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The endothelial glycocalyx, a gel-like layer that lines the luminal surface of blood vessels, is composed of proteoglycans, glycoproteins, and glycosaminoglycans. The endothelial glycocalyx plays an essential role in vascular homeostasis, and its degradation in trauma and sepsis can lead to microvascular dysfunction and organ injury. While there are no proven therapies for preventing or treating endothelial glycocalyx degradation, some initial literature suggests that plasma may have a therapeutic role in trauma and sepsis patients. Overall, the literature suggesting the use of plasma as a therapy for endothelial glycocalyx degradation is non-clinical basic science or exploratory. Plasma is an established therapy in the resuscitation of patients with hemorrhage for restoration of coagulation factors. However, plasma also contains other bioactive components, including sphingosine-1 phosphate, antithrombin, and adiponectin, which may protect and restore the endothelial glycocalyx, thereby helping to maintain or restore vascular homeostasis. This narrative review begins by describing the endothelial glycocalyx in health and disease: we discuss the overlapping disease mechanisms in trauma and sepsis that lead to its damage and introduce plasma transfusion as a potential therapy for prevention and treatment of endothelial glycocalyx degradation. Second, we review the literature on plasma as an exploratory therapy for endothelial glycocalyx degradation in trauma and sepsis. Third, we discuss the safety of plasma transfusion by reviewing the adverse events associated with plasma and other blood product transfusions, and we examine modern transfusion precautions that have enhanced the safety of plasma transfusion. We conclude that the literature proposes that plasma may have the potential to prevent and treat endothelial glycocalyx degradation in trauma and sepsis, indicating the need for further research.

Sepsis is a heterogeneous syndrome and phenotypes have been proposed using clinical data. Less is known about the contribution of protein biomarkers to clinical sepsis phenotypes and their importance for treatment effects in randomized trials of resuscitation. The objective is to use both clinical and biomarker data in the Protocol-Based Care for Early Septic Shock (ProCESS) randomized trial to determine sepsis phenotypes and to test for heterogeneity of treatment effect by phenotype comparing usual care to protocolized early, goal-directed therapy(EGDT). In this secondary analysis of a subset of patients with biomarker sampling in the ProCESS trial (n = 543), we identified sepsis phenotypes prior to randomization using latent class analysis of 20 clinical and biomarker variables. Logistic regression was used to test for interaction between phenotype and treatment arm for 60-day inpatient mortality. Among 543 patients with severe sepsis or septic shock in the ProCESS trial, a 2-class model best fit the data (p = 0.01). Phenotype 1 (n = 66, 12%) had increased IL-6, ICAM, and total bilirubin and decreased platelets compared to phenotype 2 (n = 477, 88%, p < 0.01 for all). Phenotype 1 had greater 60-day inpatient mortality compared to Phenotype 2 (41% vs 16%; p < 0.01). Treatment with EGDT was associated with worse 60-day inpatient mortality compared to usual care (58% vs. 23%) in Phenotype 1 only (p-value for interaction = 0.05). The 60-day inpatient mortality was similar comparing EGDT to usual care in Phenotype 2 (16% vs. 17%). We identified 2 sepsis phenotypes using latent class analysis of clinical and protein biomarker data at randomization in the ProCESS trial. Phenotype 1 had increased inflammation, organ dysfunction and worse clinical outcomes compared to phenotype 2. Response to EGDT versus usual care differed by phenotype.

Liquid xenon particle detectors rely on excellent light collection efficiency for their performance. This depends on the high reflectivity of polytetrafluoroethylene (PTFE) at the xenon scintillation wavelength of 178 nm, but the angular dependence of this reflectivity is not well-understood. IBEX is designed to directly measure the angular distribution of xenon scintillation light reflected off PTFE in liquid xenon. These measurements are fully described by a microphysical reflectivity model with few free parameters. Dependence on PTFE type, surface finish, xenon pressure, and wavelength of incident light is explored. Total internal reflection is observed, which results in the dominance of specular over diffuse reflection and a reflectivity near 100% for high angles of incidence.

