Aspirin Use and Incidence of Colorectal Cancer According to Lifestyle Risk.

Importance: Aspirin reduces the risk of colorectal cancer (CRC). Identifying individuals more likely to benefit from regular aspirin use for CRC prevention is a high priority. Objective: To assess whether aspirin use is associated with the risk of CRC across different lifestyle risk factors. Design, Setting, and Participants: A prospective cohort study among women in the Nurses' Health Study (1980-2018) and men in the Health Professionals Follow-Up Study (1986-2018) was conducted. Data analysis was performed from October 1, 2021, to May 22, 2023. Exposures: A healthy lifestyle score was calculated based on body mass index, alcohol intake, physical activity, diet, and smoking with scores ranging from 0 to 5 (higher values corresponding to a healthier lifestyle). Regular aspirin use was defined as 2 or more standard tablets (325 mg) per week. Main Outcome and Measures: Outcomes included multivariable-adjusted 10-year cumulative incidence of CRC, absolute risk reduction (ARR), and number needed to treat associated with regular aspirin use by lifestyle score and multivariable-adjusted hazard ratios for incident CRC across lifestyle scores. Results: The mean (SD) baseline age of the 107 655 study participants (63 957 women from the Nurses' Health Study and 43 698 men from the Health Professionals Follow-Up Study) was 49.4 (9.0) years. During 3 038 215 person-years of follow-up, 2544 incident cases of CRC were documented. The 10-year cumulative CRC incidence was 1.98% (95% CI, 1.44%-2.51%) among participants who regularly used aspirin compared with 2.95% (95% CI, 2.31%-3.58%) among those who did not use aspirin, corresponding to an ARR of 0.97%. The ARR associated with aspirin use was greatest among those with the unhealthiest lifestyle scores and progressively decreased with healthier lifestyle scores (P < .001 for additive interaction). The 10-year ARR for lifestyle scores 0 to 1 (unhealthiest) was 1.28%. In contrast, the 10-year ARR for lifestyle scores 4 to 5 (healthiest) was 0.11%. The 10-year number needed to treat with aspirin was 78 for participants with lifestyle scores 0 to 1, 164 for score 2, 154 for score 3, and 909 for scores 4 to 5. Among the components of the healthy lifestyle score, the greatest differences in ARR associated with aspirin use were observed for body mass index and smoking. Conclusions and Relevance: In this cohort study, aspirin use was associated with a greater absolute reduction in risk of CRC among individuals with less healthy lifestyles. The findings of the study suggest that lifestyle risk factors may be useful to identify individuals who may have a more favorable risk-benefit profile for cancer prevention with aspirin.

Intestinal Blastocystis is linked to healthier diets and more favorable cardiometabolic outcomes in 56,989 individuals from 32 countries.

Diet impacts human health, influencing body adiposity and the risk of developing cardiometabolic diseases. The gut microbiome is a key player in the diet-health axis, but while its bacterial fraction is widely studied, the role of micro-eukaryotes, including Blastocystis, is underexplored. We performed a global-scale analysis on 56,989 metagenomes and showed that human Blastocystis exhibits distinct prevalence patterns linked to geography, lifestyle, and dietary habits. Blastocystis presence defined a specific bacterial signature and was positively associated with more favorable cardiometabolic profiles and negatively with obesity (p < 1e-16) and disorders linked to altered gut ecology (p < 1e-8). In a diet intervention study involving 1,124 individuals, improvements in dietary quality were linked to weight loss and increases in Blastocystis prevalence (p = 0.003) and abundance (p < 1e-7). Our findings suggest a potentially beneficial role for Blastocystis, which may help explain personalized host responses to diet and downstream disease etiopathogenesis.

High Prevalence of Highly Pathogenic Avian Influenza: A Virus in Vietnam's Live Bird Markets.

