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Background: Cognitive-motor training in form of exergames has been found to be feasible and effective for the improvement of motor and cognitive functioning in older adults and several patient populations. Exergame training under unstable conditions might increase the proprioceptive resources needed and thus might be a superior training approach compared to exergame training on stable ground for stroke patients, who often have proprioceptive deficits., Objective: Aim of this study is to assess the feasibility and effects of exergame-based cognitive-motor training on a labile platform on physical and cognitive functioning in stroke inpatients., Methods: This is two-armed pilot randomized controlled trial taking place in an inpatient neurologic rehabilitation clinic. A total of 30 persons that are undergoing inpatient rehabilitation due to a stroke will be randomly assigned to either the intervention group (IG) or the control group (CG). Participants of the IG will receive exergame-based motor-cognitive training on a labile surface, whereas participants of the CG will train on a stable surface. Primary outcome is feasibility comprising measures of adherence, attrition, safety and usability. Secondary outcomes will be measures of cognitive (psychomotor speed, inhibition, selective attention, cognitive flexibility, brain activity) and motor (functional mobility, gait speed, balance, proprioception) functioning., Results: Data collection started in February 2024 and is expected to be completed by August 2024., Conclusion: This is the first study looking into exergame training on labile surface in stroke patients. It will give valuable insights into the feasibility and potential added value of this type of training and thus inform further implementation efforts in the context of inpatient rehabilitation., Clinical Trial Registration: ClinicalTrials.gov, NCT06296069., Competing Interests: The Senso-Swing prototype formally belongs to Dividat AG. Dividat AG provides the Senso-Swing free of charge for the duration of the study. Dividat AG was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Büttiker, Marks, Hanke, Ludyga, Marsico, Eggimann and Giannouli.)

Background Aims: Culture-derived mesenchymal stromal cells (MSCs) exhibit variable characteristics when manufactured using different methods, source material and culture media. The purpose of this multicenter study was to assess the impact on MSC expansion, gene expression and other characteristics when different laboratories expanded MSCs from cultures initiated with bone marrow-MSC aliquots derived from the same donor source material yet with different growth media., Methods: Eight centers expanded MSCs using four human platelet lysate (HPL) and one fetal bovine serum (FBS) products as media supplements. The expanded cells were taken through two passages then assessed for cell count, viability, doubling time, immunophenotype, cell function, immunosuppression and gene expression. Results were analyzed by growth media and by center., Results: Center methodologies varied by their local seeding density, feeding regimen, inoculation density, base media and other growth media features (antibiotics, glutamine, serum). Doubling times were more dependent on center than on media supplements. Two centers had appropriate immunophenotyping showing all MSC cultures were positive for CD105, CD73, CD90 and negative for CD34, CD45, CD14, HLA-DR. MSCs cultured in media supplemented with FBS compared with HPL featured greater T-cell inhibition potential. Gene expression analysis showed greater impact of the type of media supplement (HPL versus FBS) than the manufacturing center. Specifically, nine genes were decreased in expression and six increased when combining the four HPL-grown MSCs versus FBS (false discovery rate [FDR] <0.01), however, without significant difference between different sources of HPL (FDR <0.01)., Conclusions: Local manufacturing process plays a critical role in MSC expansion while growth media may influence function and gene expression. All HPL and FBS products supported cell growth., Competing Interests: Declaration of Competing Interest The authors have no commercial, proprietary, or financial interest in the products or companies described in this article., (Copyright © 2023 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

There are some syndromes that present with unique manifestations pertaining to the spinal column. A good working understanding of these common syndromes is useful for the spinal deformity surgeons and related healthcare providers. This review attempts to encompass these unique features and discuss them in three broad groups: hypermobility syndromes, muscle pathology-related syndromes, and syndromes related to poor bone quality. This review explores the features of these syndromes underpinning the aspects of surgical and medical management. This review represents the proceedings of the Paediatric Half-Day Course at the 57th Annual Meeting of the Scoliosis Research Society., (© 2024. The Author(s), under exclusive licence to Scoliosis Research Society.)

Background: In deep plane rhytidectomy, it is accepted that a more vertical vector will lead to a more natural rejuvenated look than a horizontal vector of pull. Objective: Among patients undergoing deep plane rhytidectomy, can skin angle measurements designed by the authors be used as a proxy for vector of tension to confirm a vertical vector? Methods: Case series measuring the rhytidectomy vector of pull for a series of patients performed by a single surgeon. Results were compared between the vectors of the pre- and postauricular flaps as well as comparing the vector of pull in male versus female patients, patients undergoing facelift alone versus in conjunction with other rejuvenation procedures, and between primary versus revision rhytidectomy patients. Results: Patient characteristics: Average age 64.4 (range 47-79), predominantly female (26/28, 92.9%), primary rhytidectomy (24/28, 85.7%), with concomitant brow lift (12/28, 42.9%). Results reveal a more vertical than horizontal vector of pull on both the pre- and postauricular superficial musculoaponeurotic system flaps with the vector of the anterior flap being more vertical than that of the posterior flap. Conclusion: Utilizing a novel proxy measurement, the vector of pull of the deep plane facelift was more vertical than horizontal.

This study examined the sustained and moderating effects of a behavioural sleep intervention for autistic children in a randomised controlled trial. Autistic children (5-13 years) with sleep problems were randomised to the Sleeping Sound intervention or Treatment as Usual (TAU). At 12-month follow-up (n = 150), caregivers of children in the Sleeping Sound group reported greater reduction in child sleep problems compared to TAU (p < .001, effect size: - 0.4). The long-term benefits of the intervention were greater for children taking sleep medication, children of parents who were not experiencing psychological distress, and children with greater autism severity. The Sleeping Sound intervention demonstrated sustained improvements in child sleep. Identified moderators may inform treatment by indicating which subgroups may benefit from further support., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Report the rate and severity of degenerative disc disease (DDD) in non-surgical adolescent idiopathic scoliosis (AIS) patients and correlate these findings with patient-reported symptomatology scores. Additionally, to quantify the rate of concurrent pathological radiological findings in this group., Methods: This was a retrospective chart review study at a single tertiary centre. AIS patients aged 10-16 who had received a whole spine MRI between September 2007 and January 2019 and who had not received surgical intervention to their spine were included. MRI scan reports were screened to extract those who had evidence of DDD. These were then reviewed by a blinded second reviewer who graded every disc using the Pfirrmann grading system. SRS-22 scores were extracted for patients when available., Results: In total, 968 participants were included in the study. Of these, 93 (9.6%) had evidence of DDD, which was Pfirrmann grade ≥ 3 in 28 (2.9%). The most commonly affected level was L5/S1 (59.1% of DDD cases). A total of 55 patients (5.7%) had evidence of syringomyelia, 41 (3.4%) had evidence of spondylolisthesis (all L5/S1), 14 (1.4%) had bilateral L5 pars defects, and 5 (0.5%) had facet joint degeneration. Spondylolisthesis and bilateral pars defects were more common in patients with DDD identified on MRI scan (p < 0.001 and p = 0.04, respectively). Function (p = 0.048) and pain (p = 0.046) scores were worse in patients with DDD., Conclusion: We present a baseline for the rate and severity of DDD in the non-operative AIS cohort. This should assist in decision-making and counselling of patients prior to surgery., Level of Evidence: III., (© 2024. The Author(s).)

Recent breakthroughs in AI coupled with the rapid accumulation of protein sequence and structure data have radically transformed computational protein design. New methods promise to escape the constraints of natural and laboratory evolution, accelerating the generation of proteins for applications in biotechnology and medicine. To make sense of the exploding diversity of machine learning approaches, we introduce a unifying framework that classifies models on the basis of their use of three core data modalities: sequences, structures and functional labels. We discuss the new capabilities and outstanding challenges for the practical design of enzymes, antibodies, vaccines, nanomachines and more. We then highlight trends shaping the future of this field, from large-scale assays to more robust benchmarks, multimodal foundation models, enhanced sampling strategies and laboratory automation., (© 2024. Springer Nature America, Inc.)

Objective: To determine whether differences exist for older persons presenting to Emergency Departments (EDs) with lower back pain (LBP) in terms of management, health service resource use and cost when compared to younger patients with LBP., Methods: Retrospective analysis of routinely collected electronic medical record data from January 2015 to July 2021. Data from 11,098 adults presenting with LBP to two large regional Australian EDs were analysed over a 5-year period. Rates of presentation, investigation, medication use, spinal surgery and cost were assessed for all participants with respect to age groups (over or under 65 years of age), diagnosis and time. Multivariable logistic regression analysis was employed to assess the contribution of presentation characteristics to the risk of inpatient admission and to investigate the variable effect of patient age., Results: Older people represented 23% (n = 2565) of all LBP presentations, with a growing proportion of presentations over time. More than 1 in 4 patients over 65 were admitted (n = 703, 27%), with CT imaging being proportionately three times more prevalent (24% vs. 6%), and average cost double (AU$3973 vs. $1671) that of the younger population. Consultation by an ED physiotherapist was associated with lower admission risk across all adult presentations (OR 0.52, 95% CI [0.40 to 0.67])., Conclusions: Older persons are over-represented amongst gradually increasing rates of LBP presentations to EDs and associated with escalating cost of care and hospital resource use. Older patients present a different clinical and economic profile to younger patients, supporting the provision of individualised management recommendations., (© 2023 The Authors. Australasian Journal on Ageing published by John Wiley & Sons Australia, Ltd on behalf of AJA Inc’.)

