A systematic review of the treatment of primary acromioclavicular joint osteoarthritis.

Background: This systematic review aims to comprehensively summarise and present the available evidence for the treatment of primary acromioclavicular joint (ACJ) osteoarthritis (OA). Methods: Five databases were searched for studies investigating the management of ACJ OA. Included were studies with participants with clinical/radiological signs of primary ACJ OA, an intervention and included a functional outcome measure. Results: Forty-eight studies were included. Treatments consisted of physiotherapy (n = 1 study), medical only (n = 11) and operative management (n = 36). Operative studies included five comparative trials - physiotherapy versus surgery (n = 1) and open versus arthroscopic resection (n = 4). A total of 1902 shoulders were treated for ACJ OA, mean age (51 years), 58% male and mean follow-up (28.5 months). Treatment with injection showed a mean improvement of 50% in pain levels at follow-up (mean = 7.5 months). The commonest surgical procedure was arthroscopic excision of the distal clavicle and operative studies averaged 6 months of conservative management and a mean functional outcome of 87.8%. Conclusion: Studies varied in indication, intervention and quality but it did not provide evidence that both non-operative and operative interventions are effective. There was no significant difference between open or arthroscopic distal clavicle excision (DCE). Participants having between 0.5 and 2 cm of clavicle excised had good outcomes and those requiring concomitant shoulder procedures had similarly good outcomes.

Sex differences in energy balance, body composition, and metabolic and endocrine markers during prolonged arduous military training.

This study investigated sex differences in energy balance, body composition, and metabolic and endocrine markers during prolonged military training. Twenty-three trainees (14 women) completed 44-wk military training (three terms of 14 wk with 2-wk adventurous training). Dietary intake and total energy expenditure were measured over 10 days during each term by weighed food and doubly labeled water. Body composition was measured by dual-energy X-ray absorptiometry (DXA) at baseline and at the end of each term. Circulating metabolic and endocrine markers were measured at baseline and at the end of terms 2 and 3. Absolute energy intake and total energy expenditure were higher, and energy balance was lower, for men than women (P ≤ 0.008). Absolute energy intake and balance were lower, and total energy expenditure was higher, during term 2 than terms 1 and 3 (P < 0.001). Lean mass did not change with training (P = 0.081). Fat mass and body fat increased from term 1 to terms 2 and 3 (P ≤ 0.045). Leptin increased from baseline to terms 2 and 3 in women (P ≤ 0.002) but not in men (P ≥ 0.251). Testosterone and free androgen index increased from baseline to term 3 (P ≤ 0.018). Free thyroxine (T4) decreased and thyroid-stimulating hormone (TSH) increased from baseline to term 2 and term 3 (P ≤ 0.031). Cortisol decreased from baseline to term 3 (P = 0.030). IGF-I and total triiodothyronine (T3) did not change with training (P ≥ 0.148). Men experienced greater energy deficits than women during military training due to higher total energy expenditure.NEW & NOTEWORTHY Energy deficits are common in military training and can result in endocrine and metabolic disturbances. This study provides first investigation of sex differences in energy balance, body composition, and endocrine and metabolic markers in response to prolonged and arduous military training. Men experienced greater energy deficits than women due to higher energy expenditure, which was not compensated for by increased energy intake. These energy deficits were not associated with decreases in fat or lean mass or metabolic or endocrine function.

Strategies to Mitigate Bleeding in Shoulder Arthroplasty in the Setting of an Arteriovenous Fistula: A Report of 3 Cases.

CASE: Arteriovenous (AV) fistula in the ipsilateral extremity for hemodialysis presents unique challenges during shoulder arthroplasty. We describe 3 cases of shoulder arthroplasty performed through a deltopectoral approach on the ipsilateral side of an AV fistula. In all cases, the cephalic vein was found to be arterialized with increased diameter and thickness. All procedures were successfully performed without injury to the arterialized cephalic vein. CONCLUSION: This report highlighted strategies to mitigate catastrophic bleeding from an arterialized cephalic vein during shoulder arthroplasty, which includes preoperative cross-matching, expeditious vascular surgery availability, meticulous surgical dissection, and careful retractor placement.

