The VITAH Trial-Vitamin D Supplementation and Cardiac Autonomic Tone in Patients with End-Stage Kidney Disease on Hemodialysis: A Blinded, Randomized Controlled Trial

End-stage kidney disease (ESKD) patients are at increased cardiovascular risk. Vitamin D deficiency is associated with depressed heart rate variability (HRV), a risk factor depicting poor cardiac autonomic tone and risk of cardiovascular death. Vitamin D deficiency and depressed HRV are highly prevalent in the ESKD population. We aimed to determine the effects of oral vitamin D supplementation on HRV ((low frequency (LF) to high frequency (HF) spectral ratio (LF:HF)) in ESKD patients on hemodialysis. Fifty-six subjects with ESKD requiring hemodialysis were recruited from January 2013-March 2015 and randomized 1:1 to either conventional (0.25 mcg alfacalcidol plus placebo 3×/week) or intensive (0.25 mcg alfacalcidol 3×/week plus 50,000 international units (IU) ergocalciferol 1×/week) vitamin D for six weeks. The primary outcome was the change in LF:HF. There was no difference in LF:HF from baseline to six weeks for either vitamin D treatment (conventional: p = 0.9 vs. baseline; intensive: p = 0.07 vs. baseline). However, participants who remained vitamin D-deficient (25-hydroxyvitamin D < 20 ng/mL) after treatment demonstrated an increase in LF:HF (conventional: n = 13, ∆LF:HF: 0.20 ± 0.06, p < 0.001 vs. insufficient and sufficient vitamin D groups; intensive: n = 8: ∆LF:HF: 0.15 ± 0.06, p < 0.001 vs. sufficient vitamin D group). Overall, six weeks of conventional or intensive vitamin D only augmented LF:HF in ESKD subjects who remained vitamin D-deficient after treatment. Our findings potentially suggest that while activated vitamin D, with or without additional nutritional vitamin D, does not appear to improve cardiac autonomic tone in hemodialysis patients with insufficient or sufficient baseline vitamin D levels, supplementation in patients with severe vitamin D deficiency may improve cardiac autonomic tone in this higher risk sub-population of ESKD. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01774812

Consensus on circulatory shock and hemodynamic monitoring. Task force of the European Society of Intensive Care Medicine.

OBJECTIVE: Circulatory shock is a life-threatening syndrome resulting in multiorgan failure and a high mortality rate. The aim of this consensus is to provide support to the bedside clinician regarding the diagnosis, management and monitoring of shock. METHODS: The European Society of Intensive Care Medicine invited 12 experts to form a Task Force to update a previous consensus (Antonelli et al.: Intensive Care Med 33:575-590, 2007). The same five questions addressed in the earlier consensus were used as the outline for the literature search and review, with the aim of the Task Force to produce statements based on the available literature and evidence. These questions were: (1) What are the epidemiologic and pathophysiologic features of shock in the intensive care unit ? (2) Should we monitor preload and fluid responsiveness in shock ? (3) How and when should we monitor stroke volume or cardiac output in shock ? (4) What markers of the regional and microcirculation can be monitored, and how can cellular function be assessed in shock ? (5) What is the evidence for using hemodynamic monitoring to direct therapy in shock ? Four types of statements were used: definition, recommendation, best practice and statement of fact. RESULTS: Forty-four statements were made. The main new statements include: (1) statements on individualizing blood pressure targets; (2) statements on the assessment and prediction of fluid responsiveness; (3) statements on the use of echocardiography and hemodynamic monitoring. CONCLUSIONS: This consensus provides 44 statements that can be used at the bedside to diagnose, treat and monitor patients with shock

Antecedent Avian Immunity Limits Tangential Transmission of West Nile Virus to Humans

