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Aims Heart failure (HF) and atrial fibrillation (AF) frequently coexist and are both associated with increased levels of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). It is known that AF impairs the diagnostic accuracy of NT‐proBNP for HF. The aim of the present study was to compare the diagnostic and predictive accuracy of NT‐proBNP for HF and AF in stable outpatients with cardiovascular risk factors. Methods and results Data were obtained from the DIAST‐CHF trial, a prospective cohort study that recruited individuals with cardiovascular risk factors and followed them up for 12 years. Data were validated in three independent population‐based cohorts using the same inclusion/exclusion criteria: LIFE‐Adult (n = 2869), SHIP (n = 2013), and SHIP‐TREND (n = 2408). Serum levels of NT‐proBNP were taken once at baseline. The DIAST‐CHF study enrolled 1727 study participants (47.7% female, mean age 66.9 ± 8.1 years). At baseline, patients without AF or HF (n = 1375) had a median NT‐proBNP of 94 pg/mL (interquartile range 51;181). In patients with AF (n = 93), NT‐proBNP amounted to 667 (215;1130) pg/mL. It was significantly higher than in the first group (P 50% [n = 38; 603 (175;1070) pg/mL] and those without HF (P = 1.0). Receiver‐operating characteristic curves of NT‐proBNP showed a similar area under the curve (AUC) for the detection of AF at baseline (0.84, 95% CI [0.79–0.88]) and for HF with EF 50% was significantly lower (0.61 [0.56–0.65]) than for AF (P = 0.001). During follow‐up, AF was newly diagnosed in 157 (9.1%) and HF in 141 (9.6%) study participants. NT‐proBNP was a better predictor of incident AF during the first 2 years (AUC: 0.79 [0.75–0.83]) than of newly diagnosed HF (0.59 [0.55–0.63]; P 50% is very limited.

Purpura fulminans can result in significant full-thickness wounds, posing a challenge in the pediatric population, given the paucity of donor sites for reconstruction. The authors present the case of an 11-month-old patient for whom a split-thickness skin allograft (TheraSkin) was successfully implemented as a temporizing measure for a large leg wound.

Background Anemia is a worldwide concern. Nutritional deficiencies and inflammation are considered main contributors, but zinc deficiency has only recently been associated with anemia. Objectives In this study we assessed associations between zinc status and hemoglobin (Hb) concentrations and anemia in preschool children 6-59 mo old (PSC) and nonpregnant women of reproductive age 15-49 y old (WRA) in population-based nutrition surveys. Methods Cross-sectional data from 13 (PSC) and 12 (WRA) countries within the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were used. Multivariable linear models were constructed that included zinc status (plasma/serum zinc concentrations), Hb concentrations and anemia, iron status, age, sex, and inflammation (C-reactive protein and α-1-acid glycoprotein). Zinc was adjusted for inflammation in PSC according to the BRINDA algorithm. Results Data were available for 18,658 PSC and 22,633 WRA. Prevalence of anemia ranged from 7.5% to 73.7% and from 11.5% to 94.7% in PSC and WRA, respectively. Prevalence of zinc deficiency ranged from 9.2% to 78.4% in PSC and from 9.8% to 84.7% in WRA, with prevalence of zinc deficiency >20% in all countries except Azerbaijan (PSC), Ecuador (PSC), and the United Kingdom (WRA). Multivariable linear regression models showed that zinc concentrations were independently and positively associated with Hb concentrations in 7 of 13 countries for PSC and 5 of 12 countries for WRA. In the same models, ferritin concentration was also significantly associated with Hb among PSC and WRA in 9 and 10 countries, respectively. Zinc deficiency was significantly associated with anemia in PSC and WRA in 5 and 4 countries respectively. Conclusions Zinc deficiency was prevalent in most countries and associations between zinc and Hb in roughly half of the countries examined suggesting that strategies to combat zinc deficiency may help reduce anemia prevalence. More research on mechanisms by which zinc deficiency is associated with anemia and the reasons for the heterogeneity among countries is warranted.

The prevalence of preeclampsia and obesity have increased. Although obesity is a major risk factor for preeclampsia, the mechanisms linking these morbidities are poorly understood. Circulating leptin levels increase in proportion to fat mass. Infusion of this adipokine elicits hypertension in nonpregnant rats, but less is known about how hyperleptinemia impacts blood pressure during placental ischemia, an initiating event in the pathophysiology of hypertension in preeclampsia. We tested the hypothesis that hyperleptinemia during reduced uterine perfusion pressure (RUPP) exaggerates placental ischemia-induced hypertension. On gestational day (GD) 14, Sprague–Dawley rats were implanted with osmotic mini-pumps delivering recombinant rat leptin (1 µg/kg/min iv) or vehicle concurrently with the RUPP procedure to induce placental ischemia or Sham. On GD 19, plasma leptin was elevated in Sham + Leptin and RUPP + Leptin. Leptin infusion did not significantly impact mean arterial pressure (MAP) in Sham. MAP was increased in RUPP + Vehicle vs. Sham + Vehicle. In contrast to our hypothesis, placental ischemia-induced hypertension was attenuated by leptin infusion. To examine potential mechanisms for attenuation of RUPP-induced hypertension during hyperleptinemia, endothelial-dependent vasorelaxation to acetylcholine was similar between Sham and RUPP; however, endothelial-independent vasorelaxation to the nitric oxide (NO)-donor, sodium nitroprusside, was increased in Sham and RUPP. These findings suggest that NO/cyclic guanosine monophosphate (cGMP) signaling was increased in the presence of hyperleptinemia. Plasma cGMP was elevated in Sham and RUPP hyperleptinemic groups compared with vehicle groups but plasma and vascular NO metabolites were reduced. These data suggest that hyperleptinemia during placental ischemia attenuates hypertension by compensatory increases in NO/cGMP signaling. NEW & NOTEWORTHY Ours is the first study to examine the impact of hyperleptinemia on the development of placental ischemia-induced hypertension using an experimental animal model.

OBJECTIVES This study sought to further understand the mechanisms underlying effect of spironolactone and assessed its impact on multiple plasma protein biomarkers and their respective underlying biologic pathways.BACKGROUND In addition to their beneficial effects in established heart failure (HF), mineralocorticoid receptor antagonists may act upstream on mechanisms, preventing incident HF. In people at risk for developing HF, the HOMAGE (Heart OMics in AGEing) trial showed that spironolactone treatment could provide antifibrotic and antiremodeling effects, potentially slowing the progression to HF.METHODS Baseline, 1-month, and 9-month (or last visit) plasma samples of HOMAGE participants were measured for protein biomarkers (n = 276) by using Olink Proseek-Multiplex cardiovascular and inflammation panels (Olink, Uppsala, Sweden). The effect of spironolactone on biomarkers was assessed by analysis of covariance and explored by knowledgebased network analysis. RESULTS A total of 527 participants were enrolled; 265 were randomized to spironolactone (25 to 50 mg/day) and 262 to standard care ("control"). The median (interquartile range) age was 73 years (69 to 79 years), and 26% were female. Spironolactone reduced biomarkers of collagen metabolism (e.g., COL1A1, MMP-2); brain natriuretic peptide; and biomarkers related to metabolic processes (e.g., PAPPA), inflammation, and thrombosis (e.g., IL17A, VEGF, and urokinase). Spironolactone increased biomarkers that reflect the blockade of the mineralocorticoid receptor (e.g., renin) and increased the levels of adipokines involved in the anti-inflammatory response (e.g., RARRES2) and biomarkers of hemostasis maintenance (e.g., tPA, UPAR), myelosuppressive activity (e.g., CCL16), insulin suppression (e.g., RETN), and inflammatory regulation (e.g., IL-12B).CONCLUSIONS Proteomic analyses suggest that spironolactone exerts pleiotropic effects including reduction in fibrosis, inflammation, thrombosis, congestion, and vascular function improvement, all of which may mediate cardiovascular protective effects, potentially slowing progression toward heart failure. (HOMAGE [Bioprofiling Response to Mineralocorticoid Receptor Antagonists for the Prevention of Heart Failure]; NCT02556450) (C) 2021 by the American College of Cardiology Foundation.

Thiamine deficiency is a public health issue in Cambodia. Thiamine fortification of salt has been proposed; however, the salt intake of lactating women, the target population, is currently unknown. We estimated salt intakes among lactating women (, Thiamine deficiency is a public health issue in Cambodia. Thiamine fortification of salt has been proposed; however, the salt intake of lactating women is currently unknown. We estimated salt intakes among lactating women using three methods. Based on these data, a thiamine salt fortification scenario was modeled, which allowed the calculation of a suitable fortification dose of thiamine to add to salt.

