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Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.

Object Permanence (OP) is the understanding that objects continue to exist when not directly observable. To date, this ability has proven difficult to build into AI systems, with Deep Reinforcement Learning (DRL) systems performing significantly worse than human children. Here, DRL Agents, PPO and Dreamer-v3 were tested against a number of comparators (Human children, random agents and hard coded Heuristic agents) on three object permanence tasks (OP) and a range of control tasks. As expected, the children performed well across all tasks, while performance of the DRL agents was mixed. Overallthe pattern of performance across OP and control tasks did not suggest that any agent tested except children showed evidence of robust OP.

Objective: To investigate the initial set of patient-reported outcomes (PROs) in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) and their associations with 30-day surgical outcomes. Background: PROs provide important information that can be used to improve routine care and facilitate quality improvement. The American College of Surgeons conducted a demonstration project to capture PROs into the NSQIP to complement clinical data. Methods: From February 2020 to March 2023, 65 hospitals collected Patient-Reported Outcomes Measurement Information System measures assessing global health, pain interference, fatigue, and physical function from patients accrued into the NSQIP. Using multivariable mixed regression, we compared the scores of patients with and without 30-day complications and further analyzed scores exceeding 1-SD worse than national benchmarks. Results: Overall, 33842 patients completed the Patient-Reported Outcomes Measurement Information System measures with a median of 58 days (IQR: 47-72) postoperatively. Among patients without complications (n = 31210), 33.9% had PRO scores 1-SD worse than national benchmarks. Patients with complications were 1.7 times more likely to report worse PROs (95% CI: 1.6-1.8). Patients with complications had lower scores for global physical health [adjusted mean difference (AMD): 2.6, 95% CI: 2.2-3.0], lower for global mental health (AMD: 1.8, 95% CI: 1.4-2.2), higher for pain interference (AMD: 2.4, 95% CI: 2.0-2.8), higher fatigue (AMD: 2.7, 95% CI: 2.3-3.1), and lower physical function (AMD: 3.2, 95% CI: 2.8-3.5). Conclusions: Postoperative complications negatively affect multiple key dimensions of patients' health-related quality of life. PROs were well below national benchmarks for many patients, even among those without complications. Identifying solutions to improve PROs after surgery remains a tremendous quality improvement opportunity. [ABSTRACT FROM AUTHOR]

Context Active surveillance for papillary thyroid cancer (PTC) meeting criteria for surgical resection is uncommon. Which patients may prove reasonable candidates for this approach is not well defined. Objective This work aimed to examine the feasibility and safety of active surveillance for patients with known or suspected intrathyroidal PTC up to 4 cm in diameter. Methods A retrospective review was conducted of all consecutive patients who underwent nonoperative active surveillance of suspicious or malignant thyroid nodules over a 20-year period from 2001 to 2021. We included patients with an initial ultrasound–fine-needle aspiration confirming either (a) Bethesda 5 or 6 cytology or (b) a "suspicious" Afirma molecular test. The primary outcomes and measures included the rate of adverse oncologic outcomes (mortality and recurrence), as well as the cumulative incidence of size/volume growth. Results Sixty-nine patients were followed with active surveillance for 1 year or longer (average 55 months), with 26 patients (38%) having nodules 2 cm or larger. No patients were found to develop new-incident occurrence of lymph node or distant metastasis. One patient, however, demonstrated concern for progression to a dedifferentiated cancer on repeat core biopsy 17 years after initial start of nonoperative selection. A total of 21% of patients had an increase in maximum diameter more than 3 mm, while volume increase of 50% or greater was noted in 25% of patients. Thirteen patients ultimately underwent delayed (rescue) surgery, and no disease recurrence was noted after such treatment. Age and initial nodule size were not predictors of nodule growth. Conclusion These data expand consideration of active surveillance of PTC in select patients with intrathyroidal suspected malignancy greater than 1 cm in diameter. Rescue surgery, if required at a later time point, appears effective. [ABSTRACT FROM AUTHOR]

