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BackgroundThe emotional health of adolescent and young adult (AYA) cancer survivors is compromised both during and after cancer treatment. Targeted programs designed to support AYAs’ ability to cope with stress in the years following treatment completion are lacking. Mind-body programs may ameliorate the negative psychological and emotional effects of stress and assist AYAs with managing the psychosocial challenges of early survivorship. ObjectiveOur randomized waitlist-control trial aims to assess the feasibility, acceptability, and preliminary efficacy of a virtual group program (Bounce Back) to promote stress management and resiliency among posttreatment AYAs. MethodsBounce Back is a stress management and resiliency program delivered via videoconference by a trained mental health clinician. Sessions were adapted from an evidence-based mind-body program (Stress Management and Resiliency Training - Relaxation Response Resiliency Program [SMART-3RP]) grounded in relaxation response elicitation, mindfulness, cognitive behavioral therapy, and positive psychology. Seventy-two AYAs (diagnosed with cancer between ages 14 years and 29 years and had completed cancer treatment within the last 5 years) were randomly assigned to the Bounce Back program or waitlist-control group and completed assessments at baseline, 3 months postbaseline, and 6 months postbaseline. The primary aim of the study is to determine the feasibility and acceptability of the Bounce Back program. Descriptive statistics, including means, frequencies, and ranges supplemented by qualitative exit interview feedback will be used to characterize the sample and to summarize feasibility and acceptability. The exploratory aims are to evaluate the preliminary effects of the program on stress coping and psychosocial outcome measures (ie, anxiety, depression) collected across the 3 time points. ResultsThis study was funded by the National Cancer Institute in July 2017. Study procedures were approved by the Dana-Farber Harvard Cancer Center Institutional Review Board in October 2018 (Protocol 18-428). The randomized trial was conducted from July 2019 to March 2021. Quantitative data collection is complete, and qualitative exit interview data collection is ongoing. Results are expected to be published in peer-reviewed journals and presented at local, national, or international meetings in the coming years. ConclusionsFew evidence-based programs exist that tackle the key transitional issues faced by AYA cancer survivors. Future analyses will help us determine the feasibility and acceptability of the Bounce Back program and its impact on AYA stress coping and psychological well-being. Trial RegistrationClinicalTrials.gov NCT03768336; https://clinicaltrials.gov/ct2/show/NCT03768336 International Registered Report Identifier (IRRID)DERR1-10.2196/34033

Introduction Patient adherence to adjuvant endocrine therapy (AET) after a diagnosis of hormone-sensitive breast cancer is poor. Previous interventions have failed to produce changes in adherence, address patient preferences or include theoretically informed and evidence-based components. Therefore, we iteratively developed a patient-centred, evidence-based, small-group, videoconference intervention to improve adherence and symptom management as well as reduce distress for patients taking AET after breast cancer (Symptom-Targeted Randomised Intervention for Distress and Adherence to Adjuvant Endocrine Therapy, STRIDE).Methods and analysis The current study is a non-blinded, randomised, controlled, feasibility trial of STRIDE compared with a medication monitoring control group. The primary objective is to examine the feasibility and acceptability of STRIDE, while secondary objectives are to assess changes in objective and subjective adherence, symptom distress and satisfaction with AET. Patients will be recruited from the Massachusetts General Hospital Cancer Center in Boston, Massachusetts. The total number of patients accrued will be 75, with ≥60 patients completing the study. All patients will store their AET in an electronic pill bottle for objective adherence monitoring. Patients randomly assigned to the STRIDE intervention will receive 6 weekly 1-hour sessions, in small groups of two, delivered via videoconferencing by a trained mental health professional. Patients assigned to the control group will store their medication in the electronic pill bottle and receive follow-up oncology care as usual. All participants will complete self-report psychosocial measures at baseline, 12 weeks and 24 weeks postbaseline.Ethics and dissemination The study is funded by the National Cancer Institute of the National Institutes of Health and is approved by the Dana-Farber/Harvard Cancer Center Institutional Review Board (Protocol #18–603, V.1.2, first approval date 1 February 2019). The study will be reported in accordance with the Consolidated Standards of Reporting Trials statement for non-pharmacological trials. Results will be published in peer-reviewed academic journals, presented at scientific meetings and disseminated to patient organisations and media outlets.Trial registration numberNCT03837496; Pre-results.

