Cardiogenic control of affective behavioural state.

Emotional states influence bodily physiology, as exemplified in the top-down process by which anxiety causes faster beating of the heart1-3. However, whether an increased heart rate might itself induce anxiety or fear responses is unclear3-8. Physiological theories of emotion, proposed over a century ago, have considered that in general, there could be an important and even dominant flow of information from the body to the brain9. Here, to formally test this idea, we developed a noninvasive optogenetic pacemaker for precise, cell-type-specific control of cardiac rhythms of up to 900 beats per minute in freely moving mice, enabled by a wearable micro-LED harness and the systemic viral delivery of a potent pump-like channelrhodopsin. We found that optically evoked tachycardia potently enhanced anxiety-like behaviour, but crucially only in risky contexts, indicating that both central (brain) and peripheral (body) processes may be involved in the development of emotional states. To identify potential mechanisms, we used whole-brain activity screening and electrophysiology to find brain regions that were activated by imposed cardiac rhythms. We identified the posterior insular cortex as a potential mediator of bottom-up cardiac interoceptive processing, and found that optogenetic inhibition of this brain region attenuated the anxiety-like behaviour that was induced by optical cardiac pacing. Together, these findings reveal that cells of both the body and the brain must be considered together to understand the origins of emotional or affective states. More broadly, our results define a generalizable approach for noninvasive, temporally precise functional investigations of joint organism-wide interactions among targeted cells during behaviour.

Platelet Transfusion in Cardiac Surgery: An Entropy-Balanced, Weighted, Multicenter Analysis.

BACKGROUND: Platelet transfusion is common in cardiac surgery, but some studies have suggested an association with harm. Accordingly, we investigated the association of perioperative platelet transfusion with morbidity and mortality. METHODS: We conducted a retrospective analysis of prospectively collected data from the Australian Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database. We included consecutive adults from 2005 to 2018 across 40 centers. We used inverse probability of treatment weighting via entropy balancing to investigate the association of perioperative platelet transfusion with our 2 primary outcomes, operative mortality (composite of both 30-day and in-hospital mortality) and 90-day mortality, as well as multiple other clinically relevant secondary outcomes. RESULTS: Among 119,132 eligible patients, 25,373 received perioperative platelets and 93,759 were considered controls. After entropy balancing, platelet transfusion was associated with reduced operative mortality (odds ratio [OR], 0.63; 99% confidence interval [CI], 0.47-0.84; P < .0001) and 90-day mortality (OR, 0.66; 99% CI, 0.51-0.85; P < .0001). Moreover, it was associated with reduced odds of deep sternal wound infection (OR, 0.57; 99% CI, 0.36-0.89; P = .0012), acute kidney injury (OR, 0.84; 99% CI, 0.71-0.99; P = .0055), and postoperative renal replacement therapy (OR, 0.71; 99% CI, 0.54-0.93; P = .0013). These positive associations were observed despite an association with increased odds of return to theatre for bleeding (OR, 1.55; 99% CI, 1.16-2.09; P < .0001), pneumonia (OR, 1.26; 99% CI, 1.11-1.44; P < .0001), intubation for longer than 24 hours postoperatively (OR, 1.13; 99% CI, 1.03-1.24; P = .0012), inotrope use for >4 hours postoperatively (OR, 1.14; 99% CI, 1.11-1.17; P < .0001), readmission to hospital within 30 days of surgery (OR, 1.22; 99% CI, 1.11-1.34; P < .0001), as well as increased drain tube output (adjusted mean difference, 89.2 mL; 99% CI, 77.0 mL-101.4 mL; P < .0001). CONCLUSIONS: In cardiac surgery patients, perioperative platelet transfusion was associated with reduced operative and 90-day mortality. Until randomized controlled trials either confirm or refute these findings, platelet transfusion should not be deliberately avoided when considering odds of death.

Association of perioperative transfusion of fresh frozen plasma and outcomes after cardiac surgery.