Background: West Nile virus (WNV) is a mosquito-borne flavivirus maintained and amplified among birds and tangentially transmitted to humans and horses which may develop terminal neuroinvasive disease. Outbreaks typically have a three-year pattern of silent introduction, rapid amplification and subsidence, followed by intermittent recrudescence. Our hypothesis that amplification to outbreak levels is contingent upon antecedent seroprevalence within maintenance host populations was tested by tracking WNV transmission in Los Angeles, California from 2003 through 2011. Methods: Prevalence of antibodies against WNV was monitored weekly in House Finches and House Sparrows. Tangential or spillover transmission was measured by seroconversions in sentinel chickens and by the number of West Nile neuroinvasive disease (WNND) cases reported to the Los Angeles County Department of Public Health. Results: Elevated seroprevalence in these avian populations was associated with the subsidence of outbreaks and in the antecedent dampening of amplification during succeeding years. Dilution of seroprevalence by recruitment resulted in the progressive loss of herd immunity following the 2004 outbreak, leading to recrudescence during 2008 and 2011. WNV appeared to be a significant cause of death in these avian species, because the survivorship of antibody positive birds significantly exceeded that of antibody negative birds. Cross-correlation analysis showed that seroprevalence was negatively correlated prior to the onset of human cases and then positively correlated, peaking at 4–6 weeks after the onse

The stellar halo of the Galaxy

Stellar halos may hold some of the best preserved fossils of the formation history of galaxies. They are a natural product of the merging processes that probably take place during the assembly of a galaxy, and hence may well be the most ubiquitous component of galaxies, independently of their Hubble type. This review focuses on our current understanding of the spatial structure, the kinematics and chemistry of halo stars in the Milky Way. In recent years, we have experienced a change in paradigm thanks to the discovery of large amounts of substructure, especially in the outer halo. I discuss the implications of the currently available observational constraints and fold them into several possible formation scenarios. Unraveling the formation of the Galactic halo will be possible in the near future through a combination of large wide field photometric and spectroscopic surveys, and especially in the era of Gaia.Comment: 46 pages, 16 figures. References updated and some minor changes. Full-resolution version available at http://www.astro.rug.nl/~ahelmi/stellar-halo-review.pd

Human papillomavirus ‘reflex' testing as a screening method in cases of minor cytological abnormalities

The aim was to evaluate human papillomavirus (HPV) ‘reflex genotyping' in cases of minor cytological abnormalities detected in the gynaecological screening programme in Stockholm, Sweden. Liquid-based cytology samples showing minor cytological abnormalities were analysed using HPV genotyping (Linear Array, Roche diagnostics). Colposcopically directed cervical biopsies were obtained and the HPV test results were correlated with the histological results. In all, 63% (70/112) of the samples were high-risk (HR) HPV (HR-HPV) positive. A statistically significant correlation was found between high-grade cervical lesions and HR-HPV (P=0.019), among which HPV 16, 18, and 31 were the most important. The negative predictive value of HR-HPV detection for histologically confirmed high-grade lesions was 100%. An age limit for HPV reflex testing may be motivated in cases of low-grade squamous intraepithelial neoplasia (LSIL), because of high HR-HPV prevalence among younger women. By using HPV reflex genotyping, additional extensive workup can safely be avoided in about 50% of all cases of atypical squamous cells of undetermined significance (ASCUS) and LSIL among women ⩾30 years. This screening strategy could potentially reduce the total abnormal cytology-reporting rate in the Swedish screening programme by about 1% and provide more accurately directed follow-up, guided by cytological appearance and HPV test results

The basidiomycetous yeast Trichosporon may cause severe lung exacerbation in cystic fibrosis patients - clinical analysis of Trichosporon positive patients in a Munich cohort

Background: The relevance of Trichosporon species for cystic fibrosis (CF) patients has not yet been extensively investigated. Methods: The clinical course of CF patients with Trichosporon spp. in their respiratory secretions was analysed between 2003 and 2010 in the Munich CF center. All respiratory samples of 360 CF patients (0 - 52.4 years; mean FEV1 2010 81.4% pred) were investigated. Results: In 8 patients (2.2%, 3 male, mean age 21.8 years) Trichosporon was detected at least once. One patient carried T. asahii. One patient carried T. mycotoxinivorans and one patient T. inkin as determined by DNA sequencing. As potential risk factors for Trichosporon colonization steroid treatment, allergic bronchopulmonary aspergillosis (ABPA) and CF associated diabetes were identified in 6, 5, and 2 patients respectively. For one patient, the observation period was not long enough to determine the clinical course. One patient had only a single positive specimen and exhibited a stable clinical course determined by change in forced expiratory volume in one second (FEV1), body-mass-index (BMI), C-reactive protein (CRP) and immunoglobulin G (IgG). Of 6 patients with repeatedly positive specimen (mean detection period 4.5 years), 4 patients had a greater decline in FEV1 than expected, 2 of these a decline in BMI and 1 an increase in IgG above the reference range. 2 patients received antimycotic treatment: one patient with a tormenting dry cough subjectively improved under Amphotericin B inhalation; one patient with a severe exacerbation due to T. inkin was treated with i.v. Amphotericin B, oral Voriconazole and Posaconazole which stabilized the clinical condition. Conclusions: This study demonstrates the potential association of Trichosporon spp. with severe exacerbations in CF patients

