Left Atrial Structure and Function in Heart Failure with Preserved Ejection Fraction: A RELAX Substudy

Given the emerging recognition of left atrial structure and function as an important marker of disease in heart failure with preserved ejection fraction (HF-pEF), we investigated the association between left atrial volume and function with markers of disease severity and cardiac structure in HF-pEF. We studied 100 patients enrolled in the PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) trial who underwent cardiac magnetic resonance (CMR), cardiopulmonary exercise testing, and blood collection before randomization. Maximal left atrial volume index (LAVi; N = 100), left atrial emptying fraction (LAEF; N = 99; including passive and active components (LAEF_P, LAEF_A; N = 80, 79, respectively) were quantified by CMR. After adjustment for multiple testing, maximal LAVi was only associated with age (ρ = 0.39), transmitral filling patterns (medial E/e’ ρ = 0.43), and N-terminal pro-BNP (NT-proBNP; ρ = 0.65; all p<0.05). Lower LAEF was associated with older age, higher transmitral E/A ratio and higher NT-proBNP. Peak VO₂ and V_E/VCO₂ slope were not associated with left atrial structure or function. After adjustment for age, sex, transmitral E/A ratio, CMR LV mass, LV ejection fraction, and creatinine clearance, NT-proBNP remained associated with maximal LAVi (β = 0.028, p = 0.0007) and total LAEF (β = -0.033, p = 0.001). Passive and active LAEF were most strongly associated with age and NT-proBNP, but not gas exchange or other markers of ventricular structure or filling properties. Left atrial volume and emptying function are associated most strongly with NT-proBNP and diastolic filling properties, but not significantly with gas exchange, in HFpEF. Further research to explore the relevance of left atrial structure and function in HF-pEF is warranted.     

Mortality,Morbidity, and Developmental Outcomes in Infants Born to Women Who Received Either Mefloquine or Sulfadoxine-Pyrimethamine as Intermittent Preventive Treatment of Malaria in Pregnancy: A Cohort Study

Background

Little is known about the effects of intermittent preventive treatment of malaria in pregnancy (IPTp) on the health of sub-Saharan African infants. We have evaluated the safety of IPTp with mefloquine (MQ) compared to sulfadoxine-pyrimethamine (SP) for important infant health and developmental outcomes.

Methods and Findings

In the context of a multicenter randomized controlled trial evaluating the safety and efficacy of IPTp with MQ compared to SP in pregnancy carried out in four sub-Saharan countries (Mozambique, Benin, Gabon, and Tanzania), 4,247 newborns, 2,815 born to women who received MQ and 1,432 born to women who received SP for IPTp, were followed up until 12 mo of age. Anthropometric parameters and psychomotor development were assessed at 1, 9, and 12 mo of age, and the incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were determined until 12 mo of age. No significant differences were found in the proportion of infants with stunting, underweight, wasting, and severe acute malnutrition at 1, 9, and 12 mo of age between infants born to women who were on IPTp with MQ versus SP. Except for three items evaluated at 9 mo of age, no significant differences were observed in the psychomotor development milestones assessed. Incidence of malaria, anemia, hospital admissions, outpatient visits, and mortality were similar between the two groups. Information on the outcomes at 12 mo of age was unavailable in 26% of the infants, 761 (27%) from the MQ group and 377 (26%) from the SP group. Reasons for not completing the study were death (4% of total study population), study withdrawal (6%), migration (8%), and loss to follow-up (9%).

Conclusions

No significant differences were found between IPTp with MQ and SP administered in pregnancy on infant mortality, morbidity, and nutritional outcomes. The poorer performance on certain psychomotor development milestones at 9 mo of age in children born to women in the MQ group compared to those in the SP group may deserve further studies.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00811421","term_id":"NCT00811421"}}NCT00811421     

Population attenuation in zooplankton communities during transoceanic transfer in ballast water

Successful biological invasion requires introduction of a viable population of a nonindigenous species (NIS). Rarely have ecologists assessed changes in populations while entrained in invasion pathways. Here, we investigate how zooplankton communities resident in ballast water change during transoceanic voyages. We used next‐generation sequencing technology to sequence a nuclear small subunit ribosomal DNA fragment of zooplankton from ballast water during initial, middle, and final segments as a vessel transited between Canada and Brazil. Operational taxonomic unit (OTU) diversity decreased as voyage duration increased, indicating loss of community‐based genetic diversity and development of bottlenecks for zooplankton taxa prior to discharge of ballast water. On average, we observed 47, 26, and 24 OTUs in initial, middle, and final samples, respectively. Moreover, a comparison of genetic diversity within taxa indicated likely attenuation of OTUs in final relative to initial samples. Abundance of the most common taxa (copepods) declined in all final relative to initial samples. Some taxa (e.g., Copepoda) were represented by a high number of OTUs throughout the voyage, and thus had a high level of intraspecific genetic variation. It is not clear whether genotypes that were most successful in surviving transit in ballast water will be the most successful upon introduction to novel environments. This study highlights that population bottlenecks may be common prior to introduction of NIS to new ecosystems.     

