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We hypothesised that the inclusion of immunosuppressive and inflammatory biomarkers in HGSOC patients would improve the sensitivity and specificity of the preoperative marker prediction of malignancy in patients with ovarian masses. We tested a panel of 29 soluble immune factors by multiplex bead immunoassay and 16 phenotypic T cell markers by flow cytometry in pre-treatment blood samples from 66 patients undergoing surgery for suspected ovarian cancer or ovarian cancer risk reduction. The potential diagnostic utility of all parameters was explored using Volcano plots, principal component analysis (PCA) and receiver operator characteristic (ROC) analysis. We also assessed the effect of culturing PBMCs from 20 healthy donors in the presence of malignant ascites fluid. The combination of TNFR2+ Tregs and IL-6 in the pre-treatment blood of patients with advanced HGSOC effectively discriminated patients with benign or malignant ovarian masses. In vitro culturing of the PBMCs of healthy donors in malignant ascites promoted an increase in TNFR2-expressing Tregs, which were decreased following blockade with IL-6 or STAT3 activity. Pre-treatment serum IL-6 and peripheral blood TNFR2+ Tregs may be potential clinical biomarkers that can discriminate patients with malignant compared to benign ovarian cancer masses, and the relationship between IL-6 and TNFR2+ Treg is likely to be mediated via the STAT3 signalling pathway.

Background Australia has one of the highest rates of methamphetamine (MA) use in the world; however, uptake of in-person psychological treatment remains extremely low due to numerous individual (e.g., stigma, shame) and structural (e.g., service accessibility, geographical location) barriers to accessing care. Telephone-delivered interventions are ideally placed to overcome many of the known barriers to treatment access and delivery. This randomised controlled trial (RCT) will examine the efficacy of a standalone, structured telephone-delivered intervention to reduce MA problem severity and related harms. Methods This study is a double-blind, parallel group RCT. We will recruit 196 ± 8 individuals with mild to moderate MA use disorder from across Australia. After eligibility and baseline assessments, participants will be randomly allocated to receive either the Ready2Change-Methamphetamine (R2C-M) intervention (n = 98 ± 4; four to six telephone-delivered intervention sessions, R2C-M workbooks, and MA information booklet) or control (n = 98 ± 4; four to six ≤ 5-minute telephone check-ins and MA information booklet including information on accessing further support). Telephone follow-up assessments will occur at 6-weeks and 3-, 6- and 12-months post-randomisation. The primary outcome is change in MA problem severity (Drug Use Disorders Identification Test, DUDIT) at 3 months post-randomisation. Secondary outcomes are: MA problem severity (DUDIT) at 6- and 12-months post-randomisation; amount of methamphetamine used, methamphetamine use days, methamphetamine use disorder criteria met, cravings, psychological functioning, psychotic-like experiences, quality of life, and other drug use days (at some or all timepoints of 6-weeks and 3-, 6- and 12-month post-randomisation). Mixed-methods program evaluation will be performed and cost effectiveness will be examined. Discussion This study will be the first RCT internationally to assess the efficacy of a telephone-delivered intervention for MA use disorder and related harms. The proposed intervention is expected to provide an effective, low-cost, scalable treatment for individuals otherwise unlikely to seek care, preventing future harms and reducing health service and community costs. Trial registration: ClinicalTrials.gov NCT04713124, pre-registered 19 January, 2021. Protocol version V5 01 September 2022

Gastric cancer; Metastasectomy; Oligometastasis Cáncer gástrico; Metastasectomía; Oligometástasis Càncer gàstric; Metastasectomia; Oligometàstasi Background Local treatment improves the outcomes for oligometastatic disease (OMD, i.e. an intermediate state between locoregional and widespread disseminated disease). However, consensus about the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer is lacking. The aim of this study was to develop a multidisciplinary European consensus statement on the definition, diagnosis and treatment of oligometastatic oesophagogastric cancer. Methods In total, 65 specialists in the multidisciplinary treatment for oesophagogastric cancer from 49 expert centres across 16 European countries were requested to participate in this Delphi study. The consensus finding process consisted of a starting meeting, 2 online Delphi questionnaire rounds and an online consensus meeting. Input for Delphi questionnaires consisted of (1) a systematic review on definitions of oligometastatic oesophagogastric cancer and (2) a discussion of real-life clinical cases by multidisciplinary teams. Experts were asked to score each statement on a 5-point Likert scale. The agreement was scored to be either absent/poor (2 years, either upfront local treatment or systemic treatment followed by restaging was considered as treatment (fair agreement). Conclusion The OMEC project has resulted in a multidisciplinary European consensus statement for the definition, diagnosis and treatment of oligometastatic oesophagogastric adenocarcinoma and squamous cell cancer. This can be used to standardise inclusion criteria for future clinical trials.