Background: In recent years, Vietnam has suffered multiple epizootics of influenza in poultry. Methods: From 10 January 2019 to 26 April 2021, we employed a One Health influenza surveillance approach at live bird markets (LBMs) and swine farms in Northern Vietnam. When the COVID-19 pandemic permitted, each month, field teams collected oral secretion samples from poultry and pigs, animal facility bioaerosol and fecal samples, and animal worker nasal washes at 4 LBMs and 5 swine farms across 5 sites. Initially samples were screened with molecular assays followed by culture in embryonated eggs (poultry swabs) or Madin-Darby canine kidney cells (human or swine swabs). Results: Many of the 3493 samples collected had either molecular or culture evidence for influenza A virus, including 314 (37.5%) of the 837 poultry oropharyngeal swabs, 144 (25.1%) of the 574 bioaerosol samples, 438 (34.9%) of the 1257 poultry fecal swab samples, and 16 (1.9%) of the 828 human nasal washes. Culturing poultry samples yielded 454 influenza A isolates, 83 of which were H5, and 70 (84.3%) of these were highly pathogenic. Additionally, a positive human sample had a H9N2 avian-like PB1 gene. In contrast, the prevalence of influenza A in the swine farms was much lower with only 6 (0.4%) of the 1700 total swine farm samples studied, having molecular evidence for influenza A virus. Conclusions: This study suggests that Vietnam's LBMs continue to harbor high prevalences of avian influenza A viruses, including many highly pathogenic H5N6 strains, which will continue to threaten poultry and humans.

Ultraprocessed food consumption and risk of gallstone disease: analysis of 3 prospective cohorts.

BACKGROUND: Majority of dietary intake in United States adults comes from ultraprocessed foods (UPFs), which have been linked to several adverse health outcomes. Gallstone disease is highly prevalent and constitutes a significant burden to the United States health system but remains understudied. OBJECTIVES: This study aimed to investigate the association between UPF consumption and incident gallstone disease risk. METHODS: In this analysis, 44,149 males in the Health Professionals' Follow-up Study (HPFS: 1986-2022), 71,145 females in the Nurses' Health Study (NHS: 1986-2021), and 90,932 females in the NHS II (1991-2021) were prospectively followed. Dietary intake was quadrennially assessed with semiquantitative food frequency questionnaires and used to identify UPFs. The primary outcome was defined as cholecystectomy. Cox proportional hazards model was used to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). RESULTS: Baseline median age was 54 y in HPFS, 53 y in NHS, and 36 y in NHS II. We identified 32,374 incident gallstone disease cases over 5,077,059 person-years. Participants in the highest UPF quintile had a higher incidence of gallstone disease than those in the lowest quintile (aHR: 1.29; 95% CI: 1.24, 1.36; P < 0.001). Incremental risk of incident gallstone disease was 2.8% per daily serving (95% CI: 2.4%, 3.2%; P < 0.001). This risk was driven by sugar-sweetened beverages and artificially sweetened beverages on UPF subgroup analyses. The proportion of risk mediated by obesity was 12.8% (95% CI: 7.7%, 20.5%; P < 0.001) in HPFS, 14.3% (95% CI: 10.4%, 19.4%; P < 0.001) in NHS, and 39.4% (95% CI: 31.2%, 48.1%; P < 0.001) in NHS II. The partial population attributable risk was estimated at 15.9% (95% CI: 13.4%, 18.3%). CONCLUSIONS: UPF consumption is associated with a higher risk of gallstone disease, particularly consumption of sugar-sweetened beverages and artificially sweetened beverages. A substantial proportion of this risk is potentially mediated by obesity in younger females.

Chemo-, Regio-, and Stereoselective cis-Hydroboration of 1,3-Enynes: Copper-Catalyzed Access to (Z,Z)- and (Z,E)-2-Boryl-1,3-dienes.

A copper-catalyzed alkyne-selective hydroboration of 1,3-enynes is disclosed, providing access to the previously elusive 2-boryl-1,3-dienes. Using CuOAc, Xantphos, and HBpin, Bpin was installed on the internal carbon of a series of symmetric and nonsymmetric 1,3-enynes, affording products with excellent Z:E selectivity. The utility of the 2-boryl-1,3-diene products was demonstrated by transformation to useful functional groups.

Abbreviated MRI in the evaluation of dizziness: report turnaround times and impact on length of stay compared to CT, CTA, and conventional MRI.

