BCL-XL-targeting antibody-drug conjugates are active in preclinical models and mitigate on-mechanism toxicity of small-molecule inhibitors.

Overexpression of the antiapoptotic protein B-cell lymphoma-extra large (BCL-XL) is associated with drug resistance and disease progression in numerous cancers. The compelling nature of this protein as a therapeutic target prompted efforts to develop selective small-molecule BCL-XL inhibitors. Although efficacious in preclinical models, we report herein that selective BCL-XL inhibitors cause severe mechanism-based cardiovascular toxicity in higher preclinical species. To overcome this liability, antibody-drug conjugates were constructed using altered BCL-XL-targeting warheads, unique linker technologies, and therapeutic antibodies. The epidermal growth factor receptor-targeting antibody-drug conjugate AM1-15 inhibited growth of tumor xenografts and did not cause cardiovascular toxicity nor dose-limiting thrombocytopenia in monkeys. While an unprecedented BCL-XL-mediated toxicity was uncovered in monkey kidneys upon repeat dosing of AM1-15, this toxicity was mitigated via further drug-linker modification to afford AM1-AAA (AM1-25). The AAA drug-linker has since been incorporated into mirzotamab clezutoclax, the first selective BCL-XL-targeting agent to enter human clinical trials.

Mosaic and mixed HIV-1 glycoprotein nanoparticles elicit antibody responses to broadly neutralizing epitopes.

An effective human immunodeficiency virus 1 (HIV-1) vaccine will most likely have to elicit broadly neutralizing antibodies (bNAbs) to overcome the sequence diversity of the envelope glycoprotein (Env). So far, stabilized versions of Env, such as SOSIP trimers, have been able to induce neutralizing antibody (NAb) responses, but those responses are mainly strain-specific. Here we attempted to broaden NAb responses by using a multivalent vaccine and applying a number of design improvements. First, we used highly stabilized SOSIP.v9 trimers. Second, we removed any holes in the glycan shields and optimized glycan occupancy to avoid strain-specific glycan hole responses. Third, we selected five sequences from the same clade (B), as we observed previously that combining Env trimers from clade A, B and C did not improve cross-reactive responses, as they might have been too diverse. Fourth, to improve antibody (Ab) responses, the Env trimers were displayed on two-component I53-50 nanoparticles (NPs). Fifth, to favor activation of cross-reactive B cells, the five Env trimers were co-displayed on mosaic NPs. Sixth, we immunized rabbits four times with long intervals between vaccinations. These efforts led to the induction of cross-reactive B cells and cross-reactive binding Ab responses, but we only sporadically detected cross-neutralizing responses. We conclude that stabilized HIV-1 Env trimers that are not modified specifically for priming naive B cells are unable to elicit strong bNAb responses, and infer that sequential immunization regimens, most likely starting with specific germline-targeting immunogens, will be necessary to overcome Env's defenses against the induction of NAbs. The antigens described here could be excellent boosting immunogens in a sequential immunization regimen, as responses to bNAb epitopes were induced.

Protocol for COACH, an evidence-based intervention for improved head impact safety in youth American football developed using a community-engaged approach.

Subconcussive, repetitive head impacts sustained in collision sports may negatively affect brain health. American football practices are controlled environments amenable to intervention. Engaging community members is essential for successful development, implementation, and sustainability of viable interventions. The objective of this study is to develop and pilot test an evidence-based intervention to reduce head impact exposure in youth American football (i.e., football), using a community-engaged approach. This manuscript describes the co-design of the intervention and associated implementation plan and the study protocol for evaluating the effectiveness and feasibility of the intervention and implementation plan. In the first part of this study, focus groups with parents and coaches, and individual interviews with organizational leaders associated with two teams at the middle school level were conducted. An anonymous survey assessing beliefs and perceptions of non-concussive head impacts was given to parents, coaches, and organizational leaders within the local youth football league. Following the football season, qualitative and quantitative data describing determinants of head acceleration events in football were shared with 12 stakeholders of coaches, league and school administrators, parents, an athletic trainer, and local university player development director. Together, we co-designed COACH (COmmunities Aligned to reduce Concussion and Head impact exposure) and implementation plan using a strategic planning approach. The preliminary effectiveness and feasibility were assessed in the second part of this study. Youth football players participating on the teams in year 1 (control teams) were fitted with mouthpiece-based head kinematic sensors which measure head acceleration events (HAEs). HAEs were collected and quantified during team activities. Preliminary effectiveness of the intervention to reduce HAEs was measured among two new teams pilot testing COACH with mouthpiece-based sensors, while simultaneously monitoring implementation of the intervention. We report our study design and evaluation, and opportunities and challenges with our approach. The results will inform a future full-scale pragmatic trial to assess the implementation and effectiveness of the intervention program. NCT04908930.

