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Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative condition. Despite significant advances in pre-clinical models that enhance understanding of disease pathobiology, translation of candidate drugs to effective human therapies has been disappointing. There is increasing recognition of the need for a precision medicine approach toward drug development, as many failures in translation can be attributed in part to disease heterogeneity in humans. PRECISION-ALS is an academic industry collaboration between clinicians, Computer Scientists, Information engineers, technologists, data scientists and industry partners that will address the key clinical, computational, data science and technology associated research questions to generate a sustainable precision medicine based approach toward new drug development. Using extant and prospectively collected population based clinical data across nine European sites, PRECISION-ALS provides a General Data Protection Regulation (GDPR) compliant framework that seamlessly collects, processes and analyses research-quality multimodal and multi-sourced clinical, patient and caregiver journey, digitally acquired data through remote monitoring, imaging, neuro-electric-signaling, genomic and biomarker datasets using machine learning and artificial intelligence. PRECISION-ALS represents a first-in-kind modular transferable pan-European ICT framework for ALS that can be easily adapted to other regions that face similar precision medicine related challenges in multimodal data collection and analysis. ispartof: AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION vol:24 issue:5-6 ispartof: location:England status: Published online

This study explored the lived experience of transition from adolescence to adulthood for young people with cerebral palsy to inform occupational therapy practitioners as to what might promote positive life opportunities. A phenomenological methodology was used with six participants, aged 18 to 25 years with cerebral palsy. The findings are presented in the form of hermeneutic stories and three themes: The storm of uncertainty; time, space and the body, Capsizing in a world of others and, Securing anchorage; being heard and understood. Recommendations include service integration across health, social care and education based on partnership and provision of coordinators. peerReviewed

Background: Evidence suggests that APOE ɛ4 carriers have worse memory performances compared to APOE ɛ4 non-carriers and effects may vary by sex and age. Estimates of biological age, using DNA methylation may enhance understanding of the associations between sex and APOE ɛ4 on cognition. Objective: To investigate whether associations between APOE ɛ4 status and memory vary according to rates of biological aging, using a DNA methylation age biomarker, in older men and women without dementia. Methods: Data were obtained from 1,771 adults enrolled in the 2016 wave of the Health and Retirement Study. A series of ANCOVAs were used to test the interaction effects of APOE ɛ4 status and aging rates (defined as 1 standard deviation below (i.e., slow rate), or above (i.e., fast rate) their sex-specific mean rate of aging on a composite measure of verbal learning and memory. Results: APOE ɛ4 female carriers with slow rates of GrimAge had significantly better memory performances compared to fast and average aging APOE ɛ4 female carriers. There was no effect of aging group rate on memory in the female non-carriers and no significant differences in memory according to age rate in either male APOE ɛ4 carriers or non-carriers. Conclusion: Slower rates of aging in female APOE ɛ4 carriers may buffer against the negative effects of the ɛ4 allele on memory. However, longitudinal studies with larger sample sizes are needed to evaluate risk of dementia/memory impairment based on rates of aging in female APOE ɛ4 carriers.

In order to determine the main theories and explanations of international migration on the migratory human flow of the Venezuelan population to Ecuador, who are forced to move to other countries in the world. The phenomenon of emigration is very old as the very existence of the human being, the flow of various people who go to Ecuador in recent years has increased; It is necessary to carry out a deep analysis, a detailed and supported study that is permissible to understand the national and international migratory reality, the consequences that the Ecuadorian government implies to attend this human wave with the productive, legal apparatus, based on internal regulations, treaties and international conventions. The objective is to identify the reasons and consequences of the Venezuelan individual and their internal displacement in the country, the documentary-bibliographical review was applied to know the different causes of migration, in addition to the quantitative and qualitative method that helped to assess the causes of This to be clear about the complexity of the issue and the migration structure.

Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI).The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEVFrom Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEVIn individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment.

