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Although bicuspid aortic valve (BAV) is one of the most common congenital heart diseases, clinical data associated with valve dysfunction are still limited. We evaluated clinical characteristics and echocardiography of French patients with BAV associated with leaking and stenosis degeneration. We initiated a prospective registry from 2014 to 2018 at a tertiary center. A total of 223 patients (168 males [75%], age 53 ± 17 years) were enrolled. Among these patients 83% had left–right coronary cusps fusion, 80% Sievers type 1 BAV and 49% showed aortic dilatation. Twenty-four patients (11%) had normal valve function, 66 patients (31%) had aortic stenosis (AS), 91 patients (41%) had aortic regurgitation (AR) and 40 patients (17%) had AR and AS. BAV phenotype did not predict neither AS nor AR (all p > 0.1). By multivariable analysis, age > 50 (41.6[10.3–248.2], p < 0.001) and presence of raphe/fusion (12.8[2.4–87.4], p < 0.001) were significantly associated with AS, whereas male gender was associated with AR (5[1.6–16.4], p = 0.005). In addition, leaking degeneration was observed at a much younger age than stenosis (44 ± 14 years vs. 66 ± 10 years, p < 0.01) and among patients with valve dysfunction younger age was independently associated with AR (1.9[1.85–1.94], p < 0.001). In this study we confirmed high prevalence of valve dysfunction at first diagnosis of BAV in a referred population. The degenerative process differs according to type of dysfunction and is mainly dependent on age and gender.

Monitoring rumination activity is considered a useful indicator for the early detection of diseases and metabolic disorders. Accelerometer-based sensor systems provide health alerts based on individual thresholds of rumination times in dairy cows. Detailed knowledge of the relationship between sensor-based rumination times and rumen physiology would help detect conspicuous animals and evaluate the treatment’s success. This study aimed to investigate the association between sensor-based health alerts and rumen fluid characteristics in Holstein-Friesian cows at different stages of lactation. Rumen fluid was collected via a stomach tube from 63 pairs of cows with and without health alerts (ALRT vs NALRT). Pairs were matched based on the day of lactation, the number of lactations, and health criteria. Rumen fluid was collected during and after health alerts. The parameters of color, odor, consistency, pH, redox potential, sedimentation flotation time, and the number of protozoa were examined. Results showed differences between both groups in odor, rumen pH, sedimentation flotation time, and protozoan count at the first rumen fluid collection. Within the groups, greater variations in rumen fluid parameters were found for ALRT cows compared to NALRT cows. The interaction between health alert and stage of lactation did not affect the rumen fluid parameters.

Establishing fresh cow monitoring procedures is considered beneficial for cow health, welfare, and productivity. However, they are time consuming and require the cows to be locked up, which restricts their natural behavior. In this study, different fresh cow monitoring procedures were evaluated. Two experiments were conducted to determine: (1) the duration of various examinations and treatments; (2) the time cows remain locked up in headlocks; and (3) the proportion of examination and treatment times relative to the total headlock time. In advance, standard operating procedures were established. Three veterinarians conducted the examinations and treatments based on changes in milk yield, clinical symptoms, and alarms by an accelerometer system. The headlock time was evaluated for three workflow strategies, which differed in the order of examinations and treatments. To determine the duration, cameras were installed, and the video footage was analyzed. The examinations lasted between 1 and 227 s, and the cows were locked up in headlocks between 0.01 and 1.76 h. The lock-up times differed significantly among the three strategies, as well as the proportion. This study provides information that can be used as a basis for the development of time-efficient strategies, and to minimize the impact on cows’ time budgets.

