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Botryosphaeriaceae species are the major causal agents of walnut dieback worldwide, along with Diaporthe species. Botryosphaeria dothidea and Neofusicoccum parvum are the only two Botryosphaeriaceae species associated with this recently emergent disease in France, and little is known about their diversity, structure, origin and dispersion in French walnut orchards. A total of 381 isolates of both species were genetically typed using a sequence-based microsatellite genotyping (SSR-seq) method. This analysis revealed a low genetic diversity and a high clonality of these populations, in agreement with their clonal mode of reproduction. The genetic similarity among populations, regardless of the tissue type and the presence of symptoms, supports the hypothesis that these pathogens can move between fruits and twigs and display latent pathogen lifestyles. Contrasting genetic patterns between N. parvum populations from Californian and Spanish walnut orchards and the French ones suggested no conclusive evidence for pathogen transmission from infected materials. The high genetic similarity with French vineyards populations suggested instead putative transmission between these hosts, which was also observed with B. dothidea populations. Overall, this study provides critical insight into the epidemiology of two important pathogens involved in the emerging dieback of French walnut orchards, including their distribution, potential to mate, putative origin and disease pathways.

Pierre Louis Bernard,1 Xavier de la Tribonniere,2 Alessandra Pellecchia,2 Lucie Gamon,3 Fanchon Herman,3 Marie-Christine Picot,3 Nathalie J Raffort,4 Thierry Paillard,5 Jean-Baptiste Robiaud,6 Gregory Ninot,7 Jean Bousquet,8 Hubert Blain6 1Euromov Digital Health in Motion, Université de Montpellier, IMT Mines d’Ales, France; 2Transversal Patient Education Unit (UTEP), University Hospital of Montpellier, Montpellier, France; 3Centre d’Investigation Clinique 1411, University Hospital of Montpellier, Montpellier, France; 4Balaruc-les-bains balneotherapy centre, Balaruc-les-bains, France; 5Movement, Balance, Performance and Health Laboratory, University of Pau and Pays de l’Adour, Tarbes, France; 6Department of Geriatrics, University of Montpellier, Montpellier, France; 7Desbrest Institute of Epidemiology and Public Health UMR 1318 Inserm - University of Montpellier, Montpellier, France; 8Institute of Allergology, Charite - Universitätsmedizin Berlin, Berlin, GermanyCorrespondence: Hubert Blain, Email h-blain@chu-montpellier.frBackground: The effects on gait and posture of balneotherapy in fallers are unknown. We assessed the effects on physical functioning and fear of falling of a balneotherapy program alone or combined with a physical activity and educational program in older adult fallers.Methods: A multicenter randomized controlled trial enrolled patients aged 65 or older referred to a 3-week balneotherapy program, and screened for risk of falling (a history of falls in the last year and a timed up and go test or a five chair rising test > 12 sec or a 4-meter walk test > 4 sec). In addition to balneotherapy, patients had either no intervention (controls) or twelve 60-minute sessions of physical activity including 15 minutes of health education and three 90-minute sessions of an educational program (intervention).Results: There were 118 control and 105 intervention patients. The balneotherapy program alone had a clinically significant effect on (i) the grip strength, (ii) the five chair rising test, (iii) the 4-meter walk test, and (iv) the short physical performance battery (Cohen’s d 0.29– 0.46). It had no effect on (i) the maximum time stood on one foot, and (ii) the timed up and go test. Furthermore, it worsened the falls efficacy scale (d = 0.27). Adding a physical activity and educational program significantly improved (i) the time stood on one foot (Cohen’s d =− 0.34), and (ii) the timed up and go test (d=- 0.44), (iii) and reduced the concern about falling (Falls Efficacy scale, d=− 0.25), and (iv) the fear of falling (d=− 0.34).Conclusion: Older patients referred to a balneotherapy program and at high risk of falling when screened at the entrance of the center should be offered an additional physical and educational program to further improve the functional effects of balneotherapy on the timed up and go test, balance, and the fear of falling.Keywords: balneotherapy, falls, physical activity, educational program, fear of falling, physical performances

Abstract Botryosphaeriaceae species are the major causal agents of walnut dieback worldwide, along with Diaporthe species. Botryosphaeria dothidea and Neofusicoccum parvum are the only two Botryosphaeriaceae species associated with this recently emergent disease in France, and little is known about their diversity, structure, origin and dispersion in French walnut orchards. A total of 381 isolates of both species were genetically typed using a sequence-based microsatellite genotyping (SSR-seq) method. This analysis revealed a low genetic diversity and a high clonality of these populations, in agreement with their clonal mode of reproduction. The genetic similarity among populations, regardless of the tissue type and the presence of symptoms, supports the hypothesis that these pathogens can move between fruits and twigs and display latent pathogen lifestyles. Contrasting genetic patterns between N. parvum populations from Californian and Spanish walnut orchards and the French ones suggested no conclusive evidence for pathogen transmission from infected materials. The high genetic similarity with French vineyards populations suggested instead putative transmission between these hosts, which was also observed with B. dothidea populations. Overall, this study provides critical insight into the epidemiology of two important pathogens involved in the emerging dieback of French walnut orchards, including their distribution, potential to mate, putative origin and disease pathways.

