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Women with Alcohol use disorder (AUD) are more likely than men to have co-occurring depression, drink to cope with negative affect (NA), and cite negative affect as a contributor to relapse. Among AUD treatment seekers, low behavioral activation, NA, and reduced self-efficacy in abstaining from alcohol (e.g., in tempting situations) are relapse risk factors. This study investigated the association between behavioral activation, affective states, and self-efficacy among treatment-seeking women. Participants were 70 women (M = 40.50, SD = 11.59 years of age) with elevated depressive symptoms seeking AUD treatment. The Behavioral Activation for Depression Scale (BADS) was used to assess environmental engagement. The Alcohol Abstinence Self-Efficacy (AASE) scale was used to assess temptation to drink in contexts of positive and negative affect, and general positive and negative affect were assessed with the Positive and Negative Affect Schedule. Results indicated that behavioral activation was directly correlated with positive affect (PA; r = .62, p < .001) and inversely correlated with depression (r = -.35, p = .004), negative affect (r = -.39, p = .001), and temptation to drink in the context of negative affect (r = -.33, p = .006). After controlling for depressive symptoms, behavioral activation continued to be associated with greater general positive affect (β = .595, p < .001) and lower temptation to drink in the context of negative affect (β = -.348 p = .008). Our results suggest a nuanced association between behavioral activation, negative affect, and temptations to drink that is not accounted by depressive symptoms. Self-efficacy to abstain from drinking in a negative affect context should be considered when designing AUD interventions for women. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objective A genomic test to predict personal risk of colorectal cancer (CRC) that targets screening and could be feasibly implemented in primary care. We explored informed decision-making and attitudes towards genomic testing in this setting. Methods A CRC genomic test was offered to 150 general practice patients with brief discussion of its implications. We measured informed choice about the test, consisting knowledge, attitudes and test uptake. Sixteen purposively-sampled participants were interviewed. Results Of 150, 142 (95%) completed the informed choice measure and of 27 invited, 16 (59%) completed an interview. 73% made an informed choice about the test. Interviews revealed that participants with inadequate knowledge on the informed choice scale still understood the gist of the test. While positive attitudes were most prevalent, some had concerns, and many were indifferent to the test. Positive attitudes included: that risk information could facilitate risk reduction; negative attitudes included: that risk results could cause worry and be used for insurance discrimination; indifferent attitudes included: that the test seemed benign and it was easy to do. Conclusions Our study adds to the evidence that genomic tests for CRC risk do not pose significant concern to patients in community settings. Practice implications As genomic tests become more prevalent, this study’s findings can be used to facilitate informed decision-making and ensure equitable access.

ObjectivesThe human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis.MethodsWe performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA).ResultsMeta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not.ConclusionsHLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA.

Background Increasing participation in the Australian National Bowel Cancer Screening Program (NBCSP) is the most efficient and cost-effective way of reducing mortality associated with colorectal cancer by detecting and treating early-stage disease. Currently, only 44% of Australians aged 50–74 years complete the NBCSP. This efficacy trial aims to test whether this SMS intervention is an effective method for increasing participation in the NBCSP. Furthermore, a process evaluation will explore the barriers and facilitators to sending the SMS from general practice. Methods We will recruit 20 general practices in the western region of Victoria, Australia to participate in a cluster randomised controlled trial. General practices will be randomly allocated with a 1:1 ratio to either a control or intervention group. Established general practice software will be used to identify patients aged 50 to 60 years old who are due to receive a NBCSP kit in the next month. The SMS intervention includes GP endorsement and links to narrative messages about the benefits of and instructions on how to complete the NBCSP kit. It will be sent from intervention general practices to eligible patients prior to receiving the NBCSP kit. We require 1400 eligible patients to provide 80% power with a two-sided 5% significance level to detect a 10% increase in CRC screening participation in the intervention group compared to the control group. Our primary outcome is the difference in the proportion of eligible patients who completed a faecal occult blood test (FOBT) between the intervention and control group for up to 12 months after the SMS was sent, as recorded in their electronic medical record (EMR). A process evaluation using interview data collected from general practice staff (GP, practice managers, nurses) and patients will explore the feasibility and acceptability of sending and receiving a SMS to prompt completing a NBCSP kit. Discussion This efficacy trial will provide initial trial evidence of the utility of an SMS narrative intervention to increase participation in the NBCSP. The results will inform decisions about the need for and design of a larger, multi-state trial of this SMS intervention to determine its cost-effectiveness and future implementation. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12620001020976. Registered on 17 October 2020.

Study Design Retrospective observational survey-based study. Introduction In France, intracranial aneurysm (IA) patients are managed by neurosurgeons and by interventional neuroradiologists. The growth of endovascular treatment led us to reflect on the role of neurosurgeons in the management of patients with IA. The present study aimed to highlight the current organization of IA management in France. Method A 60-question survey was sent to the neurosurgeons in 34 hospitals managing IA patients. Thirty-three questions dealt with standards of care, follow-up procedures and the involvement of the specific specialist. Results Twenty-seven centers (79.4%) responded to the survey. A Vascular Multidisciplinary Discussion Team was organized, including both surgeons and neuroradiologists, in 92% of responding centers. There were department protocols in 66% of centers, a local registry in 33% and clinical trials in IA in 60%. Patients with unruptured IA were first seen by a neurosurgeon or by an interventional neuroradiologist, with different practices. For ruptured IA, the neurosurgeons were contacted first in 93% of cases, and were systematically involved in initial intensive care unit management. The patients were hospitalized in the neurosurgery department in 89% of the centers. The neurosurgeons took care of initial follow-up in 85% of the centers, and of lifetime follow-up in 36%. In most centers, radiological monitoring of IA was based on MRI angiography for patients who were embolized or under surveillance, and on CT angiography after microsurgery. Conclusion Despite the growth of endovascular treatments, the present survey and the literature highlight a major role of neurosurgeons in treatment, follow-up and care coordination.

Despite the large and growing number of studies on workplace deviance, the field currently lacks a complete understanding of who perpetrates this behavior. In one stream of research, scholars have examined the relationship between more "traditional" personality traits (i.e., the Big Five, which consists of conscientiousness, agreeableness, emotional stability, openness to experience, and extraversion) and workplace deviance. In an alternate stream, scholars have examined the relationship between workplace deviance and more malevolent personality traits (i.e., the Dark Triad, which consists of Machiavellianism, narcissism, and psychopathy). We synthesize these two perspectives using a meta-analytic approach to examine the incremental importance and relative importance of the Dark Triad beyond the Big Five for predicting workplace deviance. Our results supported our incremental importance hypothesis, as the Dark Triad predicted variance in both forms of workplace deviance beyond the Big Five. However, the results of the relative importance analyses were more nuanced, as agreeableness, Machiavellianism, and psychopathy were the most important predictors of interpersonal deviance, and conscientiousness, Machiavellianism, and psychopathy were the most important predictors of organizational deviance. Overall, our results make a contribution by explicating the relative effects of employee personality domains to paint a clearer picture of a workplace deviant. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The aim of this study was to investigate sport-related injury rates, types, locations, and mechanisms in female youth team sports. This was a secondary analysis of a cross-sectional study. An anonymous online survey was administered to high school students (ages 14-19) in Alberta, Canada. The survey included questions regarding demographic information, sport participation and self-reported injuries sustained in the past year. Results were analyzed for girls who reported playing a top ten team sports for female participation. For girls participating in team sports, the overall injury rate was 55.5 injuries/100 participants/year. The rate of at least one concussion was 9.4 concussions/100 participants/year. Injury and concussion rates were highest in ringette (Injury rate=42.9 injuries/100 participants/year, Concussion rate=19.0 concussions/100 participants/year) and rugby (Injury rate=40.0, Concussion rate=15.3). The top three most serious injury locations were the knee (24.7%), ankle (21.6%) and head (16.1%). The most common injury types were joint/ligament sprain (26.71%), fracture (13.0%) and concussion (11.8%). Contact mechanisms accounted for 73.4% of all serious injuries reported in girls team sports. Team sport injury rates are high in female youth team sports. Specific consideration of sport-specific injury rates, types and mechanisms in girls’ team sports will inform development and evaluation of targeted sport-specific prevention strategies.

OBJECTIVES To describe injury and concussion rates and mechanisms in female high school rugby players. DESIGN Two-year prospective cohort study. SETTING High school rugby. PARTICIPANTS Participants included 214 female High school rugby players (year 1) and 207 female High school players (year 2) from the Calgary Senior High School Athletics Association 2018 and 2019 rugby competition. INTERVENTION None. MAIN OUTCOME MEASURES Match and training injury and concussion. Injury definition included any injury resulting in time loss, inability to complete a session, and/or requiring medical attention. Details of reported injuries were collected on injury report forms and validated by a certified athletic therapist on a validated online injury surveillance platform. Exposure hours for players were tracked using paper or virtual weekly exposure forms by team designates. RESULTS A match incidence rate (IR) = 93.7 injuries/1000 match hours (95% confidence intervals (CI): 78.6-11.7) and training IR = 5.3 injuries/1000 training hours (95% CI: 4.0-6.9) were estimated. The tackle accounted for 109 (70%) match and 37 (44%) training injuries. Tackling was the most frequent mechanism of injury (IR = 37.5 injuries/1000 match hours, 95% CI: 27.5-51.8 and 1.2 injuries/1000 training hours, 95% CI: 0.7-2.4). Sixty-two match concussions (IR = 37.5 concussions/1000 match hours, 95% CI: 26.8-52.3) and 16 training concussions (IR = 1.0 concussions/1000 training hours, 95% CI: 0.7-1.4) occurred. Of 78 reported concussions, 78% for match and 56% for training were physician diagnosed. Tackling was the most frequent mechanism of concussion in matches (IR = 18.1 concussions/1000 match hours, 95% CI:11.4-28.6). CONCLUSIONS Injury and concussion rates in female high school rugby are high. The tackle accounted for the highest proportion of injuries. Prevention strategies (eg, tackle policy change, tackle-training programs, and neuromuscular training) should be explored to increase sport safety.

