High-dose Alemtuzumab-Cyclosporine vs Tacrolimus-Methotrexate-Sirolimus for Chronic Graft-versus-Host Disease Prevention.

Chronic graft-versus-host disease (cGVHD) remains a significant problem for patients after allogeneic hematopoietic stem cell transplants (allo-HSCT). While in vivo lymphodepletion by antibodies for cGVHD prophylaxis has been explored in the myeloablative setting, its effects after reduced intensity conditioning (RIC) are not well described. Patients (n=83) with hematologic malignancies underwent targeted lymphodepletion chemotherapy followed by a RIC allo-HSCT using peripheral blood stem cells from unrelated donors. Patients were randomized to two GVHD prophylaxis arms: high-dose alemtuzumab/cyclosporine (AC, n=44) and tacrolimus/methotrexate/sirolimus (TMS, n=39) with the primary endpoint of cumulative incidence of severe cGVHD. The incidence of severe cGVHD was lower with AC vs TMS prophylaxis at 1- and 5-years (0% vs 10.3% and 4.5% vs 28.5%, overall p=0.0002), as well as any grade (p=0.003) and moderate-severe (p<0.0001) cGVHD. AC was associated with higher rates of grade III-IV infections (p=0.02) and relapse (52% vs 21%, p=0.003) with a shorter 5-year PFS (18% vs 41%, p=0.01) and no difference in 5-year GRFS, OS, or NRM. AC severely depleted naïve T-cells reconstitution, resulting in reduced TCR repertoire diversity, smaller populations of CD4 Treg and CD8 Tscm, but a higher ratio of Treg to naïve T-cells at 6 months. In summary, an alemtuzumab-based regimen successfully reduced the rate and severity of cGVHD after RIC allo-HSCT and resulted in a distinct immunomodulatory profile which may have reduced cGVHD incidence and severity. However, increased infections and relapse resulted in a lack of survival benefit after long-term follow-up. ClinicalTrials.gov identifier: NCT00520130.

Evaluation of different models of general practitioners working in or alongside emergency departments: a mixed-methods realist evaluation.

Background: Emergency healthcare services are under intense pressure to meet increasing patient demands. Many patients presenting to emergency departments could be managed by general practitioners in general practitioner-emergency department service models. Objectives: To evaluate the effectiveness, safety, patient experience and system implications of the different general practitioner-emergency department models. Design: Mixed-methods realist evaluation. Methods: Phase 1 (2017-8), to understand current practice: rapid realist literature review, national survey and follow-up key informant interviews, national stakeholder event and safety data analysis. Phase 2 (2018-21), to collect and analyse qualitative (observations, interviews) and quantitative data (time series analysis); cost-consequences analysis of routine data; and case site data for 'marker condition' analysis from a purposive sample of 13 case sites in England and Wales. Phase 3 (2021-2), to conduct mixed-methods analysis for programme theory and toolkit development. Results: General practitioners commonly work in emergency departments, but delivery models vary widely in terms of the scope of the general practitioner role and the scale of the general practitioner service. We developed a taxonomy to describe general practitioner-emergency department service models (Integrated with the emergency department service, Parallel within the emergency department, Outside the emergency department on the hospital site) and present a programme theory as principal output of the study to describe how these service models were observed to operate. Routine data were of variable quality, limiting our analysis. Time series analysis demonstrated trends across intervention sites for: increased time spent in the emergency department; increased emergency department attendances and reattendances; and mixed results for hospital admissions. Evidence on patient experience was limited but broadly supportive; we identified department-level processes to optimise the safety of general practitioner-emergency department models. Limitations: The quality, heterogeneity and extent of routine emergency department data collection during the study period limited the conclusions. Recruitment was limited by criteria for case sites (time series requirements) and individual patients (with 'marker conditions'). Pandemic and other pressures limited data collection for marker condition analysis. Data collected and analysed were pre pandemic; new approaches such as 'telephone first' and their relevance to our findings remains unexplored. Conclusion: Findings suggest that general practitioner-emergency department service models do not meet the aim of reducing the overall emergency department waiting times and improving patient flow with limited evidence of cost savings. Qualitative data indicated that general practitioners were often valued as members of the wider emergency department team. We have developed a toolkit, based on our findings, to provide guidance for implementing and delivering general practitioner-emergency department services. Future work: The emergency care data set has since been introduced across England to help standardise data collection to facilitate further research. We would advocate the systematic capture of patient experience measures and patient-reported outcome measures as part of routine care. More could be done to support the development of the general practitioner in emergency department role, including a core set of competencies and governance structure, to reflect the different general practitioner-emergency department models and to evaluate the effectiveness and cost effectiveness to guide future policy. Study registration: This study is registered as PROSPERO CRD42017069741. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme (NIHR award ref: 15/145/04) and is published in full in Health and Social Care Delivery Research; Vol. 12, No. 10. See the NIHR Funding and Awards website for further award information.

