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BMC Genomics Jun 2024Ancient northern East Asians (ANEA) from the Yellow River region, who pioneered millet cultivation, play a crucial role in understanding the origins of...
BACKGROUND
Ancient northern East Asians (ANEA) from the Yellow River region, who pioneered millet cultivation, play a crucial role in understanding the origins of ethnolinguistically diverse populations in modern China and the entire landscape of deep genetic structure and variation discovery in modern East Asians. However, the direct links between ANEA and geographically proximate modern populations, as well as the biological adaptive processes involved, remain poorly understood.
RESULTS
Here, we generated genome-wide SNP data for 264 individuals from geographically different Han populations in Shandong. An integrated genomic resource encompassing both modern and ancient East Asians was compiled to examine fine-scale population admixture scenarios and adaptive traits. The reconstruction of demographic history and hierarchical clustering patterns revealed that individuals from the Shandong Peninsula share a close genetic affinity with ANEA, indicating long-term genetic continuity and mobility in the lower Yellow River basin since the early Neolithic period. Biological adaptive signatures, including those related to immune and metabolic pathways, were identified through analyses of haplotype homozygosity and allele frequency spectra. These signatures are linked to complex traits such as height and body mass index, which may be associated with adaptations to cold environments, dietary practices, and pathogen exposure. Additionally, allele frequency trajectories over time and a haplotype network of two highly differentiated genes, ABCC11 and SLC10A1, were delineated. These genes, which are associated with axillary odor and bilirubin metabolism, respectively, illustrate how local adaptations can influence the diversification of traits in East Asians.
CONCLUSIONS
Our findings provide a comprehensive genomic dataset that elucidates the fine-scale genetic history and evolutionary trajectory of natural selection signals and disease susceptibility in Han Chinese populations. This study serves as a paradigm for integrating spatiotemporally diverse ancient genomes in the era of population genomic medicine.
Topics: Humans; China; Genetics, Population; Haplotypes; Polymorphism, Single Nucleotide; Genomics; Evolution, Molecular; Gene Frequency; Asian People; Genome, Human
PubMed: 38890579
DOI: 10.1186/s12864-024-10514-9 -
American Journal of Clinical Dermatology Jul 2024Abrocitinib, an oral, once-daily, Janus kinase 1-selective inhibitor, is efficacious in moderate-to-severe atopic dermatitis with a manageable long-term safety profile. (Clinical Trial)
Clinical Trial
BACKGROUND
Abrocitinib, an oral, once-daily, Janus kinase 1-selective inhibitor, is efficacious in moderate-to-severe atopic dermatitis with a manageable long-term safety profile.
OBJECTIVE
We aimed to provide updated integrated long-term safety results for abrocitinib from available data accrued up to a maximum of almost 4 years in patients with moderate-to-severe atopic dermatitis from the JADE clinical development program.
METHODS
Analysis included 3802 patients (exposure: 5213.9 patient-years) from the phase II monotherapy study (NCT02780167) and the phase III studies JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871), JADE TEEN (NCT03796676), JADE COMPARE (NCT03720470), JADE DARE (NCT04345367; 200 mg only), JADE REGIMEN (NCT03627767), and JADE EXTEND (NCT03422822; data cutoff 25 September, 2021). Data from patients receiving one or more doses of abrocitinib 200 mg or 100 mg were pooled in a consistent-dose cohort (patients were allocated to receive the same abrocitinib dose throughout exposure in the qualifying parent study and/or long-term study) or a variable-dose cohort (patients received open-label abrocitinib 200 mg; responders were randomized to abrocitinib 200 mg, 100 mg, or placebo, and could then receive abrocitinib 200 mg plus topical corticosteroids as rescue therapy). Incidence rates of adverse events of special interest were assessed. Cox regression analysis of risk factors for herpes zoster and serious infections was performed.
