Control Individuals Research Articles

KRAS Mutations in Duodenal Lavage Fluid after Secretin Stimulation for Detection of Pancreatic Cancer.

Although pancreatic ductal adenocarcinoma (PDAC) is still a devastating disease, the survival rate for surgically removed PDACs has significantly improved in recent years. Early detection is essential in managing PDAC. The presence of KRAS mutations in PDAC leads to the initial genetic abnormality and offers a significant timeframe for identifying resectable PDACs. A minimally invasive and highly specific PDAC screening test is necessary to prevent the need for invasive follow-up tests. Between July 2021 and March 2023, 169 cases were enrolled in 7 institutions. By administering secretin before esophagogastroduodenoscopy (EGD), the excretion of pancreatic juice into the papillary fluid can be stimulated, creating a resource for testing. Washing fluid was collected using a specialized catheter from control individuals (n=75) and patients with resectable PDAC (n=89) at the initial diagnosis. A highly sensitive technique was employed to study KRAS gene mutations. This study obtained an AUC of 0.934 [95%CI: 0.904, 0.964] when using KRAS mutations in duodenal lavage fluid to differentiate between patients with resectable PDAC and healthy controls. The estimated sensitivities were calculated with specificity set at 100%, resulting in a sensitivity of 83.1% [95%CI: 71.7%, 91.2%]. The McNemer test showed a significantly higher sensitivity for KRAS mutations than serum CEA and CA19-9 (P<0.0001). We created a method to identify resectable PDACs by analyzing KRAS mutation levels in duodenal fluid collected during EGD with secretin stimulation of pancreatic juice secretion.

Epidemiology of clinically significant migraine in Israel: a retrospective database study

BackgroundEpidemiological studies on migraine are valuable for tracking disease trends, identifying risk factors, and informing treatment strategies. This study assessed the prevalence and annual incidence of clinically significant migraine in Israel from 2017 to 2022, with analyses stratified by age, sex, socioeconomic status, and district. Additionally, we compared relevant characteristics between adult migraine and non-migraine members of Leumit Healthcare Services (LHS), a national health provider in Israel.MethodsThis retrospective study used LHS electronic health records to evaluate migraine prevalence and annual incidence from 2017 to 2022 among adult LHS members. Clinically significant migraine patients were identified using stringent criteria, including repeated diagnostic codes for migraine, confirmation by a neurologist, or the use of migraine-specific therapies. Each migraine patient was matched 1:1 with a control individual of similar age, sex, socioeconomic status, and ethnic background.ResultsThe prevalence of clinically significant migraine increased from 4.5% in 2017 to 5.2% in 2022, with significantly higher rates in women compared to men (8% vs. 2.4% in 2022). The mean age of migraine patients was 46.8 years in 2022. The annual incidence of migraine in 2022 was 43 per 10,000 individuals over 18, with approximately 75% of new cases occurring in women, with a mean age of 36.5 years. The annual incidence of migraine slightly decreased over the period. Approximately two-thirds of new patients were diagnosed by neurologists, with only 19% diagnosed by family physicians. Compared to a matched control population, migraine patients showed a higher prevalence of low body mass index (BMI) and higher diastolic blood pressure (BP). Additionally, distinct differences in laboratory findings were observed among migraine patients, notably lower glucose and hemoglobin A1c levels, lower rate of microalbuminuria, with higher hemoglobin, which may be associated with migraine pathophysiology.ConclusionThis study provides a detailed epidemiological and clinical profile of patients with clinically significant migraine in LHS from 2017 to 2022. Notable trends include higher rates of migraine among patients with lower BMI, higher diastolic BP, lower glucose, and higher hemoglobin, suggesting potential modifiable risk factors.

P-1850. Acute Babesia microti Infection in Humans Is Associated With Marked Changes In The Expression Of Peripheral Blood Coding And Noncoding RNA