Hospital emergency departments are under huge pressure. Patients are waiting many hours to be seen, some with problems that general practitioners could deal with. To reduce waiting times and improve patient care, arrangements have been put in place for general practitioners to work in or alongside emergency departments (general practitioner­emergency department models). We studied the different ways of working to find out what works well, how and for whom. We brought together a lot of information. We reviewed existing evidence, sent out surveys to 184 emergency departments, spent time in the emergency departments observing how they operated and interviewing 106 staff in 13 hospitals and 24 patients who visited those emergency departments. We also looked at statistical information recorded by hospitals. Two public contributors were involved from the beginning, and we held two stakeholder events to ensure the relevance of our research to professionals and patients. Getting reliable figures to compare the various general practitioner­emergency department set-ups (inside, parallel to or outside the emergency department) was difficult. Our findings suggest that over time more people are coming to emergency departments and overall waiting times did not generally improve due to general practitioner­emergency department models. Evidence that general practitioners might admit fewer patients to hospital was mixed, with limited findings of cost savings. Patients were generally supportive of the care they received, although we could not speak to as many patients as we planned. The skills and experience of general practitioners were often valued as members of the wider emergency department team. We identified how the care provided was kept safe with: strong leaders, good communication between different types of staff, highly trained and experienced nurses responsible for streaming and specific training for general practitioners on how they were expected to work. We have produced a guide to help professionals develop and improve general practitioner­emergency department services and we have written easy-to-read summaries of all the articles we published.

Programme theories to describe how different general practitioner service models work in different contexts in or alongside emergency departments (GP-ED): realist evaluation.

BACKGROUND: Addressing increasing patient demand and improving ED patient flow is a key ambition for NHS England. Delivering general practitioner (GP) services in or alongside EDs (GP-ED) was advocated in 2017 for this reason, supported by £100 million (US$130 million) of capital funding. Current evidence shows no overall improvement in addressing demand and reducing waiting times, but considerable variation in how different service models operate, subject to local context. METHODS: We conducted mixed-methods analysis using inductive and deductive approaches for qualitative (observations, interviews) and quantitative data (time series analyses of attendances, reattendances, hospital admissions, length of stay) based on previous research using a purposive sample of 13 GP-ED service models (3 inside-integrated, 4 inside-parallel service, 3 outside-onsite and 3 with no GPs) in England and Wales. We used realist methodology to understand the relationship between contexts, mechanisms and outcomes to develop programme theories about how and why different GP-ED service models work. RESULTS: GP-ED service models are complex, with variation in scope and scale of the service, influenced by individual, departmental and external factors. Quantitative data were of variable quality: overall, no reduction in attendances and waiting times, a mixed picture for hospital admissions and length of hospital stay. Our programme theories describe how the GP-ED service models operate: inside the ED, integrated with patient flow and general ED demand, with a wider GP role than usual primary care; outside the ED, addressing primary care demand with an experienced streaming nurse facilitating the 'right patients' are streamed to the GP; or within the ED as a parallel service with most variability in the level of integration and GP role. CONCLUSION: GP-ED services are complex . Our programme theories inform recommendations on how services could be modified in particular contexts to address local demand, or whether alternative healthcare services should be considered.