Objective: To understand how diabetes mellitus (DM) diagnosed at different ages of adulthood are associated with various incident subsequent non-communicable diseases (NCDs). Methods: We performed a nationwide population-based analysis comparing 212 participants first diagnosed with DM at 20–39, 40–49, 50–59, or 60–69 years of age, with 17,541 participants without DM history, using data from the Indonesian Family Life Survey. Subsequent NCDs that were examined included hypertension, lung diseases, heart diseases, arthritis, liver diseases, kidney diseases, and digestive diseases. We estimated weighted risk ratios and 95% confidence intervals using Poisson regression, adjusting for age, sex, urbanicity, and tobacco use history. Results: Those diagnosed with DM in all age groups had significantly higher risk of hypertension, compared with those without DM history. Compared with those without DM history, younger individuals with DM diagnosed at 20–39 years of age had significantly higher risks of lung diseases and arthritis, and those with DM diagnosed at 20–49 years of age had significantly higher risk of digestive diseases. Older individuals with DM diagnosed at 40–69 years of age had significantly higher risk of liver diseases, and those with DM diagnosed at 40–59 years of age had significantly higher risk of heart diseases, compared with those without DM history. Participants with DM were diagnosed with subsequent NCDs at younger ages compared with those without DM history. Conclusion: Our findings contribute to health surveillance and may promote beneficial lifestyle changes in those with early-onset and later-onset DM, which can help prevent subsequent NCDs and improve public health. [ABSTRACT FROM AUTHOR]

Cancer survivors are especially vulnerable to the carcinogenic effects of tobacco smoking, but there lacks a study comprehensively examining the sociodemographic disparities in current smoking prevalence in this population. In this study, we quantified the current cigarette smoking prevalence in cancer survivors and those without cancer history by sociodemographic factors, to identify subpopulations with high current smoking burden. We conducted a cross-sectional study of 3,679 cancer survivors and 27,350 participants without cancer history who were 18 years of age or above in the 2019 National Health Interview Survey. Data for the study variables were obtained from computer-assisted personal or telephone interviews. Weighted Poisson regression was used to estimate prevalence ratios and 95% confidence intervals. Although the current smoking prevalence for cancer survivors was slightly lower than for those without cancer history, the prevalence exceeded 30% in cancer survivors in poverty or without health insurance. Individuals with significantly higher current smoking prevalence had lower education levels, were unmarried, did not have health insurance, or lived in poverty. The associations of age, sex, race, health insurance status, and poverty status with current smoking significantly differed between cancer survivors and those without cancer history. Sociodemographic disparities in current smoking prevalence were found in survivors of either smoking-related or nonsmoking-related cancers. High current smoking prevalence still exists in subpopulations of cancer survivors and those without cancer history. Our findings may strengthen efforts to reduce sociodemographic disparities in current smoking prevalence and to lower the overall smoking prevalence. [ABSTRACT FROM AUTHOR]

Background: Skin cancer survivors are more vulnerable to subsequent skin cancers and other malignancies, but previous studies have not examined in detail their sun protection behavior prevalence by sociodemographic factors. We aimed to understand the sociodemographic disparities in the prevalence of three important types of sun protection behaviors: using sunscreen, seeking shade, and wearing protective clothing, among skin cancer survivors and those without skin cancer history. Methods: We used the 2015 U.S. National Health Interview Survey to analyze 29,523 participants, of which 772 were skin cancer survivors and 28,751 were those without skin cancer history. We assessed overall and specific sun protection behavior prevalence based on using sunscreen, seeking shade, and wearing protective clothing. Weighted Poisson regression was used to estimate prevalence ratios. Results: Melanoma and nonmelanoma skin cancer survivors had similar overall sun protection behavior (p >.05). Among all skin cancer survivors, 36.0% infrequently used sunscreen, 50.2% infrequently wore protective clothing, 47.8% infrequently sought shade, and 30.0% lacked frequent overall sun protection, which significantly differed from those without skin cancer history (p <.0001). The prevalence of frequent overall sun protection behavior was lower for those who were younger at survey, males, less educated, single or never married, or lived in poverty, regardless of their skin cancer history (p <.01). Conclusions: By identifying subpopulations with higher prevalence of infrequent sun protection among those with or without skin cancer history, our findings may encourage efforts to reduce sociodemographic disparities in sun protection behaviors and promote primary and tertiary skin cancer prevention. [ABSTRACT FROM AUTHOR]

