Body Mass Index and Hypertension as Mediators of the Association Between Age at Menarche and Subclinical Atherosclerosis: A Sex-Specific Mendelian Randomization Analysis.

BACKGROUND: Early age at menarche (AAM) has been associated with a higher risk of carotid artery intima-media thickness (cIMT), an indicator of subclinical vascular disease, albeit the mechanisms underlying this association remain elusive. A better understanding of the relationship between AAM, modifiable cardiometabolic risk factors, and subclinical atherosclerosis may contribute to improved primary prevention and cardiovascular disease treatment. We aimed to investigate the putative causal role of AAM on cIMT, and to identify and quantify the potentially mediatory effects of cardiometabolic risk factors underlying this relationship. METHODS AND RESULTS: We conducted linkage disequilibrium score regression analyses between our exposure of interest, AAM, our outcome of interest, cIMT and potential mediators of the AAM-cIMT association to gauge cross-trait genetic overlap. We considered as mediators the modifiable anthropometric risk factors body mass index (BMI), systolic blood pressure (SBP), lipid traits (total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and glycemic traits (fasting glucose). We then leveraged the paradigm of Mendelian randomization to infer causality between AAM and cIMT, and to identify whether cardiometabolic risk factors served as potential mediators of this effect. Our analyses showed that genetically predicted AAM was inversely associated with cIMT, BMI, SBP, and triglycerides, and positively associated with high-density lipoprotein, low-density lipoprotein, and total cholesterol. We showed that the effect of genetically predicted AAM on cIMT may be partially mediated through BMI (20.1% [95% CI, 1.4% to 38.9%]) and SBP (13.5% [95% CI, 0.5%-26.6%]). Our cluster-specific Mendelian randomization revealed heterogeneous causal effect estimates of age at menarche on BMI and SBP. CONCLUSIONS: We highlight supporting evidence for a potential causal association between earlier AAM and cIMT, and almost one third of the effect of AAM on cIMT may be mediated by BMI and SBP. Early intervention aimed at lowering BMI and hypertension may be beneficial in reducing the risk of developing subclinical atherosclerosis due to earlier age at menarche.

The Polyamine Analogue Ivospemin Increases Chemotherapeutic Efficacy in Murine Ovarian Cancer.

Polyamines are small polycationic alkylamines that are absolutely required for the continual growth and proliferation of cancer cells. The polyamine analogue ivospemin, also known as SBP-101, has shown efficacy in slowing pancreatic and ovarian tumor progression in vitro and in vivo and has demonstrated encouraging results in early pancreatic cancer clinical trials. We sought to determine if ivospemin was a viable treatment option for the under-served platinum-resistant ovarian cancer patient population by testing its efficacy in combination with commonly used chemotherapeutics. We treated four ovarian adenocarcinoma cell lines in vitro and found that each was sensitive to ivospemin regardless of cisplatin sensitivity. Next, we treated patients with ivospemin in combination with four commonly used chemotherapeutics and found that ivospemin increased the toxicity of each; however, only gemcitabine and topotecan combination treatments were more effective than ivospemin alone. Using the VDID8+ murine ovarian cancer model, we found that the addition of ivospemin to either topotecan or gemcitabine increased median survival over untreated animals alone, delayed tumor progression, and decreased the overall tumor burden. Our results indicate that the combination of ivospemin and chemotherapy is a worthwhile treatment option to further explore clinically in ovarian cancer.

The Benefits and Challenges of Providing School Meals during the First Year of California's Universal School Meal Policy as Reported by School Foodservice Professionals.

