Mental health of non-binary youth: a systematic review and meta-analysis.

BACKGROUND: Non-binary identities are increasingly recognized within the spectrum of gender diversity, yet there is a dearth of research exploring the mental health challenges specific to this population. Therefore, this systematic review and meta-analysis aimed to comprehensively assess the mental health outcomes of non-binary youth in comparison to their transgender and cisgender peers. METHODS: A systematic search was conducted to identify relevant studies across three electronic databases (PubMed, Scopus, Web of Science) covering the period from inception to October 2023. The meta-analysis was performed employing a random-effects model. Inclusion criteria encompassed studies comparing non-binary youth with transgender or cisgender youth, providing data on mental health outcomes such as general mental health, depressive and anxiety symptoms, self-harm and suicidality. RESULTS: Twenty-one studies, meeting the inclusion criteria and originating from six different countries, were included in the analysis. The sample encompassed 16,114 non-binary, 11,925 transgender, and 283,278 cisgender youth, with ages ranging from 11 to 25 years. Our meta-analysis revealed that non-binary youth exhibit significantly poorer general mental health compared to both transgender (d = 0.24, 95% CI, 0.05-0.43, p =.013) and cisgender youth (d = 0.48, 95% CI, 0.35-0.61, p <.001), indicating a more impaired general mental health in non-binary youth. Regarding depressive symptoms, when comparing non-binary and cisgender individuals, a moderate and significant effect was observed (d = 0.52, 95% CI, 0.41-0.63, p <.001). For anxiety symptoms, a small but significant effect was observed in the comparison with cisgender individuals (d = 0.44, 95% CI, 0.19-0.68, p =.001). Furthermore, non-binary individuals exhibited lower rates of past-year suicidal ideation than transgender peers (OR = 0.79, 95% CI, 0.65-0.97, p =.023) and higher rates of lifetime suicidal ideation than cisgender youth (OR = 2.14, 95% CI, 1.46-3.13, p <.001). CONCLUSION: Non-binary youth face distinct mental health challenges, with poorer general mental health, elevated depressive and anxiety symptoms compared to cisgender, and similar rates of self-harm and suicidal behavior compared to transgender individuals. These findings underscore the urgent need for targeted interventions, including gender-affirming mental health support, to address the specific needs of non-binary youth.

Expansion in situ genome sequencing links nuclear abnormalities to hotspots of aberrant euchromatin repression.

Microscopy and genomics are both used to characterize cell function, but approaches to connect the two types of information are lacking, particularly at subnuclear resolution. While emerging multiplexed imaging methods can simultaneously localize genomic regions and nuclear proteins, their ability to accurately measure DNA-protein interactions is constrained by the diffraction limit of optical microscopy. Here, we describe expansion in situ genome sequencing (ExIGS), a technology that enables sequencing of genomic DNA and superresolution localization of nuclear proteins in single cells. We applied ExIGS to fibroblast cells derived from an individual with Hutchinson-Gilford progeria syndrome to characterize how variation in nuclear morphology affects spatial chromatin organization. Using this data, we discovered that lamin abnormalities are linked to hotspots of aberrant euchromatin repression that may erode cell identity. Further, we show that lamin abnormalities heterogeneously increase the repressive environment of the nucleus in tissues and aged cells. These results demonstrate that ExIGS may serve as a generalizable platform for connecting nuclear abnormalities to changes in gene regulation across disease contexts.

The Metabolic Programming of Pubertal Onset.

BACKGROUND: There is increasing evidence that maternal factors such as nutritional status (both under and over-nutrition) and diabetes, alongside prenatal exposure to endocrine disrupting chemicals (EDCs), are associated with early pubertal onset in offspring. Such children are also at increased risk of the metabolic syndrome during adolescence and young adulthood. AIM: This literature review focuses on the role of the prenatal environment in programming pubertal onset, and the impact of prenatal metabolic stressors on the declining average age of puberty. METHOD: A review of all relevant literature was conducted in PubMed by the authors. OUTCOME: The mechanism for this appears to be mediated through metabolic signals, such as leptin and insulin, on the kisspeptin-neuronal nitric oxide-gonadotropin releasing hormone (KiNG) axis. Exposed children have an elevated risk of childhood obesity and display a phenotype of hyperinsunlinaemia and hyperleptinaemia. These metabolic changes permit an earlier attainment of the nutritional "threshold" for puberty. Unfortunately, this cycle may be amplified across subsequent generations, however early intervention may help "rescue" progression of this programming.