A parametric study of the effect of 3D plaque shape on local hemodynamics and implications for plaque instability.

The vast majority of heart attacks occur when vulnerable plaques rupture, releasing their lipid content into the blood stream leading to thrombus formation and blockage of a coronary artery. Detection of these unstable plaques before they rupture remains a challenge. Hemodynamic features including wall shear stress (WSS) and wall shear stress gradient (WSSG) near the vulnerable plaque and local inflammation are known to affect plaque instability. In this work, a computational workflow has been developed to enable a comprehensive parametric study detailing the effects of 3D plaque shape on local hemodynamics and their implications for plaque instability. Parameterized geometric 3D plaque models are created within a patient-specific coronary artery tree using a NURBS (non-uniform rational B-splines)-based vascular modeling pipeline. Realistic blood flow features are simulated by using a Navier-Stokes solver within an isogeometric finite-element analysis framework. Near wall hemodynamic quantities such as WSS and WSSG are quantified, and vascular distribution of an inflammatory marker (VCAM-1) is estimated. Results show that proximally skewed eccentric plaques have the most vulnerable combination of high WSS and high positive spatial WSSG, and the presence of multiple lesions increases risk of rupture. The computational tool developed in this work, in conjunction with clinical data, -could help identify surrogate markers of plaque instability, potentially leading to a noninvasive clinical procedure for the detection of vulnerable plaques before rupture.

Photoactive imaging and therapy for colorectal cancer using a CEA-Affimer conjugated Foslip nanoparticle.

Theranostic nanoparticles hold promise for simultaneous imaging and therapy in colorectal cancer. Carcinoembryonic antigen can be used as a target for these nanoparticles because it is overexpressed in most colorectal cancers. Affimer reagents are synthetic proteins capable of binding specific targets, with additional advantages over antibodies for targeting. We fabricated silica nanoparticles using a water-in-oil microemulsion technique, loaded them with the photosensitiser Foslip, and functionalised the surface with anti-CEA Affimers to facilitate fluorescence imaging and photodynamic therapy of colorectal cancer. CEA-specific fluorescence imaging and phototoxicity were quantified in colorectal cancer cell lines and a LS174T murine xenograft colorectal cancer model. Anti-CEA targeted nanoparticles exhibited CEA-specific fluorescence in the LoVo, LS174T and HCT116 cell lines when compared to control particles (p < 0.0001). No toxicity was observed in LS174T cancer mouse xenografts or other organs. Following photo-irradiation, the anti-CEA targeted particles caused significant cell death in LoVo (60%), LS174T (90%) and HCT116 (70%) compared to controls (p < 0.0001). Photodynamic therapy (PDT) at 24 h in vivo showed a 4-fold reduction in tumour volume compared to control mouse xenografts (p < 0.0001). This study demonstrates the efficacy of targeted fluorescence imaging and PDT using Foslip nanoparticles conjugated to anti-CEA Affimer nanoparticles in in vitro and in vivo colorectal cancer models.

The effect of SARS-COV-2 variant on non-respiratory features and mortality among vaccinated and non-fully vaccinated patients.

OBJECTIVE: To determine the effect of SARS-CoV-2 variants on non-respiratory features of COVID-19 in vaccinated and not fully vaccinated patients using a University of California database. METHODS: A longitudinal retrospective review of medical records (n = 63,454) from 1/1/2020-4/26/2022 using the UCCORDS database was performed to compare non-respiratory features, vaccination status, and mortality between variants. Chi-square tests were used to study the relationship between categorical variables using a contingency matrix. RESULTS: Fever was the most common feature across all variants. Fever was significantly higher in not fully vaccinated during the Delta and Omicron waves (p = 0.001; p = 0.001). Cardiac features were statistically higher in not fully vaccinated during Omicron; tachycardia was only a feature of not fully vaccinated during Delta and Omicron; diabetes and GI reflux were features of all variants regardless of vaccine status. Odds of death were significantly increased among those not fully vaccinated in the Delta and Omicron variants (Delta OR: 1.64, p = 0.052; Omicron OR: 1.96, p < 0.01). Vaccination was associated with a decrease in the frequency of non-respiratory features. CONCLUSIONS: Risk of non-respiratory features of COVID-19 is statistically higher in those not fully vaccinated across all variants. Risk of death and correlation with vaccination status varied.