States in the U.S. are newly implementing universal school meal (USM) policies, yet little is known about the facilitators of their success and the challenges they confront. This study evaluated the challenges and facilitators faced by school food authorities (SFAs) implementing California's universal school meal (USM) policy during its inaugural year (2022-2023) using an online survey. In March 2023, 430 SFAs reported many benefits, including increased meal participation (64.2% of SFAs) and revenues (65.7%), reduced meal debt (41.8%) and stigma (30.9%), and improved meal quality (44.3%) and staff salaries (36.9%). Reported challenges include product/ingredient availability (80.9%), staffing shortages (77.0%), vendor/distributor logistics issues (75.9%), and administrative burden (74.9%). Top facilitators included state funding (78.2%) and increased federal reimbursement (77.2%). SFAs with fewer students eligible for free or reduced-price meals (as opposed to SFAs with more) reported greater increases in meal participation and reductions in stigma but also more administrative burdens. Larger SFAs reported greater increases in revenues, staff salaries, and improvements in meal quality than smaller SFAs but also more challenges. Overall, California's USM policy has enhanced student access to healthy meals while mitigating social and financial barriers. Understanding California's experience can inform other jurisdictions considering or implementing similar policies.

Transcriptomic profiling and gene network analysis revealed regulatory mechanisms of bract development in Bougainvillea glabra.

BACKGROUND: Bracts are important for ornamental plants, and their developmental regulation process is complex; however, relatively little research has been conducted on bracts. In this study, physiological, biochemical and morphological changes in Bougainvillea glabra leaves, leaf buds and bracts during seven developmental periods were systematically investigated. Moreover, transcriptomic data of B. glabra bracts were obtained using PacBio and Illumina sequencing technologies, and key genes regulating their development were screened. RESULTS: Scanning electron microscopy revealed that the bracts develop via a process involving regression of hairs and a color change from green to white. Transcriptome sequencing revealed 79,130,973 bp of transcript sequences and 45,788 transcripts. Differential gene expression analysis revealed 50 expression patterns across seven developmental periods, with significant variability in transcription factors such as BgAP1, BgFULL, BgCMB1, BgSPL16, BgSPL8, BgDEFA, BgEIL1, and BgBH305. KEGG and GO analyses of growth and development showed the involvement of chlorophyll metabolism and hormone-related metabolic pathways. The chlorophyll metabolism genes included BgPORA, BgSGR, BgPPH, BgPAO and BgRCCR. The growth hormone and abscisic acid signaling pathways involved 44 and 23 homologous genes, and coexpression network analyses revealed that the screened genes BgAPRR5 and BgEXLA1 are involved in the regulation of bract development. CONCLUSIONS: These findings improve the understanding of the molecular mechanism of plant bract development and provide important guidance for the molecular regulation and genetic improvement of the growth and development of ornamental plants, mainly ornamental bracts.

Molecular genotyping of Babesia caballi.

Babesia caballi is an intra-erythrocytic parasite causing equine piroplasmosis. Three B. caballi genotypes (A, B, and C) have been identified based on the 18 S rRNA and rhoptry-associated protein (rap-1) gene sequences. These variant parasite genotypes compromise the diagnostic utility of the WOAH-recommended serological assays in declaring horses free of equine piroplasmosis. Although a gene encoding a spherical body protein 4 (sbp4) has recently been identified as a potential antigen for the serological detection of B. caballi, the ability of this antigen to detect the different geographical strains has not been determined. The molecular distinction between variant B. caballi genotypes is limited and therefore we developed molecular typing assays for the rapid detection and quantification of distinct parasite genotypes. Field samples were screened for the presence of B. caballi using an established multiplex equine piroplasmosis qPCR assay. In this study, B. caballi genotype A was not detected in any field samples screened. However, phylogenetic analysis of the amplified sbp4 and 18 S rRNA genes confirmed the phylogenetic groupings of the South African isolates into either B. caballi genotypes B or C. A multiple sequence alignment of the sbp4 gene sequences obtained in this study together with the published sbp4 sequences representing B. caballi genotype A, were used to identify conserved regions within the gene to design three primer pairs and three genotype-specific TaqMan minor-groove binder (MGB™) probes. The qPCR assays were shown to be specific and efficient in the detection and differentiation between B. caballi genotypes A, B, and C and could be used as a diagnostic assay to prevent the unintentional spread of variant B. caballi genotypes globally.

Determinants of Orthostatic Hypotension in Type 2 Diabetes: Is Cardiac Autonomic Neuropathy the Main Factor?