Heron: Visualizing and Controlling Chemical Reaction Explorations and Networks.

Automated and high-throughput quantum chemical investigations into chemical processes have become feasible in great detail and broad scope. This results in an increase in complexity of the tasks and in the amount of generated data. An efficient and intuitive way for an operator to interact with these data and to steer virtual experiments is required. Here, we introduce Heron, a graphical user interface that allows for advanced human-machine interactions with quantum chemical exploration campaigns into molecular structure and reactivity. Heron offers access to interactive and automated explorations of chemical reactions with standard electronic structure modules, haptic force feedback, microkinetic modeling, and refinement of data by automated correlated calculations including black-box complete active space calculations. It is tailored to the exploration and analysis of vast chemical reaction networks. We show how interoperable modules enable advanced workflows and pave the way for routine low-entrance-barrier access to advanced modeling techniques.

Δ-Machine Learning to Elevate DFT-Based Potentials and a Force Field to the CCSD(T) Level Illustrated for Ethanol.

Progress in machine learning has facilitated the development of potentials that offer both the accuracy of first-principles techniques and vast increases in the speed of evaluation. Recently, Δ-machine learning has been used to elevate the quality of a potential energy surface (PES) based on low-level, e.g., density functional theory (DFT) energies and gradients to close to the gold-standard coupled cluster level of accuracy. We have demonstrated the success of this approach for molecules, ranging in size from H3O+ to 15-atom acetyl-acetone and tropolone. These were all done using the B3LYP functional. Here, we investigate the generality of this approach for the PBE, M06, M06-2X, and PBE0 + MBD functionals, using ethanol as the example molecule. Linear regression with permutationally invariant polynomials is used to fit both low-level and correction PESs. These PESs are employed for standard RMSE analysis for training and test data sets, and then general fidelity tests such as energetics of stationary points, normal-mode frequencies, and torsional potentials are examined. We achieve similar improvements in all cases. Interestingly, we obtained significant improvement over DFT gradients where coupled cluster gradients were not used to correct the low-level PES. Finally, we present some results for correcting a recent molecular mechanics force field for ethanol and comment on the possible generality of this approach.

A Case of Persistent Intra-Abdominal Stenotrophomonas maltophilia Infection Despite Bacteriophage Therapy.

Multidrug resistant infections are a challenge in the health care setting and a cause of patient morbidity and mortality. Bacteriophages (phages) are viruses that target and kill bacteria and have been used in patients to treat bacterial infections. We present a case of disseminated Stenotrophomonas maltophilia infection, with pulmonary, intra-abdominal and bloodstream involvement. The patient was treated with a combination of antibiotics and personalized phage therapy, administered daily for 12 days both intravenously as well as via intra-abdominal drains. Phage therapy was well-tolerated, the patient cleared S. maltophilia from their bloodstream and their intra-abdominal abscesses were stable or decreased in size. However, the intra-abdominal fluid cultures remained positive for S. maltophilia. Unfortunately, the patient passed away 2 months after completion of phage therapy due to multiorgan failure. These data highlight the difficulty of treating critically ill patients and clearing complex, biofilm mediated infections, even with phages. More information is needed regarding the optimal treatment protocols for phage therapy in complex multifocal infections.

The effect of alcohol, tobacco, and other drug use on vaccine acceptance, uptake, and adherence: a systematic review.

