Endoscopic and Surgical Management of Bouveret Syndrome: Gastric Outlet Obstruction From an Impacted Gallstone.

Impacted gallstones in the stomach and the duodenum lead to a rare presentation of gastric outlet obstruction known as Bouveret syndrome. Diagnosis and management is often challenging because of lack of streamlined protocol. However, when a diagnosis is made, there is an extensive toolkit available to endoscopists and surgeons to ensure favorable outcomes for the patient. In this article, we present a challenging case of Bouveret syndrome that required multidepartmental coordination and intervention.

Efficacy of Ustekinumab and Vedolizumab Among Postoperative Crohn's Disease Patients as Postoperative Prophylaxis and Rescue Therapy: Real-world Data.

BACKGROUND: Almost half of patients with Crohn's disease (CD) require bowel surgeries in their lifetime. Due to the high risk of postoperative disease recurrence and high rate of previous antitumor necrosis factor (anti-TNF) failure, often alternative therapy options such as ustekinumab (UST) and vedolizumab (VDZ) are used. We aimed to evaluate the efficacy of UST and VDZ among postoperative CD patients as postoperative prophylaxis and rescue therapy. METHODS: Consented CD patients who underwent initial ileocecal resection and were treated with UST and VDZ were included in this study. Demographics, clinical characteristics, health care utilization, endoscopy scores, and surgery outcomes were collected. Postoperative early CD recurrence was defined as a Rutgeerts endoscopic score ≥i2 within the first 2 years. The rescue therapy group was defined as patients who received either UST or VDZ after having Rutgeerts endoscopic score ≥i2 postoperatively. RESULTS: During 2009 to 2019, 98 CD patients were treated with UST or VDZ postoperatively. Postoperative early recurrence rates were 5% (n = 1 out of 20) and 6% (1 out of 15) for the UST and VDZ groups, respectively. Two patients from the UST group and 1 patient from the VDZ group required bowel surgery during follow-up with median drug exposure of 51 (95% confidence interval [CI], 29-61) and 30 (95% CI, 14-63) months, respectively; 55% and 69% of patients had at least 1 point of improvement on postoperative endoscopic Rutgeerts score, respectively, for UST and VDZ. Only 3 out of 40 and 1 out of 23 patients required bowel surgery during follow-up while receiving UST and VDZ as rescue therapy. CONCLUSIONS: Both UST and VDZ were effective as postoperative therapies either as prophylaxis or rescue therapy.

This retrospective 11-year data examines the efficacy of ustekinumab and vedolizumab among postoperative Crohn's disease patients. When utilizing postoperative Rutgeerts score, this study confirms that both ustekinumab and vedolizumab were effective as postoperative therapies either as prophylaxis or rescue therapy.

Mammalian lures monitored with time-lapse cameras increase detection of pythons and other snakes.

Background: Enhancing detection of cryptic snakes is critical for the development of conservation and management strategies; yet, finding methods that provide adequate detection remains challenging. Issues with detecting snakes can be particularly problematic for some species, like the invasive Burmese python (Python bivittatus) in the Florida Everglades. Methods: Using multiple survey methods, we predicted that our ability to detect pythons, larger snakes and all other snakes would be enhanced with the use of live mammalian lures (domesticated rabbits; Oryctolagus cuniculus). Specifically, we used visual surveys, python detection dogs, and time-lapse game cameras to determine if domesticated rabbits were an effective lure. Results: Time-lapse game cameras detected almost 40 times more snakes (n = 375, treatment = 245, control = 130) than visual surveys (n = 10). We recorded 21 independent detections of pythons at treatment pens (with lures) and one detection at a control pen (without lures). In addition, we found larger snakes, and all other snakes were 165% and 74% more likely to be detected at treatment pens compared to control pens, respectively. Time-lapse cameras detected almost 40 times more snakes than visual surveys; we did not detect any pythons with python detection dogs. Conclusions: Our study presents compelling evidence that the detection of snakes is improved by coupling live mammalian lures with time-lapse game cameras. Although the identification of smaller snake species was limited, this was due to pixel resolution, which could be improved by changing the camera focal length. For larger snakes with individually distinctive patterns, this method could potentially be used to identify unique individuals and thus allow researchers to estimate population dynamics.