BACKGROUND: Fresh frozen plasma (FFP) transfusion is used to manage coagulopathy and bleeding in cardiac surgery patients despite uncertainty about its safety and effectiveness. METHODS: We performed a propensity score matched analysis of the Australian and New Zealand Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database including patients from 39 centres from 2005 to 2018. We investigated the association of perioperative FFP transfusion with mortality and other clinical outcomes. RESULTS: Of 119,138 eligible patients, we successfully matched 13,131 FFP recipients with 13,131 controls. FFP transfusion was associated with 30-day mortality (odds ratio (OR), 1.41; 99% CI, 1.17-1.71; p < .0001), but not with long-term mortality (hazard ratio (HR), 0.92; 99% CI, 0.85-1.00; p = .007, Holm-Bonferroni α = 0.0004). FFP was also associated with return to theatre for bleeding (OR, 1.97; 99% CI, 1.66-2.34; p < .0001), prolonged intubation (OR, 1.15; 99% CI, 1.05-1.26; p < .0001) and increased chest tube drainage (Mean difference (MD) in mL, 131; 99% CI, 120-141; p < .0001). It was also associated with reduced postoperative creatinine levels (MD in g/L, -6.33; 99% CI, -10.28 to -2.38; p < .0001). CONCLUSION: In a multicentre, propensity score matched analysis, perioperative FFP transfusion was associated with increased 30-day mortality and had variable associations with secondary clinical outcomes.

Sex Differences in Opioid Administration After Cardiac Surgery.

OBJECTIVES: To assess whether there are sex-based differences in the administration of opioid analgesic drugs among inpatients after cardiac surgery. DESIGN: A retrospective cohort study. SETTING: At a tertiary academic referral center. PARTICIPANTS: Adult patients who underwent cardiac surgery from 2014 to 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the cumulative oral morphine equivalent dose (OMED) for the postoperative admission. Secondary outcomes were the daily difference in OMED and the administration of nonopioid analgesics. The authors developed multivariate regression models controlling for known confounders, including weight and length of stay. A total of 3,822 patients (1,032 women and 2,790 men) were included. The mean cumulative OMED was 139 mg for women and 180 mg for men, and this difference remained significant after adjustment for confounders (adjusted mean difference [aMD], -33.21 mg; 95% CI, -47.05 to -19.36 mg; p < 0.001). The cumulative OMED was significantly lower in female patients on postoperative days 1 to 5, with the greatest disparity observed on day 5 (aMD, -89.83 mg; 95% CI, -155.9 to -23.80 mg; p = 0.009). By contrast, women were more likely to receive a gabapentinoid (odds ratio, 1.91; 95% CI, 1.42-2.58; p < 0.001). The authors found no association between patient sex and the administration of other nonopioid analgesics or specific types of opioid analgesics. The authors found no association between patient sex and pain scores recorded within the first 48 hours after extubation, or the number of opioids administered in close proximity to pain assessments. CONCLUSIONS: Female sex was associated with significantly lower amounts of opioids administered after cardiac surgery.

Platelet Transfusion After Cardiac Surgery.

OBJECTIVES: To investigate the independent association of platelet transfusion with hospital mortality and key relevant clinical outcomes in cardiac surgery. DESIGN: A single-center, propensity score-matched, retrospective, cohort study. SETTING: At an American tertiary teaching hospital data from the Medical Information Mart for Intensive Care III and IV databases from 2001 to 2019. PARTICIPANTS: Consecutive adults undergoing coronary artery bypass graft and/or cardiac valvular surgery. INTERVENTIONS: Platelet transfusion during perioperative intensive care unit (ICU) admission. MEASUREMENTS AND MAIN RESULTS: Overall, 12,043 adults met the study inclusion criteria. Of these, 1,621 (13.5%) received apheresis-leukoreduced platelets, with a median of 1.19 units per recipient (IQR: 0.93-1.19) at a median of 1.78 hours (IQR: 0.75-4.25) after ICU admission. The platelet count was measured in 1,176 patients (72.5%) before transfusion, with a median count of 120 × 109/L (IQR: 89.0-157.0), and only 53 (3.3%) had platelet counts below 50 × 109/L. After propensity matching of 1,046 platelet recipients with 1,046 controls, perioperative platelet transfusion carried no association with in-hospital mortality (odds ratio [OR]: 1.28; 99% CI: 0.49-3.35; p = 0.4980). However, it was associated with a pattern of decreased odds of suspected infection (eg, respiratory infection, urinary tract infection, septicaemia, or other; OR: 0.70; 99% CI: 0.50-0.97; p = 0.0050), days in the hospital (adjusted mean difference [AMD]: 0.86; 99% CI: -0.27 to 1.98; p = 0.048), or days in intensive care (AMD 0.83; 99% CI: -0.15 to 1.82; p = 0.0290). CONCLUSIONS: Platelet transfusion was not associated with hospital mortality, but it was associated with decreased odds of suspected infection and with shorter ICU and hospital stays.