OBJECTIVES: To evaluate the determinants of orthostatic hypotension (OH) in type 2 diabetes (T2D) and the usefulness of Δheart rate (HR)/Δsystolic blood pressure (SBP), index of cardiac baroreflex function, in identifying neurogenic OH. METHODS: In 208 participants with T2D, we diagnosed early cardiovascular autonomic neuropathy (CAN) and confirmed CAN according to 1 and 2 HR-based cardiovascular reflex tests (HR-CARTs). Through OH test we defined OH as SBP falls of ≥20 and ≥30 mm Hg with supine SBPs of <140 and ≥140 mm Hg, respectively. In participants with OH, we used the lying-to-standing and OH test and its diagnostic accuracy for neurogenic OH (as OH plus confirmed HR-CAN). RESULTS: OH was present in 25 participants and associated with lower HR-CART scores, higher glycosylated hemoglobin level, the presence of CAN, retinopathy, and peripheral vascular disease, the absence of hypertension, and physical activity (all, P < .05) but not with interfering drugs and ß-blockers. In a multiple logistic regression, HR-CAN was the main determinant of OH (odds ratio, 4.74) with physical activity and hypertension (odds ratios, 0.16 and 0.23; R2 = 0.22). ΔHR/ΔSBP had a good diagnostic accuracy for neurogenic OH (area under the receiver operating characteristic curve, 0.816 ± 0.087) and, at the cutoff of 0.5 bpm/mm Hg, a sensitivity of 100% and specificity of 63.2%. CONCLUSION: CAN remains the primary determinant of OH in T2D but does not explain all its variance. The index ΔHR/ΔSBP may represent a useful clinical tool to identify neurogenic OH.

Parent perceptions of school meals and how perceptions differ by race and ethnicity.

Parental perceptions of school meals can affect student participation and overall support for school meal policies. Little is known about parental school meal perceptions under universal free school meals (UFSM) policies. We assessed California parents' perceptions of school meals during the COVID-19 emergency response with federally funded UFSM and whether perceptions differed by race/ethnicity. Among 1110 California parents of K-12 students, most reported school meals benefit their families, saving them money (81.6%), time (79.2%), and stress (75.0%). Few reported that their child would be embarrassed to eat school meals (11.7%), but more parents of White students than Hispanic students reported this. Many parents reported that their child likes to eat lunch to be with friends (64.7%); about half felt their child has enough time to eat (54.2%). Fewer parents perceived school lunches to be of good quality (36.9%), tasty (39.6%), or healthy (44.0%). Parents of Hispanic and Asian students had less favorable perceptions of school meal quality, taste, and healthfulness than parents of White students. Parents report that school meals benefit their families, but policy efforts are needed to ensure schools have the resources needed to address cultural appropriateness. Schools should address parental perceptions of meals to optimize participation, nutrition security, and health.

Bacterial profile, drug resistance pattern, clinical and laboratory predictors of ascites infection in cirrhosis patients.

Ascites is a pathological collection of free fluid in the peritoneal cavity, which is a common complication in patients with cirrhosis, an advanced liver disease. Bacterial infection increases the mortality rate of hospitalized patients with cirrhosis, irrespective of the severity of the liver disease. Around 60% of patients with compensated cirrhosis developed ascites within 10 years during the course of their disease. The in-hospital mortality rate due to spontaneous bacterial peritonitis (SBP) could exceed 90%, but with early diagnosis and prompt antibiotic therapy, this rate has been shown to decrease to 20%. Here, we enrolled adult (age ≥ 18) patients with liver disease with evidence of cirrhosis who developed ascites and assessed the presence of spontaneous ascites fluid infection (SAFI) in these patients. Of the total 218 patients, 22.9% (50/218) develop ascites infection. The liver organ function tests like alanine aminotransferase, aspartate aminotransferase, total bilirubin, and direct bilirubin were found to be significantly (P < 0.05) higher in patients with ascites fluid infection compared to patients with non-ascites fluid infection. Of the gram-negative bacteria, K. pneumonia and E. coli were isolated and found to be 100% resistant to amoxicillin and clavulanate. From the gram-positive bacterial isolates, S. aureus was only resistant to penicillin, whereas Str. viridans was resistant to ceftriaxone, cefotaxime, cefepime, and penicillin. On the other hand, clinical features such as a history of jaundice, low arterial blood pressure, and ultrasound results such as a shrunken liver and enlarged spleen were also independent predictors of spontaneous bacterial peritonitis. In conclusion, given the high probability of death following SAFI, early detection, and treatment, as well as knowledge of the microbial agent, resistance profile, and predictive markers in various contexts, are essential for the timely diagnosis and management of SAFI in these patients.