Background Objective: To compare overall (OS) and recurrence-free survival (RFS) in esophageal adenocarcinoma patients with a complete pathological response (pCR) following neoadjuvant chemotherapy (nCT) or neoadjuvant chemoradiotherapy (nCRT). Background In the absence of survival differences in several prior studies comparing nCT with nCRT, the higher rate of pCR after nCRT has been suggested as reason to prefer this modality over nCT. Methods An international cohort study included data from 8 high-volume centers. Inclusion criteria was patients with esophageal adenocarcinoma, between 2008 and 2018, who had a pCR following nCT or nCRT. Univariate analysis was used to compare demographic factors, and Kaplan-Meier survival analysis used to compare 5-year OS and RFS between groups. Results 465 patients with pCR following neoadjuvant treatment were included; 132 received nCT and 333 received nCRT. There was no statistically significant difference in 5-year OS between groups (78.8% (nCT) vs. 65.5% (nCRT), p=0.099), with a similar result demonstrated in multivariate analysis (HR=1.19, 95%CI 0.77 to 1.84). 5-year RFS was significantly reduced in patients with a pCR following neoadjuvant chemoradiotherapy (75.3% (nCRT) vs. 87.1% (nCT), p=0.026). Multivariate analysis confirmed nCRT was associated with a poorer 5-year RFS (HR=1.70, 95%CI 1.22 to 2.99). nCRT associated with a significantly greater prevalence of 5-year distant recurrence (Odds ratio = 2.50, 95%CI 1.25–4.99). Conclusions The results of this international cohort study show that the prognosis of pCR following different neoadjuvant regimes differs, bringing into question the validity of this measure as an oncological surrogate when comparing neoadjuvant treatment schemes for esophageal adenocarcinoma.

Background Professionalism is a core competency that is difficult to assess. We examined the incidence of publication inaccuracies in Electronic Residency Application Service applications to our training program as potential indicators of unprofessional behavior. Study Design We reviewed all 2019-2020 National Resident Matching Program applicants being considered for interview. Applicant demographic characteristics recorded included standardized examination scores, gender, medical school, and medical school ranking (2019 US News & World Report). Publication verification by a medical librarian was performed for peer-reviewed journal articles/abstracts, peer-reviewed book chapters, and peer-reviewed online publications. Inaccuracies were classified as “nonserious” (eg incorrect author order without author rank promotion) or “serious” (eg miscategorization, non-peer-reviewed journal, incorrect author order with author rank promotion, nonauthorship of cited existing publication, and unverifiable publication). Multivariate logistic regression analysis was performed for demographic characteristics to identify predictors of overall inaccuracy and serious inaccuracy. Results Of 319 applicants, 48 (15%) had a total of 98 inaccuracies; after removing nonserious inaccuracies, 37 (12%) with serious inaccuracies remained. Seven publications were reported in predatory open access journals. In the regression model, none of the variables (US vs non-US medical school, gender, or medical school ranking) were significantly associated with overall inaccuracy or serious inaccuracy. Conclusions One in 8 applicants (12%) interviewing at a general surgery residency program were found to have a serious inaccuracy in publication reporting on their Electronic Residency Application Service application. These inaccuracies might represent inattention to detail or professionalism transgressions.

Objective To perform a systematic review on the effects of testicular sparing surgery (TSS) on the oncological, functional, and hormonal outcomes of adults with testicular tumors. Methods A literature search was performed after PROSPERO registration (CRD42020200842) and reported in compliance with Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) methods. We conducted a systematic search of Medline (Ovid), Embase, Cochrane CENTRAL, CINAHL, Scopus, Web of Science, ClinicalTrials.gov, and the WHO/ICTRP from inception to November 20, 2020. Manuscripts and published abstracts were included if they involved testis‐sparing surgery (TSS) and contained data on any outcomes related to fertility, hormonal parameters, or oncological control, or if they evaluated surgical technique. Results Our initial search yielded 3,370 manuscripts, with 269 of these screened for full‐text eligibility. After our exclusion criteria were applied, 32 studies were included in the final analysis. Oncological outcomes were obtained from 12 studies (average follow‐up 57.8 months), functional data from 26 studies (average follow‐up 49.6 months), fertility information from 10 studies (average follow‐up 55.8 months), and data on nonpalpable tumors from 11 studies (average follow‐up 32.1 months). Oncological control appears to be excellent in studies that reported these outcomes. Presence of germ cell neoplasia in situ was controlled with adjuvant radiation in nearly all cases. Functional outcomes are also promising, as development of primary and compensated hypogonadism was rare. Semen parameters are poor preoperatively among men with benign and malignant testis tumors, with occasional decline after TSS. Frozen section analysis at the time of surgery appears to be very reliable, and the majority of nonpalpable tumors appear to be benign. Conclusions TSS is a safe and efficacious technique with regards to oncological control and postoperative hormonal function based on retrospective, noncontrolled studies. TSS avoids unnecessary removal of benign testicular tissue, and should be given serious consideration in cases of nonpalpable, small tumors under 2 cm. In cases of malignancy, TSS can safely avoid anorchia in men with bilateral tumors and in men with solitary testicles. The use of the operating microscope, while theoretically promising, does not necessarily lead to better outcomes, however data are limited.

Cervicogenic headache (CGH) can often be difficult to treat, given the overlapping clinical features of other headaches and the varying sources of pain that patients report. While imaging is not useful in diagnosing CGH, anesthetic blockade of the atlanto-occipital joint, lateral atlantoaxial joint, or specific cervical zygapophyseal joints can be used to confirm the diagnosis. When conservative treatment measures, such as physical therapy, fail, interventional techniques, such as intraarticular steroid injections, have been shown in observational studies to provide relief in some patients.To determine the efficacy of intraarticular cervical facet steroid injections in the treatment of CGH.Systematic review and meta-analysis.We conducted a comprehensive search of Ovid Medline, Embase, Cochrane Central Register of Controlled Trials , Cumulative Index to Nursing and Allied Health Literature Plus with Full Text, Scopus, and the Web of Science platform, from inception to April 2021, for studies using intraarticular cervical facet injections to treat CGH in adults aged 18 or older. Primary outcomes included mean postinjection pain scores. Outcomes were pooled using a random effects model and reported as mean differences (MD) with 95% confidence intervals (CI).Three studies with a total of 64 patients met the inclusion criteria. According to data from each of the included studies, intraarticular cervical facet injections were shown to demonstrate improvement in the mean pain score from baseline to postintervention. The overall effect size-pooled MD in the Visual Analog Scale score-was 3.299 (95% CI: 2.045 to 4.552, P0.001). Heterogeneity (I2) was 36.11%.Small sample size, lack of control group, and varying pain generators and interventional technique between studies contribute to the limitations of the analysis.Our findings suggest that therapeutic intraarticular cervical facet injections may be effective in the treatment of CGH. Because of the heterogeneity among the studies, these results should be interpreted with caution.