This article addresses the real‐time reachable set problem on nonlinear time‐delay switched singular systems with state jump, which is subject to initial state and peak‐bound disturbance. Initially, based on the system state decomposition method, a state jump lemma is proposed, which combines the nonlinear function and the system state at the switching instant. Then, a real‐time bounded lemma is developed, premised on using the idea of average dwell‐time and analyzing subinterval function changes. Afterwards, the sufficient conditions for estimating the real‐time and nonreal‐time reachable set are established, which ensures that the reachable state of system can be restricted within a real‐time or nonreal‐time closed set. Finally, simulation results of the typical Direct Current boost chopper are performed to exhibit the effectiveness of the devised estimation scheme for the real‐time reachable set of system. [ABSTRACT FROM AUTHOR]

Lipid nanoparticles (LNPs) have demonstrated their enormous potential as therapeutic delivery vehicles, as evidenced by the approval and global usage of two COVID-19 messenger RNA (mRNA) vaccines. On a small scale, LNPs are often made using microfluidics; however, the limitations of these devices preclude their use on a large scale. The COVID-19 vaccines are manufactured in large quantities using confined impinging jet (CIJ) turbulent mixers. CIJ technology enables production at a laboratory scale with the confidence that it can be scaled to production volumes. The key concepts in CIJ mixing are that the mixing length and time scale are determined by the turbulence intensity in the mixing cavity and that the nanoparticle formation occurs away from walls, eliminating the problem of deposition on surfaces and fouling. This work demonstrates the process of making LNPs using confined impinging jet mixer technology with two geometries: the two-jet CIJ and the four-jet multi-inlet vortex mixer (MIVM). The advantages and disadvantages of each mixing geometry are discussed. In these geometries, LNPs are formed by rapid mixing of an organic solvent stream (usually ethanol containing the ionizable lipids, co-lipids, and stabilizing PEG-lipids) with an aqueous anti-solvent stream (aqueous buffer containing RNA or DNA). The operating parameters for the CIJ and MIVM mixers are presented to prepare reproducible LNPs with controlled size, zeta potential, stability, and transfection effectiveness. The differences between LNPs made with poor mixing (pipetting solutions) compared to CIJ mixing are also presented.

In this brief, we study the decentralized H 2 state-feedback control problem for networked discrete-time systems with positivity constraint. This problem (for a single positive system), raised recently in the area of positive systems theory, is known to be challenging due to its inherent nonconvexity. In contrast to most works, which only provide sufficient synthesis conditions for a single positive system, we study this problem within a primal-dual scheme, in which necessary and sufficient synthesis conditions are proposed for networked positive systems. Based on the equivalent conditions, we develop a primal-dual iterative algorithm for solution, which helps prevent from converging to a local minimum. In the simulation, two illustrative examples are employed for verification of our proposed results.

