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Genetics in Medicine : Official Journal... Jun 2024The aim of this study is to identify likely pathogenic (LP) and pathogenic (P) genetic results for autism that can be returned to participants in SPARK...
PURPOSE
The aim of this study is to identify likely pathogenic (LP) and pathogenic (P) genetic results for autism that can be returned to participants in SPARK (SPARKforAutism.org): a large recontactable cohort of people with autism in the United States. We also describe the process to return these clinically confirmed genetic findings.
METHODS
We present results from microarray genotyping and exome sequencing (ES) of 21,532 individuals with autism and 17,785 of their parents. We returned LP and P (American College of Medical genetics (ACMG) criteria) copy number variants (CNVs), chromosomal aneuploidies, and variants in genes with strong evidence of association with autism and intellectual disability.
RESULTS
We identified 1903 'returnable' LP/P variants in 1861 individuals with autism (8.6%). 89.5% of these variants were not known to participants. The diagnostic genetic result was returned to 589 participants (53% of those contacted). Features associated with a higher probability of having a returnable result include cognitive and medically complex features, being female, being White (versus non-White) and being diagnosed more than 20 years ago. We also find results among autistics across the spectrum, as well as in transmitting parents with neuropsychiatric features but no autism diagnosis.
CONCLUSION
SPARK offers an opportunity to assess returnable results among autistic people who have not been ascertained clinically. SPARK also provides practical experience returning genetic results for a behavioral condition at a large scale.
PubMed: 38958063
DOI: 10.1016/j.gim.2024.101202 -
Histology and Histopathology Jun 2024Electroacupuncture (EA) pretreatment can effectively increase the tolerance of the brain to ischemic stroke. The mechanism of ischemic tolerance induced by EA is related...
OBJECTIVE
Electroacupuncture (EA) pretreatment can effectively increase the tolerance of the brain to ischemic stroke. The mechanism of ischemic tolerance induced by EA is related to Nrf2, but its specific mechanism has not been elucidated. This paper was designed to explore the effect of EA pretreatment on brain injury and the related mechanisms.
METHODS
Rats were pretreated with EA before middle cerebral artery occlusion (MCAO) modeling. The symptoms of neurological deficit and the volume of cerebral infarction were measured. The levels of inflammatory factors, oxidative stress-related factors, LPO, ROS, and Fe were evaluated by the corresponding kits. Cell apoptosis was determined through TUNEL staining. The mRNA expression of inflammatory factors was examined by RT-qPCR, and the protein expression of ferroptosis-related factors, pyroptosis-related proteins, Keap1, Nrf2, HO-1, and NQO1 by western blotting.
RESULTS
EA pretreatment improved the symptoms of neurological deficit and reduced the volume of cerebral infarction. EA pretreatment significantly inhibited oxidative stress, inflammatory response, ferroptosis, pyroptosis, and apoptosis in brain tissues of MCAO rats. Mechanistically, EA pretreatment could activate Nrf2 expression and reduce Keap1 expression.
CONCLUSION
EA pretreatment reduced inflammation and oxidative stress and inhibited ferroptosis by activating Nrf2 expression, ultimately delaying the development of ischemic stroke.
PubMed: 38958062
DOI: 10.14670/HH-18-780 -
Journal of Medicinal Chemistry Jul 2024(Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their...
(Mtb), the infectious agent of tuberculosis (TB), causes over 1.5 million deaths globally every year. Host-directed therapies (HDT) for TB are desirable for their potential to shorten treatment and reduce the development of antibiotic resistance. Previously, we described a modular biomimetic strategy to identify , targeting PPM1A (IC = 1.19 μM), a metal-dependent phosphatase exploited by Mtb to survive intracellularly. restricted the survival of Mtb in macrophages and lungs of infected mice. Herein, we redesigned to create , which is a more potent inhibitor for PPM1A (IC = 180 nM). efficiently increased the level of phosphorylation of S403-p62 and the expression of LC3B-II to activate autophagy, resulting in the dose-dependent clearance of Mtb in infected macrophages. possesses a good pharmacokinetic profile and oral bioavailability ( = 74%). In vivo, is well tolerated up to 50 mg/kg and significantly reduces the bacteria burden in the spleens of infected mice.
PubMed: 38958057
DOI: 10.1021/acs.jmedchem.4c00513 -
Journal of Clinical Sleep Medicine :... Jul 2024Behavioral sleep medicine (BSM) is a subspecialty that combines behavioral psychology and sleep medicine specialties. The objective of this study was to analyze referral...
STUDY OBJECTIVES
Behavioral sleep medicine (BSM) is a subspecialty that combines behavioral psychology and sleep medicine specialties. The objective of this study was to analyze referral patterns to a BSM clinic. The three specific aims were: (1) describe factors that predict referral acceptance, (2) identify barriers to attending initial appointment, and (3) describe variables associated with the number of visits attended.