Clinical Decision Making in Inflammatory Bowel Disease Mimics: Practice Management from Inflammatory Bowel Disease LIVE.

Background: Since 2009, inflammatory bowel disease (IBD) specialists have utilized "IBD LIVE," a weekly live video conference with a global audience, to discuss the multidisciplinary management of their most challenging cases. While most cases presented were confirmed IBD, a substantial number were diseases that mimic IBD. We have categorized all IBD LIVE cases and identified "IBD-mimics" with consequent clinical management implications. Methods: Cases have been recorded/archived since May 2018; we reviewed all 371 cases from May 2018-February 2023. IBD-mimics were analyzed/categorized according to their diagnostic and therapeutic workup. Results: Confirmed IBD cases made up 82.5% (306/371; 193 Crohn's disease, 107 ulcerative colitis, and 6 IBD-unclassified). Sixty-five (17.5%) cases were found to be mimics, most commonly medication-induced (n = 8) or vasculitis (n = 7). The evaluations that ultimately resulted in correct diagnosis included additional endoscopic biopsies (n = 13, 21%), surgical exploration/pathology (n = 10, 16.5%), biopsies from outside the GI tract (n = 10, 16.5%), genetic/laboratory testing (n = 8, 13%), extensive review of patient history (n = 8, 13%), imaging (n = 5, 8%), balloon enteroscopy (n = 5, 8%), and capsule endoscopy (n = 2, 3%). Twenty-five patients (25/65, 38%) were treated with biologics for presumed IBD, 5 of whom subsequently experienced adverse events requiring discontinuation of the biologic. Many patients were prescribed steroids, azathioprine, mercaptopurine, or methotrexate, and 3 were trialed on tofacitinib. Conclusions: The diverse presentation of IBD and IBD-mimics necessitates periodic consideration of the differential diagnosis, and reassessment of treatment in presumed IBD patients without appropriate clinical response. The substantial differences and often conflicting treatment approaches to IBD versus IBD-mimics directly impact the quality and cost of patient care.

Association Between Symptoms of Anxiety and Depression, Hip Pathology, and Patient-Reported Outcomes After Hip Arthroscopy for Femoroacetabular Impingement.

BACKGROUND: In patients with femoroacetabular impingement (FAI), mental health has been implicated in both symptom severity and postoperative outcomes. However, there are limited data regarding the independent influences of baseline mental health and hip pathology on patient-reported outcomes over time after hip arthroscopy. PURPOSE: To evaluate the association between mental health and structural hip pathology with pain, hip function, and quality of life (QOL). STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Patient records from a single surgeon's hip outcomes registry were retrospectively reviewed. Mental health was evaluated using the Patient-Reported Outcomes Measurement Information System Anxiety and Depression scores. Pain was evaluated with the Single Assessment Numeric Evaluation score for Activities of Daily Living (SANE-ADL), while hip-related QOL was evaluated with the 12-item International Hip Outcome Tool (iHOT-12). Hip function was assessed with the Hip Outcome Score (HOS) Sport-Specific (SS) and ADL subscales. Separate mixed models were used to predict pain, QOL, and hip function, including hip pathology measures (size of labral tear, grade of chondral damage, preoperative alpha angle), anxiety, depression, and time as fixed effects and individuals as a random effect. RESULTS: A total of 312 patients were included in this study. The preoperative alpha angle, degree of intraoperative cartilage damage, and size of the labral tear were not associated with pain or QOL (P > .05 for all). However, higher levels of anxiety and depression were significantly associated with lower SANE-ADL scores (estimate ± SE) (anxiety: -0.59 ± 0.07, P < .0001; depression: -0.64 ± 0.08, P < .0001), iHOT-12 scores (anxiety: -0.72 ± 0.07, P < .0001; depression: -0.72 ± 0.08, P < .0001), HOS-SS scores (anxiety: -0.68 ± 0.09, P < .0001; depression: -0.57 ± 0.10, P < .0001), and HOS-ADL scores (anxiety: -0.43 ± 0.05, P < .0001; depression: -0.43 ± 0.06, P < .0001). CONCLUSION: Patients had similar improvements in pain scores, QOL, and hip function after hip arthroscopy for FAI irrespective of their degree of hip pathology. Additionally, preoperative symptoms of anxiety and depression symptoms were associated with greater pain, decreased QOL, and worse hip function both pre- and postoperatively, independent of the degree of hip pathology. This suggests that efforts to directly address symptoms of anxiety and depression may improve outcomes after hip arthroscopy.