Background: Musculoskeletal shoulder pain is a common problem and its symptoms often become persistent. The experience of pain is multidimensional, and therefore, a range of patient characteristics may influence treatment response. An altered sensory processing has been associated with persistent musculoskeletal pain states and may contribute to outcomes in patients with musculoskeletal shoulder pain. The presence and potential impact of altered sensory processing in this patient cohort is not currently known. The aim of this prospective longitudinal cohort study is to investigate if baseline sensory characteristics are associated with clinical outcomes in patients presenting to a tertiary hospital with persistent musculoskeletal shoulder pain. If found, a relationship between sensory characteristics and outcome may lead to the creation of more effective treatment strategies and improvements in risk adjustment and prognosis., Methods: This is a single-centre prospective cohort study with 6-, 12- and 24-month follow-up. A total of 120 participants aged ≥18 years with persistent musculoskeletal shoulder pain (≥3 months) will be recruited from an Australian public tertiary hospital orthopaedic department. Baseline assessments, including quantitative sensory tests and a standardised physical examination, will be performed. In addition, information will be obtained from patient interviews, self-report questionnaires and medical records. Follow-up outcome measures will comprise information from the Shoulder Pain and Disability Index and a six-point Global Rating of Change scale., Analysis: Descriptive statistics will be used to report baseline characteristics and outcome measures over time. Change in outcome measures at the primary endpoint of six months from baseline will be calculated using paired t-tests. Associations between baseline characteristics and outcomes at a 6-month follow-up will be reported using multivariable linear and logistic regression models., Discussion: Understanding the relationship between sensory profile and the variable response to treatment in people with persistent musculoskeletal shoulder pain may enhance our understanding of the mechanisms contributing to the presentation. In addition, through better understanding of the contributing factors, the results of this study may contribute to the development of an individualised, patient-centred approach to treatment for people with this highly prevalent and debilitating condition., (© 2023 The Authors. Musculoskeletal Care published by John Wiley & Sons Ltd.)

Artificial intelligence (AI) is being increasingly integrated into scientific discovery to augment and accelerate research, helping scientists to generate hypotheses, design experiments, collect and interpret large datasets, and gain insights that might not have been possible using traditional scientific methods alone. Here we examine breakthroughs over the past decade that include self-supervised learning, which allows models to be trained on vast amounts of unlabelled data, and geometric deep learning, which leverages knowledge about the structure of scientific data to enhance model accuracy and efficiency. Generative AI methods can create designs, such as small-molecule drugs and proteins, by analysing diverse data modalities, including images and sequences. We discuss how these methods can help scientists throughout the scientific process and the central issues that remain despite such advances. Both developers and users of AI toolsneed a better understanding of when such approaches need improvement, and challenges posed by poor data quality and stewardship remain. These issues cut across scientific disciplines and require developing foundational algorithmic approaches that can contribute to scientific understanding or acquire it autonomously, making them critical areas of focus for AI innovation., (© 2023. Springer Nature Limited.)

Purpose: To address the anatomical challenges facing complex and revision spinal surgery, patient-specific 3D-printed models (3D-PMs) have received growing attention worldwide, primarily in adults. We report the use of a 3D-PM in the treatment of a case of wound breakdown over a component of a VEPTR (Vertical Expandable Prosthetic Titanium Rib; DePuy-Synthes) system, requiring replacement of Dunn-McCarthy hook and sleeve with components contoured to a patient-specific 3D-PM of the spine., Method: A two-year-old born with myelomeningocele (MMC), repaired at birth, developed progressive MMC-associated kyphoscoliosis. Elective insertion of a rib-to-pelvis 'Eiffel Tower' bilateral VEPTR growing rods construct was performed without initial complication. Prominence of the right VEPTR sleeve and Dunn-McCarthy hook side-to-side connector resulted in breakdown of overlying poor-quality soft tissues, necessitating washout, partial implant removal, intravenous antibiotic therapy and delayed primary wound closure. A patient-specific 3D-PM, utilising pre-operative CT spine and pelvis 3D-reconstructions, allowed pre-operative formation of a contoured implant, which was inserted without need for further revision., Results: The patient underwent further VEPTR lengthening without recurrent infection, wound breakdown or implant failure at 24-month follow-up. Satisfactory control of the deformity has been achieved with continued improvement in sitting height and radiographic indices., Conclusion: This case illustrates the possibility, in certain cases, of using 3D-PM to develop complex components of spinal implant systems pre-operatively, removing the time and difficulty of intra-operative contouring. Consequently, custom-contoured implants may be produced, sterilised and implanted. This technique may be an option, in infants, including MMC-associated kyphoscoliosis, where midline fixation is not possible., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: The burden of Musculoskeletal disorders (MSD) is large. Surgery is an important management option but the factors that shape patients' surgical decisions are not well understood. As prior reviews have explored only single data types or conditions, a mixed methods appraisal across the musculoskeletal spectrum was undertaken., Methods: A mixed-methods systematic, convergent segregated approach was used, with PubMed, Cumulated Index to Nursing and Allied Health Literature (CINHAL), Embase and PsycINFO searched to identify studies of adult patients' decisions about whether to undergo surgery. A narrative synthesis was conducted, with identified themes integrated across quantitative, qualitative and mixed-methods studies., Results: Forty-six studies were included (24 quantitative, 19 qualitative and three mixed methods), with four decision-making themes identified (symptoms, sociodemographic and health factors, information and perceptions). Decision-making involves a complex interaction of individual sociodemographic, health and symptom information, integrated with individual perceptions of candidacy and surgical expectations. While most studies investigated hip and knee surgery, across all included conditions, patients are more likely to favour surgery if symptoms and/or dysfunction are higher, and if perceptions of surgical candidacy and processes (outcomes, inconvenience, and risk) are favourable. Other factors including age, general health, race, financial context, professional and non-professional communication, and information sources also impact decision-making but exert a less consistent impact upon the propensity to prefer surgery., Conclusion: Patients are more likely to choose surgery for MSD when they have higher levels of symptoms or dysfunction and positive perceptions of surgical suitability and expectations. Other factors important to individuals, have a less consistent impact upon the propensity to prefer surgery. These findings have potential to aid the efficient referral of patients to orthopaedics. More research is needed to validate these findings across the spectrum of MSD., (© 2022 The Authors. Musculoskeletal Care published by John Wiley & Sons Ltd.)

Background: Subacromial injection is known to influence pain of subacromial origin, yet its association with conservative care outcomes is unknown. This study investigated whether immediate response to subacromial injection of corticosteroid and local anaesthetic is associated with conservative care outcomes at 12 weeks post injection and/or progression to surgery., Design: prospective prognostic cohort study., Methods: Sixty-four participants with subacromial related shoulder pain attending initial orthopaedic outpatient appointment at an Australian public hospital, received subacromial injection of corticosteroid and local anaesthetic followed by up to 12 weeks of physiotherapy. Immediate response to injection was measured by change in shoulder range of motion (ROM) and pain immediately (within 20 min) before and after injection. The Shoulder Pain and Disability Index (SPADI) was measured at baseline, 6 and 12-weeks., Results: Backward stepwise linear regression revealed immediate post-injection improvement in pain-free ROM (p = 0.001) and higher baseline symptoms (p = 0.016) were significantly associated with better 12-week SPADI outcomes. Longer symptom duration (p = 0.029) and higher age (p = 0.013) were significantly associated with poorer outcomes. Only 11 individuals progressed to surgery. The resultant model could explain 35% of the variation in change in SPADI at 12 weeks., Conclusion: Improvement in pain-free shoulder ROM immediately post injection is significantly associated with better 12-week conservative care outcomes. This information, derived from within consultation injection responses, could help inform decisions about potential treatment options. Further research with higher numbers and longer-term patient-reported outcomes could further clarify these findings., Registration: Australia and New Zealand Clinical Trials Registry 21 May 2012: 12612000532808., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This review aimed to explore the available literature to update our understanding of the long head of biceps (LHB) at the shoulder. Synthesise our findings to identify emergent themes and knowledge gaps to inform future research and management directions., Methods: PubMed, Embase, Cinahl, SportDiscus, CENTRAL, and Web of Science were searched from inception to 31st December 2021. Articles were included if they referenced adult participants > 18 years of age and were written in English., Results: 214 articles were included in the final analysis, and results were categorised into six emergent themes: (1) Anatomy - Normal anatomical variation of the biceps from aberrant origins, third and fourth accessory heads, and an absence of the LHB tendon (LHBT) are not necessarily benign, with shoulder pain and instability a commonly reported theme. (2) Function - Bicep's role in glenohumeral elevation and stability in healthy shoulders is minimal. In contrast, LHB has a more significant role in shoulder stability and humeral head depression in subjects with rotator cuff failure or an absent LHBT. (3) Pathology - There is an association between LHB tendinopathy, rotator cuff disease, LHBT instability and occult rotator cuff tears. Early recruitment and hyperactivity of the LHB in subjects with symptomatic rotator cuff tears and instability suggest a potential compensatory role. (4) Assessment - The limited diagnostic utility of special orthopaedic tests in assessing LHBT pathology was a consistent theme. The utility of magnetic resonance imaging and ultrasound to identify full-thickness tendon tears and instability of the LHBT was moderate to high. However, the utility of clinical tests and imaging may be underestimated due to arthroscopy's limitations in fully visualising the proximal LHBT. (5) Non-Surgical Management - Ultrasound-guided injections into the biceps sheath show greater accuracy and patient outcomes than blinded injections; however, the entry of injectate into the intraarticular glenohumeral joint may have unwanted complications. (6) Surgical management - For the surgical management of biceps pathology with or without rotator cuff pathology, both biceps tenodesis and tenotomy report similar improvements in pain without any significant adverse effect on strength or function. Tenodesis favoured higher overall constant scores and a lower incidence of Popeye deformity and cramping arm pain, with tenotomy trending to be more cost and time effective. For patients with a healthy LHBT, rotator cuff repair with adjunctive tenodesis or tenotomy fails to provide additional clinical improvements compared to rotator cuff repair in isolation., Conclusions: The scoping review highlights the variability of biceps anatomy, which is not necessarily benign and suggests a minimal role of the LHB in shoulder elevation and stability in healthy individuals. In contrast, individuals with rotator cuff tears experience proximal humeral migration and demonstrate hyperactivity of the LHB, suggesting a potential compensation role. The observed prevalence of LHBT pathology with rotator cuff tears is well established; however, the cause-and-effect relationship between LHBT pathology and rotator cuff disease is undetermined. The diagnostic utility of clinical tests and imaging to exclude LHBT pathology may be understated due to the limitations of arthroscopy to visualise the proximal LHBT fully. Rehabilitation programs for the LHB are understudied. Similar post-surgical clinical outcomes are observed for tenodesis and tenotomy for biceps and rotator cuff-related shoulder pain. Subjects undergoing biceps tenodesis are less likely to have cramping arm pain and a Popeye deformity than patients undergoing biceps tenotomy. The significance of routine surgical removal of the LHBT and sequelae on rotator cuff tear progression to failure and long-term shoulder function is unknown, and further research is required., Pre-Registration: OSF: https://osf.io/erh9m., (© 2023. Crown.)

