Association of nutritional risk and adverse medical outcomes across different medical inpatient populations

OBJECTIVE The aim of this study was to examine the prevalence of nutritional risk and its association with multiple adverse clinical outcomes in a large cohort of acutely ill medical inpatients from a Swiss tertiary care hospital. METHODS We prospectively followed consecutive adult medical inpatients for 30 d. Multivariate regression models were used to investigate the association of the initial Nutritional Risk Score (NRS 2002) with mortality, impairment in activities of daily living (Barthel Index <95 points), hospital length of stay, hospital readmission rates, and quality of life (QoL; adapted from EQ5 D); all parameters were measured at 30 d. RESULTS Of 3186 patients (mean age 71 y, 44.7% women), 887 (27.8%) were at risk for malnutrition with an NRS ≥3 points. We found strong associations (odds ratio/hazard ratio [OR/HR], 95% confidence interval [CI]) between nutritional risk and mortality (OR/HR, 7.82; 95% CI, 6.04-10.12), impaired Barthel Index (OR/HR, 2.56; 95% CI, 2.12-3.09), time to hospital discharge (OR/HR, 0.48; 95% CI, 0.43-0.52), hospital readmission (OR/HR, 1.46; 95% CI, 1.08-1.97), and all five dimensions of QoL measures. Associations remained significant after adjustment for sociodemographic characteristics, comorbidities, and medical diagnoses. Results were robust in subgroup analysis with evidence of effect modification (P for interaction < 0.05) based on age and main diagnosis groups. CONCLUSION Nutritional risk is significant in acutely ill medical inpatients and is associated with increased medical resource use, adverse clinical outcomes, and impairments in functional ability and QoL. Randomized trials are needed to evaluate evidence-based preventive and treatment strategies focusing on nutritional factors to improve outcomes in these high-risk patients.

Thyroid disruption in zebrafish (Danio rerio) larvae: Different molecular response patterns lead to impaired eye development and visual functions

The vertebrate thyroid system is important for multiple developmental processes, including eye development. Thus, its environmentally induced disruption may impact important fitness-related parameters like visual capacities and behaviour. The present study investigated the relation between molecular effects of thyroid disruption and morphological and physiological changes of eye development in zebrafish (Danio rerio). Two test compounds representing different molecular modes of thyroid disruption were used: propylthiouracil (PTU), which is an enzyme-inhibitor of thyroid hormone synthesis, and tetrabromobisphenol A (TBBPA), which interacts with the thyroid hormone receptors. Both chemicals significantly altered transcript levels of thyroid system-related genes (TRα, TRβ, TPO, TSH, DIO1, DIO2 and DIO3) in a compound-specific way. Despite these different molecular response patterns, both treatments resulted in similar pathological alterations of the eyes such as reduced size, RPE cell diameter and pigmentation, which were concentration-dependent. The morphological changes translated into impaired visual performance of the larvae: the optokinetic response was significantly and concentration-dependently decreased in both treatments, together with a significant increase of light preference of PTU-treated larvae. In addition, swimming activity was impacted. This study provides first evidence that different modes of molecular action of the thyroid disruptors can be associated with uniform apical responses. Furthermore, this study is the first to show that pathological eye development, as it can be induced by exposure to thyroid disruptors, indeed translates into impaired visual capacities of zebrafish early life stages.

Pitfalls of practicing cancer epidemiology in resource-limited settings: the case of survival and loss to follow-up after a diagnosis of Kaposi's sarcoma in five countries across sub-Saharan Africa.

BACKGROUND Survival after diagnosis is a fundamental concern in cancer epidemiology. In resource-rich settings, ambient clinical databases, municipal data and cancer registries make survival estimation in real-world populations relatively straightforward. In resource-poor settings, given the deficiencies in a variety of health-related data systems, it is less clear how well we can determine cancer survival from ambient data. METHODS We addressed this issue in sub-Saharan Africa for Kaposi's sarcoma (KS), a cancer for which incidence has exploded with the HIV epidemic but for which survival in the region may be changing with the recent advent of antiretroviral therapy (ART). From 33 primary care HIV Clinics in Kenya, Uganda, Malawi, Nigeria and Cameroon participating in the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Consortia in 2009-2012, we identified 1328 adults with newly diagnosed KS. Patients were evaluated from KS diagnosis until death, transfer to another facility or database closure. RESULTS Nominally, 22% of patients were estimated to be dead by 2 years, but this estimate was clouded by 45% cumulative lost to follow-up with unknown vital status by 2 years. After adjustment for site and CD4 count, age <30 years and male sex were independently associated with becoming lost. CONCLUSIONS In this community-based sample of patients diagnosed with KS in sub-Saharan Africa, almost half became lost to follow-up by 2 years. This precluded accurate estimation of survival. Until we either generally strengthen data systems or implement cancer-specific enhancements (e.g., tracking of the lost) in the region, insights from cancer epidemiology will be limited.

Multiple regulatory variants located in cell type-specific enhancers within the PKP2 locus form major risk and protective haplotypes for canine atopic dermatitis in German shepherd dogs.

