Leveraging type 1 diabetes human genetic and genomic data in the T1D knowledge portal.

To address the challenge of translating genetic discoveries for type 1 diabetes (T1D) into mechanistic insight, we have developed the T1D Knowledge Portal (T1DKP), an open-access resource for hypothesis development and target discovery in T1D.

Hydraulic control of mammalian embryo size and cell fate.

Size control is fundamental in tissue development and homeostasis1,2. Although the role of cell proliferation in these processes has been widely studied, the mechanisms that control embryo size-and how these mechanisms affect cell fate-remain unknown. Here we use the mouse blastocyst as a model to unravel a key role of fluid-filled lumen in the control of embryo size and specification of cell fate. We find that there is a twofold increase in lumenal pressure during blastocyst development, which translates into a concomitant increase in cell cortical tension and tissue stiffness of the trophectoderm that lines the lumen. Increased cortical tension leads to vinculin mechanosensing and maturation of functional tight junctions, which establishes a positive feedback loop to accommodate lumen growth. When the cortical tension reaches a critical threshold, cell-cell adhesion cannot be sustained during mitotic entry, which leads to trophectoderm rupture and blastocyst collapse. A simple theory of hydraulically gated oscillations recapitulates the observed dynamics of size oscillations, and predicts the scaling of embryo size with tissue volume. This theory further predicts that disrupted tight junctions or increased tissue stiffness lead to a smaller embryo size, which we verified by biophysical, embryological, pharmacological and genetic perturbations. Changes in lumenal pressure and size can influence the cell division pattern of the trophectoderm, and thereby affect cell allocation and fate. Our study reveals how lumenal pressure and tissue mechanics control embryo size at the tissue scale, which is coupled to cell position and fate at the cellular scale.

As the Worm Turns-A Rare Cause of Intestinal Obstruction.

BACKGROUND: Anisakiasis, a zoonotic disease caused by the nematode Anisakis, poses a significant concern for public health, particularly in regions with high consumption of raw or undercooked fish. CASE PRESENTATION: We present a case report of a 41-year-old woman who developed severe abdominal symptoms, ultimately diagnosed with intestinal obstruction due to Anisakis infestation, requiring surgery. Despite the absence of prominent eosinophilia or specific radiological findings, the diagnosis was confirmed through histological examination, highlighting the importance of considering anisakiasis in patients with a history of raw seafood consumption. CONCLUSION: The case underscores the diagnostic challenges associated with anisakiasis, emphasizing the need for increased awareness among healthcare professionals and the public regarding the risks of consuming raw or undercooked seafood. Effective management requires a multidisciplinary approach, including clinical assessment, imaging studies, and histological evaluation, to ensure timely diagnosis and appropriate treatment.

Acute heart failure: current pharmacological treatment and perspectives.

Acute heart failure (AHF) represents the most frequent cause of unplanned hospital admission in patients older than 65 years. Symptoms and clinical signs of AHF (e.g. dyspnoea, orthopnoea, oedema, jugular vein distension, and variation of body weight) are mostly related to systemic venous congestion secondary to various mechanisms including extracellular fluids, increased ventricular filling pressures, and/or auto-transfusion of blood from the splanchnic into the pulmonary circulation. Thus, the initial management of AHF patients should be mostly based on decongestive therapies on admission followed, before discharge, by rapid implementation of guideline-directed oral medical therapies for heart failure. The therapeutic management of AHF requires the identification and rapid diagnosis of the disease, the diagnosis of the cause (or triggering factor), the evaluation of severity, the presence of comorbidities, and, finally, the initiation of a rapid treatment. The most recent guidelines from ESC and ACC/AHA/HFSA have provided updated recommendations on AHF management. Recommended pharmacological treatment for AHF includes diuretic therapy aiming to relieve congestion and achieve optimal fluid status, early and rapid initiation of oral therapies before discharge combined with a close follow-up. Non-pharmacological AHF management requires risk stratification in the emergency department and non-invasive ventilation in case of respiratory failure. Vasodilators should be considered as initial therapy in AHF precipitated by hypertension. On the background of recent large randomized clinical trials and international guidelines, this state-of-the-art review describes current pharmacological treatments and potential directions for future research in AHF.