Abstract In acute ischemic stroke, even when successful recanalization is obtained, downstream microcirculation may still be obstructed by microvascular thrombosis, which is associated with compromised brain reperfusion and cognitive decline. Identifying these microthrombi through non-invasive methods remains challenging. We developed the PHySIOMIC (Polydopamine Hybridized Self-assembled Iron Oxide Mussel Inspired Clusters), a MRI-based contrast agent that unmasks these microthrombi. In a mouse model of thromboembolic ischemic stroke, our findings demonstrate that the PHySIOMIC generate a distinct hypointense signal on T2*-weighted MRI in the presence of microthrombi, that correlates with the lesion areas observed 24 hours post-stroke. Our microfluidic studies reveal the role of fibrinogen in the protein corona for the thrombosis targeting properties. Finally, we observe the biodegradation and biocompatibility of these particles. This work demonstrates that the PHySIOMIC particles offer an innovative and valuable tool for non-invasive in vivo diagnosis and monitoring of microthrombi, using MRI during ischemic stroke.

Background People with suspected prostate cancer are usually offered either a local anaesthetic transrectal ultrasound-guided prostate biopsy or a general anaesthetic transperineal prostate biopsy. Transperineal prostate biopsy is often carried out under general anaesthetic due to pain caused by the procedure. However, recent studies suggest that performing local anaesthetic transperineal prostate biopsy may better identify cancer in particular regions of the prostate and reduce infection rates, while being carried out in an outpatient setting. Devices to assist with freehand methods of local anaesthetic transperineal prostate may also help practitioners performing prostate biopsies. Objectives To evaluate the clinical effectiveness and cost-effectiveness of local anaesthetic transperineal prostate compared to local anaesthetic transrectal ultrasound-guided prostate and general anaesthetic transperineal prostate biopsy for people with suspected prostate cancer, and local anaesthetic transperineal prostate with specific freehand devices in comparison with local anaesthetic transrectal ultrasound-guided prostate and transperineal prostate biopsy conducted with a grid and stepping device conducted under local or general anaesthetic. Data sources and methods We conducted a systematic review of studies comparing the diagnostic yield and clinical effectiveness of different methods for performing prostate biopsies. We used pairwise and network meta-analyses to pool evidence on cancer detection rates and structured narrative synthesis for other outcomes. For the economic evaluation, we reviewed published and submitted evidence and developed a model to assess the cost-effectiveness of the different biopsy methods. Results We included 19 comparative studies (6 randomised controlled trials and 13 observational comparative studies) and 4 single-arm studies of freehand devices. There were no statistically significant differences in cancer detection rates for local anaesthetic transperineal prostate (any method) compared to local anaesthetic transrectal ultrasound-guided prostate (relative risk 1.00, 95% confidence interval 0.85 to 1.18) (n = 5 randomised controlled trials), as was the case for local anaesthetic transperineal prostate with a freehand device compared to local anaesthetic transrectal ultrasound-guided prostate (relative risk 1.40, 95% confidence interval 0.96 to 2.04) (n = 1 randomised controlled trial). Results of meta-analyses of observational studies were similar. The economic analysis indicated that local anaesthetic transperineal prostate is likely to be cost-effective compared with local anaesthetic transrectal ultrasound-guided prostate (incremental cost below £20,000 per quality-adjusted life-year gained) and less costly and no less effective than general anaesthetic transperineal prostate. local anaesthetic transperineal prostate with a freehand device is likely to be the most cost-effective strategy: incremental cost versus local anaesthetic transrectal ultrasound-guided prostate of £743 per quality-adjusted life-year for people with magnetic resonance imaging Likert score of 3 or more at first biopsy. Limitations There is limited evidence for efficacy in detecting clinically significant prostate cancer. There is comparative evidence for the PrecisionPoint™ Transperineal Access System (BXTAccelyon Ltd, Burnham, UK) but limited or no evidence for the other freehand devices. Evidence for other outcomes is sparse. The cost-effectiveness results are sensitive to uncertainty over cancer detection rates, complication rates and the numbers of core samples taken with the different biopsy methods and the costs of processing them. Conclusions Transperineal prostate biopsy under local anaesthetic is equally efficient at detecting prostate cancer as transrectal ultrasound-guided prostate biopsy under local anaesthetic but it may be better with a freehand device. local anaesthetic transperineal prostate is associated with urinary retention type complications, whereas local anaesthetic transrectal ultrasound-guided prostate has a higher infection rate. local anaesthetic transperineal prostate biopsy with a freehand device appears to meet conventional levels of costeffectiveness compared with local anaesthetic transrectal ultrasound-guided prostate. Study registration This study is registered as PROSPERO CRD42021266443. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR134220) and is published in full in Health Technology Assessment Vol. 28, No. 60. See the NIHR Funding and Awards website for further award information. Plain language summary A prostate biopsy can help determine if a person has prostate cancer. The main ways of performing a prostate biopsy involve taking small samples of the prostate out through the rectum (back passage) or through the perineum – the skin area between the anus and the scrotum (testicles). Both methods use ultrasound images from a probe inserted into the rectum to help the clinician see what they are doing. Taking samples through the rectum is usually carried out under local anaesthetic, whereas taking samples through the perineum is usually carried out under general anaesthetic. We wanted to find out if taking samples through the perineum under local anaesthetic (instead of general anaesthetic) would be equally effective at detecting prostate cancer as the other biopsy methods and whether there was any improvement or change in the sorts of side effects people may have. We also wanted to know if people found the biopsy painful or not. We carried out searches of computer research databases to find relevant clinical and cost-effectiveness studies and compared the effectiveness of the different biopsy methods they used. We read and summarised the results of the studies we found in our search. Our findings showed that taking biopsy samples through the perineum under local anaesthetic had rates of detecting prostate cancer similar to those of the other biopsy methods. But if the clinician also used a freehand device that helps guide the biopsy needle as part of the procedure, then this may be a better method for detecting cancer. The studies we found agreed that performing this prostate biopsy under local anaesthetic was not too painful for most people. Our economic estimates suggest that using a freehand device for local anaesthetic perineal (through the skin of the perineum) biopsy may be a cost-effective use of National Health Service resources. Scientific summary Background Prostate cancer accounts for 30% of all cancers diagnosed in men in the UK