PURPOSE: Neuroimaging is often used in the emergency department (ED) to evaluate for posterior circulation strokes in patients with dizziness, commonly with CT/CTA due to speed and availability. Although MRI offers more sensitive evaluation, it is less commonly used, in part due to slower turnaround times. We assess the potential for abbreviated MRI to improve reporting times and impact on length of stay (LOS) compared to conventional MRI (as well as CT/CTA) in the evaluation of acute dizziness. MATERIALS AND METHODS: We performed a retrospective analysis of length of stay via LASSO regression for patients presenting to the ED with dizziness and discharged directly from the ED over 4 years (1/1/2018-12/31/2021), controlling for numerous patient-level and logistical factors. We additionally assessed turnaround time between order and final report for various imaging modalities. RESULTS: 14,204 patients were included in our analysis. Turnaround time for abbreviated MRI was significantly lower than for conventional MRI (4.40 h vs. 6.14 h, p < 0.001) with decreased impact on LOS (0.58 h vs. 2.02 h). Abbreviated MRI studies had longer turnaround time (4.40 h vs. 1.41 h, p < 0.001) and was associated with greater impact on ED LOS than non-contrast CT head (0.58 h vs. 0.00 h), however there was no significant difference in turnaround time compared to CTA head and neck (4.40 h vs. 3.86 h, p = 0.06) with similar effect on LOS (0.58 h vs. 0.53 h). Ordering both CTA and conventional MRI was associated with a greater-than-linear increase in LOS (additional 0.37 h); the same trend was not seen combining CTA and abbreviated MRI (additional 0.00 h). CONCLUSIONS: In the acute settings where MRI is available, abbreviated MRI protocols may improve turnaround times and LOS compared to conventional MRI protocols. Since recent guidelines recommend MRI over CT in the evaluation of dizziness, implementation of abbreviated MRI protocols has the potential to facilitate rapid access to preferred imaging, while minimizing impact on ED workflows.

Online digital compensation of pump dithering induced phase and amplitude distortions in transmission links with cascaded fibre-optical parametric amplifiers.

We present an advanced online digital signal processing (DSP) method for correcting the phase and amplitude distortions caused by the phase modulation of the pump source and its interaction with the dispersive fibre channel in transmission systems using cascaded fibre-optical parametric amplifiers. The proposed algorithm is numerically demonstrated to achieve significant (up to 3.7 dB for a four-tone pump-phase modulation scheme) Q2-factor performance improvement over conventional DSP in 16 quadrature-amplitude modulation signal transmission.

Efficacy of Daoyin combined with lower limb robot as a comprehensive rehabilitation intervention for stroke patients: a randomized controlled trial.

OBJECTIVE: To assess the effectiveness of a comprehensive rehabilitation approach combining Traditional Chinese Medicine Daoyin with lower limb robotics during the recovery phase of stroke patients. METHODS: Stroke patients meeting the specified criteria were randomly assigned to one of four groups using a random number table: Control group, Daoyin group, lower limb robot group (LLR group), and Daoyin and lower limb robot group (DLLR group). Each group received distinct treatments based on conventional rehabilitation training. The treatment duration spanned two weeks with two days of rest per week. Pre- and post-intervention assessments included various scales: Fugl-Meyer Assessment (FMA), Berg balance scale (BBS), Barthel index (BI), Fatigue Scale-14 (FS-14), Pittsburgh sleep quality index (PSQI), Hamilton Anxiety Scale (HAMA), and Hamilton Depression Scale (HAMD). RESULTS: Statistically significant differences were observed in the lower limb function measured by FAM between the Control group (15 ± 5) and the DLLR group (18 ± 5) (P = 0.049). In the Barthel index, a statistically significant difference was noted between the Control group (54 ± 18) and the DLLR group (64 ± 11) (P = 0.041). Additionally, significant differences were found in the Berg balance scale between the Control group (21 ± 10) and the DLLR group (27 ± 8) (P = 0.024), as well as between the Control group (21 ± 10) and the LLR group (26 ± 10) (P = 0.048). CONCLUSION: The findings of this study suggest that the combined use of Daoyin and robotics not only enhances motor function in stroke patients but also has a positive impact on fatigue, sleep quality, and mood. This approach may offer a more effective rehabilitation strategy for stroke patients.

An interactive, online decision aid assessing patient goals and preferences for treatment of aortic stenosis to support physician-led shared decision-making: Early feasibility pilot study.