Curative treatment for esophageal cancer requires local and systemic disease control. Neoadjuvant treatment increases long-term survival, but the evidence to date is insufficient to determine if neoadjuvant chemoradiotherapy (nCRT) with focus on local control or neoadjuvant chemotherapy (nCT) with focus on systemic control, is more beneficial. In this analysis of the ENSURE study we aimed to compare recurrence patterns and survival between nCRT and nCT in a large multicenter European cohort study. All patients treated with neoadjuvant therapy and esophagectomy for cancer from 2009-2015 in the ENSURE study (NCT03461341) were included. Univariable and multivariable logistic regression and Cox proportional hazard models were used to compare recurrence pattern, diseases-free, and overall survival. Results are shown as odds ratios (OR), hazard ratios (HR) and 95% confidence intervals (CI). The multivariable model was pre-specified and included age, sex, clinical tumor stage, and tumor histology. In total 3267/4682 (69.8%) patients were treated with neoadjuvant therapy and were included in the study. nCRT was given to 1798 (55.0%) patients, and nCT was given to 1496 (45.0%) patients. Median age for nCRT was 63 vs. 64 for nCRT, 65.5% in the nCRT group had adenocarcinoma vs. 81.4% in the nCT group. In the nCRT group 38.7% of patients had tumor stage III-IV compared to 61.3% in the nCT group. Multivariable adjusted OR for local recurrence comparing nCRT to nCT was 1.31 (95% CI: 1.08-1.59), distant recurrence OR 1.87 (95% CI: 1.57-2.22), and combined recurrence 1.49 (95% CI: 1.26-1.76). Adjusted HR for disease specific survival comparing nCRT to nCT was 1.38 (95% CI: 1.24-1.55), disease free survival: 1.39 (95% CI: 1.25-1.54), and for overall survival: 1.44 (95% CI: 1.30-1.60). The results of the study show significantly increased risk for recurrent disease and decreased survival after nCRT compared to nCT for esophageal cancer. nCRT is administered with a lower total dose of chemotherapy compared to nCT. Radiotherapy is given for local control, which is also achieved with adequate lymphadenectomy. The results indicate that effective systemic treatment with nCT might be beneficial compared to nCRT in curative intended treatment of esophageal cancer.

We present the case of a 41-year-old female who underwent bilateral lung transplantation after the donor lungs were placed on a normothermic ex vivo lung perfusion and ventilation device and flown nearly 5000 miles from Honolulu, Hawaii to Durham, North Carolina. The patient experienced no primary graft dysfunction. One year after transplantation she has remained rejection-free and exhibits excellent pulmonary function. This case highlights the challenge that active organ preservation systems pose to questions of organ allocation and geographic sharing.

Recent analyses have found waves of neural activity traveling across entire visual cortical areas in awake animals. These traveling waves modulate excitability of local networks and perceptual sensitivity. The general computational role for these spatiotemporal patterns in the visual system, however, remains unclear. Here, we hypothesize that traveling waves endow the brain with the capacity to predict complex and naturalistic visual inputs. We present a new network model whose connections can be rapidly and efficiently trained to predict natural movies. After training, a few input frames from a movie trigger complex wave patterns that drive accurate predictions many frames into the future, solely from the network’s connections. When the recurrent connections that drive waves are randomly shuffled, both traveling waves and the ability to predict are eliminated. These results show traveling waves could play an essential computational role in the visual system by embedding continuous spatiotemporal structures over spatial maps.

IntroductionAbortion providers may be reluctant to commence abortion before ultrasound evidence of intrauterine pregnancy (IUP) due to concerns of missed ectopic pregnancy. In 2017, very early medical abortion (VEMA) was introduced at an abortion service in Edinburgh, UK. Following ultrasound, patients without confirmed IUP, and without symptoms or risk factors for ectopic pregnancy, could commence treatment immediately after baseline serum-human chorionic gonadotrophin (hCG) measurement, and return for follow-up serum-hCG a week later to determine treatment success (≥80% decline from baseline). This study aimed to compare clinical outcomes between two pathways: (1) VEMA; and (2) standard-of-care delayed treatment where treatment is only commenced on IUP confirmation by serial serum-hCG monitoring and/or repeat ultrasound.MethodsA retrospective database review was conducted of VEMA eligible patients from July 2017 to December 2021. Study groups were determined by patient preference. Records were searched for abortion outcomes, duration of care, number of appointments (clinic visits, ultrasounds, serum-hCG) and clinical data entries.ResultsOf 181 patients included, 77 (43%) chose VEMA and 104 (57%) chose delayed treatment. 11/181 (6.1%) were lost to follow-up. Cohort ectopic prevalence was 4.4% and was not statistically different between groups (2.6% vs 5.8%, VEMA vs delayed group, respectively, p=0.305), as with complete abortion rates (93.3% vs 97.6%, p=0.256). All VEMA group ectopics were detected on the seventh day (from initial visit) while time-to-diagnosis for delayed group ectopics ranged from 7 days to 3 weeks. VEMA patients had significantly reduced duration of care (12 vs 21 days, pConclusionsVEMA is safe, effective and reduces the duration of care, number of appointments and clinical administrative time. It should be offered to medically eligible patients.