BACKGROUND Postinjury hypercoagulability occurs in >25% of injured patients, increasing risk of thromboembolic complications despite chemoprophylaxis. However, few clinically relevant animal models of posttraumatic hypercoagulability exist. We aimed to evaluate a rodent model of bilateral hindlimb injury as a preclinical model of postinjury hypercoagulability. METHODS Forty Wistar rats were anesthetized with isoflurane: 20 underwent bilateral hindlimb fibula fracture, soft tissue and muscular crush injury, and bone homogenate injection intended to mimic the physiological severity of bilateral femur fracture. Twenty sham rats underwent anesthesia only. Terminal citrated blood samples were drawn at 0, 6, 12, and 24 hours (n = 5 per timed group) for analysis by native thromboelastography in the presence and absence of taurocholic acid to augment fibrinolysis. Plasminogen activator inhibitor 1 and α-2 antiplasmin levels in plasma were assessed via enzyme-linked immunosorbent assay. RESULTS Injured rats became hypercoagulable relative to baseline by 6 hours based on thromboelastography maximal amplitude (MA) and G (p < 0.005); sham rats became hypercoagulable to a lesser degree by 24 hours (p < 0.005). Compared with sham animals, injured rats were hypercoagulable by MA and G within 6 hours of injury, remained hypercoagulable by MA and G through at least 24 hours (all p < 0.01), and showed impaired fibrinolysis by taurocholic acid LY30 at 12 hours (p = 0.019) and native LY30 at 24 hours (p = 0.045). In terms of antifibrinolytic mediators, α-2 antiplasmin was elevated in trauma animals at 24 hours (p = 0.009), and plasminogen activator inhibitor 1 was elevated in trauma animals at 6 hours (p = 0.004) and 12 hours (p < 0.001) when compared with sham. CONCLUSIONS Orthopedic injury in rodents induced platelet and overall hypercoagulability within 6 hours and fibrinolytic impairment by 12 to 24 hours, mimicking postinjury hypercoagulability in injured patients. This rodent model of orthopedic injury may serve as a preclinical testing ground for potential therapies to mitigate hypercoagulability, maintain normal fibrinolysis, and prevent thromboembolic complications.

Objectives Although epidemiological studies have shown that obesity is associated with increased incidence of hypertension during pregnancy, the mechanisms linking these two comorbidities are not as well studied. Previous investigations detected lower levels of the anti-hypertensive and pregnancy-related factor, placental growth factor (PlGF), in obese hypertensive pregnancies. Therefore, we examined whether obese hypertensive pregnant rats have reduced PlGF and whether increasing its levels by administering recombinant human (rh)PlGF reduces their blood pressure. Methods We utilized a genetic model of obesity characterized to be heavier, hypertensive and fertile, namely rats having heterozygous deficiency of the melanocortin-4 receptor (MC4R-def). Results MC4R-def obese rats had lower circulating levels of PlGF than wild-type lean controls at gestational day 19. Also, assessment of the PlGF receptor, Flt-1, in the vasculature showed that its levels were reduced in aorta and kidney glomeruli but increased in small mesenteric arteries. Chronic intraperitoneal administration of rhPlGF from gestational day 13-19 significantly increased circulating PlGF levels in both obese and lean rats, but reduced blood pressure only in the obese pregnant group. The rhPlGF treatment did not alter maternal body and fat masses or circulating levels of the adipokines, leptin and adiponectin. In addition, this treatment did not impact average foetal weights but increased placental weights regardless of obese or lean pregnancy. Conclusion PlGF is reduced in MC4R-def obese hypertensive pregnant rats, which is similar to findings in obese hypertensive pregnant women, while increasing its levels with exogenous rhPlGF reduces their blood pressure.

Early work in germ-free rodents highlighted the gut microbiota’s importance in metabolic disease, including Type II Diabetes Mellitus (T2DM) and obesity. Glucagon-like peptide-1 (GLP-1) is an incretin secreted by enteroendocrine L-cells lining the gastrointestinal epithelium. GLP-1 has important functions including promoting insulin secretion, insulin sensitivity, and β-cell mass, while inhibiting gastric emptying and appetite. We set out to elucidate how the microbiota can modulate GLP-1 secretion, with the goal to identify microbial strains with GLP-1 stimulatory activity as a metabolic disease therapeutic. Over 1500 human-derived strains were isolated from fecal, breast milk, and colon and intestinal biopsy samples from healthy individuals. In vitro screening for GLP-1 modulation was performed by incubating bacterial cell-free supernatants with NCI H716 human L-cells. Approximately 45 strains capable of increasing GLP-1 levels, measured by ELISA, were discovered. Interestingly, all positive strains were identified as Staphylococcus epidermidis by 16S rRNA sequencing. Non-GLP-1 stimulatory S. epidermidis strains were also identified. Mass spectrometry analysis identified a 3 kDa peptide, termed GLP-1 stimulating peptide (GspA), present in GLP-1 positive but absent in GLP-1 neutral S. epidermidis. Studies in human L-cells and intestinal enteroids demonstrated that GspA alone is sufficient to enhance GLP-1 secretion. When administered in high-fat-fed mice, GspA-producing S. epidermidis significantly reduced markers associated with obesity and T2DM, including adiposity and hyperinsulinemia. Further characterization of GspA suggests a GLP-1 stimulatory action via calcium signaling. The presented results identify a novel host-microbe interaction which may ultimately lead to the development of a microbial peptide-based therapeutic for obesity and T2DM.ImportanceThe human gastrointestinal microbiota has been shown to modulate metabolic disease, including Type II Diabetes Mellitus and obesity, through mechanisms involving gut hormone secretion. We initiated this study to identify bacterial strains that can stimulate one of these hormones, glucagon-like peptide-1. We first identified that some strains of Staphylococcus epidermidis have such stimulatory activity. We then found that these strains could be used in a mouse model of high-fat feeding to reduce markers associated with metabolic disease, including adiposity and elevated insulin levels. We also identified the peptide from S. epidermidis that stimulates glucagon-like peptide-1 and propose a mode of action through calcium signaling. This newly identified microbial-derived peptide and host-microbe interaction provide a promising therapeutic approach against Type II Diabetes Mellitus and obesity.

Rationale: Despite therapeutic progress in treating cystic fibrosis (CF) airway disease, airway inflammation with associated mucociliary dysfunction remains largely unaddressed. Inflammation reduces the activity of apically expressed large-conductance Ca2+-activated and voltage-dependent K+ (BK) channels, critical for mucociliary function in the absence of CFTR (CF transmembrane conductance regulator).Objectives: To test losartan as an antiinflammatory therapy in CF using CF human bronchial epithelial cells and an ovine model of CF-like airway disease.Methods: Losartan's antiinflammatory effectiveness to rescue BK activity and thus mucociliary function was tested in vitro using primary, fully redifferentiated human airway epithelial cells homozygous for F508del and in vivo using a previously validated, now expanded pharmacologic sheep model of CF-like, inflammation-associated mucociliary dysfunction.Measurements and Main Results: Nasal scrapings from patients with CF showed that neutrophilic inflammation correlated with reduced expression of LRRC26 (leucine rich repeat containing 26), the γ subunit mandatory for BK function in the airways. TGF-β1 (transforming growth factor β1), downstream of neutrophil elastase, decreased mucociliary parameters in vitro. These were rescued by losartan at concentrations achieved by nebulization in the airway and oral application in the bloodstream: BK dysfunction recovered acutely and over time (the latter via an increase in LRRC26 expression), ciliary beat frequency and airway surface liquid volume improved, and mucus hyperconcentration and cellular inflammation decreased. These effects did not depend on angiotensin receptor blockade. Expanding on a validated and published nongenetic, CF-like sheep model, ewes inhaled CFTRinh172 and neutrophil elastase for 3 days, which resulted in prolonged tracheal mucus velocity reduction, mucus hyperconcentration, and increased TGF-β1. Nebulized losartan rescued both mucus transport and mucus hyperconcentration and reduced TGF-β1.Conclusions: Losartan effectively reversed CF- and inflammation-associated mucociliary dysfunction, independent of its angiotensin receptor blockade.

