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We identify and investigate cosmic ray Forbush decreases (FDs) observed in the E > 50 MeV data from the Helios 1 and 2 spacecraft, spanning from 1974–1985 and covering heliocentric distances in the range 0.28–1 au. A Helios FD catalogue is compiled, including the characteristics of the cosmic ray variations, as well as those of the solar wind (SW) and the interplanetary magnetic field (IMF) of the associated interplanetary disturbances. An extended statistical study considers the radial dependence of the FD magnitude, the SW velocity, and the IMF intensity in these disturbances. It is found that the Helios FD sizes at different distances from the Sun are determined by the parameters of the interplanetary disturbances. In particular, the FD magnitudes observed at Helios, as well as near Earth, correlate well with VB, which is the product of the maximum SW velocity and the IMF intensity when normalized by the average values of these parameters at the radial distance of the observations. However, we found that, on average, the Helios FD sizes are statistically independent of the radial distance in the range of 0.28–1 au.

PURPOSE With the initial analysis of POLLUX at a median follow-up of 13.5 months, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly prolonged progression-free survival versus lenalidomide and dexamethasone (Rd) alone in patients with relapsed or refractory multiple myeloma (RRMM). We report updated efficacy and safety results at the time of final analysis for overall survival (OS). METHODS POLLUX was a multicenter, randomized, open-label, phase III study during which eligible patients with ≥ 1 line of prior therapy were randomly assigned 1:1 to D-Rd or Rd until disease progression or unacceptable toxicity. After positive primary analysis and protocol amendment, patients receiving Rd were offered daratumumab monotherapy after disease progression. RESULTS Significant OS benefit was observed with D-Rd (hazard ratio, 0.73; 95% CI, 0.58 to 0.91; P = .0044) at a median (range) follow-up of 79.7 months (0.0-86.5). The median OS was 67.6 months for D-Rd compared with 51.8 months for Rd. Prespecified analyses demonstrated an improved OS with D-Rd versus Rd in most subgroups, including patients age ≥ 65 years and patients with one, two, or three prior lines of therapy, International Staging System stage III disease, high-risk cytogenetic abnormalities, and refractoriness to their last prior line of therapy or a proteasome inhibitor. The most common (≥ 10%) grade 3/4 treatment-emergent adverse events with D-Rd versus Rd were neutropenia (57.6% v 41.6%), anemia (19.8% v 22.4%), pneumonia (17.3% v 11.0%), thrombocytopenia (15.5% v 15.7%), and diarrhea (10.2% v 3.9%). CONCLUSION D-Rd significantly extended OS versus Rd alone in patients with RRMM. To our knowledge, for the first time, our findings, together with the OS benefit observed with daratumumab plus bortezomib and dexamethasone in the phase III CASTOR trial, demonstrate OS improvement with daratumumab-containing regimens in RRMM (ClinicalTrials.gov identifier: NCT02076009 [POLLUX]).

Aims/hypothesis We investigated whether the impacts of childhood adiposity on adult-onset diabetes differ across proposed diabetes subtypes using a Mendelian randomisation (MR) design. Methods We performed MR analysis using data from European genome-wide association studies of childhood adiposity, latent autoimmune diabetes in adults (LADA, proxy for severe autoimmune diabetes), severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD) and mild age-related diabetes (MARD). Results Higher levels of childhood adiposity had positive genetically predicted effects on LADA (OR 1.62, 95% CI 1.05, 2.52), SIDD (OR 2.11, 95% CI 1.18, 3.80), SIRD (OR 2.76, 95% CI 1.60, 4.75) and MOD (OR 7.30, 95% CI 4.17, 12.78), but not MARD (OR 1.06, 95% CI 0.70, 1.60). Conclusions/interpretation Childhood adiposity is a risk factor not only for adult-onset diabetes primarily characterised by obesity or insulin resistance, but also for subtypes primarily characterised by insulin deficiency or autoimmunity. These findings emphasise the importance of preventing childhood obesity. Graphical abstract

