Advancing the scale of synthetic biology via cross-species transfer of cellular functions enabled by iModulon engraftment.

Machine learning applied to large compendia of transcriptomic data has enabled the decomposition of bacterial transcriptomes to identify independently modulated sets of genes, such iModulons represent specific cellular functions. The identification of iModulons enables accurate identification of genes necessary and sufficient for cross-species transfer of cellular functions. We demonstrate cross-species transfer of: 1) the biotransformation of vanillate to protocatechuate, 2) a malonate catabolic pathway, 3) a catabolic pathway for 2,3-butanediol, and 4) an antimicrobial resistance to ampicillin found in multiple Pseudomonas species to Escherichia coli. iModulon-based engineering is a transformative strategy as it includes all genes comprising the transferred cellular function, including genes without functional annotation. Adaptive laboratory evolution was deployed to optimize the cellular function transferred, revealing mutations in the host. Combining big data analytics and laboratory evolution thus enhances the level of understanding of systems biology, and synthetic biology for strain design and development.

Thyroid Dysfunction after Atezolizumab and Bevacizumab Is Associated with Favorable Outcomes in Hepatocellular Carcinoma.

Introduction: Atezolizumab and bevacizumab (Ate/Bev) combination has become the new first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). Although several studies reported thyroid dysfunction after treatment with immune checkpoint inhibitors, the clinical and immunological significance of thyroid dysfunction in patients treated with Ate/Bev has not been comprehensively addressed. We aimed to comprehensively evaluate the clinical and immunological implications of thyroid dysfunction in unresectable HCC patients treated with Ate/Bev. Methods: We enrolled 208 patients with unresectable HCC treated with Ate/Bev from three Korean cancer centers. Thyroid adverse events (AEs) were reviewed, and cytokines and T cells in the blood samples were analyzed at baseline. For external validation, we analyzed clinical outcomes according to thyroid AEs in patients treated with Ate/Bev in the IMbrave150 study. Results: Forty-one (19.7%) out of 208 patients experienced thyroid dysfunction (hypothyroidism [17.3%] and thyrotoxicosis [5.8%]) after Ate/Bev treatment. Median time to onset of hypothyroidism and thyrotoxicosis after Ate/Bev treatment was 3.5 and 1.3 months, respectively. Patients with thyroid AEs demonstrated significantly better progression-free survival, overall survival, and objective response rate than those without thyroid AEs. These findings were still consistent even after adjusting for confounding factors. Furthermore, favorable survival outcomes in patients with thyroid AEs were also validated in a cohort of IMbrave150 patients. While patients with thyrotoxicosis showed a significantly lower level of baseline IL-6, those with hypothyroidism did not show significant differences in circulating cytokine levels and CD8+ T-cell fractions. Conclusions: A fraction of patients with HCC treated with Ate/Bev experienced thyroid dysfunction, and the development of thyroid AEs was associated with favorable clinical outcomes.

Getting patients to the right level of trauma center after motorcycle crashes in a rural trauma system.

PURPOSE: After a motorcycle crash (MCC), emergency medical services (EMS) responders must balance trauma center proximity with clinical needs of patients, which is especially challenging in rural states. The study purpose was to determine if MCC patients treated at lower-level trauma centers (LLTC) experienced higher mortality when compared to patients transported directly to the highest level of trauma care available in the state at Level II trauma centers. PROCEDURES: A retrospective study was conducted on MCC patients transported by EMS to Montana hospitals and met registry inclusion criteria in 2020-2021. The first study group included patients initially transported to state-designated trauma centers (equivalent to Level III-V) or non-designated hospitals (LLTC), and the second group included patients transported directly to American College of Surgeon verified Level II trauma centers (L2TC). Secondary transfer was defined as initial transport to a LLTC and subsequent transfer to a L2TC. Primary study outcome was mortality at the L2TC. Chi-square tests and Wilcoxon rank sum tests were used for analysis. FINDINGS: In the study period, 337 MCC patients were transported by EMS; 186 (55%) patients were transported to a LLTC while 151 patients (45%) were transported to a L2TC. There were no statistically significant differences in mortality (12% vs 8%, p = 0.30) when comparing secondary transfer patients to patients transported directly to a L2TC. CONCLUSIONS: Nearly half of patients initially evaluated at a LLTC required transfer to a higher-level of care. Secondary transfer was not associated with increased mortality.