Air pollution below US regulatory standards and cardiovascular diseases using a double negative control approach.

Growing evidence suggests that long-term air pollution exposure is a risk factor for cardiovascular mortality and morbidity. However, few studies have investigated air pollution below current regulatory limits, and causal evidence is limited. We use a double negative control approach to examine the association between long-term exposure to air pollution at low concentration and cardiovascular hospitalizations among US Medicare beneficiaries aged ≥65 years between 2000 and 2016. The expected values of the negative outcome control (preceding-year hospitalizations) regressed on exposure and negative exposure control (subsequent-year exposure) are treated as a surrogate for omitted confounders. With analyses separately restricted to low-pollution areas (PM2.5 < 9 µg/m³, NO2 < 75.2 µg/m3 [40 ppb], warm-season O3 < 88.2 µg/m3 [45 ppb]), we observed positive associations of the three pollutants with hospitalization rates of stroke, heart failure, and atrial fibrillation and flutter. The associations generally persisted in demographic subgroups. Stricter national air quality standards should be considered.

Double Teeth and Coexistent Anomalies: Examples From Continental Africa.

OBJECTIVES: Whether gemination or fusion, double teeth are rare worldwide, including Africa based on few published data. New cases from the continent are tallied, and anomalies potentially associated with double teeth are identified. These findings should interest a range of dental researchers. METHODS: The presence of double teeth was recorded in 97 modern and premodern North and sub-Saharan African samples (5631 inds.). They and coexistent anomalies are described relative to published examples. Prevalence was estimated as possible, using a Poisson model for 95% confidence intervals (CI). RESULTS: Three maxillary double teeth were identified: a primary left lateral incisor in a Nubian child (1938-1756 BC), permanent left central incisor in an adult Egyptian (3650-3500 BC), and permanent right central incisor in a modern (19th century) adult from Guinea. Each co-occurs, respectively, with a talon cusp, peg lateral incisor and, in the latter individual, second premolar crown variation with rotation, and third molar dens evaginatus. Double tooth prevalence is 0.048% (CI 0.001%-0.270%), with regional variation, in premodern, and 0.000% in modern North Africans. It is 0.000% for premodern and 0.048% for modern sub-Saharan Africans (0.008%-1.714%). CONCLUSIONS: The double incisors are comparable to other global examples, indicative of common developmental processes during odontogenesis. Prevalence is lower than published modern rates, to suggest some exceptionality in Africans as reported earlier for other dental variants. Finally, though circumstantial, double teeth and accompanying anomalies may share an etiology. Continuing research overall, and in Africa specifically, will promote an improved understanding of double teeth formation and expression.

Open Burn Pit Exposure in Headache Disorder and Migraine.