Mean Recency Period for Estimation of HIV-1 Incidence with the BED-Capture EIA and Bio-Rad Avidity in Persons Diagnosed in the United States with Subtype B

HIV incidence estimates are used to monitor HIV-1 infection in the United States. Use of laboratory biomarkers that distinguish recent from longstanding infection to quantify HIV incidence rely on having accurate knowledge of the average time that individuals spend in a transient state of recent infection between seroconversion and reaching a specified biomarker cutoff value. This paper describes five estimation procedures from two general statistical approaches, a survival time approach and an approach that fits binomial models of the probability of being classified as recently infected, as a function of time since seroconversion. We compare these procedures for estimating the mean duration of recent infection (MDRI) for two biomarkers used by the U.S. National HIV Surveillance System for determination of HIV incidence, the Aware BED EIA HIV-1 incidence test (BED) and the avidity-based, modified Bio-Rad HIV-1/HIV-2 plus O ELISA (BRAI) assay. Collectively, 953 specimens from 220 HIV-1 subtype B seroconverters, taken from 5 cohorts, were tested with a biomarker assay. Estimates of MDRI using the non-parametric survival approach were 198.4 days (SD 13.0) for BED and 239.6 days (SD 13.9) for BRAI using cutoff values of 0.8 normalized optical density and 30%, respectively. The probability of remaining in the recent state as a function of time since seroconversion, based upon this revised statistical approach, can be applied in the calculation of annual incidence in the United States.     

Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model

B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-X_L and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL.     

Serotypes and Clonal Diversity of Streptococcus pneumoniae Causing Invasive Disease in the Era of PCV13 in Catalonia,Spain

The aim of this study was to study the serotypes and clonal diversity of pneumococci causing invasive pneumococcal disease in Catalonia, Spain, in the era of 13-valent pneumococcal conjugate vaccine (PCV13). In our region, this vaccine is only available in the private market and it is estimated a PCV13 vaccine coverage around 55% in children. A total of 1551 pneumococcal invasive isolates received between 2010 and 2013 in the Molecular Microbiology Department at Hospital Sant Joan de Déu, Barcelona, were included. Fifty-two serotypes and 249 clonal types—defined by MLST—were identified. The most common serotypes were serotype 1 (n = 182; 11.7%), 3 (n = 145; 9.3%), 19A (n = 137; 8.8%) and 7F (n = 122; 7.9%). Serotype 14 was the third most frequent serotype in children < 2 years (15 of 159 isolates). PCV7 serotypes maintained their proportion along the period of study, 16.6% in 2010 to 13.4% in 2013, whereas there was a significant proportional decrease in PCV13 serotypes, 65.3% in 2010 to 48.9% in 2013 (p<0.01). This decrease was mainly attributable to serotypes 19A and 7F. Serotype 12F achieved the third position in 2013 (n = 22, 6.4%). The most frequent clonal types found were ST306 (n = 154, 9.9%), ST191 (n = 111, 7.2%), ST989 (n = 85, 5.5%) and ST180 (n = 80, 5.2%). Despite their decrease, PCV13 serotypes continue to be a major cause of disease in Spain. These results emphasize the need for complete PCV13 vaccination.     

Functional Dentition in Brazilian Adults: An Investigation of Social Determinants of Health (SDH) Using a Multilevel Approach

Objectives

Estimate the prevalence of functional dentition among Brazilian adults using four different definitions and identify associated factors.

Methods

A cross-sectional study was conducted involving 9564 Brazilian adults aged 35–44 years who participated in the 2010 National Oral Health Survey. Data collection involved oral examinations and the administration of questionnaires. The following definitions were used: 1—WHO Functional Dentition (FDWHO: ≥ 20 teeth present); 2—well-distributed teeth (WDT: ≥ 10 teeth in each arch); 3 –Functional dentition classified by esthetics and occlusion (FD_Class5: dentitions that sequentially exhibit at least one tooth in each arch, at least 10 teeth in each arch, all maxillary and mandibular anterior teeth, three or four premolar posterior occluding pairs [POPs], and at least one molar POP bilaterally); 4—Functional dentition classified by esthetics, occlusion and periodontal status (FD_Class6: corresponds to FD_Class5 with the addition of periodontal status of all sextants in the oral cavity with, at most, shallow pockets and/or clinical attachment level of 5 mm (CPI ≤ 3 and/or CAL ≤ 1). The independent variables were individual factors (gender, self-declared skin color, schooling, monthly household income, age group, self-rated treatment need, dental pain, dental appointment in the previous 12 months and dental services) and contextual factors (Municipal Human Development Index [MHDI]), Gini coefficient, fluoridated water supply and oral health coverage). Multilevel mixed-effect Poisson regression analyses were performed.