Aims Incorporating a steerable sheath that can be visualized using an electroanatomical mapping (EAM) system may allow for more efficient mapping and catheter placement, while reducing radiation exposure, during ablation procedures for atrial fibrillation (AF). This study evaluated fluoroscopy usage and procedure times when a visualizable steerable sheath was used compared with a non-visualizable steerable sheath for catheter ablation for AF. Methods and results In this retrospective, observational, single-centre study, patients underwent catheter ablation for AF using a steerable sheath that is visualizable using the CARTO EAM (VIZIGO; n = 57) or a non-visualizable steerable sheath (n = 34). The acute procedural success rate was 100%, with no acute complications in either group. Use of the visualizable sheath vs. the non-visualizable sheath was associated with a significantly shorter fluoroscopy time [median (first quartile, third quartile), 3.4 (2.1, 5.4) vs. 5.8 (3.8, 8.6) min; P = 0.003], significantly lower fluoroscopy dose [10.0 (5.0, 20.0) vs. 18.5 (12.3, 34.0) mGy; P = 0.015], and significantly lower dose area product [93.0 (48.0, 197.9) vs. 182.2 (124.5, 355.0) μGy·m2; P = 0.017] but with a significantly longer mapping time [12.0 (9.0, 15.0) vs. 9.0 (7.0, 11.0) min; P = 0.004]. There was no significant difference between the visualizable and non-visualizable sheaths in skin-to-skin time [72.0 (60.0, 82.0) vs. 72.0 (55.5, 80.8) min; P = 0.623]. Conclusion In this retrospective study, use of a visualizable steerable sheath for catheter ablation of AF significantly reduced radiation exposure vs. a non-visualizable steerable sheath. Although mapping time was longer with the visualizable sheath, the overall procedure time was not increased.

Background: American Indians have high prevalence of risk factors for Alzheimer’s disease and related dementias (ADRD) compared to the general population, yet dementia onset and frequency in this population are understudied. Intraindividual cognitive variability (IICV), a measure of variability in neuropsychological test performance within a person at a single timepoint, may be a novel, noninvasive biomarker of neurodegeneration and early dementia. Objective: To characterize the cross-sectional associations between IICV and hippocampal, total brain volume, and white matter disease measured by magnetic resonance imaging (MRI) among older American Indians. Methods: IICV measures for memory, executive function, and processing speed, and multidomain cognition were calculated for 746 American Indians (aged 64–95) who underwent MRI. Regression models were used to examine the associations of IICV score with hippocampal volume, total brain volume, and graded white matter disease, adjusting for age, sex, education, body mass index, intracranial volume, diabetes, stroke, hypertension, hypercholesterolemia, alcohol use, and smoking. Results: Higher memory IICV measure was associated with lower hippocampal volume (Beta = –0.076; 95% CI –0.499, –0.023; p = 0.031). After adjustment for Bonferroni or IICV mean scores in the same tests, the associations were no longer significant. No IICV measures were associated with white matter disease or total brain volume. Conclusion: These findings suggest that the IICV measures used in this research cannot be robustly associated with cross-sectional neuroimaging features; nonetheless, the results encourage future studies investigating the associations between IICV and other brain regions, as well as its utility in the prediction of neurodegeneration and dementia in American Indians.

Background: Lower cerebral blood flow (CBF) and excessive brain atrophy are linked to Alzheimer’s disease (AD). It is still undetermined whether reduced CBF precedes or follows brain tissue loss. Objective: We compared total CBF (tCBF), global cerebral perfusion (GCP), and volumes of AD-prone regions between cognitively normal (CN) and early amnestic mild cognitive impairment (aMCI) and tested their associations with cognitive performance to assess their predictive value for differentiation between CN and early aMCI. Methods: A total of 74 participants (mean age 69.9±6.2 years, 47 females) were classified into two groups: 50 CN and 24 aMCI, of whom 88% were early aMCI. tCBF, GCP, and global and regional brain volumetry were measured using phase-contrast and T1-weighted MRI. Neuropsychological tests tapping global cognition and four cognitive domains (memory, executive function, language, and visuospatial) were administered. Comparisons and associations were investigated using analyses of covariance (ANCOVA) and linear regression analyses, respectively. Results: Women had significantly higher GCP than men. Both, tCBF and GCP were significantly reduced in aMCI compared with CN, while differences in volumes of cerebral gray matter, white matter, and AD-prone regions were not significant. tCBF and GCP were significantly associated with global cognition (standardized beta (stβ) = 0.324 and stβ= 0.326) and with memory scores (stβ≥0.297 and stβ≥0.264) across all participants. Associations of tCBF and GCP with memory scores were also significant in CN (stβ= 0.327 and stβ= 0.284) and in aMCI (stβ= 0.627 and stβ= 0.485). Conclusion: Reduced tCBF and GCP are sensitive biomarkers of early aMCI that likely precede brain tissue loss.