IntroductionAnkylosing spondylitis (AS) is a chronic inflammatory disease whose main hallmark is involvement of the axial skeleton. Non-steroidal anti-inflammatory drugs (NSAIDs) are the first line treatment; however, their use is limited because of side-effects. Tumour necrosis factor inhibitors (TNFi) are a safe and effective therapy, and they have been approved for the management of AS.Areas coveredThis is a review of the efficacy of TNFi in disease modification in AS. It is focused on results from early phase clinical trials; however, it also discusses the most relevant findings in order to optimise anti-TNF treatment. A literature search was done using PubMed, Medline, Embase, Google Scholar and Cochrane library, looking for scientific publications from inception to August 2021. Further information was retrieved from ClinicalTrial.gov and Clinicaltrialsregister.eu.Expert opinionTNFi have demonstrated short and long-term improvements in all aspects of disease activity, as well as physical function in patients with AS. They have drastically revolutionised the management of the disease; and even though new drugs have become available in the market, TNFi have not been displaced for the treatment of AS, and still constitute the best alternative when NSAIDs are no-longer an option.

Summary Rheumatoid arthritis (RA) is associated with a ten-fold increased risk of interstitial lung disease (ILD). The presence of ILD in a patient with RA influences both prognosis and the choice of therapeutic intervention. Although there has been increasing awareness of the relevance of ILD to the outcome of patients with RA, there remains limited consensus around several important aspects of disease diagnosis and management. This Review emphasises two of the main areas in which a much greater standardisation of approach is urgently needed. First, the development of a screening approach based on established risk factors is a priority. Learning how to identify patients with RA-associated ILD early and then monitoring their condition to assess progression and measure the potential influence of therapeutic interventions is essential. Second, there is a need to consolidate the therapeutic evidence base to agree a standard approach to intervention. Although we already have a range of potentially effective treatments, further clinical trials are required to optimise therapeutic intervention.

Objective To assess the rate of immediate postpartum long-acting reversible contraceptive (LARC) use in a multihospital health care system 2 years before and after the policy was implemented, and to assess factors associated with LARC use and repeat pregnancy rates within 12 months after delivery. Methods We conducted a retrospective chart review of all patients giving birth at three Cleveland Clinic Ohio hospitals from July 1, 2015, to June 30, 2019. We reviewed the inpatient medication reconciliation to identify the LARC initiation rate. We compared all patients who received inpatient postpartum LARC to a 1:3 matched sample of patients who did not receive LARC, matched by delivery date and location, to identify patient characteristics associated with LARC use. The electronic medical record (Epic) was reviewed to identify new pregnancies occurring within 12 months postdelivery. Results We identified 17,848 deliveries prepolicy and 18,555 deliveries postpolicy. Immediate postpartum LARC was used by 0.5% (monthly range 0-2.1%) of patients prepolicy and 11.6% (monthly range 8.3-15.4%) of patients postpolicy. Levonorgestrel intrauterine devices (IUDs) were used by 56.5%, implants by 29.1%, and copper IUDs by 14.5% of LARC users. Characteristics associated with LARC use included younger age, public insurance, non-White race, Hispanic or Latina ethnicity, higher body mass index, sexually transmitted infection in pregnancy, and tobacco use. Long-acting reversible contraceptive users had a lower rate of repeat pregnancy at 12 months postpartum compared with the non-LARC group (1.9% vs 3.6%, P Conclusion Immediate postpartum LARC use increased after a state policy change mandated universal access and was associated with decreased pregnancy rates in the first year postdelivery.

OBJECTIVE: Although stress is a well-known predictor of alcohol use lapses among individuals seeking recovery from alcohol use disorder (AUD), most research has relied on retrospective self-report using conventional questionnaires that explore stress effects at the level of the mean. Ecological momentary assessment (EMA) overcomes many of the shortcomings of questionnaire-based, retrospective self-report by using real-time, in-the-environment evaluations for the acquisition of ecologically valid data that can also capture stress variability. The present investigation used EMA to disentangle stress effects on alcohol lapses among individuals in the first year of an AUD recovery attempt by exploring associations between mean-level stress, stress variability, and subsequent alcohol use. METHOD: Participants (N = 42) completed 6 days of EMA monitoring and were then followed up 90 days later to assess alcohol use. Putative associations were explored using hierarchical regression controlling for demographic factors and pre-baseline alcohol use, with percentage days abstinent from alcohol at follow-up as the outcome variable. RESULTS: An interaction effect was observed such that the combination of high mean stress level and high stress variability was associated with the lowest percentage of days abstinent. For those with high mean stress levels, this relationship was attenuated as stress variability decreased. CONCLUSIONS: The findings support previous research linking stress to alcohol use lapses; however, these results indicate that the stress/alcohol use relationship is more nuanced than previously described. Our findings suggest that stress variability should also be considered in clinical contexts when assessing risk conferred by mean-level stress.

Context Causes of anterior knee pain (AKP) in jumping athletes include patellofemoral pain and patellar tendinopathy. The differential diagnosis of AKP is challenging, with variations in clinical presentations. No previous research has used pain location to describe AKP in basketball players. Objective To (1) describe the prevalence and pain distribution of AKP in collegiate basketball players and (2) report the prevalence of focal inferior pole pain using 2 outcome measures. Design Cross-sectional study. Setting University and collegiate basketball facilities in Alberta, Canada. Patients or Other Participants A total of 242 collegiate basketball athletes (138 women, 104 men). Main Outcome Measure(s) The single-legged decline squat test (SLDS) was used to capture pain location via pain mapping (dichotomized as focal or diffuse) and pain severity (numeric rating scale). The Oslo Sports Trauma Research Centre Knee questionnaire (OSTRC-Knee) and adapted version for patellar tendinopathy (OSTRC-Patellar Tendinopathy Questionnaire [OSTRC-P]) were used to report the prevalence of AKP and patellar tendinopathy, respectively. Focal inferior pole pain during the SLDS was used to classify patellar tendinopathy. Results Of the 242 players, 146 (60%) reported pain with the SLDS (unilateral = 64 [26%]; bilateral = 82 [34%]). A total of 101 (43%) described knee pain using the OSTRC-Knee. Pain mapping captured the variability in pain locations. Diffuse pain was more prevalent (left, 70%; right, 72%) than focal pain (left, 30%; right, 28%). Low prevalence of patellar tendinopathy was noted using the OSTRC-P (n = 21, 8.7%) and inferior pole pain during the SLDS (n = 25, 10.3%). Conclusions Diffuse AKP was common in Canadian basketball players; however, pain mapped to the inferior pole of the patella was not common. Few players reported tendinopathy using the OSTRC-P, suggesting that patellar tendinopathy was not a primary knee pain presentation in this jumping cohort. Pain location, rather than the presence or severity of pain alone, may better describe the clinical presentation of AKP in jumping athletes.

Introduction and hypothesis Describe the modified autologous fascial sling procedure that has been employed in the largest randomized controlled trial comparing autologous slings, mesh slings and xenografts. Methods The video aims to demonstrate the modified Aldridge technique. The surgical procedure is demonstrated. A 6-cm suprapubic incision is made to harvest the rectus sheath fascia. Loop-0-PDS sutures are attached on either end of the sling. A marking suture is placed in the middle of the graft to facilitate tension-free adjustment. A vaginal incision is made at the mid-urethra. Paraurethral dissection is performed to create a tunnel for the fascial graft to be passed through (in the same manner as with transvaginal mesh slings). The ends of the graft PDS sutures are passed through the paraurethral tunnel. One hand is placed abdominally below the rectus muscles to palpate the pelvic floor from above. The graft sutures are passed through the pelvic floor with control on either side. A cystoscopy is performed to check the bladder integrity. The graft placement is adjusted to be tenson-free. The incisions are closed. The short- and long-term outcomes of this technique have been investigated and published. Results The cure rates and complication rates were no different in the mesh and autologous slings. The xenograft had inferior outcomes. Conclusion Autologous fascial slings can be used in the surgical management of urodynamic stress incontinence. The technique demonstrated in this video is the technique employed in the largest randomized controlled trial investigating the efficacy of autologous fascial slings to xenografts and tapes.