RESULTS
Overall, this safety analysis of long-term data up to a maximum of ~ 4 years of abrocitinib exposure does not indicate any changes from the previously reported risk profile. The most frequent serious infections (per Medical Dictionary for Regulatory Activities preferred term) with consistent-dose abrocitinib 200 mg and 100 mg were herpes zoster (0.5% and 0.2%), pneumonia (0.2% with either dose), and herpes simplex (0.1% with either dose). Risk factors for herpes zoster were a history of herpes zoster, abrocitinib 200-mg dose, age ≥ 65 years, absolute lymphocyte count < 1 × 10/mm before the event, and residing in Asia. For serious infections, > 100 kg body weight was a risk factor. Incidence rate/100 patient-years (95% confidence interval) with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in older (aged ≥ 65 years) patients versus younger (aged 18 to < 65 years) patients for serious adverse events (17.6 [11.7‒25.4] vs 6.7 [5.8‒7.8]), malignancy excluding non-melanoma skin cancer (2.4 [0.6‒6.0] vs 0.1 [0.0‒0.4]), non-melanoma skin cancer (2.4 [0.6‒6.1] vs 0.2 [0.1‒0.4]), lymphopenia (3.5 [1.3‒7.6] vs 0.1 [0.0‒0.3]), and venous thromboembolism (1.7 [0.4‒5.1] vs 0.1 [0.0‒0.3]). Incident rate/100 patient-years (95% confidence interval) of non-melanoma skin cancer with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in current/former smokers (0.9 [0.4‒1.6]) vs never-smokers (0.0 [0.0‒0.1]).
CONCLUSIONS
This safety update showed a consistent profile for abrocitinib with no new safety signals and continues to support that abrocitinib has a manageable long-term safety profile in patients with moderate-to-severe atopic dermatitis. Risk of specific adverse events was higher in certain patient populations, especially those aged ≥ 65 years. [Video abstract available.] CLINICAL TRIAL REGISTRATION: NCT02780167; study start date: April, 2016; primary completion date: March, 2017; study completion date: April, 2017. NCT03349060; study start date: 7 December, 2017; study completion date: 26 March, 2019. NCT03575871; study start date: 29 June, 2018; study completion date: 13 August, 2019. NCT03720470; study start date: 29 October, 2018; primary completion date: 27 December, 2019; study completion date: 6 March, 2020. NCT03796676; study start date: 18 February, 2019; study completion date: 8 April, 2020. NCT03627767; study start date: 11 June, 2018; primary completion date: 2 September, 2020; study completion date: 7 October, 2020. NCT04345367; study start date: 11 June, 2020; primary completion date: 16 December, 2020; study completion date: 13 July, 2021. NCT03422822; study start date: 8 March, 2018; study completion date: ongoing (estimated completion date: 31 January, 2026).
Topics: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Young Adult; Administration, Oral; Boron Compounds; Dermatitis, Atopic; Herpes Zoster; Janus Kinase Inhibitors; Pyrimidines; Severity of Illness Index; Sulfonamides; Treatment Outcome
PubMed: 38888681
DOI: 10.1007/s40257-024-00869-w -
Translational Vision Science &... Jun 2024Recombinant human nerve growth factor (rhNGF; cenegermin-bkbj, OXERVATE) is the first and only U.S. Food and Drug Administration-approved treatment for moderate to...
PURPOSE
Recombinant human nerve growth factor (rhNGF; cenegermin-bkbj, OXERVATE) is the first and only U.S. Food and Drug Administration-approved treatment for moderate to severe neurotrophic keratopathy. The aim of this study was to determine the feasibility of incorporating a version of rhNGF in a mucoadhesive hydrogel capable of sustained drug release to the ocular surface.
METHODS
Hydrogels loaded with rhNGF were synthesized by conjugating chitosan with azidobenzoic acid (Az-Ch), adding rhNGF, and exposing the solution to ultraviolet (UV) radiation to induce photocrosslinking. Az-Ch hydrogels were evaluated for physical properties and rhNGF release profiles. Cytocompatbility of Az-Ch was assessed using immortalized human corneal limbal epithelial (HCLE) cells. TF1 erythroleukemic cell proliferation and HCLE cell proliferation and migration were used to assess the bioactivity of rhNGF released from Az-Ch hydrogels.
RESULTS
Az-Ch formed hydrogels in <10 seconds of UV exposure and demonstrated high optical transparency (75-85 T%). Az-Ch hydrogels exhibited good cytocompatibility with no demonstratable effect on HCLE cell morphology or viability. rhNGF was released gradually over 24 hours from Az-Ch hydrogels and retained its ability to induce TF1 cell proliferation. No significant difference was observed between rhNGF released from Az-Ch and freshly prepared rhNGF solutions on HCLE cell proliferation or percent wound closure after 12 hours; however, both were significantly better than control (P < 0.01).