Background CROSS regimen (41.4Gy;carboplatin&paclitaxel) is a standard trim-modality treatment for locally advanced oesophageal adenocarcinoma (OAC). The addition of adjuvant immunotherapy targeting PD-L1 may improve outcomes, hence the impact of radiation therapy on the tumour microenvironment is of considerable interest. The dosing has not been studied in this context, especially hypofractionation, and this study explored immunogenic cell death, specifically Damage Associated Molecular Pattern (DAMPs) release,and the impact of immune checkpoint blockade(ICB). Methods The ability of CROSS-regimen (3×1.8Gy) and hypo-fractionation (3×4Gy) to induce immunogenic cell death was assessed by flow cytometry of DAMPs calreticulin&HMGB-1.Expression of DAMPs were evaluated on OAC tumour and whole blood samples (n=10) pre and post conventional therapies versus hypofractionation. The immunostimulatory effect of CROSS and hypofractionation using post-treatment tumour cell secretomes with/without ICB on the cytolytic ability of OAC-donor lymphocytes was interrogated by CCK8-assay. Results The expression of Calreticulin&HMGB1 was significantly higher on tumour tissue compared to whole blood post chemo(radio)therapy(p Conclusions The current CROSS regimen radiation for OAC is immunogenic,however,hypo-fractionated doses boosted the immune response to OAC, and was synergistic with ICB. This may warrant further exploration in a clinical and translational trial.

Background Adjuvant immunotherapy for oesophageal cancer is set to become a standard of care following the Checkmate-577 trial proving the efficacy of adjuvant nivolumab. Scientifically, the key mechanisms are unclear. This study profiled systemic anti-/pro-tumour immunity and circulating pro-metastatic factors perioperatively in patients, and the impact of immune checkpoint blockade on key pathways. Methods Systemic immunity in oesophageal cancer patients (n=14) was immunophenotyped prior to surgery (postoperative day(POD)-0) and POD-1,3,7 and week-6, using flow cytometry. Longitudinal serological profiling was conducted by multiplex ELISA characterising systemic immunity and pro-metastatic signalling. The cytolytic ability of circulating lymphocytes against oesophageal cancer cell lines was assessed with and without immunotherapies; nivolumab/ipililmumab. Results PD-1+ and CTLA-4+ T-cells peaked on POD-1, significantly decreasing by week 6(p Conclusions Major oesophageal cancer surgery promotes a switch from Th1 to Th2 cellular immunity, dampening the cytolytic ability of T-lymphocytes. In an ex-vivo model, PD-1/CTLA-4 inhibition induced a shift to a Th1-like cytotoxic phenotype, highlighting a potential pathway through which such therapies can effect minimal residual disease, and a need to study optimal timing of adjuvant therapy.

An essential aim of biomedical research is to translate basic science information obtained from preclinical research using small and large animal models into clinical practice for the benefit of humans. Research on rodent models has enhanced our understanding of complex pathophysiology, thus providing potential translational pathways. However, the success of translating drugs from pre-clinical to clinical therapy has been poor, partly due to the choice of experimental model. The sheep model, in particular, is being increasingly applied to the field of biomedical research and is arguably one of the most influential models of human organ systems. It has provided essential tools and insights into cardiovascular disorder, orthopaedic examination, reproduction, gene therapy, and new insights into neurodegenerative research. Unlike the widely adopted rodent model, the use of the sheep model has an advantage over improving neuroscientific translation, in particular due to its large body size, gyrencephalic brain, long lifespan, more extended gestation period, and similarities in neuroanatomical structures to humans. This review aims to summarise the current status of sheep to model various human diseases and enable researchers to make informed decisions when considering sheep as a human biomedical model.

Inhaled formulations of amphotericin B are the most widely used antifungal prophylactic agents in lung transplant recipients, yet there are limited data on their safety. We performed a single-center retrospective cohort study of 603 consecutive patients who underwent lung transplantation between 2012 and 2017 and received antifungal prophylaxis with inhaled amphotericin B lipid complex (iABLC) from the day of transplantation until hospital discharge. Of 603 patients, 600 (99.5%) received ≥1 dose of iABLC, and 544 (90.2%) completed the recommended prophylactic course. In total, 4,128 iABLC doses (median, 5; range, 1 to 48 per patient) were administered; 24 patients received >3 months of therapy. Only one (0.2%) patient discontinued therapy due to a drug-attributable adverse event. During the first posttransplant year, 80 (13.3%) patients died (median time to death, 171 days; interquartile range [IQR], 80 to 272 days), and 3,352 (median, 6 per patient) lung biopsies were performed; 414 (68.7%) patients developed biopsy-proven acute cellular rejection. One-year adverse events in our cohort of lung transplant recipients treated with iABLC during transplant hospitalization matched national outcomes for rejection, graft loss, and death. iABLC is a safe and well-tolerated antifungal prophylactic agent in lung transplant recipients.