Marine mammal abundance and distribution in New Jersey’s nearshore waters are not well known due to limited dedicated studies. The first yearround systematic surveys were conducted to determine the spatial/temporal distribution and estimate the abundance of marine mammals in this region prior to wind power development. Eight marine mammal species were observed: North Atlantic right whale (Eubalaena glacialis), humpback whale (Megaptera novaeangliae), minke whale (Balaenoptera acutorostrata), fin whale (Balaenoptera physalus), bottlenose dolphin (Tursiops truncatus), common dolphin (Delphinus delphis), harbour porpoise (Phocoena phocoena) and harbour seal (Phoca vitulina). Results indicate clear seasonal patterns in distribution and abundance. The fin whale, humpback whale and bottlenose dolphin were sighted during all seasons. The abundance of large whales in the study area was relatively low while the abundance of dolphin and porpoise species was high and largely seasonal. The bottlenose dolphin was the most abundant species; however, abundance was high only during spring and summer. Common dolphins and harbour porpoises were common in the study area during winter and spring. These baseline data will be used to assess potential environmental impacts of the construction and operation of offshore wind power facilities in this region.

What is this summary about? This is a summary of a publication about Black participants of the GRIFFIN clinical study that was published in Blood Cancer Journal in April 2022. The GRIFFIN clinical study looked at the treatment combination of daratumumab plus a standard therapy for multiple myeloma (called RVd therapy, which stands for lenalidomide, bortezomib, and dexamethasone) in adult patients who had not been treated before for multiple myeloma and so were considered to have newly diagnosed multiply myeloma. Multiple myeloma is a blood cancer of plasma cells. Based on the participants' age, medical history, and indicators of good general health, the participants in the GRIFFIN study were also eligible to receive autologous stem cell transplant as part of their therapy. This summary describes results for the Black participants of the GRIFFIN clinical study who received daratumumab plus RVd therapy (called D-RVd) to see if D-RVd therapy is better than RVd therapy at reducing the amount of multiple myeloma cancer cells in a patient's body. Why did the researchers evaluate the results for Black patients in the GRIFFIN study? Due to racial disparities leading to historically low representation of minority groups in clinical studies, optimal treatments are not defined for Black patients with newly diagnosed multiple myeloma. Since previously published results from the overall population in the GRIFFIN study indicated that D-RVd therapy was better than RVd therapy, the researchers wanted to determine if this was also the case among Black participants. What were the results? Out of 207 participants in the GRIFFIN study, 15% (32 participants) were Black and 78% (161 participants) were White. In both Black and White participants, D-RVd therapy reduced the amount of myeloma cancer cells more than RVd therapy. Additionally, D-RVd and RVd therapy had similar safety results for Black and White participants. What do the results mean? This analysis of GRIFFIN by race shows that Black people benefit from the daratumumab-containing D-RVd therapy as much as White people. Additionally, D-RVd therapy had similar safety results to RVd therapy for both Black and White people. Clinical Trial Registration: NCT02874742 ( ClinicalTrials.gov )

Patients with multiple myeloma are at increased risk of vascular thromboembolic events (VTEs). This post hoc analysis evaluated VTEs in the randomised phase 2 GRIFFIN study (ClinicalTrials.gov Identifier: NCT02874742) that investigated lenalidomide/bortezomib/dexamethasone (RVd) ± daratumumab (D). Patients with newly diagnosed multiple myeloma who were eligible for autologous stem cell transplantation (ASCT) received D-RVd/RVd induction, high-dose therapy and ASCT, D-RVd/RVd consolidation and up to 2 years of lenalidomide maintenance therapy ± D. VTE prophylaxis was recommended (at least aspirin, ≥162 mg daily) in accordance with International Myeloma Working Group guidelines. In the safety population (D-RVd, n = 99; RVd, n = 102), VTEs occurred in 10.1% of D-RVd patients and 15.7% of RVd patients; grade 2-4 VTEs occurred in 9.1% and 14.7%, respectively. Median time to the first onset of VTE was longer for D-RVd versus RVd patients (305 days vs 119 days). Anti-thrombosis prophylaxis use was similar between arms (D-RVd, 84.8% vs RVd, 83.3%); among patients with VTEs, prophylaxis use at time of first VTE onset was 60.0% for D-RVd and 68.8% for RVd. In summary, the addition of daratumumab to RVd did not increase the incidence of VTEs, but the cumulative VTE incidence was relatively high in this cohort and anti-thrombotic prophylaxis use was suboptimal.