Background: People with Parkinson`s disease (PD) often suffer from both motor and cognitive impairments. Simultaneous motor and cognitive training stimulates neurobiological processes which are important especially for people with PD. The aim of this study is to test the feasibility and effects of simultaneous cognitive-motor training in form of exergames in the setting of inpatient rehabilitation of persons with PD., Methods: Forty participants (72.4 ± 9.54 years; Hoehn and Yahr stage 1-4) were randomly assigned to either the intervention group, which trained five times a week in addition to the conventional rehabilitation program, or the control group, which underwent the standard rehabilitation treatment only. Primary outcome was feasibility (measured by adherence rate, attrition rate, occurrence of adverse events, system usability scale (SUS), and NASA TLX score). In addition, various cognitive (Go/No-Go test, reaction time test (RTT), color word interference test (D-KEFS) and Trail Making Test A and B (TMT)) and motor (preferred gait speed, maximum gait speed, dual-task gait speed, Short Physical Performance Battery (SPPB), Timed Up and Go (TUG) and 5 times Sit-to-Stand (5xStS)) tests were conducted before and after the intervention phase in order to determine training effects RESULTS: Adherence rate was 97%, there were just two dropouts due to reasons unrelated to the study and there were no adverse events. The mean NASA TLX value was 56.2 and the mean value of the SUS was 76.7. Significant time-group interaction effects were observed for the 5xStS, the SPPB, the RTT, the Go/No-Go test and the D-KEFS 2., Discussion: Exergaming, as applied in this study, showed to be feasible, safe and likely effective for the improvement of cognitive and motor functions of PD inpatients. Because of this future randomized controlled trials with a main focus on testing the efficacy of this new intervention are warranted., Trial Registration: The study has been registered at ClinicalTrials.gov (ID: NCT04872153)., (© 2023. The Author(s).)

Purpose: Poor patient adherence to compression stockings remains a difficult and pervasive problem for clinicians, with costly repercussions for patients and health-care systems. The purpose of this paper was to describe the application of behavior change theory to the systematic development of a suite of resources, aimed at improving patient adherence to wearing compression stockings., Methods: Employing a non-empirical approach, behavior-change theory was used to develop an innovative intervention as part of a multi-phase project. Target behaviors, barriers and potential enablers were identified in relation to stocking adherence. An impact-likelihood matrix for behavior prioritization was used to identify possible areas for intervention within occupational therapy outpatient clinics. Selection of suitable resources and their consequent development were based on a narrative and problem-solving process by a panel of clinical experts., Results: Of 14 potential domains embedded in the Theoretical Domains Framework, the key target behaviors and barriers were associated with eight domains. Michie's Behavior Change Wheel revealed recommendations in six subdivisions and of these, four intervention functions were selected by the panel, based on their potential impact and likelihood of adoption in clinical practice. Findings led to the development of a suite of resources comprising a new questionnaire, a clinical decision tree, augmented by clinical answer sheets corresponding to each of the barriers., Conclusion: Application of behavior change theory informed the design of a behavior change intervention comprising an integrated suite of resources for novice and experienced clinicians., Practice Implications: These novel resources have potential to improve patient adherence to compression stockings and consequently generate health-care savings through reduced need for wound care products, and medical interventions with translation to other settings and conditions requiring compression stockings. Patient outcomes will likely be improved with reduced pain, improved quality of life and earlier resumption of usual occupations., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Bar et al.)

Safety concerns associated with foetal bovine serum (FBS) have restricted its translation into clinics. We hypothesised that platelet lysate (PL) can be utilised as a safe alternative to produce serum-free 3D-engineered skin. PL supported a short-term expansion of fibroblasts, with negligible replication-induced senescence and directed epidermal stratification. PL-expanded fibroblasts were phenotypically separated into three subpopulations of CD90 + FAP + , CD90 + FAP - and CD90 - FAP + , based on CD90 (reticular marker) and FAP (papillary marker) expression profile. PL drove the expansion of the intermediate CD90 +  FAP +  subpopulation in expense of reticular CD90 + FAP - , which may be less fibrotic once grafted. The 3D-engineered skin cultured in PL was analysed by immunofluorescence using specific markers. Detection of ColIV and LMN-511 confirmed basement membrane. K10 confirmed near native differentiation pattern of neo-epidermis. CD29- and K5-positive interfollicular stem cells were also sustained. Transmission and scanning electron microscopies detailed the ultrastructure of the neo-dermis and neo-epidermis. To elucidate the underlying mechanism of the effect of PL on skin maturation, growth factor contents in PL were measured, and TGF-β1 was identified as one of the most abundant. TGF-β1 neutralising antibody reduced the number of Ki67-positive proliferative cells, suggesting TGF-β1 plays a role in skin maturation. Moreover, the 3D-engineered skin was exposed to lucifer yellow on days 1, 3 and 5. Penetration of lucifer yellow into the skin was used as a semi-quantitative measure of improved barrier function over time. Our findings support the concept of PL as a safe and effective serum alternative for bioengineering skin for cell therapies., (© 2022. The Author(s).)

Objectives: To assess primary impact of selective Licensing (SL), an area-based intervention in the private rented housing market, on individual self-reported anxiety and neighbourhood mental health (MHI-Mental Healthcare Index) and secondary impacts on antisocial behaviour (ASB), population turnover and self-reported well-being., Design: Difference-in-difference (DiD) was used to evaluate effects of SL schemes initiated 2012-2018. 921 intervention areas (lower super output areas) were matched 3:1 using propensity scores derived from sociodemographic and housing variables (N=3.684 including controls). Average treatment effect on treated (ATT) was calculated for multiple time period DiD in area-level analyses. Canonical DiD was used for individual-level analysis by year of treatment initiation while adjusting for age, sex, native birth and occupational class., Setting: Intervention neighbourhoods and control areas in Greater London, UK, 2011-2019., Participants: We sampled 4474 respondents renting privately in intervention areas (N=17 347 including controls) in Annual Population Survey and obtained area-level MHI population data., Interventions: Private landlords in SL areas must obtain a licence from the local authority, allow inspection and maintain minimum housing standards., Results: ATT after 5 years was significantly lower for MHI (-7.5%, 95% CI -5.6% to -8.8%) than controls. Antidepressant treatment days per population reduced by -5.4% (95% CI -3.7% to -7.3), mental health benefit receipt by -9.6% (95% CI -14% to -5.5%) and proportion with depression by -12% (95% CI -7.7% to -16.3%). ASB reduced by -15% (95% CI -21% to -8.2%). Population turnover increased by 26.5% (95% CI 22.1% to 30.8%). Sensitivity analysis suggests overlap with effects of London 2012 Olympic regeneration. No clear patterns were observed for self-reported anxiety., Conclusions: We found associations between SL and reductions in area-based mental healthcare outcomes and ASB, while population turnover increased. A national evaluation of SL is feasible and necessary., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: While the efficacy of telehealth in musculoskeletal physiotherapy has been supported, its cost effectiveness has not been established. Therefore, the objective of this review was to ascertain the health economic impact of outpatient musculoskeletal physiotherapy delivered by telehealth and describe methodology utilized to date., Methods: Electronic searching of PubMed, CINHAL, PEDro, and Web of Science databases was undertaken alongside handsearching for publications comprising: population: adults with musculoskeletal disorders managed in any type of outpatient ambulatory setting; intervention: physiotherapy delivered by telehealth comparison: traditional in-person physiotherapy; and, outcomes: economic analyses reporting costs and consequences. Appraisal was undertaken with the Downs and Black Questionnaire and the Consolidated Health Economic Evaluation Reporting Standards Checklist., Results: Eleven studies of mixed methodological quality were included. Most were conducted in the public sector, from the economic perspective of the health service funder. Telehealth consistently produced health outcomes akin to in-person care. In all but one, telehealth was less costly, with savings achieved by reducing in-person consultations and travel costs., Conclusion: Telehealth is as effective and cheaper than in-person physiotherapy for musculoskeletal disorders in public hospital outpatients. Further health economic research is needed to clarify the economic impact of telehealth upon non-government providers of musculoskeletal physiotherapy., (Copyright © 2022 Darryn Marks, Sarah Kitcher, Elodie Attrazic, Wayne Hing, Michelle Cottrell.)

