Mycobacterium tuberculosis Affects Protein and Lipid Content of Circulating Exosomes in Infected Patients Depending on Tuberculosis Disease State

Tuberculosis (TB), which is caused by the bacterium Mycobacterium tuberculosis (Mtb), is still one of the deadliest infectious diseases. Understanding how the host and pathogen interact in active TB will have a significant impact on global TB control efforts. Exosomes are increasingly recognized as a means of cell-to-cell contact and exchange of soluble mediators. In the case of TB, exosomes are released from the bacillus and infected cells. In the present study, a comprehensive lipidomics and proteomics analysis of size exclusion chromatography-isolated plasma-derived exosomes from patients with TB lymphadenitis (TBL) and treated as well as untreated pulmonary TB (PTB) was performed to elucidate the possibility to utilize exosomes in diagnostics and knowledge building. According to our findings, exosome-derived lipids and proteins originate from both the host and Mtb in the plasma of active TB patients. Exosomes from all patients are mostly composed of sphingomyelins (SM), phosphatidylcholines, phosphatidylinositols, free fatty acids, triacylglycerols (TAG), and cholesterylesters. Relative proportions of, e.g., SMs and TAGs, vary depending on the disease or treatment state and could be linked to Mtb pathogenesis and dormancy. We identified three proteins of Mtb origin: DNA-directed RNA polymerase subunit beta (RpoC), Diacyglycerol O-acyltransferase (Rv2285), and Formate hydrogenase (HycE), the latter of which was discovered to be differently expressed in TBL patients. Furthermore, we discovered that Mtb infection alters the host protein composition of circulating exosomes, significantly affecting a total of 37 proteins. All TB patients had low levels of apolipoproteins, as well as the antibacterial proteins cathelicidin, Scavenger Receptor Cysteine Rich Family Member (SSC5D), and Ficolin 3 (FCN3). When compared to healthy controls, the protein profiles of PTB and TBL were substantially linked, with 14 proteins being coregulated. However, adhesion proteins (integrins, Intercellular adhesion molecule 2 (ICAM2), CD151, Proteoglycan 4 (PRG4)) were shown to be more prevalent in PTB patients, while immunoglobulins, Complement component 1r (C1R), and Glutamate receptor-interacting protein 1 (GRIP1) were found to be more abundant in TBL patients, respectively. This study could confirm findings from previous reports and uncover novel molecular profiles not previously in focus of TB research. However, we applied a minimally invasive sampling and analysis of circulating exosomes in TB patients. Based on the findings given here, future studies into host–pathogen interactions could pave the way for the development of new vaccines and therapies

Peginesatide in patients with anemia undergoing hemodialysis

BACKGROUND: Peginesatide, a synthetic peptide-based erythropoiesis- stimulating agent (ESA), is a potential therapy for anemia in patients with advanced chronic kidney disease. METHODS: We conducted two randomized, controlled, open-label studies (EMERALD 1 and EMERALD 2) involving patients undergoing hemodialysis. Cardiovascular safety was evaluated by analysis of an adjudicated composite safety end point - death from any cause, stroke, myocardial infarction, or serious adverse events of congestive heart failure, unstable angina, or arrhythmia - with the use of pooled data from the two EMERALD studies and two studies involving patients not undergoing dialysis. In the EMERALD studies, 1608 patients received peginesatide once monthly or continued to receive epoetin one to three times a week, with the doses adjusted as necessary to maintain a hemoglobin level between 10.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 95% confidence interval was -1.0 g per deciliter or higher in the comparison of peginesatide with epoetin. The aim of evaluating the composite safety end point in the pooled cohort was to exclude a hazard ratio with peginesatide relative to the comparator ESA of more than 1.3. RESULTS: In an analysis involving 693 patients from EMERALD 1 and 725 from EMERALD 2, peginesatide was noninferior to epoetin in maintaining hemoglobin levels (mean between-group difference, -0.15 g per deciliter; 95% confidence interval [CI], -0.30 to -0.01 in EMERALD 1; and 0.10 g per deciliter; 95% CI, -0.05 to 0.26 in EMERALD 2). The hazard ratio for the composite safety end point was 1.06 (95% CI, 0.89 to 1.26) with peginesatide relative to the comparator ESA in the four pooled studies (2591 patients) and 0.95 (95% CI, 0.77 to 1.17) in the EMERALD studies. The proportions of patients with adverse and serious adverse events were similar in the treatment groups in the EMERALD studies. The cardiovascular safety of peginesatide was similar to that of the comparator ESA in the pooled cohort. CONCLUSIONS: Peginesatide, administered monthly, was as effective as epoetin, administered one to three times per week, in maintaining hemoglobin levels in patients undergoing hemodialysisSupported by Affymax and Takeda Pharmaceutica

Effect of Lowering Dialysate Sodium Concentration on Interdialytic Weight Gain and Blood Pressure in Patients Undergoing Thrice-Weekly In-center Nocturnal Hemodialysis: A Quality Improvement Study