Abstract Background Babesiosis is a potentially life-threatening disease transmitted by ticks. However, host and parasite determinants of human babesiosis are completely unknown. In the current study we evaluated the impact of B. microti infection, the primary cause of human babesiosis in the US, on the peripheral blood transcriptome. Figure 1. PCA of top 500 differentially expressed genes. PCA distinguishes Babesia patients at presentation from healthy controls. Methods Patients with confirmed B. microti acute infection were enrolled into a 1-year follow up cohort study at Stony Brook University Hospital, NY. Total RNA was isolated from blood using PaxGene RNA tubes and library preparation performed using Illumina's Stranded Total RNAPrep with Ribo-zero plus kit to remove human ribosomal RNA and globin RNA. 100 M RNA paired end reads were sequenced (2 x 151 bps). Low expression RNAs with less than 10 reads in 17 samples were filtered out prior to identification of differentially expressed genes (DEGs) (p&amp;lt; 0.05).Figure 2.Volcano Plot comparing differential gene and noncoding RNA expression between healthy controls and patients with babesiosis at presentation.Red circles represent genes whose expression are increased or decreased in patients with babesiosis at presentation compared to healthy controls. Blue circles represent genes whose expression are not significantly different. Results The peripheral blood transcriptome from 20 healthy controls was compared to 42 patients at presentation for B. microti infection and 1, 3, 6, 9 and 12 months after treatment for patients who completed the longitudinal protocol after the first visit. A total of 1860 genes or noncoding RNAs were differentially expressed in patients with babesiosis at presentation (V0) compared to healthy controls; 370 were decreased in patients with babesiosis and 1490 were increased (adj p &amp;lt; 0.01; expression fold change &amp;gt;+/- 1.) PCA analysis (Fig 1), and the Volcano Plot (Fig. 2) demonstrate that patients with babesiosis have a distinct peripheral blood gene expression profile compared to healthy control individuals. The heat map of DEGs in Fig. 3 shows the peripheral blood transcriptome in patients with babesiosis largely returned to baseline levels by 1-month post-treatment. The Qiagen IPA Graphical Summary based on DEGs is shown in Figure 4 and highlights activation of diverse immune-mediators, including TNF and interferon families, as well as growth factors, and vascularization pathways in response to B. microti infection.Figure 3.Heat map of differentially expressed genes of patients with babesiosis at presentation (0) and 1, 3, 6, 9 and 12 months post-treatment compared to healthy control individuals.Gene expression in patients with babesiosis is markedly different at presentation but is similar to levels for healthy controls by 1 month post-treatment. Conclusion Infection with B. microti results in marked changes in expression of genes and noncoding RNA in peripheral blood that largely returns to baseline by 1-month post-treatment.Figure 4:Qiagen IPA Graphical Summary of pathways likely increased (orange) or decreased (blue) in patients presenting with babesiosis. Disclosures Paul Arnaboldi, PhD, Biopeptides, Corp: Patent Holder|Biopeptides, Corp: Employee|DiaSorin: Advisor/Consultant

Evaluation of Serum Zonulin Level and Intestinal Permeability in Patients with Chronic Spontaneous Urticaria and the Relationship Between Serum Zonulin Level and Disease Severity

Introduction: An emerging hypothesis suggests a potential link between enhanced intestinal permeability and the advancement of chronic spontaneous urticaria (CSU). Objective: This study aimed to investigate the role of intestinal permeability in the etiopathogenesis of CSU by measuring serum zonulin levels, a marker of intestinal permeability, in both CSU patients and control subjects. Additionally, the study sought to explore the correlation between the severity of the illness and zonulin levels. Methods: The study involved 61 patients with CSU and 59 healthy control individuals. For the CSU patients, comprehensive data was collected, encompassing various aspects: age at onset of the condition, duration of the most recent attack, presence of any comorbid conditions, dosage of antihistamines being used, the urticaria activity score, as well as detailed personal and family medical histories. Additionally, demographic information for these patients was also meticulously documented. Result: The study revealed a statistically significant difference in zonulin levels between the CSU patient group and the control group, with a p-value of 0.000 indicating a highly significant disparity. Furthermore, among the CSU patients, those who were presented with angioedema exhibited considerably higher zonulin levels compared to those without angioedema. This variation in zonulin levels based on the presence of angioedema was also statistically significant, with a p-value of 0.023. Conclusion: The observed results suggest that increased intestinal permeability, as indicated by elevated zonulin levels, may play a crucial role in the pathophysiology of both CSU and angioedema. This association highlights the potential significance of intestinal permeability in the development and manifestation of these conditions.

Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer’s disease

Studies of the genetics of Alzheimer’s disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, most of the disease heritability has yet to be uncovered, suggesting that there is substantial genetic risk conferred by other forms of genetic variation. There are over one million short tandem repeats (STRs) in the genome, and their link to AD risk has not been assessed. As pathogenic expansions of STR cause over 30 neurologic diseases, it is important to ascertain whether STRs may also be implicated in AD risk. Here, we genotype 312,731 polymorphic STR tracts genome-wide using PCR-free whole genome sequencing data from 2981 individuals (1489 AD case and 1492 control individuals). We implement an approach to identify STR expansions as STRs with tract lengths that are outliers from the population. We then test for differences in aggregate burden of expansions in case versus control individuals. AD patients harbor a 1.19-fold increase of STR expansions compared to healthy elderly controls (p = 8.27×10-3, two-sided Mann-Whitney test). Individuals carrying >30 STR expansions have a 3.69-fold higher odds of having AD and have more severe AD neuropathology. AD STR expansions are highly enriched within active promoters in post-mortem hippocampal brain tissues and particularly within SINE-VNTR-Alu (SVA) retrotransposons. Together, these results demonstrate that expanded STRs within active promoter regions of the genome associate with risk of AD.