International consensus statement on the design, delivery and evaluation of sport-based interventions aimed at promoting social, psychological and physical well-being in prison.

OBJECTIVE: To develop an international consensus statement to advise on designing, delivering and evaluating sport-based interventions (SBIs) aimed at promoting social, psychological and physical well-being in prison. DESIGN: Modified Delphi using two rounds of survey questionnaires and two consensus workshops. PARTICIPANTS: A multidisciplinary panel of more than 40 experts from 15 international jurisdictions was formed, including representation from the following groups and stakeholders: professionals working in the justice system; officials from sport federations and organisations; academics with research experience of prisons, secure forensic mental health settings and SBIs; and policy-makers in criminal justice and sport. RESULTS: A core research team and advisory board developed the initial rationale, statement and survey. This survey produced qualitative data which was analysed thematically. The findings were presented at an in-person workshop. Panellists discussed the findings, and, using a modified nominal group technique, reached a consensus on objectives to be included in a revised statement. The core research team and advisory board revised the statement and recirculated it with a second survey. Findings from the second survey were discussed at a second, virtual, workshop. The core research team and advisory board further revised the consensus statement and recirculated it asking panellists for further comments. This iterative process resulted in seven final statement items; all participants have confirmed that they agreed with the content, objectives and recommendations of the final statement. CONCLUSIONS: The statement can be used to assist those that design, deliver and evaluate SBIs by providing guidance on: (1) minimum levels of competence for those designing and delivering SBIs; (2) the design and delivery of inclusive programmes prioritising disadvantaged groups; and (3) evaluation measures which are carefully calibrated both to capture proposed programme outcomes and to advance an understanding of the systems, processes and experiences of sport engagement in prison.

Improvements in Orthostatic Tolerance with Exercise Are Augmented by Heat Acclimation: A Randomised Controlled Trial.

INTRODUCTION: Heat adaptation is protective against heat illness however its role in heat syncope, due to reflex mechanisms, has not been conclusively established. The aim of this study was to evaluate if heat acclimation (HA) was protective against heat syncope and to ascertain underlying physiological mechanisms. METHODS: 20 (15 males, 5 females) endurance trained athletes were randomised to either 8 days of mixed active and passive HA (HEAT) or climatically temperate exercise (CONTROL). Prior to, and following, the interventions participants underwent a head up tilt (HUT) with graded lower body negative pressure (LBNP), in a thermal chamber (32.0 ± 0.3 °C), continued until presyncope with measurement of cardiovascular parameters. Heat stress tests (HST) were performed to determine physiological and perceptual measures of HA. RESULTS: There was a significant increase in orthostatic tolerance (OT), as measured by HUT/LBNP, in the HEAT group (pre-intervention; 28 ± 9 mins, post-intervention; 40 ± 7 mins) compared to CONTROL (pre-intervention; 30 ± 8 mins, post-intervention; 33 ± 5 mins) (p = 0.01). HA resulted in a significantly reduced peak and mean rectal and skin temperature (p < 0.01), peak heat rate (p < 0.003), thermal comfort (p < 0.04) and rating of perceived exertion (p < 0.02) during HST. There was a significantly increased plasma volume (PV) in the HEAT group in comparison to CONTROL (p = 0.03). CONCLUSIONS: HA causes improvements in OT and is likely to be beneficial in patients with heat exacerbated reflex syncope. HA mediated PV expansion is a potential physiological mechanism underlying improved OT.

Recurrence of the frozen shoulder after hydrodilatation, what is the true incidence?