Importance: Open burn pits have commonly been used for waste disposal by the US military but have not been systematically investigated as an independent risk factor for headache disorders. Objective: To evaluate the association between exposure to open burn pits and incidence of headache and migraine. Design, Setting, and Participants: This retrospective cohort study used data from the Veterans Health Administration Headache Cohort along with data from the US Department of Defense and the Airborne Hazards and Open Burn Pit (AH&OBP) Registry to assess registry participants with potential exposure to open burn pits in the Veterans Health Administration from April 1, 2014, through October 31, 2022. Participants were included by linking data from the AH&OBP Registry to their US Department of Defense and Veterans Health Administration electronic health records. Those with preexisting headache were removed from the analytic sample. The analysis was conducted between November 1, 2022, and January 31, 2024. Exposure: Open burn pit exposure composite variables based on the registry questionnaire were examined, specifically being near open burn pits, days near open burn pits, and having open burn pit duties. Main Outcomes and Measures: Primary incident outcomes included medically diagnosed headache disorders and medically diagnosed migraine. Results: The analytic sample included 247 583 veterans (mean [SD] age, 27.9 [7.7] years; 222 498 [89.9%] male). After covariates were controlled for at baseline, participants who were near an open burn pit with open burn pit duties had the highest adjusted odds of medically diagnosed headache disorders (adjusted odds ratio [AOR], 1.59; 95% CI, 1.46-1.74), migraine (AOR, 1.60; 95% CI, 1.43-1.79), and self-reported disabling migraine (AOR, 1.93; 95% CI, 1.69-2.20) compared with those without exposure. The 2 highest quartiles of cumulative burn pit exposure (290-448 days and >448 days) had significantly higher adjusted odds of medically diagnosed headache (290-448 days: AOR, 1.20; 95% CI, 1.09-1.31; >448 days: AOR, 1.55; 95% CI, 1.41-1.70) and migraine (290-448 days: AOR, 1.19; 95% CI, 1.07-1.34; >448 days: AOR, 1.48; 95% CI, 1.32-1.65). Conclusions and Relevance: In this cohort study, a dose-dependent association existed between open burn pit exposure and medically diagnosed headache and migraine. These new data identify potentially important associations between open burn bit exposure and new-onset headache among service personnel as well as a possible health condition that may be encountered more frequently in Veterans Health Administration facilities during mandatory screening for military exposures.

Long-term nighttime aircraft noise exposure and risk of hypertension in a prospective cohort of female nurses.

There is growing interest in cardiometabolic outcomes associated with nighttime noise, given that noise can disturb sleep and sleep disturbance can increase cardiometabolic risk such as hypertension. However, there is little empirical research evaluating the association between nighttime aircraft noise and hypertension risk. In this study, we expand on previous work to evaluate associations between nighttime aircraft noise exposure and self-reported hypertension incidence in the Nurses' Health Studies (NHS/NHSII), two US-wide cohorts of female nurses. Annual nighttime average aircraft sound levels (Lnight) surrounding 90 airports for 1995-2015 (in 5-year intervals) were modeled using the Aviation Environmental Design Tool and assigned to participants' geocoded addresses over time. Hypertension risk was estimated for each cohort using time-varying Cox proportional-hazards models for Lnight dichotomized at 45 dB (dB), adjusting for individual-level hypertension risk factors, area-level socioeconomic status, region, and air pollution. Random effects meta-analysis was used to combine cohort results. Among 63,229 NHS and 98,880 NHSII participants free of hypertension at study baseline (1994/1995), we observed 33,190 and 28,255 new hypertension cases by 2014/2013, respectively. Although ∼1% of participants were exposed to Lnight ≥45 dB, we observed an adjusted hazard ratio (HR) of 1.10 (95% CI: 0.96, 1.27) in NHS and adjusted HR of 1.12 (95% CI: 0.98, 1.28) in NHSII, comparing exposure to Lnight ≥45 versus <45 dB(A). In meta-analysis, we observed an adjusted HR of 1.11 (95% CI: 1.01, 1.23). These results were attenuated with adjustment for additional variables such as body mass index. Our findings support a modest positive association between nighttime aircraft noise and hypertension risk across NHS/NHSII, which may reinforce the concept that sleep disturbance contributes to noise-related disease burden.

Racial and Ethnic Differences in Mobile App Use for Meeting Sexual Partners Among Young Men Who Have Sex With Men and Young Transgender Women: Cross-Sectional Study.