The Relationship of the Pathogenic Variant rs721048 in the Intron of the EHBP1 Gene with the Development of Prostate Cancer and Colorectal Cancer in the Kazakh Population

Background: Prostate cancer (PC) is one of the most common oncological diseases among men. Up to 20% of PC cases are associated with hereditary risks or syndromes. The impact of common variants, particularly EHBP1 c.1185+30064G&gt;A rs721048, on developing PC and other malignancies remains unclear. There are also no data on the frequency of this variant in the Kazakh population or its association with PC, nor its potential connection with other malignancies, particularly colorectal cancer (CRC). Methods: We utilized the TruSight Cancer Sequencing Panel to assess pathological genomic variants in 72 male patients with histologically verified aggressive PC and 119 patients of Kazakh nationality with histologically confirmed CRC compared to the control group. Results: A variant in the intron of the EHBP1 gene c.1185+30064G&gt;A rs721048 was identified in 18 patients (25%) out of 72 with PC, while in the control group of 41 healthy males, the rs721048 variant was found in only 4 (9.8%) individuals. In the CRC group, rs721048 was detected in 17 cases (14.2%) and eight control individuals (10%). Conclusions: The frequency of the EHBP1 c.1185+30064G&gt;A rs721048 variant in the PC group was significantly higher (p &lt; 0.05) than in healthy males of Kazakh nationality. Identifying EHBP1 c.1185+30064G&gt;A among the male population of Kazakhstan will help form the high-risk groups for PC to prevent the development of malignant neoplasms. The presence of rs721048 was not significantly associated with the risk of developing CRC in our study.

The circulating plasma microRNA signature in human visceral leishmaniasis.

Visceral leishmaniasis (VL) is a vector-borne disease caused by the obligate intracellular protozoan Leishmania donovani in India. VL can be complicated by post-kala-azar dermal leishmaniasis (PKDL), a macular or nodular rash that develops in 10%-20% of patients after treatment of VL in India. Patients with PKDL are infectious to sand flies, promoting further transmission of the parasite. MicroRNAs (miRNAs) are 18-25 nt, non-coding RNAs that simultaneously regulate the expression of several or many target transcripts. This study was based on the hypothesis that the host response to L. donovani is modified by distinct sets of miRNAs in VL or PKDL and that these might differ from healthy controls. We investigated this hypothesis using a NanoString panel to profile the miRNAs expressed in the plasma of patients with VL or PKDL diagnosed at a hospital in Bihar, India. We compared these to plasma microRNAs of healthy control individuals from the same endemic villages. miRNAs hsa-miR-223-3p, hsa-miR-191-5p, hsa-miR-23a-3p, and hsa-1285-5p were significantly higher in the plasma samples from patients with VL compared to either PKDL or endemic controls. Prediction programs highlighted potential mRNA targeted by these miRNAs, among which we verified the down-modulation of several transcripts belonging to the NFκB and NLRP3 inflammasome pathways in circulating leukocytes of VL patients. By contrast, miRNA patterns in subjects with PKDL were similar to control subjects, possibly suggesting that the pathogenic immune response during PKDL is primarily localized in the skin.IMPORTANCEInfection of humans with the protozoan Leishmania donovani can be asymptomatic or it can cause fatal visceral leishmaniasis (VL), sometimes followed by the cutaneous complication PKDL. Parasites are spread through sand fly bites in endemic regions, and parasites in post-kala-azar dermal leishmaniasis (PKDL) skin lesions are a source of prolonged parasite transmission to sand flies, compromising disease eradication efforts. Since microRNAs can simultaneously modify the expression of multiple genes, we examined microRNAs in the blood that might be partial determinants of pathogenic responses leading to VL or PKDL. Our studies revealed several miRNAs expressed that are elevated in the plasma of patients with VL, which suppress some of the inflammatory responses that promote parasite killing. However, miRNA profiles were very similar between PKDL patients and controls, raising the possibility that major factors that lead to prolonged retention of parasites in the skin during PKDL are not systemic but are localized in the skin.

Pharmacy Subscription Program and Medication Refills, Days’ Supply, and Out-of-Pocket Costs

Medication nonadherence imposes high morbidity, mortality, and costs but is challenging to address given its multiple causes. Subscription models are increasingly used in health care to encourage healthy behaviors; in January 2023, Amazon Pharmacy launched RxPass, a subscription program offering Amazon Prime members (hereafter, company members) in 45 states access to 60 common generic medications for a flat $5 monthly fee. To evaluate the associations of program enrollment with medication refills, days' supply, and out-of-pocket costs. In this retrospective, population-based cohort study, a difference-in-differences approach with doubly robust estimation was used to assess outcomes 6 months before and after program enrollment, compared with a contemporaneous control group (study period included July 24, 2022, to January 24, 2024). Participants were younger than 65 years, company members, and not enrolled in Medicare or Medicaid. Exposure individuals were enrolled in the program in the first 6 months of program launch. Control individuals resided in the 5 states where the program was not available but who clicked on the enrollment webpage in the first 6 months of program launch. Subscription program enrollment. The primary outcome was the number of days' supply of medications on the subscription program list per person per month (PPPM). Secondary outcomes were the number of prescription refills and out-of-pocket costs of medications on the program list, including program subscription costs, PPPM. After propensity score weighting, there were 5003 enrollees (mean [SD] age, 45.9 [11.1] years; 2076 female [41.5%]) and 5137 controls (mean [SD] age, 45.8 [11.1] years; 2116 female [41.2%]). The program was associated with an increase in days' supply of 10.39 days PPPM (95% CI, 10.29-10.48 days PPPM), a 27% increase, an increase in prescription refills of 0.19 PPPM (95% CI, 0.19-0.19 refills PPPM), a 29% increase, and a decrease in out-of-pocket spending by $2.35 PPPM (95% CI, $2.37-$2.33 PPPM), a 30% decrease. In this cohort study, program enrollment was associated with increased medication refills and total days' supply and reduced out-of-pocket costs. Future research should investigate the potential cognitive and/or behavioral mechanisms by which subscription programs encourage healthy behaviors and whether the results could be replicated among other pharmacies or cohorts.