In this review, we first provide a brief overview of the nitric oxide synthase (NOS) isoforms and biochemistry. This is followed by describing what is known about NOS-mediated blood pressure control during normal pregnancy. Circulating nitric oxide (NO) bioavailability has been assessed by measuring its metabolites, nitrite (NO2) and/or nitrate (NO3), and shown to rise throughout normal pregnancy in humans and rats and decline postpartum. In contrast, placental malperfusion/ischemia leads to systemic reductions in NO bioavailability leading to maternal endothelial and vascular dysfunction with subsequent development of hypertension in PE. We end this article by describing emergent risk factors for placental malperfusion and ischemic disease and discussing strategies to target the NOS system therapeutically to increase NO bioavailability in preeclamptic patients. Throughout this discussion, we highlight the critical importance that experimental animal studies have played in our current understanding of NOS biology in normal pregnancy and their use in finding novel ways to preserve this signaling pathway to prevent the development, treat symptoms, or reduce the severity of PE.

Background Echocardiography is considered the cornerstone of the diagnostic workup of heart failure with preserved ejection fraction. Thus far, validation of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) echo‐algorithm for evaluation of diastolic (dys)function in a patient suspected of heart failure with preserved ejection fraction has been limited. Methods and Results The diagnostic performance of the 2016 ASE/EACVI algorithm was assessed in 204 patients evaluated for unexplained dyspnea or pulmonary hypertension with echocardiogram and right heart catheterization. Invasively measured pulmonary capillary wedge pressure (PCWP) was used as the gold standard. In addition, the diagnostic performance of H 2 FPEF score and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) were evaluated. There was a poor correlation between indexed left atrial volume, E/e′ (septal and average) or early mitral inflow (E), and PCWP ( r =0.25–0.30, P values all r =0.17, P 2 FPEF score had a modest correlation with PCWP ( r =0.44, P r =0.24, P Conclusions The 2016 ASE/EACVI algorithm for the assessment of diastolic function has a limited diagnostic accuracy in patients evaluated for unexplained dyspnea and/or pulmonary hypertension, and especially sensitivity to detect diastolic dysfunction was low.

Introduction Smoking among adults with major depressive disorder (MDD) is at least double that of the general US population. More effective smoking cessation interventions for depressed smokers may be facilitated through a better understanding of the smoking and depression-related characteristics of this population. Methods We used baseline data from 300 participants enrolled in randomized clinical trial for smokers with current or past MDD. We described history of smoking cessation behaviors (ie, quit attempts, quit motivation, and cessation treatment utilization) and used multivariate regression to identify demographic and depression-related correlates of these behaviors. Results Sixty-eight percent of participants reported at least one quit attempt in the past year, nearly 51% reported motivation to quit in the subsequent 30 days, and 83% reported prior use of a nicotine replacement therapy. A greater readiness to quit smoking was associated with increased age (p = .04) and lower cigarettes per day (p = .01). Greater use of smoking cessation medication was associated with greater education and nicotine dependence, minority race, and greater use of complementary reinforcers (eg, activities associated with increased reinforcing value of smoking; p’s < .05). Conclusions These data indicate that smokers with current or past MDD are highly motivated to quit smoking and have a history of engaging in efforts to quit. Interventions to promote smoking cessation behaviors should address younger and lighter smokers, who may perceive less risk from tobacco use, and efforts to promote smoking cessation medications and counseling should address minority smokers who are engaging in complementary reinforcers. Implications These data are inconsistent with the assumption that smokers with serious mental illness are not willing to quit smoking and suggest the need for studies that test behavioral interventions that address complementary reinforcers to treat tobacco use in this community.

Micronutrient deficiencies are highly prevalent worldwide, including in South-East Asia, and have a profound impact on public health. Most efforts towards eliminating micronutrient deficiencies have focused on vitamin A, iron, and iodine deficiency. But deficiency of other micronutrients also affect public health. The purpose of the present review is to provide an overview of micronutrient deficiency prevalence in South-East Asia and potential public health impact.Representative and up-to-date data on micronutrient status in South-East Asia is limited. Although anemia is still prevalent in South-East Asia, iron deficiency appears not to be prevalent in Cambodia, and less prevalent than thought in Vietnam and Indonesia. Estimates of prevalence of vitamin A deficiency range widely, but most recent data suggest a prevalence of deficiency in children less than 5 years of age less than 15% in most countries. Zinc deficiency is highly prevalent in the region (affecting30% of subjects). Thiamine deficiency is highly prevalent in Cambodia, Laos, and Myanmar.A better coordination of efforts to reduce micronutrient deficiency, and a focus more inclusive for other micronutrients than iron, vitamin A, and iodine is urgently needed for South-East Asia.

Background Duplex ultrasound vein mapping (DUVM) may increase autogenous dialysis access procedures but has not been universally adopted by surgeons. Methods We determined reliability and accuracy of arm vein measurements on physical examination (PE) and DUVM, compared to direct measurements in the operating room (OR, gold standard). Operative plans were developed from each set of measurements and we evaluated which approach identified more options for autogenous procedures. Results Vein diameters measured on DUVM correlated well with OR measurements but those made on PE did not. Autogenous access options were identified in 34.8% of patients based on PE and in 96.6% based on their DUVM. The 6-month primary-patency was 86.4%; assisted primary-patency was 89.8%. Conclusions Duplex ultrasound vein mapping is more reliable and accurate for assessing arm vein anatomy than physical examination. It identifies more autogenous options than physical-examination alone. It is essential for the preoperative evaluation for dialysis access.

During a quit attempt, high negative affect predicts relapse to smoking. In this study, we evaluated bidirectional longitudinal associations between smoking and negative affect among cancer patients treated with varenicline. Participants (N = 119, 50% female, Mage = 59 years) were smokers (≥5 cigarettes/week) who were diagnosed with cancer and were recruited for a 24-week trial of extended duration varenicline plus behavioral counseling; data for this secondary analyses were drawn from the 12-week open-label phase of the trial. Smoking was assessed via self-reported number of cigarettes in the past 24 h. Negative affect was assessed using the Positive and Negative Affect Scale (PANAS). Data were collected at pre-quit (week 0), target quit day (week 1), week 4, and week 12. We evaluated cross-lagged panel models for negative affect and smoking using PROC CALIS in SAS. Models were run separately for participants who were adherent (≥80% of medication taken) or nonadherent to varenicline. Among adherent participants (n = 96), smoking accounted for up to 22% of variance in subsequent negative affect throughout treatment. Cross-lagged associations were not observed between smoking and negative affect among non-adherent participants (n = 23). Negative affect did not predict subsequent smoking among either adherent or nonadherent participants. These results suggest that varenicline may attenuate abstinence-induced negative affect among cancer patients treated for nicotine dependence.

Study objectives Aim of the study was to investigate the association between obstructive sleep apnoea (OSA) and cardiovascular morbidity and mortality in a cohort of patients with cardiovascular risk factors. Methods In this prospective study, 378 patients of the DIAST-CHF cohort were screened for OSA by home polygraphy. Inclusion criteria were risk factors for diastolic heart failure, such as hypertension, diabetes mellitus, atherosclerotic disease, or history of chronic heart failure. Patients were followed up after 1, 2, 5, 9 and 10 years for the occurrence of major adverse cardiac and cerebrovascular events (MACE and MACCE). Results 344 patients were included in the analysis, of which 60% were diagnosed with OSA (apnoea-hypopnoea index ≥5/h). Overall mortality was higher in the OSA group (14.9% vs. 5.9%; p = 0.007), but significance disappeared after adjustment for age and sex (hazard ratio (HR) 1.89, 95% confidence interval (CI) 0.86–4.16, p = 0.12). There was no significant difference in the occurrence of MACE or MACCE in patients with OSA compared to those without OSA (MACE: 31% vs. 30%; p = 0.61; MACCE: 32% vs. 30%; p = 0.53). Conclusion We did not find evidence of an adverse effect of OSA on cardiovascular morbidity and mortality in a cohort of patients with cardiovascular risk factors.