Objective: The aim of the current study was to evaluate parental perceptions of the acceptability of a brief behavioural sleep intervention for autistic children (aged 5-13 years) using the Theoretical Framework of Acceptability (TFA)., Methods: Qualitative data were collected during a large randomised controlled trial evaluating the efficacy of the Sleeping Sound intervention: 123 families were randomised to the intervention group, of which 115 (93%) completed at least one intervention session and 82 (67%) provided qualitative evaluation data in the 3-month follow-up survey. Consultation records from intervention sessions and parent surveys were qualitatively analysed post hoc using a hybrid approach to thematic analysis., Results: Findings were categorised under the seven themes of the TFA (affective attitude, burden, ethicality, intervention coherence, opportunity costs, perceived effectiveness, self-efficacy) in addition to three themes that were defined following inductive and deductive coding (barriers to implementation, facilitators to implementation, suggestions for improvement). Participants spoke positively about their experience participating in the intervention and perceived the intervention to be appropriate and effective. Most parents (95.5%) reported that they would recommend the Sleeping Sound intervention to other families of autistic children. Barriers to implementation included child and parent anxiety, child health problems, parental preferences, family circumstances, and other (e.g., school holidays). Facilitators to implementation included family support and consistency with strategies., Conclusions: The Sleeping Sound intervention was considered acceptable to parents of autistic children as evidenced by largely positive feedback regarding their experience. The results highlighted areas for improvement which can be used to inform future iterations of the intervention., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Anthracycline cardiotoxicity is a significant clinical challenge. Biomarkers to improve risk stratification and identify early cardiac injury are required., Objectives: The purpose of this pilot study was to prospectively characterize anthracycline cardiotoxicity using cardiovascular magnetic resonance (CMR), echocardiography and MicroRNAs (MiRNAs), and identify baseline predictors of LVEF recovery., Methods: Twenty-four patients (age 56 range 18-75 years; 42 % female) with haematological malignancy scheduled to receive anthracycline chemotherapy (median dose 272 mg/m 2 doxorubicin equivalent) were recruited and evaluated at three timepoints (baseline, completion of chemotherapy, and 6 months after completion of chemotherapy) with multiparametric 1.5 T CMR, echocardiography and circulating miRNAs sequencing., Results: Seventeen complete datasets were obtained. CMR left ventricular ejection fraction (LVEF) fell significantly between baseline and completion of chemotherapy (61 ± 3 vs 53 ± 3 %, p < 0.001), before recovering significantly at 6-month follow-up (55 ± 3 %, p = 0.018). Similar results were observed for 3D echocardiography-derived LVEF and CMR-derived longitudinal, circumferential and radial feature-tracking strain. Patients were divided into tertiles according to LVEF recovery (poor recovery, partial recovery, good recovery). CMR-derived mitral annular plane systolic excursion (MAPSE) was significantly different at baseline in patients exhibiting poor LVEF recovery (11.7 ± 1.5 mm) in comparison to partial recovery (13.7 ± 2.7 mm), and good recovery (15.7 ± 3.1 mm; p = 0.028). Furthermore, baseline miRNA-181-5p and miRNA-221-3p expression were significantly higher in this group. T2 mapping increased significantly on completion of chemotherapy compared to baseline (54.0 ± 4.6 to 57.8 ± 4.9 ms, p = 0.001), but was not predictive of LVEF recovery. No changes to LV mass, extracellular volume fraction, T 1 mapping or late gadolinium enhancement were observed., Conclusions: Baseline CMR-derived MAPSE, circulating miRNA-181-5p, and miRNA-221-3p were associated with poor recovery of LVEF 6 months after completion of anthracycline chemotherapy, suggesting their potential predictive role in this context. T2 mapping increased significantly on completion of chemotherapy but was not predictive of LVEF recovery., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier B.V.)

Background: Behavioural sleep problems are common in children with autism spectrum disorder (ASD); however, evidence for the efficacy of behavioural sleep interventions is limited. This study examined the efficacy of a brief behavioural sleep intervention in autistic children. It was hypothesised that the intervention would reduce overall child sleep problems (primary outcome), in addition to improvements in children's social, emotional, cognitive, academic functioning, and quality of life, and parent/caregivers' stress, quality of life, and mental health (secondary outcomes)., Methods: A randomised controlled trial was conducted with participants randomised via a computer-generated sequence to the sleeping sound intervention (n = 123) or treatment as usual (n = 122) group. Participants comprised 245 children with an ASD diagnosis. Inclusion criteria were as follows: confirmation of DSM IV or DSM-5 diagnosis of ASD, participants aged between 5 and 13 years and parent/caregiver report of moderate-severe sleep problems. Exclusion criteria were as follows: parent/caregiver intellectual disability or lacking sufficient English to complete questionnaires; and child participant with co-occurring medical conditions known to impact sleep. The intervention group received the sleeping sound intervention (2 × 50-min face-to-face sessions plus follow-up phone call) by a trained clinician., Results: Change in children's sleep problems was measured by the Children's Sleep Habits Questionnaire (CSHQ) at 3 months post randomisation. Parents/caregivers of children in the intervention group reported a reduction in child sleep problems at 3 months post randomisation (effect size: E.S -0.7). There were also small effects in a number of child (internalising symptoms, emotional behavioural disturbance and quality of life) and parent/caregiver (mental health, parenting stress and quality of life) outcomes; however, these did not remain significant when controlling for multiple comparisons., Conclusions: The sleeping sound ASD intervention is an efficacious and practical way to reduce sleep problems for autistic children. This brief behavioural intervention has the potential to be embedded easily into the Australian healthcare system., (© 2022 The Authors. Journal of Child Psychology and Psychiatry published by John Wiley & Sons Ltd on behalf of Association for Child and Adolescent Mental Health.)

Southeast Asia is considered to have some of the highest levels of marine plastic pollution in the world. It is therefore vitally important to increase our understanding of the impacts and risks of plastic pollution to marine ecosystems and the essential services they provide to support the development of mitigation measures in the region. An interdisciplinary, international network of experts (Australia, Indonesia, Ireland, Malaysia, the Philippines, Singapore, Thailand, the United Kingdom, and Vietnam) set a research agenda for marine plastic pollution in the region, synthesizing current knowledge and highlighting areas for further research in Southeast Asia. Using an inductive method, 21 research questions emerged under five non-predefined key themes, grouping them according to which: (1) characterise marine plastic pollution in Southeast Asia; (2) explore its movement and fate across the region; (3) describe the biological and chemical modifications marine plastic pollution undergoes; (4) detail its environmental, social, and economic impacts; and, finally, (5) target regional policies and possible solutions. Questions relating to these research priority areas highlight the importance of better understanding the fate of marine plastic pollution, its degradation, and the impacts and risks it can generate across communities and different ecosystem services. Knowledge of these aspects will help support actions which currently suffer from transboundary problems, lack of responsibility, and inaction to tackle the issue from its point source in the region. Being profoundly affected by marine plastic pollution, Southeast Asian countries provide an opportunity to test the effectiveness of innovative and socially inclusive changes in marine plastic governance, as well as both high and low-tech solutions, which can offer insights and actionable models to the rest of the world., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Debate exists as to whether anterior-posterior spinal fusion (APSF), rather than posterior-only spinal fusion (PSF), provides benefit for treating severe thoracic adolescent idiopathic scoliosis (AIS). This systematic review and meta-analysis compare (1) Cobb angle correction, (2) complication and reoperation rate, (3) pulmonary function, (4) number of fused segments, and 5) patient-reported outcome measures (PROMs) in both groups., Methods: Electronic databases were searched to identify studies that met the following inclusion criteria: comparative studies (level 3 or above), severe thoracic curves (≥ 70°), age ≤ 16, AIS aetiology, Lenke 1-4 curves and follow-up ≥ 1 year for ≥ 95% of patient population. Literature was graded for quality and bias using GRADE and MINORS criteria ., Results: Eight studies were included, defined by GRADE as low or moderate level evidence. Three studies showed superior curve correction in the APSF group; however, the meta-analysis showed no significant difference in curve correction between groups (95% CI - 3.45-12.96, P  = 0.26). There were more complications in the APSF group, without statistical significance (95% CI 0.53-3.39, P  = 0.54; I 2  = 0%, P  = 0.78). There were no re-operations in either group. Two studies reported pulmonary function; one showed better function in the APSF group, the other better function in the PSF group. One study showed fewer fused segments in the APSF group, however, no significance was observed in the meta-analysis (95%CI - 1.65-0.31, P  = 0.18). Three studies reported PROMs with no differences reported between groups., Conclusions: APSF and PSF have been found to have comparable results. The present evidence cannot support recommendations for guidelines on future practice with regards to effect on curve correction, complications, re-operations, pulmonary function or PROMs., Level of Evidence: Level III, Systematic review of Level-III studies., Competing Interests: Conflict of interestNone of the authors have conflict of interests to disclose., (© Crown 2022.)