Background: Young men who have sex with men and young transgender women (YMSM-YTW) use online spaces to meet sexual partners with increasing regularity, and research shows that experiences of racism online mimics the real world. Objective: We analyzed differences by race and ethnicity in web-based and mobile apps used to meet sexual partners as reported by Chicago-based YMSM-YTW in 2016-2017. Methods: A racially and ethnically diverse sample of 643 YMSM-YTW aged 16-29 years were asked to name websites or mobile apps used to seek a sexual partner in the prior 6 months, as well as provide information about sexual partnerships from the same period. We used logistic regression to assess the adjusted association of race and ethnicity with (1) use of any website or mobile apps to find a sexual partner, (2) use of a "social network" to find a sexual partner compared to websites or mobile apps predominantly used for dating or hookups, (3) use of specific websites or mobile apps, and (4) reporting successfully meeting a sexual partner online among website or mobile app users. Results: While most YMSM-YTW (454/643, 70.6%) used websites or mobile apps to find sexual partners, we found that Black non-Hispanic YMSM-YTW were significantly less likely to report doing so (comparing White non-Hispanic to Black non-Hispanic: adjusted odds ratio [aOR] 1.74, 95% CI 1.10-2.76). Black non-Hispanic YMSM-YTW were more likely to have used a social network site to find a sexual partner (comparing White non-Hispanic to Black non-Hispanic: aOR 0.20, 95% CI 0.11-0.37), though this was only reported by one-third (149/454, 32.8%) of all app-using participants. Individual apps used varied by race and ethnicity, with Grindr, Tinder, and Scruff being more common among White non-Hispanic YMSM-YTW (93/123, 75.6%; 72/123, 58.5%; and 30/123, 24.4%, respectively) than among Black non-Hispanic YMSM-YTW (65/178, 36.5%; 25/178, 14%; and 4/178, 2.2%, respectively) and Jack'd and Facebook being more common among Black non-Hispanic YMSM-YTW (105/178, 59% and 64/178, 36%, respectively) than among White non-Hispanic YMSM-YTW (6/123, 4.9% and 8/123, 6.5%, respectively). Finally, we found that while half (230/454, 50.7%) of YMSM-YTW app users reported successfully meeting a new sexual partner on an app, Black non-Hispanic YMSM-YTW app users were less likely to have done so than White non-Hispanic app users (comparing White non-Hispanic to Black non-Hispanic: aOR 2.46, 95% CI 1.50-4.05). Conclusions: We found that Black non-Hispanic YMSM-YTW engaged with websites or mobile apps and found sexual partners systematically differently than White non-Hispanic YMSM-YTW. Our findings give a deeper understanding of how racial and ethnic sexual mixing patterns arise and have implications for the spread of sexually transmitted infections among Chicago's YMSM-YTW.

The effect of safety modifications on head kinematics experienced during common skills in women's artistic gymnastics.

The objective of this study was to evaluate the effect of skill modifications on head motion experienced during women's artistic gymnastics skills. Nine gymnasts (four beginner and five advanced) completed three trials of up to 24 skill progressions, each consisting of a skill and two progressive safety modifications. Gymnasts were instrumented with mouthpiece sensors embedded with an accelerometer and gyroscope collecting motion data at 200, 300, and 500 Hz during each skill performance. Peak-to-peak linear and rotational kinematics during contact phases and peak rotational kinematics during non-contact phases were computed. A mixed-effects model was used to compare differences in modification status nested within skill categories. Timer skills (i.e. drills that simulate performance of a gymnastics skill) resulted in the highest median ΔLA and ΔRA of all skill categories, and 132 skill performances exceeded 10 g ΔLA during a contact phase. Modifications were associated with significant reductions in head kinematics during contact phases of timers, floor skills, bar releases, and vault skills. Gymnasts can be exposed to direct and indirect head accelerations at magnitudes consistent with other youth contact sports, and common safety modifications may be effective at reducing head motion during contact and non-contact phases of gymnastics skills.

Neural network architecture of a mammalian brain.

Connectomics research is making rapid advances, although models revealing general principles of connectional architecture are far from complete. Our analysis of 106 published connection reports indicates that the adult rat brain interregional connectome has about 76,940 of a possible 623,310 axonal connections between its 790 gray matter regions mapped in a reference atlas, equating to a network density of 12.3%. We examined the sexually dimorphic network using multiresolution consensus clustering that generated a nested hierarchy of interconnected modules/subsystems with three first-order modules and 157 terminal modules in females. Top-down hierarchy analysis suggests a mirror-image primary module pair in the central nervous system's rostral sector (forebrain-midbrain) associated with behavior control, and a single primary module in the intermediate sector (rhombicbrain) associated with behavior execution; the implications of these results are considered in relation to brain development and evolution. Bottom-up hierarchy analysis reveals known and unfamiliar modules suggesting strong experimentally testable hypotheses. Global network analyses indicate that all hubs are in the rostral module pair, a rich club extends through all three primary modules, and the network exhibits small-world attributes. Simulated lesions of all regions individually enabled ranking their impact on global network organization, and the visual path from the retina was used as a specific example, including the effects of cyclic connection weight changes from the endogenous circadian rhythm generator, suprachiasmatic nucleus. This study elucidates principles of interregional neuronal network architecture for a mammalian brain and suggests a strategy for modeling dynamic structural connectivity.