ABSTRACT BACKGROUND to describe spectrum of valve function in bicuspid aortic valve (BAV) patients referred to a tertiary care center and to investigate genetic pathways associated with valve degeneration. METHODS All consecutive patients with BAV were prospectively included from 2014 to 2018. BAV was defined according to embryologic and Sievers classifications. Clinical and echo variables were compared according to aortic valve function. Aortic valve tissues were collected from BAV patients (n=15) operated for severe aortic stenosis (AS-BAV, n=7) or aortic regurgitation (AR-BAV, n=8). RT-qPCR was performed to compare gene expression level in AS-BAV, AR-BAV and controls corresponding to healthy tricuspid aortic valves collected on human heart explant immediately after transplantation (n=5). RESULTS Out of 223 adults with BAV, mean age 53±17 years, 83% had left-right coronary cusps fusion, 80% Sievers type 1 BAV and 49% aortopathy. Twenty-four patients had normal valve function, 66 patients had AS-BAV, 91 patients had AR-BAV and 40 patient had AR+AS BAV. BAV phenotype did not predict neither AS-BAV nor AR-BAV (all p>0.1). By multivariable analysis, age >50 (41.6[10.3-248.2],p<0.001) and presence of raphe(12.8[2.4-87.4],p<0.001) were significantly associated with AS-BAV and male gender of AR-BAV(5[1.6-16.4], p=0.005). RT-qPCR revealed overexpression of RUNX2 in AS-BAV (17.67±1.83 vs 3.25±0.93, p=0.04), and overexpression of COL1A1 (4.01±0.6vs2.25±0.5,p=0.03) and FLNA (23.31±7.5vs1.97±0.3,p=0.03) in AR-BAV. CONCLUSIONS This prospective study confirmed high prevalence of valve dysfunction at first diagnosis of BAV in a referred population. Clinical and echo variables are poorly associated with BAV dysfunction. The leaking or stenotic processes could be both supported by dysregulation of specific genetic pathways

SEPN1-related myopathy (SEPN1-RM) is a muscle disorder due to mutations of the SEPN1 gene, which is characterized by muscle weakness and fatigue leading to scoliosis and life-threatening respiratory failure. Core lesions, focal areas of mitochondria depletion in skeletal muscle fibers, are the most common histopathological lesion. SEPN1-RM underlying mechanisms and the precise role of SEPN1 in muscle remained incompletely understood, hindering the development of biomarkers and therapies for this untreatable disease. To investigate the pathophysiological pathways in SEPN1-RM, we performed metabolic studies, calcium and ATP measurements, super-resolution and electron microscopy on in vivo and in vitro models of SEPN1 deficiency as well as muscle biopsies from SEPN1-RM patients. Mouse models of SEPN1 deficiency showed marked alterations in mitochondrial physiology and energy metabolism, suggesting that SEPN1 controls mitochondrial bioenergetics. Moreover, we found that SEPN1 was enriched at the mitochondria-associated membranes (MAM), and was needed for calcium transients between ER and mitochondria, as well as for the integrity of ER-mitochondria contacts. Consistently, loss of SEPN1 in patients was associated with alterations in body composition which correlated with the severity of muscle weakness, and with impaired ER-mitochondria contacts and low ATP levels. Our results indicate a role of SEPN1 as a novel MAM protein involved in mitochondrial bioenergetics. They also identify a systemic bioenergetic component in SEPN1-RM and establish mitochondria as a novel therapeutic target. This role of SEPN1 contributes to explain the fatigue and core lesions in skeletal muscle as well as the body composition abnormalities identified as part of the SEPN1-RM phenotype. Finally, these results point out to an unrecognized interplay between mitochondrial bioenergetics and ER homeostasis in skeletal muscle. They could therefore pave the way to the identification of biomarkers and therapeutic drugs for SEPN1-RM and for other disorders in which muscle ER-mitochondria cross-talk are impaired.