Background: Although primary hyperparathyroidism (PHPT) is readily diagnosed biochemically and can be cured with low-risk surgery, it is often underrecognized and undertreated. Our objectives were to characterize, within our health system, how often patients with hypercalcemia were evaluated for PHPT and how often patients with PHPT underwent definitive treatment with parathyroidectomy., Methods: Ambulatory patients aged 18 years or older seen at our health system between January 2018 and June 2023 with chronic hypercalcemia were identified from the medical record. After excluding causes of secondary hyperparathyroidism, the proportion of patients with parathyroid hormone (PTH) tests was calculated. Among patients with biochemical evidence of PHPT, the proportion of patients who underwent parathyroidectomy was calculated. Multivariable logistic regression was used to identify factors associated with an evaluation for PHPT and, separately, with parathyroidectomy., Results: Of 7,675 patients with chronic hypercalcemia, 3,323 (43.3%) had a PTH test obtained within 6 months. An age between 40-49 vs. <30 years [(odds ratio (OR) =3.2; 95% confidence interval (CI): 1.8-5.6; P<0.001], a serum calcium level between 11.6-12.0 vs. <11.0 mg/dL (OR =3.9; 95% CI: 3.2-4.7; P<0.001), and osteoporosis (OR =3.1; 95% CI: 2.7-3.5; P<0.001) were associated with an evaluation for PHPT. Among those with PTH levels, 1,327 (39.9%) had PHPT but only 916 (69.0%) were recognized. Three hundred and forty-five (26.0%) patients with PHPT underwent parathyroidectomy. An increasing number of surgical indications was associated with parathyroidectomy (P<0.001), though overall rates remained less than 40%. Among indications for surgery, including age and serum total calcium level, only osteoporosis was associated with parathyroidectomy (OR =2.0; 95% CI: 1.4-2.8; P<0.001)., Conclusions: In this study, more than half of patients with chronic hypercalcemia were not evaluated for PHPT. Among patients with biochemical evidence of PHPT, one-third were unrecognized and only one-in-four received curative treatment. Opportunities to improve the management of PHPT exist within our large integrated health system., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-128/coif). D.W.B. reports grants and personal fees from EarlySense, personal fees from CDI Negev, equity from ValeraHealth, equity from Clew, equity from MDClone, personal fees and equity from AESOP, personal fees and equity from FeelBetter, personal fees and equity from Guided Clinical Solutions and grants from IBM Watson Health, all outside the submitted work. J.B.L. received the Brigham and Women’s Hospital Department of Surgery 2023 Bruce A. Beal and Robert L. Beal Surgical Fellowship, which supported this work. The other authors have no conflicts of interest to declare., (2024 Gland Surgery. All rights reserved.)

The female reproductive lifespan depends on egg quality, particularly euploidy. Mistakes in meiosis leading to egg aneuploidy are common, but the genetic landscape causing this is not well understood due to limited phenotypic data. We identify genetic determinants of reproductive aging via egg aneuploidy using a biobank of maternal exomes linked with maternal age and embryonic aneuploidy data. We found 404 genes with variants enriched in individuals with high egg aneuploidy rates and implicate kinesin protein family genes in aneuploidy risk. Experimental perturbations showed that motor domain variants in these genes increase aneuploidy in mouse oocytes. A knock-in mouse model validated that a specific variant in kinesin KIF18A accelerates reproductive aging and diminishes fertility. These findings suggest potential non-invasive biomarkers for egg quality, aiding personalized fertility medicine., One Sentence Summary: The study identifies novel genetic determinants of reproductive aging linked to egg aneuploidy by analyzing maternal exomes and demonstrates that variants in kinesin genes, specifically KIF18A , contribute to increased aneuploidy and accelerated reproductive aging, offering potential for personalized fertility medicine.

Background: Herpes simplex virus encephalitis (HSE) is a rare but serious neurological infection that causes neurological dysfunction. Research is lacking on the clinical predictors of neurological outcomes and the optimal duration of therapy for pediatric HSE patients. In this study of pediatric HSE patients, we identified factors predicting neurological disability at hospital discharge and examined associations of acyclovir therapy duration with neurological outcomes., Methods: This was a retrospective cohort study on 37 children diagnosed with HSE confirmed by polymerase chain reaction at age 1 month to 16 years from 2015 to 2021 in Ho Chi Minh City's Children's Hospital No. 2, Vietnam. For the acyclovir duration analysis, we examined 22 children with negative polymerase chain reaction on day 14 of treatment. Poisson regression was used to obtain the risk ratio and 95% confidence interval., Results: The study population consisted of 73% males, with a median age of 14 months (interquartile range: 9-35). Coma at acyclovir treatment, hypotension and the need for mechanical ventilation ≥48 hours significantly predicted neurological disability in the bivariate analysis. There were no significant associations between acyclovir duration (14 vs. 21 days) and neurological outcomes, adjusting for age at diagnosis and pediatric Glasgow Coma Scale score at acyclovir initiation., Conclusion: We identified significant predictors of neurological disability unaffected by postacyclovir treatment factors. Among patients with negative HSE polymerase chain reaction on day 14, 14 days of acyclovir treatment may be as effective as 21 days. Additional studies on the effects of acyclovir duration are needed., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.