Results

The prevalence of functional dentition based on the FDWHO, WDT, FD_Class5 and FD_Class6 definitions was 77.9%, 72.9%, 42.6% and 40.3%, respectively. Adults with ≥12 years of schooling and monthly household income from US$ 853 to 2557 had higher prevalence rates of FDWHO (PR: 1.41 and 1.10, respectively), WDT (PR: 1.58 and 1.14, respectively), FD_Class5 (PR: 2.03 and 1.27, respectively) and FD_Class6 (PR: 2.15 and 1.35, respectively). These values in the final models were adjusted for gender, self-declared skin color (FD_Class5), age group, self-rated treatment need (FDWHO, FD_Class5 and FD_Class6), dental appointment in the previous 12 months (FDWHO and WDT), dental services (FDWHO and WDT) and contextual factors. A very high MHDI and presence of fluoridated water supply were associated with higher prevalence rates of the four outcomes.

Conclusions

The incorporation of the criteria of new definitions of functional dentition led to a lower prevalence rate among Brazilian adults. Striking individual and contextual inequalities were identified with regard to the four definitions analyzed, which need to be addressed through inter-sector efforts.     

Aging Dogs Manifest Myopia as Measured by Autorefractor

Objective

Dogs, like humans, experience eye changes with aging: hardening and clouding of the lens and accumulated oxidative damage from UV sunlight. It has been debated whether such changes could be affecting the visual function of dogs. The objective of this study was to determine if autorefractometry could be used to measure visual function in dogs.

Animals and Methods

Nine Beagle dogs (ages 1 to 14 years) were examined by a veterinary ophthalmologist and their eyes determined to be free of cataracts. Spherical equivalent refractive error was measured by handheld autorefractor (Welch Allyn SureSight) under both indirect and direct lighting conditions with five measurements per condition, per eye. Measures were repeated on three different days for each dog within six weeks. Nonparametric statistics were used to detect differences among lighting conditions and test days, and between eyes. Spearmen correlation assessed the visual measurement outcomes’ association with age.

Results

There was no difference for day-to-day or between-eye measurements. Significantly, the Beagles showed a myopic shift with aging (average spherical equivalent ranged from plano to -3.00 diopters), suggesting that dogs become more near-sighted as they age (r = -0.48 and -0.73 under direct and indirect lights; p<0.05 both). Younger dogs were able to make larger accommodation changes from indirect light to direct light conditions, indicating a more flexible lens (r = -0.50, p<0.05).

Conclusions

Although designed for humans, the hand-held autorefractor technique is applicable to dogs and sensitive to light conditions. The age-associated myopic shift could be expected to compromise dogs’ visual functions.     

The formation of titan cells in Cryptococcus neoformans depends on the mouse strain and correlates with induction of Th2‐type responses

Cryptococcus neoformans is a pathogenic yeast that can form titan cells in the lungs, which are fungal cells of abnormal enlarged size. Little is known about the factors that trigger titan cells. In particular, it is not known how the host environment influences this transition. In this work, we describe the formation of titan cells in two mouse strains, CD1 and C57BL/6J. We found that the proportion of C. neoformans titan cells was significantly higher in C57BL/6J mice than in CD1. This higher proportion of titan cells was associated with a higher dissemination of the yeasts to the brain. Histology sections demonstrated eosinophilia in infected animals, although it was significantly lower in the CD1 mice which presented infiltration of lymphocytes. Both mouse strains presented infiltration of granulocytes, but the amount of eosinophils was higher in C57BL/6J. CD1 mice showed a significant accumulation of IFN‐γ, TNF‐α and IL17, while C57BL/BL mice had an increase in the anti‐inflammatory cytokine IL‐4. IgM antibodies to the polysaccharide capsule and total IgE were more abundant in the sera from C57BL/6J, confirming that these animals present a Th2‐type response. We conclude that titan cell formation in C. neoformans depends, not only on microbe factors, but also on the host environment.     

Potential use of high levels of vegetal proteins in diets for market-sized gilthead sea bream (Sparus aurata)

The effect of partial or total dietary substitution of fishmeal (FM) by vegetal protein sources on growth and feed efficiency was carried out in on-growing gilthead sea bream (mean initial weight 131 g). The Control diet (FM 100) contained FM as the primary protein source, while in Diets FM 25 and FM 0 the FM protein was replaced at 75% and 100%, respectively, by a vegetable protein mixture consisting of wheat gluten, soybean meal, rapeseed meal and crystalline amino acids. Diets FM 25 and FM 0 also contained krill meal at 47 g/kg in order to improve palatability. At the end of the trial (after 158 d), fish survival was above 90%. Final weight and the specific growth rate were statistically lower in fish fed the Control diet (361 g and 0.64%/d), compared with 390–396 g and 0.69–0.70%/d after feeding vegetal diets. No significant differences were found regarding feed intake and feed conversion ratio. The digestibility of protein and amino acids (determined with chromium oxide as indicator) was similar in all diets. The blood parameters were not significantly affected by treatments. The activity of trypsin and pepsin was significantly reduced after feeding Diet FM 0. In the distal intestine, the villi length in fish fed Diet FM 25 was significantly longer and the intestine of the fish fed the FM 100 diet showed a smaller number of goblet cells. In conclusion, a total FM substitution by a vegetal mix supplemented with synthetic amino acids in on-growing sea bream is feasible.