CONCLUSIONS
rhNGF-loaded Az-Ch hydrogels exhibited favorable physical, optical, and drug-release properties, as well as retained drug bioactivity. This drug delivery system has the potential to be further developed for in vivo and translational clinical applications.
TRANSLATIONAL RELEVANCE
Az-Ch hydrogels may be used to enhance rhNGF therapy in patients with NK.
Topics: Nerve Growth Factor; Humans; Chitosan; Hydrogels; Cell Proliferation; Cell Movement; Ultraviolet Rays; Cross-Linking Reagents; Limbus Corneae; Recombinant Proteins; Drug Delivery Systems
PubMed: 38888287
DOI: 10.1167/tvst.13.6.12 -
Tobacco Induced Diseases 2024Cigarette package inserts that describe quitting benefits and tips may promote cessation; however, research is needed to understand better their effects, including...
INTRODUCTION
Cigarette package inserts that describe quitting benefits and tips may promote cessation; however, research is needed to understand better their effects, including potentially enhancing the effects of pictorial health warning labels (PHWLs).
METHODS
A randomized trial with a 2×2 factorial design was conducted with adult smokers (n=356) assigned to either small text-only health warning labels (HWLs; control); inserts with cessation messages, and the small text-only HWLs (inserts-only); large PHWLs (PHWLs-only); both inserts and PHWLs (inserts + PHWLs). Participants received a 14-day supply of their preferred cigarettes with packs labeled to reflect their group. Upon finishing the trial, participants reported their past 14-day frequency of noticing, reading, thinking about smoking harms and cessation benefits, talking about labels, and forgoing cigarettes because of the labels. Ordered logistic models regressed these outcomes on labeling groups, and mediation analyses assessed whether attention (i.e. noticing, reading) to labels mediated effects of labeling exposure on other outcomes (i.e. thinking about harms/benefits, talking, forgoing).
RESULTS
The inserts + PHWLs group reported higher frequencies than the control group for all outcomes. Compared to the control group, both the inserts-only and PHWLs-only groups reported higher frequency of noticing (AOR=3.53 and 2.46, respectively) and reading labels (AOR=2.89 and 1.71), thinking about smoking risks because of the labels (AOR=1.93 and 1.82), and talking about labels (AOR=2.30 and 2.70). Participants in the inserts-only group also reported more frequent thinking about quitting benefits (AOR=1.98). Attention mediated all labeling effects except for the contrast between PHWLs only and control.
CONCLUSIONS
Compared to text-only HWLS, cigarette labeling that involves inserts, PHWLs, or both appears more effective at drawing attention to warnings, which mediated the effects on cessation-related psychosocial and behavioral outcomes.
PubMed: 38887598
DOI: 10.18332/tid/189198 -
Frontiers in Immunology 2024The rate and prognosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with solid cancer tumors actively treated with immune... (Meta-Analysis)
Meta-Analysis
UNLABELLED
The rate and prognosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with solid cancer tumors actively treated with immune checkpoint inhibitors (ICIs) have not been fully determined. The goal of this meta-analysis was to explore this issue, which can be helpful to clinicians in their decision-making concerning patient treatment. We conducted a thorough search for relevant cohort studies in the databases PubMed, Embase, Cochrane Library, and Web of Science. Mortality and infection rate were the primary endpoints, and the incidence of severe or critical disease was the secondary result. A total of 6,267 cases (individual patients) were represented in 15 studies. Prior exposure to ICIs was not correlated with an elevated risk of SARS-CoV-2 infection (relative risk (RR) 1.04, 95% CI 0.57-1.88, z = 0.12, = 0.905) or mortality (RR 1.22, 95% CI 0.99-1.50, z = 1.90, = 0.057). However, the results of the meta-analysis revealed that taking ICIs before SARS-CoV-2 diagnosis increased the chance of developing severe or critical disease (RR 1.51, 95% CI 1.09-2.10, z = 2.46, = 0.014). No significant inter-study heterogeneity was observed. The infection and mortality rates of SARS-CoV-2 in patients with solid tumors who previously received ICIs or other antitumor therapies did not differ significantly. However, secondary outcomes showed that ICIs treatment before the diagnosis of SARS-CoV-2 infection was significantly associated with the probability of severe or critical illness.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/#recordDetails PROSPERO, identifier CRD42023393511.