BACKGROUND: Guidelines recommend shared decision making when choosing treatment for severe aortic stenosis but implementation has lagged. We assessed the feasibility and impact of a novel decision aid for severe aortic stenosis at point-of-care. METHODS: This prospective multi-site pilot cohort study included adults with severe aortic stenosis and their clinicians. Patients were referred by their heart team when scheduled to discuss treatment options. Outcomes included shared decision-making processes, communication quality, decision-making confidence, decisional conflict, knowledge, stage of decision making, decision quality, and perceptions of the tool. Patients were assessed at baseline (T0), after using the intervention (T1), and after the clinical encounter (T2); clinicians were assessed at T2. Before the encounter, patients reviewed the intervention, Aortic Valve Improved Treatment Approaches (AVITA), an interactive, online decision aid. AVITA presents options, frames decisions, clarifies patient goals and values, and generates a summary to use with clinicians during the encounter. RESULTS: 30 patients (9 women [30.0%]; mean [SD] age 70.4 years [11.0]) and 14 clinicians (4 women [28.6%], 7 cardiothoracic surgeons [50%]) comprised 28 clinical encounters Most patients [85.7%] and clinicians [84.6%] endorsed AVITA. Patients reported AVITA easy to use [89.3%] and helped them choose treatment [95.5%]. Clinicians reported the AVITA summary helped them understand their patients' values [80.8%] and make values-aligned recommendations [61.5%]. Patient knowledge significantly improved at T1 and T2 (p = 0.004). Decisional conflict, decision-making stage, and decision quality improved at T2 (p = 0.0001, 0.0005, and 0.083, respectively). Most patients [60%] changed treatment preference between T0 and T2. Initial treatment preferences were associated with low knowledge, high decisional conflict, and poor decision quality; final preferences were associated with high knowledge, low conflict, and high quality. CONCLUSIONS: AVITA was endorsed by patients and clinicians, easy to use, improved shared decision-making quality and helped patients and clinicians arrive at a treatment that reflected patients' values. TRIAL REGISTRATION: Trial ID: NCT04755426, Clinicaltrials.gov/ct2/show/NCT04755426.

Cardiovascular Magnetic Resonance Radiomics to Identify Components of the Extracellular Matrix in Dilated Cardiomyopathy.

BACKGROUND: Current cardiovascular magnetic resonance sequences cannot discriminate between different myocardial extracellular space (ECSs), including collagen, noncollagen, and inflammation. We sought to investigate whether cardiovascular magnetic resonance radiomics analysis can distinguish between noncollagen and inflammation from collagen in dilated cardiomyopathy. METHODS: We identified data from 132 patients with dilated cardiomyopathy scheduled for an invasive septal biopsy who underwent cardiovascular magnetic resonance at 3 T. Cardiovascular magnetic resonance imaging protocol included native and postcontrast T1 mapping and late gadolinium enhancement (LGE). Radiomic features were computed from the midseptal myocardium, near the biopsy region, on native T1, extracellular volume (ECV) map, and LGE images. Principal component analysis was used to reduce the number of radiomic features to 5 principal radiomics. Moreover, a correlation analysis was conducted to identify radiomic features exhibiting a strong correlation (r>0.9) with the 5 principal radiomics. Biopsy samples were used to quantify ECS, myocardial fibrosis, and inflammation. RESULTS: Four histopathological phenotypes were identified: low collagen (n=20), noncollagenous ECS expansion (n=49), mild to moderate collagenous ECS expansion (n=42), and severe collagenous ECS expansion (n=21). Noncollagenous expansion was associated with the highest risk of myocardial inflammation (65%). Although native T1 and ECV provided high diagnostic performance in differentiating severe fibrosis (C statistic, 0.90 and 0.90, respectively), their performance in differentiating between noncollagen and mild to moderate collagenous expansion decreased (C statistic: 0.59 and 0.55, respectively). Integration of ECV principal radiomics provided better discrimination and reclassification between noncollagen and mild to moderate collagen (C statistic, 0.79; net reclassification index, 0.83 [95% CI, 0.45-1.22]; P<0.001). There was a similar trend in the addition of native T1 principal radiomics (C statistic, 0.75; net reclassification index, 0.93 [95% CI, 0.56-1.29]; P<0.001) and LGE principal radiomics (C statistic, 0.74; net reclassification index, 0.59 [95% CI, 0.19-0.98]; P=0.004). Five radiomic features per sequence were identified with correlation analysis. They showed a similar improvement in performance for differentiating between noncollagen and mild to moderate collagen (native T1, ECV, LGE C statistic, 0.75, 0.77, and 0.71, respectively). These improvements remained significant when confined to a single radiomic feature (native T1, ECV, LGE C statistic, 0.71, 0.70, and 0.64, respectively). CONCLUSIONS: Radiomic features extracted from native T1, ECV, and LGE provide incremental information that improves our capability to discriminate noncollagenous expansion from mild to moderate collagen and could be useful for detecting subtle chronic inflammation in patients with dilated cardiomyopathy.