Background: Greater mindfulness, the practice of awareness and living in the moment without judgement, has been linked to positive caregiving outcomes in dementia caregivers and its impact attributed to greater decentering and emotion regulation abilities. Whether the impact of these mindfulness-based processes varies across caregiver subgroups is unclear. Objective: Analyze cross-sectional associations between mindfulness and caregiver psychosocial outcomes, considering different caregiver and patient characteristics. Methods: A total of 128 family caregivers of persons living with Alzheimer’s disease and related disorders were assessed on several mindfulness measures (i.e., global; decentering, positive emotion regulation, negative emotion regulation) and provided self-reported appraisals of caregiving experience; care preparedness; confidence, burden, and depression/anxiety. Bivariate relationships between mindfulness and caregiver outcomes were assessed with Pearson’s correlations and stratified by caregiver (women versus men; spouse versus adult child) and patient (mild cognitive impairment (MCI) versus Dementia; AD versus dementia with Lewy bodies; low versus high symptom severity) characteristics. Results: Greater mindfulness was associated with positive outcomes and inversely associated with negative outcomes. Stratification identified specific patterns of associations across caregiver groups. Significant correlations were found between all mindfulness measures and caregiving outcomes in male and MCI caregivers while the individual mindfulness component of positive emotion regulation was significantly correlated to outcomes in most caregiver groups. Conclusion: Our findings support a link between caregiver mindfulness and improved caregiving outcomes and suggest directions of inquiry into whether the effectiveness of dementia caregiver-support interventions may be improved by targeting specific mindfulness processes or offering a more inclusive all-scope approach depending on individual caregiver or patient characteristics.

Routine clinical investigations in the memory clinic may identify a degree of cognitive impairment that does not reach threshold criteria for a dementia diagnosis. A mild cognitive impairment may be the beginnings of a progressive decline for some people. How should services respond to those people, for whom a MCI is the beginning of a progressive decline and ensure a timely diagnosis is ultimately provided? This article describes our attempt at a solution.

“Weedy” red rice is a problematic weed with phenotypic similarities to cultivated rice. Limited herbicide availability has driven a need for nonchemical control options for managing this pest. One preplanting strategy that is being explored is the stale seedbed methodology, which aims to maximize soil seedbank withdrawals via germination. This technique is adapted in rice by flooding a field, waiting for germination and emergence of weed seedlings, and completing the method with a mechanical or chemical control application. Optimization of this process is dependent on maximizing weed seed germination, which is primarily influenced by both temperature and moisture availability. Germinability across a range of these factors is not well understood in California red rice. Thus, this study aimed to determine germinability of California red rice accessions under various temperature and water potential treatments. Previously described red rice accessions 1, 2, 3, and 5, along with ‘M206’, a common California rice cultivar, were exposed to temperatures from 10 to 40 C in 5 C increments in combination with water potentials of 0, −0.2, −0.4, or −0.8 MPa until either germination or weed seed decay occurred. Statistical analysis indicated a three-way interaction between accession, temperature, and water potential. Germination reached 95% or greater when seeds were exposed to temperatures from 20 to 35 C in combination with 0 or −0.2 MPa. Germination was lowest when seeds were water stressed (−0.8 MPa) and when temperatures were colder than 20 C or warmer than 35 C. The ‘M206’ cultivar was utilized for comparison and demonstrated cold tolerance by germinating at 10 C, whereas weedy accessions 1, 2, and 3 did not. When temperatures were at or above 15 C, however, ‘M206’ germinated less often compared with all weedy accessions. Historical preplant temperatures in this region align with those required for weedy rice germination. Thus, the stale seedbed methodology is a viable strategy in years when ample floodwater is available.

Dementia of Alzheimer's Type (DAT) is a complex disorder influenced by numerous factors, and it is difficult to predict individual progression trajectory from normal or mildly impaired cognition to DAT. An in-depth examination of multiple modalities of data may yield an accurate estimate of time-to-conversion to DAT for preclinical subjects at various stages of disease development. We used a deep-learning model designed for survival analyses to predict subjects' time-to-conversion to DAT using the baseline data of 401 subjects with 63 features from MRI, genetic, and CDC (Cognitive tests, Demographic, and CSF) data in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Our study demonstrated that CDC data outperform genetic or MRI data in predicting DAT time-to-conversion for subjects with Mild Cognitive Impairment (MCI). On the other hand, genetic data provided the most predictive power for subjects with Normal Cognition (NC) at the time of the visit. Furthermore, combining MRI and genetic features improved the time-to-event prediction over using either modality alone. Finally, adding CDC to any combination of features only worked as well as using only the CDC features.