Use of magnetic resonance imaging (MRI) as a tool to aid in neuroprognostication after cardiac arrest (CA) has been described, yet details of specific indications, timing, and sequences are unknown. We aim to define the current practices in use of brain MRI in prognostication after pediatric CA.A survey was distributed to pediatric institutions participating in three international studies. Survey questions related to center demographics, clinical practice patterns of MRI after CA, neuroimaging resources, and details regarding MRI decision support.Response rate was 31% (44 of 143). Thirty-four percent (15 of 44) of centers have a clinical pathway informing the use of MRI after CA. Fifty percent (22 of 44) of respondents reported that an MRI is obtained in nearly all patients with CA, and 32% (14 of 44) obtain an MRI in those who do not return to baseline neurological status. Poor neurological examination was reported as the most common factor (91% [40 of 44]) determining the timing of the MRI. Conventional sequences (T1, T2, fluid-attenuated inversion recovery, and diffusion-weighted imaging/apparent diffusion coefficient) are routinely used at greater than 97% of centers. Use of advanced imaging techniques (magnetic resonance spectroscopy, diffusion tensor imaging, and functional MRI) were reported by less than half of centers.Conventional brain MRI is a common practice for prognostication after CA. Advanced imaging techniques are used infrequently. The lack of standardized clinical pathways and variability in reported practices support a need for higher-quality evidence regarding the indications, timing, and acquisition protocols of clinical MRI studies.

Background Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. Methods In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0–2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Findings Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60–72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61–72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0–8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2–5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64–0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4–22·8) in the melflufen group and 16·3 months (10·1–23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1–25·6) at a median follow-up of 19·8 months (IQR 12·0–25·0) in the melflufen group and 25·0 months (95% CI 18·1–31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8–23·7; HR 1·10 [95% CI 0·85–1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). Interpretation Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma., Oncopeptides AB

Aims/hypothesis Determining how high BMI at different time points influences the risk of developing type 2 diabetes and affects insulin secretion and insulin sensitivity is critical. Methods By estimating childhood BMI in 441,761 individuals in the UK Biobank, we identified which genetic variants had larger effects on adulthood BMI than on childhood BMI, and vice versa. All genome-wide significant genetic variants were then used to separate the independent genetic effects of high childhood BMI from those of high adulthood BMI on the risk of type 2 diabetes and insulin-related phenotypes using Mendelian randomisation. We performed two-sample MR using external studies of type 2 diabetes, and oral and intravenous measures of insulin secretion and sensitivity. Results We found that a childhood BMI that was one standard deviation (1.97 kg/m2) higher than the mean, corrected for the independent genetic liability to adulthood BMI, was associated with a protective effect for seven measures of insulin sensitivity and secretion, including increased insulin sensitivity index (β=0.15; 95% CI 0.067, 0.225; p=2.79Å~10−4) and reduced fasting glucose levels (β=−0.053; 95% CI −0.089, −0.017; p=4.31Å~10−3). However, there was little to no evidence of a direct protective effect on type 2 diabetes (OR 0.94; 95% CI 0.85, 1.04; p=0.228) independently of genetic liability to adulthood BMI. Conclusions/interpretation Our results provide evidence of the protective effect of higher childhood BMI on insulin secretion and sensitivity, which are crucial intermediate diabetes traits. However, we stress that our results should not currently lead to any change in public health or clinical practice, given the uncertainty regarding the biological pathway of these effects and the limitations of this type of study