Pre-diagnostic plasma proteomics profile for hepatocellular carcinoma.

OBJECTIVE: Proteomics may discover pathophysiological changes related to hepatocellular carcinoma (HCC), an aggressive and lethal type of cancer with low sensitivity for early-stage diagnosis. DESIGN: We measured 1,305 pre-diagnostic (median 12.7 years) SOMAscan proteins from 54 pairs of healthy individuals who subsequently developed HCC and matched non-HCC controls from the Nurses' Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). Candidate proteins were validated in the independent, prospective UK Biobank Pharma Proteomics Project (UKB-PPP). RESULTS: In NHS/HPFS, we identified 56 elevated proteins in HCC with absolute fold-change >1.2 and Wald test P < .05 in conditional logistic regression analysis. Ingenuity Pathway Analysis identified enrichment of pathways associated with cell viability, adhesion, proteolysis, apoptosis, and inflammatory response. Four proteins, chitinase-3-like protein 1, growth/differentiation factor 15, interleukin-1 receptor antagonist protein, and E-selectin, showed strong positive associations with HCC and were thus validated by ELISA (odds ratio ranged 2.48-14.7, all P < .05) in the NHS/HPFS and by Olink platform (hazard ratio ranged 1.90-3.93, all P < .05) in the UKB-PPP. Adding these four proteins to a logistic regression model of traditional HCC risk factors increased the area under the curve (AUC) from 0.67 to 0.87 in the NHS/HPFS. Consistently, model AUC was 0.88 for HCC risk prediction in the UKB-PPP. CONCLUSION: However, the limited number of HCC cases in the cohorts necessitates caution in interpreting our findings, emphasizing the need for further validation in high-risk populations.

Gut microbiome composition and metabolic activity in women with diverticulitis.

The etiopathogenesis of diverticulitis, among the most common gastrointestinal diagnoses, remains largely unknown. By leveraging stool collected within a large prospective cohort, we performed shotgun metagenomic sequencing and untargeted metabolomics profiling among 121 women diagnosed with diverticulitis requiring antibiotics or hospitalizations (cases), matched to 121 women without diverticulitis (controls) according to age and race. Overall microbial community structure and metabolomic profiles differed in diverticulitis cases compared to controls, including enrichment of pro-inflammatory Ruminococcus gnavus, 1,7-dimethyluric acid, and histidine-related metabolites, and depletion of butyrate-producing bacteria and anti-inflammatory ceramides. Through integrated multi-omic analysis, we detected covarying microbial and metabolic features, such as Bilophila wadsworthia and bile acids, specific to diverticulitis. Additionally, we observed that microbial composition modulated the protective association between a prudent fiber-rich diet and diverticulitis. Our findings offer insights into the perturbations in inflammation-related microbial and metabolic signatures associated with diverticulitis, supporting the potential of microbial-based diagnostics and therapeutic targets.

Racial and Ethnic Disparities in Opioid Prescribing on Hospital Discharge Among Older Adults: A National Retrospective Cohort Study.