Evaluation of the Therapeutic Effects of Harmine on Anaplastic Thyroid Cancer Cells.

Anaplastic thyroid carcinoma (ATC) is an extremely difficult disease to tackle, with an overall patient survival of only a few months. The currently used therapeutic drugs, such as kinase inhibitors or immune checkpoint inhibitors, can prolong patient survival but fail to eradicate the tumor. In addition, the onset of drug resistance and adverse side-effects over time drastically reduce the chances of treatment. We recently showed that Twist1, a transcription factor involved in the epithelial mesenchymal transition (EMT), was strongly upregulated in ATC, and we wondered whether it might represent a therapeutic target in ATC patients. To investigate this hypothesis, the effects of harmine, a ß-carboline alkaloid shown to induce degradation of the Twist1 protein and to possess antitumoral activity in different cancer types, were evaluated on two ATC-derived cell lines, BHT-101 and CAL-62. The results obtained demonstrated that, in both cell lines, harmine reduced the level of Twist1 protein and reverted the EMT, as suggested by the augmentation of E-cadherin and decrease in fibronectin expression. The drug also inhibited cell proliferation and migration in a dose-dependent manner and significantly reduced the anchorage-independent growth of both ATC cell lines. Harmine was also capable of inducing apoptosis in BHT-101 cells, but not in CAL-62 ones. Finally, the activation of PI3K/Akt signaling, but not that of the MAPK, was drastically reduced in treated cells. Overall, these in vitro data suggest that harmine could represent a new therapeutic option for ATC treatment.

Sustained Reduction in Pulmonary Artery Pressures and Hospitalizations During 2 Years of Ambulatory Monitoring.

BACKGROUND: Therapy guided by pulmonary artery (PA) pressure monitoring reduces PA pressures and heart failure hospitalizations (HFH) during the first year, but the durability of efficacy and safety through 2 years is not known. METHODS AND RESULTS: The CardioMEMS Post-Approval Study investigated whether benefit and safety were generalized and sustained. Enrollment at 104 centers in the United States included 1200 patients with NYHA Class III symptoms on recommended HF therapies with prior HFH. Therapy was adjusted toward PA diastolic pressure 8-20 mmHg. Intervention frequency and PA pressure reduction were most intense during first 90 days, with sustained reduction of PA diastolic pressure from baseline 24.7 mmHg to 21.0 at 1 year and 20.8 at 2 years for all patients. Patients completing two year follow-up (n = 710) showed similar 2-year reduction (23.9 to 20.8 mmHg), with reduction in PA mean pressure (33.7 to 29.4 mmHg) in patients with reduced left ventricular ejection. The HFH rate was 1.25 events/patient/year prior to sensor implant, 0.54 at 1 year, and 0.37 at 2 years, with 59% of patients free of HFH during follow-up. CONCLUSIONS: Reduction in PA pressures and hospitalizations were early and sustained during 2 years of PA pressure-guided management, with no signal of safety concerns regarding the implanted sensor.

Heart transplantation: focus on donor recovery strategies, left ventricular assist devices, and novel therapies.

Heart transplantation is advocated in selected patients with advanced heart failure in the absence of contraindications. Principal challenges in heart transplantation centre around an insufficient and underutilized donor organ pool, the need to individualize titration of immunosuppressive therapy, and to minimize late complications such as cardiac allograft vasculopathy, malignancy, and renal dysfunction. Advances have served to increase the organ donor pool by advocating the use of donors with underlying hepatitis C virus infection and by expanding the donor source to use hearts donated after circulatory death. New techniques to preserve the donor heart over prolonged ischaemic times, and enabling longer transport times in a safe manner, have been introduced. Mechanical circulatory support as a bridge to transplantation has allowed patients with advanced heart failure to avoid progressive deterioration in hepato-renal function while awaiting an optimal donor organ match. The management of the heart transplantation recipient remains a challenge despite advances in immunosuppression, which provide early gains in rejection avoidance but are associated with infections and late-outcome challenges. In this article, we review contemporary advances and challenges in this field to focus on donor recovery strategies, left ventricular assist devices, and immunosuppressive monitoring therapies with the potential to enhance outcomes. We also describe opportunities for future discovery to include a renewed focus on long-term survival, which continues to be an area that is under-studied and poorly characterized, non-human sources of organs for transplantation including xenotransplantation as well as chimeric transplantation, and technology competitive to human heart transplantation, such as tissue engineering.