Design and immunogenicity of an HIV-1 clade C pediatric envelope glycoprotein stabilized by multiple platforms.

Various design platforms are available to stabilize soluble HIV-1 envelope (Env) trimers, which can be used as antigenic baits and vaccine antigens. However, stabilizing HIV-1 clade C trimers can be challenging. Here, we stabilized an HIV-1 clade C trimer based on an Env isolated from a pediatric elite-neutralizer (AIIMS_329) using multiple platforms, including SOSIP.v8.2, ferritin nanoparticles (NP) and an I53-50 two-component NP, followed by characterization of their biophysical, antigenic, and immunogenic properties. The stabilized 329 Envs showed binding affinity to trimer-specific HIV-1 broadly neutralizing antibodies (bnAbs), with negligible binding to non-neutralizing antibodies (non-nAbs). Negative-stain electron microscopy (nsEM) confirmed the native-like conformation of the Envs. Multimerization of 329 SOSIP.v8.2 on ferritin and two-component I53-50 NPs improved the overall affinity to HIV-1 bnAbs and immunogenicity in rabbits. These stabilized HIV-1 clade C 329 Envs demonstrate the potential to be used as antigenic baits and as components of multivalent vaccine candidates in future.

Improving Timely Administration of Essential Outpatient Medications in a Pediatric ED.

BACKGROUND AND OBJECTIVES: The complexity of pediatric patients' outpatient medication regimens is increasing, and risk for medication errors is compounded in a busy emergency department (ED). As ED length of stay (LOS) increases, timely and accurate administration of essential outpatient medications has become increasingly challenging. Our objective was to increase the frequency of ordering of essential outpatient medications for patients with ED LOS >4 hours from 56% to 80% by June 2023. METHODS: We conducted a quality improvement (QI) initiative in a pediatric ED with ∼60 000 annual visits comprising a total of 91 000 annual medication orders. We defined essential outpatient medications as antiepileptic drugs, cardiovascular medications, and immunosuppressants. Our QI interventions included a combination of electronic health record interventions, a triage notification system to identify patients with essential outpatient medications, and widespread educational interventions including trainee orientation and individualized nursing education. The primary outcome measure was percentage of essential outpatient medications ordered among patients with an ED LOS >4 hours, with a secondary measure of outpatient medication safety events. RESULTS: Baseline monthly ordering rate of selected medications for patients with an ED LOS >4 hours was 54%, with an increase to 66% over the study period. Refining our population yielded a rate of 81%. Outpatient medication safety events remained unchanged, with an average of 952 ED encounters between events. CONCLUSIONS: A multidisciplinary QI initiative led to increased essential outpatient medication ordering for patients in a pediatric ED with no change in safety events.

Long-term air pollution exposure and incident physical disability in older US adults: a cohort study.

BACKGROUND: Disability is a key marker of overall physical health in older adults and is often preceded by chronic disease. Although air pollution is a well recognised risk factor for multiple chronic diseases, its association with physical disability has not been well characterised. We investigated the associations of air pollutants with physical disability in a large cohort representative of older adults in the USA. METHODS: We used biennial data on incident activities of daily living (ADL) disability collected from respondents of the Health and Retirement Survey between 2000 and 2016. As part of the Environmental Predictors of Cognitive Health and Aging study, we estimated 10-year average PM2·5, PM10-2·5, nitrogen dioxide (NO2), and ozone (O3) concentrations at participant residences before each survey using spatiotemporal prediction models. We used a time-varying, weighted Cox model to estimate hazard ratios (HRs) for incident physical disability per interquartile increase of air pollution with detailed adjustments for confounders. FINDINGS: Among 15 411 respondents aged 65 years and older (mean age 70·2 [SD 6·5] years; 55% female, 45% male), 48% of respondents reported newly having ADL disability during a mean follow-up of 7·9 years (SD 4·7). In fully adjusted models, we found greater risks of ADL disability associated with higher concentrations of PM2·5 (HR 1·03 per 3·7 µg/m³ [95% CI 0·99-1·08], p=0·16), PM10-2·5 (1·05 per 4·9 µg/m³ [1·00-1·11], p=0·022), and NO2 (1·03 per 7·5 ppb [0·99-1·08]. p=0·064), although not all these associations were statistically significant. In contrast, O3 was associated with a lower risk of ADL disability (0·95 per 3·7 ppb [0·91-1·00], p=0·030). In a multi-pollutant model, associations were similar to the single-pollutant models for PM10-2·5 (1·05 per 4·9 µg/m³ [1·00-1·11], p=0·041) and O3 (0·94 per 3·7 ppb [0·88-1·01], p=0·083). INTERPRETATION: Our findings suggest that air pollution might be an underappreciated risk factor for physical disability in later life, although additional research is needed. FUNDING: National Institutes of Environmental Health Sciences and National Institute on Aging.