Focused cardiac ultrasound (FoCUS) has become a valuable tool to assess unexplained hypotension in critically ill patients. Due to increasing availability of transthoracic echocardiography (TTE) equipment in the operating room, there is a widespread interest in its usefulness for intraoperative diagnosis of hypotension as an alternative to transesophageal echocardiography (TEE). The objective of this systematic review is to evaluate the utility of intraoperative FoCUS to assess patients experiencing unexplained hypotension while undergoing noncardiac surgery. We performed a systematic literature search of multiple publication databases for studies that evaluated the utility of intraoperative FoCUS for assessment and management of unexplained hypotension in patients undergoing noncardiac surgery, including retro- and prospective clinical studies. A summary of the study findings, study quality, and assessment of level of evidence is presented. We identified 2227 unique articles from the literature search, of which 27 were potentially relevant, and 9 were included in this review. The number of patients pooled from these studies was 255, of whom 228 had intraoperative diagnoses with the aid of intraoperative FoCUS. The level of evidence of all studies included was very low according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. This systematic review has demonstrated that FoCUS may be a useful, noninvasive method to differentiate causes of intraoperative hypotension and guide correcting interventions, although the quality of evidence is very low. Further prospective high-quality studies are needed to investigate whether intraoperative FoCUS has a diagnostic utility that is associated with improved outcomes.

Background Wide variation exists globally in the treatment and outcomes of stage III patients with non–small cell lung cancer (NSCLC). We conducted an up-to-date patterns of care analysis in the state of Victoria, Australia, with a particular focus on the proportion of patients receiving treatment with radical intent, treatment trends over time, and survival. Materials and Methods Stage III patients with NSCLC were identified in the Victorian Lung Cancer Registry and categorized by treatment received and treatment intent. Logistic regression was used to explore factors predictive of receipt of radical treatment and the treatment trends over time. Cox regression was used to explore variables associated with overall survival (OS). Covariates evaluated included age, sex, ECOG performance status, smoking status, year of diagnosis, Australian born, Aboriginal or Torres Strait Islander status, socioeconomic status, rurality, public/private status of notifying institution, and multidisciplinary meeting discussion. Results A total of 1396 patients were diagnosed between 2012 and 2019 and received treatment with radical intent 67%, palliative intent 23%, unknown intent 5% and no treatment 5%. Radical intent treatment was less likely if patients were >75 years, ECOG ≥1, had T3-4 or N3 disease or resided rurally. Surgery use decreased over time, while concurrent chemoradiotherapy and immunotherapy use increased. Median OS was 38.0, 11.1, and 4.4 months following radical treatment, palliative treatment or no treatment, respectively. Conclusion Almost a third of stage III patients with NSCLC still do not receive radical treatment. Strategies to facilitate radical treatment and better support decision making between increasing multimodality options are required.

Glacier lake outburst floods (GLOF) are cryospheric hazards of severe destructive potential. GLOFs are prevalent in all glacierized mountain ranges globally and can cause high economic losses and pose a threat to people and livelihoods, potentially impacting agricultural land, lives and infrastructure. This underlines the importance of effective GLOF disaster risk management (DRM). GLOF DRM experiences are reported on in mountain ranges globally. However, there are relevant gaps in their documentation, analysis, and evaluation.This study compiled GLOF DRM experiences in South and North America, Europe, and Asia. We categorized the different structural and non-structural measures that have been taken and systematically analysed the temporal scope in which they function (i.e., short-term, long-term), as well as the risk component they influence (i.e., hazard, exposure, vulnerability). We analysed for the different DRM measures, in what context they were practiced, what their benefits were, what challenges were faced, as well looking at aspects of sustainability.We found that the biggest share of DRM measures is based on and applied in a limited spatial context often aiming at the reduction of a physical hazard emerging from a specific glacial lake. Examples of such activities are syphoning and pumping of lakes, drainage channels (with/out sluice gates) and tunnels for lake level regulation, flow channel adaptation, dam reinforcement, etc. Such measures, while generally taken once and aimed at short-term fixes (e.g., lake level lowering by pumping) as well as at long-term fixes (definitive lake level lowering by outflow tunnel), can face issues of sustainability. This can be the case for structural measures, for instance, when structures become unfit due to environmental changes (e.g., climate-related, earthquakes). While there are short-term as well as long-term measures in all three risk management components (hazard, exposure, vulnerability), there is a tendency for hazard reduction measures to be more short-term focused, and for exposure reduction (e.g., early warning systems, spatial planning, relocation, etc.) and vulnerability reduction (e.g., information, governance, preparedness, economic diversification, disaster relief, etc.) to be more mid- and long-term focused. Different challenges were found for all examined DRM measures mostly arising from issues in the technical feasibility (due to harsh climatic and environmental settings), the financial cost (of deploying people and material, and maintaining structures), and social acceptance and appropriation.While the findings from this study should not be generalized and strictly imposed on all other GLOF DRM cases, the knowledge gained by it is urgently needed to develop recommendations for GLOF DRM based on best practice experiences. GLOF DRM will become increasingly important in warming and increasingly exposed mountain environments globally. It will, thus, be important to further investigate the cost and benefit as well as the effectiveness of different DRM strategies. For sustainable DRM it is important to not look at GLOF hazard in isolation, but to take into account also other physical hazards in the same catchment.It should be considered within the wider context of integrated multi-hazard assessment in order to appropriately tackle/approach the interrelated effects of events that may occur simultaneously, cascadingly or cumulatively.