Placental Hypoxia-Induced Ferroptosis Drives Vascular Damage in Preeclampsia.

Iron is an essential micronutrient for cell survival and growth; however, excess of this metal drives ferroptosis. Although maternal iron imbalance and placental hypoxia are independent contributors to the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy, the mechanisms by which their interaction impinge on maternal and placental health remain elusive. We used placentae from normotensive and preeclampsia pregnancy cohorts, human H9 embryonic stem cells differentiated into cytotrophoblast-like cells, and placenta-specific Phd2-/- preeclamptic mice. Lipid peroxidation and iron cargo of placenta-derived small extracellular vesicles (sEVs) isolated from the maternal circulation of control and preeclampsia individuals were examined by mass spectrometry, flow cytometry, and colorimetry. Human microvascular endothelial cells' angiogenic capacity and function were examined after exposure to control and pathological sEVs. Placentae from preeclampsia pregnancies contain increased ferrous iron and lipid peroxidation byproduct, malondialdehyde. Antioxidant capacity is significantly lower in preeclampsia placentae, with decreased glutathione content, and GPx4 (glutathione peroxidase 4) expression and activity. Hypoxia triggers the occurrence of ferroptosis in human trophoblast cells and mouse Phd2-/-placentae. Disrupted placental iron homeostasis in preeclampsia is accompanied by improper extrusion of iron through sEVs mediated by the pentaspan protein prominin-2. Heightened lipid peroxidation content was found in villous explants and maternal circulating sEVs of preeclampsia individuals. Exposure of human microvascular endothelial cells to preeclampsia-derived placental sEVs results in endothelial activation and impaired angiogenesis, which is rescued by treatment with hinokitiol, a compound known to restore tissue iron balance. In pregnancy, iron and oxygen work synergistically to conserve an operative antioxidant system to maintain iron homeostasis and protect the placenta from ferroptotic death. Hindrance to this system due to hypoxia results in heightened ferroptosis rates and sEV-mediated extrusion of harmful lipid peroxides from trophoblast cells into the circulation thereby contributing to maternal endothelial dysfunction characterizing preeclampsia.

P1028 Personalised co-culture model of intestinal organoids and immune cells for evaluating biological therapy response in ulcerative colitis patients

Abstract Background Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) affecting approximately 5 million people worldwide and is characterised by mucosal inflammation that may spread throughout the colon1. Existing therapies often have limited effectiveness or cause severe side effects2. Due to the absence of standardised criteria for selecting the most effective treatment for IBD, innovative preclinical drug testing systems are urgently needed. Methods The effect of upadacitinib (UPA) was tested in personalized co-cultures of colonic epithelial cells and macrophages derived from UC patients (n=12) and control (Con) individuals (n=11). Inflammation was induced with inflammatory cytokines TNF-α (10 ng/mL) and IFN-γ (10 ng/mL). Barrier integrity was measured by transepithelial electrical resistance (TEER). Expression of TNF-α, CCL5, and CXCL9 genes was evaluated using qRT-PCR. Data comparison was conducted using the Wilcoxon rank-sum test. A difference between the values was considered significant when p ≤ 0.05 or padj. ≤ 0.05. Results In cell cultures stimulated with inflammatory cytokines, barrier permeability increased (TEER decreased – Con: by 452.03 Ω·cm2, UC: 39.3 Ω·cm2), which partially recovered after removal of inflammatory factors (TEER increased – Con: by 65.91 Ω·cm2, UC – only 47.31 Ω·cm2). Epithelial integrity was restored after incubation with UPA (TEER increased – Con: by 116.82 Ω·cm2; UC: by 226.64 Ω·cm2). At the molecular level, overnight stimulation with TNF-α and IFN-γ increased expression of CXCL9 gene in epithelial cells (UC: fold change (FC) = 3064.49 padj. = 2.07 x 10-5; Con: FC = 664.44, padj. = 2.00 x 10-2) and macrophages (UC: FC = 140.47 padj. = 0.01; Con: FC = 314.43, padj. = 0.01) in both groups. Co-culture treatment with UPA showed an important trend of patient-specific response to therapeutic agent, which probably was the most important factor of non-significant values for observed changes in CCL5, CXCL9, TNF-α expression analysing summarized data. Conclusion To conclude, treatment with TNF-α and IFN-γ reduced epithelial barrier integrity and increased the expression of the inflammatory gene CXCL9 in both epithelial cells and macrophages. UPA tended to restore this disrupted barrier integrity. However, the effects of UPA on gene expression in both cell types showed variable impacts and effectiveness, revealing an individualized response to this biological agent.

P0897 Association of HLA Genotypes with Anti-Drug Antibody Development in Taiwanese Inflammatory Bowel Disease Patients Undergoing Biologic Therapies

Abstract Background Anti-drug antibodies (ADAs) are a primary factor in the loss of response to infliximab and other adverse drug reactions. The genetic variant HLA-DQA1*05 has been associated with infliximab antibody development in Crohn’s disease (CD) among European populations. This study aims to assess the relationship between HLA genotypes and ADA formation in non-European inflammatory bowel disease (IBD) patients receiving anti-tumor necrosis factor (TNF), anti-integrin, or anti-IL-12/23 therapies. Methods This prospective cohort study enrolled patients with IBD receiving anti-TNF, anti-integrin, or anti-IL-12/23 therapy between January 2022 and March 2024. NGS-based HLA genotyping was performed for all participants. The occurrence of ADAs was assessed, and the frequencies of specific HLA alleles were compared between patients who developed ADAs and those who did not. Additionally, HLA allele frequencies in ADA-positive patients were analyzed against the general population in Taiwan. Results A total of 95 patients with IBD were included in the study, along with HLA genotype data from 1,097 control individuals obtained from the Taiwan Biobank. Among the IBD patients, 58 received anti-TNF therapy, 27 underwent anti-integrin therapy, and 10 were treated with anti-IL-12/23 therapy. According to the reimbursement criteria in Taiwan, all patients have to be treated with conventional therapy and when with inadequate response or with adverse effects, then biologics would be reimbursed. Therefore, all the 95 patients were under the biologics and immunosuppressive agents (either thiopurine or methotrexate) combination therapy. No ADA development was observed in patients treated with anti-integrin or anti-IL-12/23 therapies. However, among the 58 patients treated with anti-TNF therapy (38 with infliximab and 20 with adalimumab), 21 developed ADAs (18 infliximab-related and 3 adalimumab-related). A comparison of patients with and without ADAs revealed a significant association between the HLA-C*03:04:01 allele and ADA development (33.3% vs. 10.8%, p=0.035), whereas the HLA-DQA1*05 allele showed no association (52.3% vs. 51.4%, p=0.940). The frequency of the HLA-C*03:04:01 allele was comparable between IBD patients and the broader Taiwanese population (16.8% vs. 11.2%, p=0.0915). Conclusion This study demonstrated that the different HLA locus associated with ADA development among different ethnics. While HLA-DQA1*05 was found in European cohort, our data showed that HLA-C*03:04:01 was significantly associated with an increased risk of anti-TNF antibodies formation in Taiwanese IBD patients.

Exposure of Apis mellifera (Hymenoptera: Apidae) colonies to imidacloprid impairs larval development, promotes oxidative stress in pupae, and induces changes in the midgut of adult bees

Bees are essential pollinators that contribute to maintaining biodiversity and increasing agricultural production. However, by foraging on agricultural crops, bees may become contaminated with compounds used for pest control. In this study, we exposed bee (Apis mellifera L.) colonies to the insecticide imidacloprid (IMD) under field conditions to assess the occurrence of oxidative stress in larvae and pupae and investigate morphological changes in the fat body and midgut of larvae and midgut of adult bees. The apiary area was divided into three groups: control, commercial formulation containing IMD (Evidence® 700WG) (IMDCF), and IMD active ingredient (Sigma–Aldrich) (IMDAI). Treatment groups were fed syrup containing 1 µg L−1 IMD, whereas the control group was fed syrup only. Compared with the control, larvae exposed to IMDCF or IMDAI for 42 days exhibited morphological changes in the external body, midgut, and fat body. The midgut of adult bees contaminated with IMDCF showed only structural remnants of the peritrophic membrane and absence of regenerative cell nests. Oxidative stress analyses revealed that IMDCF-exposed larvae had higher nitrite and carbonylated protein contents and lower catalase and superoxide dismutase activity than control individuals. In pupae, IMDAI decreased catalase activity while increasing superoxide dismutase activity. These findings indicate that IMD has the potential to significantly impact the development of bees and their colonies by disrupting vital organs responsible for normal physiological functioning and overall activities of individuals. Oxidative stress, which was detected at different stages of bee development, may induce lipid, protein, and DNA oxidation, leading to cell death.Graphical

Serum Medium-Chain Fatty Acids and the Risk of Incident Diabetes: Findings From the 4C Study.

Emerging studies have revealed associations between dietary medium-chain fatty acids (MCFAs) and glucose homeostasis. However, the relationship between serum MCFAs and the incidence of diabetes, and potential interactions with genetic predisposition, remains unclear in prospective cohort studies. This work aimed to investigate associations and genetic susceptibility between serum MCFAs and diabetes risk. We investigated baseline serum MCFAs (n = 5) in a nested case-control study comprising incident diabetes cases (n = 1707) and matched normoglycemic control individuals (n = 1707) from the China Cardiometabolic Disease and Cancer Cohort Study. Associations between MCFAs and type 2 diabetes mellitus (T2DM) were examined, both overall and stratified by diabetes genetic susceptibility. Genetic risk scores (GRS) were calculated based on 86 T2DM-associated genetic variants. In the fully adjusted conditional logistic regression model, serum octanoic acid and nonanoic acid exhibited inverse dose-response relationships with diabetes risk, showing odds ratios (95% CI) of 0.90 (0.82-0.98) and 0.84 (0.74-0.95), respectively. Subgroup analysis demonstrated that inverse associations between MCFAs and incident diabetes were more pronounced among individuals with physical inactivity (Pinteraction = .042, .034, and .037, for octanoic, nonanoic and decanoic acid, respectively). Moreover, inverse associations of octanoic acid with diabetes risk were notably enhanced among individuals with high genetic risk compared to those with low genetic risk. Statistically significant interactions were observed between octanoic acid and GRS on T2DM risk (Pinteraction = .003). These findings provide evidence supporting inverse associations between serum MCFAs and T2DM risk, and reveal potential interplay between genetic susceptibility and circulating octanoic acid in modulating diabetes risk.