Background In 2020, 14% of diagnosed persons living with HIV (PLWH) in Kenya were not taking antiretroviral therapy (ART), and 19% of those on ART had unsuppressed viral loads. Long-acting antiretroviral therapy (LA-ART) may increase viral suppression by promoting ART uptake and adherence. We conducted key informant (KI) interviews with HIV experts in Kenya to identify product and delivery attributes related to the acceptability and feasibility of providing LA-ART to PLWH in Kenya. Methods Interviews were conducted via Zoom on potential LA-ART options including intra-muscular (IM) injections, subcutaneous (SC) injections, implants, and LA oral pills. KI were asked to discuss the products they were most and least excited about, as well as barriers and facilitators to LA-ART roll-out. In addition, they were asked about potential delivery locations for LA-ART products such as homes, pharmacies, and clinics. Interviews were recorded and transcribed, and data were analyzed using a combination of inductive and deductive coding. Results Twelve KI (5 women, 7 men) participated between December 2021 and February 2022. Overall, participants reported that LA-ART would be acceptable and preferable to PLWH because of fatigue with daily oral pills. They viewed IM injections and LA oral pills as the most exciting options to ease pill burden and improve adherence. KI felt that populations who could benefit most were adolescents in boarding schools and stigmatized populations such as sex workers. SC injections and implants were less favored, as they would require new training initiatives for patients or healthcare workers on administration. In addition, SC injections would require refrigeration and needle disposal after use. Some KI thought patients, especially men, might worry that IM injections and implants would impact fertility, given their role in family planning. Pharmacies were perceived by most KI as suboptimal delivery locations; however, given ongoing work in Kenya to include pharmacies in antiretroviral delivery, they recommended asking patients their views. Conclusion There is interest and support for LA-ART in Kenya, especially IM injections and LA oral pills. Identifying patient preferences for modes and delivery locations and addressing misconceptions about specific products as they become available will be important before wide-scale implementation.

Background For people with HIV (PWH), long-acting antiretroviral therapies (LA-ART) are promising treatment alternatives to daily oral regimens, with potential to improve adherence and achieve viral suppression. Understanding patient preferences is crucial for successful and efficient implementation and scaling of LA-ART in resource-limited settings such as Kenya. We conducted a discrete choice experiment (DCE) to elicit preferences for LA-ART attributes among PWH in Kenya. Methods We recruited 700 PWH taking daily oral ART from Kenyatta National Hospital and two Sex Workers Outreach Program clinics in Nairobi. In 17 choice scenarios, participants chose between their current daily oral regimen and two hypothetical LA-ART alternatives defined by seven attributes: delivery mode (long-acting oral, subcutaneous or intramuscular injection, implant), administration location (clinic, chemist, home), frequency (weekly, every 1, 2, 3, 6, or 12 months), delivery-site pain (none, mild, moderate), pre-treatment viral suppression (required, not required), pre-treatment negative reaction testing (required, not required), and late-dose leeway (short, long). We used conditional logistic regressions with interactions between mode and pain to determine the relative importance in participants’ choices across attributes. Results Participants had a median age of 36 years (interquartile range [IQR]: 28–46); 64% were female, 83% were virally suppressed, 51% were from key populations (e.g., sex workers or men who have sex with men), and median time on ART was 9 years (IQR: 5–15). Participants generally preferred the hypothetical LA-ART options over their current daily oral ART, and the interaction of delivery mode and pain was the most important attribute combination. Oral LA-ART was the most preferred mode; 1-year implants with mild pain was the next preferred option. Participants favored administration at clinics to chemists or home and preferred less frequent dosing. Conclusions LA-ART would be highly acceptable in Kenya, with oral LA-ART and administration at clinics as the preferred formulation and location. Our findings provide valuable evidence to guide the development of novel LA-ART products. Future research should evaluate preference heterogeneity and investigate ways to effectively scale LA-ART in Kenya and similar settings, while taking into account patient preferences. Clinical trial number Not applicable.

The postpartum period can be challenging for women living with HIV. Understanding how the postpartum period impacts ART adherence and condomless sex could inform the development of comprehensive sexual and reproductive health and HIV services tailored to the needs of women living with HIV during this critical interval. In a longitudinal cohort study of HIV-seropositive Kenyan women, late ART refills and self-reported condomless sex were compared between the woman's pregnancy and the postpartum period. Analyses were conducted using generalized estimating equations and adjusted for alcohol use, depressive symptoms, intimate partner violence (IPV), and having a recent regular partner. Effect modification was explored for selected variables. 151 women contributed visits. Late ART refills occurred at 7% (32/439) of pregnancy visits compared to 18% (178/1016) during the postpartum period (adjusted relative risk [aRR] 2.44, 95% confidence interval [CI] 1.62-3.67). This association differed by women's education level. Women with ≥8 years of education had late ART refills more during the postpartum period than pregnancy (aRR 3.00, 95%CI 1.95-4.62). In contrast, in women with <8 years of education, late ART refills occurred similarly during pregnancy and the postpartum period (aRR 0.88, 95%CI 0.18-4.35). Women reported condomless sex at 10% (60/600) of pregnancy visits compared to 7% (72/1081) of postpartum visits (aRR 0.76, 95%CI 0.45-1.27). This association differed by whether women had experienced recent IPV. Women without recent IPV had a significant decline in condomless sex from pregnancy to postpartum (aRR 0.53, 95%CI 0.30-0.95) while women with recent IPV had no significant change in condomless sex from pregnancy to postpartum (aRR 1.76, 95%CI 0.87-3.55). Improved support for ART adherence during the postpartum period and addressing IPV to limit condomless sex could improve HIV treatment and prevention outcomes for HIV-seropositive women as well as their infants and sexual partners.