Although caregivers of patients with multiple myeloma (MM) play a critical role in supporting their loved ones throughout the illness course, studies examining caregiver quality of life (QOL), psychological distress, and prognostic awareness are lacking. We conducted a cross-sectional, multisite study of patients undergoing treatment with MM and their caregivers. Eligible caregivers were enrolled to 1 of 3 cohorts based on lines of therapy. Caregivers completed validated questionnaires to assess their QOL, psychological distress, and perceptions of prognosis. We enrolled 127 caregivers of patients with MM (newly diagnosed [n = 43], 2-3 lines of therapy [n = 40], and ≥4 lines of therapy [n = 44]). Caregiver QOL and psychological distress did not differ by line of therapy. The rate of clinically significant anxiety, depression, and posttraumatic stress disorder symptoms were 44.1% (56/127), 15.8% (20/127), and 24.4% (31/127), respectively. When examined in dyads, caregivers reported higher rates of clinically significant anxiety (44.4% [55/124] vs 22.5% [28/124]) compared with patients with MM. Most caregivers (84.2%, 101/120) reported that the oncologist had informed them that the patient’s cancer was incurable; however, only 50.9% (58/114) and 53.6% (59/110) of caregivers acknowledged the patient’s cancer was terminal and incurable, respectively. Caregivers of patients undergoing treatment for MM experience substantial psychological distress across the disease continuum, particularly anxiety. The majority of caregivers of patients with MM report that knowing the patient’s prognosis is extremely important and report that the oncologist told them that the patient was incurable. Nevertheless, a significant portion of caregivers believe that the patient’s MM is curable.

For patients with newly diagnosed multiple myeloma, survival outcomes continue to improve significantly: however, nearly all patients will relapse following induction treatment. Optimisation of induction therapy is essential to provide longer term disease control and the current standard of care for most patients incorporates an immunomodulatory agent and proteasome inhibitor, most commonly lenalidomide and bortezomib in combination with dexamethasone (RVD), with maintenance until progression. Historically there has been limited access to RVD as an induction strategy outside of the United States; fortunately, there is now increasing access worldwide. This review discusses the rationale for use of RVD as induction therapy and aims to provide guidance in prescribing this regimen in order to optimise efficacy while minimising the toxicities of treatment. We also highlight the increasing evidence for the utility of addition of a monoclonal antibody to the RVD backbone to deepen responses and potentially provide longer disease control.

Insights into the mechanisms of protein homeostasis and proteasomal degradation have led to new strategies of redirecting the ubiquitin-proteasome system (UPS) to reduce or eliminate proteins or survival factors key to malignant pathobiology, multiple myeloma (MM) in particular. These strategies have enabled researchers to target proteins that were previously considered difficult to modulate by pharmacological means.This review provides a brief overview of UPS biology, particularly the role of the CRL4Since a high proportion of patients develop drug resistance, it is vital to have novel therapeutic agents for treating relapsed patients with MM more effectively. It is encouraging that the expanding pathophysiological insight into cellular signaling pathways in MM increasingly translates into the development of novel therapeutic agents such as targeted protein degraders. This holds promise for improving outcomes in MM and beyond.

BACKGROUND: Elotuzumab plus lenalidomide and dexamethasone has shown improved progression-free and overall survival versus lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma. We aimed to assess these regimens in patients with newly diagnosed multiple myeloma who are ineligible for haematopoietic stem-cell transplantation (HSCT). METHODS: ELOQUENT-1 is an open-label, multicentre, randomised, phase 3 trial conducted at 185 hospitals, oncology practices, and research centres in 19 countries. Eligible patients were aged 18 years or older with newly diagnosed, untreated, symptomatic myeloma and not candidates for high-dose therapy plus HSCT, and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or lower. Patients were randomly assigned (1:1) to receive elotuzumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone using an interactive voice response system, stratified by the International Staging System (ISS; stage I-II vs III), age (

Background: In this study, we investigated the capability of polygenic risk scores to stratify a cohort of young individuals into risk deciles based on 10 different cardiovascular traits and circulating biomarkers. Methods: We first conducted large-scale genome-wide association studies using data on adults (mean age 56.5 years) enrolled in the UK Biobank study (n=393 193 to n=461 460). Traits and biomarkers analyzed were body mass index, systolic blood pressure, diastolic blood pressure, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, apolipoprotein B, apolipoprotein A-I, C-reactive protein and vitamin D. Findings were then leveraged to build whole genome polygenic risk scores in participants from the Avon Longitudinal Study of Parents and Children (mean age, 9.9 years) which were used to stratify this cohort into deciles in turn and analyzed against their respective traits. Results: For each of the 10 different traits assessed, we found strong evidence of an incremental trend across deciles (all P Conclusions: Although the use of polygenic prediction in a clinical setting may currently be premature, our findings suggest they are becoming increasingly powerful as a means of predicting complex trait variation at an early stage in the lifecourse.