Chronic shedding of a SARS-CoV-2 Alpha variant in wastewater.

BACKGROUND: Central Michigan University (CMU) participated in a state-wide SARS-CoV-2 wastewater monitoring program since 2021. Wastewater samples were collected from on-campus sites and nine off-campus wastewater treatment plants servicing small metropolitan and rural communities. SARS-CoV-2 genome copies were quantified using droplet digital PCR and results were reported to the health department. RESULTS: One rural, off-campus site consistently produced higher concentrations of SARS-CoV-2 genome copies. Samples from this site were sequenced and contained predominately a derivative of Alpha variant lineage B.1.1.7, detected from fall 2021 through summer 2023. Mutational analysis of reconstructed genes revealed divergence from the Alpha variant lineage sequence over time, including numerous mutations  in the Spike RBD and NTD. CONCLUSIONS: We discuss the possibility that a chronic SARS-CoV-2 infection accumulated adaptive mutations that promoted long-term infection. This study reveals that small wastewater treatment plants can enhance resolution of rare events and facilitate reconstruction of viral genomes due to the relative lack of contaminating sequences.

PB101, a VEGF- and PlGF-targeting decoy protein, enhances antitumor immunity and suppresses tumor progression and metastasis.

Antiangiogenic therapy is a recognized method for countering the immunosuppressive tumor microenvironment (TME) and improving anti-tumor immunity. PB101 is a glycosylated decoy receptor that binds to VEGF-A and PlGF with high affinity, based on the VEGFR1 backbone. Here, we elucidated PB101-induced remodeling of tumor angiogenesis and immunity, which enhances anti-PD-L1 immune checkpoint blockade. PB101 inhibited tumor growth by suppressing angiogenesis and enhancing CD8+ T cell infiltration into the tumors. PB101 induced robust reprogramming of antitumor immunity and activates intratumoral CD8+ T cells. Anti-tumor efficacy of PB101 is mostly dependent on CD8+ T cells and IFN-γ. PB101 reprograms tumor immunity in a manner distinct from that of the conventional VEGF decoy receptor, VEGF-trap. With its potent immune-modulating capability, PB101 synergizes with an anti-PD-L1, triggering strengthened antitumor immunity. Combining PB101 and anti-PD-L1 could establish durable protective immunity against tumor recurrence and metastasis. The findings of this study offer scientific rationales for further clinical development of PB101, particularly when used in combination with immune checkpoint inhibitors, as a potential treatment for advanced cancers.

Systemic Delivery of a STING Agonist-Loaded Positively Charged Liposome Selectively Targets Tumor Immune Microenvironment and Suppresses Tumor Angiogenesis.

Although stimulator of interferon genes (STING) agonists has shown great promise in preclinical studies, the clinical development of STING agonist therapy is challenged by its limited systemic delivery. Here, positively charged fusogenic liposomes loaded with a STING agonist (PoSTING) are designed for systemic delivery and to preferentially target the tumor microenvironment. When PoSTING is administered intravenously, it selectively targets not only tumor cells but also immune and tumor endothelial cells (ECs). In particular, delivery of STING agonists to tumor ECs normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti-tumor T cell immunity within the tumor microenvironment. Therefore, PoSTING can be used as a systemic delivery platform to overcome the limitations of using STING agonists in clinical trials.

High levels of baseline serum IL-10 are associated with reduced clinical benefit from first-line immune checkpoint inhibitor therapy in advanced renal cell carcinoma.