Advances in the understanding and management of glenoid bone loss in shoulder instability have led to the development of alternative bony reconstruction techniques to the Latarjet using free bone grafts, but little is known about surgeon adoption of these procedures. This study sought to characterize surgeon variation in the use of glenoid bone reconstruction procedures for shoulder instability and ascertain reasons underlying procedure choice.A 9-question survey was created and distributed to 160 shoulder surgeons members of the PacWest Shoulder and Elbow Society, of whom 65 (41%) responded. The survey asked questions regarding fellowship training, years in practice, surgical volume, preferred methods of glenoid bone reconstruction, and reasons underlying treatment choice.All surgeons completed a fellowship, with an equal number of sports medicine fellowship-trained (46%) and shoulder and elbow fellowship-trained (46%) physicians. The majority had been in practice for at least 6 years (6-10 years: 25%;10 years: 59%). Most (78%) performed ≤10 glenoid bony reconstructions per year, and 66% indicated that bony procedures represented10% of their total annual shoulder instability case volume. The open Latarjet was the preferred primary reconstruction method (69%), followed by open free bone block (FBB) (22%), arthroscopic FBB (8%), and arthroscopic Latarjet (1%). Distal tibia allograft (DTA) was the preferred graft (74%) when performing an FBB procedure, followed by iliac crest autograft (18%), and distal clavicle autograft (6%). The top 5 reasons for preferring Latarjet over FBB were the sling effect (57%), the autologous nature of the graft (37%), its robust clinical evidence (22%), low cost (17%), and availability (11%). The top 5 reasons for choosing an FBB procedure were less anatomic disruption (58%), lower complication rate (21%), restoration of articular cartilage interface (16%), graft versatility (11%), and technical ease (11%). Only 20% of surgeons indicated always performing a bony glenoid reconstruction procedure in the noncontact athlete with less than 20% glenoid bone loss. However, that percentage rose to 62% when considering a contact athlete with the same amount of bone loss.Although open Latarjet continues to be the most popular glenoid bony primary reconstruction procedure in shoulder instability, nearly 30% of shoulder surgeons in the western United States have adopted FBB techniques as their preferred treatment modality--with DTA being the most frequently used graft. High-quality comparative clinical effectiveness research is needed to reduce decisional conflict and refine current evidence-based treatment algorithms.

Moral problems such as climate change and global poverty result from widespread human action, and hence, are unaffected by changes in any individual's behavior—for instance, the harms of climate change will obtain whether I drive my car or not. This problem of causal impotence seems potentially devastating for consequentialists, but more easily addressed by deontologists. The deontologist can argue that (e.g.) even if our acts will have no effect on climate change, our using fossil fuels makes us complicit in, and hence, blameworthy for, these wrongs. We argue that, despite initial appearances, appeals to complicity do not extricate deontologists from this problem. When our actions do not make a difference, we cannot be held responsible for being complicit in wrongs such as climate change and global poverty. As a result, we conclude that the problem of causal impotence is as vexing for deontologists as it is for consequentialists.

A diabetic foot ulcer is present in approximately 2.4% of hospitalized patients. Care for diabetic foot ulcers is highly variable. We sought to describe care practice patterns and risk factors for poor outcomes for patients hospitalized with a diabetic foot ulcer in our institution, an 894-bed tertiary care academic hospital located in downtown Chicago, IL. We conducted a retrospective cohort study of patients hospitalized with a diabetic foot ulcer between March 3rd, 2018 and December 31st, 2019. We categorized patients into having an uncomplicated ulcer or a complicated ulcer with cellulitis, wound infection, osteomyelitis, or gangrene. We evaluated rates of diagnostic resource utilization (imaging, cultures, biopsies, and antibiotics) and outcomes of osteomyelitis, amputation, and death. There were 305 patients of interest in the study cohort. A complicated lower extremity ulcer was found in 79% of patients. Amputation was required in 25% of patients, 21% were readmitted, and 13% died. Imaging was obtained in less than 50% of all patients, and in 60% or less of those with osteomyelitis. Bone biopsies were rarely acquired. Empiric antibiotics were prescribed in 77% of patients with osteomyelitis. Male, Black or African-American patients, and those with high Charlson score had the highest risk of poor outcomes. Care practices for patients hospitalized with diabetic foot ulcers were highly variable. Future interventions should target standardization to improve outcomes, with particular attention to health inequities as vulnerable populations have a higher risk of poor outcomes.

Purpose: The purpose of this study was to explore the perspectives of audiologists to provide input into development of a smartphone application (app) to document the real-life listening difficulties and the listening environment of hearing aid candidates and users. Method: Two focus groups were conducted. Facilitators utilized a topic guide to generate participants' input and perspectives. The focus groups were audio-recorded and transcribed verbatim. The transcripts were then qualitatively analyzed using content analysis. Study Sample: The study samples were 10 audiologists (seven females) with 2- to 10-plus years of hearing aid fitting experience. Results: Three main categories were identified: (a) The mobile device app could provide meaningful information to help audiologists to counsel their clients, (b) the app could give clients an insight into their hearing difficulties, and (c) the app could help clients to self-manage their hearing condition. Conclusion: These findings suggest that audiologists may better understand their clients' real-life listening difficulties through the use of a mobile device app; however, further research is required to harness the benefits of such an app.