BACKGROUND: Vaccine hesitancy is increasingly recognized as a health challenge affecting populations worldwide. Given the biological vulnerabilities and structural barriers people who use substances and/or have behavioral addictions face, this systematic review aims to evaluate whether this subpopulation is less prone to adhere to vaccination recommendations. METHODS: Electronic searches of published original research were conducted in PubMed, EMBASE, Scopus, and PsycINFO from database inception to December 2022. Our strategy encompassed retrievals regardless of languages and date of publication. Animal studies, abstracts without a full manuscript, and studies which were considered to have lower robustness of scientific evidence were excluded. Outcomes measured were vaccine acceptance, uptake, and adherence. Results were interpreted through a narrative synthesis. RESULTS: The search yielded 103 retrievals encompassing data collected on 5 576 374 persons who were predominantly residents of Europe (n = 39) and North America (n = 27). Tobacco use, the substance for which many studies were found (n = 91), was significantly associated with poorer vaccine acceptance, uptake and adherence for influenza, COVID-19, human papillomavirus (HPV), and maternal and childhood vaccines. Peri-natal and parental substance use was identified as a risk factor for suboptimal vaccine-related outcomes concerning maternal COVID-19 and childhood vaccines. Finally, people identified as 'using', 'abusing', or 'misusing' drugs or substances may be at decreased odds of all outcomes in various vaccines. CONCLUSIONS: Collectively, the studies identified several groups with statistically significant greater vaccine hesitancy and decreased engagement among whom targeted measures could be beneficial. Timely evidence, especially on behavioral addictions and substances besides tobacco, is lacking, and warrants urgent attention.

A systematic review and meta-analysis on the efficacy of dialectical behavior therapy variants for the treatment of post-traumatic stress disorder.

Background: While there are well-established treatments for post-traumatic stress disorder (PTSD), these interventions appear to be less effective for individuals with comorbid borderline personality disorder (BPD) symptoms. Dialectical Behavior Therapy (DBT) for PTSD and DBT Prolonged Exposure (PE) are both effective interventions for treating these patients, but a comprehensive analysis evaluating the efficacy of these two interventions is lacking.Objective: To determine the effect sizes of PTSD-specific DBT treatments.Methods: We conducted a systematic review and pre-registered meta-analysis of the DBT literature for treating PTSD (osf.io/62rfq). Eligible trials and treatment evaluations published before September 2023 were searched in SCOPUS, PubMed, and the Cochrane Library databases. Thirteen articles were identified, and data were extracted for primary (PTSD symptoms) and secondary outcomes (BPD, depression, dissociation, non-suicidal self-injury [NSSI]). Treatment effects were calculated for randomised controlled trials, controlled clinical trials, and pre-post evaluations.Results: Overall, the studies involved 663 participants. Compared with control groups, PTSD-specific DBT treatments showed moderate effects in reducing PTSD symptom severity g = -0.69 (95% CI -1.03 to -0.34, p < .001) and depression g = -0.62 (95% CI -1.13 to -0.12, p = .016). Moreover, the pre-post changes showed an overall effect size for dissociative symptoms of g = -0.72 (95% CI -1.05 to -0.40, p < .001), for BPD-associated symptoms of g = -0.82 (95% CI -1.06 to -0.59, p < .001), and for NSSI frequency (g = -0.70, 95% CI -1.12 to -0.28, p = .001).Conclusions: Based on the results of our meta-analysis, DBT-PTSD and DBT PE were effective in reducing PTSD symptom severity and comorbid depressive symptoms. Further research on stage-based treatments should focus on systematically assessing NSSI, BPD symptoms, and suicidality.

We conducted the first meta-analysis assessing the efficacy of Dialectical Behavior Therapy for PTSD (DBT-PTSD) and Dialectical Behavior Therapy Prolonged Exposure (DBT PE) for individuals with comorbid PTSD and BPD symptoms.Based on RCTs/CCTs, we found moderately beneficial effects on PTSD symptoms, and depression for both stage-based interventions and large effects on non-suicidal self-injury frequency for DBT PE.DBT-PTSD and DBT PE resulted in pre-post improvements in dissociative symptoms, BPD-associated symptoms, and non-suicidal self-injury frequency.

Radiation therapy for HPV-Positive oropharyngeal squamous cell carcinoma: an ASTRO clinical practice guideline