Baicalin is a biologically active flavone glucuronide with poor water solubility that can be enhanced via glucosylation. In this study, the transglucosylation of baicalin was successfully achieved with CGTases from Thermoanaerobacter sp. and Bacillus macerans using α-cyclodextrin as a glucosyl donor. The synthesis of baicalin glucosides was optimized with CGTase from Thermoanaerobacter sp. Enzymatically modified baicalin derivatives were α-glucosylated with 1 to 17 glucose moieties. The two main glucosides were identified as Baicalein-7-O-α-D-Glucuronidyl-(1→4′)-O-α-D-Glucopyranoside (BG1) and Baicalein-7-O-α-D-Glucuronidyl-(1→4′)-O-α-D-Maltoside (BG2), thereby confirming recent findings reporting that glucuronyl groups are acceptors of this CGTase. Optimized conditions allowed for the attainment of yields above 85% (with a total glucoside content higher than 30 mM). BG1 and BG2 were purified via centrifugal partition chromatography after an enrichment through deglucosylation with amyloglucosidase. Transglucosylation increased the water solubility of BG1 by a factor of 188 in comparison to that of baicalin (molar concentrations), while the same value for BG2 was increased by a factor of 320. Finally, BG1 and BG2 were evaluated using antioxidant and anti-glycation assays. Both glucosides presented antioxidant and anti-glycation properties in the same order of magnitude as that of baicalin, thereby indicating their potential biological activity.

Prostate cancer is characterized by considerable geo-ethnic disparity. African ancestry is a significant risk factor, with mortality rates across sub-Saharan Africa of 2.7-fold higher than global averages 1 . The contributing genetic and non-genetic factors, and associated mutational processes, are unknown 2 , 3 . Here, through whole-genome sequencing of treatment-naive prostate cancer samples from 183 ancestrally (African versus European) and globally distinct patients, we generate a large cancer genomics resource for sub-Saharan Africa, identifying around 2 million somatic variants. Significant African-ancestry-specific findings include an elevated tumour mutational burden, increased percentage of genome alteration, a greater number of predicted damaging mutations and a higher total of mutational signatures, and the driver genes  NCOA2 , STK19 , DDX11L1 , PCAT1  and  SETBP1 . Examining all somatic mutational types, we describe a molecular taxonomy for prostate cancer differentiated by ancestry and defined as global mutational subtypes (GMS). By further including Chinese Asian data, we confirm that GMS-B (copy-number gain) and GMS-D (mutationally noisy) are specific to African populations, GMS-A (mutationally quiet) is universal (all ethnicities) and the African–European-restricted subtype GMS-C (copy-number losses) predicts poor clinical outcomes. In addition to the clinical benefit of including individuals of African ancestry, our GMS subtypes reveal different evolutionary trajectories and mutational processes suggesting that both common genetic and environmental factors contribute to the disparity between ethnicities. Analogous to gene–environment interaction—defined here as a different effect of an environmental surrounding in people with different ancestries or vice versa—we anticipate that GMS subtypes act as a proxy for intrinsic and extrinsic mutational processes in cancers, promoting global inclusion in landmark studies. A molecular taxonomy for prostate cancer reveals a subtype associated with copy-number loss found in African and European populations that predicts poor outcomes and two subtypes—one associated with high mutational noise and one with copy-number gain—specific to African populations.