Sustained Reduction of Subclinical Inflammation in the years after Breastfeeding.

CONTEXT: Lactation is associated with lower future risk of cardiovascular disease in women but the mechanism(s) underlying this relationship remain unclear. OBJECTIVE: We sought to characterize the relationship between duration of exclusive breastfeeding and cardiovascular risk factors over the first 5-years postpartum. DESIGN/SETTING/PATIENTS: In this prospective cohort study, 328 women underwent serial cardiometabolic characterization (anthropometry, blood pressure, lipids, fasting glucose, adiponectin, C-reactive protein (CRP)) at 1-year, 3-years, and 5-years postpartum. OUTCOME: Cardiovascular risk factors in 3 groups defined by duration of exclusive breastfeeding, as follows: <3 months (n=107), 3-6 months (n=101), and ≥6 months (n=120). RESULTS: The prevalence of metabolic syndrome did not differ between the groups at 3-years but, by 5-years postpartum, was higher in women who had exclusively breastfed <3 months than in those who did so for 3-6 and ≥6 months, respectively (14.0% vs 6.9% vs 4.2%; p=0.02). However, after adjustment for covariates (including BMI), there were no significant differences between groups in blood pressure, glucose, LDL cholesterol, HDL cholesterol, triglycerides or adiponectin. Indeed, the only cardiovascular risk factor difference that persisted after covariate adjustment was that women who had exclusively breastfed <3 months had higher CRP at both 3-years (p=0.04) and 5-years (p=0.01). Moreover, generalized estimating equation analyses with adjustment for covariates (including time-dependent BMI) showed that CRP remained higher over time in these women, as compared to their peers, from 1-year to 3-years to 5-years postpartum (p=0.03). CONCLUSION: Sustained reduction of subclinical inflammation may contribute to the cardioprotective effect of lactation in women.

Intersectionality of gender with social determinants of health and asymptomatic Alzheimer's disease neuropathology.

BACKGROUND: Women comprise approximately two-thirds of Alzheimer's disease cases. OBJECTIVE: This is the first known study to investigate the role of intersectionality between gender and other social determinants of health (SDOH) in the presentation of cognitive symptoms (i.e., being asymptomatic or symptomatic) among those with pathologically confirmed Alzheimer's disease. METHODS: We studied 3107 individuals with Alzheimer's disease neuropathology (ADNP) confirmed at autopsy. Asymptomatic ADNP was defined as the absence of a clinical diagnosis of mild cognitive impairment (MCI) or dementia before death (versus symptomatic: diagnosis of MCI/dementia). SDOH included gender, education, ethnoracial group, living alone, and primary language. Multivariable logistic regression tested associations between SDOH and asymptomatic ADNP (versus symptomatic); models were also stratified by gender. RESULTS: Women, Hispanics, those living alone, and more educated individuals were found to have higher odds of asymptomatic ADNP. Non-English speakers had lower odds of asymptomatic ADNP. Both women and men had higher odds of asymptomatic ADNP if Hispanic or living alone. In only women, non-English speakers had lower odds while in only men, more education was associated with higher odds of asymptomatic ADNP. CONCLUSIONS: Gender, education, ethnicity, primary language, and living alone, and intersectionality of gender with primary language, may differentially influence MCI and dementia diagnosis prior to death among those with underlying ADNP. These findings emphasize the need for future Alzheimer's disease research to prioritize social determinants of brain health including their intersectionality with gender and how to inform targeted interventions.

Synthesis and Biological Evaluation of New Chalcogen Semicarbazone (S, Se) and Their Azole Derivatives against Chagas Disease.

Chagas disease is caused by the eukaryote parasite Trypanosoma cruzi. Current treatment exhibits limited efficacy and selenium-based compounds emerged as promising candidates for new therapies which is surpassing its bioisoster, sulfur. We designed new thiosemicarbazones, thiazoles, selenosemicarbazones and selenazoles, using isosteric substitution. We synthesized 57 new chalcogen compounds which were evaluated against T. cruzi, C2C12 cells and cruzain, the main target of this parasite. Additionally, human cathepsin L, was tested for selectivity. Three compounds were selected, based on their activity against the intracellular amastigotes (EC50 < 1 µM, SI > 10) and cruzain (IC50 < 100 nM, SI > 5.55) which compared favorably with the approved drug, Benznidazole, and the well-established cruzain inhibitor K777. Seleno-compounds demonstrated enhanced activity and selenazoles showed a decrease in selenium-associated toxicity. Compound 4-methyl-2-(2-(1-(3-nitrophenyl)ethylidene)hydrazineyl)-1,3-selenazole (Se2h) emerged as a promising candidate, and its binding to cruzain was investigated. Pharmacokinetic assessment was conducted, showing a favorable profile for subsequent in vivo assays.

Visible-Light-Mediated Vicinal Dihalogenation of Unsaturated C-C Bonds Using Dual-Functional Group Transfer Reagents.

The growing demand for chemical production continues to drive the development of sustainable and efficient methods for introducing molecular complexity. In this context, the exploration of unconventional functional group transfer reagents (FGTRs) has led to significant advancements in practical and atom-efficient synthetic protocols. Aiming to advance the field of valuable organic synthesis, herein we report the successful development of carbon-based, bench-stable, modular, and inexpensive reagents implemented in dual halogen transfer to unsaturated hydrocarbons via photocatalytic activation of reagents based on a radical-polar crossover mechanism. This method beneficially enables vicinal dichlorination, dibromination, and bromo-chlorination reactions of olefins, offering practical alternatives to the use of toxic binary halogens. Detailed mechanistic studies, combining experimental, spectroscopic, and theoretical investigations, revealed a distinctive photocatalytic single-electron transfer reduction of FGTR. This process triggers mesolytic carbon-halogen bond cleavage, followed by a radical 1,2-halide rearrangement, leading to the continuous generation of dihalogen species in the reaction medium. The wide applicability of the developed protocol is demonstrated through an extensive scope of unsaturated molecules, including additional operations on strain-release dihalogenation.

Widespread pain phenotypes impact treatment efficacy results in randomized clinical trials for interstitial cystitis/bladder pain syndrome: a Multidisciplinary Approach to the Study of Chronic Pelvic Pain network study.

ABSTRACT: Pain clinical trials are notoriously complex and often inefficient in demonstrating efficacy, even for known efficacious treatments. A major issue is the difficulty in the a priori identification of specific phenotypes to include in the study population. Recent work has identified the extent of widespread pain as an important determinant of the likelihood of response to therapy, but it has not been tested in clinical trials for the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS). We explored this hypothesis using data from 3 previously published trials testing treatments for IC/BPS, which suggested modest benefits but did not meet a priori primary outcome statistical significance criteria. Importantly, these studies also collected symptom questionnaire data that allowed us to retrospectively identify participants with and without widespread pain. Analyzing the treatment by the degree of widespread pain revealed a difference in outcome and statistical significance level for each trial. Participants with predominately local pain (ie, limited widespread pain symptoms) responded to therapy targeting local symptoms, whereas those with widespread pain did not. Alternatively, participants with widespread pain beyond their local pelvic pain responded to more centrally acting treatments. Our results suggest that differentiating patients based on widespread vs more localized pain is a key consideration for designing future clinical trials for conditions with variable pain profiles, such as IC/BPS and potentially other pain-based syndromic disorders.

A cross-attention-based deep learning approach for predicting functional stroke outcomes using 4D CTP imaging and clinical metadata.

Acute ischemic stroke (AIS) remains a global health challenge, leading to long-term functional disabilities without timely intervention. Spatio-temporal (4D) Computed Tomography Perfusion (CTP) imaging is crucial for diagnosing and treating AIS due to its ability to rapidly assess the ischemic core and penumbra. Although traditionally used to assess acute tissue status in clinical settings, 4D CTP has also been explored in research for predicting stroke tissue outcomes. However, its potential for predicting functional outcomes, especially in combination with clinical metadata, remains unexplored. Thus, this work aims to develop and evaluate a novel multimodal deep learning model for predicting functional outcomes (specifically, 90-day modified Rankin Scale) in AIS patients by combining 4D CTP and clinical metadata. To achieve this, an intermediate fusion strategy with a cross-attention mechanism is introduced to enable a selective focus on the most relevant features and patterns from both modalities. Evaluated on a dataset comprising 70 AIS patients who underwent endovascular mechanical thrombectomy, the proposed model achieves an accuracy (ACC) of 0.77, outperforming conventional late fusion strategies (ACC = 0.73) and unimodal models based on either 4D CTP (ACC = 0.61) or clinical metadata (ACC = 0.71). The results demonstrate the superior capability of the proposed model to leverage complex inter-modal relationships, emphasizing the value of advanced multimodal fusion techniques for predicting functional stroke outcomes.

Valorizing Waste Streams to Enhance Sustainability and Economics in Microbial Oil Production.

Driven by demand for more sustainable products, research and capital investment has been committed to developing microbially produced oils. While researchers have shown oleaginous yeasts and other microbes can produce low-carbon footprint oils by leveraging waste streams as energy sources, previous analyses have not fully explored the quantity of available waste streams and in turn economy-of-scale enabled on capital and operating expenses. This paper makes parallels to 2G ethanol facilities, enabling a data-driven understanding of large-scale production economics. Production costs are broken down for a variety of scenarios. The analysis finds that reaching price parity with large-scale commodity oils (e.g., palm oil, high-oleic cooking oils, biofuels feedstock oils, lauric acid) is not possible today and unlikely even under aggressive future assumptions about strain productivity. Instead, commercial production must be targeted at end markets where sustainability-conscious consumers are willing to pay the price premiums identified in this paper.

Long-Term Impact of the Bloor Viaduct Suicide Barrier on Suicides in Toronto: A Time-Series Analysis: Effet à long terme de la barrière anti-suicide du viaduc Bloor sur les suicides à Toronto : une analyse chronologique.

BACKGROUND: A suicide prevention barrier was installed at Toronto's Bloor Viaduct bridge in 2003. It was associated with short-term location substitution, possibly mediated by media effects that did not persist over 1 decade. The long-term impact of the barrier is unknown. METHODS: We examined rates of suicides by jumping from the Bloor Viaduct, other bridges and by other methods using coroner's records in Toronto (1998-2020). We used interrupted time-series Poisson regression analyses to model changes in quarterly bridge-related suicides after barrier installation. A secondary analysis explored the potential substitution effects of suicide by other methods. RESULTS: Of 5219 suicides from 1998 to 2020, 303 were by jumping from bridges. After controlling for covariates, installation of the Bloor Viaduct suicide barrier was associated with a 49% step decrease in bridge-related suicide in the next quarter in Toronto (incidence rate ratio [IRR] = 0.51, 95% CI, 0.30 to 0.86) with no rebound increase in bridge-related suicide during the subsequent 17 years after the original drop (IRR = 0.99, 95% CI, 0.96 to 1.03). There was also no associated change in suicides by other methods after the barrier (IRR = 1.04, 95% CI, 0.90 to 1.20). CONCLUSIONS: Contrary to initial findings, these results indicate an enduring suicide prevention effect of the Bloor Viaduct suicide barrier. They support the long-term utility of structural interventions at high-frequency sites for suicide.

Psilocybin reduces grooming in the SAPAP3 knockout mouse model of compulsive behaviour.

Psilocybin is a serotonergic psychedelic compound which shows promise for treating compulsive behaviours. This is particularly pertinent as compulsive disorders require research into new pharmacological treatment options as the current frontline treatments such as selective serotonin reuptake inhibitors, require chronic administration, have significant side effects, and leave almost half of the clinical population refractory to treatment. In this study, we investigated psilocybin administration in male and female SAPAP3 knockout (KO) mice, a well-validated mouse model of obsessive compulsive and related disorders. We assessed the effects of acute psilocybin (1 mg/kg, intraperitoneal) administration on head twitch and locomotor behaviour as well as anxiety- and compulsive-like behaviours at multiple time-points (1, 3 and 8 days post-injection). While psilocybin did not have any effect on anxiety-like behaviours, we revealed that acute psilocybin administration led to enduring reductions in compulsive behaviour in male SAPAP3 KO mice and reduced grooming behaviour in female wild-type (WT) and SAPAP3 KO mice. We also found that psilocybin increased locomotion in WT littermates but not in SAPAP3 KO mice, suggesting in vivo serotonergic dysfunctions in KO animals. On the other hand, the typical head-twitch response following acute psilocybin (confirming its hallucinogenic-like effect at this dose) was observed in both genotypes. Our novel findings suggest that acute psilocybin may have potential to reduce compulsive-like behaviours (up to 1 week after a single injection). Our study can inform future research directions as well as supporting the utility of psilocybin as a novel treatment option for compulsive disorders.

Piezo2 interacts with E-cadherin in specialized gastrointestinal epithelial mechanoreceptors.

Piezo2 is a mechanically gated ion channel most commonly expressed by specialized mechanoreceptors, such as the enteroendocrine cells (EECs) of the gastrointestinal epithelium. A subpopulation of EECs expresses Piezo2 and functionally resembles the skin's touch sensors, called Merkel cells. Low-magnitude mechanical stimuli delivered to the mucosal layer are primarily sensed by mechanosensitive EECs in a process we term "gut touch." Piezo2 transduces cellular forces into ionic currents, a process that is sensitive to bilayer tension and cytoskeletal depolymerization. E-cadherin is a widely expressed protein that mediates cell-cell adhesion in epithelia and interacts with scaffold proteins that anchor it to actin fibers. E-cadherin was shown to interact with Piezo2 in immortalized cell models. We hypothesized that the Piezo2-E-cadherin interaction is important for EEC mechanosensitivity. To test this, we used super-resolution imaging, co-immunoprecipitation, and functional assays in primary tissues from mice and gut organoids. In tissue EECs and intestinal organoids, we observed multiple Piezo2 cellular pools, including one that overlaps with actin and E-cadherin at the cells' lateral walls. Further, E-cadherin co-immunoprecipitated with Piezo2 in the primary colonic epithelium. We found that E-cadherin knockdown decreases mechanosensitive calcium responses in mechanically stimulated primary EECs. In all, our results demonstrate that Piezo2 localizes to the lateral wall of EECs, where it physically interacts with E-cadherin and actin. They suggest that the Piezo2-E-cadherin-actin interaction is important for mechanosensitivity in the gut epithelium and possibly in tissues where E-cadherin and Piezo2 are co-expressed in epithelial mechanoreceptors, such as skin, lung, and bladder.

Pre-emptive therapeutic decisions based on measurable residual disease status in acute myeloid leukemia: ready for prime time?

The use of measurable residual disease (MRD) as a biomarker for prognostication, risk stratification, and therapeutic decision-making in acute myeloid leukemia (AML) is gaining prominence. MRD monitoring for NPM1-mutated and core-binding factor AML using PCR techniques is well-established for assessing disease after intensive chemotherapy. AML with persistent FLT3-ITD MRD post-intensive chemotherapy and pre-allogeneic hematopoietic cell transplantation (pre-allo-HCT) is associated with an increased risk of relapse and lower survival. Pre-allo-HCT MRD is an independent risk factor for post-allo-HCT outcomes, including relapse and death. Therefore, preemptive interventions on the natural history of MRD positivity are an active area of research beyond its initial prognostic function. Targeting MRD in AML with innovative treatment strategies can improve patient outcomes.

Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC.

The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with hallmark pathways of metastasis along with classical and non-classical epithelial-mesenchymal transition. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered ligands ephrinB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggests that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.

Experiences of Midwestern obstetric clinicians during the Coronavirus disease 2019 pandemic.

Background: The Coronavirus disease 2019 (COVID-19) pandemic led to healthcare system changes aimed at minimizing disease transmission that impacted experiences with obstetric healthcare. Objective: To explore experiences of clinicians providing obstetric care during the COVID-19 pandemic. Study Design: Qualitative, in-depth, semi-structured interviews were conducted with five nurse practitioners and 16 obstetrical physicians providing a mix of outpatient and inpatient obstetric care during the COVID-19 pandemic in a mid-sized, Midwestern city in the United States. Interviews elucidated challenges and facilitators of obstetric care provision and vaccination of pregnant patients against COVID-19 during the pandemic. Transcripts were coded inductively then deductively using the Health Equity Implementation Framework (HEIF), which integrates a disparities framework and implementation framework to highlight multilevel factors that influence obstetric care. Thematic analysis was conducted, and thematic saturation was reached. Results: We interviewed 21 clinicians. Clinicians recounted personal challenges such as social isolation and burnout that could be countered by social support. Challenges within the clinical encounter included implementation of infection mitigation efforts, vaccine counseling, and limitations of telehealth. However, when successfully implemented, telehealth facilitated care and circumvented barriers. Clinicians cited challenges at the healthcare system level such as rapidly evolving knowledge and recommendations, restrictive visitor policies, personnel shortage, and inadequate institutional resources to support pandemic-related stressors. However, interdisciplinary care and guidelines available for clinicians facilitated care. Clinicians reported that challenges at the societal level included financial strain, lack of childcare, medical mistrust, politicization of medicine, misinformation, and racism. Societal-level facilitators included insurance access, community outreach, positive policy changes, and fostering trust in medicine. Conclusion: The pandemic produced unique stressors and exacerbated existing challenges for clinicians providing obstetric care. Applying the HEIF to the findings emphasizes the influence of societal factors on all other levels. Identified facilitators can inform interventions to address stressors in obstetric care that have resulted from the changed sociopolitical landscape of the pandemic.

Promising biomarker panel to monitor therapeutic efficacy of neoadjuvant chemotherapy in pancreatic cancer patients.

BACKGROUND: Neoadjuvant chemotherapy (NAC) can provide improved survival outcomes in pancreatic ductal adenocarcinoma (PDAC) patients who respond to treatment, but currently available biomarkers cannot reliably predict NAC response. This study aimed to determine the potential of a previously identified diagnostic and prognostic biomarker panel (i.e. Ca-125, S100A2, S100A4, Mesothelin and Ca19-9) for the monitoring of NAC-response in PDAC patients. METHODS: This single-centre, retrospective study, utilised serum from NAC treated PDAC patients to determine the levels of biomarkers by Enzyme-Linked Immunosorbent Assay (ELISA). The percentage of the tumour bed occupied by viable carcinoma (PVC) was used to divide patients into good (PVC < 50%) and poor (PVC ≥ 50%) NAC-responders. Statistical analysis was performed to measure the ability of individual biomarkers and a biomarker panel in NAC treatment response and patient survival. RESULTS: Serum specimens from a total of 108 PDAC patients were assessed. Ca-125, Ca19-9 and S100A2 showed a significant positive correlation with PVC. Ca-125 demonstrated a superior ability to monitor NAC treatment response (Area under receiver operating curve (AUC): .6954) compared to the more widely used clinical biomarker, Ca19-9 (AUC: .6291). A panel of Ca-125 and Ca19-9 showed good ability to monitor NAC response in PDAC patients (AUC: .7349). Patients with high levels of both Ca-125 and Ca19-9 were shown to have the poorest overall survival (median overall survival: 17 vs. 30 months). CONCLUSION: A serum biomarker panel of Ca-125 and Ca19-9 could be used for effective clinical management of PDAC patients undergoing NAC treatment.

Factors and Reasons Associated with Hesitating to Seek Care for Migraine: Results of the OVERCOME (US) Study.

INTRODUCTION: Despite a variety of available treatment options for migraine, many people with migraine do not seek medical care, thereby reducing opportunities for diagnosis and effective treatment and potentially leading to missed opportunities to reduce the burden of disease. Understanding why people hesitate to seek care for migraine may help healthcare professionals and advocates address barriers and improve outcomes. The aim of this study, in a large adult population sample in the United States (US), was to identify factors associated with and reasons for hesitating to seek healthcare for migraine. METHODS: The web-based OVERCOME (US) survey study identified adults with active migraine in a demographically representative US sample who answered questions about hesitating to seek care from a healthcare provider for migraine and reasons for hesitating. Supervised machine learning (random forest, least absolute shrinkage and selection operator) identified factors associated with hesitation; logistic regression models assessed association of factors on hesitation. RESULTS: The study results show that of the 58,403 participants with active migraine who completed the OVERCOME (US) baseline survey and provided responses to the question on hesitating to seek care for migraine, 45.1% (n = 26,330/58,403) with migraine indicated that they had ever hesitated to seek care for migraine. Factors most associated with hesitating to seek care were hiding migraine (odds ratio [OR] = 2.69; 95% confidence interval [CI]: 2.50, 2.89), experiencing migraine-related stigma (OR = 2.13; 95% CI 1.95, 2.33), higher migraine-related disability (OR = 1.30; 95% CI 1.23, 1.38), and higher ictal cutaneous allodynia (OR = 1.26; 95% CI 1.19, 1.35). The most common reasons participants stated for hesitating included (1) 44.2% wanting to try and take care of migraine on their own, (2) 33.8% feeling that their migraine or headache would not be taken seriously, (3) 29.2% thinking that their migraine was not serious/painful enough, and (4) 27.4% not being able to afford it or not wanting to spend the money. The main limitation of the study includes the requirement for respondents to have internet, access which may have reflected cohort bias, and the quota sampling rather than random sampling to create a demographically representative sample. CONCLUSIONS: Hesitating to seek migraine care is common and is most strongly associated with hiding the disease and migraine-related stigma. Those experiencing higher migraine-related burden are more hesitant to seek the care that might alleviate the burden. These findings suggest that migraine's social context (e.g., stigma) is a major determinant of hesitance to seek migraine care.

The Relationship between Sleep and Physical Activity by Age, Race, and Gender.