Immune checkpoint inhibitor (ICI) became a standard treatment for advanced renal cell carcinoma (RCC). However, clinically valid biomarkers of therapeutic outcome are lacking. We investigated the role of interleukin-10 (IL-10) as a predictive biomarker for first-line ICI therapy in patients with advanced RCC. Baseline serum samples were prospectively collected and analyzed using a cytometric bead assay. Patients were divided into two groups according to their serum IL-10 levels using maximally selected rank statistics. A fraction (13.0%) of patients had high levels of serum IL-10 at baseline. High serum IL-10 levels (> 4.3 ng/mL) were associated with a significantly shorter progression-free (median: 5.2 months vs. not reached, P = 0.007) and overall survival (median: 13.9 months vs. not reached, P < 0.001). Multivariate Cox regression analysis confirmed the independent association between high serum IL-10 levels and poor survival outcomes. Effector cytokine production and the proliferative response of CD8+ T cells were significantly lower in patients with high serum IL-10 levels, who also had a shorter duration of response to first-line ICI therapy (4.6 months vs. not reached, P < 0.001). In conclusion, elevated serum IL-10 levels at baseline were associated with reduced clinical benefit from first-line ICI therapy in patients with advanced RCC.

Associations of life course obesity with endometrial cancer in the Epidemiology of Endometrial Cancer Consortium (E2C2).

BACKGROUND: Adult obesity is a strong risk factor for endometrial cancer (EC); however, associations of early life obesity with EC are inconclusive. We evaluated associations of young adulthood (18-21 years) and adulthood (at enrolment) body mass index (BMI) and weight change with EC risk in the Epidemiology of Endometrial Cancer Consortium (E2C2). METHODS: We pooled data from nine case-control and 11 cohort studies in E2C2. We performed multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for BMI (kg/m2) in young adulthood and adulthood, with adjustment for BMI in adulthood and young adulthood, respectively. We evaluated categorical changes in weight (5-kg increments) and BMI from young adulthood to adulthood, and stratified analyses by histology, menopausal status, race and ethnicity, hormone replacement therapy (HRT) use and diabetes. RESULTS: We included 14 859 cases and 40 859 controls. Obesity in adulthood (OR = 2.85, 95% CI = 2.47-3.29) and young adulthood (OR = 1.26, 95% CI = 1.06-1.50) were positively associated with EC risk. Weight gain and BMI gain were positively associated with EC; weight loss was inversely associated with EC. Young adulthood obesity was more strongly associated with EC among cases diagnosed with endometrioid histology, those who were pre/perimenopausal, non-Hispanic White and non-Hispanic Black, among never HRT users and non-diabetics. CONCLUSIONS: Young adulthood obesity is associated with EC risk, even after accounting for BMI in adulthood. Weight gain is also associated with EC risk, whereas weight loss is inversely associated. Achieving and maintaining a healthy weight over the life course is important for EC prevention efforts.

High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma.

Background & Aims: We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. Results: In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05 pg/ml, p = 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49 pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Impact and implications: Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Environmental Correlates of Physical Activity and Screen-Time in Youth with Autism Spectrum Disorder: A Seven-Country Observational Study.

This cross-sectional observational study sought to examine the environmental correlates of physical activity and screen-time among youth with autism spectrum disorder (ASD). Parents of youth with ASD (n = 1,165) from seven countries/regions provided responses to an online survey form measuring environmental correlates (i.e., physical activity neighborhood environment, social network, social trust and cohesion, bedroom media, social home environment) and outcomes (i.e., physical activity, screen-time). Multiple linear regression analyses were conducted to determine environmental predictors of the outcomes. Physical activity neighborhood environment (B = 0.15, p = 0.047), social network (B = 0.16, p = 0.02), and social home environment (B = 1.07, p < 0.001) were significantly associated with physical activity, whereas social trust and cohesion and bedroom media were not. Further, social trust and cohesion (B = -0.14, p = 0.001), bedroom media (B = 0.10, p = 0.001), and social home environment (B = -0.16, p < 0.001) were significantly associated with screen-time while neighborhood environment and social network were not. The identified environmental attributes of physical activity and screen-time behaviors should be targeted for health promotion among youth with ASD.

Risk prediction models for endometrial cancer: development and validation in an international consortium.

BACKGROUND: Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. METHODS: We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses' Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. RESULTS: Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). CONCLUSIONS: Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

Risk prediction model of peritoneal seeding in advanced gastric cancer: A decision tool for diagnostic laparoscopy.