Mindfulness Practice Is Associated With Improved Well-Being and Reduced Injury Risk in Female NCAA Division I Athletes.

BACKGROUND: Injury in sport is an inherent risk to participation, and it can have devastating consequences for the athlete, both mentally and physically. Previous research has found that impairments in well-being can increase the risk of injury, and that various forms of mindfulness training and practice can improve well-being and mental health in various populations. HYPOTHESIS: Mindfulness would be associated with greater well-being and lower risk of injury. STUDY DESIGN: Cohort study. LEVEL OF EVIDENCE: Level 3. METHODS: A total of 21 female Division I athletes underwent a formal 6-week mindfulness training program and were encouraged to continue mindfulness exercises. The athletes completed daily surveys on their smartphones in relation to mood, muscle readiness (soreness), readiness to train, energy level, daily training load, and whether they had participated in mindfulness training that day. Linear mixed effects models were used to evaluate well-being variables and mindfulness state, and separate mixed effects logistics regression models were used to evaluate injury incidence and wellness variables. RESULTS: On days with mindfulness practice, athletes reported higher mood (19.6 [18.8-20.3] vs 19.4 [18.6-20.1, P = 0.03), muscle readiness (18.9 [17.8-20.0] vs 18.6 [17.5-19.6], P = 0.03), readiness to train (78.7 [75.9-81.5] vs 77.4 [74.7-80.2], P < 0.01), and energy level (19.3 [18.6-20.1] vs 18.8 [18.1-19.5, P < 0.01) than on the days when they did not participate in mindfulness training. Mindfulness practice was associated with significantly reduced likelihood of suffering an acute injury the following day (odds ratio, 0.42; 95% CI, 0.42-0.43; P < 0.01). CONCLUSION: On an individual level, participation in mindfulness by female collegiate athletes was associated with a dramatic reduction in injury risk the following day. In addition, mindfulness was associated with significantly improved mood, muscle readiness, readiness to train, and energy level. CLINICAL RELEVANCE: These findings suggest that mindfulness training in athletes may improve well-being and reduce the risk of injury among high-level athletes.

The Influence of Race, Socioeconomic Status, and Physical Activity on the Mental Health Benefits of Sport Participation During COVID-19.

BACKGROUND: The purpose of this study was to compare the benefits of sport participation with no sport participation during the COVID-19 pandemic and determine the moderating effects of race and ethnicity, socioeconomic status (SES), and physical activity (PA) on mental health in adolescent athletes. HYPOTHESIS: Sport participation would be associated with greater improvements in mental health for athletes from racial and ethnic minority and lower SES groups compared with White and high SES groups. PA would mediate <30% of the mental health benefits of sport participation. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 4. METHODS: In May 2021, adolescent athletes completed an online survey (demographics, sport participation, measures of anxiety and depression, PA). Participants were classified as those who played sports (PLY) and those who did not (DNP). Mental health symptoms for the PLY and DNP groups were compared via analysis of variance models that controlled for demographic variables. Moderating analyses assessed the interaction of sport participation status by (1) race and ethnicity (White/non-White) and (2) SES (high/low) with mental health. Mediation analyses assessed the degree that PA scores explained the differences in anxiety and depression between the 2 groups. RESULTS: Participants included 4874 adolescent athletes (52% female; age, 16.1 ± 1.3 years; PLY, 91%). Athletes who returned to sport from racial minority groups and low SES had greater decreases in anxiety (race and ethnicity: interaction estimate (b) = -1.18 ± 0.6, P = 0.04; SES, b = -1.23 ± 0.5, P = 0.02), and depression (race and ethnicity: b = -1.19 ± 0.6, P = 0.05; SES, b = -1.21 ± 0.6, P = 0.03) compared with White and high SES athletes, respectively. PA explained 24% of anxiety (P < 0.01) and 20% of depression scores (P < 0.01). CONCLUSION: Athletes who identify as a racial or ethnic minority and from areas of lower household income experienced disproportionately greater negative mental health impacts from sport restrictions during COVID-19. CLINICAL RELEVANCE: Improving access to sports in traditionally underserved areas may have significant mental health impact for adolescents.