The GUIDE-HF trial of pulmonary artery pressure monitoring in heart failure: impact of the COVID-19 pandemic.

AIMS: During the coronavirus disease 2019 (COVID-19) pandemic, important changes in heart failure (HF) event rates have been widely reported, but few data address potential causes for these changes; several possibilities were examined in the GUIDE-HF study. METHODS AND RESULTS: From 15 March 2018 to 20 December 2019, patients were randomized to haemodynamic-guided management (treatment) vs. control for 12 months, with a primary endpoint of all-cause mortality plus HF events. Pre-COVID-19, the primary endpoint rate was 0.553 vs. 0.682 events/patient-year in the treatment vs. control group [hazard ratio (HR) 0.81, P = 0.049]. Treatment difference was no longer evident during COVID-19 (HR 1.11, P = 0.526), with a 21% decrease in the control group (0.536 events/patient-year) and no change in the treatment group (0.597 events/patient-year). Data reflecting provider-, disease-, and patient-dependent factors that might change the primary endpoint rate during COVID-19 were examined. Subject contact frequency was similar in the treatment vs. control group before and during COVID-19. During COVID-19, the monthly rate of medication changes fell 19.2% in the treatment vs. 10.7% in the control group to levels not different between groups (P = 0.362). COVID-19 was infrequent and not different between groups. Pulmonary artery pressure area under the curve decreased -98 mmHg-days in the treatment group vs. -100 mmHg-days in the controls (P = 0.867). Patient compliance with the study protocol was maintained during COVID-19 in both groups. CONCLUSION: During COVID-19, the primary event rate decreased in the controls and remained low in the treatment group, resulting in an effacement of group differences that were present pre-COVID-19. These outcomes did not result from changes in provider- or disease-dependent factors; pulmonary artery pressure decreased despite fewer medication changes, suggesting that patient-dependent factors played an important role in these outcomes. Clinical Trials.gov: NCT03387813.

Effects of time and temperature of storage on chemical and nutritional characteristics of raw milk for Provolone Valpadana PDO cheesemaking: a multivariate approach.

We evaluated the possibility of increasing the storage temperature of raw milk for Provolone Valpadana cheesemaking, to identify the most suitable conditions of time and temperature for a pre-maturation process. We used Principal Component Analysis (PCA) to analyze the overall effects of different storage conditions on chemical, nutritional and technological characteristics of the raw milk. Four different thermal storage cycles, two at fixed temperature/time (6 and 12°C for 60 h) and two with two-phase thermal cycle (10 and 12°C for 15 h, followed by refrigeration at 4°C for 45 h) were studied. Although a moderate heterogeneity among raw milks from the 11 producers of Provolone Valpadana cheese was observed, PCA revealed the critical aspects of the extreme storage conditions (60 h of refrigeration). Some samples resulted in anomalous behaviors, probably related to unexpected fermentation phenomena occurring with increasing storage temperature. The acidification and the increase in the contents of lactic acid, soluble calcium, and degree of retinol isomerization observed in the anomalous samples can compromise the technological functionality of milk. Conversely, the storage with a two-phase thermal cycle did not lead to variations in any measured characteristic, suggesting that mild refrigeration conditions (10 or 12°C for 15 h followed by 4°C for 45 h) could be a good compromise in favoring milk pre-maturation without altering its quality characteristics.

Haemodynamic-guided management of heart failure (GUIDE-HF): a randomised controlled trial.