Comprehensiveness of State Insurance Laws and Perceived Access to Pediatric Mental Health Care.

Importance: Many US children and adolescents with mental and behavioral health (MBH) conditions do not access MBH services. One contributing factor is limited insurance coverage, which is influenced by state MBH insurance parity legislation. Objective: To investigate the association of patient-level factors and the comprehensiveness of state MBH insurance legislation with perceived poor access to MBH care and perceived inadequate MBH insurance coverage for US children and adolescents. Design, Setting, and Participants: This retrospective cross-sectional study was conducted using responses by caregivers of children and adolescents aged 6 to 17 years with MBH conditions in the National Survey of Children's Health and State Mental Health Insurance Laws Dataset from 2016 to 2019. Data analyses were conducted from May 2022 to January 2024. Exposure: MBH insurance legislation comprehensiveness defined by State Mental Health Insurance Laws Dataset (SMHILD) scores (range, 0-7). Main Outcomes and Measures: Perceived poor access to MBH care and perceived inadequacy of MBH insurance were assessed. Multivariable regression models adjusted for individual-level characteristics. Results: There were 29 876 caregivers of children and adolescents with MBH conditions during the study period representing 14 292 300 youths nationally (7 816 727 aged 12-17 years [54.7%]; 8 455 171 male [59.2%]; 292 543 Asian [2.0%], 2 076 442 Black [14.5%], and 9 942 088 White [69.6%%]; 3 202 525 Hispanic [22.4%]). A total of 3193 caregivers representing 1 770 492 children and adolescents (12.4%) perceived poor access to MBH care, and 3517 caregivers representing 1 643 260 of 13 175 295 children and adolescents (12.5%) perceived inadequate MBH insurance coverage. In multivariable models, there were higher odds of perceived poor access to MBH care among caregivers of Black (adjusted odds ratio [aOR], 1.35; 95% CI, 1.04-1.75) and Asian (aOR, 1.69; 95% CI, 1.01-2.84) compared with White children and adolescents. As exposures to adverse childhood experiences (ACEs) increased, the odds of perceived poor access to MBH care increased (aORs ranged from 1.68; 95%, CI 1.32-2.13 for 1 ACE to 4.28; 95% CI, 3.17-5.77 for ≥4 ACEs compared with no ACEs). Compared with living in states with the least comprehensive MBH insurance legislation (SMHILD score, 0-2), living in states with the most comprehensive legislation (SMHILD score, 5-7) was associated with lower odds of perceived poor access to MBH care (aOR, 0.79; 95% CI, 0.63-0.99), while living in states with moderately comprehensive legislation (score, 4) was associated with higher odds of perceived inadequate MBH insurance coverage (aOR, 1.23; 95% CI, 1.01-1.49). Conclusions and Relevance: In this study, living in states with the most comprehensive MBH insurance legislation was associated with lower odds of perceived poor access to MBH care among caregivers for children and adolescents with MBH conditions. This finding suggests that advocacy for comprehensive mental health parity legislation may promote improved child and adolescent access to MBH services.

Netrin-1 and UNC5B Cooperate with Integrins to Mediate YAP-Driven Cytostasis.