Proper vascular tone and blood pressure regulation during pregnancy are important for immediate and long-term cardiovascular health of the mother and her offspring. Preeclampsia is clinically defined as new-onset maternal hypertension accompanied by cardiovascular, renal, and/or neural abnormalities presenting in the second half of pregnancy. There is strong evidence to support that preeclampsia is mediated by attenuations in uteroplacental vascular remodeling and increases in vasoconstriction with subsequent placental ischemia/reperfusion-induced release of hypertensive substances into the maternal circulation. These include antiangiogenic and pro-inflammatory factors. There is also evidence implicating increased sympathetic nervous system activity (SNA) in this maternal disorder, but this mostly includes data correlating severity of disease with catecholamine levels and elevated muscle SNA. These measurements have not confirmed a causative role for SNA in the pathogenesis of preeclampsia. Therefore, studies are needed to provide a comprehensive understanding of SNA and its control of vascular function and blood pressure regulation during normal pregnancy in order to set the stage for exploring the mechanisms mediating the exaggerated SNA and signaling during preeclampsia. This review examines the role of SNA in control of uteroplacental vascular tone and blood pressure regulation during normal pregnancy. Furthermore, it is proposed that over-activation of the SNA contributes to altered uteroplacental vascular tone and perfusion leading to placental ischemic events and modulates the systemic vasoconstriction and hypertensive responses to soluble placenta ischemic factors. Recognizing the integrative role and importance of SNA in the pathophysiology of preeclampsia will advance our understanding of this maternal disorder.

Using data from the multicenter, observational Diast-CHF (Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure) study, this post-hoc analysis aimed at assessing the association between serum concentrations of C-terminal pro-arginine vasopressin (CT-proAVP) and anxiety in patients with cardiovascular risk factors.Animal studies have demonstrated that centrally released AVP is involved in the development of anxiety-like behaviors, however, it is unknown whether, also in humans, CT-proAVP used as a proxy for the co-secreted AVP is associated with self-reported anxiety.In 1463 study participants with cardiovascular risk factors (mean age 66.7 ± 8.1 years, 51.3% males, mean left ventricular ejection fraction 59.8 ± 8.3%), serum concentrations of CT-proAVP were measured by means of an ELISA assay, and anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS).Data showed that there was a significant and inverse correlation between HADS anxiety and CT-proAVP (rho = -0.074; p = 0.005). Serum CT-proAVP and the HADS anxiety differed between the two sexes: men displayed lower anxiety (4.7 ± 3.5 versus 5.5 ± 3.7) and had higher CT-proAVP levels (5.8 pmol/L, interquartile range 3.5-9.9 pmol/L versus 3.0 pmol/L, interquartile range 2.0-4.7) than women (both, p 0.001). Using univariate ANOVA adjusted for age, body-mass index, estimated glomerular filtration rate, left ventricular ejection fraction, 6-minute walking distance, SF-36 physical functioning, and the natriuretic peptides NT-proBNP and MR-proANP, the interaction term sex*CT-proAVP was significantly associated with anxiety (p = 0.006). Further analysis showed that CT-proAVP was inversely related to anxiety only in men (B = -0.991; 95%CI = -1.650 to -0.331; p = 0.003), but not in women (p = 0.335).In male study participants with cardiovascular risk factors, serum concentrations of CT-proAVP showed an inverse association with anxiety, which was independent from the severity of physical impairment.

Clinical studies have shown that obesity negatively impacts large arteries’ function. We reported that rats exposed to maternal separation (MatSep), a model of early life stress, display enhanced angiotensin II (ANG II)-induced vasoconstriction in aortic rings cleaned of perivascular adipose tissue (PVAT) under normal diet (ND) conditions. We hypothesized that exposure to MatSep promotes a greater loss of PVAT-mediated protective effects on vascular function and loss of blood pressure (BP) rhythm in rats fed a high-fat diet (HFD) when compared with controls. MatSep was performed in male Wistar-Kyoto rats from days 2 to 14 of life. Normally reared littermates served as controls. On ND, aortic rings from MatSep rats with PVAT removed showed increased ANG II-mediated vasoconstriction versus controls; however, rings from MatSep rats with intact PVAT displayed blunted constriction. This effect was exacerbated by an HFD in both groups; however, the anticontractile effect of PVAT was greater in MatSep rats. Acetylcholine-induced relaxation was similar in MatSep and control rats fed an ND, regardless of the presence of PVAT. HFD impaired aortic relaxation in rings without PVAT from MatSep rats, whereas the presence of PVAT improved relaxation in both groups. On an HFD, immunolocalization of vascular smooth muscle-derived ANG-(1–7) and PVAT-derived adiponectin abundances were increased in MatSep. In rats fed an HFD, 24-h BP and BP rhythms were similar between groups. In summary, MatSep enhanced the ability of PVAT to blunt the heightened ANG II-induced vasoconstriction and endothelial dysfunction in rats fed an HFD. This protective effect may be mediated via the upregulation of vasoprotective factors within the adipovascular axis.

Introduction The degree to which smokers quit successfully with varenicline is strongly associated with their adherence to the medication regimen. Thus, measuring varenicline adherence to identify smokers needing additional intervention is a priority. Few studies, however, have examined the validity of self-reported varenicline adherence, using a biological assessment of adherence as a reference. No study has examined this issue among cancer patients trying to quit smoking, who may show unique patterns of adherence given their medical comorbidity. Methods This study used data from 76 cancer patients who received varenicline and provided self-reported varenicline adherence data (pill count) and a blood sample to determine varenicline metabolites 4 weeks after initiating varenicline. Results Receiver operating characteristic (ROC) curve analyses of plasma varenicline levels showed that 4 ng/ml was the optimal cut-point for differentiating adherence with significant (p's, Highlights • First study of the validity of self-reported varenicline use among cancer patients • Identified cut-point for varenicline plasma adherence • Supports the validity of short-term self-reported varenicline adherence • Cancer-related variables influence varenicline adherence • Varenicline adherence may be higher among cancer patients

The Cardiac Lipid Panel (CLP) is a novel panel of metabolomic biomarkers that has previously shown to improve the diagnostic and prognostic value for CHF patients. Several prognostic scores have been developed for cardiovascular disease (CVD) risk, but their use is limited to specific populations and precision is still inadequate. We compared a risk score using the CLP plus NT-proBNP to three commonly used risk scores: The Seattle Heart Failure Model (SHFM), Framingham Risk Score (FRS), and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score. We included 280 elderly CHF patients from the Cardiac Insufficiency Bisoprolol Study in Elderly (CIBIS-ELD) trial. Cox Regression and hierarchical cluster analysis was performed. Integrated area under the curves (IAUC) was used as criterium for comparison. The mean (SD) follow-up period was 81 (33) months, and 95 (34%) subjects met the primary endpoint. The IAUC for FRS was 0.53, SHFM 0.61, MAGGIC 0.68, and CLP 0.78. Subjects were partitioned into three risk clusters: low, moderate, high with the CLP score showing the best ability to group patients into their respective risk cluster. A risk score composed of a novel panel of metabolite biomarkers plus NT-proBNP outperformed other common prognostic scores in predicting 10-year cardiovascular death in elderly ambulatory CHF patients. This approach could improve the clinical risk assessment of CHF patients.

Inadequate child nutrition during the first ‘1000 days’ is widespread in Cambodia, resulting in a high prevalence of child malnutrition. Access to processed complementary food in packages (PCFP) may support caretakers in improving diet of young children. This study aimed to evaluate the caretakers' preferences and willingness‐to‐pay (WTP) for PCFP in Cambodia. The study was conducted in urban and rural settings, involving 520 caretakers with children aged 7–24 months in Phnom Penh (urban) and Prey Veng (rural). Four PCFPs were included: a commercial brand, a social‐commercial brand, a worldwide distributed fortified complementary food aid product (CSB++) and an experimental fortified rice‐and‐fish‐based PCFP developed in Cambodia (WF‐L). Sensory analysis was conducted for all products, stated WTP was assessed for three products (excluding CSB++) and actual WTP experiment was conducted on WF‐L only. Our results show that overall, WF‐L was preferred by the rural participants over food aid CSB++. Further improvements in the organoleptic qualities of WF‐L should focus on consistency and taste. The participants were, on average, willing to pay 1,667 Cambodian riel (KHR, $0.4) and 1,192 KHR ($0.3) in urban and rural settings, respectively, for 35 g of WF‐L. We also found that despite being nutritionally inadequate, most participants considered homemade porridge to be healthier, more practical and preferred by the children. Therefore improving the quality of homemade foods merits urgent consideration. When applying PCFP in nutrition programmes as a supplementary option to homemade complementary foods, locally produced products could be a more viable supplementary option than global food aid.