Topics: Humans; COVID-19; Neoplasms; Immune Checkpoint Inhibitors; SARS-CoV-2; Prognosis
PubMed: 38887296
DOI: 10.3389/fimmu.2024.1259112 -
Causal effects between gut microbiota and endometriosis: a two-sample Mendelian randomisation study.Journal of Obstetrics and Gynaecology :... Dec 2024Previous observational evidence has indicated the potential involvement of the gut microbiota (GM) in the development of endometriosis. However, the causal relationship...
BACKGROUND
Previous observational evidence has indicated the potential involvement of the gut microbiota (GM) in the development of endometriosis. However, the causal relationship of the association remains to be investigated.
METHOD
Genome-wide association study (GWAS) data of GM was obtained from the MiBioGen consortium, and GWAS for endometriosis data was from the FinnGen consortium. Initially, a two-sample Mendelian randomisation (MR) analysis was performed to identify specific bacteria associated with endometriosis. Inverse variance-weighted (IVW) was used as the main MR analysis to infer causal relationships. The other four popular MR methods including MR-Egger regression, weighted mode, weighted median, and simple mode were used for secondary confirmation. Subsequently, these selected bacteria were employed as exposure to investigate their causal effects on six sub-types of endometriosis. Furthermore, reverse MR analysis was implemented to evaluate the reverse causal effects. Cochran's Q statistics was used to test the heterogeneity of instrumental variables (IVs); MR-Egger regression was used to test horizontal pleiotropy; MR-PRESSO and leave-one-out sensitivity analysis were applied to find significant outliers.
RESULT
A total of 1131 single nucleotide polymorphisms (SNPs) were collected as IVs for 196 GM taxa with endometriosis as the outcome. We identified 12 causal relationships between endometriosis and GM taxa including 1 phylum, 3 families, 2 orders, and 6 genera (Rikenellaceae RC9 gut group, Eubacterium ruminantium group, Faecalibacterium, Peptococcus, Clostridium sensu stricto 1, and Ruminococcaceae UCG005). Utilizing the Bonferroni method, we identified phylum Cyanobacteria as the strongest associated GM taxa. Subsequently, 6 significant causal effects were uncovered between the 12 selected specific GM and 6 sub-types of endometriosis. Meanwhile, no reverse causal relationship was found. Further, no horizontal pleiotropy and no significant outliers were detected in the sensitive analysis.
CONCLUSIONS
This MR analysis revealed significant causal effects between GM and endometriosis and phylum Cyanobacteria had the strongest association.
Topics: Endometriosis; Humans; Female; Mendelian Randomization Analysis; Genome-Wide Association Study; Gastrointestinal Microbiome; Polymorphism, Single Nucleotide; Causality
PubMed: 38885114
DOI: 10.1080/01443615.2024.2362415 -
JAMA Network Open Jun 2024Persistent symptoms and disability following SARS-CoV-2 infection, known as post-COVID-19 condition or "long COVID," are frequently reported and pose a substantial...
IMPORTANCE
Persistent symptoms and disability following SARS-CoV-2 infection, known as post-COVID-19 condition or "long COVID," are frequently reported and pose a substantial personal and societal burden.
OBJECTIVE
To determine time to recovery following SARS-CoV-2 infection and identify factors associated with recovery by 90 days.
DESIGN, SETTING, AND PARTICIPANTS
For this prospective cohort study, standardized ascertainment of SARS-CoV-2 infection was conducted starting in April 1, 2020, across 14 ongoing National Institutes of Health-funded cohorts that have enrolled and followed participants since 1971. This report includes data collected through February 28, 2023, on adults aged 18 years or older with self-reported SARS-CoV-2 infection.
EXPOSURE
Preinfection health conditions and lifestyle factors assessed before and during the pandemic via prepandemic examinations and pandemic-era questionnaires.
MAIN OUTCOMES AND MEASURES
Probability of nonrecovery by 90 days and restricted mean recovery times were estimated using Kaplan-Meier curves, and Cox proportional hazards regression was performed to assess multivariable-adjusted associations with recovery by 90 days.