BACKGROUND: Selective diagnostic laparoscopy in gastric cancer patients at high risk of peritoneal metastasis is essential for optimal treatment planning. In this study available clinicopathologic factors predictive of peritoneal seeding in advanced gastric cancer (AGC) were identified, and this information was translated into a clinically useful tool. METHODS: Totally 2833 patients underwent surgery for AGC between 2003 and 2013. The study identified clinicopathologic factors associated with the risk of peritoneal seeding for constructing nomograms using a multivariate logistic regression model with backward elimination. A nomogram was constructed to generate a numerical value indicating risk. Accuracy was validated using bootstrapping and cross-validation. RESULTS: The proportion of seeding positive was 12.7% in females and 9.6% in males. Of 2833 patients who underwent surgery for AGC, 300 (10.6%) were intraoperatively identified with peritoneal seeding. Multivariate analysis revealed the following factors associated with peritoneal seeding: high American Society of Anesthesiologists score, fibrinogen, Borrmann type 3 or 4 tumors, the involvement of the middle, anterior, and greater curvature, cT3 or cT4cN1 or cN2 or cN3, cM1, and the presence of ascites or peritoneal thickening or plaque or a nodule on the peritoneal wall on computed tomography. The bootstrap analysis revealed a robust concordance between mean and final parameter estimates. The area under the ROC curve for the final model was 0.856 (95% CI, 0.835-0.877), which implies good performance. CONCLUSIONS: This nomogram provides effective risk estimates of peritoneal seeding from gastric cancer and can facilitate individualized decision-making regarding the selective use of diagnostic laparoscopy.

Leveraging Clinical Informatics to Address the Quintuple Aim for End-of-Life Care.

As the population of older adults grows at an unprecedented rate, there is a large gap to provide culturally tailored end-of-life care. This study describes a payor-led, informatics-based approach to identify Medicare members who may benefit from a Compassionate CareSM Program (CCP), which was designed to provide specialized care management services and support to members who have end-stage and/or life-limiting illnesses by addressing the quintuple aim. Potential participants are identified through machine learning models whereby nurse care managers then provide tailored outreach via telephone. A retrospective, observational cohort analysis of propensity-weighted Medicare members was performed to compare decedents who did or did not participate in the CCP. This program enhanced the end-of-life care experience while providing equitable outcomes regardless of age, gender, and geography and decreased inpatient (-37%) admissions with concomitant reduced (-59%) medical spend when compared to decedents that did not utilize the end-of-life care management program.

High Serum Levels of IL-6 Predict Poor Responses in Patients Treated with Pembrolizumab plus Axitinib for Advanced Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is the most common type of kidney malignancy worldwide with Pembrolizumab and axitinib treatment (Pembro/Axi) amongst the most effective first-line immunotherapies for advanced RCC. However, it remains difficult to predict treatment response and early resistance. Therefore, we evaluated whether baseline serum interleukin-6 (IL-6) could be a predictive biomarker. Between November 2019 and December 2021, 58 patients with advanced RCC were enrolled, administered first-line Pembro/Axi, and baseline blood samples were analyzed using flow cytometry. The mean baseline serum IL-6 concentration was 8.6 pg/mL in responders and 84.1 pg/mL in patients with progressive disease. The IL-6 cut-off value was set at 6.5 pg/mL using time-dependent receiver operating characteristic curves, with 37.9% of patients having high baseline serum IL-6 levels and 62.1% having low levels. Objective response rates were 58.3% and 36.4% in low and high IL-6 groups, respectively. Overall survival and progression-free survival were longer in patients with low IL-6 levels than in those with high levels. High IL-6 levels were related to reduced interferon-γ and tumor necrosis factor-α production from CD8+ T cells. Overall, high baseline serum IL-6 levels were associated with worse survival outcomes and reduced T-cell responses in Pembro/Axi-treated advanced RCC patients.

Association of High Levels of Antidrug Antibodies Against Atezolizumab With Clinical Outcomes and T-Cell Responses in Patients With Hepatocellular Carcinoma.