The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide-dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis.In this randomised, multicentre, open-label, phase 3 study adult patients (aged ≥18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions. Patients were excluded if they had anti-CD38 refractory disease or previously received pomalidomide. Patients were randomly assigned (1:1), using an interactive response technology with permuted blocked randomisation (block size of four) and stratified by number of previous treatment lines (2-3 vs3) and aged (75 vs ≥75 years), to isatuximab-pomalidomide-dexamethasone (isatuximab group) or pomalidomide-dexamethasone (control group). In the isatuximab group, intravenous isatuximab 10 mg/kg was administered on days 1, 8, 15, and 22 of the first 4-week cycle, and then on days 1 and 15 of subsequent cycles. Both groups received oral pomalidomide 4 mg on days 1-21 of each cycle, and weekly oral or intravenous dexamethasone 40 mg (20 mg if aged ≥75 years) on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Here' we report a prespecified second interim analysis of overall survival (time from randomisation to any-cause death), a key secondary endpoint, in the intention-to-treat population (ie, all patients who provided informed consent and allocated a randomisation number) at 24 months after the primary analysis. Safety was assessed in all patients who received at least one dose or part dose of study treatment. The prespecified stopping boundary for the overall survival analysis was when the derived p value was equal to or less than 0·0181. This study is registered with ClinicalTrials.gov, NCT02990338, and is active, but not recruiting.Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-up at data cutoff (Oct 1, 2020) was 35·3 months (IQR 33·5-37·4). Median overall survival was 24·6 months (95% CI 20·3-31·3) in the isatuximab group and 17·7 months (14·4-26·2) in the control group (hazard ratio 0·76 [95% CI 0·57-1·01]; one-sided log-rank p=0·028, not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergent adverse events in the isatuximab group versus the control group were neutropenia (76 [50%] of 152 patients vs 52 [35%] of 149 patients), pneumonia (35 [23%] vs 31 [21%]), and thrombocytopenia (20 [13%] vs 18 [12%]). Serious treatment-emergent adverse events were observed in 111 (73%) patients in the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-related deaths occurred in the isatuximab group (one due to sepsis and one due to cerebellar infarction) and two (1%) occurred in the control group (one due to pneumonia and one due to urinary tract infection).Addition of isatuximab plus pomalidomide-dexamethasone resulted in a 6·9-month difference in median overall survival compared with pomalidomide-dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing.Sanofi.

BACKGROUND University-life usually happens during a period of transition in life during which the incidence of mental health and substance use problems and disorders peak. However, relatively few students obtain effective treatment and support. E-interventions have been proven effective in improving psychological outcomes of university students and they have the potential to provide scalable services that can be easily integrated into existing models of care. Minder is a mobile application co-developed with university students that offers users a collection of evidence-based interventions that have been tailored to help university students maintain their mental health and wellbeing, as well as manage their substance use. OBJECTIVE The aim of this protocol paper is to provide a description of the randomized controlled trial that aims to assess the effectiveness of the Minder mobile app in improving the mental health and substance use outcomes of university students. METHODS This is a 2-arm parallel assignment single blinded 30-day randomized controlled trial with 1 intervention group and 1 waitlist control group. A total of 1496 (748 per trial arm) university students at the Vancouver Campus of the University of British Columbia (N = 54000) who are 17 years of age or older, have a smartphone with Wi-Fi or cellular data, and speak English will be recruited via a variety of online and offline strategies. Participants will be randomized into either the intervention or control group after completion of a baseline survey. Those randomized into the intervention group will gain immediate access to the Minder app and be assessed at 2 weeks and 30 days. Those randomized into the control group will be given access to the app content after their follow-up assessment at 30 days. The primary outcomes are measured from baseline to follow-up at 30 days and include changes in general anxiety symptomology, changes in anxious and depressive symptomology, as well as changes in alcohol consumption risk measured by the General Anxiety Disorder 7-Item (GAD-7) scale, Patient Health Questionnaire 9-item (PHQ-9) scale, and the consumption component of the Alcohol Use Disorders Identification Test, adapted for Use in the United States (USAUDIT-C) respectively. Secondary outcomes include measures related to changes in frequency of substance use, changes in mental well-being, changes in self-efficacy in managing mental health and substance use, changes in readiness to change, and changes in self-reported use of mental health services and supports (including referral) from baseline to follow-up at 30 days. RESULTS This study was registered on ClinicalTrials.gov (NCT05606601) on November 4, 2022. Trial recruitment and data collection began in September 2022 and completion of data collection for trial is anticipated by June 2023. As of May 10, 2022, 1425 participants have been enrolled. CONCLUSIONS The randomized controlled trial described in this protocol paper will assess whether the Minder app is effective in improving the mental health (PHQ-9 and GAD-7) and substance use outcomes (USAUDIT-C) of a general population of Canadian university students. Further secondary outcome research aims to explore additional outcomes of interest for further research and to better understand how to support students' general mental wellbeing. CLINICALTRIAL ClinicalTrials.gov NCT05606601; https://clinicaltrials.gov/ct2/show/NCT05606601