Objective To quantify differences in fatigue and disordered sleep between adolescents with cerebral palsy (CP) and their typically developing peers. A secondary aim was to investigate the association between fatigue and disordered sleep in adolescents with CP.Methods A convenience sample of 36 youth with CP aged 10–18 years was matched for age and sex with 36 typically developing peers. The Fatigue Impact and Severity Self-Assessment (FISSA), the Patient-Reported Outcome Measurement Information System (PROMIS) fatigue profile, and the Sleep Disturbance Scale for Children (SDSC) were collected.Results Higher fatigue was reported in participants with CP than in their typically developing peers based on the FISSA total score (mean paired difference=19.06; 99% confidence interval [CI], 6.06–32.1), the FISSA impact subscale (mean paired difference=11.19; 99% CI, 3.96–18.4), and the FISSA Management and Activity Modification subscale (mean paired difference=7.86; 99% CI, 1.1–14.6). There were no differences between groups in the PROMIS fatigue profile (mean paired difference=1.63; 99% CI, -1.57–4.83) or the SDSC total score (mean paired difference=2.71; 99% CI, -2.93–8.35).Conclusion Youth with CP experienced significantly more fatigue than their peers as assessed by a comprehensive measure that considered both general and diagnosis-specific concerns. Sleep did not differ between youth with CP and their typically developing peers. These findings underscore the need to consider the clinical management of fatigue across the lifespan of individuals with CP to prevent the associated deterioration of functional abilities.

Objectives We measured the production of cytokines, chemokines and antibodies involved in allergic responses and sCD23 levels during Schistosoma mansoni infection. Methods Individuals (n = 164) were selected using the ISAAC questionnaire and parasitological exams. The subjects were divided as follows: those infected individuals with allergy-related symptoms (A-I), those with allergy-related symptoms only (A-NI); those only infected (NA-I); and those non-infected individuals without allergy-related symptoms (NA-NI). We used supernatants from cell culture (mitogenic stimulation) to measure cytokine and chemokine levels using cytometric bead arrays. Serum levels of anti-Ascaris lumbricoides (Asc) and anti-Blomia tropicalis IgE were measured using ImmunoCAP, and sCD23 was measured using ELISA. Results Schistosoma mansoni infection was associated with a lower risk of allergy-related symptoms. In A-I, there were higher levels of TNF-α, IL-10, IL-6, IFN-γ and CXCL8 than in NA-NI group, with TNF-α and IL-6 also at higher levels compared to A-NI group. Levels of IL-6, CXCL8, total and anti-Asc IgE, as well as the numbers of eosinophils, were higher in NA-I than in NA-NI, and the antibodies were also lower in A-NI than in NA-I group. In AI and NA-I, there was less production of CCL2 than in NA-NI. There were no differences in the levels of IL-2, IL-4, IL-17, CCL5, sCD23 and anti-Blomia IgE. Conclusions Patients with allergy-related symptoms and infected (simultaneously) had higher levels of IL-10; due to the infection, there was increased production of IL-6 and CXCL8 and less CCL2. These data may characterize deviation to Th1 or attenuation of the Th2 response in allergy sufferers in areas endemic for schistosomiasis.

OBJECTIVE Juvenile idiopathic arthritis (JIA) is associated with altered body structure and function outcomes that may expose youth with JIA to a greater risk of secondary joint injury. This study aimed to examine differences in vertical drop jump (VDJ) biomechanics for youth with JIA and healthy youth (control group). METHODS The present study was a matched pair cohort study. Youth with JIA (n = 30) and their age- and sex-matched control peers participated in this ethics-approved study. Lower-extremity biomechanics information was obtained using a motion analysis system (Motion Analysis) and 2 force plates (AMTI). Biomechanics outcomes included hip, knee, and ankle joint angles, ground reaction forces (GRF), and VDJ phase durations. Other outcomes included disease activity, physical disability, and sports participation. Matched pairs data (JIA-control) were analyzed using a multivariate random coefficient model (version 3.5.0, R Core Team; joint angles, potential confounders) and paired samples t-tests with Bonferroni correction (α = 0.0125; GRF, VDJ phase durations). RESULTS Youth with JIA had low disease activity, pain, and disability scores. Youth with JIA maintained a more erect posture at the hip (β = -4.0°, P = 0.004), knee (β = 7.5°, P = 0.004) and ankle (β = -2.6°, P = 0.001). GRF and phase durations outcomes did not meet criteria for significant differences. Knee extension increased with participant age (β = -1.0°, P = 0.002), while female participants displayed greater hip flexion (β = -6.6°, P = 0.001) and less ankle dorsiflexion (β = 2.3°, P = 0.006). CONCLUSION This study provides evidence for a stiff knee landing strategy by youth with JIA. These findings inform targets for physical therapy management to mitigate the risks of a secondary joint injury in sports participation.

Introduction Invasive meningococcal disease (IMD) is an uncommon but serious infectious disease. Its economic burden is known to be high but is poorly characterised. The objective of this study was to determine costs, as captured in the healthcare claims database, incurred by all patients hospitalised for IMD in France over a 6-year period. Methods This case–control study was performed using the French national public health insurance database (SNDS). Cases comprised all individuals hospitalised with acute IMD in France between 2012 and 2017 inclusive. For each case, three controls were identified, matched for age, gender and region of residence. All healthcare resource consumption by cases and controls during the follow-up period was documented. Costs were analysed for the index hospitalisation in cases, 1 year following the index date and then for 5 years following the index date. Costs were assigned from national tariffs. The analysis was performed from a societal perspective. IMD sequelae were identified from hospital discharge summaries. Results A total of 3532 cases and 10,590 controls were evaluated. The mean per capita cost of the index IMD hospitalisation was €11,256, and increased with age and with the presence of sequelae. In the year following the index date, mean per capita direct medical costs were €6564 in cases and €2890 in controls. Annual costs were €4254 in cases without sequelae, €10,799 in cases with one sequela and €20,096 in cases with more than one sequela. In the fifth year of follow-up, mean per capita costs were €2646 in cases and €1478 in controls. The excess cost in cases was principally due to the management of sequelae. Amputation, skin scarring and mental retardation generated per capita costs in excess of €20,000 in the first year and in excess of €10,000 for subsequent years. Conclusion The economic burden of IMD in France is high and, over the long-term, is driven by sequelae management. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00468-w.

Background: Gut microbial communities are increasingly being linked to diseases in animals and humans. Obesity and its associated diseases are a concern for horse owners and veterinarians, and there is a growing interest in the link between diet, the intestinal microbiota and metabolic disease. Objectives: Assess the influence of long-term hay or haylage feeding on the microbiota and metabolomes of 20 Welsh mountain ponies. Study design: Longitudinal study. Methods: Urine, faeces and blood were collected from 20 ponies on a monthly basis over a 13-month period. Urine and faeces were analysed using proton magnetic resonance (1 H NMR) spectroscopy and faecal bacterial DNA underwent 16S rRNA gene sequencing. Results: Faecal bacterial community profiles were observed to be different for the two groups, with discriminant analysis identifying 102 bacterial groups (or operational taxonomic units, OTUs) that differed in relative abundance in accordance with forage type. Urinary metabolic profiles of the hay and haylage fed ponies were significantly different during 12 of the 13 months of the study. Notably, the urinary excretion of hippurate was greater in the hay fed ponies for the duration of the study, while ethyl-glucoside excretion was higher in the haylage fed ponies. Main limitations: The study was undertaken over a 13-month period and both groups of ponies had access to pasture during the summer months. Conclusions: The data generated from this study, suggest that the choice of forage may have implications for the intestinal microbiota and metabolism of ponies and therefore, potentially their health status. Understanding the potential implication of feeding a particular type of forage will enable horse owners to make more informed choices with regard to feed, especially if their horse or pony is prone to weight gain.

Secondary consequences of juvenile idiopathic arthritis (JIA) may impact long-term health outcomes. This study examined differences in physical activity, cardiorespiratory fitness, adiposity, and functional performance in children and adolescents with JIA compared to their typically developing (TD) peers. Participants with JIA (n = 32; 10–20 years old) and their TD peers (n = 35) volunteered for assessments of: daily moderate-to-vigorous physical activity (MVPA, body-worn accelerometer); peak oxygen consumption (VO2 Peak, incremental bike test); fat mass index (FMI, dual-energy X-ray absorptiometry); and triple-single-leg-hop (TSLH) distance. Statistical analyses were performed in R using four linear mixed-effect models with Bonferroni adjustment (⍺ = 0.0125). Fixed effects were group, sex, and age. Participant clusters based on sex and age (within 1.5 years) were considered as random effects. Participants with JIA displayed lower mean daily MVPA than their TD peers [p = 0.006; β (98.75% CI); −21.2 (−40.4 to −2.9) min]. VO2 Peak [p = 0.019; −1.4 (−2.5 to −0.2) ml/kg/min] decreased with age. Females tended to have lower VO2 Peak [p = 0.045; −6.4 (−13.0 to 0.4) ml/kg/min] and greater adiposity [p = 0.071; 1.4 (−0.1 to 3.0) kg/m2] than males. The findings support the need for strategies to promote MVPA participation in children and adolescents with JIA. Sex and age should be considered in research on the consequences of JIA.