BACKGROUND: Disparities in opioid prescribing among racial and ethnic groups have been observed in outpatient and emergency department settings, but it is unknown whether similar disparities exist at discharge among hospitalized older adults. OBJECTIVE: To determine filled opioid prescription rates on hospital discharge by race/ethnicity among Medicare beneficiaries. DESIGN: Retrospective cohort study. PARTICIPANTS: Medicare beneficiaries 65 years or older discharged from hospital in 2016, without opioid fills in the 90 days prior to hospitalization (opioid-naïve). MAIN MEASURES: Race/ethnicity was categorized by the Research Triangle Institute (RTI), grouped as Asian/Pacific Islander, Black, Hispanic, other (American Indian/Alaska Native/unknown/other), and White. The primary outcome was an opioid prescription claim within 2 days of hospital discharge. The secondary outcome was total morphine milligram equivalents (MMEs) among adults with a filled opioid prescription. KEY RESULTS: Among 316,039 previously opioid-naïve beneficiaries (mean age, 76.8 years; 56.2% female), 49,131 (15.5%) filled an opioid prescription within 2 days of hospital discharge. After adjustment, Black beneficiaries were 6% less likely (relative risk [RR] 0.94, 95% CI 0.91-0.97) and Asian/Pacific Islander beneficiaries were 9% more likely (RR 1.09, 95% CI 1.03-1.14) to have filled an opioid prescription when compared to White beneficiaries. Among beneficiaries with a filled opioid prescription, mean total MMEs were lower among Black (356.9; adjusted difference - 4%, 95% CI - 7 to - 1%), Hispanic (327.0; adjusted difference - 7%, 95% CI - 10 to - 4%), and Asian/Pacific Islander (328.2; adjusted difference - 8%, 95% CI - 12 to - 4%) beneficiaries when compared to White beneficiaries (409.7). CONCLUSIONS AND RELEVANCE: Black older adults were less likely to fill a new opioid prescription after hospital discharge when compared to White older adults and received lower total MMEs. The factors contributing to these differential prescribing patterns should be investigated further.

Incidence and survival of secondary malignancies after external beam radiotherapy for prostate cancer in the SEER database.

INTRODUCTION: We investigated the incidence of secondary bladder (BCa) and rectal cancers (RCa) after external beam radiotherapy (EBRT) for prostate cancer (PCa) compared to radical prostatectomy (RP) alone, and compared cancer-specific survival (CSS) of these secondary neoplasms to their primary counterparts. METHODS: This retrospective cohort study included men in the SEER cancer registry with a diagnosis of non-metastatic, clinically node-negative PCa treated with either RP or EBRT from 1995-2011 and allowed a minimum five-year lag period for the development of secondary BCa or RCa. Patients were divided into two eras, 1995-2002 and 2003-2011, to examine differences in incidence of secondary malignancies over time. Univariable and multivariable competing risk analyses with Fine-Gray subdistribution hazard and cause-specific hazard models were used to examine the risk of developing a secondary BCa or RCa. Competing risks analyses were used to compare CSS of primary vs. secondary BCa and RCa. RESULTS: A total of 198 184 men underwent RP and 190 536 underwent EBRT for PCa. The cumulative incidence of secondary BCa at 10 years was 1.71% for RP, and 3.7% for EBRT (p<0.001), while that of RCa was 0.52% for RP and 0.99% for EBRT (p<0.001). EBRT was associated with almost twice the risk of developing a secondary BCa and RCa compared to RP. The hazard of secondary BCa following EBRT delivered during 2003-2011 was 20% less than from 1995-2002 (p<0.09, Fine-Gray model), while that of secondary RCa was 31% less (p<0.001) (hazard ratio 0.78, p<0.001) for Fine-Gray and cause-specific hazard models. In the Fine-Gray model, the risk of death from BCa was 27% lower for secondary BCa after RP compared to primary BCa, while the risk of death was 9% lower for secondary BCa after EBRT compared to primary BCa. There was no difference in RCa-specific survival between primary or secondary RCa after RP or EBRT. CONCLUSIONS: The risk of BCa and RCa is almost twice as high for men undergoing EBRT for localized PCa vs. RP, but that risk is declining, likely reflecting advances in radiation delivery. The development of secondary RCa or BCa does not confer elevated risk of death compared to their primary counterparts.

ReTimeML: a retention time predictor that supports the LC-MS/MS analysis of sphingolipids.