and the incidence is rising. It is more common in men over 45 years of age. Symptoms that cannot be attributed to other health conditions include lower back or bone pain, lethargy, erectile dysfunction, haematuria, weight loss and lower urinary tract symptoms. National Institute for Health and Care Excellence (NICE) guideline NG12 advises on recognition and referral of people presenting with possible prostate cancer. A prostate-specific antigen (PSA) test and digital rectal examination should be performed. If PSA levels are raised above normal or if the prostate feels malignant, then the person should be referred for suspected cancer. NICE guideline NG131 advises on diagnosis and management. It recommends a multiparametric magnetic resonance imaging (mpMRI) test with the results reported using a five-point Likert scale to indicate how likely the presence of prostate cancer is. The Likert scale score, or alternatively the Prostate Imaging Reporting and Data System (PI-RADS score, not mentioned in the NICE guideline), is used to assess whether the person is offered a prostate biopsy. People with a score of 3 or above should be offered a multiparametric magnetic resonance imaging (mpMRI)-influenced prostate biopsy. People with a score of 1 or 2 will discuss risks and benefits with a clinician and if a prostate biopsy goes ahead, it should be a systematic biopsy. Two main options for biopsy are transrectal ultrasound prostate biopsy under local anaesthetic (LATRUS) and transperineal prostate biopsy under general anaesthetic (GATP). Biopsies can be either targeted (based on mpMRI findings) or systematic (samples are taken according to a predefined scheme) or both. Recent studies suggest that performing transperineal prostate biopsy under local anaesthetic (LATP) could better identify cancer in particular regions of the prostate and could have lower infection rates than transrectal biopsies while also being able to be carried out in an outpatient setting. Transperineal prostate biopsy is usually carried out under general anaesthetic due to pain caused by the procedure and tolerability is a key issue. Various freehand devices to assist with LATP prostate biopsy are being introduced to the market. The six specific freehand devices specified in the NICE scope for this review are: Cambridge Prostate Biopsy Device (CamPROBE) (JEB Technologies Ltd, Suffolk, UK); EZU-PA3U (Hitachi Ltd, Tokyo, Japan); PrecisionPoint™ Transperineal Access System (BXTAccelyon Ltd, Burnham, UK); SureFire Guide (LeapMed, Jiangsu, China); Trinity® Perine Grid (KOELIS®, NJ, USA); UA1232 puncture attachment (BK Medical, MA, USA). Objectives The aim of this review is to evaluate the diagnostic yield, clinical effectiveness and cost-effectiveness of LATP prostate biopsies performed with or without available specialist devices and equipment, in people with suspected prostate cancer. Two decision questions were prioritised by NICE for this assessment, with input from relevant stakeholders: Decision question 1. Do LATP prostate biopsies in patients with suspected prostate cancer represent a clinically and cost-effective use of National Health Service (NHS) resources? Decision question 2. Do freehand transperineal biopsy devices for LATP prostate biopsies in patients with suspected prostate cancer represent a clinically effective and cost-effective use of NHS resources? There are five comparisons required to address the two decision questions in the NICE scope: LATP-any (using coaxial needle or grid and stepping device or freehand device) versus LATRUS LATP-any (using coaxial needle or grid and stepping device or freehand device) versus GATP LATP-freehand (freehand device only) versus LATRUS LATP-freehand (freehand device only) versus GATP LATP-freehand (freehand device only) versus LATP-grid and stepping device. Methods Systematic review of diagnostic test evaluation and clinical effectiveness A systematic review of diagnostic and clinical effectiveness evidence was conducted following a peer-reviewed protocol. Searches were based on a comprehensive search strategy. Bibliographic databases, including MEDLINE, EMBASE, Web of Science, The Cochrane Library and the International HTA database, were searched for English-language references in July 2021, and these searches were updated at the end of October 2021. Urology conferences and freehand-device company submissions were hand-searched, and reference lists of identified systematic reviews and meta-analyses were checked. Relevant studies were sought through contact with study authors and NICE Specialist Committee members. Studies were eligible if they included people with suspected prostate cancer with an indication for prostate biopsy and reported diagnostic yield, for example, cancer detection rates, or other clinical or patient-reported outcomes. The eligible interventions were any LATP biopsy (of which LATP-freehand biopsy is a subset) and the eligible comparators were LATRUS and GATP; the LATP-grid and stepping device was an eligible comparator when compared with the LATP-freehand intervention. The Cochrane risk of bias tool (version 1) was used to assess risk of bias for the included randomised controlled trials (RCTs) and The Joanna Briggs Institute critical appraisal checklists were used to assess the included observational studies. Two reviewers carried out study selection, data extraction and critical appraisal, with any disagreements resolved through discussion and referred to a third reviewer for resolution as necessary. We conducted meta-analysis of the cancer detection rate outcomes for which sufficient comparative data were available. Pairwise meta-analysis was conducted for the above comparisons, with randomised and non-randomised studies analysed separately. Network meta-analysis was conducted for the two decision questions specified in the NICE scope. We synthesised the data for other outcomes narratively, as evidence was too sparse for meta-analysis. Review of economic evaluations We conducted a systematic review of the cost-effectiveness of the prostate biopsy methods in scope. The search strategies were based on an early version of the clinical effectiveness searches with the addition of an economics search filter. Included studies were full economic evaluations that assessed both costs and consequences for the different prostate biopsy methods. Outcomes included measures of resource use and costs and health outcomes: life-years or quality-adjusted life-years (QALYs) gained. Economic evaluations not meeting the inclusion criteria and studies that reported on resource use and costs, and health-related quality of life (utilities) were assessed as potential sources of information for the economic model. External Assessment Group independent economic assessment We developed a decision model to estimate the cost-effectiveness of alternative biopsy methods for people referred for biopsy with suspected prostate cancer. The model includes a decision tree to estimate diagnostic outcomes and biopsy-related complications, and a Markov model that predicts the long-term costs and consequences of false-negative biopsy results. We assessed cost-effectiveness for four subgroups at different prior levels of risk, based on previous mpMRI results (Likert 1 or 2; or Likert 3 or more) and history of prostate biopsy (none; previous negative biopsy). The decision tree used published results from the economic evaluation of the Prostate MR imaging study (PROMIS) to estimate baseline prevalence in the subgroups of interest, and diagnostic yield of LATRUS biopsy. Cancer detection rates were adjusted for the other biopsy methods using relative risks (RRs) from our network meta-analyses, and evidence