Background: Low- and middle-income countries (LMIC) are experiencing major increases in diabetes and cardiovascular conditions linked to overweight and obesity. We evaluated an adapted version of the Diabetes Prevention Program (DPP) named Lifestyle Africa, tailored for an under-resourced community in South Africa. Methods: Participants with BMI ≥ 25 kg/m2 who were members of existing social support groups or “clubs” based in low-income townships were enrolled in a cluster-randomized controlled trial that compared the adapted intervention to usual care. The Lifestyle Africa intervention consisted of 17 video-based group sessions delivered by trained community health workers (CHWs). CHWs, participants, and research team members could not be blinded to condition. Percentage weight loss (primary outcome), HbA1c, blood pressure, triglycerides, and LDL cholesterol were assessed 7–9 months after enrollment. An individual-level intention-to-treat analysis was conducted adjusting for clustering within clubs and baseline values. Findings: Between February 2018 and May 2019, 782 individuals were screened and 494 (89% female) were enrolled. Participants from 28 clusters were allocated to Lifestyle Africa (15, n=240) or usual care (13, n=254). Fidelity assessments indicated the intervention was generally delivered as intended. The modal number of sessions held across all clubs was 17 and the mean attendance of participants across all sessions was 61%. Outcome assessment was completed by 215 (90%) intervention and 223 (88%) control participants. Average weight change was -0·67% (95% CI = -1·28 – -0·06) in Lifestyle Africa and 0·47% (95% CI = -1·08 – 0·14) in control with no significant difference (group difference = -0·20%, 95% CI -1·06 – 0·67; p = 0·65). However, HbA1c was significantly lower at follow-up in Lifestyle Africa compared to the usual care group (mean difference = -0·26, 95% CI -0·41 – -0·11, p = 0·0009). There were no significant differences between groups in the other outcomes. Interpretation: Lifestyle Africa was feasible for CHWs to deliver and although it had no effect on weight loss it had a significant effect on HbA1c. The intervention holds promise for addressing cardiovascular disease and diabetes at scale in LMIC. Clinical Trial Registration Details: ClinicalTrials.gov (NCT03342274). Funding Information: Supported by the National Heart Lung and Blood Institute of the National Institutes of Health (R01HL126099). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The study was approved by the ethics committees at the University of Cape Town (primary) and Children’s Mercy Kansas City. Participants completed written informed consent.

Background Acute disease outbreaks such as the COVID-19 pandemic cause a high burden of psychological distress in people worldwide. Interventions to enable people to better cope with such distress should be based on the best available evidence. We therefore performed a scoping review to systematically identify and summarize the available literature of interventions that target the distress of people in the face of highly contagious disease outbreaks. Methods MEDLINE, Cochrane CENTRAL, Web of Science (January 2000 to May 7, 2020), and reference lists were systematically searched and screened by two independent reviewers. Quantitative and qualitative studies investigating the effects of psychological interventions before, during, and after outbreaks of highly contagious emerging infectious diseases, such as SARS, MERS, Ebola, or COVID-19 were included. Study effects were grouped (e.g. for healthcare professionals, community members, people at risk) and intervention contents at the individual and organizational level summarized. We assessed the level of evidence using a modified scheme from the Oxford Centre for Evidence-based Medicine and the Australian National Health and Medical Research Council. Results Of 4030 records found, 19 studies were included (two RCTs). Most interventions were delivered during-exposure and face-to-face, focused on healthcare workers and crisis personnel, and combined psychoeducation with training of coping strategies. Based on two high-quality studies, beneficial effects were reported for resilience factors (e.g. positive cognitive appraisal) and professional attitudes of healthcare workers, with mixed findings for mental health (e.g. depression). Across all studies, there was positive qualitative feedback from participants and facilitators. We identified seven ongoing studies mostly using online- and mobile-based deliveries. Conclusions There is preliminary evidence for beneficial effects of interventions to enable people to better cope with the distress of highly contagious emerging disease outbreaks. Besides the need for more high-quality studies, the summarized evidence may inform decision makers to plan interventions during the current pandemic and to develop pandemic preparedness plans.

Introduction: Selective internal radiation therapy (SIRT) is a local treatment option for patients with hepatocellular carcinoma (HCC). Its exact role next to other HCC therapies has yet to be defined. In order to identify patients most suitable for SIRT, a SIRT-specific prognostic score should be developed. Methods: A cohort of 72 SIRT patients treated at the University Hospital of Munich was retrospectively analyzed. The prognostic performance of 12 HCC staging systems and prognostic scores was assessed. Cox-regression analysis was used to identify independent prognostic factors, which formed the basis of the Munich-SIRT score (M-SIRT). All scores were ranked by calculating the c-Index and Akaike information criterion (AIC). External validation was performed in a cohort of 128 SIRT patients treated at the University Hospital of Pamplona, Spain. Results: median overall survival was 13 months (95% confidence interval 9.9–21.9). AFP (p = 0.005; hazard ratio [HR] 2.38), albumin (p < 0.001; HR 5.87), and alkaline phosphatase (p < 0.001; HR 8.38) were identified as independent prognostic factors. M-SIRT comprises 3 prognostic groups with a median survival of 38.9, 14.6, and 7.7 months, respectively (I vs. II: p = 0.003, II vs. III: p < 0.001). AIC (318) and concordance index (0.711) ranked M-SIRT superior to the established HCC staging systems, and the score successfully passed external validation in an independent SIRT cohort (I vs. II: p = 0.03; II vs. III: p = 0.007). Conclusion: Therapy-specific prognostic scores can facilitate treatment decisions and prognostication for HCC patients. Considering its performance in 200 SIRT patients, M-SIRT is a promising prognostic tool for HCC patients evaluated for SIRT.

Preeclampsia (PE), a hypertensive disorder, occurs in 3% to 8% of pregnancies in the United States and affects over 200,000 women and newborns per year. The United States has seen a 25% increase in the incidence of PE, largely owing to increases in risk factors, including obesity and cardiovascular disease. Although the etiology of PE is not clear, it is believed that impaired spiral artery remodeling of the placenta reduces perfusion, leading to placental ischemia. Subsequently, the ischemic placenta releases antiangiogenic and pro-inflammatory factors, such as cytokines, reactive oxygen species, and the angiotensin II type 1 receptor autoantibody (AT1-AA), among others, into the maternal circulation. These factors cause widespread endothelial activation, upregulation of the endothelin system, and vasoconstriction. In turn, these changes affect the function of multiple organ systems including the kidneys, brain, liver, and heart. Despite extensive research into the pathophysiology of PE, the only treatment option remains early delivery of the baby and importantly, the placenta. While premature delivery is effective in ameliorating immediate risk to the mother, mounting evidence suggests that PE increases risk of cardiovascular disease later in life for both mother and baby. Notably, these women are at increased risk of hypertension, heart disease, and stroke, while offspring are at risk of obesity, hypertension, and neurological disease, among other complications, later in life. This article aims to discuss the current understanding of the diagnosis and pathophysiology of PE, as well as associated organ damage, maternal and fetal outcomes, and potential therapeutic avenues. © 2021 American Physiological Society. Compr Physiol 11:1315-1349, 2021.

Previous studies using male rodents showed the adipocyte-derived hormone leptin acts in the brain to regulate cardiovascular function, energy balance, and glucose homeostasis. The importance of sex differences in cardiometabolic responses to leptin, however, is still unclear. We examined potential sex differences in leptin’s chronic central nervous system (CNS)-mediated actions on blood pressure (BP), heart rate (HR), appetite, and glucose homeostasis in normal and type 1 diabetic rats. Female and male Sprague-Dawley (SD) rats were instrumented with intracerebroventricular cannulas for continuous 7-day leptin infusion (15 µg/day), and BP and HR were measured by telemetry 24 h/day. At baseline, females had lower mean arterial pressure (MAP) (96 ± 3 vs. 104 ± 4 mmHg, P < 0.05) but higher HR (375 ± 5 vs. 335 ± 5 beats/min, P < 0.05) compared with males. After leptin treatment, we observed similar increases in BP (∼3 mmHg) and HR (∼25 beats/min) in both sexes. Females had significantly lower body weight (BW, 283 ± 2 vs. 417 ± 7 g, P < 0.05) and caloric intake (162 ± 20 vs. 192 ± 9 kcal/kg of body wt, P < 0.05) compared with males, and leptin infusion reduced BW (−10%) and caloric intake (−62%) similarly in both sexes. In rats with streptozotocin-induced diabetes ( n = 5/sex), intracerebroventricular leptin treatment for 7 days completely normalized glucose levels. The same dose of leptin administered intraperitoneally did not alter MAP, HR, glucose levels, or caloric intake in normal or diabetic rats. These results show that leptin’s CNS effects on BP, HR, glucose regulation, and energy homeostasis are similar in male and female rats. Therefore, our results provide no evidence for sex differences in leptin’s brain-mediated cardiovascular or metabolic actions.

