leading causes of death throughout the world.

Stercoral perforation of the colon is rare but carries with it significant morbidity and mortality. Stercoral perforation usually occurs in elderly, immobile patients with chronic constipation. In this manuscript, we report the case of stercoral perforation in a patient due to chronic heroin dependence. We report the case of a 56-year-old male patient with stercoral perforation, diagnosed by computed tomography, secondary to heroin dependence, requiring proctocolectomy and an end ileostomy. There are very few reports in the literature describing cases of stercoral perforation and questions have been asked about the importance of preoperative cross-sectional imaging. In our case, the diagnosis of stercoral perforation was made only on CT. Although this is not the first such case to be reported, it is significant as preoperative CT imaging was influential not only in determining the aetiology of the abdominal distension seen on the plain film, but also in detecting the pneumoperitoneum which was not evident clinically or on plain radiographs.