Purpose of the study: To assess the outcome and recurrence rates of frozen shoulder treated by hydrodilatation in an independent hospital setting. Method: Patients presenting to a shoulder clinic from August 2019 to July 2021 with a diagnosis of frozen shoulder were offered hydrodilatation. Data included primary or secondary frozen shoulder, length of symptoms, and diabetic status. An Oxford Shoulder Score was completed prior to hydrodilatation. Using ultrasound guidance, 40 mg Triamcinolone and local anaesthetic (10-25 mL depending on patient tolerance) were injected into the rotator interval. At a mean of 9 months, patients recorded their tolerance of the procedure, subsequent progress, the need for further treatment, and their current Oxford Shoulder Score. Results: From 55 shoulders, six patients had a failure to improve and 10 patients had a transient improvement followed by recurrence (29%). 2/21 (9.5%) patients had 25 mL injected compared to 14/34 (41%) who had < = 20 mL (p = 0.012). 14/43 (33%) of primary frozen shoulder patients had a recurrence, compared with 2/12 (16%) secondary frozen shoulder patients, p = 0.019. Conclusion: Further treatment was indicated in 14/34 (41%) of patients who underwent hydrodilatation in the frozen stage of frozen shoulder and could not tolerate more than 20 mL of injection, and was more commonly required in primary (33%) versus secondary (16%) frozen shoulder.

Recruitment of medical graduates from Prague to foundation programme jobs in a UK hospital: results of a 6-year project.

Introduction: International medical graduates (IMGs) are required to fill foundation-level posts in the NHS. Recruiting for these posts is difficult and time consuming. In 2016, we created a link between the Great Western Hospital, Swindon and Charles University, Prague to recruit to these posts. Here, we describe in detail the recruitment process, level of support and outcomes after 6 years, including the success rate of completion of foundation training and their career progression. Methods: Formal structured interviews occurred in Prague or online. Support included tailored educational/clinical supervision and additional simulation sessions. Data collected included exception reports and sick leave records. In 2022, a survey established satisfaction levels with the project and subsequent career progression. Results: All 51 doctors (100%) recruited as IMGs completed foundation training. Exception reporting and sick leave were below the Trust average. Of those doctors, 39 (76%) replied to the survey. All reported that the appointments helped them progress in their careers and 23 (45%) have subsequently been appointed successfully to a national Specialty Training Scheme. Conclusions: This project improved recruitment of non-deanery foundation doctors, prevented rota gaps and provided adequate staffing of junior doctors in our hospital. Concerns around employment of IMGs can be offset by providing a supportive and developmental environment.

Advancing a grounded theory of parental support in competitive girls' golf.

Parental support in youth sport has been associated with positive athlete outcomes, such as sport enjoyment and continued participation. Although research has demonstrated the significant and influential role parents fulfil in the youth sport context, there remains a dearth of theoretical frameworks detailing parental support in youth sport and an absence of empirical research examining parental support across athlete development stages and sports. The present study sought to examine athletes' perceptions of parental support, with a view to advancing a grounded theory of parental support in youth golf. Fourteen online synchronous focus groups were conducted with an international sample (Australia, Canada, England, Finland, Ireland, New Zealand, Scotland) of 61 girls, in the specialising (n = 27) and investment stages (n = 34) of athlete development. Data were analysed in three phases: open-coding, axial coding, and theoretical integration. The substantive grounded theory is constructed on the core category of 'Individual Parental Support Preferences'. This core category is underpinned by four sub-categories of parental support which were evident across development stages: instrumental, informational, emotional, and autonomy support, and is influenced by a host of athlete (e.g., athletes' performance), parent (e.g., parents' knowledge), and contextual characteristics (e.g., location). Unconditional parental support is an important aspect of emotional support, however the concept of adopting a person-first approach to sport parenting is novel. These results provide a rich and novel insight of parental support in girls' golf, advancing a grounded theoretical understanding of parental support mechanisms in a youth sport context.

A Population of Tumor-Infiltrating CD4+ T Cells Co-Expressing CD38 and CD39 Is Associated with Checkpoint Inhibitor Resistance.