Overuse Injuries, Overtraining, and Burnout in Young Athletes.

Sports participation can have tremendous physical and mental health benefits for children. Properly implemented progressive training programs can yield a broad range of beneficial physiologic adaptations, but imbalances of training load and recovery can have important negative consequences. Overuse injuries, for example, can result from repetitive stress without sufficient recovery that leads to accumulated musculoskeletal damage. In addition, extended periods of increased training loads that exceed the intervening recovery can have systemic consequences such as overtraining syndrome, which results in decreased performance, increased injury and illness risk, and derangement of endocrine, neurologic, cardiovascular, and psychological systems. Burnout represents one of the primary reasons for attrition in youth sports. Broadly defined as physical or mental exhaustion and a reduced sense of accomplishment that leads to devaluation of sport, burnout represents a direct threat to the goal of lifelong physical activity and the wide-ranging health benefits that it provides. This clinical report is intended to provide pediatricians with information regarding the risk factors, diagnosis, management, and prevention of these conditions to assist in the identification of at-risk children, the treatment of young athletes, and the guidance of families in the promotion of safe and healthy sport participation.

Changes in Quality of Life Among Collegiate Athletes During COVID-19.

BACKGROUND: The COVID-19 pandemic has had a significant effect on the mental health of athletes. How this has affected quality of life (QoL), specifically in the college population, is poorly defined. HYPOTHESIS: During the COVID-19 pandemic, the mental and physical QoL will have decreased in collegiate athletes as compared with before the pandemic. STUDY DESIGN: Cross-sectional study. LEVEL OF EVIDENCE: Level 3. METHODS: Division I athletes from a total of 23 varsity teams at a single institution completed surveys between 2018 and 2022. QoL was assessed using the Veterans RAND 12-Item Health Survey (VR-12). VR-12 scores were separated into mental component scores (MCS) and physical component scores (PCS). Separate linear mixed effects models evaluated changes in MCS and PCS from pre-COVID to during COVID overall, as well as differences in changes by sex and sport type (individual, team). RESULTS: For all athletes, the PCS increased (54.6 [95% CI 54.4-54.7] vs 55.1 [54.9-55.3]; P < 0.01) and the MCS decreased (55.2 [54.9-55.5] vs 53.5 [53.1-53.8]; P < 0.01) from pre-COVID to during COVID. When evaluating for sex, women demonstrated a greater increase in PCS (0.57 ± 0.22; P = 0.01) and greater decrease in MCS (1.06 ± 0.38; P < 0.01). With respect to sport type, individual sports demonstrated a greater decrease in MCS (1.46 ± 0.39; P < 0.01), but no interaction was identified for PCS (0.42 ± 0.23; P = 0.07). CONCLUSION: Collegiate athletes demonstrated a decrease in their self-reported mental QoL during the COVID-19 pandemic, as compared with before the pandemic. This effect was most evident in women and in individual sports. Athletes also reported an increase in physical QoL during COVID that was also larger in women, but not related to sport. CLINICAL RELEVANCE: This study demonstrates the impact of the COVID-19 pandemic on collegiate athletes' QoL, including negative effects on mental health. It also identifies cohorts of athletes (women, individual) who may be more significantly affected.

The Associations Between Wellbeing and Injury Differ by Time Loss in Collegiate Athletes.

BACKGROUND: Self-reported wellbeing measures such as mood and soreness have been identified as predictors of injury risk. However, most research has focused on investigating time-loss injuries even though nontime-loss injuries are more prevalent. HYPOTHESIS: Impairments in sleep and subjective wellbeing would be associated with increased injury for both time-loss and nontime-loss injuries. STUDY DESIGN: Prospective longitudinal study. LEVEL OF EVIDENCE: Level 3. METHODS: During 2022, 127 athletes completed a daily survey that inquired about training load and sleep from the previous day along with mood, stress, and soreness on the current day. Incidence of injury was also monitored using documentation provided by athletes' respective athletic trainers. Mixed effect models were used to analyze the relationship between wellbeing and sleep measures with injury. RESULTS: Self-reported wellbeing, based most closely on soreness the day of injury, by National Collegiate Athletic Association Division 1 collegiate athletes was predictive of time-loss injuries, whereas no significant relationship was identified for nontime-loss injuries. Specifically, 1 unit increase in soreness was associated with a 39% increase in odds of sustaining a time-loss injury. CONCLUSION: This study found that subjective wellbeing and sleep have a different relationship with injury dependent upon whether the resulting injury leads to time loss. CLINICAL RELEVANCE: Self-reported wellbeing appears to be a relevant predictor of injury among collegiate athletes for time-loss injuries.