Psychometric evaluation of a novel tool for assessing gestational diabetes and hypertension care: knowledge, attitudes, and practices of midwives and nurses.

While standardized assessment of knowledge, attitudes, and practices (KAP) related to gestational diabetes and hypertension is possible with a valid tool, existing research remains limited. This prospective validation study aimed to develop and validate a novel tool to assess the KAP of midwives and obstetric nurses. We included 125 midwives and obstetric nurses who routinely care for patients with gestational diabetes and hypertension. The tool demonstrated good internal consistency (Cronbach's alpha): knowledge (0.729, 95% CI, 0.654-0.776), attitude (0.756, 95% CI, 0.690-0.814), and practices (0.925, 95% CI, 0.905-0.943). Difficulty indices (d) ranged from 0.38 to 0.99 (knowledge), 0.41 to 0.99 (attitudes), and 0.41 to 0.93 (practices), indicating appropriate item difficulty. Discrimination indices (D) confirmed items could differentiate between respondents with low and high knowledge levels (D range: 0.02-0.77 for knowledge, 0.06-0.64 for attitudes, 0.20-0.84 for practices). The robust psychometric properties of this tool support its use in future research on KAP related to diabetes and gestational hypertension management in midwives and nurses. This instrument has the potential to be valuable in various settings, including baseline assessment before educational programs or evaluation of learning outcomes after interventions.

Comparison of Rifaximin Alone and With Quinolones in the Primary Prevention of Spontaneous Bacterial Peritonitis in Patients With Decompensated Chronic Liver Disease.

Background In cirrhotic patients with ascites, primary prevention of spontaneous bacterial peritonitis (SBP) is a key strategy to lower morbidity and death. Rifaximin and fluoroquinolone used alternately as main prophylaxis are as effective as reported. This study aimed to compare the frequency of occurrence of SBP in patients with decompensated chronic liver disease treated with rifaximin alone and in combination with fluoroquinolone. Methodology A total of 76 patients with hepatitis C virus-related decompensated chronic liver disease and ascites were divided into two groups based on matching age, sex, and Child-Pugh class. Group A (38 patients) received rifaximin 1,100 mg/day in two divided doses with daily fluoroquinolone 400 mg/day, whereas group B (38 patients) received rifaximin 1,100 mg/day alone as a two dosage. The patients were monitored for up to three months. The study's endpoints were SBP, hepatocellular carcinoma, compliance failure, death, or liver transplantation. Results In this comparative study involving 76 patients, the demographic and clinical characteristics were assessed across two treatment groups: rifaximin alone (n = 38) and rifaximin with fluoroquinolone (n = 38). The combination therapy demonstrated a statistically significant reduction in SBP compared to rifaximin alone. Additionally, the overall survival rate was higher in the combination group. These findings suggest potential benefits of the combined approach in managing hepatic encephalopathy-related complications. Conclusions When compared to rifaximin alone for primary SBP prophylaxis, the combination of rifaximin with fluoroquinolone exhibited greater effectiveness with the same safety profile.

Association of Pre-PCI Blood Pressure and No-Reflow in Patients with Acute ST-Elevation Coronary Infarction.