Objectives: English local authorities (LAs) are interested in reducing alcohol-related harms and may use discretionary powers such as the Late Night Levy (LNL) to do so. This study aims to describe how system stakeholders hypothesise the levy may generate changes and to explore how the system, its actors and the intervention adapt and co-evolve over time., Design: A process evaluation from a complex systems perspective, using qualitative methods., Setting: A London LA with high densities of residential and commercial properties, which implemented the LNL in 2014., Participants: Data were generated through interviews with LNL implementers and alcohol consumers, observations in bars and during LNL patrols and documentary review., Intervention: The LNL allows LAs to charge late-night alcohol retailers an annual fee (£299-£4440) to manage and police the night-time economy (NTE)., Results: When the LNL was being considered, stakeholders from different interest groups advanced diverse opinions about its likely impacts while rarely referencing supporting research evidence. Proponents of the levy argued it could reduce crime and anti-social behaviour by providing additional funds to police and manage the NTE. Critics of the levy hypothesised adverse consequences linked to claims that the intervention would force venues to vary their hours or close, cluster closing times, reduce NTE diversity and undermine public-private partnerships. In the first 2 years, levy-funded patrols developed relationships with the licensed trade and the public. The LNL did not undermine public-private partnerships and while some premises varied their hours, these changes did not undermine the intervention's viability, nor significantly cluster venue closing times, nor obviously damage the area's reputation for having a diverse NTE., Conclusions: This study applies a framework for process evaluation from a complex systems perspective. The evaluation could be extended to measure alcohol-related outcomes and to consider the interplay between the national and local systems., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Providing information to patients is an essential aspect of care. The way in which such information is transmitted is also important and is affected by different variables. The perceptions of dishonest nursing staff have not been sufficiently discussed to date., Aim: The purpose is to explore the reasons for dishonesty in transmitting information to patients., Design and Method: In this qualitative content analysis study, data were collected using semi-structured interviews with Twelve Iranian Critical Care Nurses from January 2020 till August 2020. Data were analyzed according to Graneheim and Lundman approach., Ethical Consideration: The research protocol was authorized by the Ethics Committee of the Medical Sciences University of Tehran (Register number: 95-04-99-33485)., Results: The findings indicated that dishonesty in giving information to the patients has many reasons. Although lying is not compatible with ethical care, working conditions sometimes forced nurses to hide the truth., Discussion and Conclusion: Nurses believed honesty was an integral aspect of professional practice, but situational specifics have an effect on whether the truth is told or withheld. Finally, the nurses noticed a big gap between what they want to tell and what they were doing in practice.

Competing Interests: Conflicts of interest None disclosed.

Background: The entire school community contributes to the safety of students with food allergy. We sought to determine the food allergy perceptions and education needs of parents, students and school staff, with the goal of enhancing food allergy education in schools., Methods: With ethics approval from the University of Manitoba and participating school divisions, elementary school principals emailed SurveyMonkey ® Questionnaire Links to their parent/caregiver contact list and school staff. We compared anonymous responses of parents of children with and without food allergy, students with and without food allergy, and parents and school staff using chi-squared tests., Results: Participants included 561 parents of school-age children (ages 7-12 years, 19% with food allergy), 61 students (23% with food allergy), and 203 school staff (62% teachers, 88% with experience managing food allergies in the classroom). Parents of children with and without food allergy considered food allergy when sending food to school (98% vs. 96%, p = 0.39). More parents of children with food allergy thought that greater information and awareness about food allergy was needed (74% vs. 44%, p < 0.0001). Students with food allergy were most interested (100%) in having other students learn not to bully and how to help during a reaction. Students without food allergy were most interested in learning how to prevent a reaction (70%). Fewer parents than school staff thought that food allergies in the classroom impacted teachers' time (2.1% vs. 21%, p < 0.0001) and that teachers knew how to treat allergic reactions to foods (34% vs. 94%, p < 0.0001). More parents than school staff thought that banning foods from classrooms kept allergic students safe (65% vs. 34%, p = 0.006) and that having a Food Allergy Educator speak at school would be helpful (99% vs. 67%, p < 0.0001)., Conclusions: Food allergy education is necessary for the entire school community and should include parents of school-aged children with and without food allergy, students with and without food allergy, and teachers and school staff. These members of the school community recognized their own and others' needs for increased food allergy education and awareness in the school setting., (© 2022. The Author(s).)

Introduction: The UK private rental housing market has poorer quality housing compared with other sectors and is subjected to calls for better regulation. Poor quality housing poses risks to mental and physical health, and housing improvement can potentially benefit health and well-being. Local authorities have powers to implement selective licencing (SL) schemes in specific localities. Such schemes involve landlord registration, payment of licence fees, local authority inspection and requirements that landlords conduct any necessary renovation works to ensure housing standards are met. We aim to evaluate SL in Greater London and to test the feasibility of a national evaluation., Methods and Analysis: We will measure individual-level and area-level impacts of SL in Greater London between 2011 and 2019. A difference-in-differences approach with propensity score-matched controls will be used. We propose to exploit data from the Annual Population Survey (APS) and health and social benefit registers to measure mental health and well-being at individual (self-reported anxiety) and area (Small Area Mental Health Index) level. We estimate 633 APS participants in our intervention groups compared with 1899 participants in control areas (1:3 ratio of intervention to control). Secondary outcomes will be self-reported well-being and residential stability at the individual level and incidence of police-recorded antisocial behaviour calls and population turnover at the area level. The study size of the area-level analyses will be 3684 lower layer super output areas (including controls). Qualitative semistructured interviews with lead implementers in several London boroughs will produce insights into variations and commonalities between schemes., Ethics and Dissemination: Ethical approval was obtained from London School of Hygiene and Tropical Medicine's Ethics Committee (reference number 26481) and London Borough of Hackney. All interviewees will be asked for informed written consent. Study findings will be published in a peer-reviewed journal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Oncologists and palliative specialists prescribe opioids for millions of cancer patients despite limited research on effective screening and mitigation strategies to reduce risk of opioid-related harm in that population. Objective: To evaluate the efficacy of a novel opioid risk stratification process for predicting significant aberrant behaviors (SABs) related to prescribed opioid medications. Design and Setting/Subjects: This is a prospective, longitudinal study of 319 consecutive patients referred to an outpatient palliative care clinic between 2010 and 2012, a period during which prescription opioid-related deaths began to increase in the United States. Measures: Patients completed a psychodiagnostic/substance use risk assessment with a licensed clinical psychologist or social worker at the initial palliative clinic visit. Patients were assigned to Low-, Moderate-, or High-Risk groups based on predetermined stratification criteria and were managed via an opioid harm reduction approach. The primary dependent measure was the presence of at least one SAB after the initial visit. Results: Eighteen percent of patients ( n  = 56) demonstrated at least one major aberrant behavior. Odds of future aberrant behavior was 15 times greater in the High-Risk versus the Low-Risk category. Five risk factors significantly enhanced our risk model: age 18 to 45 years, job instability, history of bipolar diagnosis, history of substance abuse, and theft. Conclusion: Our risk stratification process provides a useful model for predicting those at greatest risk of future aberrant behaviors and most in need of comanagement. We recommend additional studies to test our proposed streamlined risk stratification tool.

Background and Objectives: In many countries, whole blood (WB) donations with collection times between 12 and 15 min are not allowed to be used for platelet concentrates (PC). Since the development of guidelines, many process-related changes have been introduced. We aimed to determine the effect of WB with long collection times on PC quality., Materials and Methods: Five participating centres tested buffy coat (BC)-derived PC in platelet additive solution type E prepared from only WB collections lasting <12 min (control) versus similar PC including one BC from a collection lasting >12 min (study group, n = 8). One centre produced platelet-rich plasma (PRP)-derived PC from single donations (<10 or >12 min). All PC were stored at 22 ± 2°C and sampled on Days 1, 6 and 8 post-collection for in vitro quality determination., Results: Average collection time was significantly longer in the study group compared to controls (8.9 ± 2.6 vs. 7.3 ± 1.3 min, p < 0.001). There were no differences in volume, platelet concentration, basal CD62P expression, soluble-CD62P and CCL5 levels, or nucleotide content between the groups. Stimulation with TRAP-6 resulted in comparable levels of cell surface CD62P. On Day 8, all PC fulfilled requirements for pH. The findings from single PRP-derived PC centre were similar., Conclusion: PC with one BC and single PRP derived from collections lasting >12 min had equivalent in vitro quality to controls during storage. This study provides evidence that 12-15 min donations should not be excluded for PC preparation and justifies to readdress the guidelines to <15 min instead of <12 min of collection in line with current practice in some countries., (© 2022 International Society of Blood Transfusion.)

The β- and γ-secretase-driven cleavage of the amyloid precursor protein (APP) gives rise to the amyloid β peptide, which is believed to be the main driver of neurodegeneration in Alzheimer's disease (AD). As it is prominently detectable in extracellular plaques in post-mortem AD brain samples, research in recent decades focused on the pathological role of extracellular amyloid β aggregation, widely neglecting the potential meaning of very early generation of amyloid β inside the cell. In the last few years, the importance of intracellular amyloid β (iAβ) as a strong player in neurodegeneration has been indicated by a rising number of studies. In this review, iAβ is highlighted as a crucial APP cleavage fragment, able to manipulate intracellular pathways and foster neurodegeneration. We demonstrate its relevance as a pathological marker and shed light on initial studies aiming to modulate iAβ through pharmacological treatment, which has been shown to have beneficial effects on cognitive properties in animal models. Finally, we display the relevance of viral infections on iAβ generation and point out future directions urgently needed to manifest the potential relevance of iAβ in Alzheimer's disease.

Unselected population-based personalised ovarian cancer (OC) risk assessments combining genetic, epidemiological and hormonal data have not previously been undertaken. We aimed to understand the attitudes, experiences and impact on the emotional well-being of women from the general population who underwent unselected population genetic testing (PGT) for personalised OC risk prediction and who received low-risk (<5% lifetime risk) results. This qualitative study was set within recruitment to a pilot PGT study using an OC risk tool and telephone helpline. OC-unaffected women ≥ 18 years and with no prior OC gene testing were ascertained through primary care in London. In-depth, semi-structured and 1:1 interviews were conducted until informational saturation was reached following nine interviews. Six interconnected themes emerged: health beliefs; decision making; factors influencing acceptability; effect on well-being; results communication; satisfaction. Satisfaction with testing was high and none expressed regret. All felt the telephone helpline was helpful and should remain optional. Delivery of low-risk results reduced anxiety. However, care must be taken to emphasise that low risk does not equal no risk. The main facilitators were ease of testing, learning about children’s risk and a desire to prevent disease. Barriers included change in family dynamics, insurance, stigmatisation and personality traits associated with stress/worry. PGT for personalised OC risk prediction in women in the general population had high acceptability/satisfaction and reduced anxiety in low-risk individuals. Facilitators/barriers observed were similar to those reported with genetic testing from high-risk cancer clinics and unselected PGT in the Jewish population.