from the literature on biopsy complication rates and the probability of repeat biopsy. Costs of the biopsy methods were estimated in a microcosting analysis, as well as from submitted evidence and published sources. The Markov model was a replicated version of a model developed for the 2019 update of the NICE guideline (NG131). Model parameters were based on those in the NG131 model, with some adjustments to costs and utilities from more recent published sources. Results Systematic review of diagnostic test evaluation and clinical effectiveness The literature searches identified a total of 1969 references of which 111 references were subjected to full-text screening. Twenty-seven publications reported 23 studies meeting the inclusion criteria for this review: 19 comparative studies of which 6 were RCTs and 13 were observational studies (1 of which is unpublished); and 4 single-arm studies for LATP-freehand devices where no comparative evidence was identified. There were no statistically significant differences in cancer detection rates for LATP (any method) compared to LATRUS with RR = 1.00 [95% confidence interval (CI) 0.85 to 1.18] (n = 5 RCTs). A single randomised trial estimated a non-significant difference in cancer detection rates in favour of LATP using a freehand device (PrecisionPoint) compared to LATRUS RR = 1.40, 95% CI 0.96 to 2.04. This finding was supported by meta-analysis of observational comparative studies RR = 1.21 (95% CI 1.08 to 1.34) (n = 4 studies). There were no statistically significant differences in cancer detection rates in meta-analyses comparing other biopsy methods. Evidence from the systematic review for other clinical outcomes, biopsy-related complications and patient-reported outcomes was sparse. Review of economic evaluations One economic evaluation was eligible for inclusion in the economic review out of 725 results from the original and update searches. This study evaluated the CamPROBE (LATP-freehand) device versus LATRUS for use in diagnosing prostate cancer from the perspective of the UK NHS. It used a decision-tree model with a Markov model at the terminal nodes and was informed by a prospective case series for the CamPROBE device and data from the PROMIS study. The study suggested that compared with LATRUS, LATP using the CamPROBE freehand device would be cost saving at a device price below £41 per procedure, or more cost-effective at the £20,000 per QALY threshold with a price below £81 per procedure. These calculations assume a zero rate of infection for LATP and equal diagnostic accuracy for LATP using CamPROBE and LATRUS. We considered 13 excluded economic studies as sources to inform our model structure and inputs, including the cost-effectiveness analysis for the PROMIS study and the analysis for the update of the NICE guideline on prostate cancer published in May 2019 (NG131). Evidence from the BXTAccelyon company submission included a cost minimisation study developed in 2020 by the York Health Consortium that compared the costs of LATP (with the PrecisionPoint freehand device) with different combinations of LATRUS and GATP for UK NHS Trusts. The study suggests that LATP using the PrecisionPoint freehand device is cost saving, assuming equal diagnostic yield of the different biopsy methods. Independent economic assessment The base-case economic analysis comparing LATP (all methods) with LATRUS and GATP indicated that LATP is likely to be the most cost-effective option in all four subgroups, with incremental cost-effectiveness ratio (ICER) estimates for LATP compared with LATRUS below £20,000 per QALY gained, and GATP estimated as more expensive and less effective than LATP. These conclusions were supported by probabilistic sensitivity analysis and a wide range of scenario analyses, although the results for LATP compared with LATRUS were sensitive to some alternative sources of cancer detection rates, rates of biopsy-related hospital admissions, numbers of core samples and histopathology costs. The economic analysis including LATP-freehand compared with other LATP methods, as well as LATRUS and GATP, indicated that LATP with a freehand device was the most cost-effective strategy, with an ICER of £743 per QALY for the highest-risk subgroup with MRI Likert score of 3 or more at first biopsy, and £4595 per QALY for the subgroup with a MRI Likert score 1 or 2 at first biopsy. For the subgroups with a previous negative biopsy, the ICER remained below £20,000 per QALY. Again, probabilistic sensitivity analysis supported these results, but scenario analysis highlighted uncertainty related to the cost of the devices, the number of core samples and costs of processing them, and the use of other sources of evidence for cancer detection and biopsy-related complication rates. The more favourable cost-effectiveness estimates for LATP with a freehand device are mostly driven by the cancer detection rates, which rest on a single RCT for LATP with a freehand device (PrecisionPoint). In the scenario based on observational evidence of cancer detection rates, the ICERs for LATP with a freehand device were less favourable, although still well below £20,000 per QALY. Increasing the cost of LATP with a freehand device by assuming the cost of the most expensive device, the ICER remained below £20,000 per QALY for the highest-risk subgroup but not for the other subgroups. Conclusions Transperineal prostate biopsy under local anaesthetic is equally efficient at detecting prostate cancer as transrectal ultrasound-guided prostate biopsy under local anaesthetic but evidence from one RCT, supported by observational studies, suggests that it might be better when using a freehand device. Local anaesthetic transperineal prostate biopsy is associated with urinary retention-type complications, whereas local anaesthetic transrectal ultrasound-guided prostate biopsy has a higher infection rate. Economic evaluation suggests that LATP with a freehand device is likely to be cost-effective compared with LATP with other methods, LATRUS and GATP for patients with no previous biopsy at high risk of having prostate cancer indicated by previous MRI results. This result is sensitive to the estimated cost of the freehand device, the number of and cost of core samples taken, and the sources for biopsy complication rates. Recommendations for research Evidence for freehand devices. There was no comparative evidence for several of the freehand devices in the NICE scope. The TRANSLATE study is expected to help address this question, as it is evaluating the PrecisionPoint, UA1232 and ‘any ultrasound probe-mounted needle guidance device’. Outcomes not covered in included available evidence. We suggest that incidence of defined complications (standardised for grading of severity and length of follow-up), health-related quality of life and longer-term clinical outcomes could be defined in a core outcome set. LATP versus GATP. Evidence for this comparison is sparse (we identified one RCT reporting cancer detection rates). Repeat biopsy population. There is a need for separate reporting of results for this subgroup, or a separate prospective RCT. UK NHS setting. The three UK studies included in our review were single-centre observational studies with a limited set of outcomes. The TRANSLATE study is expected to remedy this; it is a multicentre randomised study across nine NHS Trusts in England. Study registration This study is registered as PROSPERO CRD42021266443. Funding This awardproject was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR134220) and is published in full in Health Technology Assessment Vol. 28, No. 60. See the NIHR Funding and Awards website for further award information.