Advanced Model-based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers.

PURPOSE: NV-5138 ([S]-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid) is an orally bioavailable, small-molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in development for treatment-resistant depression. The authors established a model to describe the relationship between plasma and cerebrospinal fluid (CSF) concentrations of NV-5138 and between CSF concentrations and potential biomarkers thought to be associated with mTORC1 activity (ie, orotic acid, N-acetylmethionine, and N-formylmethionine). METHODS: Data were collected from a randomized, double-blind, placebo-controlled, tolerability, and pharmacokinetic (PK) parameter study of 5 ascending (400, 800, 1600, 2400, and 3000 mg), once-daily oral doses of NV-5138 in healthy subjects. NV-5138 plasma PK parameter samples were collected at 15 time points over 24 hours on days 1 and 7, and at pre dose on days 2-6 for all doses. NV-5138 CSF PK parameter and CSF biomarker samples were collected on days 1 and 7 at pre dose and 4, 8, and 12 hours post dose for all doses except 3000 mg. A model-based approach was used to develop and validate a model that describes the relationship between NV-5138 in CSF and biomarker concentrations. FINDINGS: Twenty-four of the 42 enrolled subjects had simultaneous plasma and CSF measurements of NV-5138 and CSF biomarker concentrations and were included in the PK parameter and pharmacodynamic (PD) analyses. A 2-compartment plasma and CSF PK parameter, with indirect PD effects, model was developed and validated. NV-5138 plasma concentrations were positively correlated with those in CSF, although CSF concentrations lagged slightly behind those in plasma, as indicated by a counterclockwise hysteresis effect. Similarly, the relationship between the PD measures of mTORC1 activation and NV-5138 was also characterized by counterclockwise hysteresis, when the increase in CSF biomarker concentrations lagged behind those of NV-5138, consistent with a signaling intermediary/cascade, such as mTORC1. Maximal biomarker activation was achieved at NV-5138 CSF concentrations of approximately 3 µg/mL, which were associated with daily doses of 1600 mg NV-5138. The safety profile analysis (n = 42) found that most of the reported adverse events were mild in severity, with no severe, serious, unusual, or unexpected adverse events or any dissociative effects; 2 subjects (400-mg cohort) discontinued due to adverse events that were judged to be unrelated to study medication. IMPLICATIONS: The model will be used for designing future efficacy and tolerability studies. Consecutive daily doses of NV-5138 were well tolerated in this healthy volunteer study.

Fournier's gangrene: a review of predictive scoring systems and practical guide for patient management.

This article aims to provide a practical guide for patient management and an overview of the predictive scorings for Fournier's gangrene (FG) that are available to aid clinicians. A literature was performed reviewing currently used scoring systems for FG and presenting a practical guide for its management based on the available evidence. There are four specific scoring systems available for the assessment of FG although few other non-specific and generic tools also exist. These specific tools include Laboratory Risk Indicator for Necrotizing Fasciitis, Fournier's Gangrene Severity Index, Uludag Fournier's Gangrene Severity Index, and Simplified Fournier's Gangrene Severity Index and help calculate expected mortality. Our proposed algorithm covers primary assessment, resuscitative interventions, initial investigations, urgent care, post-operative care, and long-term follow-up. The management of the FG patient can be divided into initial resuscitation, surgical debridement, ongoing ward management with antibiotic therapy, wound reconstruction, and long-term follow-up. Each facet of care is vital and requires multidisciplinary team expertise for optimal outcomes. Whilst mortality continues to improve, it remains significant, reflecting the severe and life-threatening nature of FG. More research is certainly needed into how this care is individualised, and to ensure that long-term outcomes in FG include quality of life measures after discharge.