BackgroundDiseases diagnosed in adulthood may have antecedents throughout – including prenatal – life. Gaining a better understanding of how exposures at different stages in the lifecourse influence health outcomes is key to elucidating the potential benefits of specific disease prevention strategies. However, confounding is highly likely in studies with earlier life or time-varying exposures. Mendelian randomisation (MR) is therefore increasingly used to estimate causal effects of exposures across the lifecourse on later life outcomes.MethodsThis systematic literature review aims to identify MR methods used to perform lifecourse investigations and review previous work that has utilised MR to elucidate the effects of factors acting at different stages of the lifecourse. We conducted a systematic search in PubMed, Embase, Medline and MedRXiv databases to comprehensively obtain lifecourse epidemiology studies that have employed MR.ResultsThirteen methodological studies were identified. Four studies focused on the impact of time-varying exposures on the interpretation of “standard” MR techniques, five presented methods for analysing repeat measures of the same exposure, and four described novel methodological approaches to handling parental exposures in relation to offspring outcomes. A further 84 studies presented the results of an applied research question with relevance to lifecourse epidemiology. Over half of these estimated effects in a single generation and were largely confined to the exploration of questions regarding body composition. Of the one generational studies employed in this review, 59% estimated the effect of exposures at birth, birth to/and childhood, birth to/and adolescence or birth to/and adulthood, 30% at childhood, childhood to/and adolescence or childhood to/and adulthood, and 11% at adolescence or adulthood. The remaining looked across two generations. These estimated effects of maternal exposures, with one study additionally examining paternal exposures, in relation to offspring outcomes.ConclusionThere is a growing body of research focused on the development and application of MR methods to address lifecourse research questions. The possibility that genetic effects have different levels of importance in the progression of an exposure at different ages should be more commonly considered for application in an MR context. Limitations exist, however, specifically regarding data constraints.

BackgroundObesity particularly during childhood is considered a global public health crisis and has been linked with later life health consequences including mental health.However, there is lack of causal understanding if childhood adiposity has a direct effect on mental health or has an indirect effect after accounting for adulthood body size.ObjectiveTo investigate the total and direct effect of childhood adiposity on later life anxiety and depression.MethodTwo-sample Mendelian randomization (MR) was performed to estimate the total effect and direct effect (accounting for adulthood body size) of childhood body size on anxiety and depression. We used summary statistics from a genome-wide association study (GWAS) of UK Biobank (n=453,169) and large-scale consortia of anxiety (Million Veteran Program) and depression (Psychiatric Genomics Consortium) (n=175,163 and n=173,005, respectively).ResultUnivariable MR did not indicate genetically predicted effects of childhood body size with later life anxiety (beta=-0.05, 95% CI=-0.13, 0.02), and depression (OR=1.06, 95% CI=0.94, 1.20). However, using multivariable MR, we observed that the higher body size in childhood reduced the risk of later life anxiety (beta=-0.19, 95% CI=-0.29, -0.08) and depression (OR=0.83, 95% CI=0.71, 0.97). Both univariable and multivariable MR indicated that higher body size in adulthood increased the risk of later life anxiety and depression.ConclusionOur findings suggest that the higher body size in childhood has a protective effect on later life anxiety and depression, if obesity is not present into adulthood. Higher body size in adulthood was a risk factor for later life anxiety and depression.