Umbilical cord blood transplantation (UCBT) has increased access to potentially curative therapy for patients with life-threatening disorders of the bone marrow and immune system. The introduction of reduced intensity conditioning (RIC) regimens and double umbilical cord unit infusions (DUCBT) has broadened the applicability of UCBT to more frail or larger recipients. The kinetics of chimerism after RIC DUCBT and their clinical utility are poorly understood. The RIC CBT trial reported here sought to prospectively evaluate the role of lineage-specific chimerism after DUCBT in adult patients with hematologic malignancies in the United Kingdom. Fifty-eight patients with a median age of 52 years were recruited, with overall and progression-free survivals of 59% (95% confidence interval [CI], 45%-71%) and 52% (95% CI, 39%-64%), respectively, at 2 years. Nonrelapse mortality was 4% (95% CI, 1%-13%) at day 100, and the relapse rate was 31% (95% CI, 21%-45%) at 1 year. Peripheral blood lineage-specific chimerism was feasible from day 7 after transplant onward. Five patterns of chimerism were observed including (1) complete single unit dominance (39 patients), (2) sustained donor-donor mixed chimerism (3 patients), (3) sustained donor-recipient mixed chimerism (5 patients), (4) dominance reversion (1 patient), and (5) primary graft failure (4 patients). The RIC CBT trial enabled adult patients with high-risk hematologic malignancies to safely access UCBT in the United Kingdom and provided novel insights into the kinetics of donor and recipient chimerism after RIC DUCBT that are clinically relevant. This trial was registered at https://www.clinicaltrialsregister.eu/ctr-search/trial/2004-003845-41/GB as #NCT00959231 and EudraCT 2004-003845-41., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T-cells are genetically engineered autologous T-cells that express a high-affinity melanoma-associated antigen (MAGE)-A10-specific T-cell receptor (TCR) targeting MAGE-A10-positive tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-004 is a phase 1, dose-escalation trial to evaluate the safety and anti-tumor activity of ADP-A2M10 in three malignancies (https://clinicaltrials.gov: NCT02989064)., Methods: Eligible patients were HLA-A*02 positive with advanced head and neck squamous cell carcinoma (HNSCC), melanoma, or urothelial carcinoma (UC) expressing MAGE-A10. Patients underwent apheresis; T-cells were isolated, transduced with a lentiviral vector containing the MAGE-A10 TCR, and expanded. Patients underwent lymphodepletion with fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 was administered in two dose groups receiving 0.1×10 9 and >1.2 to 6×10 9 transduced cells, respectively, and an expansion group receiving 1.2 to 15×10 9 transduced cells., Results: Ten patients (eight male and two female) with HNSCC (four), melanoma (three), and UC (three) were treated. Three patients were treated in each of the two dose groups, and four patients were treated in the expansion group. The most frequently reported adverse events grade ≥3 were leukopenia (10), lymphopenia (10), neutropenia (10), anemia (nine), and thrombocytopenia (five). Two patients reported cytokine release syndrome (one each with grade 1 and grade 3), with resolution. Best response included stable disease in four patients, progressive disease in five patients, and not evaluable in one patient. ADP-A2M10 cells were detectable in peripheral blood from patients in each dose group and the expansion group and in tumor tissues from patients in the higher dose group and the expansion group. Peak persistence was greater in patients from the higher dose group and the expansion group compared with the lower dose group., Conclusions: ADP-A2M10 has shown an acceptable safety profile with no evidence of toxicity related to off-target binding or alloreactivity in these malignancies. Persistence of ADP-A2M10 in the peripheral blood and trafficking of ADP-A2M10 into the tumor was demonstrated. Because MAGE-A10 expression frequently overlaps with MAGE-A4 expression in tumors and responses were observed in the MAGE-A4 trial (NCT03132922), this clinical program closed, and trials with SPEAR T-cells targeting the MAGE-A4 antigen are ongoing., Competing Interests: ABG: holds stock options in Adaptimmune. AS, DB, DM, EN, FB, JB, J-MN, JS, RB, RW, SF, and ZW: employees of Adaptimmune. DH: research/ grant funding from AbbVie, Adaptimmune, Aldi-Norte, Amgen, AstraZeneca, Bayer, BMS, Daiichi-Sankyo, Deciphera, Eisai, Erasca, Fate Therapeutics, Genentech, Genmab, Infinity, Kite, Kyowa, Lilly, LOXO, MedImmune, Merck, Mirati, Mologen, Navier, NCI-CTEP, Novartis, Numab, Pfizer, Pyramid Bio, SeaGen, Takeda, Turning Point Therapeutics, Verastem, and VM Oncology; compensation for travel, accommodations, and expenses from AACR, ASCO, Bayer, Genmab, SITC, and Telperian; consulting, speaker, or advisory roles for Acuta, Adaptimmune, Alkermes, Alpha Insights, Amgen, Atheneum, AUM Biosciences, Axiom, Barclays, Baxter, Bayer, Boxer Capital, BridgeBio, CDR-life AG, COG, COR2ed, Ecor1, Genentech, Gilead, GLG, Group H, Guidepoint, HCW Precision, Immunogen, Infinity, Janssen, Liberium, Medscape, Numab, Oncologia Brasil, Pfizer, Pharma Intelligence, POET Congress, Prime Oncology, Seattle Genetics, ST Cube, Takeda, Tavistock, Trieza Therapeutics, Turning Point, WebMD, and Ziopharm; other ownership interests in OncoResponse (Founder) and Telperian Inc (Advisor). ED: grant/research support from Aileron Therapeutics, Amgen, Aprea Therapeutics, Astex Pharmaceuticals, Bayer HealthCare Pharmaceuticals Inc., Bellicum Pharmaceuticals, BOLT Therapeutics, Compugen Ltd, Immunocore LTD, Immunomedics, Mereo BioPharma 5 Inc, NCI, PMV Pharma, Sanofi, SeaGen, TRACON Pharmaceuticals Inc., Triumvira, and Unum Therapeutics; advisory board for BOLT Therapeutics. MB: grant/contract funding for investigator-initiated clinical trials from Merck and Takara Bio; advisory boards for Adaptimmune, BMS, EMD Serono, GlaxoSmithKline, Immunocore, Instil Bio, Iovance, Merck, Novartis, Pfizer, and Sanofi; has attended speaking engagements for BMS, Merck, Novartis, and Pfizer; Safety Review Committees for Adaptimmune and GlaxoSmithKline. MF: consultant for Arcellx, BMS, Iovance, Kite, and Novartis. PF: employee of Adaptimmune; holds stock in Adaptimmune and Bristol-Myers Squibb; has received compensation for travel and congress meetings. RS: research support from Amgen and Merck; has received fees as a consultant or SAB member from Array Biopharma, Asana Biosciences, AstraZeneca, BMS, Eisai, Iovance, Merck, Novartis, OncoSec, Pfizer, and Replimune. RP: grant funding from Janssen; personal fees from AstraZeneca, Bayer, BMS, Dendreon, EMD, Genentech/ Roche, Genomic Health, Jounce Therapeutics, Merck, Sanofi, and Serono/Pfizer; nonfinancial support from BMS and Genentech/Roche. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare that this study received funding from Adaptimmune Ltd. The funder had the following involvement with the study: study design and analysis and interpretation of the data., (Copyright © 2022 Hong, Butler, Pachynski, Sullivan, Kebriaei, Boross-Harmer, Ghobadi, Frigault, Dumbrava, Sauer, Brophy, Navenot, Fayngerts, Wolchinsky, Broad, Batrakou, Wang, Solis, Duose, Sanderson, Gerry, Marks, Bai, Norry and Fracasso.)

Cerebral organoids are a promising model to study human brain function and disease, although the high inter-organoid variability is still challenging. To overcome this limitation, we introduce the method of labeled mixed organoids generated from two different human induced pluripotent stem cell (hiPSC) lines, which enables the identification of cells from different origin within a single organoid. The method combining gene editing and organoid differentiation offers a unique tool to study gene function in a complex human three-dimensional model. Using a CRISPR-Cas9 gene-editing approach, different fluorescent proteins were fused to β-actin or lamin B1 in hiPSCs, and mixtures of differently edited cells were seeded to induce cerebral organoid differentiation. Consequently, the development of the organoids was detectable by live confocal fluorescence microscopy of whole organoids and immunofluorescence staining in fixed samples. We demonstrate that a direct comparison of the individual cells is possible by having the edited and the control (or the two differentially labeled) cells within the same organoid, thus overcoming the inter-organoid inhomogeneity limitations. Furthermore, the approach enables mosaic analysis of mutant clones in a wild-type three-dimensional cellular environment. It paves the way for the reliable analysis of human genetic disorders using organoids and the gain of fundamental understanding of the molecular mechanisms underlying pathological conditions.