Fournier's gangrene: a review of predictive scoring systems and practical guide for patient management The management of Fourniers gangrene can be divided into initial resuscitation, surgical debridement, ongoing ward management with antibiotic therapy, wound reconstruction, and long-term follow-up. Each facet of care is vital and requires multidisciplinary team expertise for optimal outcomes. More research is certainly needed into how this care is individualised, and to ensure that long-term outcomes in FG includes quality of life measures after discharge.

A Pilot Study on Patient-specific Computational Forecasting of Prostate Cancer Growth during Active Surveillance Using an Imaging-informed Biomechanistic Model.

Active surveillance (AS) is a suitable management option for newly diagnosed prostate cancer, which usually presents low to intermediate clinical risk. Patients enrolled in AS have their tumor monitored via longitudinal multiparametric MRI (mpMRI), PSA tests, and biopsies. Hence, treatment is prescribed when these tests identify progression to higher-risk prostate cancer. However, current AS protocols rely on detecting tumor progression through direct observation according to population-based monitoring strategies. This approach limits the design of patient-specific AS plans and may delay the detection of tumor progression. Here, we present a pilot study to address these issues by leveraging personalized computational predictions of prostate cancer growth. Our forecasts are obtained with a spatiotemporal biomechanistic model informed by patient-specific longitudinal mpMRI data (T2-weighted MRI and apparent diffusion coefficient maps from diffusion-weighted MRI). Our results show that our technology can represent and forecast the global tumor burden for individual patients, achieving concordance correlation coefficients from 0.93 to 0.99 across our cohort (n = 7). In addition, we identify a model-based biomarker of higher-risk prostate cancer: the mean proliferation activity of the tumor (P = 0.041). Using logistic regression, we construct a prostate cancer risk classifier based on this biomarker that achieves an area under the ROC curve of 0.83. We further show that coupling our tumor forecasts with this prostate cancer risk classifier enables the early identification of prostate cancer progression to higher-risk disease by more than 1 year. Thus, we posit that our predictive technology constitutes a promising clinical decision-making tool to design personalized AS plans for patients with prostate cancer. SIGNIFICANCE: Personalization of a biomechanistic model of prostate cancer with mpMRI data enables the prediction of tumor progression, thereby showing promise to guide clinical decision-making during AS for each individual patient.

IDHwt glioblastomas can be stratified by their transcriptional response to standard treatment, with implications for targeted therapy.

BACKGROUND: Glioblastoma (GBM) brain tumors lacking IDH1 mutations (IDHwt) have the worst prognosis of all brain neoplasms. Patients receive surgery and chemoradiotherapy but tumors almost always fatally recur. RESULTS: Using RNA sequencing data from 107 pairs of pre- and post-standard treatment locally recurrent IDHwt GBM tumors, we identify two responder subtypes based on longitudinal changes in gene expression. In two thirds of patients, a specific subset of genes is upregulated from primary to recurrence (Up responders), and in one third, the same genes are downregulated (Down responders), specifically in neoplastic cells. Characterization of the responder subtypes indicates subtype-specific adaptive treatment resistance mechanisms that are associated with distinct changes in the tumor microenvironment. In Up responders, recurrent tumors are enriched in quiescent proneural GBM stem cells and differentiated neoplastic cells, with increased interaction with the surrounding normal brain and neurotransmitter signaling, whereas Down responders commonly undergo mesenchymal transition. ChIP-sequencing data from longitudinal GBM tumors suggests that the observed transcriptional reprogramming could be driven by Polycomb-based chromatin remodeling rather than DNA methylation. CONCLUSIONS: We show that the responder subtype is cancer-cell intrinsic, recapitulated in in vitro GBM cell models, and influenced by the presence of the tumor microenvironment. Stratifying GBM tumors by responder subtype may lead to more effective treatment.

Injury Profile in Youth Female Athletes: A Systematic Review and Meta-Analysis.