Objective To evaluate the feasibility of implementing an integrated multicomponent survivorship care model for men affected by prostate cancer. Methods Using a single arm prospective cohort study design, men with prostate cancer were recruited from two regional public hospitals in Australia for a 6‐months program that provided information and decision support, exercise and nutrition management, specialised clinical support, and practical support through localised and central care coordination. Carers of the men were also invited to the program. Data were collected from multiple sources to evaluate: (1) recruitment capability and participant characteristics; (2) appropriateness and feasibility of delivering the specific intervention components using an electronic care management tool; and (3) suitability of data collection procedures and proposed outcome measures. Results Of the 105 eligible men, 51 (consent rate 49%) participated in the program. Of the 31 carers nominated by the men, 13 consented (consent rate 42%). All carers and 50 (98%) men completed the program. Most (92%) men were newly diagnosed with localised prostate cancer. All men attended initial screening and assessment for supportive care needs; a total of 838 episodes of contact/consultation were made by the intervention team either in person (9%) or remotely (91%). The intervention was implemented as proposed with no adverse events. The proposed outcome measures and evaluation procedures were found to be appropriate. Conclusions Our results support the feasibility of implementing this integrated multicomponent care model for men affected by prostate cancer.

A young French Bulldog was presented with clinical signs of chronic gastrointestinal disease, unresponsive to medical therapies. Parasite screenings and abdominal ultrasound failed to identify the etiology of the clinical signs. Cytologic evaluation of a rectal scraping sample diagnosed presumptive granulomatous colitis (GC) based on the presence of numerous macrophages with characteristic abundant, pink, granular cytoplasm, which showed an intense pink color when stained with periodic acid-Schiff. Tissue biopsy samples and Escherichia coli fluorescence in situ hybridization analysis confirmed the cytologic diagnosis. The cytologic, histopathologic, and clinical features and staining properties of GC in a French Bulldog are reported. Rectal scraping should be considered a part of the diagnostic evaluation in patients with suspected GC.

Syringomyelia is a rare disorder in which a fluid-filled cyst forms within the spinal cord, resulting in myelopathy. Meanwhile, the abnormal dilatation of the central canal is referred to as hydromyelia or slit-like syrinx. The most prevailing classification is based on anatomical features and pathogeny rather than pathophysiological mechanisms. It is usual to distinguish foraminal syringomyelia related mainly to abnormalities at the craniocervical junction, non-foraminal syringomyelia dealing with any cause of arachnoiditis (infection, inflammation, trauma…) and more rarely syringomyelia associated with intramedullary tumors. Although many pathophysiological theories have been argued over time, the prevailing one is that disturbances in cerebrospinal fluid (CSF) flow in the sub-arachnoid spaces disrupt flow velocity leading to the syrinx. Symptoms of paralysis, sensory loss and chronic pain commonly develop during the third/fourth decades of life. The natural history of syringomyelia is typically one of gradual, stepwise neurological deterioration extending over many years. Diagnosis is based on magnetic resonance imaging (MRI) including excellent morphological sequences (T1-, T2-, FLAIR-, T2*-, enhanced T1-) and dynamic MRI with careful study of CSF velocity (CISS, cine-MR sequences). Surgical management is at first dedicated to treat the cause of the syringomyelia, mainly to re-establish a physiological CSF pathway in the subarachnoid spaces. Mostly, the surgical goal is to enlarge the craniocervical junction with duraplasty. Other surgical strategies such as arachnoidolysis or shunt procedures are performed based on the pathogenic mechanisms or as second-line treatment. Medical treatments are also necessary as chronic pain is the main long-lasting symptom. As evolutive syringomyelia is a severe disease with a high impact on quality of life, it is recommended to treat without delay. There is no evidence for surgery for incidental asymptomatic syringomyelia or hydromyelia. Finally, syringomyelia associated with intramedullary tumors resolves spontaneously after tumor resection. Syringomyelia is a rare disease, which requires a dedicated multidisciplinary approach, emphasizing the need for a nationwide scientific organization so as to offer optimal care to the patient.

Intracranial aneurysms (IA) in children are rare, accounting for less than 5% of all IA. Due to their scarcity, the epidemiology is poorly understood and differs from adults in term of clinical presentation, size, location, and origin. Consequently, the treatment strategies are specific and cannot be only based on data from adult series. The aim of our study was to report the characteristics, management, and outcomes of children treated for IA in two university hospitals located in Normandy (France) over the last 17 years and to perform a literature review of this rare pathology.This retrospective study included 18 consecutive children ( 18 years old) admitted with cerebral aneurysm treated in two neurosurgery departments in Normandy, from 2001 to 2018. Computerized tomography and cerebral angiography established the diagnosis. Both endovascular and surgical procedures were discussed in all cases. Data focused on clinical condition at admission, characteristics of the IA, choice of the treatment modalities, and complications. The outcome at follow-up is based on Glasgow outcomes scale (GOS) at 1 year.During the study period, 18 children (mean age: 12.6 years; sex ratio male/female: 2.3) were admitted with 21 IA. Aneurysms had a mean size of 13.6 mm with 4 giant aneurysms and were mostly located in the anterior circulation (16/21). Clinical presentations at onset were sudden symptoms related to a subarachnoid hemorrhage in 13 patients, headaches in 4 patients with giant aneurysm, and asymptomatic in one patient. Among the 13 patients with ruptured IA, 6 presented in poor preoperative condition (Hunt and Hess Grade ≥ 4). Treatment modalities consisted in embolization in 9 patients and surgery in 9 patients including 2 by-pass surgeries in fusiform aneurysms. Complications were similar in the two groups, but two cases of recanalization were observed in the endovascular group. At 1 year of follow-up, 14 children were in good condition (GOS Score 4) and one died. Three children presented associated IA treated by the same technique as initial aneurysm.Pediatric aneurysm is a different pathology compared with adults, occurring more frequently in male population with a higher proportion of giant aneurysms and aneurysms located in the internal carotid bifurcation. The use of endovascular techniques has progressed in the last years, but surgery was proposed for half of our population.

OBJECTIVE The RELIEF study assessed rates of hospitalization for acute diabetes complications in France before and after initiation of the FreeStyle Libre system. RESEARCH DESIGN AND METHODS A total of 74,011 patients with type 1 diabetes or type 2 diabetes who initiated the FreeStyle Libre system were identified from the French national claims database with use of ICD-10 codes, from hospitalizations with diabetes as a contributing diagnosis, or the prescription of insulin. Patients were subclassified based on self-monitoring of blood glucose (SMBG) strip acquisition prior to starting FreeStyle Libre. Hospitalizations for diabetic ketoacidosis (DKA), severe hypoglycemia, diabetes-related coma, and hyperglycemia were recorded for the 12 months before and after initiation. RESULTS Hospitalizations for acute diabetes complications fell in type 1 diabetes (−49.0%) and in type 2 diabetes (−39.4%) following FreeStyle Libre initiation. DKA fell in type 1 diabetes (−56.2%) and in type 2 diabetes (−52.1%), as did diabetes-related comas in type 1 diabetes (−39.6%) and in type 2 diabetes (−31.9%). Hospitalizations for hypoglycemia and hyperglycemia decreased in type 2 diabetes (−10.8% and −26.5%, respectively). Before initiation, hospitalizations were most marked for people noncompliant with SMBG and for those with highest acquisition of SMBG, which fell by 54.0% and 51.2%, respectively, following FreeStyle Libre initiation. Persistence with FreeStyle Libre at 12 months was at 98.1%. CONCLUSIONS This large retrospective study on hospitalizations for acute diabetes complications shows that a significantly lower incidence of admissions for DKA and for diabetes-related coma is associated with use of flash glucose monitoring. This study has significant implications for patient-centered diabetes care and potentially for long-term health economic outcomes.

BackgroundSuccessful breast cancer screening relies on timely follow-up of abnormal mammograms. Delayed or failure to follow-up abnormal mammograms undermines the potential benefits of screening and is associated with poorer outcomes. However, a comprehensive review of inadequate follow-up of abnormal mammograms in primary care has not previously been reported in the literature. This review could identify modifiable factors that influence follow-up, which if addressed, may lead to improved follow-up and patient outcomes.MethodsA systematic literature review to determine the extent of inadequate follow-up of abnormal screening mammograms in primary care and identify factors impacting on follow-up was conducted. Relevant studies published between 1 January, 1990 and 29 October, 2020 were identified by searching MEDLINE®, Embase, CINAHL® and Cochrane Library, including reference and citation checking. Joanna Briggs Institute Critical Appraisal Checklists were used to assess the risk of bias of included studies according to study design.ResultsEighteen publications reporting on 17 studies met inclusion criteria; 16 quantitative and two qualitative studies. All studies were conducted in the United States, except one study from the Netherlands. Failure to follow-up abnormal screening mammograms within 3 and at 6 months ranged from 7.2–33% and 27.3–71.6%, respectively. Women of ethnic minority and lower education attainment were more likely to have inadequate follow-up. Factors influencing follow-up included physician-patient miscommunication, information overload created by automated alerts, the absence of adequate retrieval systems to access patient’s results and a lack of coordination of patient records. Logistical barriers to follow-up included inconvenient clinic hours and inconsistent primary care providers. Patient navigation and case management with increased patient education and counselling by physicians was demonstrated to improve follow-up.ConclusionsFollow-up of abnormal mammograms in primary care is suboptimal. However, interventions addressing amendable factors that negatively impact on follow-up have the potential to improve follow-up, especially for populations of women at risk of inadequate follow-up.