Background: Acceptance of the role of the fallopian tube in 'ovarian' carcinogenesis and the detrimental sequelae of surgical menopause in premenopausal women following risk-reducing salpingo-oophorectomy (RRSO) has resulted in risk-reducing early-salpingectomy with delayed oophorectomy (RRESDO) being proposed as an attractive alternative risk-reducing strategy in women who decline/delay oophorectomy. We present the results of a qualitative study evaluating the decision-making process among BRCA carriers considering prophylactic surgeries (RRSO/RRESDO) as part of the multicentre PROTECTOR trial (ISRCTN:25173360)., Methods: In-depth semistructured 1:1 interviews conducted using a predeveloped topic-guide (development informed by literature review and expert consultation) until informational saturation reached. Wording and sequencing of questions were left open with probes used to elicit additional information. All interviews were audio-recorded, transcribed verbatim, transcripts analysed using an inductive theoretical framework and data managed using NVIVO-v12., Results: Informational saturation was reached following 24 interviews. Seven interconnected themes integral to surgical decision making were identified: fertility/menopause/cancer risk reduction/surgical choices/surgical complications/sequence of ovarian-and-breast prophylactic surgeries/support/satisfaction. Women for whom maximising ovarian cancer risk reduction was relatively more important than early menopause/quality-of-life preferred RRSO, whereas those more concerned about detrimental impact of menopause chose RRESDO. Women managed in specialist familial cancer clinic settings compared with non-specialist settings felt they received better quality care, improved hormone replacement therapy access and were more satisfied., Conclusion: Multiple contextual factors (medical, physical, psychological, social) influence timing of risk-reducing surgeries. RRESDO offers women delaying/declining premenopausal oophorectomy, particularly those concerned about menopausal effects, a degree of ovarian cancer risk reduction while avoiding early menopause. Care of high-risk women should be centralised to centres with specialist familial gynaecological cancer risk management services to provide a better-quality, streamlined, holistic multidisciplinary approach., Competing Interests: Competing interests: RM declares research funding from Cancer Research UK and The Eve Appeal outside this work, an honorarium for grant review from Israel National Institute for Health Policy Research and honorarium for advisory board membership from Astrazeneca/MSD. RM is supported by an NHS Innovation Accelerator (NIA) Fellowship for population testing., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The Millon series (i.e., MCMI-II/MCMI-III) has a longstanding history of use in clinical and forensic settings. For forensic psychologists, the Millon series can serve as a unique tool in evaluations related to parental fitness due to its incorporation of DSM diagnostic categories and the use of base rate (BR) scores. There is limited research on parental fitness populations broadly, though previous research has found a common positive impression management style referred to as the normal quartet with forensic populations on the MCMI-III. It is unknown if there is a continued presence of the normal quartet in the MCMI-IV, published in 2015. With the current study, we examined parental fitness litigant response patterns on the MCMI-IV and assessed the presence of a normal quartet . The sample consisted of 330 parental fitness litigants in the northeast region of the United States. Results of the current study suggest a new normal quartet: elevations on the Desirability (Y), Histrionic (4A), Turbulent (4B), and Compulsive (7) scales. The clinical implications for the use of the MCMI-IV by forensic psychologists with parental fitness litigants are discussed including limitations and areas for future research.

Background: It is unclear whether traditional growing rod (TGR) treatment outcomes vary by early-onset scoliosis (EOS) subtype. The goal of this study was to compare radiographic outcomes and complications of TGR treatment by EOS subtype., Methods: We queried an international database of EOS patients from 20 centers to identify "graduates" who had (1) undergone primary TGR treatment from 1993 to 2014; (2) completed TGR treatment; and (3) had an uneventful clinical examination within 6 months after completion of TGR treatment with no anticipated further intervention. We included 202 patients in 4 etiologic subgroups: neuromuscular (n=65), syndromic (n=57), idiopathic (n=52), and congenital (n=28). Mean age at surgery was 7.1 years (range, 1.6 to 14.9 y); mean duration of follow-up was 8 years (range, 2 to 18.6 y). The groups did not differ by mean age, body mass index, sex, number of lengthenings, or duration of follow-up. The following preoperative differences were significant: (1) greater mean major curve in the neuromuscular versus idiopathic subgroup; (2) shorter spinal height (T1-S1) in the congenital versus idiopathic subgroup; and (3) smaller proportion of ambulatory patients in the neuromuscular subgroup versus all other subgroups., Results: We found no significant differences among subgroups in mean major curve correction or changes in thoracic height (T1-T12), spinal height, or global kyphosis at any point. Rates of deep surgical site infection, implant-related complications, and neurological complications were not different among subgroups. The medical complication rate was significantly lower in the idiopathic group compared with the other groups., Conclusions: Major curve correction and spinal and thoracic height increases did not differ significantly at any point by EOS subtype. Rates of deep surgical site infection, implant-related complications, and neurological complications did not differ by subtype. Except for the lower rate of medical complications in the idiopathic group, our findings suggest that, after TGR treatment, patients can expect similar outcomes regardless of their EOS subtype., Level of Evidence: Level III, therapeutic., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Law enforcement recruits (LER) often encounter shoulder injuries, which may cause attrition from academies. Investigating required upper body muscular fitness may inform of muscular balance around shoulder joints through anterior and posterior ratios in LER., Objective: To investigate push to pull ratios (P2P) and factors related with P2P in LER., Methods: LER (95 males; 12 females) completed testing during a single session in the academy's first week: body mass, one-repetition maximum (1RM) bench press, push-up repetitions (reps) to failure, and pull-up reps to failure. Calculations were: estimated pull-up 1RM=body mass+0.033*(body mass x pull-ups); endurance P2P (eP2P)=push-ups / pull-ups; strength P2P (sP2P)=bench press 1RM / estimated pull-up 1RM. Pearson correlation coefficients assessed relationships among tests and P2P (p < 0.05)., Results: The sP2P was positively correlated with bench press 1RM and push-ups. The eP2P was negatively associated with pull-up reps and 1RM. Females had similar eP2P, but lower sP2P than male recruits (p < 0.05)., Conclusion: Practitioners may benefit from examining eP2P and sP2P as they should not be used interchangeably. Future research should examine whether the P2P ratios are associated with injury and subsequent inability to successfully complete law enforcement training academies.