Abstract Background This cross-sectional controlled study aims to assess health-related quality of life (HRQoL) of children and adolescents with a molecular diagnosis of Marfan syndrome (MFS) or related disorders and to evaluate the factors associated with HRQoL in this population. Sixty-three children with MFS and 124 age- and sex-matched healthy children were recruited. HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL™) generic questionnaire. The correlation between HRQoL scores and the different continuous parameters (age, body mass index, disease severity, systemic score, aortic sinus diameter, and aerobic physical capacity) was evaluated using Pearson’s or Spearman’s coefficient. A multiple linear regression analysis was performed on the two health summary self-reported PedsQL™ scores (physical and psychosocial) to identify the factors associated with HRQoL in the MFS group. Results Except for emotional functioning, all other domains of HRQoL (psychosocial and physical health, social and school functions) were significantly lower in children with MFS compared to matched healthy children. In the MFS group, the physical health summary score was significantly lower in female than in male patients (self-report: absolute difference [95%CI] = -8.7 [-17.0; -0.47], P = 0.04; proxy-report: absolute difference [95%CI] = -8.6 [-17.3; 0.02], P = 0.05) and also negatively correlated with the systemic score (self-report: R = -0.24, P = 0.06; proxy-report: R = -0.29, P = 0.03) and with the height Z-score (proxy-report: R = -0.29, P = 0.03). There was no significant difference in the physical health summary scores between the different genetic subgroups. In the subgroup of 27 patients who performed a cardiopulmonary exercise test, self- and proxy-reported physical health summary scores were highly correlated with their aerobic physical capacity assessed by peak oxygen consumption (VO2max) and ventilatory anaerobic threshold (VAT). In the multivariate analysis, the most important independent predictors of decreased physical health were increased height, decreased body mass index, decreased VAT and use of prophylactic therapy. Conclusions This study reports an impaired HRQoL in children and adolescents with MFS or related conditions, in comparison with matched healthy children. Educational and rehabilitation programs must be developed and evaluated to improve exercise capacity and HRQoL in these patients. Trial registration ClinicalTrials.gov, NCT03236571 . Registered 28 July 2017.