BACKGROUND: Previous studies have suggested that haemodynamic-guided management using an implantable pulmonary artery pressure monitor reduces heart failure hospitalisations in patients with moderately symptomatic (New York Heart Association [NYHA] functional class III) chronic heart failure and a hospitalisation in the past year, irrespective of ejection fraction. It is unclear if these benefits extend to patients with mild (NYHA functional class II) or severe (NYHA functional class IV) symptoms of heart failure or to patients with elevated natriuretic peptides without a recent heart failure hospitalisation. This trial was designed to evaluate whether haemodynamic-guided management using remote pulmonary artery pressure monitoring could reduce heart failure events and mortality in patients with heart failure across the spectrum of symptom severity (NYHA funational class II-IV), including those with elevated natriuretic peptides but without a recent heart failure hospitalisation. METHODS: The randomised arm of the haemodynamic-GUIDEed management of Heart Failure (GUIDE-HF) trial was a multicentre, single-blind study at 118 centres in the USA and Canada. Following successful implantation of a pulmonary artery pressure monitor, patients with all ejection fractions, NYHA functional class II-IV chronic heart failure, and either a recent heart failure hospitalisation or elevated natriuretic peptides (based on a-priori thresholds) were randomly assigned (1:1) to either haemodynamic-guided heart failure management based on pulmonary artery pressure or a usual care control group. Patients were masked to their study group assignment. Investigators were aware of treatment assignment but did not have access to pulmonary artery pressure data for control patients. The primary endpoint was a composite of all-cause mortality and total heart failure events (heart failure hospitalisations and urgent heart failure hospital visits) at 12 months assessed in all randomly assigned patients. Safety was assessed in all patients. A pre-COVID-19 impact analysis for the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT03387813. FINDINGS: Between March 15, 2018, and Dec 20, 2019, 1022 patients were enrolled, with 1000 patients implanted successfully, and follow-up was completed on Jan 8, 2021. There were 253 primary endpoint events (0·563 per patient-year) among 497 patients in the haemodynamic-guided management group (treatment group) and 289 (0·640 per patient-year) in 503 patients in the control group (hazard ratio [HR] 0·88, 95% CI 0·74-1·05; p=0·16). A prespecified COVID-19 sensitivity analysis using a time-dependent variable to compare events before COVID-19 and during the pandemic suggested a treatment interaction (pinteraction=0·11) due to a change in the primary endpoint event rate during the pandemic phase of the trial, warranting a pre-COVID-19 impact analysis. In the pre-COVID-19 impact analysis, there were 177 primary events (0·553 per patient-year) in the intervention group and 224 events (0·682 per patient-year) in the control group (HR 0·81, 95% CI 0·66-1·00; p=0·049). This difference in primary events almost disappeared during COVID-19, with a 21% decrease in the control group (0·536 per patient-year) relative to pre-COVID-19, virtually no change in the treatment group (0·597 per patient-year), and no difference between groups (HR 1·11, 95% CI 0·80-1·55; p=0·53). The cumulative incidence of heart failure events was not reduced by haemodynamic-guided management (0·85, 0·70-1·03; p=0·096) in the overall study analysis but was significantly decreased in the pre-COVID-19 impact analysis (0·76, 0·61-0·95; p=0·014). 1014 (99%) of 1022 patients had freedom from device or system-related complications. INTERPRETATION: Haemodynamic-guided management of heart failure did not result in a lower composite endpoint rate of mortality and total heart failure events compared with the control group in the overall study analysis. However, a pre-COVID-19 impact analysis indicated a possible benefit of haemodynamic-guided management on the primary outcome in the pre-COVID-19 period, primarily driven by a lower heart failure hospitalisation rate compared with the control group. FUNDING: Abbott.

The cost of non-response to cardiac resynchronization therapy: characterizing heart failure events following cardiac resynchronization therapy.