This paper elaborates on how design rules emerge and evolve as firms’ micro-level choices of product and organization architectures coevolve with changes in product markets and an industry’s competitive and cooperative dynamics. We suggest that the design rules a firm adopts will vary according to firms’ strategic choices of product and organization architectures that they believe are or may become feasible in a given industry. Building on the mirroring hypothesis that product designs a firm adopts will influence the organization designs it uses, we develop a model that identifies key relationships that influence firms’ strategic choices of product and organization architectures and associated design rules. We then elaborate on key interactions between firm-level architectural choices and the architecture-enabled competitive and cooperative dynamics that obtain in an industry. Our model identifies strategically important aspects of open- and closed-system architectures and modular and nonmodular architectures that impact industry structures, interfirm interactions, and resulting industry dynamics. Drawing on these analyses, we suggest how firms’ strategic choices of architectures are influenced by their assessments of (i) the potential for capturing value through both gains from specialization and gains from trade that firms believe will be enabled by their architectural choices and (ii) both ex ante and ex post transaction costs implied by their architecture decisions. We conclude by suggesting how the perspective on firm’s strategic architectural decisions we develop here enables new approaches to understanding evolutions of both product markets and industry structures for serving product markets.

Remote, or tele-, consultations became a necessary form of mental healthcare provision during the COVID-19 pandemic. As the prevalence of mental health problems rises, they may have a role in future mental health services. We aimed to review the literature on patient and provider perspectives on factors influencing the implementation of remote consultations for community-dwelling people with mental health conditions. We searched five electronic databases (PubMed, EMBASE, Web of Science, CINAHL, and PsycINFO) for empirical research up to July 13th, 2022. Only studies of synchronous, interactive remote consultations conducted via video, phone, or live-messaging between patients and providers were included. Two reviewers independently assessed the quality of included studies using the Mixed Methods Appraisal Tool. We integrated qualitative and quantitative data from 39 studies into a single mixed-methods synthesis. We mapped reported factors to the domains of the Consolidated Framework for Implementation Research (CFIR). Acceptability was generally high among participants, despite concerns about the quality of care and the perceived impeded therapeutic relationship. A prominent facilitator was the increased accessibility and convenience of remote consultations, while lack of appropriate infrastructure and low patient comfort and competence were among the most prevalent barriers. This review highlights the importance of patient preferences and provider buy-in to the future of remote consultations.

Despite significant scholarly attention and practical importance regarding who emerges as informal and formal leaders in organizations, an integrative framework of the leadership emergence literature remains elusive. The presence of such a framework proves integral for the advancement of work in this area due to the complexity of the field, coupled with its sprawling nature across multiple disciplines (e.g., management, communication, education, economics). Accordingly, in this review, we utilize a database of 270 primary studies to put forth a distal-proximal framework of leadership emergence. In particular, we systematically review past research to answer four questions: (1) what do we know about the phenomenon of leadership emergence itself, (2) what are the antecedents of leadership emergence, (3) what outcomes are associated with leader emergence, and (4) what are the boundary conditions of leadership emergence? By introducing a conceptual framework for informal and formal emergent leadership, we highlight areas of research maturity and nascency and offer several recommendations for future work in this domain. Altogether, we highlight broad theoretical implications for the leadership, teams, and individual differences literature-and elaborate upon several benefits that an integrated framework of emergent leadership provides for organizations. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

There is limited information on return to shooting following shoulder surgery. The purpose of this study is to determine the rate and timing for resuming shooting a rifle following shoulder surgery.We performed a retrospective review of prospectively collected data. The study included patients undergoing arthroscopic and open shoulder stabilization for unidirectional shoulder instability, and arthroscopic surgery for rotator cuff tears, SLAP lesions, biceps tendinopathy, and acromioclavicular pathology. Data collected included the laterality of surgery, shooting dominance, and patient-reported outcome measures at the preoperative and postoperative visits. Starting at the 4.5-month clinic visit, patients were asked if they could shoot a military rifle.One hundred patients were identified with arthroscopic and open shoulder surgery with a mean age of 30 years (range, 18-45) and a mean follow-up of 24 months (range, 12-32). The cohort consisted of patients undergoing arthroscopic Bankart repair (n = 23), arthroscopic posterior labral repair (n = 18), open Latarjet (n = 16), mini-open subpectoral biceps tenodesis (OBT) (n = 25), OBT with open distal clavicle resection (DCR) (n = 10), open DCR (n = 4), and arthroscopic rotator cuff repair with concomitant OBT (n = 4). Significant improvement in SSV, VAS, ASES, and WOSI was shown at 1-year postoperative, SSV 85, VAS 2, ASES 85, WOSI 239,Patients undergoing arthroscopic and open shoulder surgery have a high rate of return to shooting. Approximately 60% of patients resume shooting at 6 months postoperatively and 85% return at 1 year. Patients undergoing shoulder surgery on the contralateral side of their shooting dominance return to shooting significantly faster than those with shoulder surgery ipsilateral to their shooting dominance. Additionally, those undergoing arthroscopic posterior shoulder stabilization return to shooting at a slower rate than anterior stabilization surgery.