Importance: Administration of atezolizumab could be immunogenic and induce undesirable antidrug antibody (ADA) responses. This may interfere with atezolizumab-mediated actions, affecting drug clearance and serum concentration or inducing antibody neutralization. Objective: To determine the clinical and immunological associations of highly elevated ADA levels with clinical outcomes after atezolizumab/bevacizumab (Atezo/Bev) treatment in patients with advanced hepatocellular carcinoma (HCC). Design, Setting, and Participants: This cohort study prospectively enrolled 174 patients with advanced HCC treated with first-line Atezo/Bev (discovery cohort: 61 patients from 1 center; validation cohort: 113 patients from 4 centers). Exposures: Serum ADA levels at pretreatment and 3 weeks (cycle 2 day 1 [C2D1]) were analyzed using competitive enzyme-linked immunosorbent assays. In addition, samples were subjected to serological and flow cytometric analyses. Main Outcomes and Measures: Overall, ADA positivity was associated with treatment outcomes and T-cell functions. Results: After excluding patients with inadequate samples, follow-up loss, or consent withdrawal, 132 patients (discovery cohort: 50 patients; 41 [82.0%] men; median age [IQR], 61 [55-70] years; validation cohort: 82 patients; 70 [85.4%] men; median age [IQR], 61 [53-68] years) were analyzed, and robust ADA (≥1000 ng/mL) responses at C2D1 were identified in 23 (17.4%) of the patients. Patients with progressive disease exhibited higher ADA levels (median [IQR], 65.2 [0-520.4] ng/mL) at C2D1 than in responders (median [IQR], 0 [0-117.5] ng/mL). In both discovery and validation cohorts, patients with high ADA levels at C2D1 were associated with a reduced response rate (discovery cohort: 34% vs 11%; validation cohort: 29% vs. 7%) and worse progression-free survival (discovery cohort: hazard ratio [HR], 2.84; 95% CI, 1.31-6.13; P = .005; validation cohort: HR, 2.52; 95% CI, 1.27-5.01; P = .006) and overall survival (discovery cohort: HR, 3.30; 95% CI, 1.43-7.64; P = .003; validation cohort: HR, 5.81, 95% CI, 2.70-12.50; P = .001) with Atezo/Bev compared with those with low ADA levels. In multivariable Cox regression, the clinical implication of high ADA levels persisted even after adjusting for various confounding factors and was most significant at 1000 ng/mL or greater. Compared with patients with low ADA levels, patients with high ADA levels exhibited reduced serum atezolizumab concentrations, impaired CD8-positive T-cell proliferation, and had decreased interferon-γ and tumor necrosis factor-α from CD8-positive T cells compared with patients with low ADA levels. Conclusions and Relevance: This cohort study found that highly elevated ADA levels at C2D1 may be associated with poor clinical outcomes in patients with advanced HCC treated with Atezo/Bev. High ADA levels may reduce atezolizumab exposure and attenuate the anticancer efficacy of the drug.

Intratumoral immunotherapy using a TLR2/3 agonist, L-pampo, induces robust antitumor immune responses and enhances immune checkpoint blockade.

BACKGROUND: Toll-like receptors (TLRs) are critical innate immune sensors that elicit antitumor immune responses in cancer immunotherapy. Although a few TLR agonists have been approved for the treatment of patients with early-stage superficial cancers, their therapeutic efficacy is limited in patient with advanced invasive cancers. Here, we identified the therapeutic role of a TLR2/3 agonist, L-pampo (LP), which promotes antitumor immunity and enhances the immune checkpoint blockade. METHODS: We generated LP by combining a TLR2 agonist, Pam3CSK4, with a TLR3 agonist, Poly (I:C). Immune responses to stimulation with various TLR agonists were compared. Tumor-bearing mice were intratumorally treated with LP, and their tumor sizes were measured. The antitumor effects of LP treatment were determined using flow cytometry, multiplexed imaging, and NanoString nCounter immune profiling. The immunotherapeutic potential of LP in combination with α-programmed cell death protein-1 (PD-1) or α-cytotoxic T-lymphocytes-associated protein 4 (CTLA-4) was evaluated in syngeneic MC38 colon cancer and B16F10 melanoma. RESULTS: The LP treatment induced a potent activation of T helper 1 (Th1) and 2 (Th2)-mediated immunity, tumor cell apoptosis, and immunogenic tumor cell death. Intratumoral LP treatment effectively inhibited tumor progression by activating tumor-specific T cell immunity. LP-induced immune responses were mediated by CD8+ T cells and interferon-γ, but not by CD4+ T cells and CD25+ T cells. LP simultaneously activated TLR2 and TLR3 signaling, thereby extensively changing the immune-related gene signatures within the tumor microenvironment (TME). Moreover, intratumoral LP treatment led to systemic abscopal antitumor effects in non-injected distant tumors. Notably, LP treatment combined with ɑPD-1 and ɑCTLA-4 further enhanced the efficacy of monotherapy, resulting in complete tumor regression and prolonged overall survival. Furthermore, LP-based combination immunotherapy elicited durable antitumor immunity with tumor-specific immune memory in colon cancer and melanoma. CONCLUSIONS: Our study demonstrated that intratumoral LP treatment improves the innate and adaptive antitumor immunity within the TME and enhances the efficacy of αPD-1 and αCTLA-4 immune checkpoint blockade.