Human Papilloma Virus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is a distinct disease from other head and neck tumors. This guideline provides evidence-based recommendations on the critical decisions in its curative treatment, including both definitive and postoperative radiation therapy (RT) management. ASTRO convened a task force to address 5 key questions on the use of RT for management of HPV-associated OPSCC. These questions included indications for definitive and postoperative RT and chemoradiation; dose-fractionation regimens and treatment volumes; preferred RT techniques and normal tissue considerations; and posttreatment management decisions. The task force did not address indications for primary surgery versus RT. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. Concurrent cisplatin is recommended for patients receiving definitive RT with T3-4 disease and/or 1 node >3 cm, or multiple nodes. For similar patients who are ineligible for cisplatin, concurrent cetuximab, carboplatin/5-fluorouracil, or taxane-based systemic therapy are conditionally recommended. In the postoperative setting, RT with concurrent cisplatin (either schedule) is recommended for positive surgical margins or extranodal extension. Postoperative RT alone is recommended for pT3-4 disease, >2 nodes, or a single node >3 cm. Observation is conditionally recommended for pT1-2 disease and a single node ≤3 cm without other risk factors. For patients treated with definitive RT with concurrent systemic therapy, 7000 cGy in 33 to 35 fractions is recommended, and for patients receiving postoperative RT without positive surgical margins and extranodal extension, 5600 to 6000 cGy is recommended. For all patients receiving RT, intensity modulated RT over 3-dimensional techniques with reduction in dose to critical organs at risk (including salivary and swallowing structures) is recommended. Reassessment with positron emission tomography-computed tomography is recommended approximately 3 months after definitive RT/chemoradiation, and neck dissection is recommended for convincing evidence of residual disease; for equivocal positron emission tomography-computed tomography findings, either neck dissection or repeat imaging is recommended. The role and practice of RT continues to evolve for HPV-associated OPSCC, and these guidelines inform best clinical practice based on the available evidence.

Opioid Prescriptions for US Patients Undergoing Long-Term Dialysis or with Kidney Transplant from 2011 to 2020.

BACKGROUND: Pain is important for patients with kidney failure, but opioid medication prescriptions are associated with morbidity and mortality. The Centers for Disease Control and Prevention issued opioid prescription guidelines in 2016 and 2022, associated with dramatically decreased prescription rates in the United States. It is critical to know if nationwide opioid prescription rates for patients with kidney failure have decreased. METHODS: We analyzed the USRDS database from 2011 to 2020 to describe trends in the proportion of ESKD patients who received one or more, or long-term opioid prescriptions, examined factors associated with long-term opioid prescriptions, and evaluated associations of all-cause death with short-term or long-term opioid prescriptions. RESULTS: From 2011-2022, the percentage of patients with kidney failure (dialysis and kidney transplant) who received at least one or more, or who had received long-term opioid medication prescriptions decreased steadily, from 60% to 42%, and from 23% to 13%, respectively (both P for trend <0.001). The largest reductions in prescription rates were for hydrocodone and oxycodone. Similar trends existed for dialysis and kidney transplant patients. Women, the poor and those in rural settings were more likely to receive long-term opioid prescriptions. Prescription rates were highest in White patients and those 45 to 64 years old. Short-term and long-term opioid medication prescriptions were associated with higher mortality in both dialysis and kidney transplant patients. CONCLUSIONS: ESKD patients' opioid prescription rates decreased between 2011 and 2020. Higher mortality risk was associated with both short-term and long-term opioid prescriptions. Mortality risk was monotonically associated with morphine milligram equivalents in patients with kidney failure who received long-term opioid prescriptions.

Young children's understanding and experience of insight.

An insight is a moment of sudden understanding followed by characteristic feelings of suddenness, positive affect, certainty, and ease, commonly known as an aha experience. Despite evidence from studies with adults that aha experiences benefit learning, little systematic research on children's aha experiences exists. The present study asks how children understand and experience insight. We presented a community sample of 160 children (age: 4-8 years, 47% girls, 51% boys, 2% nonbinary) with an illustrated clues task inspired by the Remote Associate Test, a task commonly used to study insight in adults. In this task, children saw three clues and were asked to find a solution word that was associated with the three clues. Self-reported and observed aha experiences were recorded, along with children's solution accuracy and confidence. Children also answered a set of questions to assess their understanding of aha experiences. We found that although the number of aha experiences remained stable across age, there was a clear developmental increase in the understanding of aha experiences. Children's ability to recognize their own aha experiences as well as their general understanding of the aha concept increased with age. This suggests a lag between the occurrence of children's aha experiences and their understanding of such experiences; children first have aha experiences and later develop an understanding of those experiences. Aha experiences were associated with higher accuracy, but not with higher confidence ratings. Observed aha experiences, but not self-reported aha experiences, predicted increased motivation. Our findings are in line with the literature on metacognitive development and the distinction between the experience and the understanding of emotion. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Pan-cancer genomic analysis reveals FOXA1 amplification is associated with adverse outcomes in non-small cell lung, prostate, and breast cancers.