Damages to the ear are very diverse and can depend on the type of inherited metabolic diseases (IMD). Indeed, IMDs can affect all parts of the auditory system, from the outer ear to the central auditory process. We have identified 219 IMDs associated with various types of ear involvement which we classified into five groups according to the lesion site of the auditory system: congenital external ear abnormalities, acquired external ear abnormalities, middle ear involvement, inner ear or retrocochlear involvement, and unspecified hearing loss. This represents the ninth issue in a series of educational summaries providing a comprehensive and updated list of metabolic differential diagnoses according to system involvement.

Land-based exercise therapy is recommended in clinical guidelines for hip or knee osteoarthritis. Adjunctive non-pharmacological therapies are commonly used alongside exercise in hip or knee osteoarthritis management, but cumulative evidence for adjuncts to land-based exercise therapy is lacking.To evaluate the benefits and harms of adjunctive therapies used in addition to land-based exercise therapy compared with placebo adjunctive therapy added to land-based exercise therapy, or land-based exercise therapy only for people with hip or knee osteoarthritis.We searched CENTRAL, MEDLINE, PsycINFO, EMBASE, CINAHL, Physiotherapy Evidence Database (PEDro) and clinical trials registries up to 10 June 2021.We included randomised controlled trials (RCTs) or quasi-RCTs of people with hip or knee osteoarthritis comparing adjunctive therapies alongside land-based exercise therapy (experimental group) versus placebo adjunctive therapies alongside land-based exercise therapy, or land-based exercise therapy (control groups). Exercise had to be identical in both groups. Major outcomes were pain, physical function, participant-reported global assessment, quality of life (QOL), radiographic joint structural changes, adverse events and withdrawals due to adverse events. We evaluated short-term (6 months), medium-term (6 to 12 months) and long-term (12 months onwards) effects.Two review authors independently assessed study eligibility, extracted data, and assessed risk of bias and certainty of evidence for major outcomes using GRADE.We included 62 trials (60 RCTs and 2 quasi-RCTs) totalling 6508 participants. One trial included people with hip osteoarthritis, one hip or knee osteoarthritis and 59 included people with knee osteoarthritis only. Thirty-six trials evaluated electrophysical agents, seven manual therapies, four acupuncture or dry needling, or taping, three psychological therapies, dietary interventions or whole body vibration, two spa or peloid therapy and one foot insoles. Twenty-one trials included a placebo adjunctive therapy. We presented the effects stratified by different adjunctive therapies along with the overall results. We judged most trials to be at risk of bias, including 55% at risk of selection bias, 74% at risk of performance bias and 79% at risk of detection bias. Adverse events were reported in eight (13%) trials. Comparing adjunctive therapies plus land-based exercise therapy against placebo therapies plus exercise up to six months (short-term), we found low-certainty evidence for reduced pain and function, which did not meet our prespecified threshold for a clinically important difference. Mean pain intensity was 5.4 in the placebo group on a 0 to 10 numerical pain rating scale (NPRS) (lower scores represent less pain), and 0.77 points lower (0.48 points better to 1.16 points better) in the adjunctive therapy and exercise therapy group; relative improvement 10% (6% to 15% better) (22 studies; 1428 participants). Mean physical function on the Western Ontario and McMaster (WOMAC) 0 to 68 physical function (lower scores represent better function) subscale was 32.5 points in the placebo group and reduced by 5.03 points (2.57 points better to 7.61 points better) in the adjunctive therapy and exercise therapy group; relative improvement 12% (6% better to 18% better) (20 studies; 1361 participants). Moderate-certainty evidence indicates that adjunctive therapies did not improve QOL (SF-36 0 to 100 scale, higher scores represent better QOL). Placebo group mean QOL was 81.8 points, and 0.75 points worse (4.80 points worse to 3.39 points better) in the placebo adjunctive therapy group; relative improvement 1% (7% worse to 5% better) (two trials; 82 participants). Low-certainty evidence (two trials; 340 participants) indicates adjunctive therapies plus exercise may not increase adverse events compared to placebo therapies plus exercise (31% versus 13%; risk ratio (RR) 2.41, 95% confidence interval (CI) 0.27 to 21.90). Participant-reported global assessment was not measured in any studies. Compared with land-based exercise therapy, low-certainty evidence indicates that adjunctive electrophysical agents alongside exercise produced short-term (0 to 6 months) pain reduction of 0.41 points (0.17 points better to 0.63 points better); mean pain in the exercise-only group was 3.8 points and 0.41 points better in the adjunctive therapy plus exercise group (0 to 10 NPRS); relative improvement 7% (3% better to 11% better) (45 studies; 3322 participants). Mean physical function (0 to 68 WOMAC subscale) was 18.2 points in the exercise group and 2.83 points better (1.62 points better to 4.04 points better) in the adjunctive therapy plus exercise group; relative improvement 9% (5% better to 13% better) (45 studies; 3323 participants). These results are not clinically important. Mean QOL in the exercise group was 56.1 points and 1.04 points worse in the adjunctive therapies plus exercise therapy group (1.04 points worse to 3.12 points better); relative improvement 2% (2% worse to 5% better) (11 studies; 1483 participants), indicating no benefit (low-certainty evidence). Moderate-certainty evidence indicates that adjunctive therapies plus exercise probably result in a slight increase in participant-reported global assessment (short-term), with success reported by 45% in the exercise therapy group and 17% more individuals receiving adjunctive therapies and exercise (RR 1.37, 95% CI 1.15 to 1.62) (5 studies; 840 participants). One study (156 participants) showed little difference in radiographic joint structural changes (0.25 mm less, 95% CI -0.32 to -0.18 mm); 12% relative improvement (6% better to 18% better). Low-certainty evidence (8 trials; 1542 participants) indicates that adjunctive therapies plus exercise may not increase adverse events compared with exercise only (8.6% versus 6.5%; RR 1.33, 95% CI 0.78 to 2.27).Moderate- to low-certainty evidence showed no difference in pain, physical function or QOL between adjunctive therapies and placebo adjunctive therapies, or in pain, physical function, QOL or joint structural changes, compared to exercise only. Participant-reported global assessment was not reported for placebo comparisons, but there is probably a slight clinical benefit for adjunctive therapies plus exercise compared with exercise, based on a small number of studies. This may be explained by additional constructs captured in global measures compared with specific measures. Although results indicate no increased adverse events for adjunctive therapies used with exercise, these were poorly reported. Most studies evaluated short-term effects, with limited medium- or long-term evaluation. Due to a preponderance of knee osteoarthritis trials, we urge caution in extrapolating the findings to populations with hip osteoarthritis.