Trichomonas vaginalis is a neglected urogenital parasitic protist that causes 170 million cases of trichomoniasis annually, making it the most prevalent non-viral, sexually transmitted disease. Trichomoniasis treatment relies on nitroheterocyclics, such as metronidazole. However, with increasing drug-resistance, there is an urgent need for novel anti-trichomonals. Little progress has been made to translate anti-trichomonal research into commercialised therapeutics, and the absence of a standardised compound-screening platform is the immediate stumbling block for drug-discovery. Herein, we describe a simple, cost-effective growth assay for T. vaginalis and the related Tritrichomonas foetus. Tracking changes in pH were a valid indicator of trichomonad growth (T. vaginalis and T. foetus), allowing development of a miniaturised, chromogenic growth assay based on the phenol red indicator in 96- and 384-well microtiter plate formats. The outputs of this assay can be quantitatively and qualitatively assessed, with consistent dynamic ranges based on Z′ values of 0.741 and 0.870 across medium- and high-throughput formats, respectively. We applied this high-throughput format within the largest pure-compound microbial metabolite screen (812 compounds) for T. vaginalis and identified 43 hit compounds. We compared these identified compounds to mammalian cell lines, and highlighted extensive overlaps between anti-trichomonal and anti-tumour activity. Lastly, observing nanomolar inhibition of T. vaginalis by fumagillin, and noting this compound has reported activity in other protists, we performed in silico analyses of the interaction of fumagillin with its molecular target methionine aminopeptidase 2 for T. vaginalis, Giardia lamblia and Entamoeba histolytica, highlighting potential for fumagillin as a broad-spectrum anti-protistal against microaerophilic protists. Together, this new platform will accelerate drug-discovery efforts, underpin drug-resistance screening in trichomonads, and contributing to a growing body of evidence highlighting the potential of microbial natural products as novel anti-protistals., Graphical abstract Image 1

Background Micro-arteriovenous malformations (micro-AVMs) are defined as AVMs just visible on angiography with a nidus size between 0.5 and 1 cm. Their principal manifestation is intracranial hemorrhage and their diagnosis and therapeutic management are still unclear. Methods The aim of our work was to show the clinical presentation, treatment and outcome of ruptured cerebral micro-AVMs in a retrospective cohort study of 19 patients and a systematic review of the literature. Results We obtained a total of 20 micro-AVMs in 19 patients. The mean age was 47.3 years. Clinical presentation was acute bleeding. The mean volume of hematoma was 12.9 mm3 (0 - 60.4), with topographic distribution as follows: 64% cortical with supratentorial bleeding, 26% deep, and 10% in the posterior fossa. Among the 20 micro-AVMs of the series, 11 (55%) had endovascular management, 6 (30%) had surgical treatment and 3 (15%) had GK radiosurgery alone. All of our patients have been cured at the end of the follow up without re-permeabilization. In our series, clinical outcome showed good recovery with a mean score of 4.6 on Glasgow Outcome Scale (GOS). In the literature, 88% of patients had a GOS of 4 or 5. Discussion Intracerebral hematoma (ICH) was the main clinical manifestation. In the case of negative initial angiographic assessment, patients must have supraselective angiographic exploration. In the case of conservative treatment of hematoma, endovascular obliteration and microsurgical exclusion seems to be reasonable therapeutic options, according to our observations.

Supplemental Digital Content is available in the text., Background: Cardiac involvement among hospitalized patients with severe coronavirus disease 2019 (COVID-19) is common and associated with adverse outcomes. This study aimed to determine the prevalence and clinical implications of COVID-19 cardiac involvement in young competitive athletes. Methods: In this prospective, multicenter, observational cohort study with data from 42 colleges and universities, we assessed the prevalence, clinical characteristics, and outcomes of COVID-19 cardiac involvement among collegiate athletes in the United States. Data were collected from September 1, 2020, to December 31, 2020. The primary outcome was the prevalence of definite, probable, or possible COVID-19 cardiac involvement based on imaging definitions adapted from the Updated Lake Louise Imaging Criteria. Secondary outcomes included the diagnostic yield of cardiac testing, predictors for cardiac involvement, and adverse cardiovascular events or hospitalizations. Results: Among 19 378 athletes tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, 3018 (mean age, 20 years [SD, 1 year]; 32% female) tested positive and underwent cardiac evaluation. A total of 2820 athletes underwent at least 1 element of cardiac triad testing (12-lead ECG, troponin, transthoracic echocardiography) followed by cardiac magnetic resonance imaging (CMR) if clinically indicated. In contrast, primary screening CMR was performed in 198 athletes. Abnormal findings suggestive of SARS-CoV-2 cardiac involvement were detected by ECG (21 of 2999 [0.7%]), cardiac troponin (24 of 2719 [0.9%]), and transthoracic echocardiography (24 of 2556 [0.9%]). Definite, probable, or possible SARS-CoV-2 cardiac involvement was identified in 21 of 3018 (0.7%) athletes, including 15 of 2820 (0.5%) who underwent clinically indicated CMR (n=119) and 6 of 198 (3.0%) who underwent primary screening CMR. Accordingly, the diagnostic yield of CMR for SARS-CoV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR (15 of 119 [12.6%]) versus a primary screening CMR (6 of 198 [3.0%]). After adjustment for race and sex, predictors of SARS-CoV-2 cardiac involvement included cardiopulmonary symptoms (odds ratio, 3.1 [95% CI, 1.2, 7.7]) or at least 1 abnormal triad test result (odds ratio, 37.4 [95% CI, 13.3, 105.3]). Five (0.2%) athletes required hospitalization for noncardiac complications of COVID-19. During clinical surveillance (median follow-up, 113 days [interquartile range=90 146]), there was 1 (0.03%) adverse cardiac event, likely unrelated to SARS-CoV-2 infection. Conclusions: SARS-CoV-2 infection among young competitive athletes is associated with a low prevalence of cardiac involvement and a low risk of clinical events in short-term follow-up.

Objective Patients with rheumatoid arthritis (RA) in whom remission is achieved following combination therapy with methotrexate plus etanercept face an ongoing medication burden. This study was undertaken to investigate whether sustained remission achieved on combination therapy can be maintained with either methotrexate or etanercept monotherapy, as assessed following discontinuation of one or the other medication from the combination. Methods Of the 371 adult patients with RA who received combination therapy with methotrexate plus etanercept, remission (defined as a Simplified Disease Activity Index [SDAI] score of ≤3.3) was sustained in 253 patients through a 24‐week open‐label period. These 253 patients then entered a 48‐week, double‐blind period and were randomized to receive either 1) methotrexate monotherapy (n = 101), 2) etanercept monotherapy (n = 101), or 3) methotrexate plus etanercept combination therapy (n = 51). Patients who subsequently experienced disease‐worsening received rescue therapy with the combination regimen at the same dosages as used in the initial run‐in period. The primary end point was the proportion of patients in whom SDAI‐defined remission was maintained without disease‐worsening at week 48 in the etanercept monotherapy group as compared to the methotrexate monotherapy group. Secondary end points included time to disease‐worsening, and the proportion of patients in whom SDAI‐defined remission was recaptured after initiation of rescue therapy. Results Baseline demographic and clinical characteristics of the RA patients were similar across the treatment groups. At week 48, SDAI‐defined remission was maintained in significantly more patients in the etanercept monotherapy group than in the methotrexate monotherapy group (49.5% versus 28.7%; P = 0.004). Moreover, as a secondary end point, sustained SDAI‐defined remission was achieved in significantly more patients who received combination therapy than in those who received methotrexate monotherapy (52.9% versus 28.7%; P = 0.006). Time to disease‐worsening was shorter in those who received methotrexate monotherapy than in those who received etanercept monotherapy or those who received combination therapy (each P < 0.001 versus methotrexate monotherapy). Among the patients who received rescue therapy, SDAI‐defined remission was recaptured in 70–80% in each treatment group. No new safety signals were reported. Conclusion The efficacy of etanercept monotherapy was superior to that of methotrexate monotherapy and similar to that of combination therapy in maintaining remission in patients with RA. SDAI‐defined remission was recaptured in most of the patients who were given rescue therapy. These data could inform decision‐making when withdrawal of therapy is being considered to reduce treatment burden in patients with well‐controlled RA.