Assessing the energy trap of industrial agriculture in North America and Europe: 82 balances from 1830 to 2012.

Early energy analyses of agriculture revealed that behind higher labor and land productivity of industrial farming, there was a decrease in energy returns on energy (EROI) invested, in comparison to more traditional organic agricultural systems. Studies on recent trends show that efficiency gains in production and use of inputs have again somewhat improved energy returns. However, most of these agricultural energy studies have focused only on external inputs at the crop level, concealing the important role of internal biomass flows that livestock and forestry recirculate within agroecosystems. Here, we synthesize the results of 82 farm systems in North America and Europe from 1830 to 2012 that for the first time show the changing energy profiles of agroecosystems, including livestock and forestry, with a multi-EROI approach that accounts for the energy returns on external inputs, on internal biomass reuses, and on all inputs invested. With this historical circular bioeconomic approach, we found a general trend towards much lower external returns, little or no increases in internal returns, and almost no improvement in total returns. This "energy trap" was driven by shifts towards a growing dependence of crop production on fossil-fueled external inputs, much more intensive livestock production based on feed grains, less forestry, and a structural disintegration of agroecosystem components by increasingly linear industrial farm managements. We conclude that overcoming the energy trap requires nature-based solutions to reduce current dependence on fossil-fueled external industrial inputs and increase the circularity and complexity of agroecosystems to provide healthier diets with less animal products. Supplementary Information: The online version contains supplementary material available at 10.1007/s13593-023-00925-5.

Gynecological trials frequently exclude people based on their symptoms rather than their condition: a systematic review of Cochrane reviews and their component trials.

OBJECTIVES: To identify strategies used in recent randomized controlled trials (RCTs) and their associated Cochrane Reviews where patients with the same gynecological condition present with different symptoms but would plausibly benefit from a common intervention. STUDY DESIGN AND SETTING: We searched the Cochrane library (February 2022) for reviews in polycystic ovarian syndrome (PCOS) and endometriosis. Reviews were included if the intervention was intended to treat all condition-specific symptoms. For each trial we recorded the strategy used and the number of potentially eligible participants excluded as a direct result of the chosen strategy. For each review we recorded the numbers of RCTs and participants excluded on the basis of symptoms experienced. RESULTS: There were 89 distinct PCOS trials in 13 reviews, and 13 Endometriosis trials in 11 reviews. Most trials restricted their eligibility to participants with specific symptoms (55% PCOS, 46% endometriosis). The second most common strategy was to measure and analyze clinical outcomes that were not relevant to all participants (38% PCOS, 31% endometriosis). Reviews excluded 27% of trials in participants evaluating the same intervention in participants experiencing the same condition based on the outcomes measured in the trials. CONCLUSION: Most gynecological trials exclude patients who could benefit from treatment or measure outcomes not relevant to all participants. We introduce a taxonomy to describe trial design strategies for conditions with heterogeneous symptoms.

Anxiety and Depression Prevalence in Incoming Division I Collegiate Athletes From 2017 to 2021.