Fresh frozen plasma transfusion after cardiac surgery.

INTRODUCTION: Fresh frozen plasma (FFP) transfusion in the intensive care unit (ICU) is commonly used to treat coagulopathy and bleeding in cardiac surgery, despite suggestion that it may increase the risk of morbidity and mortality through mechanisms such as fluid overload and infection. METHODS: We retrospectively studied consecutive adults undergoing cardiac surgery from the Medical Information Mart for Intensive Care III and IV databases. We applied propensity score matching to investigate the independent association of within-ICU FFP transfusion with mortality and other key clinical outcomes. RESULTS: Of our 12,043 adults who met inclusion criteria, 1585 (13.2%) received perioperative FFP with a median of 2.48 units per recipient (interquartile range [IQR]: 2.04, 4.33) at a median time of 1.83 h (IQR: 0.75, 3.75) after ICU admission. After propensity matching of 952 FFP recipients to 952 controls, we found no significant association between FFP use and hospital mortality (odds ratio (OR): 1.58; 99% confidence interval (CI): 0.57, 3.71), suspected infection (OR: 0.72; 99% CI: 0.49, 1.08), or acute kidney injury (OR: 1.23; 99% CI: 0.91, 1.67). However, FFP was associated with increased days in hospital (adjusted mean difference (AMD): 1.28; 99% CI: 0.27, 2.41; p = .0050), days in intensive care (AMD: 1.28; 99% CI: 0.27, 2.28; p = .0011), and chest tube output in millilitres up to 8 h after transfusion (AMD: 92.98; 99% CI: 52.22, 133.74; p < .0001). CONCLUSIONS: After propensity matching, FFP transfusion was not associated with increased hospital mortality, but was associated with increased length of stay and no decrease in bleeding in the early post-transfusion period.

Cryoprecipitate Transfusion After Cardiac Surgery.

OBJECTIVES: The association of cryoprecipitate transfusion with patient outcomes after cardiac surgery is unclear. We aimed to investigate the predictors of, and outcomes associated with, postoperative cryoprecipitate transfusion in cardiac surgery patients. METHODS: We used the Medical Information Mart for Intensive Care III and IV databases. We included adults undergoing cardiac surgery, and propensity score matched cryoprecipitate-treated patients to controls. Using the matched cohort, we investigated the association of cryoprecipitate use with clinical outcomes. The primary outcome was in-hospital mortality. Secondary outcomes were infection, acute kidney injury, intensive care unit length of stay, hospital length of stay, and chest tube output at 2-hour intervals. RESULTS: Of 12,043 eligible patients, 283 (2.35%) patients received cryoprecipitate. The median dose was 5.83 units (IQR 4.17-7.24) given at a median first transfusion time of 1.75 hours (IQR 0.73-4.46) after intensive care unit admission. After propensity scoring, we matched 195 cryoprecipitate recipients to 743 controls. Postoperative cryoprecipitate transfusion was not significantly associated with in-hospital mortality (odds ratio [OR] 1.10; 99% confidence interval [CI] 0.43-2.84; p=0.791), infection (OR 0.77; 99% CI 0.45-1.34; p=0.220), acute kidney injury (OR 1.03; 99% CI 0.65-1.62; p=0.876) or cumulative chest tube output (adjusted mean difference 8 hrs post transfusion, 11 mL; 99% CI -104 to 125; p=0.804). CONCLUSIONS: Although cryoprecipitate was typically given to sicker patients with more bleeding, its administration was not associated with worse outcomes. Large, multicentred studies are warranted to further elucidate cryoprecipitate's safety profile and patterns of use in cardiac surgery.

Core components and strategies for suicide and risk management protocols in mental health research: a scoping review.