The analysis of ceramide (Cer) and sphingomyelin (SM) lipid species using liquid chromatography-tandem mass spectrometry (LC-MS/MS) continues to present challenges as their precursor mass and fragmentation can correspond to multiple molecular arrangements. To address this constraint, we developed ReTimeML, a freeware that automates the expected retention times (RTs) for Cer and SM lipid profiles from complex chromatograms. ReTimeML works on the principle that LC-MS/MS experiments have pre-determined RTs from internal standards, calibrators or quality controls used throughout the analysis. Employed as reference RTs, ReTimeML subsequently extrapolates the RTs of unknowns using its machine-learned regression library of mass-to-charge (m/z) versus RT profiles, which does not require model retraining for adaptability on different LC-MS/MS pipelines. We validated ReTimeML RT estimations for various Cer and SM structures across different biologicals, tissues and LC-MS/MS setups, exhibiting a mean variance between 0.23 and 2.43% compared to user annotations. ReTimeML also aided the disambiguation of SM identities from isobar distributions in paired serum-cerebrospinal fluid from healthy volunteers, allowing us to identify a series of non-canonical SMs associated between the two biofluids comprised of a polyunsaturated structure that confers increased stability against catabolic clearance.

[The mechanism of NRF2 inhibiting ROS induced autophagy to reduce ovarian granulosa cells damage].

This study explores the effects and possible mechanisms of nuclear factor E2 related factor 2 (NRF2) on ovarian granulosa cells, providing a scientific basis to prevent premature ovarian failure. An ovarian cell injury model was constructed by treating human ovarian granulosa cell (KGN cell) with 4-Vinylcyclohexene dioxide (VCD). Firstly, KGN cells were treated with different concentrations of VCD, and cell counting kit 8 (CCK-8) was used to detect ovarian cell proliferation. After determining IC50 by CCK8, the levels of estradiol and progesterone in the cell supernatant were detected using enzyme-linked immunosorbent assay (ELISA), reactive oxygen species (ROS) assay kit was used to detect the content of ROS in ovarian cells, real-time fluorescence quantitative polymerase chain reaction (qRT PCR) was used to detect the mRNA expression level of NRF2, and Western blot was used to detect the protein expression level of NRF2. Further, NRF2 silence (siNRF2) and overexpression (NRF2-OE) cell models were constructed through lentivirus transfection, and the effects of regulating NRF2 on VCD treated cell models were investigated by detecting hormone levels, oxidative stress indicators (ROS, SOD, GSH-Px), and autophagy (LC3B level). The results showed that VCD intervention inhibited the proliferation of ovarian granulosa cells in a time-dependent and dose-dependent manner (F>100, P<0.05), with an IC50 of 1.2 mmol/L at 24 hours. After VCD treatment, the level of estradiol in the cell supernatant decreased from (56.32±10.18) ng/ml to (24.59±8.75) ng/ml (t=5.78, P<0.05). Progesterone decreased from (50.25±7.03) ng/ml to (25.13±6.67) ng/ml (t=6.54, P<0.05). After VCD treatment, the SOD of cells decreased from (44.47±7.71) ng/ml to (30.92±4.97) ng/ml (t=3.61, P<0.05). GSH-Px decreased from (68.51±10.17) ng/ml to (35.19±6.59) ng/ml (t=5.73, P<0.05). Simultaneously accompanied by an increase in autophagy and a decrease in NRF2. This study successfully constructed KGN cell models that silenced NRF2 and overexpressed NRF2. Subsequently, this study treated each group of cells with VCD and found that the cell proliferation activity of the siNRF2 group was significantly reduced (t=8.37, P<0.05), while NRF2-OE could reverse the cell activity damage caused by VCD (t=3.37, P<0.05). The siNRF2 group had the lowest level of estradiol (t=5.78, P<0.05), while NRF2-OE could reverse the decrease in cellular estradiol levels caused by VCD (t=5.58, P<0.05). The siNRF2 group had the lowest progesterone levels (t=3.02, P<0.05), while NRF2-OE could reverse the decrease in cellular progesterone levels caused by VCD (t=2.41, P<0.05). The ROS level in the siNRF2 group was the highest (t=2.86, P<0.05), NRF2-OE could reverse the increase in ROS caused by VCD (t=3.14, P<0.05), the SOD enzyme content in the siNRF2 group was the lowest (t=2.98, P<0.05), and NRF2-OE could reverse the decrease in SOD enzyme content caused by VCD (t=4.72, P<0.05). The GSH-Px enzyme content in the siNRF2 group was the lowest (t=3.67, P<0.05), and NRF2-OE could reverse the decrease in antioxidant enzyme content caused by VCD (t=2.71, P<0.05). The LC3B level was highest in the siNRF2 group (t=2.45, P<0.05), and NRF2-OE was able to reverse the LC3B elevation caused by VCD (t=9.64, P<0.05). In conclusion, NRF2 inhibits ROS induced autophagy, thereby playing a role in reducing ovarian granulosa cell damage, which may be a potential target for premature ovarian failure.