BACKGROUND Canine atopic dermatitis (CAD) is a chronic inflammatory skin disease triggered by allergic reactions involving IgE antibodies directed towards environmental allergens. We previously identified a ~1.5 Mb locus on canine chromosome 27 associated with CAD in German shepherd dogs (GSDs). Fine-mapping indicated association closest to the PKP2 gene encoding plakophilin 2. RESULTS Additional genotyping and association analyses in GSDs combined with control dogs from five breeds with low-risk for CAD revealed the top SNP 27:19,086,778 (p = 1.4 × 10(-7)) and a rare ~48 kb risk haplotype overlapping the PKP2 gene and shared only with other high-risk CAD breeds. We selected altogether nine SNPs (four top-associated in GSDs and five within the ~48 kb risk haplotype) that spanned ~280 kb forming one risk haplotype carried by 35 % of the GSD cases and 10 % of the GSD controls (OR = 5.1, p = 5.9 × 10(-5)), and another haplotype present in 85 % of the GSD cases and 98 % of the GSD controls and conferring a protective effect against CAD in GSDs (OR = 0.14, p = 0.0032). Eight of these SNPs were analyzed for transcriptional regulation using reporter assays where all tested regions exerted regulatory effects on transcription in epithelial and/or immune cell lines, and seven SNPs showed allelic differences. The DNA fragment with the top-associated SNP 27:19,086,778 displayed the highest activity in keratinocytes with 11-fold induction of transcription by the risk allele versus 8-fold by the control allele (pdifference = 0.003), and also mapped close (~3 kb) to an ENCODE skin-specific enhancer region. CONCLUSIONS Our experiments indicate that multiple CAD-associated genetic variants located in cell type-specific enhancers are involved in gene regulation in different cells and tissues. No single causative variant alone, but rather multiple variants combined in a risk haplotype likely contribute to an altered expression of the PKP2 gene, and possibly nearby genes, in immune and epithelial cells, and predispose GSDs to CAD.

Estimating loss to follow-up in HIV-infected patients on antiretroviral therapy: the effect of the competing risk of death in Zambia and Switzerland

Background Loss to follow-up (LTFU) is common in antiretroviral therapy (ART) programmes. Mortality is a competing risk (CR) for LTFU; however, it is often overlooked in cohort analyses. We examined how the CR of death affected LTFU estimates in Zambia and Switzerland. Methods and Findings HIV-infected patients aged ≥18 years who started ART 2004–2008 in observational cohorts in Zambia and Switzerland were included. We compared standard Kaplan-Meier curves with CR cumulative incidence. We calculated hazard ratios for LTFU across CD4 cell count strata using cause-specific Cox models, or Fine and Gray subdistribution models, adjusting for age, gender, body mass index and clinical stage. 89,339 patients from Zambia and 1,860 patients from Switzerland were included. 12,237 patients (13.7%) in Zambia and 129 patients (6.9%) in Switzerland were LTFU and 8,498 (9.5%) and 29 patients (1.6%), respectively, died. In Zambia, the probability of LTFU was overestimated in Kaplan-Meier curves: estimates at 3.5 years were 29.3% for patients starting ART with CD4 cells <100 cells/µl and 15.4% among patients starting with ≥350 cells/µL. The estimates from CR cumulative incidence were 22.9% and 13.6%, respectively. Little difference was found between naïve and CR analyses in Switzerland since only few patients died. The results from Cox and Fine and Gray models were similar: in Zambia the risk of loss to follow-up and death increased with decreasing CD4 counts at the start of ART, whereas in Switzerland there was a trend in the opposite direction, with patients with higher CD4 cell counts more likely to be lost to follow-up. Conclusions In ART programmes in low-income settings the competing risk of death can substantially bias standard analyses of LTFU. The CD4 cell count and other prognostic factors may be differentially associated with LTFU in low-income and high-income settings.

Oral contraceptives and the risk of thrombosis and atherosclerosis.

Oral contraceptives containing synthetic oestrogens have been used successfully as birth control for > 40 years and are currently prescribed to > 100 million women worldwide. Several new progestins have been introduced and the third generation of progestins has now been available for two decades. Oral contraceptives are prescribed over a prolonged period of time and therefore substantially impact on hormonal, metabolic and plasmatic functions. Oral contraceptives increase the risk for venous thrombosis and pulmonary embolism, particularly if associated with confounding factors, such as genetic predisposition, smoking, hypertension or obesity. The risk of developing coronary artery disease is also increased in users with cardiovascular risk factors. This article discusses mechanistic and clinical issues and reviews the need for novel approaches targeting the considerable side effects in order to reduce cardiovascular morbidity in women using oral contraceptives.