While obesity is a major cause for pregnancy complications including preeclampsia and fetal demise, it is not exactly clear the precise obesity-related metabolic factors that promote these adverse outcomes. Epidemiological studies have pointed toward hyperglycemia as one such factor. Therefore, we tested the hypothesis that hyperglycemic rats have hypertension and fetal demise during pregnancy. For this purpose, we utilized the type II diabetic model, the Goto-Kakizaki (GK) rat (N=16), compared to normoglycemic Wistar Hannover (WH) rats (N=9), which were maintained on Envigo 8640 standard chow. The GK rat allows for assessment of hyperglycemia on pregnancy without confounding obesity. Maternal fasting glucose levels were significantly greater (P0.05) and circulating levels of the adipokine, leptin (1.6±0.2 ng/mL vs. 2.2±0.3 ng/mL, P>0.05) were similar between GK and WH pregnant groups, respectively. Endothelial-dependent relaxation to acetylcholine (sensitivity as logEC50: -5.2±0.3 M vs -5.2±0.4 M) and endothelial-independent relaxation to the nitric oxide-donor sodium nitroprusside (logEC50: -7.2±0.2 M vs. -7.5±0.1 M) were similar (P>0.05) in uterine arteries isolated from GK and WH rats, respectively. It was then determined if reduced uterine perfusion pressure (RUPP)-induced placental ischemia, a significant contributor to the development of preeclampsia, promoted greater maternal hypertension in GK rats. RUPP was conducted on gestational day 14 and blood pressure assessed on day 19. RUPP produced hypertension to a similar extent (P>0.05) in GK (116±5 mmHg vs. Sham 102±5 mmHg) and WH (124±4 mmHg vs. Sham 100±2 mmHg) groups. Blood pressure was similar under Sham conditions. Fetal demise was already greater in Sham GK vs. Sham WH pregnant rats (% absorptions: 13±2 vs. 2±2, P

Undernutrition is a major contributor to child morbidity and mortality and poses a large burden to the economy, in Cambodia. This study explored factors contributing to child stunting and wasting and their regional inequalities among 1,938 Cambodian children aged 6–23.9 months. Data were drawn from a longitudinal study (year 2017) conducted in six districts of two north‐eastern provinces and the capital and used as cross‐sectional. Socio‐demographic and household characteristics, children's feeding practices during the previous 24 hr, and children's length and weight measurements were collected. Gradient boosting models were used to calculate the contribution of determinants to child undernutrition whereas concentration index was used to assess the impact of those determinants on stunting and wasting inequalities among socioeconomic groups. It was found that low‐household wealth could predict 21% to 45% of child stunting and 23% to 36% of wasting across regions. After wealth, source and treatment of drinking water were found the second major predictor for stunting (15%) and wasting (21%). Combining child nutrition and household water, sanitation and hygiene indicators predicted around 30% of child undernutrition, either in the form of stunting or wasting. Mothers' education predicted >30% of stunting in the north‐eastern region. Results highlight that a complex interplay of factors contributes to child stunting and wasting. An integrated, intersectoral, equity‐focused approach that addresses children's dietary quality, household's water, sanitation and hygiene conditions, mother's education, and poverty is likely to yield the highest impact in achieving further gains in nutritional status among Cambodian children.

Unsafe drinking water is a leading cause of child morbidity, especially among young children in low‐income settings. Safe water consumption requires high‐quality water available at its source and at point of use. We examined the quality of drinking water at point of collection and point of use in 796 households in three provinces, in Cambodia. Microbiological testing for coliform and Escherichia coli contamination was conducted for samples collected. Bivariable analysis and multivariable logistic regression were used to examine associations between various factors and the deterioration in water quality (increase in the risk according coliform or E. coli concentration) between point of collection and point of use. Contamination with both coliforms and E. coli was higher at point of use than at point of collection, with contamination at point of collection to account for 76.6% (coliforms) and 46.3% (E. coli). Results suggest that child drinking water represents a considerable pathway for the ingestion of pathogens, in Cambodia. Area of residence, seasonality, type of water source, and water chlorination were associated with coliform concentration between the point of collection and point of use, whereas only seasonality was associated with E. coli contamination (OR = 1.46; 95% CI [1.05, 2.02]). Children living in rural settings were two times more likely to drink water with a deteriorating coliform concentration between the two‐time points than children living in urban settings (OR = 2.00; 95% CI [1.22, 3.30]). The increase in coliform and E. coli concentrations between point of collection and point of use indicates that water contamination mostly occurs within the household. Strengthening national legislation on water quality standards and promoting safe water management at the household are needed.

Stunting prevalence among children under 5 years remains high in Cambodia, affecting about one‐third of children. In most low‐ and middle‐income countries, linear growth faltering of young children starts in the womb. The 1,000‐days window of opportunity to improve child nutritional status includes pregnancy, as maternal nutritional status is an important determinant of birthweight and child development. In Cambodia, nutritional status of pregnant women is poor, with some studies reporting >20% of pregnant women having a low mid‐upper arm circumference (MUAC < 23 cm). Few studies have investigated associations between maternal nutritional status during pregnancy and neonatal growth. Using data from a Cambodian cohort study conducted from 2016 through 2018 in selected districts of Phnom Penh, Kratie, and Ratanakiri provinces, we investigated associations between maternal MUAC during pregnancy as indicator of maternal nutritional status and their offspring linear growth during early life. Multivariate regression models were used to assess the associations between maternal MUAC during the last trimester of pregnancy and infant's length‐for‐age z‐scores during the first 3.5 months of life. Maternal MUAC was significantly associated with infant's length‐for‐age z‐scores (regression coefficient 0.06, 95% CI [0.03, 0.09]). Infants born from mothers with a low MUAC during pregnancy had a 1.6 times higher risk (odds ratio 1.621, 95% CI [0.998, 2.636]) of being stunted during the first 3.5 months of life compared with infants born from mothers with a MUAC >23 cm. This study underlines the importance of optimum maternal MUAC during pregnancy for optimal infant growth. Interventions that aim to tackle stunting in infants should integrate improving maternal MUAC during pregnancy.

SARS-CoV-2 (COVID-19) patients with associated thromboembolic events have demonstrated poor outcomes despite the use of anticoagulation therapy and surgical intervention. We present a COVID-19 patient with acute limb ischemia, secondary to extensive thrombosis of an aortic aneurysm, iliac arteries, and infrainguinal arteries. Initial treatment with systemic thrombolysis, which restored patency of the aortoiliac occlusion, was followed by open thrombectomies of the infrainguinal occlusions.

BackgroundSuicide is one of the most common causes of death among female adolescents. A greater risk is seen among adolescent mothers who become pregnant outside marriage and consider suicide as the solution to unresolved problems. We aimed to investigate the factors associated with suicidal behavior among adolescent pregnant mothers in Kenya.MethodsA total of 27 Focus Group Discussions (FGDs) and 8 Key Informant Interviews (KIIs) were conducted in a rural setting (Makueni County) in Kenya. The study participants consisted of formal health care workers and informal health care providers (traditional birth attendants and community health workers), adolescent and adult pregnant and post-natal (up to six weeks post-delivery) women including first-time adolescent mothers, and caregivers (husbands and/or mothers-in-law of pregnant women) and local key opinion leaders. The qualitative data was analyzed using Qualitative Solution for Research (QSR) NVivo version 10.ResultsFive themes associated with suicidal behavior risk among adolescent mothers emerged from this study. These included: (i) poverty, (ii) intimate partner violence (IPV), (iii) family rejection, (iv) social isolation and stigma from the community, and (v) chronic physical illnesses. Low economic status was associated with hopelessness and suicidal ideation. IPV was related to drug abuse (especially alcohol) by the male partner, predisposing the adolescent mothers to suicidal ideation. Rejection by parents and isolation by peers at school; and diagnosis of a chronic illness such as HIV/AIDS were other contributing factors to suicidal behavior in adolescent mothers.ConclusionImproved social relations, economic and health circumstances of adolescent mothers can lead to reduction of suicidal behaviour. Therefore, concerted efforts by stakeholders including family members, community leaders, health care workers and policy makers should explore ways of addressing IPV, economic empowerment and access to youth friendly health care centers for chronic physical illnesses. Prevention strategies should include monitoring for suicidal behavior risks during pregnancy in both community and health care settings. Additionally, utilizing lay workers in conducting dialogue discussions and early screening could address some of the risk factors and reduce pregnancy- related suicide mortality in LMICs.