OBJECTIVE To determine whether high or low adiposity is associated with youth sport-related injury. DATA SOURCES Ten electronic databases were searched to identify prospective studies examining the association between adiposity [body mass index (BMI) or body fat] and a future time-loss or medical attention sport-related musculoskeletal injury or concussion in youth aged 20 years and younger. Two independent raters assessed the quality (Downs and Black criteria) and risk of bias (Joanna Briggs Institute Critical Appraisal Tool). Random-effects meta-analyses were used to calculate pooled odds ratio [95% confidence interval (CI)] of injury. MAIN RESULTS Of 11 424 potentially relevant records, 38 articles were included with 17 eligible for meta-analyses. In qualitative synthesis, no clear association was identified between adiposity and any sport injury; however, 16/22 studies identified high adiposity as a significant risk factor for lower-extremity injury. Meta-analyses revealed higher BMI in youth with any sport-related injury and lower BMI in youth who developed a bone stress injury (BSI) compared with noninjured controls. The pooled OR (95% CI) examining the association of BMI and injury risk (excluding bone injury) was 1.18 (95% CI: 1.03-1.34). A major source of bias in included articles was inconsistent adjustment for age, sex, and physical activity participation. CONCLUSIONS Level 2b evidence suggests that high BMI is associated with greater risk of youth sport injury, particularly lower-extremity injury and excluding BSI or fracture. Although pooled mean differences were low, anthropometric risk of injury seems to be dependent on type and site of injury in youth sport.

BackgroundForkhead transcription factors control cell growth in multiple cancer types.Foxd1is essential for kidney development and mitochondrial metabolism, but its significance in renal cell carcinoma (ccRCC) has not been reported.MethodsTranscriptome data from the TCGA database was used to correlateFOXD1expression with patient survival.FOXD1was knocked out in the 786-O cell line and known targets were analyzed. Reduced cell growth was observed and investigated in vitro using growth rate and Seahorse XF metabolic assays and in vivo using a xenograft model. Cell cycle characteristics were determined by flow cytometry and immunoblotting. Immunostaining for TUNEL and γH2AX was used to measure DNA damage. Association of theFOXD1pathway with cell cycle progression was investigated through correlation analysis using the TCGA database.ResultsFOXD1expression level in ccRCC correlated inversely with patient survival. Knockout ofFOXD1in 786-O cells altered expression of FOXD1 targets, particularly genes involved in metabolism (MICU1) and cell cycle progression. Investigation of metabolic state revealed significant alterations in mitochondrial metabolism and glycolysis, but no net change in energy production. In vitro growth rate assays showed a significant reduction in growth of 786-OFOXD1null. In vivo, xenografted 786-OFOXD1nullshowed reduced capacity for tumor formation and reduced tumor size. Cell cycle analysis showed that 786-OFOXD1nullhad an extended G2/M phase. Investigation of mitosis revealed a deficiency in phosphorylation of histone H3 in 786-OFOXD1null, and increased DNA damage. Genes correlate withFOXD1in the TCGA dataset associate with several aspects of mitosis, including histone H3 phosphorylation.ConclusionsWe show that FOXD1 regulates the cell cycle in ccRCC cells by control of histone H3 phosphorylation, and that FOXD1 expression governs tumor formation and tumor growth. Transcriptome analysis supports this role for FOXD1 in ccRCC patient tumors and provides an explanation for the inverse correlation between tumor expression ofFOXD1and patient survival. Our findings reveal an important role for FOXD1 in maintaining chromatin stability and promoting cell cycle progression and provide a new tool with which to study the biology of FOXD1 in ccRCC.

Introduction Surrey Downs Health and Care (SDHC) is an innovative partnership consisting of the acute trust, community provider, three local GP federations and local authority. Together they deliver integrated health and care services for the Surrey Downs population. In April 2019, SDHC formally took over the management of an acute escalation ward at Epsom General Hospital. The aim was to redesign the model of care to offer a more integrated approach towards the management of patients with frailty. Method A change in leadership with interface frailty consultants developing an integrated multidisciplinary team (MDT) with reassignment of community staff. All members of the MDT had an equal voice and this helped develop the one team ethos. There were many developments along the way, but key changes included the agreement that a patients’ time is the most valuable currency and that we should be changing conversations from “what is the matter with you?” to “what matters most to you?” Results 1. A 100% increase in average daily discharges 2. An increase to 70% being discharged to their own home, versus 20% previously 3. A reduction from an average length of stay of 40 days to 13 days compared to the same time last year 4. Reduced 30-day readmissions at 15% versus previous average of 25%. Conclusion By blurring boundaries between the acute and community, allowed a frictionless pathway for patients. This has led to improvement in patient care and outcomes for the patient and system as a whole.

There is significant uncertainty about the potential role of temperature control in the intensive care unit (ICU) in general, but more specifically in septic shock patients.1,2 Common techniques for temperature control have been limited by minimal effect (eg, paracetamol, fans or air blankets), undesirable side effects (eg, non-steroidal anti-inflammatories), or being burdensome (eg, heavy sedation, paralysis with surface cooling; intravascular cooling devices3). In contrast, the potential of newer-generation surface-cooling devices to achieve temperature control more simply has created the possibility of studying temperature modulation in the septic ICU population.

There is considerable heterogeneity across the findings of systematic reviews of oral nutritional supplement (ONS) interventions, presenting difficulties for healthcare decision-makers and patients alike. It is not known whether heterogeneity arises from differences in patient populations or relates to methodological rigor. This overview aimed to collate and compare findings from systematic reviews of ONSs compared with routine care in adult patients who were malnourished or at risk of malnutrition with any clinical condition and to examine their methodological quality. Three electronic databases were searched to July 2019, supplemented with hand-searching. Data on all outcomes were extracted and review methodological quality assessed using A MeaSurement Tool for Assessment of systematic Reviews (AMSTAR). Twenty-two reviews were included, 11 in groups from mixed clinical backgrounds and 11 in specific clinical conditions. Ninety-one meta-analyses were identified for 12 different outcomes but there was discordance between results. Significant benefits of ONSs were reported in 4 of 4 analyses of energy intake, 7 of 11 analyses of body weight, 7 of 22 analyses of mortality, 10 of 17 analyses of complications (total and infectious), 1 of 3 analyses of muscle strength, 4 of 9 analyses of body composition/nutritional status, 2 of 14 analyses of length of stay, and 2 of 5 analyses of hospital readmissions. Ten reviews were high quality (AMSTAR scores 8-11), 9 moderate (AMSTAR scores 3-8), and 3 poor (AMSTAR scores 0-3). Methodological deficiencies were limitations to searches, poor reporting of heterogeneity, and failure to incorporate quality of evidence into any recommendations. Discordance between reviews was not markedly reduced when only high-quality reviews were considered. Evidence for the effects of ONS in malnourished patients or those who are at risk of malnutrition is uncertain, and discordance in results can arise from differences in clinical background of patients or the etiological basis of malnutrition.

Background Randomized studies have shown low compliance to adjuvant chemotherapy in rectal cancer patients receiving preoperative chemotherapy and external beam radiation (CT/EBRT) with total mesorectal excision. We hypothesize that giving neoadjuvant CT before local treatment would improve CT compliance. Methods Between 2010–2017, 180 patients were randomized (2:1) to either Arm A (AA) with FOLFOX x6 cycles prior to high dose rate brachytherapy (HDRBT) and surgery plus adjuvant FOLFOX x6 cycles, or Arm B (AB), with neoadjuvant HDRBT with surgery and adjuvant FOLFOX x12 cycles. The primary endpoint was CT compliance to ≥85% of full-dose CT for the first six cycles. Secondary endpoints were ypT0N0, five-year disease free survival (DFS), local control and overall survival (OS). Results Patients were randomized to either AA (n = 120, median age (MA) 62 years) or AB (n = 60, MA 63 years). 175/180 patients completed HDRBT as planned (97.2%). In AA, two patients expired during CT; three patients post-randomization received short course EBRT because of progression under CT (n = 2, AA) or personal preference (n = 1, AB). ypT0N0 was 31% in AA and 28% in AB (p = 0.7). CT Compliance was 80% in AA and 53% in AB (p = 0.0002). Acute G3/G4 toxicity was 35.8% in AA and 27.6% in AB (p = 0.23). With a median follow-up of 48.5 months (IQR 33–72), the five-year DFS was 72.3% with AA and 68.3% with AB (p = 0.74), the five-year OS 83.8% for AA and 82.2% for AB (p = 0.53), and the five-year local recurrence was 6.3% for AA and 5.8% for AB (p = 0.71). Conclusion We confirmed improved compliance to neoadjuvant CT in this study. Although there is no statistical difference in ypT0N0 rate, local recurrence, and DFS between the two arms, a trend towards favourable oncological outcomes is observed.

Cystic fibrosis (CF) is caused by a mutation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene, which disrupts an ion channel involved in hydration maintenance via anion homeostasis. Nearly 5% of CF patients possess one or more copies of the G542X allele, which results in a stop codon at residue 542, preventing full-length CFTR protein synthesis. Identifying small-molecule modulators of mutant CFTR biosynthesis that affect the readthrough of this and other premature termination codons to synthesize a fully functional CFTR protein represents a novel target area of drug discovery. We describe the implementation and integration for large-scale screening of a homogeneous, 1536-well functional G542X-CFTR readthrough assay. The assay uses HEK 293 cells engineered to overexpress the G542X-CFTR mutant, whose functional activity is monitored with a membrane potential dye. Cells are co-incubated with a CFTR amplifier and CFTR corrector to maximize mRNA levels and trafficking of CFTR to the cell surface. Compounds that allow translational readthrough and synthesis of functional CFTR chloride channels are reflected by changes in membrane potential in response to cAMP stimulation with forskolin and CFTR channel potentiation with genistein. Assay statistics yielded Z′ values of 0.69 ± 0.06. As further evidence of its suitability for high-throughput screening, we completed automated screening of approximately 666,000 compounds, identifying 7761 initial hits. Following secondary and tertiary assays, we identified 188 confirmed hit compounds with low and submicromolar potencies. Thus, this approach takes advantage of a phenotypic screen with high-throughput scalability to identify new small-molecule G542X-CFTR readthrough modulators.