Oesophageal neoplasm; Oligometastasis; Radiosurgery Neoplàsia esofàgica; Oligometàstasi; Radiocirurgia Neoplasia esofágica; Oligometástasis; Radiocirugía Background Consensus about the definition and treatment of oligometastatic oesophagogastric cancer is lacking. Objective To assess the definition and treatment of oligometastatic oesophagogastric cancer across multidisciplinary tumour boards (MDTs) in Europe. Material and methods European expert centers (n = 49) were requested to discuss 15 real-life cases in their MDT with at least a medical, surgical, and radiation oncologist present. The cases varied in terms of location and number of metastases, histology, timing of detection (i.e. synchronous versus metachronous), primary tumour treatment status, and response to systemic therapy. The primary outcome was the agreement in the definition of oligometastatic disease at diagnosis and after systemic therapy. The secondary outcome was the agreement in treatment strategies. Treatment strategies for oligometastatic disease were categorised into upfront local treatment (i.e. metastasectomy or stereotactic radiotherapy), systemic therapy followed by restaging to consider local treatment or systemic therapy alone. The agreement across MDTs was scored to be either absent/poor (

Nevus of Ota is cosmetically burdensome and often prompts patients to seek treatment. Lasers are commonly used in removing these lesions; however, no systemic analysis has been conducted to support a gold standard laser. To conduct a meta-analysis of the efficacy and safety of Q-switched Nd:YAG lasers (QSNL), Q-switched ruby lasers (QSRL), Q-switched alexandrite lasers (QSAL), and picosecond alexandrite lasers (PSAL) in removing nevus of Ota. Inclusion criteria were nevus of Ota patients treated with QSNL, QSRL, QSAL, or PSAL and documentation of percent clearance and the rate of at least one adverse event. Articles in English, Chinese, or Japanese were included. The prespecified outcome measures were efficacy (percent clearance) and safety (rates of hyperpigmentation, hypopigmentation, scarring, and recurrence). The review included 57 studies and 13,417 patients. The pooled success rate was 64% for QSNL (95% CI 52-76%), 54% for QSRL (95% CI 39-69%), 58% for QSAL (95% CI 44-72%), and 100% for PSAL (95% CI 98-102%). The pooled adverse event rate was 5% for QSNL (95% CI 4-6%), 14% for QSRL (95% CI 9-19%), 9% for QSAL (95% CI 6-12%), and 44% (95% CI 31-57%) for PSAL. QSNL has the most evidence for effectively and safely treating nevus of Ota. PSAL potentially has a superior efficacy; however, further studies are needed to elucidate its side effect profile when treating nevus of Ota.

Rationale: Acute rejection, manifesting as lymphocytic inflammation in a perivascular (acute perivascular rejection [AR]) or peribronchiolar (lymphocytic bronchiolitis [LB]) distribution, is common...

New processing routes and materials for non-biocidal, antifouling (AF) coatings with an improved performance are currently much sought after for a range of marine applications. Here, the processing, physical properties and marine AF performance of a fluorinated coating based on a thermoplastic (non-crosslinked) fluorinated polymer are reported. It was found that the addition of lubricating oil and hydrodynamic drag reducing microstructures improved the AF properties substantially, i.e. the settlement of a marine biofilm, containing mixed microalgae including diatoms, was reduced to low levels. More importantly, the remaining fouling was removed from the coatings at low hydrodynamic shear rates and promising AF properties were obtained. Moreover, additional potential benefits were revealed originating from the thermoplastic nature of the coating material which might result in significant cost reductions.

Objectives: This study aimed to demonstrate how to estimate the value of health gain after patients with a multisystem disease achieve a condition-specific composite response endpoint. Methods: Data from patients treated in routine practice with an exemplar multisystem disease (systemic lupus erythematosus) were extracted from a national register (British Isles Lupus Assessment Group Biologics Register). Two bespoke composite response endpoints (Major Clinical Response and Improvement) were developed in advance of this study. Difference-in-differences regression compared health utility values (3-level version of EQ-5D; UK tariff) over 6 months for responders and nonresponders. Bootstrapped regression estimated the incremental quality-adjusted life-years (QALYs), probability of QALY gain after achieving the response criteria, and population monetary benefit of response. Results: Within the sample (n = 171), 18.2% achieved Major Clinical Response and 49.1% achieved Improvement at 6 months. Incremental health utility values were 0.0923 for Major Clinical Response and 0.0454 for Improvement. Expected incremental QALY gain at 6 months was 0.020 for Major Clinical Response and 0.012 for Improvement. Probability of QALY gain after achieving the response criteria was 77.6% for Major Clinical Response and 72.7% for Improvement. Population monetary benefit of response was £1 106 458 for Major Clinical Response and £649 134 for Improvement. Conclusions: Bespoke composite response endpoints are becoming more common to measure treatment response for multisystem diseases in trials and observational studies. Health technology assessment agencies face a growing challenge to establish whether these endpoints correspond with improved health gain. Health utility values can generate this evidence to enhance the usefulness of composite response endpoints for health technology assessment, decision making, and economic evaluation.

IntroductionNational guidelines advise that clinicians caring for women post-pregnancy should give women opportunities to discuss contraception, regardless of pregnancy outcome, and provide contraception to women who choose to take up a method. This study aimed to explore knowledge, views and needs of Early Pregnancy Unit (EPU) clinicians around discussing and offering contraception and discussing pregnancy intendedness with women after early pregnancy loss using a qualitative approach.MethodsSemi-structured, audio-recorded interviews with 11 clinicians from a single regional EPU in Edinburgh, Scotland. Interviews were transcribed verbatim and analysed thematically.ResultsClinicians were reluctant to discuss contraception as they believed women would find the topic overwhelming and distressing. Thoughts on discussing pregnancy intendedness were polarised; some considered it insensitive, and others essential. Barriers to discussing contraception and providing it were numerous and included time pressure, and inadequate knowledge and training on contraception. Participants suggested training on contraception, closer working with sexual and reproductive health (SRH) services, and availability of information on contraception specifically aimed at women who have experienced an early pregnancy loss could facilitate discussions and method provision.ConclusionsEPU clinicians require ongoing training and support to be effective at discussing pregnancy intendedness and discussing and providing post-pregnancy contraception. This will require close working with SRH services and development of sensitive information around contraception for women experiencing an early pregnancy loss.