AIMS: The aim of this study is to quantify healthcare resource utilization among non-responders to cardiac resynchronization therapy (CRT-NR) by heart failure (HF) events and influence of comorbidities. METHODS AND RESULTS: The ADVANCE CRT registry (2013-2015) prospectively identified responders/CRT-NRs 6 months post-implant using the clinical composite score. Heart failure event rates and associated cost, both overall and separated for inpatient hospitalizations, office visits, emergency room visits, and observational stays, were quantified. Costs of events were imputed from payments for similar real-world encounters in subjects with CRT-D/P devices in the MarketScan™ commercial and Medicare Supplemental insurance claims databases. Effects of patient demographics and comorbidities on event rates and cost were evaluated. Of 879 US patients (age 69 ± 11 years, 29% female, ischaemic disease 52%), 310 (35%) were CRT-NR. Among CRT-NRs vs. responders, more patients developed HF (41% vs. 11%, P < 0.001), HF event rate was higher (67.0 ± 21.7 vs. 11.4 ± 3.7/100 pt-year, P < 0.001), and HF readmission within 30 days was more common [hazard ratio 7.06, 95% confidence interval (2.1-43.7)]. Inpatient hospitalization was the most common and most expensive event type in CRT-NR. Comorbid HF was increased by diabetes, hypertension, and pulmonary disorders. Over 2 years, compared to CRT responders, each CRT-NR resulted in excess cost of $6388 ($3859-$10 483) to Medicare (P = 0.015) or $10 197 ($6161-$17 394) to private insurances (P = 0.014). CONCLUSION: Healthcare expenditures associated with contemporary CRT non-response management are among the highest for any HF patient group. This illustrates an unmet need for interventions to improve HF outcomes and reduce costs among some CRT recipients.

Content and Nutritional Evaluation of Zinc in PDO and Traditional Italian Cheeses.

Zinc is an essential mineral which plays a key role in several important biological processes in the human body. The determination of its level in food matrices can contribute to the food quality characterization and to the adequacy of the diet. Animal food products generally have a higher zinc content compared to vegetables. Among them, dairy products consumption can provide a great contribution to the zinc reference intakes. In this study, different Italian cheeses (38 Protected Denomination of Origin and 9 Traditional) were evaluated for their zinc content. Cow cheeses generally showed the highest zinc content (1.83-7.75 mg/100 g cheese), followed by sheep cheeses (1.34-3.69 mg/100 g), and cheeses from mixed milk (0.39-4.54 mg/100 g). The only cheese from buffalo milk (Mozzarella di Bufala Campana PDO) showed a zinc content of 2.14 mg/100 g. The great variability in the zinc content observed among the samples is the result of the influence of several factors, such as the feeding system, the species (cow, sheep, goat, and buffalo), and the cheese-making. Most of the samples resulted in a great contribution (>10%) to the zinc Daily Reference Intake set by EU (10 mg/day), with only two samples contributing to less than 4%.

The dynamic relationship between serum chloride and cardiorenal syndrome.

Low serum sodium concentration has long been recognized as an established marker of short- and long-term morbidity and mortality in patients with heart failure (HF), and is commonly included in various risk prediction models. Mechanisms leading to hyponatremia (e.g. maladaptive neurohormonal activation) could also lead to concurrent decline in serum chloride levels. Besides, chloride has distinct biological roles (e.g. modulation of renal tubular sodium transporters) that are relevant to the pathophysiology and therapy of HF, making it a potent cardiorenal connector. Several clinical studies have recently reported on a potentially overlooked link between low serum chloride levels and adverse outcomes in patients with a wide variety of HF syndromes, which could indeed be stronger than that of sodium. While evidence on predictive value of chloride is accumulating in various patient populations and settings, the limited available interventional studies have so far yielded conflicting results. It remains to be elucidated whether hypochloremia represents a marker of disease severity and prognosis, or it is an actual pathogenetic mechanism, hence being a potential novel target of therapy. Current ongoing studies are designed to better understand the mechanistic aspects of the role of hypochloremia in HF and shed light on its clinical applicability.

Conservative management of CIN2 p16 positive lesions in women with multiple HPV infection.