We evaluated interleukin-6 (IL-6) receptor-α subunit (IL-6Rα) signaling inhibition with sarilumab and tocilizumab, the association between IL-6Rα receptor occupancy (RO) and C-reactive protein (CRP), and the potential clinical relevance of any differences. For this, we measured IL-6Rα binding and signaling inhibition with sarilumab and tocilizumab in vitro, simulated soluble IL-6Rα RO over time for approved sarilumab subcutaneous (SC) and tocilizumab intravenous (IV) and SC doses, and assessed associations between calculated RO and CRP reduction, 28-joint Disease Activity Score based on CRP, and 20%/50%/70% improvement in American College of Rheumatology responses from clinical data. Sarilumab binds IL-6Rα in vitro with 15- to 22-fold higher affinity than tocilizumab, and inhibits IL-6–mediated classical and trans signaling via membrane-bound and soluble IL-6Rα. Sarilumab 200 and 150 mg SC every 2 weeks achieved >90% RO after first and second doses, respectively, maintained throughout the treatment period. At steady-state trough, RO was greater with sarilumab 200 mg (98%) and 150 mg SC every 2 weeks (94%), and tocilizumab 162 mg SC weekly (>99%) and 8 mg/kg IV every 4 weeks (99%), vs tocilizumab 162 mg SC every 2 weeks (84%) and 4 mg/kg IV every 4 weeks (60%). Higher RO was associated with greater CRP reduction and 28-joint Disease Activity Score based on CRP reduction, and more sarilumab patients achieving 20%/50%/70% improvement in American College of Rheumatology responses. The greatest reduction in CRP levels was observed with sarilumab (both doses) and tocilizumab 8 mg/kg IV every 4 weeks (reductions proportionally smaller with 4 mg/kg IV every 4 weeks). Higher IL-6Rα binding affinity translated into higher RO with sarilumab vs tocilizumab 4 mg/kg every 4 weeks or 162 mg every 2 weeks; tocilizumab required the higher dose or increased frequency to maintain the same degree of RO and CRP reduction. Higher RO was associated with clinical parameter improvements.

Vaccination of at-risk populations against Neisseria meningitidis is an important strategy to prevent invasive meningococcal disease (IMD). The objective of this study was to characterize preexisting risk factors in patients with IMD and to compare their relative importance. This case-control analysis was performed in the French national public health insurance database (SNDS). Cases consisted of all people hospitalized for IMD in France over a six-year period (2012–2017). Controls were matched by age, gender, and district of residence. Medical risk factors were identified from ICD-10 codes in the SNDS. Socioeconomic risk factors studied were low household income and social deprivation of the municipality of residence. Associations of these risk factors with hospitalization for IMD were quantified as odds ratios (ORs) between cases and controls with their 95% confidence intervals (95%CI). The medical risk factors showing the most robust associations were congenital immunodeficiency (OR: 39.1 [95%CI: 5.1–299], acquired immunodeficiency (10.3 [4.5–24.0]) and asplenia/hyposplenia (6.7 [3.7–14.7]). In addition, certain chronic medical conditions, such as autoimmune disorders (5.4 [2.5–11.8]), hemophilia (4.7 [1.8–12.2]) and severe chronic respiratory disorders (4.3 [3.1–6.2]) were also strongly associated, as was low household income (1.68 [1.49–1.80]). In conclusion, this study has documented potential risk factors associated with hospitalization for IMD in a large and comprehensive sample of individuals with IMD in France. Several of the risk factors identified may help identify groups who could benefit from targeted prevention measures (such as vaccination) in order to reduce the burden of IMD.

Baricitinib is an oral selective inhibitor of Janus kinase (JAK)1 and JAK2 that has proved effective and well tolerated in the treatment of rheumatoid arthritis (RA) in an extensive programme of clinical studies of patients with moderate-to-severe disease. In a phase 2b dose-ranging study of baricitinib in combination with traditional disease-modifying antirheumatic drugs (DMARDs) in RA patients, magnetic resonance imaging showed that baricitinib 2 mg or 4 mg once daily provided dose-dependent suppression of synovitis, osteitis, erosion and cartilage loss at weeks 12 and 24 versus placebo. These findings correlated with clinical outcomes and were confirmed in three phase 3 studies (RA-BEGIN, RA-BEAM and RA-BUILD) using X-rays to assess structural joint damage. In patients naïve to DMARDs (RA-BEGIN study), baricitinib 4 mg once daily as monotherapy or combined with methotrexate produced smaller mean changes in structural joint damage than methotrexate monotherapy at week 24. Differences versus methotrexate were statistically significant for combined therapy. In patients responding inadequately to methotrexate (RA-BEAM study), baricitinib 4 mg plus background methotrexate significantly inhibited structural joint damage at week 24 versus placebo, and the results were comparable to those observed with adalimumab plus background methotrexate. In patients responding inadequately to conventional synthetic DMARDs (csDMARDs; RA-BUILD study), baricitinib 4 mg again significantly inhibited radiographic progression compared with placebo at week 24. Benefits were also observed with baricitinib 2 mg once daily, but the effects of baricitinib 4 mg were more robust. The positive effects of baricitinib 4 mg on radiographic progression continued over 1 and 2 years in the long-term extension study RA-BEYOND, with similar effects to adalimumab and significantly greater effects than placebo. Findings from the phase 3 studies of patients with RA were supported by preclinical studies, which showed that baricitinib has an osteoprotective effect, increasing mineralisation in bone-forming cells. In conclusion, baricitinib 4 mg once daily inhibits radiographic joint damage progression in patients with moderate-to-severe RA who are naïve to DMARDs or respond inadequately to csDMARDs, including methotrexate, and the beneficial effects are similar to those observed with adalimumab. Supplementary information Supplementary information accompanies this paper at 10.1186/s13075-020-02379-6.

Guidelines endorse the use of chemoprevention for breast cancer risk reduction. This study examined the barriers and facilitators to chemoprevention use for Australian women at increased risk of breast cancer, and their clinicians. Surveys, based on the Theoretical Domains Framework, were mailed to 1,113 women at ≥16% lifetime risk of breast cancer who were enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer cohort study (kConFab), and their 524 treating clinicians. Seven hundred twenty-five women (65%) and 221 (42%) clinicians responded. Only 10 (1.4%) kConFab women had ever taken chemoprevention. Three hundred seventy-eight (52%) kConFab women, two (3%) breast surgeons, and 51 (35%) family physicians were not aware of chemoprevention. For women, the strongest barriers to chemoprevention were side effects (31%) and inadequate information (23%), which operate in the Theoretical Domains Framework domains of “beliefs about consequences” and “knowledge,” respectively. Strongest facilitators related to tamoxifen's long-term efficacy (35%, “knowledge,” “beliefs about consequences,” and “goals” domains), staying healthy for family (13%, “social role” and “goals” domains), and abnormal breast biopsy (13%, “environmental context” domain). The strongest barrier for family physicians was insufficient knowledge (45%, “knowledge” domain) and for breast surgeons was medication side effects (40%, “beliefs about consequences” domain). The strongest facilitators for both clinician groups related to clear guidelines, strong family history, and better tools to select patients (“environmental context and resources” domain). Clinician knowledge and resources, and beliefs about the side-effect consequences of chemoprevention, are key domains that could be targeted to potentially enhance uptake. Prevention Relevance: Despite its efficacy in reducing breast cancer incidence, chemoprevention is underutilised. This survey study of Australian women and their clinicians used behavioural change theory to identify modifiable barriers to chemoprevention uptake, and to suggest interventions such as policy change, educational resources and public campaigns, that may increase awareness and use. See related Spotlight by Vogel, p. 1

Introduction: A nutrient-dense, plant-rich diet may be promising as a nutrition intervention for pregnant women for a number of factors. Factors include the possibility of a decreased risk for gestational diabetes, excess weight gain, and preeclampsia. Little is known about the experience of following this type of dietary pattern while pregnant and what barriers are present that should be addressed in a large-scale intervention. Methods: Qualitative interviews were used to understand the personal experience of women who aimed to eat a nutrient-dense plant-rich diet while pregnant. Semi-structured interviews were conducted from June to August 2020. Results: Three main themes regarding a nutrient-dense plant-rich diet emerged. First, family and social influence played an important role. Second, women who had a previous pregnancy felt they had fewer pregnancy symptoms on this diet. Last, the participants may have experienced a reduced milk supply on this dietary plan. Conclusion: Future research should consider family context as a factor in adherence to a nutrient-dense plant-rich dietary pattern, investigate the possible associations between nutrient-dense plant-rich dietary patterns and reduced nausea and vomiting in early pregnancy, and determine whether nutrient-dense, plant-rich dietary patterns contribute to a reduction in milk production for women who experience over-engorgement.