BACKGROUND: An increasing number of epidemiological studies assessing the incidence, prevalence and severity of injury in youth female sport are available. However, no study has sought to synthesise the current evidence base across all youth female sport. As such, a systematic review and meta-analysis of injury in this cohort is necessary to understand the diversity of injury and its associated burden between sports in addition to identifying the density of research available. OBJECTIVE: To conduct a systematic review and meta-analysis of epidemiological data of injuries in youth female athletes with particular attention to injury incidence, mean days lost and injury burden. METHODS: Searches were performed in PubMed, EBSCO (SPORTDiscus with Full Text MEDLINE, APA PsycINFO, CINAHL, Academic Search Complete) and Cochrane databases. Studies were considered if they reported time-loss injury incidence or prevalence in youth female (≤ 19 years old) athletes. Study quality and risk of bias were assessed using STROBE-SIIS extension, Newcastle-Ottawa Scale, and funnel plots, respectively. Injury incidence and burden rate data were modelled using a mixed-effect Poisson regression model. Days lost data were modelled using a generalised linear mixed model. RESULTS: Thirty-two studies were included. The overall incidence rate, mean days lost per injury, and burden rate were 4.4 injuries per 1000 h (95% CI 3.3-5.9), 10 days (95% CI 6-15), and 46 days per 1000 h (95% CI 23-92), respectively. Forty percent of athletes sustained at least one time-loss injury. Competitive level was a significant moderator of match and training injury incidence, with elite youth athletes presenting greater pooled injury incidence estimates than non-elite athletes (p = 0.0315 and p = 0.0047, respectively). The influence of moderators on days lost and injury burden could not be determined due to an insufficient number of studies for analysis. CONCLUSION: Despite a broad inclusion criterion, there is limited injury surveillance research available across youth female sport. Outside of soccer, little research density is evidenced with single studies available in popular team sports such as Australian football and rugby union. Insufficient study numbers reporting mean days lost and injury burden data were available for analysis, and pooled days lost data could only be estimated for soccer. This highlights a need for future research to report days lost data alongside injury number and exposure so burden can be calculated and the full risk of injury to youth female athletes can be identified.

A clinical approach to the investigation and management of long COVID associated neuropathic pain.

COVID-19 has been associated with a wide range of ongoing symptoms following recovery from the acute SARS-CoV-2 infection. Around one in three people with COVID-19 develop neurological symptoms with many reporting neuropathic pain and associated symptoms, including paraesthesia, numbness, and dysesthesia. Whilst the pathophysiology of long COVID-19-associated neuropathic pain remains unclear, it is likely to be multifactorial. Early identification, exclusion of common alternative causes, and a biopsychosocial approach to the management of the symptoms can help in relieving the burden of disease and improving the quality of life for patients.

Re-Irradiation after Radical Dose Radiotherapy: A Case Report Challenging an Established Dogma.

Traditionally, external beam radiation therapy has a dogma pronouncing that re-irradiation of a region previously exposed to radical dose radiotherapy is contraindicated due to unacceptable risk to surrounding tissues. This edict is often zealously maintained to the detriment of certain, carefully selected patients that may benefit from re-irradiation. Liposarcoma is a high-grade malignancy with a poor prognosis and high rates of recurrence. A case is described of multiply recurrent liposarcoma that we treated with re-irradiation of an extended field encompassing the gross recurrent tumor mass and including the previously irradiated region. The patient had a very good cosmetic outcome and remained disease-free after 3 years of follow-up. The case demonstrates the potential to significantly improve patient care if established dogmas are challenged related to the re-irradiation of recurrent high-grade tumors. We propose that with careful patient selection, re-irradiation can be delivered safely to patients with recurrent tumors and contribute to improved clinical outcomes.

Treatment Algorithm for Management of Benign Prostatic Obstruction: An Overview of Current Techniques.