PURPOSE: We previously showed that elevated frequencies of peripheral blood CD3+CD4+CD127-GARP-CD38+CD39+ T cells were associated with checkpoint immunotherapy resistance in patients with metastatic melanoma. In the present study, we sought to further investigate this population of ectoenzyme-expressing T cells (Teee). EXPERIMENTAL DESIGN: Teee derived from the peripheral blood of patients with metastatic melanoma were evaluated by bulk RNA-sequencing (RNA-seq) and flow cytometry. The presence of Teee in the tumor microenvironment was assessed using publically available single-cell RNA-seq datasets of melanoma, lung, and bladder cancers along with multispectral immunofluorescent imaging of melanoma patient formalin-fixed, paraffin-embedded specimens. Suppressive function of Teee was determined by an in vitro autologous suppression assay. RESULTS: Teee had phenotypes associated with proliferation, apoptosis, exhaustion, and high expression of inhibitory molecules. Cells with a Teee gene signature were present in tumors of patients with melanoma, lung, and bladder cancers. CD4+ T cells co-expressing CD38 and CD39 in the tumor microenvironment were preferentially associated with Ki67- CD8+ T cells. Co-culture of patient Teee with autologous T cells resulted in decreased proliferation of target T cells. High baseline intratumoral frequencies of Teee were associated with checkpoint immunotherapy resistance and poor overall survival in patients with metastatic melanoma. CONCLUSIONS: These results demonstrate that a novel population of CD4+ T cells co-expressing CD38 and CD39 is found both in the peripheral blood and tumor of patients with melanoma and is associated with checkpoint immunotherapy resistance.

CD4 Phenotypes Are Associated with Reduced Expansion of Tumor-Infiltrating Lymphocytes in Melanoma Patients Treated with Adoptive Cell Therapy.

Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy is effective in treating malignant melanoma, but its success relies on the adequate ex vivo expansion of TIL. To assess correlates of TIL expansion, CD4+ and CD8+ TIL were analyzed by RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing of acetylated histone 3. Patients were grouped into "TIL high" and "TIL low" based on division at the median number of TIL infused. Greater numbers of TIL infused correlated with longer overall survival, and increased frequencies of CD4+ cells infused were negatively correlated with the number of TIL infused. RNA-seq analysis of CD4+ TIL showed increases in Th2/Th17/regulatory T cell-related transcripts and pathways in the TIL-low group. Analysis of a public single-cell RNA-seq dataset validated findings that increased frequencies of CD4+ cells were negatively correlated with the number of TIL infused. TIL-low patients had significantly increased frequencies of CD4+ cells expressing ETS2 and OSM and trended toward increased expression of TNFRSF18.

Long-Term Outcomes Following Manipulation Under Anaesthetic for Patients with Primary and Secondary Frozen Shoulder.

Background: Frozen Shoulder (FS) is a common, debilitating condition for which manipulation under anaesthetic (MUA) is a non-invasive and effective treatment option. Current literature evaluates short to medium-term outcomes, but there is a paucity of long-term (>10 years) studies. Knowledge of long-term outcomes is also needed to evaluate whether FS or its treatment pre-disposes to other shoulder pathology in the long-term. Methods: A retrospective analysis of 398 shoulders undergoing MUA for FS between Jan 1999 and Jan 2010; 240 complete datasets were obtained. Outcomes were Oxford Shoulder Score (OSS), recurrence and development of other shoulder pathology (arthritis or rotator cuff tear). Results: At long-term follow-up (mean 13.2 years), 71.3% had no symptoms (OSS 48), 16.6% had minor symptoms (OSS 42-47) and 12.1% had significant symptoms (OSS < 42). There were 4/240 (1.7%) self-reported recurrences > 5 years after initial MUA and 2/240 (0.8%) repeat MUAs. In the long-term 6.7% developed rotator cuff pathology and 3.8% shoulder OA. Discussion: This study suggests that long-term outcome after MUA for FS is favourable. Late recurrence of FS is uncommon and the development of OA or rotator cuff pathology is no greater than that of the general population.

Demographic Determinants of Residue Profiles of Fungicidal Compounds in Common Voles (Microtus arvalis) under Semi-Natural and Natural Conditions.