METHODS
Retrospective chart reviews were conducted as part of a quality improvement project by this study team's clinical setting. Adults over 21 years of age who were referred to a behavioral sleep medicine clinic in an urban Midwestern academic healthcare system between 2014-2019 were included in this study.
RESULTS
Sleep medicine was the main referral source for BSM patients (74.2%), followed by internal medicine (9.3%) and neurology/psychiatry (7.3%). Thirty-eight percent of patients did not schedule an appointment after a referral for BSM was initiated. Younger age, longer distance from clinic, commercial insurance and out of network insurance were all significantly greater for non-schedulers. Eighty-three percent of patients did attend the initial intake session with BSM providers. Older age was associated with lower likelihood of not attending scheduled BSM appointments.
CONCLUSIONS
Patient characteristics of older age, closer distance from clinic, and in network insurance coverage were found to significantly increase the likelihood of BSM scheduling, while younger age, Black race and not getting a primary sleep disorder diagnosis (versus a diagnosis of Insomnia Disorder) and shorter days from referral to appointment were associated with an increased likelihood of not attending the scheduled BSM treatment engagement.
PubMed: 38958056
DOI: 10.5664/jcsm.11252 -
Nephrology (Carlton, Vic.) Jul 2024IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and almost all patients are at risk of progression to end-stage kidney disease within... (Review)
Review
IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, and almost all patients are at risk of progression to end-stage kidney disease within their lifetime. The mechanisms responsible for the presentation and development of IgAN are required for the development of highly targeted therapies for this disease. In this review, we first demonstrate the current treatment strategy of IgAN recommended by the 2021 KDIGO guideline. Then, we update the new insights into disease pathogenesis based on the well acknowledged 'multiple-hit hypothesis' and provide the potential therapeutic targets involved in the upstream production of pathogenic IgA1 and the downstream complement activation. Finally, the recent large randomized controlled trials focusing on these novel targets have been summarized, among which Nefecon and Sparsentan have received approval and Telitacicept have been used off-label for IgAN. In the future, emerging treatment approaches for IgAN is likely to evolve, which will signify a shift in the management of the IgAN from traditional immunosuppressive approaches to an era of targeted treatment based on the understanding of the pathogenic mechanisms.
PubMed: 38958055
DOI: 10.1111/nep.14340 -
Journal of Clinical Sleep Medicine :... Jul 2024
PubMed: 38958054
DOI: 10.5664/jcsm.11270 -
The Laryngoscope Jul 2024Tympanostomy tube insertion (TTI) under local anesthesia (LA) is gaining popularity but literature comparing long-term outcomes for children undergoing TTI under LA...
OBJECTIVES
Tympanostomy tube insertion (TTI) under local anesthesia (LA) is gaining popularity but literature comparing long-term outcomes for children undergoing TTI under LA versus general anesthesia (GA) is limited. This study compares the long-term quality of life (QoL) between LA and GA in children undergoing TTI. Secondary objectives included long-term behavioral changes, parental satisfaction, tube durability, and postoperative complications.
METHODS
We prospectively followed children aged under 6 who underwent TTI, under LA or GA, 2 years prior. We assessed QoL using validated scales (OM6, PedsQL), analyzed behavioral changes and parental satisfaction through qualitative scales, and retrieved data on tube durability and non-immediate complications.
RESULTS
A total of 84 children (LA = 42; GA = 42) had complete data and a minimum of 1 year of follow-up. Demographic data were similar, except for younger patients in the LA group (1.4 vs. 1.9 years, p = 0.02). LA group exhibited increased fear of health care professionals following TTI (LA: Likert scale 2.1/5, GA: 1.5/5, p = 0.04). Tube retention rate was shorter in the LA group (at 15 months: GA:72%, LA:50%, p = 0.039). Two years post-TTI, there were no differences regarding QoL (OM-6 score; LA: 15.2/100, GA: 21.4/100, p = 0.18, and PedsQL score; LA: 84.3/100, GA: 83.8/100, p = 0.90), parental satisfaction with anesthesia (GA: 4.5/5, LA: 4.6/5, p = 0.56), and postoperative complications (GA: 3/42, LA: 7/42, p = 0.18).
CONCLUSIONS
TTI under LA in children is associated with an increased fear of health care professionals and shorter functionality of tympanostomy tubes as compared to GA. No difference was observed in long-term QoL, parental satisfaction, and complications rate.
LEVEL OF EVIDENCE
Level 3 Laryngoscope, 2024.
PubMed: 38958053
DOI: 10.1002/lary.31611 -
Pediatric Obesity Jul 2024This study identified metabolite modules associated with adiposity and body fat distribution in childhood using gold-standard measurements.
OBJECTIVE
This study identified metabolite modules associated with adiposity and body fat distribution in childhood using gold-standard measurements.