Abstract Background Lateral ankle sprain (LAS) is the most common sports injury, leading to a high rate of recurrence and the development of chronic ankle instability. One possible explanation is the lack of objective, evidence-based criteria to inform return to sport decisions following LAS. The aim of this study was therefore to assess the efficacy of a new functional score to distinguish patients at risk of recurrent LAS within two years after the initial injury. Methods The Ankle-GO score was used in 64 active patients two months after LAS. This composite score includes 2 self-reported questionnaires and 4 functional tests, for a maximum score of 25 points. The rate of reinjury was prospectively recorded 2 years after inclusion. Potential predictive variables for reinjury were tested using the Chi-square and independent t-tests. The area under the receiver operating characteristics curve (AUC) with the optimal cut-off score was determined to assess the predictive value of the Ankle-GO score for the risk of reinjury. Multivariate logistic regression was then used to determine the influence of risk factors of reinjury. Results Fifty-four (85%) patients were included (23 men and 31 women, 34.7 ± 13 years old) including 18 (33.3%) with a reinjury. The two-month Ankle-GO score was lower in patients with a recurrent LAS (5.4 ± 2.8 points vs. 9.1 ± 4.5, p = 0.002) and predicted the risk of reinjury (AUC = 0.75). Patients with

Multimorbidity, defined as having two or more chronic health conditions, is associated with elevated polypharmacy and mortality. Autism spectrum disorder is a whole-body chronic health condition in which comorbidities -- in particular co-occurring intellectual disability -- contribute to high clinical heterogeneity, polypharmacy and premature mortality. We aimed to determine specific multimorbidity patterns among autism spectrum disorder + intellectual disability adults, and to identify participants' subgroups based on multimorbidity features. We used baseline examination data from a previous exploratory prospective multicentric study that included 63 autism spectrum disorder + intellectual disability adults. Multimorbidity patterns and subgroups were determined using clustering approaches. We observed 84.1% multimorbidity, significantly associated with age. We identified a dominant multimorbidity pattern, combining immune dysfunction, gastrointestinal disorders, neurological, and joint diseases. Four participants' subgroups could be distinguished by multimorbidity, autonomy and polypharmacy. Two clusters were distinguished by the prevalence and consequences of multimorbidity. One cluster involved women with endocrine disorders. The final cluster was composed of older adults with the lowest autism spectrum disorder severity but greater multimorbidity, including cardiovascular and kidney diseases. Our results support a role for the gut-brain axis in the pathophysiology of autism spectrum disorder + intellectual disability multimorbidity. Furthermore, we identified patient subgroups with specific needs, underscoring the importance of a holistic approach for autism spectrum disorder + intellectual disability adults.