BACKGROUND: According to the 2006 American Society for Colposcopy and Cervical Pathology guidelines, positive CIN2 p16 in women over the age of 25 should be managed with excisional treatment. However, excisional treatment is associated with physical, psychological and obstetric morbidity and can have a negative impact on sexual function. In our study we sought to identify a clear management strategy, addressing the impact of routine use of p16 immunohistochemistry in this population and identify appropriate criteria for patient selection with the aim of reducing over-treatment. METHOD: We studied the medical records of 130 patients who had undergone laser therapy for CIN2. Each patient underwent colposcopy, biopsy and HPV test and were tested for p16 protein,. Patients were divided based on HPV infection into: single infections, multiple infections. All patients underwent ZTA laser therapy with follow-up (2-year follow-up). STATISTICAL ANALYSIS: Contingency tables were created to evaluate the correlation between single, multiple and CIN2+ infections. Values with p < 0.05 were considered statistically significant. RESULTS: Single infections had a histological regression of 61.8% (21/34) and a histological persistence rate of 35.3% (12/34), which was greater than the multiple infection rate. The common characteristic that the women with persistence and progression had was the dimension of the lesion and the genotype 16. Ten cases of histological persistence and the only case of progression had one lesion greater than three quarters of the cervix. CONCLUSIONS: With the progress of our understanding of the natural history of infection from human papillomavirus and the increasing use of colposcopy, thanks to the addition of HPV genotyping and the technique of immunohistochemistry, conservative management of these lesions is now possible.

Diagnostic and interventional implications of telemedicine in Alzheimer's disease and mild cognitive impairment: A literature review.

INTRODUCTION: Worldwide, life expectancy, and aging-related disorders as mild cognitive impairment (MCI) and Alzheimer disease (AD) are increasing, having a rising impact on patients' quality of life and caregivers' distress. Telemedicine offers many possibilities, such as remote diagnosing and monitoring of patients. OBJECTIVE: The purpose of this study is to provide a narrative synthesis of the literature about the implementation of telemedicine for diagnosis, treatment, and follow-up of patients with AD and MCI and their caregivers. METHODS: A systematic literature review was conducted on MEDLINE, EMBASE, and the Cochrane Library databases up to September 2018. MCI or AD diagnoses were the conditions of interest. We excluded other dementias. RESULTS: Fifty-six articles met inclusion criteria. We identified two main categories: diagnosis group (DG) and follow-up/interventional group (FIG). Fifteen articles suggested how to make a remote or earlier diagnosis: four were case-control accuracy studies, nine were paired comparative accuracy studies, and two were prospective single-arm accuracy studies. Among these, four focused on MCI, six on AD, and five on both. Forty one focused on supporting patients during the stages of the disease (28 articles), patient's caregivers (nine articles), or both (four articles). CONCLUSIONS: The rising use of telemedicine could actively improve AD and MCI patients' lives, reduce caregivers' burden, and facilitate an early diagnosis if patients live in remote places. However, as some studies report, it is relevant to take into account the emotional impact of telemedicine on patients and not only on the effectiveness.

Central Sleep Apnea in Patients with Heart Failure-How to Screen, How to Treat.

PURPOSE OF REVIEW: Central sleep apnea occurs in up to 50% of heart failure patients and worsens outcomes. Established therapies are limited by minimal supporting evidence, poor patient adherence, and potentially adverse cardiovascular effects. However, transvenous phrenic nerve stimulation, by contracting the diaphragm, restores normal breathing throughout sleep and has been shown to be safe and effective. This review discusses the mechanisms, screening, diagnosis, and therapeutic approaches to CSA in patients with HF. RECENT FINDINGS: In a prospective, multicenter randomized Pivotal Trial (NCT01816776) of transvenous phrenic nerve stimulation with the remede System, significantly more treated patients had a ≥ 50% reduction in apnea-hypopnea index compared with controls, with a 41 percentage point difference between group difference at 6 months (p < 0.0001). All hierarchically tested sleep, quality of life, and daytime sleepiness endpoints were significantly improved in treated patients. Freedom from serious related adverse events at 12 months was 91%. Benefits are sustained to 36 months. Transvenous phrenic nerve stimulation improves quality of life in patients with heart failure and central sleep apnea. Controlled trials evaluating the impact of this therapy on mortality/heart failure hospitalizations and "real world" experience are needed to confirm safety and effectiveness.

Vitamin D Status Modulates Inflammatory Response in HIV+ Subjects: Evidence for Involvement of Autophagy and TG2 Expression in PBMC.