BACKGROUND: Young adults report increased rates of anxiety and depression than other age groups. Furthermore, young adult athletes experience additional stressors that may negatively impact their mental health. The aim of this study was to investigate the prevalence of anxiety and depression symptoms among Division I collegiate athletes and the influences of sex, sport type, and distance from home. HYPOTHESIS: It was hypothesized that self-reported levels of anxiety and depression would increase among this population during this timeframe. STUDY DESIGN: Cross-sectional. LEVEL OF EVIDENCE: Level 3. METHODS: Participants included 792 incoming Division I collegiate athletes. The Generalized Anxiety Disorder-7 (GAD-7) and Patient Health Questionnaire-9 (PHQ-9) scores were completed by all incoming student athletes at a single institution as part of their preparticipation examination over 5 years. Both survey scores were categorized into different levels of severity and separately compared with chi-square tests. Continuous scores were modeled separately using negative binomial regression models including year, sex, sport type, and home location as covariates. RESULTS: Results showed consistent levels of anxiety and depression over time. Female athletes reported higher levels of both anxiety and depression than male athletes, and individual sport athletes reported higher levels of depression than team sport athletes. Distance from home was not associated with anxiety or depression levels. CONCLUSION: Overall, levels of anxiety and depression did not change in this population over this time period. However, differences in anxiety and depression were seen between sexes and depression between sport types. CLINICAL RELEVANCE: Understanding anxiety and depression risk factors among collegiate athletes can enhance early identification and intervention to improve mental health and allow for better allocation of resources to at-risk groups among Division I collegiate athletes.

Network analysis of inflammation and symptoms in recent onset schizophrenia and the influence of minocycline during a clinical trial.

Attempts to delineate an immune subtype of schizophrenia have not yet led to the clear identification of potential treatment targets. An unbiased informatic approach at the level of individual immune cytokines and symptoms may reveal organisational structures underlying heterogeneity in schizophrenia, and potential for future therapies. The aim was to determine the network and relative influence of pro- and anti-inflammatory cytokines on depressive, positive, and negative symptoms. We further aimed to determine the effect of exposure to minocycline or placebo for 6 months on cytokine-symptom network connectivity and structure. Network analysis was applied to baseline and 6-month data from the large multi-center BeneMin trial of minocycline (N = 207) in schizophrenia. Pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ had the greatest influence in the inflammatory network and were associated with depressive symptoms and suspiciousness at baseline. At 6 months, the placebo group network connectivity was 57% stronger than the minocycline group, due to significantly greater influence of TNF-α, early wakening, and pathological guilt. IL-6 and its downstream impact on TNF-α, and IFN-γ, could offer novel targets for treatment if offered at the relevant phenotypic profile including those with depression. Future targeted experimental studies of immune-based therapies are now needed.

Accelerating the development of a psychological intervention to restore treatment decision-making capacity in patients with schizophrenia-spectrum disorder: a study protocol for a multi-site, assessor-blinded, pilot Umbrella trial (the DEC:IDES trial).

BACKGROUND: A high proportion of patients diagnosed with schizophrenia-spectrum disorders will at some point in their lives be assessed as not having the capacity to make their own decisions about pharmacological treatment or inpatient care ('capacity'). Few will be helped to regain it before these interventions proceed. This is partly because effective and safe methods to do so are lacking. Our aim is to accelerate their development by testing, for the first time in mental healthcare, the feasibility, acceptability and safety of running an 'Umbrella' trial. This involves running, concurrently and under one multi-site infrastructure, multiple assessor-blind randomised controlled trials, each of which is designed to examine the effect on capacity of improving a single psychological mechanism ('mechanism'). Our primary objectives are to demonstrate feasibility of (i) recruitment and (ii) data retention on the MacArthur Competence Assessment Tool-Treatment (MacCAT-T; planned primary outcome for a future trial) at end-of-treatment. We selected three mechanisms to test: 'self-stigma', low self-esteem and the 'jumping to conclusions' bias. Each is highly prevalent in psychosis, responsive to psychological intervention, and hypothesised to contribute to impaired capacity. METHODS: Sixty participants with schizophrenia-spectrum diagnoses, impaired capacity and one or more mechanism(s) will be recruited from outpatient and inpatient mental health services in three UK sites (Lothian, Scotland; Lancashire and Pennine; North West England). Those lacking capacity to consent to research could take part if the key criteria were met, including either proxy consent (Scotland) or favourable Consultee advice (England). They will be allocated to one of three randomised controlled trials, depending on which mechanism(s) they have. They will then be randomised to receive, over an 8-week period and in addition to treatment as usual (TAU), 6 sessions of either a psychological intervention which targets the mechanism, or 6 sessions of assessment of the causes of their incapacity (control condition). Participants are assessed at 0 (baseline), 8 (end-of-treatment) and 24 (follow-up) weeks post-randomisation using measures of capacity (MacCAT-T), mechanism, adverse events, psychotic symptoms, subjective recovery, quality of life, service use, anxiety, core schemata and depression. Two nested qualitative studies will be conducted; one to understand participant and clinician experiences and one to investigate the validity of MacCAT-T appreciation ratings. DISCUSSION: This will be the first Umbrella trial in mental healthcare. It will produce the first 3 single-blind randomised controlled trials of psychological interventions to support treatment decision-making in schizophrenia-spectrum disorder. Demonstrating feasibility will have significant implications not only for those seeking to support capacity in psychosis, but also for those who wish to accelerate the development of psychological interventions for other conditions. TRIAL REGISTRATION: ClinicalTrials.gov NCT04309435 . Pre-registered on 16 March 2020.