Lifecourse Mendelian randomization is a causal inference technique which harnesses genetic variants with time-varying effects to develop insight into the influence of age-dependent lifestyle factors on disease risk. Here, we apply this approach to evaluate whether childhood body size has a direct consequence on 8 major disease endpoints by analysing parental history data from the UK Biobank study.Our findings suggest that, whilst childhood body size increases later risk of outcomes such as heart disease (odds ratio (OR) = 1.15, 95% CI = 1.07 to 1.23, P = 7.8 × 10− 5) and diabetes (OR = 1.43, 95% CI = 1.31 to 1.56, P = 9.4 × 10− 15) based on parental history data, these findings are likely attributed to a sustained influence of being overweight for many years over the lifecourse. Likewise, we found evidence that remaining overweight throughout the lifecourse increases risk of lung cancer, which was partially mediated by lifetime smoking index. In contrast, using parental history data provided evidence that being overweight in childhood may have a protective effect on risk of breast cancer (OR = 0.87, 95% CI = 0.78 to 0.97, P = 0.01), corroborating findings from observational studies and large-scale genetic consortia.Large-scale family disease history data can provide a complementary source of evidence for epidemiological studies to exploit, particularly given that they are likely more robust to sources of selection bias (e.g. survival bias) compared to conventional case control studies. Leveraging these data using approaches such as lifecourse Mendelian randomization can help elucidate additional layers of evidence to dissect age-dependent effects on disease risk.

Background The prevalence of atrial fibrillation (AF) is increasing with an aging worldwide population, yet a comprehensive understanding of its causes and consequences remains limited. We aim to assess the causes and consequences of AF via a bidirectional Mendelian randomization (MR) analysis. Methods We used publicly available genome-wide association study (GWAS) summary data, centralized and harmonized by an open GWAS database. We assessed the genetically predicted effects of 5048 exposures on risk of AF, and the genetically predicted effects of genetic liability to AF, on 10 308 outcomes via two-sample MR analysis. Multivariable MR analysis was further conducted to explore the comparative roles of identified risk factors. Results MR analysis suggested that 55 out of 5048 exposure traits, including four proteins, play a causal role in AF (P Conclusions Our results suggest body mass index, height, systolic blood pressure and genetic liability to coronary artery disease are independent causal risk factors for AF. Several proteins, including DUSP13, IL-6R and TNFSF12, may have therapeutic potential for AF.

Musculoskeletal conditions, including fractures, can have severe and long-lasting consequences. Higher body mass index in adulthood is widely acknowledged to be protective for most fracture sites. However, sources of bias induced by confounding factors may have distorted previous findings. Employing a lifecourse Mendelian randomisation (MR) approach by using genetic instruments to separate effects at different life stages, this investigation aims to explore how prepubertal and adult body size independently influence fracture risk in later life.Using data from a large prospective cohort, univariable and multivariable MR were conducted to simultaneously estimate the effects of age-specific genetic proxies for body size (n = 453,169) on fracture risk (n = 416,795). A two-step MR framework was additionally applied to elucidate potential mediators. Univariable and multivariable MR indicated strong evidence that higher body size in childhood reduced fracture risk (OR, 95% CI: 0.89, 0.82 to 0.96, P = 0.005 and 0.76, 0.69 to 0.85, P = 1 × 10− 6, respectively). Conversely, higher body size in adulthood increased fracture risk (OR, 95% CI: 1.08, 1.01 to 1.16, P = 0.023 and 1.26, 1.14 to 1.38, P = 2 × 10− 6, respectively). Two-step MR analyses suggested that the effect of higher body size in childhood on reduced fracture risk was mediated by its influence on higher estimated bone mineral density (eBMD) in adulthood.This investigation provides novel evidence that higher body size in childhood reduces fracture risk in later life through its influence on increased eBMD. From a public health perspective, this relationship is complex since obesity in adulthood remains a major risk factor for co-morbidities. Results additionally indicate that higher body size in adulthood is a risk factor for fractures. Protective effect estimates previously observed are likely attributed to childhood effects.