Environmental risks from plant protection products (PPPs) need to be assessed to ensure safe use. The risk assessments are generally carried out using the common vole as a focal species with conservative theoretical estimates of external exposure. These are then compared to dose-related toxicity endpoints established in toxicity studies, often with laboratory species. The aim of the present study was to determine the actual internal dosimetry of PPPs' active ingredients (AIs) in a population of common voles to provide the basis for informed higher tier risk assessment. As a proof of concept, two fungicidal AIs (fludioxonil and cyprodinil) were investigated using a range of application methodologies. Individuals were treated using oral gavage application (AI dose: 100/200 mg/kg) and fed treated grass (AI sprayed at 2 kg/ha) under laboratory, semi-natural, and natural conditions. Our results show that demographic factors play a significant role in the individual residue profile and that age structure is a key aspect that determines the overall exposure risk of a population. These results are consistent from laboratory to field conditions. Future approaches could establish dose-residue relationships that are reflective of natural food intake rates in wild common vole populations in the risk assessment of PPPs.

The safety and accuracy of various carpal tunnel injection techniques.

PURPOSE: Carpal tunnel (CT) syndrome continues to be a commonly treated hand pathology. We aimed to evaluate several CT injection techniques for (1) spatial accuracy within the CT and (2) risk of median nerve (MN) injury. Our purpose was to evaluate for any significant differences in accuracy of needle placement within the carpal tunnel and final distance between the needle tip and the MN with each technique. METHODS: Fifteen fresh frozen cadaveric arms were used for this study. Six different injection techniques for CT injection were performed on each specimen, including palmaris longus, ulnar to flexor carpi radialis, trans-flexor carpi radialis, volar radial, volar ulnar, and direct through the palm techniques. After needle placement, a standard open CT release was performed to assess for accuracy of placement within the CT and measure needle position in relation to the MN and other anatomic structures. RESULTS: Accurate intra-CT needle placement was seen in 91% of injections. While there was no significant difference between injection techniques for distance to nearest tendon (p = 0.1531), the trans-flexor carpi radialis (tFCR), volar radial (VR), and volar ulnar (VU) techniques consistently provided the greatest intra-CT distance from needle tip to median nerve (p = 0.0019). The least incidence of intraneural needle placement was found with the tFCR and VR approaches. CONCLUSION: All six injection techniques reliably enter the CT space. The lowest risk to the MN was found with tFCR and VR techniques, and we recommend these techniques for safe and effective needle placement to avoid iatrogenic intraneural injection. LEVEL OF EVIDENCE: Level V: Cadaveric Study.

Sensitivity of northwest Australian tropical cyclone activity to ITCZ migration since 500 CE.

Tropical cyclones (TCs) regularly form in association with the intertropical convergence zone (ITCZ), and thus, its positioning has implications for global TC activity. While the poleward extent of the ITCZ has varied markedly over past centuries, the sensitivity with which TCs responded remains poorly understood from the proxy record, particularly in the Southern Hemisphere. Here, we present a high-resolution, composite stalagmite record of ITCZ migrations over tropical Australia for the past 1500 years. When integrated with a TC reconstruction from the Australian subtropics, this time series, along with downscaled climate model simulations, provides an unprecedented examination of the dependence of subtropical TC activity on meridional shifts in the ITCZ. TCs tracked the ITCZ at multidecadal to centennial scales, with a more southward position enhancing TC-derived rainfall in the subtropics. TCs may play an increasingly important role in Western Australia's moisture budgets as subtropical aridity increases due to anthropogenic warming.

Global oral poliovirus vaccine stockpile management as an essential preparedness and response mechanism for type 2 poliovirus outbreaks following global oral poliovirus vaccine type 2 withdrawal.