Abstract Sleep deprivation has far-reaching consequences on the brain and behavior, impacting memory, attention, and metabolism. Previous research has focused on gene expression changes in individual brain regions, such as the hippocampus or cortex. Therefore, it is unclear how uniformly or heterogeneously sleep loss affects the brain. Here, we use spatial transcriptomics to define the impact of a brief period of sleep deprivation across the brain in male mice. We find that sleep deprivation induced pronounced differences in gene expression across the brain, with the greatest changes in the hippocampus, neocortex, hypothalamus, and thalamus. Both the differentially expressed genes and the direction of regulation differed markedly across regions. Importantly, we developed bioinformatic tools to register tissue sections and gene expression data into a common anatomical space, allowing a brain-wide comparison of gene expression patterns between samples. Our results suggest that distinct molecular mechanisms acting in discrete brain regions underlie the biological effects of sleep deprivation.

Many studies have examined relationships of microorganisms to geochemical zones in subseafloor sediment. However, responses to selective pressure and patterns of community succession with sediment depth have rarely been examined. Here we use 16S rDNA sequencing to examine the succession of microbial communities at sites in the Indian Ocean and the Bering Sea. The sediment ranges in depth from 0.16 to 332 m below seafloor and in age from 660 to 1,300,000 years. The majority of subseafloor taxonomic diversity is present in the shallowest depth sampled. The best predictor of sequence presence or absence in the oldest sediment is relative abundance in the near-seafloor sediment. This relationship suggests that perseverance of specific taxa into deep, old sediment is primarily controlled by the taxonomic abundance that existed when the sediment was near the seafloor. The operational taxonomic units that dominate at depth comprise a subset of the local seafloor community at each site, rather than a grown-in group of geographically widespread subseafloor specialists. At both sites, most taxa classified as abundant decrease in relative frequency with increasing sediment depth and age. Comparison of community composition to cell counts at the Bering Sea site indicates that the rise of the few dominant taxa in the deep subseafloor community does not require net replication, but might simply result from lower mortality relative to competing taxa on the long timescale of community burial.

The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits - multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) - in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific pathogenetic mechanisms in autoimmunity.

The association of the major histocompatibility complex (MHC) with SLE is well established yet the causal variants arising from this region remain to be identified, largely due to inadequate study design and the strong linkage disequilibrium demonstrated by genes across this locus. The majority of studies thus far have identified strong association with classical class II alleles, in particular HLA-DRB1*0301 and HLA-DRB1*1501. Additional associations have been reported with class III alleles; specifically, complement C4 null alleles and a tumor necrosis factor promoter SNP (TNF-308G/A). However, the relative effects of these class II and class III variants have not been determined. We have thus used a family-based approach to map association signals across the MHC class II and class III regions in a cohort of 314 complete United Kingdom Caucasian SLE trios by typing tagging SNPs together with classical typing of the HLA-DRB1 locus. Using TDT and conditional regression analyses, we have demonstrated the presence of two distinct and independent association signals in SLE: HLA-DRB1*0301 (nominal p = 4.9 x 10(-8), permuted p < 0.0001, OR = 2.3) and the T allele of SNP rs419788 (nominal p = 4.3 x 10(-8), permuted p < 0.0001, OR = 2.0) in intron 6 of the class III region gene SKIV2L. Assessment of genotypic risk demonstrates a likely dominant model of inheritance for HLA-DRB1*0301, while rs419788-T confers susceptibility in an additive manner. Furthermore, by comparing transmitted and untransmitted parental chromosomes, we have delimited our class II signal to a 180 kb region encompassing the alleles HLA-DRB1*0301-HLA-DQA1*0501-HLA-DQB1*0201 alone. Our class III signal importantly excludes independent association at the TNF promoter polymorphism, TNF-308G/A, in our SLE cohort and provides a potentially novel locus for future genetic and functional studies.

Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih(-/-)) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk(-/-)) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk(-/-) embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfk(s11) variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease.