Serum Calcium Levels in Patients with Essential Hypertension: A Cross-Sectional Study in a Tertiary Hospital of Bangladesh.

The exact cause of essential hypertension remains unclear. There is evidence to suggest that the development of essential hypertension is causally related to serum calcium levels. This study was designed to assess the status of serum calcium level in patients with essential hypertension and compared with healthy control. The research study was cross-sectional observational in nature. This study was done at the Department of Physiology in Sylhet MAG Osmani Medical College, Sylhet, Bangladesh. The duration of the research period was one year. All the known case of hypertension and newly diagnosed hypertensive patients were selected and compared with age-sex matched apparently healthy individual. Age below 18 years, pregnant women and patients taking supplementary calcium therapy were excluded from this study. Blood pressure was measured by auscultatory method; aneroid sphygmomanometer and standard stethoscope were used. Automated chemistry analyzer Vitrose-350, USA was used to estimate serum calcium level. Standard operating procedure strictly followed. There were 62 hypertensive (both known case of hypertension and newly diagnosed cases) were selected in hypertensive group (Group A) and 62 age-sex matched apparently healthy individuals were selected in normotensive group (Group B). The mean age of hypertensive and normotensive subjects was not statistically significant (p=0.814). There were 27(43.5%) male and 35(56.5%) female in hypertensive group, 32(51.8%) male and 30(48.4%) female in normotensive group. The distribution was statistically not significant (p=0.472). The mean value of the systolic blood pressure (SBP) was 146.45±5.82 mm Hg and the mean value of the diastolic blood pressure (DBP) was 92.90±7.66 mm Hg in hypertensive group. The mean value of the SBP was 112.74±6.88 mm Hg and the mean value of the DBP was 74.52±5.33 mm Hg of the normotensive group. The difference in mean blood pressure (BP) between the two groups was highly significant (p<0.001). The mean value of the serum calcium level was 8.59±0.55 mg/dl in hypertensive group and 9.12±0.93 mg/dl in normotensive group, which was statistically significant (p <0.001) between two groups. Serum calcium was significantly lower in hypertensive group than normotensive group. There was a negative correlation of the serum calcium level with both systolic and diastolic blood pressure.

Ligand Shell Thickness of PEGylated Gold Nanoparticles Controls Cellular Uptake and Radiation Enhancement.

The drive to improve the safety and efficacy of radiotherapies for cancers has prompted the development of nanomaterials that can locally amplify the radiation dose at a tumor without damaging the surrounding healthy tissue. Gold nanoparticles (Au NPs), in particular, exhibit promising radiosensitizing properties under kilovolt X-ray exposure, although the precise mechanism behind this enhancement is not fully understood. While most studies recognize the involvement of factors such as core composition, size, shape, and ligand chemistry in the effectiveness of Au NPs for radiation-induced cancer treatment, there is a scarcity of direct assessments that connect the photophysical properties of the nanomaterial with the observed cellular or biological outcomes. Despite previous evidence of low-energy electron (LEE) emission from Au NPs and their potential to initiate biological damage, to our knowledge, no studies directly correlate the secondary LEE emission with radiation-induced cell death. In this study we assessed Au NPs functionalized with polyethylene glycol (PEG) ligands of varying molecular weights and lengths (1, 5, and 20 kDa PEG) as potential radiosensitizers of A549 lung cancer cells using kilovolt X-ray source potentials (33-130 kVp). We assessed NP internalization using mass cytometry, radiation dose enhancement using clonogenic survival assays, and secondary LEE emission using a retarding field analyzer. Results reveal a statistically significant difference in cellular uptake and radiation dose enhancement for 5 kDa PEG-Au NPs compared to formulations using 1 and 20 kDa PEG, while analysis of secondary LEE emission spectra demonstrated that differences in the length of the PEG ligand did not cause statistically significant attenuation of secondary LEE flux. Consequently, we inferred increased cellular uptake of NPs to be the cause for the observed enhancement in radiosensitivity for 5 kDa PEGylated Au NPs. The approach used in this study establishes a more complete workflow for designing and characterizing the performance of nanomaterial radiosensitizers, allowing for quantification of secondary LEEs and cellular uptake, and ultimately correlation with localized dose enhancement that leads to cell death.

Evidence of longitudinal differences in spring migration strategies of an Arctic-nesting goose.

During spring, migratory birds are required to optimally balance energetic costs of migration across heterogeneous landscapes and weather conditions to survive and reproduce successfully. Therefore, an individual's migratory performance may influence reproductive outcomes. Given large-scale changes in land use, climate, and potential carry-over effects, understanding how individuals migrate in relation to breeding outcomes is critical to predicting how future scenarios may affect populations. We used GPS tracking devices on 56 Greater White-fronted Geese (Anser albifrons) during four spring migrations to examine whether migration characteristics influenced breeding propensity and breeding outcome. We found a strong longitudinal difference in arrival to the breeding areas (18 days earlier), pre-nesting duration (90.9% longer), and incubation initiation dates (9 days earlier) between western- and eastern-Arctic breeding regions, with contrasting effects on breeding outcomes, but no migration characteristic strongly influenced breeding outcome. We found that breeding region influenced whether an individual likely pursued a capital or income breeding strategy. Where individuals fell along the capital-income breeding continuum was influenced by longitude, revealing geographic effects of life-history strategy among conspecifics. Factors that govern breeding outcomes likely occur primarily upon arrival to breeding areas or are related to individual quality and previous breeding outcome, and may not be directly tied to migratory decision-making across broad scales.

Chronic innate immune impairment and ZIKV persistence in the gastrointestinal tract during SIV infection in pigtail macaques.

Mosquito borne flaviviruses, including dengue (DENV) and Zika (ZIKV) viruses, have caused global epidemics in areas with high HIV prevalence due to the expanded geographic range of arthropod vectors. Despite the occurrence of large flavivirus outbreaks in countries with high HIV prevalence, there is little knowledge regarding the effects of flavivirus infection in people living with HIV (PLWH). Here, we use a pigtail macaque model of HIV/AIDS to investigate the impact of simian immunodeficiency virus (SIV)-induced immunosuppression on ZIKV replication and pathogenesis. Early acute SIV infection induced expansion of peripheral ZIKV cellular targets and increased innate immune activation and peripheral blood mononuclear cells (PBMC) from SIV infected macaques were less permissive to ZIKV infection in vitro. In SIV-ZIKV co-infected animals, we found increased persistence of ZIKV in the periphery and tissues corresponding to alterations in innate cellular (monocytes, neutrophils) recruitment to the blood and tissues, decreased anti-ZIKV immunity, and chronic peripheral inflammatory and innate immune gene expression. Collectively, these findings suggest that untreated SIV infection may impair cellular innate responses and create an environment of chronic immune activation that promotes prolonged ZIKV viremia and persistence in the gastrointestinal tract. These results suggest that PLWH or other immunocompromised individuals could be at a higher risk for chronic ZIKV replication, which in turn could increase the timeframe of ZIKV transmission. Thus, PLWH are important populations to target during the deployment of vaccine and treatment strategies against ZIKV.

Elevated Plasma Matrix Metalloproteinases Are Associated With Mycobacterium tuberculosis Bloodstream Infection and Mortality in Human Immunodeficiency Virus-Associated Tuberculosis.

Mortality from human immunodeficiency virus (HIV)-associated tuberculosis (TB) is high, particularly among hospitalized patients. In 433 people with HIV hospitalized with symptoms of TB, we investigated plasma matrix metalloproteinases (MMP) and matrix-derived biomarkers in relation to TB diagnosis, mortality, and Mycobacterium tuberculosis (Mtb) bloodstream infection (BSI). Compared to other diagnoses, MMP-8 was elevated in confirmed TB and in Mtb-BSI, positively correlating with extracellular matrix breakdown products. Baseline MMP-3, -7, -8, -10, and PIIINP were associated with Mtb-BSI and 12-week mortality. These findings implicate MMP dysregulation in pathophysiology of advanced HIV-TB and support MMP inhibition as a host-directed therapeutic strategy for HIV-TB.

Multiplex imaging of localized prostate tumors reveals altered spatial organization of AR-positive cells in the microenvironment.

Mapping the spatial interactions of cancer, immune, and stromal cell states presents novel opportunities for patient stratification and for advancing immunotherapy. While single-cell studies revealed significant molecular heterogeneity in prostate cancer cells, the impact of spatial stromal cell heterogeneity remains poorly understood. Here, we used cyclic immunofluorescent imaging on whole-tissue sections to uncover novel spatial associations between cancer and stromal cells in low- and high-grade prostate tumors and tumor-adjacent normal tissues. Our results provide a spatial map of single cells and recurrent cellular neighborhoods in the prostate tumor microenvironment of treatment-naive patients. We report unique populations of mast cells that show distinct spatial associations with M2 macrophages and regulatory T cells. Our results show disease-specific neighborhoods that are primarily driven by androgen receptor-positive (AR+) stromal cells and identify inflammatory gene networks active in AR+ prostate stroma.

Effect of hormone therapy on personality traits: preliminary evidence in older men and women.

OBJECTIVE: Findings concerning the effects of hormone therapy (HT) on cognition and dementia are mixed, with some trials suggesting increased harm at older ages. Personality, like cognition, changes with dementia, but no clinical trials to date have examined the effects of HT on personality traits. This study aimed to determine the effects of HT on personality traits in older men and women. METHOD: Secondary data analysis was performed from randomized, double-blind, placebo-controlled cross-over studies of menopausal HT in women and testosterone therapy (TT) in men. Participants were community-dwelling cognitively normal adults (mean age = 75.2 years), including 29 men and 22 women. Three months of hormone intervention (for women, 0.625 mg/day conjugated equine estrogen with or without 2.5 mg/day medroxyprogesterone acetate; for men, 200 mg intramuscular testosterone enanthate every 2 weeks) were crossed over with 3 months of identical placebo with a 3-month washout between intervention phases. The main outcome measure was neuroticism and conscientiousness personality domains and facets assessed with the Revised NEO Personality Inventory (NEO-PI-R) after the active and placebo intervention phases. RESULTS: In linear mixed-effect models, HT in women decreased conscientiousness (p < 0.01) and the conscientiousness facet of achievement striving (p < 0.01), and increased vulnerability, a facet of neuroticism (p < 0.05). Testosterone in men decreased conscientiousness (p < 0.05) and the conscientiousness facet of dutifulness (p < 0.05), and increased vulnerability (p < 0.05). CONCLUSION: In a preliminary study of healthy older adults, HT and TT formulations produced adverse changes in vulnerability and conscientiousness facets that parallel personality changes in dementia.

A study on the diversity of phlebotomine sand flies (Diptera, Psychodidae) in karstic limestone areas in Vientiane Province, Laos, with a description of two new species of Sergentomyia França and & Parrot.

BACKGROUND: Southeast Asia is well known as a hotspot of biodiversity. However, very little is known about cave-dwelling hematophagous insects that are medically important. Taxonomic knowledge and ecology of phlebotomine sand flies are very poorly studied in Laos, as well as in other countries in the region. Herein, we report species diversity data and some notes on the ecology of the detected species from these karstic limestone areas of Laos. METHODS: Phlebotomine sand flies were collected using Centers for Disease Control and Prevention (CDC) light traps from limestone cave locations in three districts of Vientiane Province, Laos. Both morphological and molecular techniques were used for sand fly identification. Species diversity and abundance were analyzed according to sites, locations, collection seasons, and trapping positions. RESULTS: A total of 6564 sand flies, of which 5038 were females and 1526 were males, were morphologically identified into 20 species belonging to five genera (Chinius, Idiophlebotomus, Phlebotomus, Sergentomyia, and Grassomyia). The most abundant species were Chinius eunicegalatiae, Phlebotomus stantoni, Sergentomyia hivernus, Se. siamensis, and Idiophlebotomus longiforceps. Cytochrome b analysis results supported the morphological identification and revealed that Se. siamensis was separated from other members of the Se. barraudi group. Two new species, Se. dvoraki n. sp. and Se. marolii n. sp., were described. Sand fly density was generally high except in a cave in Vangvieng, with species richness ranging from 14 to 18 across different caves. Outside caves had higher species richness (R = 20) and diversity (H = 2.50) than cave entrances (R = 18, H = 2.41) and interiors (R = 16, H = 2.13). Seasonal variations showed high sand fly density in Feung and Hinheup during both dry and rainy seasons, while Vangvieng had a notable decrease in density during the dry season (D = 6.29). CONCLUSIONS: This study revealed that the diversity of phlebotomine sand fly fauna in Laos, particularly in karstic limestone areas, is greater than previously known. However, the taxonomic status of many species in Laos, as well as Southeast Asia, still needs more in-depth study using both morphological characters and molecular methods. Many species could be found from inside, at the entrance, and outside of caves, indicating a wide range of host-seeking behavior or possible natural breeding in the karstic cave areas.

Probing the Shape of the Weyl Fermi Surface of NbP Using Transverse Electron Focusing.

Weyl semimetals are defined by their unique Fermi surface, comprising pairs of Weyl points of opposite chirality, connected through topological surface states. Angle-resolved photoemission spectroscopy (ARPES) has been used to verify the existence of the Weyl points and the Fermi arcs. However, ARPES is limited in resolution, leading to significant uncertainty when characterizing the shape of the Fermi surface of semimetals and measuring features such as the distance between the Weyl points. Here, to surpass the resolution of ARPES, we combine quantum oscillation measurements with transverse electron focusing experiments. These techniques offer complementary information, enabling the reconstruction of the distinctive peanut-shaped cross section of the Weyl Fermi surface and accurately determining the separation between Weyl points in the Weyl semimetal NbP. Our Letter showcases the integration of quantum oscillations and transverse electron focusing, allowing for the measurements of complex Fermi surface geometries, concurrently with carriers' transport properties, in high-mobility quantum materials.

Yttrium-90 (90Y) brachytherapy for squamous carcinoma: Treatment of the conjunctiva, cornea, and sclera.

Purpose: Patients with conjunctival squamous cell carcinoma that present with persisting disease or recurrence following topical chemotherapy and/or surgery especially when invading the sclera are challenging to treat. Herein, we describe the use of high-dose-rate (HDR), FDA-cleared, yttrium-90 (90Y) plaque brachytherapy for such lesions. Observation: Three cases of invasive conjunctival squamous cell carcinoma that had exhibited a poor response or recurrence following topical chemotherapy and/or surgery are described. As treatment, HDR 90Y beta-radiation was applied to the tumor and margins for a single, continuous duration. In contrast to low-dose-rate (LDR) plaque, HDR 90Y brachytherapy did not require episcleral sutures, amniotic membrane buffering of the cornea, a Gunderson flap, outpatient dwell time, or second surgery. Radiation safety was improved by eliminating LDR-implant related post-operative radiation exposure to health care personnel, the community, family, and pets. Follow-up examination at one month revealed complete tumor resolution in all patients. At last follow-up (8, 11 and 18 months) all patients remained clinically tumor-free as confirmed by slit-lamp biomicroscopy, anterior segment optical coherence tomography, and high-frequency ultrasound imaging. There were no acute complications (e.g., corneal edema, iridocyclitis, scleropathy, keratopathy or cataract). Conclusion and Importance: 90Y brachytherapy demonstrated efficacy as a single-surgery, minimally invasive, outpatient irradiation for squamous carcinoma of the ocular surface. While short-term results were promising, long-term follow-up monitoring for side-effects and recurrence are essential.

Differential Immunoregulation by Human Surfactant Protein A Variants Determines Severity of SARS-CoV-2-induced Lung Disease.

COVID-19 remains a significant threat to public health globally. Infection in some susceptible individuals causes life-threatening acute lung injury (ALI/ARDS) and/or death. Human surfactant protein A (SP-A) is a C-type lectin expressed in the lung and other mucosal tissues, and it plays a critical role in host defense against various pathogens. The human SP-A genes ( SFTPA1 and SFTPA2 ) are highly polymorphic and comprise several common genetic variants, i.e., SP-A1 (variants 6A 2 , 6A 4 ) and SP-A2 (variants 1A 0 , 1A 3 ). Here, we elucidated the differential antiviral and immunoregulatory roles of SP-A variants in response to SARS-CoV-2 infection in vivo . Six genetically-modified mouse lines, expressing both hACE2 (SARS-CoV-2 receptor) and individual SP-A variants: (hACE2/6A 2 (6A 2 ), hACE2/6A 4 (6A 4 ), hACE2/1A 0 (1A 0 ), and hACE2/1A 3 (1A 3 ), one SP-A knockout (hACE2/SP-A KO (KO) and one hACE2/mouse SP-A (K18) mice, were challenged intranasally with 10 3 PFU SARS-CoV-2 or saline (Sham). Infected KO and 1A 0 mice had more weight loss and mortality compared to other mouse lines. Relative to other infected mouse lines, a more severe ALI was observed in KO, 1A 0 , and 6A 2 mice. Reduced viral titers were generally observed in the lungs of infected SP-A mice relative to KO mice. Transcriptomic analysis revealed an upregulation in genes that play central roles in immune responses such as MyD88 , Stat3 , IL-18 , and Jak2 in the lungs of KO and 1A 0 mice. However, Mapk1 was significantly downregulated in 6A 2 versus 1A 0 mice. Analysis of biological pathways identified those involved in lung host defense and innate immunity, including pathogen-induced cytokine, NOD1/2, and Trem1 signaling pathways. Consistent with the transcriptomic data, levels of cytokines and chemokines such as G-CSF, IL-6 and IL-1ß were comparatively higher in the lungs and sera of KO and 1A 0 mice with the highest mortality rate. These findings demonstrate that human SP-A variants differentially modulate SARS-CoV-2-induced lung injury and disease severity by differentially inhibiting viral infectivity and regulating immune-related gene expressions.

HDAC5 controls a hypothalamic STAT5b-TH axis, the sympathetic activation of ATP-consuming futile cycles and adult-onset obesity in male mice.

With age, metabolic perturbations accumulate to elevate our obesity burden. While age-onset obesity is mostly driven by a sedentary lifestyle and high calorie intake, genetic and epigenetic factors also play a role. Among these, members of the large histone deacetylase (HDAC) family are of particular importance as key metabolic determinants for healthy ageing, or metabolic dysfunction. Here, we aimed to interrogate the role of class 2 family member HDAC5 in controlling systemic metabolism and age-related obesity under non-obesogenic conditions. Starting at 6 months of age, we observed adult-onset obesity in chow-fed male global HDAC5-KO mice, that was accompanied by marked reductions in adrenergic-stimulated ATP-consuming futile cycles, including BAT activity and UCP1 levels, WAT-lipolysis, skeletal muscle, WAT and liver futile creatine and calcium cycles, and ultimately energy expenditure. Female mice did not differ between genotypes. The lower peripheral sympathetic nervous system (SNS) activity in mature male KO mice was linked to higher dopaminergic neuronal activity within the dorsomedial arcuate nucleus (dmARC) and elevated hypothalamic dopamine levels. Mechanistically, we reveal that hypothalamic HDAC5 acts as co-repressor of STAT5b over the control of Tyrosine hydroxylase (TH) gene transactivation, which ultimately orchestrates the activity of dmARH dopaminergic neurons and energy metabolism in male mice under non-obesogenic conditions.

Enhanced Venous Thrombosis and Hypercoagulability in Murine and Human Metabolic Dysfunction-Associated Steatohepatitis.

BACKGROUND: Patients with metabolic dysfunction-associated steatohepatitis (MASH) are at an increased risk of developing venous thromboembolic events (VTE), including deep vein thrombosis (DVT). To date, the study of DVT in MASH has been hampered by the lack of reliable models that mimic the pathological aspects of human disease. OBJECTIVES: To evaluate DVT severity and hypercoagulability in murine and human MASH. METHODS: Transcriptional changes in the liver, plasma markers of coagulation, and DVT severity were evaluated in mice fed a chow diet or a high-fructose, high-fat, and high-cholesterol, MASH diet for 24 weeks. Plasma analyses of coagulations markers and thrombin generation assay were performed in a well-characterized cohort of patients with or without MASH. RESULTS: Mice fed the MASH diet developed steatohepatitis and fibrosis, mimicking human MASH. Liver RNA-sequencing revealed a significant upregulation of pathways related to inflammation and coagulation concomitant with increased plasma coagulation markers including increased prothrombin fragment 1+2, thrombin-antithrombin complex, plasminogen activator inhibitor-1 levels, and endothelin 1. MASH exacerbated DVT severity in mice, as evidenced by increased thrombus weight and higher thrombosis incidence (15/15 vs. 11/15 in controls, p=0.0317). Higher endothelin 1 release and increased apoptosis were found in endothelial cells stimulated with supernatants of palmitate-stimulated HepG2 cells. Patients with MASH exhibited increased plasma coagulation markers and delayed thrombin generation. CONCLUSION: We report enhanced DVT severity and hypercoagulability, both in murine and human MASH. Our model of MASH-DVT can facilitate a better understanding of the fundamental mechanisms leading to increased VTE in patients with MASH.

Financial Hardship Among Patients With Early-Stage Colorectal Cancer.

Importance: The degree of cancer patients' financial hardship is dynamic and can change over time. Objective: To assess longitudinal changes in financial hardship among patients with early-stage colorectal cancer. Design, Setting, and Participants: In this prospective longitudinal cohort study, English-speaking adult patients with a new diagnosis of stage I to III colorectal cancer being treated with curative intent at National Cancer Institute (NCI) Community Oncology Research Program (NCORP) practices between May 2018 and July 2020 and who had not started chemotherapy and/or radiation were included. Data analysis was conducted from March to December 2023. Main Outcomes and Measures: Patients completed surveys at baseline as well as at 3, 6, 12, and 24 months after enrollment. Cost-related care nonadherence and material hardship, as adopted by Medical Expenditure Panel Survey, were measured. Factors associated with financial hardship were assessed using longitudinal multivariable logistic regression models with time interaction. Results: A total of 451 patients completed baseline questions, with 217 (48.1%) completing the 24-month follow-up. Mean (SD) age was 61.0 (12.0) years (210 [46.6%] female; 33 [7.3%] Black, 380 [84.3%] White, and 33 [7.3%] American Indian or Alaska Native, Asian, multiracial, or Native Hawaiian or Other Pacific Islander individuals or those who did not report race or who had unknown race). Among 217 patients with data at baseline and 24 months, 19 (8.8%) reported cost-related care nonadherence at baseline vs 20 (9.2%) at 24 months (P = .84), and 125 (57.6%) reported material hardship at baseline vs 76 (35.0%) at 24 months (P < .001). In multivariable analysis, lower financial worry (odds ratio [OR], 0.90; 95% CI, 0.87-0.93), higher education (OR, 0.34; 95% CI, 0.15-0.77), and older age (OR, 0.94; 95% CI, 0.91-0.98) were associated with lower nonadherence. Receipt of chemotherapy was associated with higher material hardship (OR, 2.68; 95% CI, 1.15-6.29), while lower financial worry was associated with lower material hardship (OR, 0.83; 95% CI, 0.80-0.96). Over 24 months, female sex was associated with lower nonadherence (OR, 0.90; 95% CI, 0.85-0.96), while higher education was associated with higher nonadherence (OR, 1.09; 95% CI, 1.03-1.17). Being employed was associated with lower material hardship (OR, 0.85; 95% CI, 0.78-0.93), while receipt of care at safety-net hospitals was associated with higher hardship (OR, 1.09; 95% CI, 1.01-1.17). Conclusions and Relevance: In patients with early-stage colorectal cancer, material hardship was more common than cost-related cancer care nonadherence and decreased over time, while nonadherence remained unchanged. Early and longitudinal financial screening and referral to intervention are recommended to mitigate financial hardship.

Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment.

Patients who present with breast cancer bone metastasis only have limited palliative treatment strategies and efficacious drug treatments are needed. In breast cancer patient data, high levels of the RNA helicase DDX3 are associated with poor overall survival and bone metastasis. Consequently, our objective was to target DDX3 in a mouse breast cancer bone metastasis model using a small molecule inhibitor of DDX3, RK-33. Histologically confirmed live imaging indicated no bone metastases in the RK-33 treated cohort, as opposed to placebo-treated mice. We generated a cell line from a bone metastatic lesion in mouse and found that it along with a patient-derived bone metastasis cell line gained resistance to conventional chemotherapeutics but not to RK-33. Finally, differential levels of DDX3 were observed in breast cancer patient metastatic bone samples. Overall, this study indicates that DDX3 is a relevant clinical target in breast cancer bone metastasis and that RK-33 can be a safe and effective treatment for these patients.

Associations between maternal diet, family eating habits and preschool children's dietary patterns: insights from the UPBEAT trial.

BACKGROUND: Dietary behaviours in early life often track across the life course, influencing the development of adverse health outcomes such as obesity and cardiovascular disease. This study aimed to explore the between dietary patterns (DP) in preschool children and maternal DP and family eating habits. METHODS: We conducted a secondary analysis of 488 mother-child pairs from the UK pregnancy Better Eating and Activity Trial (UPBEAT) at 3-year follow-up. Previously published DP from mothers and children (derived from food-frequency questionnaires and exploratory factor analysis) were used. Mothers' DP were "Fruits-Vegetables", "African-Caribbean", "Processed and Snacks", and children's DP were "Prudent", "Processed-Snacking", and "African-Caribbean". Family meal environments were evaluated using a 5-point Likert scale. RESULTS: Linear regression models revealed that child's prudent pattern was positively associated with maternal Fruits-Vegetables (B = 0.18 (0.08, 0.27)), Snacks patterns (B = 0.10 (0.01, 0.18)), and eating the same foods during meals (B = 0.25 (0.07, 0.43)). Child's Processed-Snacking pattern was directly associated with maternal Processed (B = 0.22 (0.13, 0.30)) and Snacks (B = 0.27 (0.18, 0.36)) patterns, receiving food as reward (B = 0.22 (0.04, 0.39)) and watching TV during meals (B = 0.27 (0.09, 0.45)). Finally, the child African-Caribbean pattern was directly associated with that from the mother (B = 0.41 (0.33, 0.50)) and watching TV during meals (B = 0.15 (0.09, 0.30)), and inversely associated with maternal processed (B=-0.09 (-0.17, -0.02)) and snacking (B=-0.08 (-0.15, -0.04)) patterns. CONCLUSIONS: Unhealthy dietary patterns in childhood are directly linked to similar maternal patterns and family meal behaviours, such as television viewing and food rewards. These findings highlight targetable behaviours for public health interventions.

Inhibition of hepatic oxalate overproduction ameliorates metabolic dysfunction-associated steatohepatitis.

The incidence of metabolic dysfunction-associated steatohepatitis (MASH) is on the rise, and with limited pharmacological therapy available, identification of new metabolic targets is urgently needed. Oxalate is a terminal metabolite produced from glyoxylate by hepatic lactate dehydrogenase (LDHA). The liver-specific alanine-glyoxylate aminotransferase (AGXT) detoxifies glyoxylate, preventing oxalate accumulation. Here we show that AGXT is suppressed and LDHA is activated in livers from patients and mice with MASH, leading to oxalate overproduction. In turn, oxalate promotes steatosis in hepatocytes by inhibiting peroxisome proliferator-activated receptor-α (PPARα) transcription and fatty acid ß-oxidation and induces monocyte chemotaxis via C-C motif chemokine ligand 2. In male mice with diet-induced MASH, targeting oxalate overproduction through hepatocyte-specific AGXT overexpression or pharmacological inhibition of LDHA potently lowers steatohepatitis and fibrosis by inducing PPARα-driven fatty acid ß-oxidation and suppressing monocyte chemotaxis, nuclear factor-κB and transforming growth factor-ß targets. These findings highlight hepatic oxalate overproduction as a target for the treatment of MASH.

Anti-cancer activity of capsaicin and its analogs in gynecological cancers.

Capsaicin is the hot and pungent ingredient of chili peppers. It is a potent pain-relieving agent and is often present in over-the-counter analgesic lotions and creams. Several convergent studies reveal that capsaicin displays growth-suppressive activity in human cancers in vitro and in vivo. Apart from its growth-suppressive activity (as a single agent), capsaicin has been found to sensitize human cancer cells to the pro-apoptotic effects of chemotherapy and radiation. The first part of this book chapter discusses the anti-cancer activity of capsaicin in gynecological cancers in cell culture experiments and mouse models. Out of all gynecological cancers, the anti-cancer activity of capsaicin (and its analogs) has only been investigated in cervical cancers and ovarian cancers. The clinical development of capsaicin as a viable anti-cancer drug has remained challenging due to its poor bioavailability and aqueous solubility properties. In addition, the administration of capsaicin is associated with adverse side effects like gastrointestinal cramps, stomach pain, irritation in the gut, nausea diarrhea and vomiting. Two strategies have been investigated to overcome these drawbacks of capsaicin. The first is to encapsulate capsaicin in sustained release drug delivery systems. The second strategy is to design non-pungent capsaicin analogs which will retain the anti-tumor activity of capsaicin. The second part of this chapter provides an overview of the anti-neoplastic (and chemosensitization activity) of capsaicin analogs and capsaicin-based sustained release formulations in cervical and ovarian cancers. The design of selective non-pungent capsaicin analogs and capsaicin-based polymeric drug delivery systems may foster the hope of novel strategies for the treatment and management of gynecological cancers.

Phase 1b/2a Study Assessing the Safety and Efficacy of Felzartamab in Anti-Phospholipase A2 Receptor Autoantibody-Positive Primary Membranous Nephropathy.

Introduction: Primary membranous nephropathy (PMN) is most often caused by autoantibodies to phospholipase A2 receptor (PLA2R). M-PLACE (NCT04145440) is an open-label, phase 1b/2a study that assessed the safety and efficacy of the fully human anti-CD38 monoclonal antibody felzartamab in high-risk anti-PLA2R+ PMN. Methods: Patients with newly diagnosed or relapsed PMN (cohort 1 [C1]; n = 18) or PMN refractory to immunosuppressive therapy (IST) (cohort 2 [C2]; n = 13) received 9 infusions of felzartamab 16 mg/kg in the 24-week treatment period, followed by a 28-week follow-up. The primary end point was the incidence and severity of treatment-emergent adverse events (TEAEs). Results: A total of 31 patients were enrolled and received felzartamab. Twenty-seven patients (87.1%) had TEAEs, including infusion-related reactions (IRRs) (29.0%), hypogammaglobulinemia (25.8%), peripheral edema (19.4%), and nausea (16.1%). Five patients (16.1%) had serious TEAEs that all resolved. Immunologic response (anti-PLA2R titer reduction ≥50%) was achieved by 20 of 26 efficacy-evaluable patients (76.9%) (C1, 13/15 [86.7%]; C2, 7/11 [63.6%]). Anti-PLA2R titer reductions were rapid (week 1 response, 44.0%; response 7 months after last felzartamab dose [end of study, EOS], 53.8%). Partial proteinuria remission (urine protein-to-creatinine ratio [UPCR] reduction ≥50%, UPCR <3.0 g/g, and stable estimated glomerular filtration rate [eGFR]) was achieved by 9 of 26 patients (34.6%) (C1, 7/15 [46.7%]; C2, 2/11 [18.2%]) before or at EOS (median follow-up, 366 days). Serum albumin increased from baseline to EOS in 20 of 26 patients (76.9%) (C1, 12/15 [80.0%]; C2, 8/11 [72.7%]). Conclusion: In this population with high-risk anti-PLA2R+ PMN, felzartamab was tolerated and resulted in rapid partial and complete immunologic responses and partial improvements in proteinuria and serum albumin in some patients.

International expert consensus statement: surgical failure in obstructive sleep apnea.

PURPOSE: Upper airway (UA) surgery is commonly employed in the treatment of patients with obstructive sleep apnea (OSA). The intricate pathophysiology of OSA, variability in sites and patterns of UA collapse, and the interaction between anatomical and non-anatomical factors in individual patients may contribute to possible surgical failures. This clinical consensus statement aims to identify areas of agreement among a development group comprising international experts in OSA surgery, regarding the appropriate definition, predictive factors in patients, and management of surgical failure in OSA treatment. METHODS: A clinical consensus statement (CCS) was developed using the Delphi method by a panel of 35 contributors from various countries. A systematic literature review adhering to PRISMA guidelines was conducted. A survey consisting of 60 statements was then formulated and presented to the experts. RESULTS: Following two rounds of the Delphi process, consensus or strong consensus was achieved on 36 items, while 24 items remained without consensus. Specifically, 5 out of 10 statements reached consensus regarding on the 'Definition of Surgical Success/Failure after OSA Surgery'. Regarding the 'Predictive Factors of Surgical Failure in OSA Surgery', consensus was reached on 10 out of 13 statements. In the context of the 'Diagnostic Workup in OSA Surgery', consensus was achieved on 9 out of 13 statements. Lastly, in 'Treatment in Surgical Failure Cases', consensus was reached on 12 out of 24 statements. CONCLUSION: The management of OSA after surgical failure presents a significant clinical challenge for sleep specialists. This CCS provides valuable guidance for defining, preventing, and addressing surgical failures in the treatment of OSA syndrome.