BACKGROUND: Suicide and risk management protocols in mental health research aim to ensure patient safety, provide vital information on how to assess suicidal ideation, manage risk, and respond to unexpected and expected situations. However, there is a lack of literature that identifies specific components and strategies to include in suicide and risk management protocols (SRMPs) for mental health research. The goal of this scoping review was to review academic and grey literature to determine core components and associated strategies, which can be used to inform SRMPs in mental health research. METHODS AND ANALYSIS: The methodological framework outlined by Arksey and O'Malley was used for this scoping review. The search strategy, conducted by a medical librarian, was multidisciplinary and included seven databases. Two reviewers independently assessed eligibility criteria in each document and used a standardized charting form to extract relevant data. The extracted data were then examined using qualitative content analysis. Specifically, summative content analysis was used to identify the core components and strategies used in SRMPs. The data synthesis process was iterative. RESULTS: This review included 36 documents, specifically 22 peer-reviewed articles and 14 documents from the grey literature. Five core components of SRMPs emerged from the reviewed literature including: training; educational resources for research staff; educational resources for research participants; risk assessment and management strategies; and clinical and research oversight. Potentials strategies for risk mitigation within each of the core components are outlined. CONCLUSIONS: The five core components and associated strategies for inclusion in SRMPs will assist mental health researchers in conducting research safely and rigorously. Findings can inform the development of SRMPs and how to tailor them across various research contexts.

Help-Seeking Behaviors of Transition-Aged Youth for Mental Health Concerns: Qualitative Study.

BACKGROUND: Transition-aged youth are particularly vulnerable to mental health problems, yet they are one of the least likely demographic groups to seek help. OBJECTIVE: The aim of this study is to explore the influences on and patterns in help-seeking for mental health concerns among transition-aged youth who attend postsecondary schools in Canada. METHODS: A qualitative research design was used, involving 12 semistructured focus groups with transition-aged youth (17-29 years) who attended postsecondary schools in Canada. A thematic analysis was conducted to code the transcripts and develop themes. RESULTS: Four main themes and subthemes regarding the process and experience of help-seeking were generated: (1) the influence of formal service providers (accessibility and experiences), (2) the influence of social factors (system navigation and stigma), (3) the influence of health literacy (symptom recognition, acting on symptoms, digital tools and the internet, and mental health awareness campaigns), and (4) the influence of low-intensity sources of support, namely, self-help. CONCLUSIONS: Transition-aged youth seek help for mental health problems in different ways. Despite efforts to improve access to mental health services, transition-aged youth continue to face barriers to accessing these services, especially formal sources of support. The factors identified in this study that either hinder or facilitate help-seeking have pragmatic implications for developing help-seeking interventions and delivering mental health services for this population. In addition to other facilitators, family physicians are an important resource in the help-seeking process. Furthermore, digital help-seeking tools have unique characteristics that may make them an important source of support for transition-aged youth.

Effects of a Mobile and Web App (Thought Spot) on Mental Health Help-Seeking Among College and University Students: Randomized Controlled Trial.

BACKGROUND: Mental health disorders are the most prevalent health issues among postsecondary students, yet few solutions to this emerging crisis exist. While mobile health technologies are touted as promising solutions for the unmet mental health needs of these students, the efficacy of these tools remains unclear. In response to these gaps, this study evaluates Thought Spot, a mobile and web app created through participatory design research. OBJECTIVE: The goal of the research is to examine the impact of Thought Spot on mental health and wellness help-seeking intentions, behaviors, attitudes, self-stigma, and self-efficacy among postsecondary students in Canada. METHODS: A 2-armed randomized controlled trial involving students from three postsecondary institutions was conducted. Students were eligible if they were aged 17 to 29 years, enrolled in full-time or part-time studies, functionally competent in English, and had access to a compatible digital device. The usual care group received a mental health services information pamphlet. The intervention group received the Thought Spot app on their digital device. Thought Spot is a standalone app that allows users to add, review, and search crowdsourced information about nearby mental health and wellness services. Users can also track their mood on the app. Outcomes were self-assessed through questionnaires collected at baseline and 3 and 6 months. The primary outcome was change in formal help-seeking intentions from baseline to 6 months, measured by the General Help-Seeking Questionnaire. A mixed-effects model was used to compare the impact of usual care and intervention on the primary outcome (formal help-seeking intentions). Secondary outcomes included changes in informal help-seeking intentions and help-seeking behaviors, help-seeking attitudes, self-stigma, and self-efficacy. RESULTS: A total of 481 students were randomized into two groups: 240 to usual care, and 241 to the intervention group. There were no significant differences in help-seeking intentions between the usual care and intervention groups over 6 months (F2,877=0.85; P=.43, f=0.04). Both groups demonstrated similar increases in formal help-seeking intentions at 3 and 6 months (F2,877=23.52; P<.001, f=0.21). Compared with males, females sought more help from formal resources (OR 1.86; 95% CI 1.22 to 2.83, P=.001). Females were less likely to seek help from informal sources than males (OR 0.80; 95% CI 0.22 to 0.73, P<.001). CONCLUSIONS: Prompting postsecondary students about mental health and help-seeking appears to increase help-seeking intentions. mHealth interventions may be as effective as information pamphlets in increasing formal help-seeking but may confer a small advantage in driving help-seeking from informal sources. Although there is enthusiasm, developers and health policy experts should exercise caution and thoroughly evaluate these types of digital tools. Future studies should explore the cost-effectiveness of digital interventions and develop strategies for improving their efficacy. TRIAL REGISTRATION: ClinicalTrials.gov NCT03412461; https://clinicaltrials.gov/ct2/show/NCT03412461. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/resprot.6446.