Respiratory syncytial virus vaccine effectiveness among US veterans, September, 2023 to March, 2024: a target trial emulation study.

New respiratory syncytial virus (RSV) vaccines have been approved in the USA for the prevention of RSV-associated lower respiratory tract disease in adults aged 60 years and older. Information on the real-world effectiveness of these vaccines is needed. We used electronic health records in the Veterans Health Administration to emulate a target trial comparing a single dose of a recombinant stabilised prefusion F protein RSV vaccine versus no vaccination among veterans aged 60 years and older. We matched eligible vaccine recipients with up to four unvaccinated individuals in four monthly nested sequential trials from Sept 1 to Dec 31, 2023. Outcomes were ascertained up to March 31, 2024. The primary outcome was any positive RSV test from day 14 following the matched index date. Secondary outcomes included hospitalisation and emergency department or urgent care encounter occurring within 1 day before or after a positive RSV test. We estimated vaccine effectiveness as 100 × (1 - risk ratio). We included 146 852 vaccinated individuals matched to 582 936 unique control individuals, weighted equally to represent 146 852 individuals. Across the two groups, 276 039 (94·0%) of 293 704 veterans were male, 17 665 (6·0%) were female, and median age was 75·9 years (IQR 71·7-79·7). Over a median follow-up of 124 days (IQR 102-150), the incidence rate of documented RSV infection was 1·7 (95% CI 1·4-2·1) events per 1000 person-years (88 total events) in the vaccinated group and 7·3 (6·6-8·1) per 1000 person-years in the unvaccinated group (372 total events), and vaccine effectiveness was estimated as 78·1% (72·6-83·5). Among the secondary outcomes, vaccine effectiveness was estimated at 78·7% (72·2-84·8) against RSV-associated emergency department or urgent care encounters, and 80·3% (65·8-90·1) against RSV-associated hospitalisation. RSV vaccination was effective in preventing RSV-related illness, including associated health-care use, in adults aged 60 years and older during the 2023-24 respiratory illness season, supporting current recommendations for vaccination in this population. US Department of Veterans Affairs Cooperative Studies Program, US Department of Health and Human Services Biomedical Advanced Research and Development Authority, and US Food and Drug Administration.

An immersive virtual reality serious game set for the clinical assessment of spatial attention impairments: Effects of avatars on perspective?

Background Hemineglect (HN) is a post-stroke condition, frequently defined as an impairment in finding spatial targets within an egocentric frame of reference, where the stimulus is coded relative to the self. However, the egocentric reference frame can change with the presence of another person. Immersive virtual reality (IVR) offers several advantages over paper-and-pencil tests typically used to assess HN, such as a realistic and controlled environment, standardised stimulus presentation, and sensitive response acquisition. We developed a new serious game in IVR to assess HN. Here we investigated (1) the feasibility and user experience of this serious game, and (2) the effect of the presence of an avatar on HN. Methods We first tested a group of 61 control individuals (CI), followed by a group of post-stroke 11 individuals without HN (SI:HN-), 6 with HN (SI:HN+), and 17 resampled age matched group of control individuals (CI). All participants performed the “Peach test”, which required them to find and respond to a target presented among distractors, either alone or in the presence of an avatar. We measured response time (RT) and omissions. The SI:HN- and SI:HN + groups also completed a paper-and-pencil test for HN and a user experience questionnaire. Results The first analysis of results with CI showed no differences in responding to the target when in ipsi- compared to contra-lateral spaces, nor in peri- compared to extra-personal spaces. There were also no differences in responding to the target in the no-avatar condition relative to the two avatars conditions. In the second analysis, SI:HN + were slower than SI:HN- and CI. Although an interaction between group and Laterality was predicted, the results showed that there was no Laterality effect for any of the groups. An interaction between group and proximity, showed that both SI groups were slower in the extra- compared to peri-personal spaces. The user experience was globally positively rated by the SI. Conclusion We developed a serious game in IVR for the assessment of HN. Although most our findings were inconclusive, the Peach test showed excellent user experience results. Trial registration http://www.clinicaltrials.gov ; Unique identifier: NCT04694833, Date of registration: 11/24/2020.

Molecular hallmarks of excitatory and inhibitory neuronal resilience and resistance to Alzheimer's disease.