Background: Previous studies have established blood pressure (BP) as a pivotal factor influencing no-reflow following primary percutaneous coronary intervention (PCI) in patients with ST-elevation acute coronary infarction (STEMI). However, no relevant study has been conducted to investigate the optimal range of BP associated with the lowest risk of no-reflow among STEMI patients so far. Therefore, our objective was to evaluate the association between pre-PCI BP and the occurrence of no-reflow in patients with STEMI. Method: We included 1025 STEMI patients undergoing primary PCI. The BP pre-PCI was categorized into 20-mmHg increments. Logistic models were employed to assess the association of no-reflow with systolic blood pressure (SBP) or diastolic blood pressure (DBP). Three sensitivity analyses were conducted to further confirm the robustness of the association between blood pressure and no-reflow. Results: SBP or DBP exhibited a U-shaped curve association with no-reflow. No-reflow was higher in patients with lower SBP (<100 mmHg) (adjusted hazard ratio (OR) 3.64, 95% confidence interval (CI) 1.84,7.21; p < 0.001) and lower DBP (<60 mmHg) (OR 3.28, 95% CI 1.63,6.49; p < 0.001) [reference: 120 ≤SBP <140; 80 ≤DBP <100 mmHg], respectively. Furthermore, no-reflow was higher in patients with higher SBP (≥160 mmHg) (OR 2.07, 95% CI 1.27,3.36; p = 0.003) and DBP (≥100 mmHg) (OR 3.36, 95% CI 2.07,5.46; p < 0.001), respectively. The results of sensitivity analyses were consistent with the above findings. Conclusion: Maintaining a pre-PCI SBP within the range of 120 to 140 mmHg and a DBP within the range of 80 to 100 mmHg may be confer benefits to patients with STEMI in no-reflow.

Ascitic Fluid Lactate Level as a Predictor of Mortality in Cirrhotic Patients Having Spontaneous Bacterial Peritonitis (SBP).

Introduction Limited studies are available for predicting mortality in patients with spontaneous bacterial peritonitis (SBP) based on ascitic fluid analysis. Recently, a proposition has been made regarding the role of ascitic fluid lactate as a better prognostic indicator of mortality in cirrhotic patients with SBP. Therefore, we aimed to evaluate the utility of ascitic fluid lactate in predicting mortality in cirrhotic patients with SBP. Methods This was a prospective, observational study that was conducted in the Hepato-Gastroenterology Department of Sindh Institute of Urology and Transplantation (SIUT), Karachi from 1 January 2022 to 31 December 2022. All the patients having liver cirrhosis with ascites, aged between 18 and 65 years, and presenting with fever and/or abdominal pain were recruited in the study in the first six months (i.e., from 1 January 2022 to 30 June 2022) and were followed for six more months for the outcome. However, those patients on dialysis or those with hepatocellular carcinoma, any other malignancy as per a history of solid organ transplant, a history of HIV infection, or those underlying systemic sepsis or infections other than SBP were excluded from the study. The presence or absence of SBP was confirmed by doing the ascitic fluid analysis. Ascitic fluid lactate levels were also requested in each patient. Mortality was assessed at one, two, three, and six months, respectively. All the data were analyzed using SPSS version 23.0. The area under the receiver operating curve (AUROC) was obtained for ascitic fluid lactate for predicting mortality in SBP. At an optimal cutoff, the diagnostic accuracy of ascitic fluid lactate was obtained. Results The total number of cirrhotic patients included in the study was 123. The majority of the patients belong to Child Turcotte Pugh (CTP) class C (n = 88; 71%). Two third of the patients (65.8%; n = 81) had viral hepatitis i.e., hepatitis B, D, and/or C, as the cause of cirrhosis. Overall mortality was observed in 51(41.5%) patients. Ascitic fluid lactate was significantly raised in patients with SBP than in patients with non-SBP (p = 0.004). The AUROC of ascitic fluid lactate was highest at three months (AUROC = 0.88) followed by six months (AUROC = 0.84), two months (AUROC = 0.804), and one month (AUROC=0.773). At an optimal cut-off of more than or equal to 22.4 mg/dl, ascitic fluid lactate had a sensitivity of 84.9%, specificity of 85.7%, positive predictive value (PPV) of 97.3%, negative predictive value of 42.8% with diagnostic accuracy of 85% in predicting overall mortality in patients with SBP. On sub-analysis, the diagnostic accuracy of ascitic fluid lactate was highest at six months followed by at three, two, and one month, respectively. Conclusion Ascitic fluid lactate showed a good diagnostic utility in predicting the overall mortality in patients with SBP with the best diagnostic accuracy in predicting long-term (six months) mortality. However, further studies are required to validate our results.