Background We developed a colorectal cancer risk prediction tool (‘CRISP’) to provide individualised risk-based advice for colorectal cancer screening. Using known environmental, behavioural, and familial risk factors, CRISP was designed to facilitate tailored screening advice to patients aged 50 to 74 years in general practice. In parallel to a randomised controlled trial of the CRISP tool, we developed and evaluated an evidence-based implementation strategy. Methods Qualitative methods were used to explore the implementation of CRISP in general practice. Using one general practice in regional Victoria, Australia, as a ‘laboratory’, we tested ways to embed CRISP into routine clinical practice. General practitioners, nurses, and operations manager co-designed the implementation methods with researchers, focussing on existing practice processes that would be sustainable. Researchers interviewed the staff regularly to assess the successfulness of the strategies employed, and implementation methods were adapted throughout the study period in response to feedback from qualitative interviews. The Consolidated Framework for Implementation Research (CFIR) underpinned the development of the interview guide and intervention strategy. Coding was inductive and themes were developed through consensus between the authors. Emerging themes were mapped onto the CFIR domains and a fidelity checklist was developed to ensure CRISP was being used as intended. Results Between December 2016 and September 2019, 1 interviews were conducted, both face-to-face and via videoconferencing (Zoom). All interviews were transcribed verbatim and coded. Themes were mapped onto the following CFIR domains: (1) ‘characteristics of the intervention’: CRISP was valued but time consuming; (2) ‘inner setting’: the practice was open to changing systems; 3. ‘outer setting’: CRISP helped facilitate screening; (4) ‘individual characteristics’: the practice staff were adaptable and able to facilitate adoption of new clinical processes; and (5) ‘processes’: fidelity checking, and education was important. Conclusions These results describe a novel method for exploring implementation strategies for a colorectal cancer risk prediction tool in the context of a parallel RCT testing clinical efficacy. The study identified successful and unsuccessful implementation strategies using an adaptive methodology over time. This method emphasised the importance of co-design input to make an intervention like CRISP sustainable for use in other practices and with other risk tools.

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in alleviating movement disability in patients with Parkinson’s disease (PD). However, its therapeutic mechanism of action is unknown. The healthy striatum exhibits rich dynamics resulting from an interaction of beta, gamma and theta oscillations. These rhythms are at the heart of selection, initiation and execution of motor programs, and their loss or exaggeration due to dopamine (DA) depletion in PD is a major source of the behavioral deficits observed in PD patients. Interrupting abnormal rhythms and restoring the interaction of rhythms as observed in the healthy striatum may then be instrumental in the therapeutic action of DBS. We develop a biophysical networked model of a BG pathway to study how abnormal beta oscillations can emerge throughout the BG in PD, and how DBS can restore normal beta, gamma and theta striatal rhythms. Our model incorporates STN projections to the striatum, long known but understudied, that were recently shown to preferentially target fast spiking interneurons (FSI) in the striatum. We find that DBS in STN is able to normalize striatal medium spiny neuron (MSN) activity by recruiting FSI dynamics, and restoring the inhibitory potency of FSIs observed in normal condition. We also find that DBS allows the re-expression of gamma and theta rhythms, thought to be dependent on high DA levels and thus lost in PD, through cortical noise control. Our study shows how BG connectivity can amplify beta oscillations, and delineates the role of DBS in disrupting beta oscillations and providing corrective input to STN efferents to restore healthy striatal dynamics. It also suggests how gamma oscillations can be leveraged to enhance or supplement DBS treatment and improve its effectiveness.

Aims: Overall survival (OS) of patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) is extremely poor. New therapeutic options emerge but need to establi...

OBJECTIVE: Loss of control over eating (LOC) is common among women, particularly those with overweight and obesity (OV/OB), and predicts weight gain. Given the importance of understanding weight and eating behaviors during pregnancy, we sought to characterize LOC across pregnancy and the postpartum period among women with pre-pregnancy OV/OB. METHODS: Pregnant women (N = 257; 28.44 ± 5.48 years old) with self-reported OV/OB prior to pregnancy were interviewed using a pregnancy-adapted version of the Eating Disorder Examination (EDE-PV). Pre-pregnancy LOC was retrospectively assessed during the first trimester and then prospectively assessed monthly throughout pregnancy and postpartum over the course of seven assessments. RESULTS: Rates of LOC were significantly higher during pregnancy compared to prior to ([Formula: see text] , p < .01) and after ([Formula: see text] , p < .01) pregnancy, with 37% (n = 95) of women reporting ≥1 LOC episode during pregnancy. LOC during pregnancy was associated with higher likelihood of LOC postpartum. Higher age (OR = 1.084, p = .04) and identifying as a minority (OR = 0.344, p = .02) was associated with greater likelihood of experiencing LOC during pregnancy only. DISCUSSION: LOC during pregnancy is common among women with pre-pregnancy OV/OB, suggesting that screening and intervention for LOC during pregnancy may be warranted. Future research is necessary to examine the relationship between LOC during pregnancy and maternal and infant health outcomes.

Objectives To evaluate real-world efficacy of approved JAK inhibitors (JAKi) tofacitinib and baricitinib in a large, single-centre cohort of RA patients across the treatment pathway, including those refractory to multiple biologic drugs. Methods All RA patients, treated with tofacitinib (from time of compassionate access scheme) or baricitinib since approval in 2017 had DAS28-CRP scores and components recorded at baseline, 3 and 6 months (with retrospective data for compassionate access scheme). Efficacy was evaluated in the total cohort, each treatment group, and subgroups of number of prior biologic classes failed. Results One hundred and fifteen patients were treated with a JAKi (tofacitinib 54, baricitinib 69, 8 both); 76.4% female; mean (s.d.) age 57.3 (14.3) years. On average patients had received three previous bDMARDs; 11 (9.6%) were bDMARD naïve. Combined group baseline DAS28-CRP (s.d.) 5.62(1.14) improved by 1.49(1.44) and 1.67(1.61) at 3 and 6 months, respectively, comparable in individual JAKi groups; with 24% in at least low disease activity at 3 months. The biggest improvement was observed in the biologic-naïve group (mean DAS28-CRP improved from 5.16–2.14 after 6 months); while those with prior exposure to minimum three bDMARD classes had DAS28-CRP improvement of >1.2. Five out of 8 patients treated with both JAKi sequentially responded. Twelve patients previously unresponsive to IL-6 blockade responded to JAKi. No unexpected safety events were recorded. Two cases of venous thromboembolism were observed. Conclusion JAK inhibition is effective in a real-world population of RA patients, including in a subset of patients refractory to multiple previous bDMARDs.

Introduction Detecting upper gastrointestinal (GI) cancers in primary care is challenging, as cancer symptoms are common, often non-specific, and most patients presenting with these symptoms will not have cancer. Substantial investment has been made to develop biomarkers for cancer detection, but few have reached routine clinical practice. We aimed to identify novel biomarkers for upper GI cancers which have been sufficiently validated to be ready for evaluation in low-prevalence populations. Methods We systematically searched MEDLINE, Embase, Emcare, and Web of Science for studies published in English from January 2000 to October 2019 (PROSPERO registration CRD42020165005). Reference lists of included studies were assessed. Studies had to report on second measures of diagnostic performance (beyond discovery phase) for biomarkers (single or in panels) used to detect pancreatic, oesophageal, gastric, and biliary tract cancers. We included all designs and excluded studies with less than 50 cases/controls. Data were extracted on types of biomarkers, populations and outcomes. Heterogeneity prevented pooling of outcomes. Results We identified 149 eligible studies, involving 22,264 cancer cases and 49,474 controls. A total of 431 biomarkers were identified (183 microRNAs and other RNAs, 79 autoantibodies and other immunological markers, 119 other proteins, 36 metabolic markers, 6 circulating tumour DNA and 8 other). Over half (n = 231) were reported in pancreatic cancer studies. Only 35 biomarkers had been investigated in at least two studies, with reported outcomes for that individual marker for the same tumour type. Apolipoproteins (apoAII-AT and apoAII-ATQ), and pepsinogens (PGI and PGII) were the most promising biomarkers for pancreatic and gastric cancer, respectively. Conclusion Most novel biomarkers for the early detection of upper GI cancers are still at an early stage of matureness. Further evidence is needed on biomarker performance in low-prevalence populations, in addition to implementation and health economic studies, before extensive adoption into clinical practice can be recommended. Electronic Supplementary Material The online version of this article (10.1007/s12325-020-01571-z) contains supplementary material, which is available to authorized users.

Background/Aims: Cognitive impairment is prevalent in older inpatients but may be unrecognized. Screening to identify cognitive deficits is therefore important to optimize care. The 10-point Abbreviated Mental Test Score (AMTS) is widely used in acute hospital settings but its reliability for mild versus more severe cognitive impairment is unknown. We therefore studied the AMTS versus the 30-point Montreal Cognitive Assessment (MoCA) in older (≥75 years) inpatients. Methods: The AMTS and MoCA were administered to consecutive hospitalized patients at ≥72 h after admission in a prospective observational study. MoCA testing time was recorded. Reliability of the AMTS for the reference standard defined as mild (MoCA