Acknowledgements: The author wishes to thank the German Federal Ministry for Economic Affairs and Climate Action (Bundesministerium für Wirtschaft und Klimaschutz, BMWK) for a grant received by the Institute for Future Energy Consumer Needs and Behavior (FCN) at RWTH Aachen University (Grant No. 03EI5230A), which part-funded the research and writing of this paper. Thanks also to colleagues at Cambridge Institute for Sustainability Leadership, University of Cambridge, UK, for support in developing the paper, and to colleagues at FCN for assistance with data acquisition., A post-World War 2 building boom in western Germany (the original Bundesrepublik) produced a cohort of some 8 million apartments, built in 1946-1979, that are relatively homogeneous in design and materials. On average, these apartments are very energy-inefficient, consuming around 147 kWh of heating energy per square meter of floor area per year (kWh/m2/y). Retrofitting them to about 50 kWh/m2/y is necessary to meet Germany's climate goals. Considerable skill and infrastructure have developed to attempt to achieve this, but it is expensive. This study investigates whether sales and rental markets disincentivise property owners from retrofitting these apartments to high energy efficiency standards. Data from sales and rental advertisements in 2019-2021 in Germany's largest online housing advertisement portal, Immoscout24, were used to estimate market sales and rental premiums for energy efficiency in these apartments. For property owners who retrofit apartments then sell them, sales premiums for energy efficiency generally fail to compensate for the retrofit costs, unless the renovation is subsidised. Meanwhile, for purchasers, the reduction in energy costs due to higher energy efficiency does not compensate for the higher purchase price. Likewise, for landlords/landladies who retrofit apartments then rent them out, the rental premiums due to higher energy efficiency are nowhere near sufficient to compensate for the retrofit costs. Tenants, however, can often offset the rental premium through energy savings. In all four cases, there is regional variation. Based on a detailed investigation of this market for energy efficiency, this study suggests specific policy interventions to compensate for these market anomalies.