Human induced pluripotent stem cell-derived lung progenitor and alveolar epithelial cells attenuate hyperoxia-induced lung injury.

BACKGROUND AIMS: Bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by disrupted lung growth, is the most common complication in extreme premature infants. BPD leads to persistent pulmonary disease later in life. Alveolar epithelial type 2 cells (AEC2s), a subset of which represent distal lung progenitor cells (LPCs), promote normal lung growth and repair. AEC2 depletion may contribute to persistent lung injury in BPD. We hypothesized that induced pluripotent stem cell (iPSC)-derived AECs prevent lung damage in experimental oxygen-induced BPD. METHODS: Mouse AECs (mAECs), miPSCs/mouse embryonic stem sells, human umbilical cord mesenchymal stromal cells (hUCMSCs), human (h)iPSCs, hiPSC-derived LPCs and hiPSC-derived AECs were delivered intratracheally to hyperoxia-exposed newborn mice. Cells were pre-labeled with a red fluorescent dye for in vivo tracking. RESULTS: Airway delivery of primary mAECs and undifferentiated murine pluripotent cells prevented hyperoxia-induced impairment in lung function and alveolar growth in neonatal mice. Similar to hUCMSC therapy, undifferentiated hiPSCs also preserved lung function and alveolar growth in hyperoxia-exposed neonatal NOD/SCID mice. Long-term assessment of hiPSC administration revealed local teratoma formation and cellular infiltration in various organs. To develop a clinically relevant cell therapy, we used a highly efficient method to differentiate hiPSCs into a homogenous population of AEC2s. Airway delivery of hiPSC-derived AEC2s and hiPSC-derived LPCs, improved lung function and structure and resulted in long-term engraftment without evidence of tumor formation. CONCLUSIONS: hiPSC-derived AEC2 therapy appears effective and safe in this model and warrants further exploration as a therapeutic option for BPD and other lung diseases characterized by AEC injury.

Volume assured pressure support mode use for non-invasive ventilation in pediatrics.

There has been increasing interest in utilizing volume assured pressure support (VAPS) modes of ventilation for children, which historically had only been favored in adult populations. In addition to patients with obesity hypoventilation syndrome, newer pediatric populations for which it has recently been prescribed include congenital central hypoventilation syndrome and children with neuromuscular disease such as Duchenne muscular dystrophy and spinal muscular atrophy. Given its expanding use in pediatrics, greater familiarity with VAPS is essential for pediatric pulmonologists and sleep physicians. This review article will highlight methods of initiation for this mode, specific ventilator settings, discussion of suitable pediatric patient populations, ventilator titrations via formal polysomnograms and detailed ventilator data downloads specific interpretation. Finally, common challenges to be aware of and how to troubleshoot relevant machine alarms will be reviewed.

Enhancing the value of digital health tools for mental health help-seeking in Canadian transitional aged youth during the pandemic: Qualitative study.