Background The impact of general surgery resident participation on operative case time and postoperative complications has been broadly studied in the United States. Although surgical trainee involvement in international humanitarian surgical care is escalating, there is limited information as to how this participation affects care rendered. This study examines the impact of trainee involvement on case length and immediate postoperative complications with regard to operations in low- and middle-income settings. Methods A retrospective chart review was conducted of humanitarian surgeries completed during annual short-term surgical missions performed by the International Surgical Health Initiative to Ghana and Peru. Between 2017 and 2019, procedures included inguinal hernia repairs and total abdominal hysterectomies (TAHs). Operative records were reviewed for case type, duration, and immediate postoperative complications. Cases were categorized as involving two attending co-surgeons (AA) or one attending and resident assistant (RA). Results There were 135 operative cases between 2017 and 2019; the majority (82%) involved a resident assistant. There were no statistically significant differences in case times between the attending assistant (AA) and resident assistant (RA) cohorts in both case types. All 23 postoperative complications were classified as Clavien-Dindo Grade I. In addition, resident assistance did not lead to a statistically significant increase in complication rate; 26% in the AA cohort versus 74% in the RA cohort (P = 0.3). Conclusions This pilot study examining 135 operative cases over 2 y of humanitarian surgeries demonstrates that there were no differences in operative duration or complication rates between the AA and RA cohorts. We propose that surgical trainee involvement in low- and middle-income settings do not adversely impact operative case times or postoperative complications.

Background In Ghana, pre-school-aged children (PSAC) are at risk of intestinal schistosomiasis and are living in need of praziquantel treatment. To better assess the infection burden within this vulnerable demographic group, we have provided a comparative assessment of the prevalence of Schistosoma mansoni in pre-school-aged children by urine circulating cathodic antigen (CCA) dipsticks, real-time PCR Taqman® faecal assays and Kato-Katz coproscopy. Methods In all, 190 pre-school-aged children were sampled from three endemic communities (viz. Tomefa, Torgahkope/Adakope, and Manheam) around Weija dam, Southern Ghana. Fresh stool and urine samples were collected from all participants for diagnosis. Results Among all the three communities, the urine-CCA assay recorded the highest prevalence values of 90.5% (95% CI 80.4–96.4), 87.9% (95% CI 76.7–95), and 81.2% (95% CI 69.9–89.6) in Tomefa, Torgahkope/Adakope, and Manheam respectively. Prevalence by real-time PCR was 50% (95% CI 35.5–64.5), 8% (95% CI 2.2–19.2) and 16.7% (95% CI 8.3–28.5), while by Kato-Katz was 55.6% (95% CI 42.5–68.1), 8.6% (95% CI 2.9–19) and 11.6% (95% CI 5.1–21.6) respectively. Children aged 1 year and over were found to be positive with the urine-CCA assay; by the ages of 3–4, over 50% were urine-CCA patent. The sensitivity and specificity of the POC-CCA dipsticks, when compared against the combined results of Kato-Katz/TaqMan results was found to be 84.1% (95% CI = 72.7–92.1) and 12.9% (95% CI = 6.6–22) respectively. Conclusions We propose that the urine-CCA dipstick may be a useful rapid diagnostic tool to estimate the prevalence of intestinal schistosomiasis in PSAC, particularly in rapid identification of at-risk areas. However, our assessment has shown that it possible to record false positives when compared to combined Kato-Katz and qPCR results. To guide PSAC praziquantel treatment needs, we propose the urine CCA assay should be included in routine surveillance of intestinal schistosomiasis alongside other diagnostics such as Kato-Katz and urine filtration.

Flexible cystoscopy is the gold standard for diagnosis and surveillance of bladder carcinoma. Most flexible cystoscopes feature a working channel allowing for bladder biopsy and diathermy if a suspicious lesion is observed. However, the working channel permits only small instruments which limit the volume of material retrieved for histological analysis. There are no published standards for quality control of biopsy specimens taken at flexible cystoscopy. We reviewed the diagnostic yield of biopsies taken at flexible cystoscopy at our institution. Theatre log books were retrospectively examined to identify cases of flexible cystoscopy where bladder biopsy was performed. Histopathology reports were reviewed. All biopsies were taken using single-use biopsy forceps, diameter 1.8 mm, open cup width 4.5 mm. From January 2014 to December 2017, a total of 143 biopsies were performed. All biopsies were taken for suspicious lesions where the differential diagnosis included malignancy. Of the 143 samples taken, 27 biopsies showed evidence of malignancy, and 9 cases were high-grade urothelial cancer. A total of 16 samples were inadequate for any histological diagnosis. All remaining samples excluded malignancy within the sample provided. A histopathological diagnosis was provided for almost 89% of cases. Approximately 18% of biopsies detected malignancy. While only small volumes of tissue are collected at flexible cystoscopy, these can help to distinguish malignancy from benign pathology. Our institution reports a non-diagnostic rate of approximately 11%, and in these cases, when there is still a suspicion of malignancy, a rigid cystoscopy and biopsy should be performed.

Author(s): McDonald, Christine M; Suchdev, Parminder S; Krebs, Nancy F; Hess, Sonja Y; Wessells, K Ryan; Ismaily, Sanober; Rahman, Sabuktagin; Wieringa, Frank T; Williams, Anne M; Brown, Kenneth H; King, Janet C | Abstract: BACKGROUND:The accurate estimation of zinc deficiency at the population level is important, as it guides the design, targeting, and evaluation of nutrition interventions. Plasma or serum zinc concentration (PZC) is recommended to estimate zinc nutritional status; however, concentrations may decrease in the presence of inflammation. OBJECTIVES:We aimed to assess the relation between PZC and inflammation in preschool children (PSC; 6-59 mo) and nonpregnant women of reproductive age (WRA; 15-49 y), and to compare different inflammation adjustment approaches, if adjustment is warranted. METHODS:Cross-sectional data from 13 nationally representative surveys (18,859 PSC, 22,695 WRA) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed. Correlation and decile analyses were conducted, and the following 3 adjustment methods were compared if a consistent negative association between PZC and C-reactive protein (CRP) or α-1-acid glycoprotein (AGP) was observed: 1) exclude individuals with CRPngn5nmg/L or AGPngn1ng/L; 2) apply arithmetic correction factors; and 3) use the BRINDA regression correction (RC) approach. RESULTS:In 6 of 12 PSC surveys, the estimated prevalence of zinc deficiency increased with increasing CRP deciles, and to a lesser extent, with increasing AGP deciles. In WRA, the association of PZC with CRP and AGP was weak and inconsistent. In the 6 PSC surveys in which adjustment methods were compared, application of RC reduced the estimated prevalence of zinc deficiency by a median of 11 (range: 4-18) percentage points, compared with the unadjusted prevalence. CONCLUSIONS:Relations between PZC and inflammatory markers were inconsistent, suggesting that correlation and decile analyses should be conducted before applying any inflammation adjustments. In populations of PSC that exhibit a significant negative association between PZC and CRP or AGP, application of the RC approach is supported. At this time, there is insufficient evidence to warrant inflammation adjustment in WRA.

Objective:To measure fatty acid composition, particularly whole-blood PUFA content, in acutely malnourished children and identify associations with markers of nutritional and health status.Design:PUFA were assessed in dried blood spots obtained from a cross-sectional study. Nutritional and health status were assessed by anthropometry, haemoglobinopathies, inflammation and blood counts.Setting:Cambodia.Participants:The study was conducted with 174 children aged 0·5–18 years with acute malnutrition.Results:Among total fatty acids (FA), the relative percentage of total PUFA was 20 % FA, with 14 % of the children having very low PUFA (mead acid (MA):arachidonic acid (AA) >0·02,n-6 docosapentaenoic acid:DHA >0·2 and totaln-6:n-3 PUFA >10·5). Wasting was not associated with any PUFA. Stunting and low height were consistently positively associated with total PUFA and positively withn-6 PUFA. Height was positively associated withn-3 long-chain PUFA (LCPUFA). The presence of haemoglobinopathies or inflammation was positively associated with MA:AA, but not total PUFA. Elevated blood platelet counts were positively correlated with linoleic acid and appeared to be influenced by anaemia (P= 0·010) and inflammation (P= 0·002). Monocyte counts were high during inflammation (P= 0·052) and correlated positively withn-6 LCPUFA andn-3 LCPUFA.Conclusions:Children with acute malnutrition or stunting had low PUFA, while elevated platelets and monocytes were associated with high PUFA. In acutely malnourished children, inflammation could lead to elevated blood cell counts resulting in increased whole-blood PUFA which does not reflect dietary intake or nutritional status.