International audience; The geological units on the floor of Jezero crater, Mars, are part of a wider regional stratigraphy of olivine-rich rocks, which extends well beyond the crater. We investigate the petrology of olivine and carbonate-bearing rocks of the Séítah formation in the floor of Jezero. Using multispectral images and x-ray fluorescence data, acquired by the Perseverance rover, we performed a petrographic analysis of the Bastide and Brac outcrops within this unit. We find that these outcrops are composed of igneous rock, moderately altered by aqueous fluid. The igneous rocks are mainly made of coarse-grained olivine, similar to some Martian meteorites. We interpret them as an olivine cumulate, formed by settling and enrichment of olivine through multi-stage cooling of a thick magma body.

We present the discovery of highly-collimated radio jets spanning a total of 355 kpc around the nearby elliptical galaxy NGC 2663, and the possible first detection of recollimation on kiloparsec scales. The small distance to the galaxy (~28.5 Mpc) allows us to resolve portions of the jets to examine their structure. We combine multiwavelength data: radio observations by the Murchison Widefield Array (MWA), the Australian Square Kilometre Array Pathfinder (ASKAP) and the Australia Telescope Compact Array (ATCA), and X-ray data from Chandra, Swift and SRG/eROSITA. We present intensity, rotation measure, polarisation, spectral index and X-ray environment maps. Regions of the southern jet show simultaneous narrowing and brightening, which can be interpreted as a signature of the recollimation of the jet by external, environmental pressure, though it is also consistent with an intermittent Active Galactic Nuclei (AGN) or complex internal jet structure. X-ray data suggest that the environment is extremely poor; if the jet is indeed recollimating, the large recollimation scale (40 kpc) is consistent with a slow jet in a low-density environment., 16 pages, 14 figures, Accepted for publication in MNRAS

Small cell lung cancer (SCLC) is characterized by morphologic, epigenetic and transcriptomic heterogeneity. Subtypes based upon predominant transcription factor expression have been defined that, in mouse models and cell lines, exhibit potential differential therapeutic vulnerabilities, with epigenetically distinct SCLC subtypes also described. The clinical relevance of these subtypes is unclear, due in part to challenges in obtaining tumor biopsies for reliable profiling. Here we describe a robust workflow for genome-wide DNA methylation profiling applied to both patient-derived models and to patients’ circulating cell-free DNA (cfDNA). Tumor-specific methylation patterns were readily detected in cfDNA samples from patients with SCLC and were correlated with survival outcomes. cfDNA methylation also discriminated between the transcription factor SCLC subtypes, a precedent for a liquid biopsy cfDNA-methylation approach to molecularly subtype SCLC. Our data reveal the potential clinical utility of cfDNA methylation profiling as a universally applicable liquid biopsy approach for the sensitive detection, monitoring and molecular subtyping of patients with SCLC.

Purpose This study aims to evaluate the effect of Alpha-Stim Anxiety, Insomnia and Depression (AID) cranial electrotherapy stimulation (CES) on anxiety, depression and health-related quality of life for primary care social prescribing service patients with anxiety symptoms. Design/methodology/approach Open-label patient cohort design with no control group. A total of 33 adult patients (average age 42 years) completed six weeks of Alpha-Stim AID use. Pre- and post-intervention assessment with participant self-report measures: Patient Health Questionnaire (PHQ-9), Generalised Anxiety Disorder (GAD-7) and European Quality of Life Five Dimension (EQ-5D-5L). Findings Reliable improvement and remission rates, respectively, were 53.39% and 33.3% for GAD-7; 46.7% and 29.5% for PHQ-9. There was a significant improvement in GAD-7 and PHQ-9 with large effect sizes. EQ-5D-5L results showed significant improvements in health-related quality of life. Perceived quality of life increased by 0.17 on the health index score, with the intervention adding 1.68 quality-adjusted life years (QALYs). Practical implications Alpha-Stim AID can be delivered through a primary health-care social prescribing service and most patients will use as prescribed and complete treatment course. Alpha-Stim AID CES may be an effective anxiety and depression treatment for people with anxiety symptoms. The widespread roll-out of Alpha-Stim AID in health-care systems should be considered. Originality/value To the best of the authors’ knowledge, this is the first study to respond to the UK’s National Institute for Health and Care (NICE) request for the collection of real-world data to understand better Alpha-Stim AID in relation to people’s treatment uptake, response rates and treatment completion rates (NICE, 2021).