The management of benign prostatic obstruction (BPO) should involve a treatment algorithm that takes into account prostate size, and patient's symptoms and preference with the aim of helping with urinary symptoms and enhance quality of life. The diagnostic assessment for men with lower urinary tract symptoms (LUTS) should be comprehensive to help choose the best management strategy. Strategies from lifestyle modifications to medical treatment with alpha blockers and/or 5-alpha-reductase inhibitors to surgical procedures can all be used in the management algorithm. Surgical management ranges from transurethral resection of prostate (TURP) to minimally invasive surgical therapies (MIST) including laser therapies such as Holmium laser enucleation (HoLEP) and photoselective vaporisation (PVP), aquablation, Rezum system, prostate artery embolisation (PAE), prostatic urethral lift (PUL), temporary implantable nitinol device (iTind) and Optilume BPH catheter system. BPO is a common urological condition that has a significant impact on quality of life and economic burden globally and is likely to become increasingly prevalent with an ageing population. Selecting the most appropriate treatment modality will depend on the individual patient preferences, availability of resources, cost, anatomical factors and the goals of treatment.

Semaphorins and Their Roles in Breast Cancer: Implications for Therapy Resistance.

Breast cancer is the most common cancer worldwide and a leading cause of cancer-related deaths in women. The clinical management of breast cancer is further complicated by the heterogeneous nature of the disease, which results in varying prognoses and treatment responses in patients. The semaphorins are a family of proteins with varied roles in development and homoeostasis. They are also expressed in a wide range of human cancers and are implicated as regulators of tumour growth, angiogenesis, metastasis and immune evasion. More recently, semaphorins have been implicated in drug resistance across a range of malignancies. In breast cancer, semaphorins are associated with resistance to endocrine therapy as well as breast cancer chemotherapeutic agents such as taxanes and anthracyclines. This review will focus on the semaphorins involved in breast cancer progression and their association with drug resistance.

Management of Fournier's gangrene: a practical guide for clinicians.

Fournier's gangrene is a localised form of necrotising fasciitis affecting the external genitalia, perineal and perianal regions. Although rare, it is associated with high rates of morbidity and mortality, so clinician awareness is essential for prompt treatment. Risk factors include diabetes mellitus, hypertension, chronic alcoholism and immunosuppression. Perineal pain in patients with sepsis should be treated with a high level of suspicion and early surgical referral is required as prompt debridement can improve outcomes. Repeated surgical intervention and antimicrobial therapy are often needed and recovery can take a long time, with a long-term impact on quality of life. This article discusses the natural history of Fournier's gangrene, aetiology, risk factors, investigations and treatments with an algorithm to support clinical practice.

Evaluating the impact of injury prevention interventions in child and adolescent sports using the RE-AIM framework and CERT: A systematic review.

BACKGROUND: Participation in sport is a popular pastime for children and adolescents that improves their physical health, mental health and motor skills. Musculoskeletal injuries are a relatively common downside of sports participation and can have negative long-term consequences. Injury prevention programmes have demonstrated effectiveness in child and adolescent sports, provided compliance is adequate. However, little is known about the factors which relate to their impact on the wider community and whether the prevention programmes have been adopted and maintained in the long-term. The objective of this review was to assess the current literature on exercise-based injury prevention interventions in child and adolescent sports (aged under 19 years) against the 'Reach', 'Effectiveness', 'Adoption', 'Implementation', 'Maintenance' (RE-AIM) framework and Consensus of Exercise Reporting Template (CERT), to ascertain level of reporting for the components which relate to external validity. METHODS: Seven electronic databases; PubMed, Medline, SPORTDiscus, PsycINFO, CINAHL, Scopus and The Cochrane Library, were searched from date of inception to July 2022 using the themes of: 'Child and Adolescent', 'Sport', 'Injury' and 'Prevention'. Eligibility criteria included: Experimental trial design, exercise-based intervention programmes, primary outcome of injury incidence and participants aged under 19 years. Two reviewers assessed each trial independently against the RE-AIM model dimension items checklist (RE-AIM MDIC) and Consensus on Exercise Reporting Template (CERT) before reaching a consensus on reporting. RESULTS: Forty-five unique trials met the eligibility criteria. Mean reporting level for all studies across the whole RE-AIM MDIC was 31% (SD ± 16.2%, Range 7-77%). The domain of 'effectiveness' was the most comprehensively reported (60%), followed by 'implementation' (48%), 'reach' (38%), 'adoption' (26%) and 'maintenance' (7%). The mean reporting score for the CERT was 50% (SD ± 20.8, range 0-81%). CONCLUSION: Published data on injury prevention in child and adolescent sports is highly focussed on the effectiveness of the intervention, with little consideration given to how it will be adopted and maintained in the long-term. This has led to considerable gaps in knowledge regarding optimal programme implementation, with a lack of data on adoption and maintenance contributing to the gap between research and practice. Future research needs to place greater focus on external validity and consider incorporating the study of implementation and feasibility as part of effectiveness trial design. This approach should provide the data that will help narrow the considerable gap between science and practice. TRIAL REGISTRATION: PROSPERO Registration number CRD42021272847.