Summary: Background: Red blood cell (RBC) transfusions are frequent in patients after cardiac surgery. This study assessed whether a bundle of care including pre-operative and post-operative administration of erythropoietin (EPO) with intravenous iron supplementation, and restrictive transfusion adjusted for ScvO2 could result in reduced postoperative transfusions. Methods: In this single-centre, randomised, open-label, parallel-group controlled pilot study, patients undergoing elective cardiac surgery with high risk of transfusion in a University Hospital were enrolled by the investigator and the randomisation procedure using a central internet-based system was made by the clinical research assistant. Since the trial was open-label, no masking was used. Patients were assigned (1:1) to either the STOP group (40,000 IU subcutaneous EPO combined with 20 mg/kg intravenous ferric carboxymaltose if Hb

This commentary reflects on the first Global Stocktake (GST) under the Paris Agreement on climate change to offer insights for advancing climate actions and informing future GST cycles. The first GST, which concluded at COP28 in 2023, demonstrates the vital importance of a comprehensive, balanced, and inclusive approach to multilateral climate action. The GST's call to transition away from fossil fuels is an important political achievement. Yet, the GST outcome also reveals gaps, shortcomings, and potential dangers ahead. Future climate negotiations, we argue, would benefit from a more integrated, holistic perspective, and more nuanced balancing of ambition and implementation. More needs to be done to protect human rights, increase loss and damage funding, go beyond technological solutions, and address gender-differentiated consequences of climate change. Moreover, a great deal of work, including by nonstate actors, will be required to ensure the first GST translates into real action on the ground.

Abstract Purpose Although multiple scales exist to evaluate psychological readiness before returning to sport post‐lateral ankle sprain (LAS), no score has been validated specifically for LAS or chronic ankle instability. The main aim of the study is to evaluate the validity and reproducibility of the ankle ligament reconstruction‐return to sport injury (ALR‐RSI) scale in assessing psychological readiness after LAS and its ability to identify patients who can return to their preinjury level. Methods A total of 64 patients (35 females and 29 males; 33.8 ± 13.2 years) who recently experienced an acute LAS were included in this study. All patients participated in a predictive validation component of the study and were assessed at 2 and 4 months following an LAS. The ALR‐RSI was completed twice by 20 patients at a 7‐day interval to evaluate the reliability of the score in patients suffering from LAS. Results The ALR‐RSI was significantly (p

Abstract Background Lamotrigine has become one of the most commonly prescribed antiseizure medications (ASM) in epileptic women during pregnancy and therefore requires regular updates regarding its safety. The aim of this study was to estimate the association between in utero exposure to lamotrigine monotherapy and the occurrence of neurodevelopmental outcomes. Methods All comparative studies assessing the occurrence of neurodevelopmental outcomes after epilepsy-indicated lamotrigine monotherapy exposure during pregnancy were searched. First, references were identified through a snowballing approach, then, through electronic databases (Medline and Embase) from 2015 to June 2022. One investigator evaluated study eligibility and extracted data and a second independent investigator reviewed the meta-analysis (MA). A systematic review and random-effects model approach were performed using a collaborative WEB-based meta-analysis platform (metaPreg.org) with a registered protocol (osf.io/u4gva). Results Overall, 18 studies were included. For outcomes reported by at least 4 studies, the pooled odds ratios and 95% confidence interval obtained with the number of exposed (N1) and unexposed children (N0) included were: neurodevelopmental disorders as a whole 0.84 [0.66;1.06] (N1 = 5,271; N0 = 22,230); language disorders or delay 1.16 [0.67;2.00] (N1 = 313; N0 = 506); diagnosis or risk of ASD 0.97 [0.61;1.53] (N1 = at least 5,262; N0 = 33,313); diagnosis or risk of ADHD 1.14 [0.75;1.72] (N1 = at least 113; N0 = 11,530) and psychomotor developmental disorders or delay 2.68 [1.29–5.56] (N1 = 163; N0 = 220). The MA of cognitive outcomes included less than 4 studies and retrieved a significant association for infants exposed to lamotrigine younger than 3 years old but not in the older age groups. Conclusion Prenatal exposure to lamotrigine monotherapy is not found to be statistically associated with neurodevelopmental disorders as a whole, language disorders or delay, diagnosis or risk of ASD and diagnosis or risk of ADHD. However, the MA found an increased risk of psychomotor developmental disorders or delay and cognitive developmental delay in less than 3 years old children. Nevertheless, these findings were based exclusively on observational studies presenting biases and on a limited number of included children. More studies should assess neurodevelopmental outcomes in children prenatally exposed to lamotrigine.