Cardiometabolic diseases remain the leading cause of death in the United States. Lifestyle factors contribute the majority of risk for these diseases. Although diet and exercise have been the primary focus of research on modifiable behaviors to target for interventions to prevent cardiometabolic disease, recent evidence suggests that sleep also plays an important role. Indeed, the updated American Heart Association campaign includes sleep as one of its "Essential Eight". This review details the reciprocally reinforcing positive relationship between sleep and daytime physical activity behaviors and explores how this relationship differs based on age, gender and race. For example, interventions to improve moderate intensity physical activity may be particularly beneficial to women, older adults, and Black Americans, who are at increased risk for sleep disturbances. Communicating to Americans the importance of managing their time to meet current physical activity and sleep recommendations is a challenge given that there are so many competing behaviors consuming large amounts of time (e.g., social media, gaming), but is critical given the importance of these behaviors for cardiometabolic health.

Abl kinases regulate FGF signaling independent of Crk phosphorylation to prevent Peters anomaly.

Peters anomaly, the most common cause of congenital corneal opacity, stems from corneal-lenticular adhesion. Despite numerous identified mutations, a cohesive molecular framework of the disease's etiology remains elusive. Here, we identified Abl kinases as pivotal regulators of FGF signaling, as genetic ablation of Abl kinases restores lens induction even in the absence of FGF signaling. Intriguingly, both Abl kinase deficiency and increased FGF-Ras activity result in Peters anomaly independent of ERK signaling, which can be rescued by allelic deletion of Abl substrate, Crk. However, contrary to the prevailing belief that Abl kinases regulate Crk proteins by direct phosphorylation, mutations at Abl kinase phosphorylation sites on Crk and CrkL did not yield any observable effects. Instead, our findings reveal that Abl kinases phosphorylate Ptpn12, which in turn inhibits p130Cas phosphorylation and Crk recruitment, crucial for Rho GTPases activation and cytoskeletal dynamics. Consequently, Abl kinase deficiency reduces actomyosin contractility within the lens vesicle and genetically interacts with RhoA inhibition. Conversely, Rac1 deletion mitigates Peters anomaly in models with aberrant FGF, Abl kinase and RhoA signaling. Our results demonstrate that Abl kinases regulate FGF signaling to balance RhoA and Rac1 activity via the Ptpn12-p130Cas pathway, suggesting that targeting tension-mediated lens vesicle separation could be a therapeutic strategy for Peters anomaly.

African origin haplotype protective for Alzheimer's disease in APOEε4 carriers: exploring potential mechanisms.

APOEε4 is the strongest genetic risk factor for Alzheimer's disease (AD) with approximately 50% of AD patients carrying at least one APOEε4 allele. Our group identified a protective interaction between APOEε4 with the African-specific A allele of rs10423769, which reduces the AD risk effect of APOEε4 homozygotes by approximately 75%. The protective variant lies 2Mb from APOE in a region of segmental duplications (SD) of chromosome 19 containing a cluster of pregnancy specific beta-1 glycoprotein genes (PSGs) and a long non-coding RNA. Using both short and long read sequencing, we demonstrate that rs10423769_A allele lies within a unique single haplotype inside this region of segmental duplication. We identified the protective haplotype in all African ancestry populations studied, including both West and East Africans, suggesting the variant has an old origin. Long-read sequencing identified both structural and DNA methylation differences between the protective rs10423769_A allele and non-protective haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2 family transcription factor binding motifs was found associated with the protective haplotype (p-value = 2.9e-10). These findings provide novel insights into the mechanisms of this African-origin protective variant for AD in APOEε4 carriers and supports the importance of including all ancestries in AD research.

Validation of a sensor system for the measurement of breath ammonia using selected-ion flow-tube mass spectrometry.

The measurement of trace breath gases is of growing interest for its potential to provide non-invasive physiological information in health and disease. While instrumental techniques such as selected-ion flow-tube mass spectrometry (SIFT-MS) can achieve this, these are less suitable for clinical application. Sensitive sensor-based systems for breath ammonia could be more widely deployed, but have proven challenging to develop. This work demonstrates the sequential analytical validation of an electrochemical impedance-based sensor system for the measurement of ammonia in breath using SIFT-MS. Qualitative and relative responses between the two methods were comparable, although there were consistent differences in absolute concentration. When tested in artificial breath ammonia, sensors had a relative impedance sensitivity of 3.43x10-5ppbv-1for each breath in the range of 249 to 1,653 ppbv (r2=0.87,p<0.05). When correlated with SIFT-MS using human breath (n=14), ammonia was detected in the range of 100 to 700 ppbv (r=0.78,p<0.001), demonstrating acceptable sensitivity, reproducibility and dynamic range for clinical application.