Following the global declaration of indigenous wild poliovirus type 2 eradication in 2015, the world switched to oral polio vaccine (OPV) that removed the type 2 component. This 'switch' included the widespread introduction of inactivated poliovirus vaccine and the creation of a stockpile of monovalent type 2 OPV (mOPV2) to respond to potential polio virus Type 2 (PV2) outbreaks and events. With subsequent detection of outbreaks of circulating vaccine-derived poliovirus type 2 (cVDPV2), it was necessary to use this stockpile for outbreak response. Not only were more outbreaks detected than anticipated in the first few years after the switch, but the number of supplemental immunization activities (SIAs) used to stop transmission was often high, and in many cases did not stop wider transmission. Use of mOPV type 2 led in some locations to the emergence of new outbreaks that required further use of the vaccine from the stockpile. In the following years, stockpile management became a critical element of the cVDPV2 outbreak response strategy and continued to evolve to include trivalent OPV and genetically stabilized 'novel OPV type 2' vaccines in the stockpile. An overview of this process and its evolution is presented to highlight several of these management challenges. The unpredictable vaccine demand, fixed production and procurement timelines, resource requirements, and multiple vaccine types contributes to the complexity of assuring appropriate vaccine availability for this critical programmatic need to stop outbreaks.

Reliability of Biomarkers of Physiological Stress at Rest and Post-exertional Heat Stress.

The purpose of this study was to assess the reliability of blood biomarkers that can signify exercise-induced heat stress in hot conditions. Fourteen males completed two heat stress tests separated by 5-7 days. Venous blood was drawn pre- and post- heat stress for the concentration of normetanephrine, metanephrine, serum osmolality, copeptin, kidney-injury molecule 1, and neutrophil gelatinase-associated lipocalin. No biomarker, except copeptin, displayed systematic trial order bias (p≥0.05). Normetanephrine, copeptin and neutrophil gelatinase-associated lipocalin presented acceptable reliability (CV range: 0.9-14.3%), while greater variability was present in metanephrine, osmolality and kidney-injury molecule 1 (CV range: 28.6-43.2%). Normetanephrine exhibited the largest increase (p<0.001) in response to heat stress (trial 1=1048±461 pmol. L-1; trial 2=1067±408 pmol. L-1), whilst kidney-injury molecule 1 presented trivial changes (trial 1=-4±20 ng. L-1; trial 2=2 ± 16 ng. L-1, p>0.05). Normetanephrine, copeptin, and neutrophil gelatinase-associated lipocalin demonstrated good reliability and sensitivity to an acute bout of heat stress. These biomarkers may be suitable for application in laboratory and field research to understand the efficacy of interventions that can attenuate the risk of thermal injury whilst exercising in the heat.

Associations of Bioavailable Serum Testosterone With Cognitive Function in Older Men: Results From the National Health and Nutrition Examination Survey.

BACKGROUND: Age-associated cognitive decline may be influenced by testosterone status. However, studies evaluating the impact of bioavailable testosterone, the active, free testosterone, on cognitive function are scarce. Our study determined the relationship between calculated bioavailable testosterone and cognitive performance in older men. METHODS: We used data from the U.S. National Health and Nutrition Examination Survey (NHANES) between 2013 and 2014. This study consisted of 208 men aged ≥60 years. Bioavailable serum testosterone was calculated based on the total serum testosterone, sex hormone-binding globulin, and albumin levels, whereas cognitive performance was assessed through the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Learning Test (WLLT), Word List Recall Test (WLRT), and Intrusion Word Count Test (WLLT-IC and WLRT-IC), the Animal Fluency Test (AFT), and the Digit Symbol Substitution Test (DSST). Multiple linear regression analyses were performed upon adjustment for age, ethnicity, socioeconomic status, education level, medical history, body mass index, energy, alcohol intake, physical activity levels, and sleep duration. RESULTS: A significant positive association between bioavailable testosterone and DSST (ß: 0.049, p = .002) score was detected, with no signs of a plateau effect. No significant associations with CERAD WLLT (p = .132), WLRT (p = .643), WLLT-IC (p = .979), and WLRT-IC (p = .387), and AFT (p = .057) were observed. CONCLUSION: Calculated bioavailable testosterone presented a significant positive association with processing speed, sustained attention, and working memory in older men above 60 years of age. Further research is warranted to elucidate the impact of the inevitable age-related decline in testosterone on cognitive function in older men.

The California Cognitive Assessment Battery (CCAB).