Background We assessed the usefulness of circulating tumor DNA (ctDNA) pre- or post-treatment initiation for outcome prediction and treatment monitoring in metastatic colorectal cancer (mCRC). Methods Droplet digital PCR was used to measure absolute mutant V-Ki-ras2 Kirsten rat sarcoma viral oncogene ((mut)KRAS) ctDNA concentrations in 214 healthy controls (plasma and sera) and in 151 tissue-based mutKRAS positive patients with mCRC from the prospective multicenter phase 3 trial AIO KRK0207. Serial mutKRAS ctDNA was analyzed prior to and 2–3 weeks after first-line chemotherapy initiation with fluoropyrimidine, oxaliplatin, and bevacizumab in patients with mCRC and correlated with clinical parameters. Results mut KRAS ctDNA was detected in 74.8% (113/151) of patients at baseline and in 59.6% (90/151) at follow-up. mutKRAS ctDNA at baseline and follow-up was associated with poor overall survival (OS) (hazard ratio [HR] =1.88, 95% confidence interval [CI] 1.20–2.95; HR = 2.15, 95% CI 1.47–3.15) and progression-free survival (PFS) (HR = 2.53, 95% CI 1.44–4.46; HR = 1.90, 95% CI 1.23–2.95), respectively. mutKRAS ctDNA clearance at follow-up conferred better disease control (P = 0.0075), better OS (log-rank P = 0.0018), and PFS (log-rank P = 0.0018). Measurable positive mutKRAS ctDNA at follow-up was the strongest and most significant independent prognostic factor on OS in multivariable analysis (HR = 2.31, 95% CI 1.40–3.25). Conclusions Serial analysis of circulating mutKRAS concentrations in mCRC has prognostic value. Post treatment mutKRAS concentrations 2 weeks after treatment initiation were associated with therapeutic response in multivariable analysis and may be an early response predictor in patients receiving first-line combination chemotherapy. Clinicaltrialsgov Identifier NCT00973609.

Quitting smoking among people living with HIV/AIDS (PLWHA) is a priority. aHowever, PLWHA and clinicians working with this population are reluctant to use tobacco use treatments out of concern that smoking cessation can diminish anti-retroviral therapy (ART) adherence and quality of life (QoL) and increase psychiatric symptoms. This secondary analysis from a placebo-controlled varenicline trial for tobacco dependence among PLWHA (N=179) examined if smoking cessation at the end of treatment (EOT) was associated with changes in ART adherence, QoL, anxiety and depression symptoms, and varenicline side effects. ART adherence was not affected by smoking cessation (p>0.05), remaining ≥98% for all participants. Across 8 subscales measuring QoL, 7 remained unchanged over time across smokers and abstainers; side effects were not associated with cessation. Controlling for baseline smoking rate, adherence to varenicline/placebo and counseling, and treatment arm, participants who had quit smoking at the EOT reported a significant reduction in depression (β = −1.657, 95% CI: −2.893, −0.422, p=.009) and anxiety (β = −1.434, 95% CI: −2.812, −0.56, p=.041) and increased life satisfaction (β = 0.88, 95% CI: 0.21, 3.275, p=.027). When PLWHA quit smoking they may not experience adverse clinical outcomes including ART non-adherence and may experience beneficial psychological effects, supporting the use of FDA-approved smoking cessation treatments in this population.

Background: Cambodia has a high prevalence of moderate acute malnutrition and severe acute malnutrition (SAM). The SAM treatment requires ready-to-use therapeutic foods (RUTFs), whereas ready-to-use supplementary foods (RUSFs) are used for prevention of acute malnutrition. Three locally produced fish-based products were developed: an RUTF paste (NumTrey-Paste) for treatment and 2 wafer versions, one for prevention (NumTrey-RUSF) and one for treatment (NumTrey-RUTF). Objective: To assess the acceptability of NumTrey-Paste and NumTrey-RUSF in comparison to a standard biscuit product (BP-100) used for the treatment of SAM. Methods: Acceptability of NumTrey-RUSF and NumTrey-Paste was tested in a nonblinded crossover taste trial among children (n = 52), aged ≥ 6 months to 18 years, and their caregivers. Eight organoleptic qualities were assessed on a 5-point hedonic scale, as well as a ranking test. A score of 1 to 3 was categorized as acceptable. The acceptability of NumTrey-RUTF was assessed using the caregivers’ perception during an SAM treatment intervention. Results: Taste trial: The proportion of children categorizing products as overall acceptable was lowest for NumTrey-Paste compared to for BP-100 and NumTrey-RUSF (21% vs 43% [BP-100] and 36% [NumTrey-RUSF]). No difference was found in the proportion of children who ranked BP-100 or NumTrey-RUSF as “liked most” ( P > .05). Acceptability of NumTrey-RUSF ranked highest in appearance and taste (caregiver), whereas acceptability of NumTrey-Paste was ranked lowest in appearance and smell among the products. Intervention trial: The acceptability of NumTrey-RUTF increased from 72% to 86%. Conclusions: The overall acceptability was ranked lowest for a pure paste product. However, filling the paste into a wafer made the product more acceptable.

PURPOSE: Assess systemic vascular endothelial growth factor-A (VEGF) levels after treatment with intravitreous aflibercept, bevacizumab or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab following a retreatment algorithm. PARTICIPANTS: Participants with available plasma samples (N=436) METHODS: Plasma samples were collected before injections at baseline, 4-week, 52-week and 104-week visits. In a pre-planned secondary analysis, systemic free-VEGF levels from an ELISA immunoassay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free-VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61, −0.31±0.54, −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted CI; P-value) were −0.01 (−0.12, +0.10; P=0.89), −0.31 (−0.44, −0.18; P

Background: Myocardial fibrosis is characterized by excessive cross‐linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross‐linking and/or deposition. Methods and results: We investigated 381 HFpEF patients from the multicentre, randomized, placebo‐controlled Aldo‐DHF trial with measures of the E:e' ratio. The ratio of serum carboxy‐terminal telopeptide of collagen type I to serum matrix metalloproteinase‐1 (CITP:MMP‐1, an inverse index of myocardial collagen cross‐linking) and serum carboxy‐terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1‐year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP‐1 and PICP tertiles at baseline. While CITP:MMP‐1 tertiles at baseline interacted (P

Elevated levels of arginine derivatives in the NO pathway, such as asymmetric dimethylarginine (ADMA), are related to disease severity and reduced exercise capacity in heart failure (HF). We investigated the influence of exercise intervention on these parameters and on L-arginine (L-Arg) and L-homoarginine (L-hArg) in HF with preserved ejection fraction (HFpEF) patients.Sixty-two patients (65 ± 6 years) were included in this analysis and randomized to supervised endurance/resistance training (ET) or to usual care (UC). EDTA-plasma was analysed for NO metabolites.There were baseline associations for adjusted values of maximum workload with ADMA (r= -0.322, p = 0.028) and L-Arg/ADMA ratio (r = 0.331, p = 0.015), and for the 6-min walk test (6MWT) with ADMA (r= -0.314, p = 0.024) and L-Arg/ADMA ratio (r = 0.346, p = 0.015). No significant differences between UC and ET changes of NO parameters were observed at 3-month follow-up. Higher L-hArg levels were associated with a greater improvement in peak oxygen uptake (peak [Formula: see text]OExercise intervention did not influence NO parameters in HFpEF patients, but L-hArg was related to change in peak [Formula: see text]O

Testicular torsion is the most concerning underlying cause of acute scrotal pain that can lead to loss of the affected testicle. Whether a torted testicle can be salvaged surgically is directly affected by prompt presentation and diagnosis. This study aims to evaluate the awareness of testicular torsion amongst Irish parents and evaluate their response to a potential torsion. An anonymous questionnaire was distributed to parents attending general paediatric clinics and an acute paediatric unit in two paediatric tertiary referral centres. SPSS statistical analysis software was used to perform multivariant analysis of the data. There were 242 completed surveys. Fifty-six percent of responders had an awareness of torsion. In the event of an episode of severe testicular pain parents who were aware of testicular torsion were 4 times more likely to present immediately than those who had no awareness of torsion (OR 4.2, 95% CI 1.4–12.2, P