It is well documented parents of children who have a disability are at an increased risk of poor mental health and wellbeing. A capacity building program designed to build key worker self-efficacy to support the mental health of parents accessing early childhood intervention services (ECIS) for their child was trialled. A stepped-wedge cluster randomised trial design was utilised to deliver and evaluate a 12-month intervention program, comprising tailored professional development, resource development and sustainability measures. The repeated measurements on individuals in six clusters over three follow-up periods were analysed using linear mixed models. Comparison of the control and new program statistical means (adjusted for period effects) were assessed with an F test. Key workers reported increased confidence to talk to parents about their own wellbeing (d = 0.51, F(1, 51.8) = 4.28, p = 0.044) and knowledge of parental mental wellbeing improved (p = 0.006). A reduction in staff sick leave partially offset the cost of the intervention. A multi-pronged intervention targeted at key workers was found to be an effective way to ensure parental wellbeing is supported at an ECIS in Australia. ACTRN12617001530314Implications for RehabilitationThere are implications for the development of children whose parents are experiencing high stress and poor mental health, whereby parents of children with disability or developmental delays are at increased risk.Findings from this study support the recommendation that a key worker is provided to holistically support families who access Early Childhood Intervention Services to aid in reducing poor parental wellbeing and child outcomes.Improved confidence to support and initiate conversations regarding parental wellbeing by key workers, in combination with support from management and the organisation to undertake this as part of their role, is a positive finding from this intervention study. There are implications for the development of children whose parents are experiencing high stress and poor mental health, whereby parents of children with disability or developmental delays are at increased risk. Findings from this study support the recommendation that a key worker is provided to holistically support families who access Early Childhood Intervention Services to aid in reducing poor parental wellbeing and child outcomes. Improved confidence to support and initiate conversations regarding parental wellbeing by key workers, in combination with support from management and the organisation to undertake this as part of their role, is a positive finding from this intervention study.

Recent prescribing trends reflect government-led efforts undertaken in both the U.S. and Canada to decrease opioid use. These provisions reflect a reduction in the use of many potent opioids in favour of tramadol. Despite the purported benefits of tramadol over other opioids, little remains known about tramadol-associated hallucinations (TAH). We conducted a systematic literature search in Embase, Medline, Cochrane CENTRAL, CINAHL, PubMed, Scopus, PAHO Virtual Health Library, MedNar, and ClinicalTrials.gov to find reported cases of hallucinations associated with the use of tramadol. For all corresponding cases reporting hallucinations secondary to tramadol use, we extracted data on patient demographics, medical management, and the details on hallucinations. Cases were categorized as “probable TAH” if the evidence supported an association between hallucinations and tramadol use, or “possible TAH” if hallucinations were attributed to tramadol use but the supporting evidence was weak. The “probable TAH” cases were further classified as “isolated TAH” if hallucinations were the primary complaint, or “other existing medical condition” if concurrent signs and symptoms alluded to a diagnosis of an existing medical condition. We then conducted a narrative synthesis of the available literature to contextualize these results. A total of 941 articles were identified in the initial search. No observational studies or randomized clinical trials were identified with our systematic review; only case reports were found. After a thorough screening, 34 articles comprising 101 patients reported an association between tramadol use and hallucinations. Among these 101 cases, 31 were “probable TAH” and 70 were “possible TAH”. Of the 31 cases of “probable TAH”, 16 cases were “isolated TAH” while the remaining 15 cases belonged to “other existing medical condition”. Tramadol-associated hallucinations can result in auditory or visual disturbances, although multisensory symptoms have also been reported. The mechanism underlying TAH remains poorly understood and likely involves numerous receptor types. The relative risk of hallucinations from tramadol compared with other opioids remains unclear.

Funder: Lupus Foundation of America, Inc, Objective: In systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence. Methods: We conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966���October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with

We present our institution's protocol for evaluating and transplanting thoracic organs from COVID-19 positive donors and report the outcomes to date. Hearts from donors testing positive for COVID-19 on any test were eligible for transplantation at our institution provided the donor exhibited no evidence of hypercoagulability or COVID-19 induced hyperinflammatory state during terminal hospitalization. Lungs were eligible if the donor first tested PCR positive on nasopharyngeal swab (NPS) for COVID-1920 days prior to procurement and had a negative lower respiratory tract specimen. We performed 14 thoracic transplants in 13 recipients using organs from COVID-19 positive donors. None of the recipients or healthcare members acquired COVID-19. No recipients suffered unexpected acute rejection. Patient survival is 92% to date, with graft survival 93%. The use of hearts from COVID-19 positive donors may be safe and effective. Transplantation of lungs is unresolved but may be cautiously pursued under the restricted circumstances.

Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous malignancy with dismal outcomes at relapse. Hypomethylating agents (HMA) have an emerging role in PTCL, supported by shared mutations with myelodysplasia (MDS). Response rates to azacitidine in PTCL of follicular helper cell origin are promising. Guadecitabine is a decitabine analogue with efficacy in MDS. In this phase II, single-arm trial, PTCL patients received guadecitabine on days 1–5 of 28-day cycles. Primary end points were overall response rate (ORR) and safety. Translational sub-studies included cell free plasma DNA sequencing and functional genomic screening using an epigenetically-targeted CRISPR/Cas9 library to identify response predictors. Among 20 predominantly relapsed/refractory patients, the ORR was 40% (10% complete responses). Most frequent grade 3-4 adverse events were neutropenia and thrombocytopenia. At 10 months median follow-up, median progression free survival (PFS) and overall survival (OS) were 2.9 and 10.4 months respectively. RHOAG17V mutations associated with improved PFS (median 5.47 vs. 1.35 months; Wilcoxon p = 0.02, Log-Rank p = 0.06). 4/7 patients with TP53 variants responded. Deletion of the histone methyltransferase SETD2 sensitised to HMA but TET2 deletion did not. Guadecitabine conveyed an acceptable ORR and toxicity profile; decitabine analogues may provide a backbone for future combinatorial regimens co-targeting histone methyltransferases.

Objectives: Women who sell sex have a high prevalence of human papilloma virus, which may cause cervical cancer. The objective of this review was to collate findings on prevalence, associated factors, screening, service provision and utilization of services in relation to human papilloma virus and cervical cancer among women who sell sex in Eastern and Southern Africa. Methods: A scoping review methodology was employed. Inclusion criteria were as follows: (1) empirical papers, (2) of studies conducted in Eastern and Southern Africa, (3) published in the last 10 years, and (4) addressing women who sell sex in relation to (5) human papilloma virus and cervical cancer. A thorough search of a range of databases surfaced 66 papers. Both authors applied inclusion and exclusion criteria, resulting in 14 papers being reviewed. Results: The reported prevalence of high-risk human papillomavirus virus varied between 23.6% and 70.5%. HIV sero-positivity, other sexually transmitted infections and Epstein-Barr virus were associated with human papilloma virus and high-grade cervical lesions. High-risk human papilloma virus was associated with women who reported younger age at first intercourse, non-barrier contraceptive use, and no history of condom use. For screening, there was overall agreement between physician- and self-collected samples. Contradictory results were found for visual inspection with acetic acid. Screening services utilization was associated with provider’s recommendation, history of sexually transmitted infections, frequency of facility visit and history of vaginal examination. A diagonal programme led to an increase in screening, attributed to the targeted services. Conclusions: Context is important in planning cervical cancer services. There is a need for enhanced sexually transmitted infections and viral management within cervical cancer prevention. Women who sell sex should be empowered in self-collection of stored-dry specimens, especially in resource-constrained regions. Cervical cancer screening services should be honed to the needs of women who sell sex.

Ischemic stroke causes brain endothelial cell (BEC) death and damages tight junction integrity of the blood-brain barrier (BBB). We harnessed the innate mitochondrial load of endothelial cell-derived extracellular vesicles (EVs) and utilized mixtures of EV/exogenous heat shock protein 27 (HSP27) as a one-two punch strategy to increase BEC survival (via EV mitochondria) and preserve their tight junction integrity (via HSP27 effects). We demonstrated that the medium-to-large (m/lEV) but not small EVs (sEV) transferred their mitochondrial load, which subsequently colocalized with the mitochondrial network of the recipient primary human BECs. BECs treated with m/lEVs increased relative ATP levels and displayed superior mitochondrial function. Importantly, m/lEVs isolated from oligomycin (mitochondrial complex V inhibitor) or rotenone (mitochondrial complex I inhibitor)-exposed BECs (RTN-m/lEVs or OGM-m/lEVs) did not increase BECs ATP levels compared to naïve m/lEVs. In contrast, RTN-sEV and OGM-sEV functionality in increasing cellular ATP levels was minimally impacted in comparison to naïve sEVs. Intravenously administered m/lEVs showed a reduction in brain infarct sizes compared to vehicle-injected mice in a mouse middle cerebral artery occlusion model of ischemic stroke. We formulated binary mixtures of human recombinant HSP27 protein with EVs: EV/HSP27 and ternary mixtures of HSP27 and EV with cationic polymer poly (ethylene glycol)-b-poly (diethyltriamine): (PEG-DET/HSP27)/EV. (PEG-DET/HSP27)/EV and EV/HSP27 mixtures decreased the paracellular permeability of small and large molecular mass fluorescent tracers in oxygen glucose-deprived primary human BECs. This one-two-punch approach to increase BEC metabolic function and tight junction integrity is a promising strategy for BBB protection and prevention of long-term neurological dysfunction post-ischemic stroke.Graphical AbstractHighlightsMedium-to-large extracellular vesicles (m/lEVs), not small EVs contain mitochondriam/lEVs increased ATP and mitochondrial function in brain endothelial cells (BECs)m/lEVs from oligomycin-exposed BECs did not increase recipient BEC ATP levelsIntravenously injected m/lEVs reduced brain infarct sizes in a mouse stroke modelEV/HSP27 mixtures reduced small and large dextran molecule permeability across BECs

We describe the performance of the Boolardy Engineering Test Array (BETA), the prototype for the Australian Square Kilometre Array Pathfinder telescope ASKAP. BETA is the first aperture synthesis radio telescope to use phased array feed technology, giving it the ability to electronically form up to nine dual-polarization beams. We report the methods developed for forming and measuring the beams, and the adaptations that have been made to the traditional calibration and imaging procedures in order to allow BETA to function as a multi-beam aperture synthesis telescope. We describe the commissioning of the instrument and present details of BETA's performance: sensitivity, beam characteristics, polarimetric properties and image quality. We summarise the astronomical science that it has produced and draw lessons from operating BETA that will be relevant to the commissioning and operation of the final ASKAP telescope., Accepted for publication in PASA