Skeleton binding protein 1 localizes to the Maurer's cleft and interacts with PfHSP70-1 and PfHSP70-x in Plasmodium falciparum gametocyte-infected erythrocytes.

Plasmodium falciparum accounts for the majority of malaria deaths, due to pathology provoked by the ability of infected erythrocytes to adhere to vascular endothelium within deep tissues. The parasite recognizes endothelium by trafficking and displaying protein ligands on the surface of asexual stage infected erythrocytes, such as members of the large family of pathogenic proteins, P. falciparum erythrocyte membrane protein 1 (PfEMP1). Parasite-encoded skeleton binding protein 1 (SBP1) plays an important role in the transport of these binding-related surface proteins, via cleft-like membranous structures termed Maurer's clefts, which are present within the cytoplasm of infected erythrocytes. Erythrocytes infected with gametocyte stages accumulate in the extravascular compartment of bone marrow; and it was suggested that their surface-expressed adhesion molecule profile and protein trafficking mechanisms might differ from those in asexual stage parasites. Protein trafficking mechanisms via Maurer's clefts have been well investigated in asexual stage parasite-infected erythrocytes; but little is known regarding the gametocyte stages. In this study, we characterized SBP1 during gametocyte maturation and demonstrated that SBP1 is expressed and localizes to dot-like Maurer's cleft structures in the cytoplasm of gametocyte-infected erythrocytes. Co-immunoprecipitation and mass spectrometry assays indicated that SBP1 interacts with the molecular chaperones PfHSP70-1 and PfHSP70-x. Localization analysis suggested that some PfHSP70-1 and/or PfHSP70-x localize in a dot-like pattern within the cytoplasm of immature gametocyte-infected erythrocytes. These findings suggest that SBP1 may interact with HSP70 chaperones in the infected erythrocyte cytoplasm during the immature gametocyte stages.

Solitary bone plasmacytoma of spine with involvement of intervertebral disk: a case report and literature review.

Primary malignant bone tumors of the spine are exceedingly rare, with solitary bone plasmacytoma (SBP) representing approximately 30% of all cases. Radiological assessments are crucial for localizing SBP and for ruling out a diagnosis of multiple myeloma (MM). Imaging features resembling a "mini-brain" appear to be distinctive for SBP. Vertebral lesions accompanied by adjacent disc space involvement typically suggest spinal infections, while the potential for SBP involvement is often overlooked. We present a case of a 61-year-old female with SBP who exhibited thoraco-lumbar spine destruction and adjacent disc space involvement. The patient sought treatment at our medical center due to lumbodorsal pain radiating bilaterally to the inguinal regions. Radiological findings revealed an osteolytic lesion involving the intervertebral disc, making it challenging to distinguish between tumor and inflammation. A biopsy of the vertebral lesion confirmed the diagnosis of SBP, which was further supported by laboratory results. Post-diagnosis, the patient underwent radiotherapy, receiving a total dose of 4000 Gy, which alleviated her symptoms. We also provide a comprehensive literature review on SBP with disc involvement to aid both clinical and radiological diagnoses.

Exercise systolic blood pressure response during cycle ergometry is associated with future hypertension in normotensive individuals.

AIMS: We aimed to investigate the association between the exercise systolic blood pressure (SBP) response and future hypertension (HTN) in normotensive individuals referred for cycle ergometry, with special regard to reference exercise SBP values and exercise capacity. METHODS AND RESULTS: In this longitudinal cohort study, data from 14 428 exercise tests were cross-linked with Swedish national registries on diagnoses and medications. We excluded individuals with a baseline diagnosis of cardiovascular disease or HTN. The peak exercise SBP (SBPpeak) was recorded and compared with the upper limit of normal (ULN) derived from SBPpeak reference equations incorporating age, sex, resting SBP, and exercise capacity. To evaluate the impact of exercise capacity, three SBP to work rate slopes (SBP/W-slopes) were calculated, relative to either supine or seated SBP at rest or to the first exercise SBP. Adjusted hazard ratios [HRadjusted (95% confidence interval, CI)] for incident HTN during follow-up, in relation to SBP response metrics, were calculated. We included 3895 normotensive individuals (49 ± 14 years, 45% females) with maximal cycle ergometer tests. During follow-up (median 7.5 years), 22% developed HTN. Higher SBPpeak and SBPpeak > ULN were associated with incident HTN [HRadjusted 1.19 (1.14-1.23) per 10 mmHg, and 1.95 (1.54-2.47), respectively]. All three SBP/W-slopes were positively associated with incident HTN, particularly the SBP/W-slope calculated as supine-to-peak SBP [HRadjusted 1.25 (1.19-1.31) per 1 mmHg/10 W]. CONCLUSION: Both SBPpeak > ULN based on reference values and high SBP/W-slopes were associated with incident HTN in normotensive individuals and should be considered in the evaluation of the cycle ergometry SBP response.