Inflammatory subgroups of schizophrenia and their association with brain structure: A semi-supervised machine learning examination of heterogeneity.

OBJECTIVE: Immune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles. METHODS: The total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups. RESULTS: An optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset. CONCLUSIONS: Inflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions.

Deletion of p66Shc Dysregulates ERK and STAT3 Activity in Mouse Embryonic Stem Cells, Enhancing Their Naive-Like Self-Renewal in the Presence of Leukemia Inhibitory Factor.

The ShcA adapter protein is necessary for early embryonic development. The role of ShcA in development is primarily attributed to its 52 and 46 kDa isoforms that transduce receptor tyrosine kinase signaling through the extracellular signal regulated kinase (ERK). During embryogenesis, ERK acts as the primary signaling effector, driving fate acquisition and germ layer specification. P66Shc, the largest of the ShcA isoforms, has been observed to antagonize ERK in several contexts; however, its role during embryonic development remains poorly understood. We hypothesized that p66Shc could act as a negative regulator of ERK activity during embryonic development, antagonizing early lineage commitment. To explore the role of p66Shc in stem cell self-renewal and differentiation, we created a p66Shc knockout murine embryonic stem cell (mESC) line. Deletion of p66Shc enhanced basal ERK activity, but surprisingly, instead of inducing mESC differentiation, loss of p66Shc enhanced the expression of core and naive pluripotency markers. Using pharmacologic inhibitors to interrogate potential signaling mechanisms, we discovered that p66Shc deletion permits the self-renewal of naive mESCs in the absence of conventional growth factors, by increasing their responsiveness to leukemia inhibitory factor (LIF). We discovered that loss of p66Shc enhanced not only increased ERK phosphorylation but also increased phosphorylation of Signal transducer and activator of transcription in mESCs, which may be acting to stabilize their naive-like identity, desensitizing them to ERK-mediated differentiation cues. These findings identify p66Shc as a regulator of both LIF-mediated ESC pluripotency and of signaling cascades that initiate postimplantation embryonic development and ESC commitment.

Selecting Normalizers for MicroRNA RT-qPCR Expression Analysis in Murine Preimplantation Embryos and the Associated Conditioned Culture Media.

Normalizing RT-qPCR miRNA datasets that encompass numerous preimplantation embryo stages requires the identification of miRNAs that may be used as stable reference genes. A need has also arisen for the normalization of the accompanying conditioned culture media as extracellular miRNAs may serve as biomarkers of embryo developmental competence. Here, we evaluate the stability of six commonly used miRNA normalization candidates, as well as small nuclear U6, using five different means of evaluation (BestKeeper, NormFinder, geNorm, the comparative Delta Ct method and RefFinder comprehensive analysis) to assess their stability throughout murine preimplantation embryo development from the oocyte to the late blastocyst stages, both in whole embryos and the associated conditioned culture media. In descending order of effectiveness, miR-16, miR-191 and miR-106 were identified as the most stable individual reference miRNAs for developing whole CD1 murine preimplantation embryos, while miR-16, miR-106 and miR-103 were ideal for the conditioned culture media. Notably, the widely used U6 reference was among the least appropriate for normalizing both whole embryo and conditioned media miRNA datasets. Incorporating multiple reference miRNAs into the normalization basis via a geometric mean was deemed beneficial, and combinations of each set of stable miRNAs are further recommended, pending validation on a per experiment basis.