While the COVID-19 pandemic has greatly exacerbated the mental health challenges of transition-aged youth (TAY) between 17 and 29 years old, it has also led to the rapid adoption of digital tools for mental health help-seeking and treatment. However, to date, there has been limited work focusing on how this shift has impacted perceptions, needs and challenges of this population in using digital tools. The current study aims to understand their perspectives on mental health help-seeking during the pandemic and emerging issues related to digital tools (e.g., digital health equity, inclusivity). A total of 16 TAY were invited from three post-secondary institutions in the Greater Toronto Area. A total of two streams of focus groups were held and participants were invited to share their perceptions, needs and experiences. Five main themes were identified: 1) Helpfulness of a centralized resource encompassing a variety of diverse mental health supports help-seeking; 2) The impact of the shift to online mental health support on the use of informal supports; 3) Digital tool affordability and availability; 4) Importance of inclusivity for digital tools; and 5) Need for additional support for mental health seeking and digital tool navigation. Future work should examine how these needs can be addressed through new and existing digital mental health help-seeking tools for TAY.

Amyloid ß (Aß) peptide directly activates amylin-3 receptor subtype by triggering multiple intracellular signaling pathways.

The two age-prevalent diseases Alzheimer disease and type 2 diabetes mellitus share many common features including the deposition of amyloidogenic proteins, amyloid ß protein (Aß) and amylin (islet amyloid polypeptide), respectively. Recent evidence suggests that both Aß and amylin may express their effects through the amylin receptor, although the precise mechanisms for this interaction at a cellular level are unknown. Here, we studied this by generating HEK293 cells with stable expression of an isoform of the amylin receptor family, amylin receptor-3 (AMY3). Aß1-42 and human amylin (hAmylin) increase cytosolic cAMP and Ca(2+), trigger multiple pathways involving the signal transduction mediators protein kinase A, MAPK, Akt, and cFos. Aß1-42 and hAmylin also induce cell death during exposure for 24-48 h at low micromolar concentrations. In the presence of hAmylin, Aß1-42 effects on HEK293-AMY3-expressing cells are occluded, suggesting a shared mechanism of action between the two peptides. Amylin receptor antagonist AC253 blocks increases in intracellular Ca(2+), activation of protein kinase A, MAPK, Akt, cFos, and cell death, which occur upon AMY3 activation with hAmylin, Aß1-42, or their co-application. Our data suggest that AMY3 plays an important role by serving as a receptor target for actions Aß and thus may represent a novel therapeutic target for development of compounds to treat neurodegenerative conditions such as Alzheimer disease.

Cerebellar Granule Cells Develop Non-neuronal 3D Genome Architecture over the Lifespan.

The cerebellum contains most of the neurons in the human brain, and exhibits unique modes of development, malformation, and aging. For example, granule cells-the most abundant neuron type-develop unusually late and exhibit unique nuclear morphology. Here, by developing our high-resolution single-cell 3D genome assay Dip-C into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we were able to resolve the first 3D genome structures of single cerebellar cells, create life-spanning 3D genome atlases for both human and mouse, and jointly measure transcriptome and chromatin accessibility during development. We found that while the transcriptome and chromatin accessibility of human granule cells exhibit a characteristic maturation pattern within the first year of postnatal life, 3D genome architecture gradually remodels throughout life into a non-neuronal state with ultra-long-range intra-chromosomal contacts and specific inter-chromosomal contacts. This 3D genome remodeling is conserved in mice, and robust to heterozygous deletion of chromatin remodeling disease-associated genes (Chd8 or Arid1b). Together these results reveal unexpected and evolutionarily-conserved molecular processes underlying the unique development and aging of the mammalian cerebellum.

Lifelong restructuring of 3D genome architecture in cerebellar granule cells.

The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell three-dimensional (3D) genome assay-diploid chromosome conformation capture, or Dip-C-into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we resolved the first 3D genome structures of single cerebellar cells, created life-spanning 3D genome atlases for both humans and mice, and jointly measured transcriptome and chromatin accessibility during development. We found that although the transcriptome and chromatin accessibility of cerebellar granule neurons mature in early postnatal life, 3D genome architecture gradually remodels throughout life, establishing ultra-long-range intrachromosomal contacts and specific interchromosomal contacts that are rarely seen in neurons. These results reveal unexpected evolutionarily conserved molecular processes that underlie distinctive features of neural development and aging across the mammalian life span.

Association of Perioperative Cryoprecipitate Transfusion and Mortality After Cardiac Surgery.