Phase II study of capecitabine and oxaliplatin given prior to and concurrently with preoperative pelvic radiotherapy in patients with locally advanced rectal cancer

This multicentre phase II study evaluated the efficacy and safety of preoperative capecitabine plus oxaliplatin and radiotherapy (RT) in patients with locally advanced rectal cancer (T3/T4 rectal adenocarcinoma with or without nodal involvement). Treatment consisted of one cycle of XELOX (capecitabine 1000 mg m−2 bid on days 1–14 and oxaliplatin 130 mg m−2 on day 1), followed by RT (1.8 Gy fractions 5 days per week for 5 weeks) plus CAPOX (capecitabine 825 mg m−2 bid on days 22–35 and 43–56, and oxaliplatin 50 mg m−2 on days 22, 29, 43 and 50). Surgery was recommended 5 weeks after completion of chemoradiotherapy. The primary end point was pathological complete tumour response (pCR). Sixty patients were enrolled. In the intent-to-treat population, the pCR rate was 23% (95% CI: 13–36%). 58 patients underwent surgery; R0 resection was achieved in 57 (98%) patients, including all 5 patients with T4 tumours. Sphincter preservation was achieved in 49 (84%) patients. Tumour and/or nodal downstaging was observed in 39 (65%) patients. The most common grade 3/4 adverse events were diarrhoea (20%) and lymphocytopaenia (43%). Preoperative capecitabine, oxaliplatin and RT achieved encouraging rates of pCR, R0 resection, sphincter preservation and tumour downstaging in patients with locally advanced rectal cancer

A Score of the Ability of a Three-Dimensional Protein Model to Retrieve Its Own Sequence as a Quantitative Measure of Its Quality and Appropriateness

BACKGROUND: Despite the remarkable progress of bioinformatics, how the primary structure of a protein leads to a three-dimensional fold, and in turn determines its function remains an elusive question. Alignments of sequences with known function can be used to identify proteins with the same or similar function with high success. However, identification of function-related and structure-related amino acid positions is only possible after a detailed study of every protein. Folding pattern diversity seems to be much narrower than sequence diversity, and the amino acid sequences of natural proteins have evolved under a selective pressure comprising structural and functional requirements acting in parallel. PRINCIPAL FINDINGS: The approach described in this work begins by generating a large number of amino acid sequences using ROSETTA [Dantas G et al. (2003) J Mol Biol 332:449-460], a program with notable robustness in the assignment of amino acids to a known three-dimensional structure. The resulting sequence-sets showed no conservation of amino acids at active sites, or protein-protein interfaces. Hidden Markov models built from the resulting sequence sets were used to search sequence databases. Surprisingly, the models retrieved from the database sequences belonged to proteins with the same or a very similar function. Given an appropriate cutoff, the rate of false positives was zero. According to our results, this protocol, here referred to as Rd.HMM, detects fine structural details on the folding patterns, that seem to be tightly linked to the fitness of a structural framework for a specific biological function. CONCLUSION: Because the sequence of the native protein used to create the Rd.HMM model was always amongst the top hits, the procedure is a reliable tool to score, very accurately, the quality and appropriateness of computer-modeled 3D-structures, without the need for spectroscopy data. However, Rd.HMM is very sensitive to the conformational features of the models' backbone

The Effect of Testing on the Retention of Coherent and Incoherent Text Material

Research has shown that testing during learning can enhance the long-term retention of text material. In two experiments, we investigated the testing effect with a fill-in-the-blank test on the retention of text material. In Experiment 1, using a coherent text, we found no retention benefit of testing compared to a restudy (control) condition. In Experiment 2, text coherence was disrupted by scrambling the order of the sentences from the text. The material was subsequently presented as a list of facts as opposed to connected discourse. For the incoherent version of the text, testing slowed down the rate of forgetting compared to a restudy (control) condition. The results suggest that the connectedness of materials can play an important role in determining the magnitude of testing benefits for long-term retention. Testing with a completion test seems most beneficial for unconnected materials and less so for highly structured materials