Introduction: We are developing the California Cognitive Assessment Battery (CCAB) to provide neuropsychological assessments to patients who lack test access due to cost, capacity, mobility, and transportation barriers. Methods: The CCAB consists of 15 non-verbal and 17 verbal subtests normed for telemedical assessment. The CCAB runs on calibrated tablet computers over cellular or Wi-Fi connections either in a laboratory or in participants' homes. Spoken instructions and verbal stimuli are delivered through headphones using naturalistic text-to-speech voices. Verbal responses are scored in real time and recorded and transcribed offline using consensus automatic speech recognition which combines the transcripts from seven commercial ASR engines to produce timestamped transcripts more accurate than those of any single ASR engine. The CCAB is designed for supervised self-administration using a web-browser application, the Examiner. The Examiner permits examiners to record observations, view subtest performance in real time, initiate video chats, and correct potential error conditions (e.g., training and performance failures, etc.,) for multiple participants concurrently. Results: Here we describe (1) CCAB usability with older (ages 50 to 89) participants; (2) CCAB psychometric properties based on normative data from 415 older participants; (3) Comparisons of the results of at-home vs. in-lab CCAB testing; (4) We also present preliminary analyses of the effects of COVID-19 infection on performance. Mean z-scores averaged over CCAB subtests showed impaired performance of COVID+ compared to COVID- participants after factoring out the contributions of Age, Education, and Gender (AEG). However, inter-cohort differences were no longer significant when performance was analyzed with a comprehensive model that factored out the influences of additional pre-existing demographic factors that distinguished COVID+ and COVID- cohorts (e.g., vocabulary, depression, race, etc.,). In contrast, unlike AEG scores, comprehensive scores correlated significantly with the severity of COVID infection. (5) Finally, we found that scoring models influenced the classification of individual participants with Mild Cognitive Impairment (MCI, z-scores < -1.50) where the comprehensive model accounted for more than twice as much variance as the AEG model and reduced racial bias in MCI classification. Discussion: The CCAB holds the promise of providing scalable laboratory-quality neurodiagnostic assessments to underserved urban, exurban, and rural populations.

Phase II clinical and immune correlate study of adjuvant nivolumab plus ipilimumab for high-risk resected melanoma.

BACKGROUND: Adjuvant therapy for high-risk resected melanoma with programmed cell-death 1 blockade results in a median relapse-free survival (RFS) of 5 years. The addition of low dose ipilimumab (IPI) to a regimen of adjuvant nivolumab (NIVO) in CheckMate-915 did not result in increased RFS. A pilot phase II adjuvant study of either standard dose or low dose IPI with NIVO was conducted at two centers to evaluate RFS with correlative biomarker studies. METHODS: Patients with resected stages IIIB/IIIC/IV melanoma received either IPI 3 mg/kg and NIVO 1 mg/kg (cohort 4) or IPI 1 mg/kg and NIVO 3 mg/kg (cohorts 5 and 6) induction therapy every 3 weeks for 12 weeks, followed by maintenance NIVO. In an amalgamated subset of patients across cohorts, peripheral T cells at baseline and on-treatment were assessed by flow cytometry and RNA sequencing for exploratory biomarkers. RESULTS: High rates of grade 3-4 adverse events precluded completion of induction therapy in 50%, 35% and 7% of the patients in cohorts 4, 5 and 6, respectively. At a median of 63.9 months of follow-up, 16/56 patients (29%) relapsed. For all patients, at 5 years, RFS was 71% (95% CI: 60 to 84), and overall survival was 94% (95% CI: 88 to 100). Expansion of CD3+CD4+CD38+CD127-GARP- T cells, an on-treatment increase in CD39 expression in CD8+ T cells, and T-cell expression of phosphorylated signal-transducer-and-activator-of-transcription (STAT)2 and STAT5 were associated with relapse. CONCLUSIONS: Adjuvant IPI/NIVO at the induction doses used resulted in promising relapse-free and overall survival, although with a high rate of grade 3-4 adverse events. Biomarker analyses highlight an association of ectoenzyme-expressing T cells and STAT signaling pathways with relapse, warranting future validation. TRIAL REGISTRATION NUMBER: NCT01176474 and NCT02970981.