A significant proportion of individuals maintain healthy cognitive function despite having extensive Alzheimer's disease (AD) pathology, known as cognitive resilience. Understanding the molecular mechanisms that protect these individuals can identify therapeutic targets for AD dementia. This study aims to define molecular and cellular signatures of cognitive resilience, protection and resistance, by integrating genetics, bulk RNA, and single-nucleus RNA sequencing data across multiple brain regions from AD, resilient, and control individuals. We analyzed data from the Religious Order Study and the Rush Memory and Aging Project (ROSMAP), including bulk (n=631) and multi-regional single nucleus (n=48) RNA sequencing. Subjects were categorized into AD, resilient, and control based on β-amyloid and tau pathology, and cognitive status. We identified and prioritized protected cell populations using whole genome sequencing-derived genetic variants, transcriptomic profiling, and cellular composition distribution. Transcriptomic results, supported by GWAS-derived polygenic risk scores, place cognitive resilience as an intermediate state in the AD continuum. Tissue-level analysis revealed 43 genes enriched in nucleic acid metabolism and signaling that were differentially expressed between AD and resilience. Only GFAP (upregulated) and KLF4 (downregulated) showed differential expression in resilience compared to controls. Cellular resilience involved reorganization of protein folding and degradation pathways, with downregulation of Hsp90 and selective upregulation of Hsp40, Hsp70, and Hsp110 families in excitatory neurons. Excitatory neuronal subpopulations in the entorhinal cortex (ATP8B1+ and MEF2Chigh) exhibited unique resilience signaling through neurotrophin (modulated by LINGO1) and angiopoietin (ANGPT2/TEK) pathways. We identified MEF2C, ATP8B1, and RELN as key markers of resilient excitatory neuronal populations, characterized by selective vulnerability in AD. Protective rare variant enrichment highlighted vulnerable populations, including somatostatin (SST) inhibitory interneurons, validated through immunofluorescence showing co-expression of rare variant associated RBFOX1 and KIF26B in SST+ neurons in the dorsolateral prefrontal cortex. The maintenance of excitatory-inhibitory balance emerges as a key characteristic of resilience. We identified molecular and cellular hallmarks of cognitive resilience, an intermediate state in the AD continuum. Resilience mechanisms include preservation of neuronal function, maintenance of excitatory/inhibitory balance, and activation of protective signaling pathways. Specific excitatory neuronal populations appear to play a central role in mediating cognitive resilience, while a subset of vulnerable SST interneurons likely provide compensation against AD-associated dysregulation. This study offers a framework to leverage natural protective mechanisms to mitigate neurodegeneration and preserve cognition in AD.

Long-acting, progestin-based contraceptives and risk of breast, gynecological, and other cancers.

Use of long-acting, reversible contraceptives has increased over the past 20 years, but an understanding of how they could influence cancer risk is limited. We conducted a nested case-control study among a national cohort of Australian women (n = 176601 diagnosed with cancer between 2004 and 2013; 882999 matched control individuals) to investigate the associations between the levonorgestrel intrauterine system, etonogestrel implants, depot-medroxyprogesterone acetate and cancer risk and compared these results with the oral contraceptive pill. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). Levonorgestrel intrauterine system and etonogestrel implant use was associated with breast cancer risk (OR = 1.26, 95% CI = 1.21 to 1.31, and OR = 1.24, 95% CI = 1.17 to 1.32, respectively), but depot-medroxyprogesterone acetate was not, except when used for 5 or more years (OR = 1.23, 95% CI = 0.95 to 1.59). Reduced risks were seen for levonorgestrel intrauterine system (≥1 years of use) in endometrial cancer (OR = 0.80, 95% CI = 0.65 to 0.99), ovarian cancer (OR = 0.71, 95% CI = 0.57 to 0.88), and cervical cancer (OR = 0.62, 95% CI = 0.51 to 0.75); for etonogestrel implant in endometrial cancer (OR = 0.21, 95% CI = 0.13 to 0.34) and ovarian cancer (OR = 0.76, 95% CI = 0.57 to 1.02); and for depot-medroxyprogesterone acetate in endometrial cancer (OR = 0.21, 95% CI = 0.13 to 0.34). Although levonorgestrel intrauterine system, etonogestrel implant and depot-medroxyprogesterone acetate were all associated with increased cancer risk overall, for etonogestrel implant, the risk returned to baseline after cessation, similar to the oral contraceptive pill. We were unable to adjust for all potential confounders, but sensitivity analyses suggested that adjusting for parity, smoking, and obesity would not have materially changed our findings. Long-acting, reversible contraceptives have similar cancer associations to the oral contraceptive pill (reduced endometrial and ovarian cancer risks and short-term increased breast cancer risk). This information may be helpful to women and their physicians when discussing contraception options.

Healthy individuals genetically at-risk for the development of Pemphigus vulgaris or Alopecia areata share disease-like cytokine dysregulation.