Conflicting results on the involvement of vitamin D deficiency in inflammatory and immune response in HIV+ subjects are reported. We aimed to characterize the possible influence of vitamin D status on changes in expression of tissue transglutaminase gene (TGM2) and other genes involved in inflammatory response and autophagy in peripheral blood mononuclear cells (PBMC) from HIV+ subjects. HIV+ subjects (n = 57) under antiretroviral therapy (ART) and healthy controls (n = 40) were enrolled. mRNA levels of 1-alpha-hydroxylase (CYP27B1), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), TGM2, microtubule-associated protein 1A/1B-light chain 3 (LC3), autophagy-related 5 homolog (ATG5), and Beclin 1 (BECN1) were quantified by real-time PCR. In HIV+ subjects, 25(OH)D3 plasma levels were negatively correlated with time since HIV diagnosis. In PBMC from HIV+ subjects, increases in gene expression of TNF-α and IFN-γ in comparison to controls were observed. The highest increase in TNF-α transcripts was observed in HIV+ subjects with deficient 25(OH)D3 levels. Autophagy-related genes LC3, ATG5, and BECN1 were down-regulated in HIV+ subjects. Moreover, TGM2 transcripts were up-regulated in PBMC from HIV+ subjects with 25(OH)D3 deficiency. Changes observed in PBMC from HIV+ subjects appeared to be dependent on vitamin D status. The present results suggest that vitamin D deficiency is associated with changes in the expression of markers of inflammation and autophagy, resulting in immune cell dysfunction.

The Cardiorenal Syndrome in Heart Failure.

Abnormal fluid handling leads to physiologic abnormalities in multiple organ systems. Deranged hemodynamics, neurohormonal activation, excessive tubular sodium reabsorption, inflammation, oxidative stress, and nephrotoxic medications are important drivers of harmful cardiorenal interactions in patients with heart failure. Accurate quantitative measurement of fluid volume is vital to individualizing therapy for such patients. Blood volume analysis and pulmonary artery pressure monitoring seem the most reliable methods for assessing fluid volume and guiding decongestive therapies. Still the cornerstone of decongestive therapy, diuretics' effectiveness decreases with progression of heart failure. Extracorporeal ultrafiltration, an alternative to diuretics, has been shown to reduce heart-failure events.

How to implant a phrenic nerve stimulator for treatment of central sleep apnea?

BACKGROUND: Central sleep apnea (CSA) is a breathing disorder caused by the intermittent absence of central respiratory drive. Transvenous phrenic nerve stimulation is a new therapeutic option, recently approved by the FDA , for the treatment of CSA. OBJECTIVE: To describe the technique used to implant the transvenous phrenic nerve stimulation system (the remede System, Respicardia, Inc). METHODS: The remede System is placed in the pectoral region, typically on the right side. A single stimulation lead is placed in either the left pericardiophrenic vein (PPV) or the right brachiocephalic vein (RBC). A sensing lead is placed into the azygous vein to detect respiration. RESULTS: In the remede System Pivotal trial, 147 of 151 (97%) patients were successfully implanted with the system. Sixty-two percent of stimulation leads were placed in the PPV and 35% in the RBC. Mean procedure time was 2.7 ± 0.8 hours and 94% of patients were free from implant-related serious adverse events through 6 months. CONCLUSION: In patients with CSA, transvenous phrenic nerve stimulation is an effective and safe therapy with an implant procedure similar to that of cardiac implantable electronic devices.

The Saccharomyces Genome Database Variant Viewer.

The Saccharomyces Genome Database (SGD; http://www.yeastgenome.org) is the authoritative community resource for the Saccharomyces cerevisiae reference genome sequence and its annotation. In recent years, we have moved toward increased representation of sequence variation and allelic differences within S. cerevisiae. The publication of numerous additional genomes has motivated the creation of new tools for their annotation and analysis. Here we present the Variant Viewer: a dynamic open-source web application for the visualization of genomic and proteomic differences. Multiple sequence alignments have been constructed across high quality genome sequences from 11 different S. cerevisiae strains and stored in the SGD. The alignments and summaries are encoded in JSON and used to create a two-tiered dynamic view of the budding yeast pan-genome, available at http://www.yeastgenome.org/variant-viewer.