Influence of Gestational Age and Parental Education on Executive Functions of Children Born Very Preterm

Background: Children born very preterm (<32 weeks’ gestational age; VPT) and/or very low birth weight (<1500 g; VLBW) are at high risk of deficits in executive functions, namely inhibition, working memory, and shifting. Both, gestational age and socioeconomic factors, such as parental education, are known to influence executive functions, with children born at lower gestational age and with lower educated parents displaying worse executive skills. This study aimed to investigate if maternal and paternal education moderated the relationship between gestational age and executive functions in VPT/VLBW children aged 8-12 years. It was hypothesised that the disadvantageous effect of low gestational age could be buffered more easily in families with higher educational background. Methods: Sixty VPT/VLBW children born in the cohort of 1998-2003 were recruited. All children completed executive function tasks (inhibition, working memory, and shifting). Results: There was a significant dose-response-relationship between gestational age and inhibition, with children being born at earlier gestational age showing worse inhibition. However, neither maternal nor paternal education moderated the relationship between gestational age and executive functions significantly. Conclusion: children than parental education. The disadvantageous effect of low gestational age was equal in children with higher and lower educated parents. However, the impact of gestational age and parental education on executive functions may differ depending on the socioeconomic spectrum of the study sample.

Designer aminoglycosides prevent cochlear hair cell loss and hearing loss.

Bacterial infections represent a rapidly growing challenge to human health. Aminoglycosides are widely used broad-spectrum antibiotics, but they inflict permanent hearing loss in up to ~50% of patients by causing selective sensory hair cell loss. Here, we hypothesized that reducing aminoglycoside entry into hair cells via mechanotransducer channels would reduce ototoxicity, and therefore we synthesized 9 aminoglycosides with modifications based on biophysical properties of the hair cell mechanotransducer channel and interactions between aminoglycosides and the bacterial ribosome. Compared with the parent aminoglycoside sisomicin, all 9 derivatives displayed no or reduced ototoxicity, with the lead compound N1MS 17 times less ototoxic and with reduced penetration of hair cell mechanotransducer channels in rat cochlear cultures. Both N1MS and sisomicin suppressed growth of E. coli and K. pneumoniae, with N1MS exhibiting superior activity against extended spectrum β lactamase producers, despite diminished activity against P. aeruginosa and S. aureus. Moreover, systemic sisomicin treatment of mice resulted in 75% to 85% hair cell loss and profound hearing loss, whereas N1MS treatment preserved both hair cells and hearing. Finally, in mice with E. coli-infected bladders, systemic N1MS treatment eliminated bacteria from urinary tract tissues and serially collected urine samples, without compromising auditory and kidney functions. Together, our findings establish N1MS as a nonototoxic aminoglycoside and support targeted modification as a promising approach to generating nonototoxic antibiotics.

Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk.

AIMS High-density lipoproteins (HDLs) are considered as anti-atherogenic. Recent experimental findings suggest that their biological properties can be modified in certain clinical conditions by accumulation of serum amyloid A (SAA). The effect of SAA on the association between HDL-cholesterol (HDL-C) and cardiovascular outcome remains unknown. METHODS AND RESULTS We examined the association of SAA and HDL-C with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, which included 3310 patients undergoing coronary angiography. To validate our findings, we analysed 1255 participants of the German Diabetes and Dialysis study (4D) and 4027 participants of the Cooperative Health Research in the Region of Augsburg (KORA) S4 study. In LURIC, SAA concentrations predicted all-cause and cardiovascular mortality. In patients with low SAA, higher HDL-C was associated with lower all-cause and cardiovascular mortality. In contrast, in patients with high SAA, higher HDL-C was associated with increased all-cause and cardiovascular mortality, indicating that SAA indeed modifies the beneficial properties of HDL. We complemented these clinical observations by in vitro experiments, in which SAA impaired vascular functions of HDL. We further derived a formula for the simple calculation of the amount of biologically 'effective' HDL-C based on measured HDL-C and SAA from the LURIC study. In 4D and KORA S4 studies, we found that measured HDL-C was not associated with clinical outcomes, whereas calculated 'effective' HDL-C significantly predicted better outcome. CONCLUSION The acute-phase protein SAA modifies the biological effects of HDL-C in several clinical conditions. The concomitant measurement of SAA is a simple, useful, and clinically applicable surrogate for the vascular functionality of HDL.

High-altitude exposure in patients with cardiovascular disease: risk assessment and practical recommendations

Because of the development of modern transportation facilities, an ever rising number of individuals including many patients with preexisting diseases visit high-altitude locations (>2500 m). High-altitude exposure triggers a series of physiologic responses intended to maintain an adequate tissue oxygenation. Even in normal subjects, there is enormous interindividual variability in these responses that may be further amplified by environmental factors such as cold temperature, low humidity, exercise, and stress. These adaptive mechanisms, although generally tolerated by most healthy subjects, may induce major problems in patients with preexisting cardiovascular diseases in which the functional reserves are already limited. Preexposure assessment of patients helps to minimize risk and detect contraindications to high-altitude exposure. Moreover, the great variability and nonpredictability of the adaptive response should encourage physicians counseling such patients to adapt a cautionary approach. Here, we will briefly review how high-altitude adjustments may interfere with and aggravate/decompensate preexisting cardiovascular diseases. Moreover, we will provide practical recommendations on how to investigate and counsel patients with cardiovascular disease desiring to travel to high-altitude locations.