Autoimmune diseases (AID) are defined by immune dysregulation characterized by specific humoral and/or cell mediated responses directed against the body's own tissues. Cytokines in particular play a pivotal role in the pathogenesis of AID, with proinflammatory cytokines contributing to the initiation and propagation of autoimmune inflammation, whereas anti-inflammatory cytokines facilitate regression of inflammation and recovery from acute phases of the disease. Parallel work by our group evaluating a comprehensive set of pro- and anti-inflammatory serum cytokines in Pemphigus vulgaris (PV) as well as Alopecia areata (AA) uncovered a similar pattern of inheritance specific immune dysregulation in these two distinct autoimmune skin diseases. In AA, we found healthy control subjects who are blood related to AA patients exhibit the same cytokine dysregulation in Th1 and Th17 pathways as do patients with AA. In PV, patients as well as individuals who are healthy but yet carry certain PV-associated HLA alleles (termed here as HLA-matched controls) share a similar, but not fully overlapping pattern of cytokine expression that is distinct from control subjects who do not type for these HLA alleles. Specifically, PV patients as well as HLA-matched controls demonstrate immunological activation of several pro-inflammatory-, Th17-, Th2-pathway associated cytokines, and the chemokine IL-8. Thus, in both AA and PV, we reveal cytokine dysregulations that are linked to genetic background. The presence of disease promoting pathways in not only patients, but also genetically related, but healthy control individuals further evokes the novel hypothesis that there may be co-existing disease counteracting immune protective mechanisms at play in thwarting the threat of disease in genetically predisposed individuals who, despite harboring disease associated immune imbalances, remain healthy. Our data underscore the known tendency of AID to cluster in families and support the notion of the shared genetic/common cause hypothesis across multiple AID.

Aberrant neural event segmentation during a continuous social narrative in trauma-exposed older adolescents and young adults.

Post-traumatic stress and major depressive disorders are associated with "overgeneral" autobiographical memory, or impaired recall of specific life events. Interpersonal trauma exposure, a risk factor for both conditions, may influence how symptomatic trauma-exposed (TE) individuals segment everyday events. The ability to parse experience into units (event segmentation) supports memory. Neural state transitions occur within a cortical hierarchy and play a key role in event segmentation, with regions like the occipital cortex, angular gyrus, and striatum involved in parsing event structure. We examined whether interpersonal trauma exposure was associated with alterations in the cortical hierarchy and striatal activity at neural state transitions in symptomatic TE versus healthy control (HC) individuals. Fifty older adolescents and young adults (29 TE, 21 HC) viewed the film "Partly Cloudy" during functional magnetic resonance imaging. A greedy-state boundary search algorithm assessed the optimal number of events, quality, and segmentation agreement of neural state transitions in the occipital cortex and angular gyrus. Striatal (nucleus accumbens, caudate, and putamen) activity was assessed at occipital and angular gyrus-evoked state transitions. Compared to HCs, TE participants displayed less occipital and greater angular gyrus-evoked optimal number of neural state transitions. TE participants also displayed lower quality of neural state segmentation solutions in occipital and angular cortices compared to HCs. Additionally, TE participants had less putamen activity at angular gyrus-evoked state transitions than HCs. This investigation provides neurobiological insights into aberrant event segmentation in symptomatic TE individuals, shedding light on mechanisms influencing overgeneral memory in trauma-related disorders.

Assessing Heat Resistance and Selecting Heat-Resistant Individuals of Largemouth Bass (Micropterus salmoides) with Tiered Thermal Exposure.

Largemouth bass (LMB, Micropterus salmoides), a commercially important farmed fish, is vulnerable to heat stress. Breeding heat-resistant LMB is highly desirable in the face of global warming. However, we still lack an efficient method to assess the heat resistance of LMB. In this study, the critical thermal maximum (CTmax) and static exposure methods were first performed to assess the heat resistance of LMB juveniles. The CTmax values of the experimental fish (average body weight 9.87 ± 3.14 g) ranged from 39 to 40 °C but were too close together to differentiate the individual heat resistance. Static exposure experiments with varying temperatures and fish groups also did not provide a clear method for determining the heat resistance. To address these limitations, we developed a tiered exposure method, where the temperature was increased step-wise, starting from 28 to 34 °C at 2 °C increments and then at 0.5 °C increments above 34 °C, with each step lasting one day. The heat resistance of the fish was quantified as the lethal cumulative temperature (LCT), allowing for the classification of fish as sensitive or resistant to heat stress based on their LCT values. To correlate the changes in tissue structure and gene expression with the heat resistance, a new batch of LMB juveniles (average body weight 23.66 ± 6.98 g) were subjected to tiered heat exposure. Brain and liver tissues were collected from the control (without heat exposure), resistant and sensitive (still alive but demonstrated abnormal symptoms) individuals when the temperature was maintained at 35.5 °C for 24 h. The liver tissues of the heat-sensitive individuals showed significant damage and increased cell apoptosis (p < 0.05) relative to those of the resistant ones. The ddit3/chop, bax and casp3 genes demonstrated differential expressions in the liver of the sensitive and resistant fish. Additionally, the LMB juveniles (average body weight 84.06 ± 20.95 g) were found to be more heat resistant than the adults from different sources (average body weight 364.29 ± 84.43 g and 545.71 ± 184.56 g). Through the tiered exposure method, extremely heat-resistant individuals were successfully selected from the population (average body weight 22.69 ± 6.89 g). These findings provide valuable insights into the thermal biology of LMB and the potential for breeding heat-resistant LMB varieties.