INTRODUCTION: Alterations in forkhead box A1 (FOXA1), a pioneer transcription factor, are associated with poor prognosis in breast cancer (BC) and prostate cancer (PC). We characterized FOXA1 genomic alterations and their clinical impacts in a large pan-cancer cohort from the AACR GENIE database. METHODS: FOXA1 alterations were characterized across >87,000 samples from >30 cancer types for primary and metastatic tumors alongside patient characteristics and clinical outcomes. FOXA1 alterations were queried in the MSK-MET cohort (a GENIE subset), allowing definition of hazard ratios (HRs) and survival estimates based on Cox proportional hazard models. RESULTS: FOXA1 was altered in 1,869 samples (2.1%), with distinct patterns across different cancers: PC enriched with indel-inframe alterations, BC with missense mutations, and lung cancers with copy number (CN) amplifications.Of 74,715 samples with FOXA1 CN profiles, amplification was detected in 834 (1.1%). Amplification was most common in non-small cell lung cancer (NSCLC, 3% in primary; 6% in metastatic) and small cell lung cancer (4.1% primary; 3.5% metastatic), followed by BC (2% primary; 1.6% metastatic) and PC (2.2% primary; 1.6% metastatic).CN amplifications were associated with decreased overall survival in NSCLC (HR: 1.45, 95%CI: 1.06-1.99, p = .02), BC (HR: 3.04, 95%CI: 1.89-4.89, p = 4e-6), and PC (HR: 1.94, 95%CI: 1.03-3.68, p = .04). Amplifications were associated with wide-spread metastases in NSCLC, BC, and PC. CONCLUSIONS: FOXA1 demonstrates distinct alteration profiles across cancer sites. Our findings suggest an association between FOXA1 amplification and both enhanced metastatic potential and decreased survival, highlighting prognostic and therapeutic potential in breast cancer, prostate cancer, and NSCLC.

mRNA-delivery of IDO1 suppresses T cell-mediated autoimmunity.

Indoleamine-2,3-dioxygenase (IDO)1 degrades tryptophan, obtained through dietary intake, into immunoregulatory metabolites of the kynurenine pathway. Deficiency or blockade of IDO1 results in the enhancement of autoimmune severity in rodent models and increased susceptibility to developing autoimmunity in humans. Despite this, therapeutic modalities that leverage IDO1 for the treatment of autoimmunity remain limited. Here, we use messenger (m)RNA formulated in lipid nanoparticles (LNPs) to deliver a human IDO1 variant containing the myristoylation site of Src to anchor the protein to the inner face of the plasma membrane. This membrane-anchored IDO1 has increased protein production, leading to increased metabolite changes, and ultimately ameliorates disease in three models of T cell-mediated autoimmunity: experimental autoimmune encephalomyelitis (EAE), rat collagen-induced arthritis (CIA), and acute graft-versus-host disease (aGVHD). The efficacy of IDO1 is correlated with hepatic expression and systemic tryptophan depletion. Thus, the delivery of membrane-anchored IDO1 by mRNA suppresses the immune response in several well-characterized models of autoimmunity.

Transfer learning of hyperparameters for fast construction of anisotropic GPR models: design and application to the machine-learned force field FFLUX.

The polarisable machine-learned force field FFLUX requires pre-trained anisotropic Gaussian process regression (GPR) models of atomic energies and multipole moments to propagate unbiased molecular dynamics simulations. The outcome of FFLUX simulations is highly dependent on the predictive accuracy of the underlying models whose training entails determining the optimal set of model hyperparameters. Unfortunately, traditional direct learning (DL) procedures do not scale well on this task, especially when the hyperparameter search is initiated from a (set of) random guess solution(s). Additionally, the complexity of the hyperparameter space (HS) increases with the number of geometrical input features, at least for anisotropic kernels, making the optimization of hyperparameters even more challenging. In this study, we propose a transfer learning (TL) protocol that accelerates the training process of anisotropic GPR models by facilitating access to promising regions of the HS. The protocol is based on a seeding-relaxation mechanism in which an excellent guess solution is identified by rapidly building one or several small source models over a subset of the target training set before readjusting the previous guess over the entire set. We demonstrate the performance of this protocol by building and assessing the performance of DL and TL models of atomic energies and charges in various conformations of benzene, ethanol, formic acid dimer and the drug fomepizole. Our experiments suggest that TL models can be built one order of magnitude faster while preserving the quality of their DL analogs. Most importantly, when deployed in FFLUX simulations, TL models compete with or even outperform their DL analogs when it comes to performing FFLUX geometry optimization and computing harmonic vibrational modes.