Opposite expression and pro- or anti-cancer function of YAP and its paralog TAZ/WWTR1 stratify cancers into binary YAPon and YAPoff classes. These transcriptional coactivators are oncogenic in YAPon cancers. In contrast, YAP/TAZ are silenced epigenetically along with their integrin and extracellular matrix adhesion target genes in neural and neuroendocrine YAPoff cancers (e.g., small cell lung cancer, retinoblastoma). Forced YAP/TAZ expression induces these targets, causing cytostasis in part through Integrin-αV/ß5, independent of the integrin-binding RGD ligand. Other effectors of this anticancer YAP function are unknown. Here, using clustered regularly interspaced short palindromic repeats (CRISPR) screens, we link the Netrin receptor UNC5B to YAP-induced cytostasis in YAPoff cancers. Forced YAP expression induces UNC5B through TEAD DNA-binding partners, as either TEAD1/4-loss or a YAP mutation that disrupts TEAD-binding (S94A) blocks, whereas a TEAD-activator fusion (TEAD(DBD)-VP64) promotes UNC5B induction. Ectopic YAP expression also upregulates UNC5B relatives and their netrin ligands in YAPoff cancers. Netrins are considered protumorigenic, but knockout and peptide/decoy receptor blocking assays reveal that in YAPoff cancers, UNC5B and Netrin-1 can cooperate with integrin-αV/ß5 to mediate YAP-induced cytostasis. These data pinpoint an unsuspected Netrin-1/UNC5B/integrin-αV/ß5 axis as a critical effector of YAP tumor suppressor activity. SIGNIFICANCE: Netrins are widely perceived as procancer proteins; however, we uncover an anticancer function for Netrin-1 and its receptor UNC5B.

Extracellular microRNAs associated with psychiatric symptoms in the Normative Aging Study.

Earlier studies have revealed microRNAs (miRNAs) as potential biomarkers for neurological conditions, however, such evidence on psychiatric outcomes is limited. We utilized the Normative Aging Study (NAS) cohort to investigate the associations between extracellular miRNAs (ex-miRNA) and psychiatric symptoms among a group of older male adults, along with the targeted genes and biological pathways. We studied 569 participants with miRNA profile primarily measured in extracellular vesicles isolated from plasma, and psychiatric symptoms reported over 1996-2014 with repeated measures. Global and dimension scales of psychiatric symptoms were measured via the administration of Brief Symptom Inventory (BSI) per visit covering nine aspects of psychiatric health, such as anxiety, depression, hostility, psychoticism, etc. Ex-miRNAs were profiled using small RNA sequencing. Associations of expression of 395 ex-miRNAs (present in >70% samples) with current mental status were assessed using single-miRNA as well as Least Absolute Shrinkage and Selection Operator (LASSO)-based multi-miRNAs linear mixed effects models adjusting for key demographic and behavioral factors. Biological functions were explored using pathway analyses. We identified ex-miRNAs associated with each BSI scale. In particular, hsa-miR-320d was consistently identified for two global scales. Similar overlapping miRNAs across global and dimension scores included hsa-miR-379-3p, hsa-miR-1976, hsa-miR-151a-5p, hsa-miR-151b, hsa-miR-144-3p, etc. Top KEGG pathways for identified miRNAs included p53 signaling, Hippo signaling, FoxO signaling, protein processing in endoplasmic reticulum and several pathways related with cancer and neurological diseases. This study provided early evidence supporting the associations between extracellular miRNAs and psychiatric conditions. MiRNAs may serve as biomarkers of subclinical psychiatric illness in older adults.

Trends in Cardiovascular Risk Factors in Canada: Variation by Migration and Temporal Factors, 2001-2018.

Background: Cardiovascular disease is a leading cause of death in Canada, but how the major cardiovascular risk factors vary across ethnicity and immigration status has yet to be examined. Methods: Using data from the Canadian Community Health Surveys, national trends in health conditions (hypertension, diabetes, high blood cholesterol level, and obesity) and health behaviours (smoking, activity levels, and alcohol consumption) were estimated for the period 2001-2018. In this cross-sectional study, the trends were then compared across sex, age, ethnicity, and immigration status. Results: A total of 1,065,391 respondents were examined, for the period 2001-2018. During the study period, the prevalence of the following risk factors increased in Canada over time, as follows: diabetes by 54.5%; hypertension by 23.4%; and obesity by 32.3%. For health behaviours, smoking prevalence decreased overall, especially in racialized populations. Heavy drinking was most prevalent for nonracialized and non-Indigenous Canadian-born populations, and was of lowest prevalence among racialized immigrants. Physical inactivity was most prevalent for racialized immigrant populations. The prevalence of self-reported heart disease decreased by 21.0%, except for racialized established immigrants (≥ 10 years since immigration to Canada), who had a 4.2% increase. Conclusions: During this study period, decreases occurred in the prevalences of smoking and physical inactivity, along with increases in obesity, diabetes, and hypertension prevalences. By migration-group status, established immigrants in Canada had a higher prevalence of cardiovascular disease risk factors compared to that among their Canadian-born counterparts. Migration gaps should be considered in future interventions targeted at reducing these cardiovascular risk factors in Canada.