We examined the systolic blood pressure (SBP) response during maximal bicycle exercise testing in individuals without hypertension (HTN) or established cardiovascular disease and found that:When applying reference values for peak SBP during cycling exercise, accounting for age, sex, resting blood pressure (BP), and exercise capacity, exceeding the upper limit of normal was associated with twice as high relative risk of future HTN, compared with having a peak SBP within normal limits.A steep increase in exercise SBP in relation to the increase in work rate was also associated with future HTN but did not always coincide with elevated peak SBP.

Hfe Permease and Haemophilus influenzae Manganese Homeostasis.

Haemophilus influenzae is a commensal of the human upper respiratory tract that can infect diverse host niches due, at least in part, to its ability to withstand both endogenous and host-mediated oxidative stresses. Here, we show that hfeA, a gene previously linked to iron import, is essential for H. influenzae manganese recruitment via the HfeBCD transporter. Structural analyses show that metal binding in HfeA uses a unique mechanism that involves substantial rotation of the C-terminal lobe of the protein. Disruption of hfeA reduced H. influenzae manganese acquisition and was associated with decreased growth under aerobic conditions, impaired manganese-superoxide dismutase activity, reduced survival in macrophages, and changes in biofilm production in the presence of superoxide. Collectively, this work shows that HfeA contributes to H. influenzae manganese acquisition and virulence attributes. High conservation of the hfeABCD permease in Haemophilus species suggests that it may serve similar roles in other pathogenic Pasteurellaceae.

Remnant cholesterol and intensive blood pressure control in older patients with hypertension: a post hoc analysis of the STEP randomized trial†.

AIMS: Emerging evidence shows a close relationship between remnant cholesterol (RC) and hypertension. However, it is unknown whether RC is associated with the effects of intensive systolic blood pressure (SBP) lowering on cardiovascular outcomes. METHODS AND RESULTS: We performed a post hoc analysis of the Strategy of Blood Pressure Intervention in the Elderly Hypertensive Patients (STEP) trial. Participants were randomly allocated to intensive (110 to <130 mmHg) or standard (130 to <150 mmHg) treatment groups. The effects of intensive SBP lowering on the primary composite outcome (stroke, acute coronary syndrome, acute decompensated heart failure, coronary revascularization, atrial fibrillation, or cardiovascular death), the components thereof, and all-cause mortality were analysed by the tertile of baseline RC (lowest, middle, and highest). We followed 8206 patients for 3.33 years (median). The adjusted hazard ratios (HRs) [95% confidence interval (CI)] for the primary outcome were 1.06 (0.73-1.56), 0.58 (0.38-0.87), and 0.67 (0.46-0.96) in the lowest, middle, and highest RC tertiles, respectively (P for interaction = 0.11). However, significant heterogeneity in the treatment effects was observed when comparing the upper two tertiles with the lowest tertile (P for interaction = 0.033). For all-cause mortality, the adjusted HRs (95% CI) were 2.48 (1.30-4.73), 1.37 (0.71-2.65), and 0.42 (0.22-0.80) in the lowest, middle, and highest RC tertiles, respectively (P for interaction <0.0001). CONCLUSION: Baseline RC concentrations were associated with the effects of intensive SBP lowering on the primary composite cardiovascular outcome and all-cause mortality in hypertensive patients. These results are hypothesis-generating and merit further study. REGISTRATION: STEP ClinicalTrials.gov number: NCT03015311.