Meeting the 24-h movement guidelines and health-related outcomes among youth with autism spectrum disorder: a seven-country observational study.

BACKGROUND: Meeting daily guidelines for physical activity, screen time, and sleep duration is associated with a host of health indicators for youth. In this cross-sectional observational study, we investigated the associations between adherence to the movement guidelines and health-related outcomes among youth with autism spectrum disorder (ASD). METHODS: Parents of youth with ASD (10-17 years) from seven countries and regions were invited to provide online proxy-reports for child's movement behaviors (i.e., physical activity, sleep and screen time), and health-related outcomes (i.e., body mass index [BMI], general health, and quality of life). A series of multiple linear regression analyses were used to examine the associations between meeting movement guidelines and health-related outcomes, adjusted for covariates. RESULTS: The final sample consisted of 1165 youth with ASD. Compared with youth meeting all three guidelines, a higher BMI z-score was observed in those who met no guidelines (B = 0.62, P = 0.04), "sedentary time only" (B = 0.60, P = 0.047), and "physical activity plus sleep only" (B = 0.85, P = 0.04). Compared with meeting all three guidelines, meeting no guidelines was associated with poorer general health (B = - 0.46, P = 0.02). Further, compared with youth meeting all three guidelines, a lower quality of life score was observed in those who met no guidelines (B = - 0.47, P = 0.02) and "physical activity only" (B = - 0.62, P = 0.03). Lastly, there were dose-response associations between the number of guidelines met and all three health-related outcomes (all Ptrend < 0.05). CONCLUSIONS: In conclusion, meeting more 24-h movement guidelines was generally associated with more favorable health-related outcomes in youth with ASD. The low level of adherence to all three guidelines (2.0%) suggests the urgent need to promote the adoption of all the guidelines in this group.

The molecular makeup of peripheral and central baroreceptors: stretching a role for Transient Receptor Potential (TRP), Epithelial Sodium Channel (ENaC), Acid Sensing Ion Channel (ASIC), and Piezo channels.

The autonomic nervous system maintains homeostasis of cardiovascular, respiratory, gastrointestinal, urinary, immune, and thermoregulatory function. Homeostasis involves a variety of feedback mechanisms involving peripheral afferents, many of which contain molecular receptors sensitive to mechanical deformation, termed mechanosensors. Here, we focus on the molecular identity of mechanosensors involved in the baroreflex control of the cardiovascular system. Located within the walls of the aortic arch and carotid sinuses, and/or astrocytes in the brain, these mechanosensors are essential for the rapid moment-to-moment feedback regulation of blood pressure (BP). Growing evidence suggests that these mechanosensors form a co-existing system of peripheral and central baroreflexes. Despite the importance of these molecules in cardiovascular disease and decades of research, their precise molecular identity remains elusive. The uncertainty surrounding the identity of these mechanosensors presents a major challenge in understanding basic baroreceptor function and has hindered the development of novel therapeutic targets for conditions with known arterial baroreflex impairments. Therefore, the purpose of this review is to (i) provide a brief overview of arterial and central baroreflex control of BP, (ii) review classes of ion channels currently proposed as the baroreflex mechanosensor, namely Transient Receptor Potential (TRP), Epithelial Sodium Channel (ENaC), Acid Sensing Ion Channel (ASIC), and Piezo, along with additional molecular candidates that serve mechanotransduction in other organ systems, and (iii) summarize the potential clinical implications of impaired baroreceptor function in the pathophysiology of cardiovascular disease.