Mode of application of sulfonated graphene modulated bioavailable heavy metal contents and microbial community composition in long-term heavy metal contaminated soil.

Nanomaterials are increasingly recognized for their potential in soil remediation. However, their impact on soil microbial communities in contaminated soil remains poorly understood. In this study, we investigated the dynamic effects of sulfonated graphene (SG) following one-time or repeated applications on heavy metal availability and soil microbial communities in long-term heavy metal-contaminated soil over 180 days. Our findings revealed that one-time SG application at 30 mg kg-1 significantly increased the bioavailable cadmium (Cd) and copper (Cu) contents by approximately 30 %-40 % after 2 and 180 days. Repeated SG applications, however, displayed no significant influence on heavy metal availability. One-time SG application, coupled with the increased available Cd, induced significant enrichment of some specific functional bacterial genera involved in glycan biosynthesis metabolism and biosynthesis of other secondary metabolites, thereby decreasing the available contents of heavy metals after 90 days. However, the shifts in bacterial community structure and function were subsequently partially recovered after 180 days. Conversely, repeated SG treatments led to minimal alterations after 90 days while leading to similar shifts in the bacterial community at 60 mg kg-1 after 180 days. The fungal community structure remained largely unaltered across all SG treatments. Intriguingly, SG treatments substantially stimulated fungal biomass, with the stimulation degree dependent on SG dosage. These results provide valuable insights for developing phytoremediation strategies, suggesting tailored SG applications during specific growth phases to optimize remediation efficiency.

The lysogenic filamentous Pseudomonas bacteriophage phage Pf slows mucociliary transport.

Pseudomonas aeruginosa is a major pulmonary pathogen causing chronic pulmonary infections in people with cystic fibrosis (CF). The P. aeruginosa filamentous and lysogenic bacteriophage, Pf phage, is abundant in the airways of many people with CF and has been associated with poor outcomes in a cross-sectional cohort study. Previous studies have identified roles for Pf phage in biofilm formation, specifically forming higher-order birefringent, liquid crystals when in contact with other biopolymers in biofilms. Liquid crystalline biofilms are more adherent and viscous than those without liquid crystals. A key feature of biofilms is to enhance bacterial adherence and resist physical clearance. The effect of Pf phage on mucociliary transport is unknown. We found that primary CF and non-CF nasal epithelial cells cultured at air-liquid interface treated with Pf phage exhibit liquid crystalline structures in the overlying mucus. On these cell cultures, Pf phage entangles cilia but does not affect ciliary beat frequency. In both these in vitro cell cultures and in an ex vivo porcine trachea model, introduction of Pf phage decreases mucociliary transport velocity. Pf phage also blocks the rescue of mucociliary transport by CF transmembrane conductance regulator modulators in CF cultures. Thus, Pf phage may contribute to the pathogenesis of P. aeruginosa-associated CF lung disease via induction of liquid crystalline characteristics to airway secretions, leading to impaired mucociliary transport. Targeting Pf phage may be useful in treatment CF as well as other settings of chronic P. aeruginosa infections.

Testosterone Recovery Following Androgen Suppression and Prostate Radiotherapy (TRANSPORT): A Pooled Analysis of Five Randomized Trials from the Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) Consortium.