In our post hoc analysis of the STEP trial, baseline remnant cholesterol (RC) concentrations were associated with the effects of intensive systolic blood pressure (SBP) lowering on the primary composite cardiovascular outcome and all-cause mortality in hypertensive patients.Patients with a higher RC experienced greater cardiovascular benefits from intensive SBP lowering, while a lower RC was associated with attenuated benefits or even negative effects of intensive SBP lowering. These results are hypothesis-generating and merit further study.If confirmed, RC measurements could permit the identification of a subset of patients with high RC and hypertension, who may receive greater benefit from intensive SBP lowering to <130 mmHg.

Association of central blood pressure with an exaggerated blood pressure response to exercise among elite athletes.

PURPOSE: The systolic blood pressure/workload (SBP/MET) slope was recently reported to be a reliable parameter to identify an exaggerated blood pressure response (eBPR) in the normal population and in athletes. However, it is unclear whether an eBPR correlates with central blood pressure (CBP) and vascular function in elite athletes. METHODS: We examined 618 healthy male elite athletes (age 25.8 ± 5.1 years) of mixed sports with a standardized maximum exercise test. CBP and vascular function were measured non-invasively with a validated oscillometric device. The SBP/MET slope was calculated and the threshold for an eBPR was set at > 6.2 mmHg/MET. Two groups were defined according to ≤ 6.2 and > 6.2 mmHg/MET, and associations of CBP and vascular function with the SBP/MET slope were compared for each group. RESULTS: Athletes with an eBPR (n = 180, 29%) displayed a significantly higher systolic CBP (102.9 ± 7.5 vs. 100 ± 7.7 mmHg, p = 0.001) but a lower absolute (295 ± 58 vs. 384 ± 68 W, p < 0.001) and relative workload (3.14 ± 0.54 vs. 4.27 ± 1.1 W/kg, p < 0.001) compared with athletes with a normal SBP/MET slope (n = 438, 71%). Systolic CBP was positively associated with the SBP/MET slope (r = 0.243, p < 0.001). In multiple logistic regression analyses, systolic CBP (odds ratio [OR] 1.099, 95% confidence interval [CI] 1.045-1.155, p < 0.001) and left atrial volume index (LAVI) (OR 1.282, CI 1.095-1.501, p = 0.002) were independent predictors of an eBPR. CONCLUSION: Systolic CBP and LAVI were independent predictors of an eBPR. An eBPR was further associated with a lower performance level, highlighting the influence of vascular function on the BPR and performance of male elite athletes.

Meta-analysis of risk of major adverse cardiovascular events in adults with type 2 diabetes treated with bexagliflozin.

AIM: To explore the risk of major adverse cardiovascular events (MACE) associated with exposure to bexagliflozin. METHODS: The analysis included 4090 participants with type 2 diabetes (T2D) enrolled in nine phase 2 and 3 double-blind randomized controlled trials. All potential MACE were adjudicated by a blinded committee. The primary endpoint for the meta-analysis was the hazard ratio (HR) for the time to first occurrence of non-fatal stroke, non-fatal myocardial infarction (MI), cardiovascular (CV) death or hospitalization for unstable angina (MACE+), tested for non-inferiority to a ratio of 1.8. The secondary endpoints were time to first occurrence of (i) non-fatal stroke, non-fatal MI or CV death (MACE), tested for non-inferiority to a ratio of 1.3; and (ii) CV death or hospitalization for heart failure, tested for superiority. RESULTS: The HR for the primary endpoint of MACE+ was 0.80 (95% confidence interval [CI] 0.58, 1.09), which fulfilled the non-inferiority objective with a P value of less than 0.0001. Non-inferiority for the first key secondary endpoint of MACE was also shown (HR = 0.82; 95% CI 0.59, 1.13; P = 0.0023). Superiority for time to CV death or first hospitalization for heart failure was not shown. CONCLUSIONS: Bexagliflozin did not increase the risk of MACE in participants with T2D when compared with placebo or active control. Both the preapproval and postapproval thresholds for CV safety were met and bexagliflozin has been approved by the US Food and Drug Administration.