BACKGROUND: Cryoprecipitate is often transfused in patients undergoing cardiac surgery. However, its safety and effectiveness remain uncertain. METHODS: This study was a propensity score-matched analysis of data from the Australian and New Zealand Society of Cardiac and Thoracic Surgeons National Cardiac Surgery Database. The study included adults undergoing cardiac surgery between 2005 and 2018 across 38 sites. The association between perioperative cryoprecipitate transfusion and clinical outcomes was estimated, with a primary outcome of operative mortality. RESULTS: Of 119,132 eligible patients, 11,239 (9.43%) patients received cryoprecipitate. The median cumulative dose was 8 U (interquartile range, 5-10 U). After propensity score matching, we matched 9055 cryoprecipitate recipients to 9055 control subjects. Postoperative cryoprecipitate transfusion was associated with reduced operative mortality (odds ratio [OR], 0.82; 99% CI, 0.69-0.97; P = .002) and long-term mortality (hazard ratio, 0.92; 99% CI, 0.87-0.97; P = .0042). It was also associated with a reduction in acute kidney injury (OR, 0.85; 99% CI, 0.73-0.98; P = .0037) and all-cause infection (OR, 0.77; 99% CI, 0.67-0.88; P < .0001). These findings were observed despite increased rates of return to the operating room (OR, 1.36; 99% CI, 1.22-1.51; P < .0001) and cumulative 4-hour postoperative chest tube output (adjusted mean difference in mL, 97.69; 99% CI, 81.65;113.74; P < .0001). CONCLUSIONS: In a large, multicenter cohort study and after propensity score matching, perioperative transfusion of cryoprecipitate was associated with reduced operative and long-term mortality.

Every gene everywhere all at once: High-precision measurement of 3D chromosome architecture with single-cell Hi-C.

The three-dimensional (3D) structure of chromosomes influences essential biological processes such as gene expression, genome replication, and DNA damage repair and has been implicated in many developmental and degenerative diseases. In the past two centuries, two complementary genres of technology-microscopy, such as fluorescence in situ hybridization (FISH), and biochemistry, such as chromosome conformation capture (3C or Hi-C)-have revealed general principles of chromosome folding in the cell nucleus. However, the extraordinary complexity and cell-to-cell variability of the chromosome structure necessitate new tools with genome-wide coverage and single-cell precision. In the past decade, single-cell Hi-C emerges as a new approach that builds upon yet conceptually differs from bulk Hi-C assays. Instead of measuring population-averaged statistical properties of chromosome folding, single-cell Hi-C works as a proximity-based "biochemical microscope" that measures actual 3D structures of individual genomes, revealing features hidden in bulk Hi-C such as radial organization, multi-way interactions, and chromosome intermingling. Single-cell Hi-C has been used to study highly dynamic processes such as the cell cycle, cell-type-specific chromosome architecture ("structure types"), and structure-expression interplay, deepening our understanding of DNA organization and function.

Pediatric Chronic Tracheostomy Care: An Evaluation of an Innovative Competency-Based Education Program for Community Health Care Providers.

Objective: To evaluate the immediate and sustained knowledge retention and sense of self-efficacy of homecare nurses following completion of a standardized competency-based tracheostomy education course. Safe discharge of children requiring tracheostomy with or without ventilation relies on the competence of homecare nurses. Study Design: Pragmatic, randomized controlled trial of 44 homecare nurses. Participants were randomized into the intervention group (n = 21), which received the tracheostomy course, or the control group (n = 23), which received an enterostomy and vascular access course. Multiple-choice question (MCQ) knowledge assessments and self-efficacy questionnaires were administered to both groups pre-course and post-course at 6 week, 3 month, 6 month, and 12 month follow-ups. Results: Twenty participants in the intervention group and 19 in the control group were included. Four withdrew from the study and two crossed over from the control into the intervention arm. The change in mean self-efficacy scores (total score = 100) was significantly higher in the intervention group than in the control group at 6 weeks (intervention (mean ± SD): 18.6 ± 14.5; control: 6.6 ± 20.4; p = 0.04) and 3 months (intervention: 19.6 ± 14.2; control: 5.2 ± 17.0; p = 0.007), and trended higher at 6 months (intervention: 18.0 ± 14.5; control: 6.9 ± 24.1; p = 0.1). The change in mean MCQ assessment scores (total score = 20) trended higher in the intervention group than in the control group at 6 weeks (intervention (mean ± SD): 1.8 ± 2.2; control: 1.6, ± 2.9; p = 0.8). Conclusions: Homecare nurses who attended the tracheostomy course demonstrated a higher sense of self-efficacy at long-term follow-up. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT04559932.