Cystine Stones: Developments in Minimally Invasive Surgery and Their Impact on Morbidity and Stone Clearance.

Cystinuria is a rare genetic condition that is responsible for cystine stones. Besides stone recurrence, patients with cystine stones have reduced health-related quality of life, increased rates of chronic kidney disease and hypertension. Although lifestyle measures, medical therapy and close follow up are essential to reduce and monitor cystine stone recurrences, surgical intervention is frequently needed for most cystinuria patients. Shock wave lithotripsy, ureteroscopy, percutaneous nephrolithotomy and active surveillance all have a role, and technological advances in endourology are vital in achieving a stone-free status and to prevent recurrences. The complexity of managing cystine stones necessitates a multidisciplinary team discussion, patient involvement and an individualised approach in a specialist centre for optimum management. Thulium fibre laser and virtual reality may have an increasing role in the future of cystine stone management.

Gastrointestinal Stromal Tumor Patients with Molecular Testing Exhibit Superior Survival Compared to Patients without Testing: Results from the Life Raft Group (LRG) Registry.

Mutational testing for Gastrointestinal Stromal Tumor (GIST) patients remains underutilized. In this retrospective analysis, the target population (n = 1556) reported: 904 had molecular testing ("Tested") vs. 652 without testing ("Untested"). Overall survival (OS) was 14.7 vs. 12.7 years (p < 0.00001), in metastatic patients 1st line OS was 8.9 vs. 5.9 years in the Tested vs. Untested group (n = 416 vs. n = 254), respectively. From 1st - 3rd-line, no difference has been (self-)reported for progression-free survival (PFS). Dropout to/for further lines of treatment was 15% for patients with a Tested mutation vs. 47% in Untested patients.

Mutations in NAKED-ENDOSPERM IDD genes reveal functional interactions with SCARECROW during leaf patterning in C4 grasses.

Leaves comprise a number of different cell-types that are patterned in the context of either the epidermal or inner cell layers. In grass leaves, two distinct anatomies develop in the inner leaf tissues depending on whether the leaf carries out C3 or C4 photosynthesis. In both cases a series of parallel veins develops that extends from the leaf base to the tip but in ancestral C3 species veins are separated by a greater number of intervening mesophyll cells than in derived C4 species. We have previously demonstrated that the GRAS transcription factor SCARECROW (SCR) regulates the number of photosynthetic mesophyll cells that form between veins in the leaves of the C4 species maize, whereas it regulates the formation of stomata in the epidermal leaf layer in the C3 species rice. Here we show that SCR is required for inner leaf patterning in the C4 species Setaria viridis but in this species the presumed ancestral stomatal patterning role is also retained. Through a comparative mutant analysis between maize, setaria and rice we further demonstrate that loss of NAKED-ENDOSPERM (NKD) INDETERMINATE DOMAIN (IDD) protein function exacerbates loss of function scr phenotypes in the inner leaf tissues of maize and setaria but not rice. Specifically, in both setaria and maize, scr;nkd mutants exhibit an increased proportion of fused veins with no intervening mesophyll cells. Thus, combined action of SCR and NKD may control how many mesophyll cells are specified between veins in the leaves of C4 but not C3 grasses. Together our results provide insight into the evolution of cell patterning in grass leaves and demonstrate a novel patterning role for IDD genes in C4 leaves.