METHODS
We used cross-sectional data from 329 children at mid-childhood (age 5.3 ± 0.3 years; BMI 15.7 ± 1.5 kg/m) from the Genetics of Glucose regulation in Gestation and Growth (Gen3G), a prospective pre-birth cohort. We quantified 1038 plasma metabolites and measured body composition using the gold-standard dual-energy x-ray absorptiometry (DXA), in addition to skinfold, waist circumference, and BMI. We applied weighted-correlation network analysis to identify a network of highly correlated metabolite modules. Spearman's partial correlations were applied to determine the associations of adiposity with metabolite modules and individual metabolites with false discovery rate (FDR) correction.
RESULTS
We identified a 'green' module of 120 metabolites, primarily comprised of lipids (mostly sphingomyelins and phosphatidylcholine), that showed positive correlations (all FDR p < 0.05) with DXA estimates of total and truncal fat (ρ = 0.11-0.19), skinfold measures (ρ = 0.09-0.26), and BMI and waist circumference (ρ = 0.15 and 0.18, respectively). These correlations were similar when stratified by sex. Within this module, sphingomyelin (d18:2/14:0, d18:1/14:1)*, a sphingomyelin sub-specie that is an important component of cell membranes, showed the strongest associations.
CONCLUSIONS
A module of metabolites was associated with adiposity measures in childhood.
PubMed: 38958048
DOI: 10.1111/ijpo.13149 -
Chinese Medical Journal Jul 2024Digestive system cancers constitute a significant number of cancer cases, but their burden is not uniform. As Global Cancer Observatory (GLOBOCAN) 2022 has recently...
BACKGROUND
Digestive system cancers constitute a significant number of cancer cases, but their burden is not uniform. As Global Cancer Observatory (GLOBOCAN) 2022 has recently updated its estimates of cancer burden, we aimed to investigate the burden of six major digestive system cancers both worldwide and in China, along with geographical and temporal variations in cancer-specific incidence and mortality.
METHODS
We extracted data on primary cancers of the esophagus, stomach, colorectum, liver, pancreas, and gallbladder from the GLOBOCAN database for 2022. Age-standardized incidence and mortality rates were calculated and stratified by sex, country, region, and human development index (HDI). We used the 2022 revision of the World Population Prospects (United Nations) to obtain demographic data for various age groups in China from 1988 to 2012 and used the joinpoint model and the average annual percentage change (AAPC) to analyze cancer incidence trends in China.
RESULTS
In 2022, the estimated global incidence of digestive system cancers reached 4,905,882, with an estimated 3,324,774 cancer-related deaths. Colorectal cancer was most prevalent in terms of incidence and mortality. There was a significant correlation between the burden of gastrointestinal cancers and country HDI. From 1988 to 2012, the incidence of esophageal, gastric, and liver cancers declined in China, whereas colorectal and pancreatic cancer incidences continued to increase. By 2050, colorectal and liver cancers are projected to remain the leading cancer types in China in terms of incidence and mortality, respectively.
CONCLUSIONS
Digestive system cancers remain a significant public health challenge globally and in China. Although progress has been made in the prevention and control of some cancers, the burden of digestive system cancers persists. The implementation of tertiary prevention strategies must be intensified to reduce the incidence and mortality of digestive system cancers, mitigating their impact on public health.
PubMed: 38958046
DOI: 10.1097/CM9.0000000000003225 -
Aging Cell Jul 2024Age-related chronic inflammatory lung diseases impose a threat on public health, including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease...
Age-related chronic inflammatory lung diseases impose a threat on public health, including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). However, their etiology and potential targets have not been clarified. We performed genome-wide meta-analysis for IPF with the largest sample size (2883 cases and 741,929 controls) and leveraged the summary statistics of COPD (17,547 cases and 617,598 controls). Transcriptome-wide and proteome-wide Mendelian randomization (MR) designs, together with genetic colocalization, were implemented to find robust targets. The mediation effect was assessed using leukocyte telomere length (LTL). The single-cell transcriptome analysis was performed to link targets with cell types. Individual-level data from UK Biobank (UKB) were used to validate our findings. Sixteen genetically predicted plasma proteins were causally associated with the risk of IPF and 6 proteins were causally associated with COPD. Therein, genetically-elevated plasma level of SCARF2 protein should reduce the risk of both IPF (odds ratio, OR = 0.9974 [0.9970, 0.9978]) and COPD (OR = 0.7431 [0.6253, 0.8831]) and such effects were not mediated by LTL. Genetic colocalization further corroborated these MR results of SCARF2. The transcriptome-wide MR confirmed that higher expression level of SCARF2 was associated with a reduced risk of both. However, the single-cell RNA analysis indicated that SCARF2 expression level was only relatively lower in epithelial cells of COPD lung tissue compared to normal lung tissue. UKB data implicated an inverse association of serum SCARF2 protein with COPD (hazard ratio, HR = 1.215 [1.106, 1.335]). The SCARF2 gene should be a novel target for COP.
PubMed: 38958042
DOI: 10.1111/acel.14266