This study proposes a novel semi-supervised multi-label emotion classification approach for French tweets based on pseudo-labeling. Human subjectivity in emotional expression makes it difficult for a machine to learn. Therefore, it necessitates training supervised learning models on large datasets annotated by multiple annotators. However, creating such datasets can be costly and time-consuming. Moreover, aggregating annotations from multiple annotators to capture their collective emotional state adds complexity to the task. Semi-supervised learning techniques have shown effectiveness with limited datasets. Furthermore, Large language Models (LLMs), particularly Chat-GPT, have demonstrated superior annotation accuracy compared to annotations obtained from crowdsourcing platforms, when both are evaluated against expert-annotated data. This work introduces a novel approach for multi-label emotion classification of French tweets by leveraging pseudo-labels generated through Chat-GPT, a robust large language model. Using zero-shot, one-shot, and few-shot learning techniques, Chat-GPT annotates the unlabelled part of our dataset. These Chat-GPT-annotated pseudo-labels are then merged with manual annotations, facilitating the training of a multi-label emotion classification model via semi-supervised learning. Furthermore, within the context of our research, we present a new French tweet dataset, containing testimonials from people affected by an urban industrial incident. This dataset features 2,350 tweets, each manually annotated by three human annotators based on 8 pre-identified emotions. Benchmark results are presented for multi-label emotion classification models employing both fully supervised and semi-supervised approaches with pseudo-labeling. Our findings demonstrate the superiority of our approach for multi-label emotion classification over standard pseudo-labeling and an established baseline.

Anthocyanins, a class of flavonoid compounds responsible for the vibrant colors of many fruits and vegetables, have received considerable attention in recent years due to their potential health benefits. This review, focusing on evidence from both in vitro and in vivo studies, provides a comprehensive overview of the current state of knowledge regarding the health-promoting properties of anthocyanins. The chemical structure and diversity of anthocyanins, their bioavailability, and their mechanisms of action at the cellular and molecular level are examined. Research on the antioxidant, anti-inflammatory, anticancer, and neuroprotective effects of anthocyanins is critically reviewed. Special emphasis is placed on the role of anthocyanins in the prevention and treatment of chronic diseases such as cardiovascular diseases, diabetes, and neurodegenerative diseases. This review also discusses the challenges of translating in vitro findings to in vivo and highlights the importance of considering dose, bioavailability, and metabolism when assessing the therapeutic potential of anthocyanins. This review concludes with the identification of gaps in current research and suggestions for future directions for anthocyanin studies, including the need for more long-term clinical trials and investigations into potential synergistic effects with other phytochemicals. This comprehensive analysis highlights the promising role of anthocyanins in promoting human health and provides valuable insights for researchers, health professionals, and the nutraceutical industry. This study provides new insights, as it comprehensively investigates the dual anti-inflammatory and anticancer effects of anthocyanins in both in vitro and in vivo models. By uncovering the biological properties of anthocyanins from a variety of natural sources, this research not only expands our knowledge of the action of these compounds at the cellular level, but also enhances their clinical relevance through in vivo validation. Furthermore, the innovative use of anthocyanins may lead to important advances in their therapeutic application in the future.

Across disciplines there is a large and increasing number of research projects that rely on data collection activities in low- and middle-income countries (LMICs). However, these are accompanied by an extensive range of ethical challenges. While the safeguarding of study participants is the primary aim of existing ethics guidelines, this paper argues that this "do no harm" principle should be extended to include research staff. This study is a comprehensive review of more than 80 existing ethics guidelines and protocols that reveals a lack of safeguarding research staff regarding the ethical challenges faced during data collection activities in LMICs. This is particularly the case when it comes to issues such as power imbalances, political risk, staff's emotional wellbeing or dealing with feelings of guilt. Lead organizations are called upon to develop guiding principles that encompass the safeguarding of research staff, which are then to be adapted and translated into specific protocols and tools by institutions.

Inclusion of students with Autism Spectrum Disorder (ASD) in mainstream schools has a positive impact on their social and daily living behaviors. Our objective was to identify clinical and socio-demographic variables promoting or limiting inclusion in mainstream school through childhood and adolescence. The EpiTED study is a long-term, prospective, multicenter cohort of 281 ASD children included before the age of 7, with a 10-year follow-up in France. Variables significantly linked to inclusion in mainstream school were identified using a mixed-effect logistic regression model: greater autonomy [OR = 1.45 (1.29-1.63)], lesser symptom severity [OR = 0.96 (0.92-0.99)] and fewer siblings [OR = 0.86 (0.75-0.99)]. In the multivariate model, the probability for a child of being included in mainstream school decreased over time [OR = 0.91 (0.85-0.97)], i.e. with age.