Contexte: Les maladies cardiovasculaires sont une cause majeure de décès au Canada, mais la manière dont les principaux facteurs de risque cardiovasculaire varient en fonction de l'origine ethnique et du statut d'immigration n'a encore jamais été évaluée. Méthodologie: Des tendances nationales dans certains problèmes de santé (hypertension, diabète, hypercholestérolémie et obésité) et certains comportements liés à la santé (tabagisme, niveaux d'activité et consommation d'alcool) ont été dégagées à partir des données de l'Enquête sur la santé dans les collectivités canadiennes pour la période de 2001 à 2018. Ces tendances ont ensuite été comparées en fonction du sexe, de l'âge, de l'origine ethnique et du statut d'immigration dans le cadre de la présente étude transversale. Résultats: Au total, 1 065 391 répondants ont été examinés pour la période de 2001 à 2018. Durant la période de l'étude, la prévalence des facteurs de risque suivants a graduellement augmenté au Canada : diabète, de 54,5 %; hypertension, de 23,4 %; obésité, de 32,3 %. Dans le cas des comportements liés à la santé, la prévalence du tabagisme a globalement diminué, surtout dans les populations racialisées. La consommation excessive d'alcool était plus fréquente dans les populations non racialisées et non autochtones d'origine canadienne, et moins fréquente chez les immigrants racialisés. L'inactivité physique était particulièrement répandue dans les populations immigrantes racialisées. La prévalence des maladies cardiaques auto-déclarées a diminué de 21,0 %, sauf chez les immigrants établis racialisés (≥ 10 ans depuis l'arrivée au Canada), qui a connu une hausse de 4,2 %. Conclusions: Durant la période de l'étude, la prévalence du tabagisme et de l'inactivité physique a diminué tandis que celle de l'obésité, du diabète et de l'hypertension a augmenté. D'après le statut du groupe de migration, la prévalence des facteurs de risque de maladies cardiovasculaires était plus élevée chez les immigrants établis au Canada que chez leurs homologues nés au Canada. Il convient de prendre en considération les différences liées à la migration dans les interventions futures visant à réduire ces facteurs de risque cardiovasculaire au Canada.

Semi-field evaluation of aquatic predators for the control of Anopheles funestus in rural south-eastern Tanzania.

BACKGROUND: Biological control is a promising alternative or complementary approach for controlling vector populations in response to the spread of insecticide resistance in malaria vectors. This study evaluated the efficacy of three selected potential predators on the density and fitness parameters of Anopheles funestus larvae in rural Tanzania. METHODS: Common predator families Aeshnidae (dragonflies), Coenagrionidae (damselflies), and Notonectidae (backswimmers) and An. funestus group larvae were collected from natural aquatic habitats in rural south-eastern Tanzania. Predators were starved for 12-h while An. funestus larvae were given fish food before starting the experiment. Anopheles funestus larvae were placed into artificial habitats containing predators, exposing them to potential predation. The number of surviving An. funestus larvae were counted every 24-h. An emergence traps were placed at the top of artificial habitats to capture emerging mosquitoes. Emerged mosquitoes were monitored until they died. Female wings were measured and used as a proxy for body size. Generalized linear mixed models (GLMM) with binomial variates at 95% CI and Cox proportional hazard models were used to assess the proportion of dead mosquitoes and the daily survival determined. RESULTS: There were significant differences in the number of emerged mosquitoes between the treatment and control groups (P < 0.001). Thus, all predator species played a significant role in reducing the density of An. funestus mosquitoes (P < 0.001). Furthermore, these predators had notable effects on the fitness parameters and survival of emerged mosquitoes (P < 0.001). Among the three predators studied, Coenagrionidae (damselflies) were most efficient followed by Notonectidae (backswimmers), with Aeshnidae (dragonflies) being the least efficient. CONCLUSION: Selected aquatic predators have the potential to reduce the survival and density of An. funestus larvae. They might eventually be included within an integrated malaria vector control strategy, ultimately leading to a reduction in malaria transmission.