RESULTS
Of 4708 participants with self-reported SARS-CoV-2 infection (mean [SD] age, 61.3 [13.8] years; 2952 women [62.7%]), an estimated 22.5% (95% CI, 21.2%-23.7%) did not recover by 90 days post infection. Median (IQR) time to recovery was 20 (8-75) days. By 90 days post infection, there were significant differences in restricted mean recovery time according to sociodemographic, clinical, and lifestyle characteristics, particularly by acute infection severity (outpatient vs critical hospitalization, 32.9 days [95% CI, 31.9-33.9 days] vs 57.6 days [95% CI, 51.9-63.3 days]; log-rank P < .001). Recovery by 90 days post infection was associated with vaccination prior to infection (hazard ratio [HR], 1.30; 95% CI, 1.11-1.51) and infection during the sixth (Omicron variant) vs first wave (HR, 1.25; 95% CI, 1.06-1.49). These associations were mediated by reduced severity of acute infection (33.4% and 17.6%, respectively). Recovery was unfavorably associated with female sex (HR, 0.85; 95% CI, 0.79-0.92) and prepandemic clinical cardiovascular disease (HR, 0.84; 95% CI, 0.71-0.99). No significant multivariable-adjusted associations were observed for age, educational attainment, smoking history, obesity, diabetes, chronic kidney disease, asthma, chronic obstructive pulmonary disease, or elevated depressive symptoms. Results were similar for reinfections.
CONCLUSIONS AND RELEVANCE
In this cohort study, more than 1 in 5 adults did not recover within 3 months of SARS-CoV-2 infection. Recovery within 3 months was less likely in women and those with preexisting cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave.
Topics: Humans; COVID-19; Female; Male; Middle Aged; SARS-CoV-2; Prospective Studies; Aged; Adult; Post-Acute COVID-19 Syndrome; Pandemics; United States
PubMed: 38884994
DOI: 10.1001/jamanetworkopen.2024.17440 -
Clinical and Experimental Medicine Jun 2024CD8 + T cells exert a critical role in eliminating cancers and chronic infections, and can provide long-term protective immunity. However, under the exposure of... (Review)
Review
CD8 + T cells exert a critical role in eliminating cancers and chronic infections, and can provide long-term protective immunity. However, under the exposure of persistent antigen, CD8 + T cells can differentiate into terminally exhausted CD8 + T cells and lose the ability of immune surveillance and disease clearance. New insights into the molecular mechanisms of T-cell exhaustion suggest that it is a potential way to improve the efficacy of immunotherapy by restoring the function of exhausted CD8 + T cells. Transforming growth factor-β (TGF-β) is an important executor of immune homeostasis and tolerance, inhibiting the expansion and function of many components of the immune system. Recent studies have shown that TGF-β is one of the drivers for the development of exhausted CD8 + T cells. In this review, we summarized the role and mechanisms of TGF-β in the formation of exhausted CD8 + T cells and discussed ways to target those to ultimately enhance the efficacy of immunotherapy.
Topics: Humans; Transforming Growth Factor beta; CD8-Positive T-Lymphocytes; Immunotherapy; Neoplasms; Animals
PubMed: 38884843
DOI: 10.1007/s10238-024-01394-0 -
JAAD Case Reports Jul 2024
PubMed: 38883174
DOI: 10.1016/j.jdcr.2024.04.019 -
ACS Omega Jun 2024In exploring the viability of perovskite solar cells (PSCs) for Mars missions, our study first delved into their temperature endurance in conditions mimicking the...
In exploring the viability of perovskite solar cells (PSCs) for Mars missions, our study first delved into their temperature endurance in conditions mimicking the Martian climate, revealing remarkable thermal stability within the temperature range of 173-303 K. We then pioneered the examination of PSC resilience to electrostatic discharge (ESD), a critical factor given the frequent Martian dust activities. In a custom-built Martian simulation chamber, we discovered that ESD exposure dramatically reduced the power conversion efficiency of these devices by more than half (55.4%) in just 90 s. This groundbreaking research not only advances our understanding of the potential of PSCs for Mars exploration but also opens new avenues for optimizing solar technology in extreme environments.
PubMed: 38882146
DOI: 10.1021/acsomega.4c02887