Background: ADP-A2M10 specific peptide enhanced affinity receptor (SPEAR) T cells (ADP-A2M10) are genetically engineered autologous T cells that express a high-affinity melanoma-associated antigen A10 (MAGE-A10)-specific T-cell receptor (TCR) targeting MAGE-A10 + tumors in the context of human leukocyte antigen (HLA)-A*02. ADP-0022-003 was a phase I dose-escalation trial that aimed to evaluate the safety and antitumor activity of ADP-A2M10 in non-small cell lung cancer (NSCLC) (NCT02592577)., Methods: Eligible patients were HLA-A*02 positive with advanced NSCLC expressing MAGE-A10. Patients underwent apheresis; T cells were isolated, transduced with a lentiviral vector containing the TCR targeting MAGE-A10, and expanded. Patients underwent lymphodepletion with varying doses/schedules of fludarabine and cyclophosphamide prior to receiving ADP-A2M10. ADP-A2M10 were administered at 0.08-0.12×10 9 (dose group 1), 0.5-1.2×10 9 (dose group 2), and 1.2-15×10 9 (dose group 3/expansion) transduced cells., Results: Eleven patients (male, n=6; female, n=5) with NSCLC (adenocarcinoma, n=8; squamous cell carcinoma, n=3) were treated. Five, three, and three patients received cells in dose group 1, dose group 2, and dose group 3/expansion, respectively. The most frequently reported grade ≥3 adverse events were lymphopenia (n=11), leukopenia (n=10), neutropenia (n=8), anemia (n=6), thrombocytopenia (n=5), and hyponatremia (n=5). Three patients presented with cytokine release syndrome (grades 1, 2, and 4, respectively). One patient received the highest dose of lymphodepletion (fludarabine 30 mg/m 2 on days -5 to -2 and cyclophosphamide 1800 mg/m 2 on days -5 to -4) prior to a second infusion of ADP-A2M10 and had a partial response, subsequently complicated by aplastic anemia and death. Responses included: partial response (after second infusion; one patient), stable disease (four patients), clinical or radiographic progressive disease (five patients), and not evaluable (one patient). ADP-A2M10 were detectable in peripheral blood and in tumor tissue. Peak persistence was higher in patients who received higher doses of ADP-A2M10., Conclusions: ADP-A2M10 demonstrated an acceptable safety profile and no evidence of toxicity related to off-target binding or alloreactivity. There was persistence of ADP-A2M10 in peripheral blood as well as ADP-A2M10 trafficking into the tumor. Given the discovery that MAGE-A10 and MAGE-A4 expression frequently overlap, this clinical program closed as trials with SPEAR T cells targeting MAGE-A4 are ongoing., Competing Interests: Competing interests: AG holds stock options in Adaptimmune. AJO has received research contracts from Alkermes, Antegene, Astellas, Checkmate, Gan & Lee, GlycoNex, InstilBio, Intensity, Istari, Kadmon, Kartos, NeoImmune, NGM, OncoSec, Sound Bio, SpringBank, Takeda; has received payment for advisory board roles from Merck, BMS, Pfizer, Takeda, Sanofi, Eisai. DB, DM, EN, JB, J-MN, JPS, MMP, NH, RB, SF are or were employees of Adaptimmune at the time of the study. GRB has received grants/contracts from Amgen, Bayer, Adaptimmune, Elelixis, Daiichi Sankyo, GlaxoSmithKline, Immatics, Immunocore, Incyte, Kite Pharma, Macrogenics, Torque, AstraZeneca, Bristol-Myers Squibb, Celgene, Genentech, MedImmune, Merck, Novartis, Roche, Xcovery, Tmunity Therapeutics, Regeneron, Beigene, Repertoire Immune Medicines, Verastem; consulting fees from Abbvie, Adicet, Amgen, Ariad, Bayer, Clovis Oncology, AstraZeneca, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Instil Bio, Genentech, Gilead, Lilly, Janssen, MedImmune, Merck, Novartis, Roche, Tyme Oncology, Xcovery, Virogin Biotech, Maverick Therapeutics; has participated on a Data Safety Monitoring Board or Advisory Board for Virogen Biotech, Maverick Therapeutics; holds stock or stock options in Virogin Biotech; and has other financial or non-financial interests in Johnson & Johnson/Janssen (immediate family member employed). JG has been a compensated consultant or received honoraria from Bristol-Myers Squibb, Genentech, Ariad/Takeda, Loxo, Pfizer, Incyte, Novartis, Merck, Agios, Amgen, Jounce, Karyopharm, GlydeBio, Mirati, AstraZeneca, Regeneron, Oncorus, Helsinn, Array, and Clovis Oncology; has been an employee (immediate family member) with equity in Ironwood Pharmaceuticals; has received research funding from Novartis, Genentech/Roche, and Ariad/Takeda; has received institutional research support from Tesaro, Moderna, Blueprint, Scholar Rock, BMS, Array, Adaptimmune, Novartis, Genentech/Roche, Alexo and Merck. JVH has received grants/contracts from AstraZeneca, GlaxoSmithKline and Spectrum; holds royalty/licenses in Spectrum; has received consulting fees from AstraZeneca, Boehringer-Ingelheim, Catalyst, Genentech, GlaxoSmithKline, Guardant Health, Foundation medicine, Hengrui Therapeutics, Eli Lilly, Novartis, Spectrum, EMD Serono, Sanofi, Takeda, Mirati Therapeutics, BMS, BrightPath Biotherapeutics, Janssen Global Services, Nexus Health Systems, EMD Serono, Pneuma Respiratory, Kairos Venture Investments, Roche, Leads Biolabs, RefleXion; has received honoraria from Medlinker, Peerview, Nexus Health Medicine, Targeted Oncology, MJH Events; has received support for attending meetings from IASLC Targeted Therapies, IASLC World Conference on Lung Cancer; has been in a leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Mechanisms of Cancer Therapeutics-1 (MCT1) (Study Section – Chair). MJ has received research funding from AbbVie, Acerta, Adaptimmune, Apexigen, Array BioPharma, AstraZeneca, Atreca, BeiGene, Boehringer Ingelheim, Checkpoint Therapeutics, Corvus Pharmaceuticals, CytomX, Daiichi Sankyo, Dynavax, Lilly, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Hengrui Therapeutics, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon Pharmaceuticals, Loxo Oncology, Lycera, Merck, Mirati Therapeutics, Neovia Oncology, Novartis, OncoMed Pharmaceuticals, Pfizer, Regeneron Pharmaceuticals, Sanofi, Seven and Eight Biopharmaceuticals, Shattuck Labs, Stem CentRx, Syndax Pharmaceuticals, Takeda Pharmaceuticals, Tarveda, University of Michigan, WindMIL, TCR2 Therapeutics, Arcus Biosciences, Ribon Therapeutics, Amgen; has held a consulting/advisory role (spouse) for Astellas, Otsuka Pharmaceuticals; has held a consulting/advisory role (self) for AbbVie, Achilles Therapeutics, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Genentech, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen, Lilly, Loxo Oncology, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, Sanofi, Association of Community Cancer Center; has received food/beverage/travel expenses from Abbvie, Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, EMD Serono, Bristol Myers Squibb, Exelixis, Genentech/Roche, Incyte, Merck, Pfizer, Sysmex Inostics, Vapotherm, Janssen, Lilly, Novartis, Sanofi. MJE has received research funding from GlaxoSmithKline, Mersana, Amgen, Windmil, Nektar, Apexigen, Adaptimmune; has received consulting fees from Kanaph, Flame; has received honoraria from Sanofi; has been a member of DSMB for AstraZeneca, Seattle Genetics, GlaxoSmithKline, Takeda; has been a consultant/on an advisory board for Windmil, Regeneron, Syndax; has been the Chair, Scientific Advisory board for Lung Cancer Foundation of America; has been the Deputy Editor of 'Lung Cancer'; has received stock options from Biomarker strategies; Creatv Biotech. MJF has been a consultant for Arcellx, BMS, Novartis, Kite, Iovance. PMF is an employee of Adaptimmune; holds stock in Adaptimmune and Bristol-Myers Squib; has received compensation for travel and congress meetings. RG has received consulting fees from BMS, Abbvie, Geneplus; has participated on a Data Safety Monitoring Board or Advisory Board for Roche Genentech. SD has been a consultant for Jacobio pharmaceuticals (without financial compensation). TH was an employee of Adaptimmune at the time of the study; has been a consultant for Adaptimmune. VKL has been in a consulting or advisory role for Takeda, Bristol-Myers Squibb, Seattle Genetics; has received research funding from GlaxoSmithKline, Bristol-Myers Squibb, Guardant Health, Takeda. VM has received consulting fees from Roche, Bayer, Pieris, BMS, Janssen and Basilea. BDdS, CB, ZW have nothing to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Law enforcement officers experience high stress levels and perform various physical tasks. Thus, law enforcement academies emphasize physical fitness training and assessment., Objective: To examine fitness test-performances and determine which entry-level fitness components best predict likelihood of successful law enforcement academy graduation., Methods: Recruits (151 males, 42 females) completed initial academy fitness testing: one-repetition maximum bench press, push-ups, sit-ups, pull-ups, sit-and-reach, 1.5-mile run, and work performance test. Chi-square and t-tests were used to examine gender differences. Correlation coefficients assessed relationships, while logistical regression determined the best fitness components for predicting graduation (p < 0.05)., Results: Males had greater fitness performances except pull-ups, sit-ups and sit and reach (p < 0.05). Distributions of below average fitness performances were similar between genders with majority of recruits performing below average on all tests. Gender, age, push-ups, and pull-ups explained 18% of the variance in graduation rates (p < 0.05). Males were 4.68 (p < 0.05) times more likely to graduate, but other predictors were not significant., Conclusions: No single fitness test predicted the likelihood of graduation and majority of performances were below average, suggesting the importance for proficiency across multiple fitness components. Considering lower fitness performances and graduation rates, females may further benefit from training programs prior to academy entrance.

The COVID-19 pandemic stressed healthcare systems all over the world. Two primary challenges that healthcare systems faced were a shortage of personal protective equipment and the need for new technologies to handle infection prevention for staff and patients. The Department of Veteran's Affairs (VA) Technology Transfer Program responded by prioritizing the development of innovations in the Technology Transfer Assistance Project which addressed the pandemic. This paper describes several innovations that addressed the needs of the VA healthcare system during the pandemic and how they were rapidly developed.

Transgender and gender diverse people can experience increased depression, anxiety, suicidal ideation, and suicide from gender dysphoria (GD). GD occurs due to a discrepancy between a person&rsquo;s gender identity, assigned gender, and physical characteristics. Gender affirming medical care, including dermatologic care, can increase body-gender congruence and decrease negative outcomes associated with GD.

Platelets are a reservoir of growth factors, cytokines and chemokines involved in spontaneous wound repair. In this study, a platelet-rich and fibrin-rich hydrogel was generated from expired platelet components that would have otherwise been transfused. The material contained physiological concentrations of transforming growth factor β1 (TGF-β1, platelet-derived growth factor AB (PDGF-AB), PDGF-BB, insulin-like growth factor-1 (IGF-1), fibroblast growth factor 2 (FGF-2), and epidermal growth factor (EGF). The effect of the hydrogel on wound repair was investigated in SKH-1 mice. Full thickness dorsal wounds were created on the mice and treated with the hydrogel at various concentrations. Immunohistochemical staining with CD31 (endothelial cell marker) revealed that wounds treated with the hydrogel showed significantly enhanced vascularisation in the wound bed. Moreover, high levels of interleukin-6 (IL-6) and KC (IL-8 functional homologue) in treated wounds were sustained over a longer period of time, compared to untreated wounds. We postulate that sustained IL-6 is a driver, at least partly, of enhanced vascularisation in full thickness wounds treated with the hydrogel. Future work is needed to explore whether this hydrogel can be utilised as a treatment option when vascularisation is a critical limitation. STATEMENT OF SIGNIFICANCE: The economic cost of wound repair is estimated in billions of dollars each year. In many cases time required to vascularise wounds is a major contributor to slow wound repair. In this study, we developed a blood-derived platelet- and fibrin-rich hydrogel. It contains a number of growth factors actively involved in spontaneous wound healing. This hydrogel significantly improved dermal repair and vascularisation in a full-thickness wound mouse model. This study provides an action mechanism for modulation of localised inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Bacteria from the orders Bacillales and Clostridiales differentiate into stress-resistant spores that can remain dormant for years, yet rapidly germinate upon nutrient sensing. How spores monitor nutrients is poorly understood but in most cases requires putative membrane receptors. The prototypical receptor from Bacillus subtilis consists of three proteins (GerAA, GerAB, GerAC) required for germination in response to L-alanine. GerAB belongs to the Amino Acid-Polyamine-Organocation superfamily of transporters. Using evolutionary co-variation analysis, we provide evidence that GerAB adopts a structure similar to an L-alanine transporter from this superfamily. We show that mutations in gerAB predicted to disrupt the ligand-binding pocket impair germination, while mutations predicted to function in L-alanine recognition enable spores to respond to L-leucine or L-serine. Finally, substitutions of bulkier residues at these positions cause constitutive germination. These data suggest that GerAB is the L-alanine sensor and that B subunits in this broadly conserved family function in nutrient detection., (© 2021. The Author(s).)