Patients on in-center nocturnal hemodialysis therapy typically experience higher interdialytic weight gain (IDWG) than patients on conventional hemodialysis therapy. We determined the safety and effects of decreasing dialysate sodium concentration on IDWG and blood pressure in patients on thrice-weekly in-center nocturnal hemodialysis therapy. Quality improvement, pre-post intervention. 15 participants in a single facility. Participants underwent three 12-week treatment phases, each with different dialysate sodium concentrations, as follows: phase A, 140 mEq/L; phase B, 136 or 134 mEq/L; and phase A +, 140 mEq/L. Participants were blinded to the exact timing of the intervention. IDWG, IDWG/dry weight (IDWG%), and blood pressure. Outcome data were obtained during the last 2 weeks of each phase and compared with mixed models. The fraction of sessions with adverse events (eg, cramping and hypotension) also was reported. IDWG, IDWG%, and predialysis systolic blood pressure decreased significantly by 0.6 ± 0.6 kg, 0.6% ± 0.8%, and 8.3 ± 14.9 mm Hg, respectively, in phase B compared with phase A ( P < 0.05 for all comparisons). No differences in predialysis diastolic and mean arterial or postdialysis blood pressures were found ( P > 0.05 for all comparisons). The proportion of treatments with intradialytic hypotension was low and similar in each phase ( P = 0.9). In phase B compared with phase A, predialysis plasma sodium concentration was unchanged ( P > 0.05), whereas postdialysis plasma sodium concentration decreased by 3.7 ± 1.9 mEq/L ( P < 0.05). Modest sample size. Decreasing dialysate sodium concentrations in patients undergoing thrice-weekly in-center nocturnal hemodialysis resulted in a clinical and statistically significant decrease in IDWG, IDWG%, postdialysis plasma sodium concentration, and predialysis systolic blood pressure without increasing adverse events. Prolonged exposure to higher than required dialysate sodium concentrations may drive IDWG and counteract some of the purported benefits of “go-slow” (longer session length) hemodialysis

The research pyramid - part 1 : theoretical and conceptual principles

Die Forschungspyramide ist ein Modell zur Bewertung und Zusammenführung von externer Evidenz aus unterschiedlichen Forschungsansätzen. Sie bietet eine Grundlage zur Aufbereitung und Systematisierung von Forschungsergebnissen, um, basierend auf wissenschaftlicher Evidenz, ergotherapeutische Fragestellungen zu beantworten und ergotherapeutische Entscheidungen in der alltäglichen Praxis zu treffen. Dieser Beitrag arbeitet die folgenden theoretischen Grundlagen des Modells auf: das Verständnis von Evidenz, von therapeutischer Entscheidungsfindung und vom therapeutischen Prozess sowie das Verständnis von Ergotherapie als komplexer Intervention. The Research Pyramid is a model that values and integrates external evidence from multiple research approaches. It provides a basis to collect and synthesize research findings for answering questions that emerge in occupational therapy practice and for subsequent decision making, based on research evidence. In this article, the following theoretical principles that underline the model are presented: the understanding of evidence, of clinical reasoning and the therapeutic process, and of occupational therapy as a complex intervention

The research pyramid - part 2 : methodological principals

Die Forschungspyramide ist ein Modell zur Bewertung und Zusammenführung von externer Evidenz aus unterschiedlichen Forschungsansätzen. Sie bietet eine Grundlage zur Aufbereitung und Systematisierung von Forschungsergebnissen, um – basierend auf wissenschaftlicher Evidenz – ergotherapeutische Fragestellungen zu beantworten und ergotherapeutische Entscheidungen in der alltäglichen Praxis zu treffen. Dieser Beitrag arbeitet die methodologischen Grundlagen des Modells auf: das Verständnis von Kausalität, Theorie und externer Evidenz in der Forschungspyramide. The Research Pyramid is a model that values and integrates external evidence from multiple research approaches. It provides a basis to collect and synthesize research findings for answering questions that emerge in occupational therapy practice and for subsequent decision making, based on research evidence. In this article, the methodological principles that underlie the model are presented: the understanding of causality, theory, and external evidence in the research pyramid

Individualized reduction in dialysate sodium in conventional in-center hemodialysis

Recent studies have focused on the association between dialysate sodium (Na(+)) prescriptions and interdialytic weight gain (IDWG). We report on a case series of 13 patients undergoing conventional, thrice-weekly in-center hemodialysis with an individualized dialysate Na(+) prescription. Individualized dialysate Na(+) was achieved in all patients through a stepwise weekly reduction of the standard dialysate Na(+) prescription (140 mEq/L) by 2-3 mEq/L until reaching a Na(+) gradient of -2 mEq/L (dialysate Na(+) minus average plasma Na(+) over the preceding 3 months). Interdialytic weight gain, with and without indexing to dry weight (IDWG%), blood pressure, and the proportion of treatments with cramps, intradialytic hypotension (drop in systolic blood pressure >30 mmHg) and intradialytic hypotension requiring an intervention were reviewed. At the beginning of the observation period, the pre-hemodialysis (HD) plasma Na(+) concentration ranged from 130 to 141 mEq/L. When switched from the standard to the individualized dialysate Na(+) concentration, IDWG% decreased from 3.4% ± 1.6% to 2.5% ± 1.0% (P = 0.003) with no change in pre- or post-HD systolic or diastolic blood pressures (all P > 0.05). We found no significant change in the proportion of treatments with cramps (6% vs. 13%), intradialytic hypotension (62% vs. 65%), or intradialytic hypotension requiring an intervention (29% vs. 33%). Individualized reduction of dialysate Na(+) reduces IDWG% without significantly increasing the frequency of cramps or hypotension