BACKGROUND AND OBJECTIVE: Time to testosterone recovery (TR) following androgen deprivation therapy (ADT) with gonadotropin-releasing hormone agonists varies widely. We evaluate TR kinetics and the oncological impact of an effective castration period in patients receiving definitive radiotherapy and ADT for prostate cancer. METHODS: We obtained individual patient data from randomized controlled trials of radiotherapy with ADT and prospectively collected serial testosterone data from the MARCAP Consortium. We estimated the times to noncastrate TR (>1.7 nmol/l) and nonhypogonadal TR (>8.0 nmol/l) were estimated for each prescribed ADT duration, and developed corresponding nomograms. The association between effective castration period and metastasis-free survival (MFS) for any given ADT duration was evaluated via multivariable Cox regression. We conducted cubic spline analyses to assess nonlinear associations. KEY FINDINGS AND LIMITATIONS: We included 1444 men from five trials in the analysis, of whom 115 received 4 mo, 880 received 6 mo, 353 received 18 mo, 36 received 28 mo, and 60 received 36 mo of ADT. Times to noncastrate TR and to nonhypogonadal TR varied considerably by ADT duration. Higher baseline testosterone and lower age were associated with a higher likelihood of TR (p < 0.001 for both). Effective castration period was not linearly associated with MFS for any ADT duration on Cox regression. Cubic spline analysis revealed that the optimal effective castration period for an MFS benefit was 10.6 mo for men who received 6 mo of ADT and 18 mo for men who received 18 mo of ADT. CONCLUSIONS AND CLINICAL IMPLICATIONS: Time to TR varies according to the ADT duration, baseline testosterone, and age. The relationship between effective castration period and MFS may be nonlinear, with a longer effective castration period being helpful for men receiving 6 mo of ADT.

Implementing changing behaviour towards aerobic and strength exercise: Results of a randomised, phase I study determining the safety, feasibility, and consumer-evaluation of an online exercise program in persons with multiple sclerosis.

BACKGROUND: Many people with MS do not meet the recommended exercise regime to elicit health benefits. This study aimed to determine the feasibility, safety, acceptability, and appropriateness of an exercise intervention delivered online to persons with MS that meets current exercise recommendations and behaviour change principles. METHODS: Seventy-two participants (age: 43.3 ± 13.3 years) with mild to moderate MS were stratified according to previous exercise behaviour and block-randomised into one of three groups: Control (CON; n = 24), General Exercise (GE; n = 24) who at screening did not meet current exercise recommendations, and Advanced Exercise, (AE; n = 24) who at screening met the current exercise recommendations. GE and AE groups received a four-month online-supervised, behaviour change theory-based exercise program and were assessed at baseline, four-months, five-months, and eleven-months for physical activity participation. The feasibility of process, resources, management, and scientific outcomes was assessed. RESULTS: Of 198 potential participants, 143 met the eligibility criteria (72 %), and 72 were randomised. Fifty-three participants completed the intervention (74 % immediate retention), and 44 were retained at the six-month follow-up (61 %). Personnel time was 369 h, and total per-participant cost was Au$1036.20. Adherence rate to ≥70 % of exercise sessions was 73 % (GE) and 38 % (AE). The GE group observed a small magnitude of improvement in physical activity (d = -0.23). CONCLUSIONS: An online exercise program embedded with behaviour interventions for either GE or AE appears feasible, acceptable, appropriate and safe and may show long-term efficacy in increased exercise behaviours for persons with mild to moderate MS. TRIAL REGISTRATION: ANZCRT number ACTRN12619000228189p.

Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS, and previous findings indicate that case-control likelihood ratios (LRs) outperform odds ratios for variant classification. As an initiative of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Analytical Working Group we analyzed germline sequencing data of BRCA1 and BRCA2 from 96,691 female breast cancer cases and 303,925 unaffected controls from three studies: the BRIDGES study of the Breast Cancer Association Consortium, the Cancer Risk Estimates Related to Susceptibility consortium, and the UK Biobank. We observed 11,227 BRCA1 and BRCA2 variants, with 6,921 being coding, covering 23.4% of BRCA1 and BRCA2 VUS in ClinVar and 19.2% of ClinVar curated (likely) benign or pathogenic variants. Case-control LR evidence was highly consistent with ClinVar assertions for (likely) benign or pathogenic variants; exhibiting 99.1% sensitivity and 95.4% specificity for BRCA1 and 92.2% sensitivity and 86.6% specificity for BRCA2. This approach provides case-control evidence for 785 unclassified variants, that can serve as a valuable element for clinical classification.