SARS-CoV-2 infection elucidates unique features of pregnancy-specific immunity.

Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with SARS-CoV-2 infection and n = 56 healthy controls) and 74 non-pregnant women (n = 55 with SARS-CoV-2 and n = 19 healthy controls). We found that SARS-CoV-2 infection was associated with altered T cell responses in pregnant compared to non-pregnant women. Differences included a lower percentage of memory T cells, a distinct clonal expansion of CD4-expressing CD8 + T cells, and the enhanced expression of T cell exhaustion markers, such as programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-3 (Tim-3), in pregnant women. We identified additional evidence of immune dysfunction in severely and critically ill pregnant women, including a lack of expected elevation in regulatory T cell (Treg) levels, diminished interferon responses, and profound suppression of monocyte function. Consistent with earlier data, we found maternal obesity was also associated with altered immune responses to SARS-CoV-2 infection, including enhanced production of inflammatory cytokines by T cells. Certain gut bacterial species were altered in pregnancy and upon SARS-CoV-2 infection in pregnant individuals compared to non-pregnant women. Shifts in cytokine and chemokine levels were also identified in the sera of pregnant individuals, most notably a robust increase of interleukin-27 (IL-27), a cytokine known to drive T cell exhaustion, in the pregnant uninfected control group compared to all non-pregnant groups. IL-27 levels were also significantly higher in uninfected pregnant controls compared to pregnant SARS-CoV-2-infected individuals. Using two different preclinical mouse models of inflammation-induced fetal demise and respiratory influenza viral infection, we found that enhanced IL-27 protects developing fetuses from maternal inflammation but renders adult female mice vulnerable to viral infection. These combined findings from human and murine studies reveal nuanced pregnancy-associated immune responses, suggesting mechanisms underlying the increased susceptibility of pregnant individuals to viral respiratory infections.

Sargramostim for Prophylactic Management of Gastrointestinal Immune-Related Adverse Events of Immune Checkpoint Inhibitor Therapy for Cancer.

Immune checkpoint inhibitor (ICI) therapy improves outcomes in several cancers. Unfortunately, many patients experience grade 3-4 treatment-related adverse events, including gastrointestinal (GI) toxicities which are common. These GI immune-related adverse events (irAEs) induced by ICIs present significant clinical challenges, require prompt intervention, and result in treatment delays or discontinuations. The treatment for these potentially severe and even fatal GI irAEs which include enterocolitis, severe diarrhea, and hepatitis may interfere with the anti-cancer approach. Sargramostim (glycosylated, yeast-derived, recombinant human GM-CSF) is an agent that has been used in clinical practice for more than 30 years with a well-recognized safety profile and has been studied in many therapeutic areas. The mechanism of action of sargramostim may treat moderate-to-severe GI irAEs without impairing the anti-cancer therapy. Some early data also suggest a potential survival benefit. Through the differentiation/maturation of monocytes, macrophages, and neutrophils and induction of anti-inflammatory T cell responses, GM-CSF aids in GI homeostasis, mucosal healing, and mucosal immunity. GM-CSF knockout mice are susceptible to severe colitis which was prevented with murine GM-CSF administration. For some patients with GI mucosa and immune cell function impairment, e.g., Crohn's disease, sargramostim reduces disease severity. In a prospective, randomized study (ECOG 1608), advanced melanoma patients had a reduction in grade 3-5 GI irAEs and less frequent colonic perforation in the sargramostim plus ipilimumab arm compared to ipilimumab alone. Sargramostim continues to be studied with ICIs for the prophylactic management of irAEs while also potentially providing a survival benefit.