Background This is a post hoc analysis of combined cohorts from two previous Phase II clinical trials to assess the effect of thiamine administration on kidney protection and mortality in patients with septic shock. Methods Patient-level data from the Thiamine in Septic Shock Trial (NCT01070810) and the Thiamine for Renal Protection in Septic Shock Trial (NCT03550794) were combined in this analysis. The primary outcome for the current study was survival without the receipt of renal replacement therapy (RRT). Analyses were performed on the overall cohort and the thiamine-deficient cohort (thiamine < 8 nmol/L). Results Totally, 158 patients were included. Overall, thiamine administration was associated with higher odds of being alive and RRT-free (adjusted odds ratio [aOR]: 2.05 [95% confidence interval (CI) 1.08–3.90]) and not needing RRT (aOR: 2.59 [95% CI 1.01–6.62]). In the thiamine-deficient group, thiamine administration was associated with higher odds of being alive and RRT-free (aOR: 8.17 [95% CI 1.79–37.22]) and surviving to hospital discharge (aOR: 6.84 [95% CI 1.54–30.36]). There was a significant effect modification by baseline thiamine deficiency for alive and RRT-free (interaction, p  = 0.016) and surviving to hospital discharge ( p  = 0.019). Conclusion In the combined analysis of two previous randomized trials, thiamine administration was associated with higher odds of being alive and RRT-free at hospital discharge in patients with septic shock. This signal was stronger in patients with thiamine deficiency.

As part of the global response to the HIV/AIDS epidemic, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) is committed to the provision of high‐quality services and ensuring testing accuracy. Two recently published papers focusing on HIV testing and misdiagnosis in sub‐Saharan Africa by Kosack et al. report on evaluations of HIV rapid diagnostic tests (RDTs) and found lower than expected specificity and sensitivity on some tests when used in certain geographic locations. The magnitude of PEPFAR's global HIV response has been possible due to the extensive use of RDTs, which have made HIV diagnosis accessible all over the world. We take the opportunity to address concerns raised about the potential implications that these findings could have on real‐world HIV testing accuracy. PEPFAR supported countries adhere to the normative guidance by World Health Organization (WHO) supporting algorithms which require sequential positive tests for diagnostic accuracy. An analysis of Médecins Sans Frontières (MSF) RDT site‐specific data applied to PEPFAR in‐country protocols demonstrate a variation in the diagnostic accuracy of the testing algorithms, but with a very small population‐level effect. The data demonstrate, with the use of these algorithms, that the RDT outcomes found in the study by Kosack et al. would be largely mitigated and would not be expected to have a significant impact on diagnostic accuracy and overall programming in most countries. Avoiding any misdiagnosis is a priority for PEPFAR, and it remains vital to gain a deeper understanding of the causes and the extent of diagnostic errors and any misclassification. Extensive quality control mechanisms and continued research are essential. With a focus on epidemic control and ensuring diagnostic accuracy, PEPFAR recommends that all countries use WHO pre‐qualified RDTs within the recommended strategies and algorithms for HIV testing. We also support validation of HIV testing algorithms using in‐country specimens to determine optimal performance, and the reverification testing of all people diagnosed with HIV prior to starting treatment as an essential quality assurance measure.

BackgroundDiabetic ketoacidosis (DKA) is a potentially life-threatening disorder associated with severe alterations in metabolism and acid–base status. Mitochondrial dysfunction is associated with diabetes and its complications. Thiamine and coenzyme Q10 (CoQ10) are important factors in aerobic metabolism. In this study, we measured cellular oxygen consumption rates (OCRs) and the effects of in vitro administration of thiamine and CoQ10 on OCRs in patients with DKA versus healthy controls.MethodsBlood samples were collected from a prospective cohort of patients with DKA and from controls. Cellular OCRs were measured in peripheral blood mononuclear cells (PBMC) without treatment and after treatment with thiamine, CoQ10, or both. The mitochondrial profile was measured using an XFe96 Extracellular Flux Analyzer and XF Cell Mito Stress Test Kit (Seahorse Bioscience). A linear quantile mixed model was used to compare OCRs and estimate treatment effects.ResultsA total of 62 patients with DKA and 48 controls were included in the study. The median basal and maximal OCRs were lower in the DKA group than in the control group (basal: 4.7 [IQR: 3.3, 7.9] vs. 7.9 [5.0, 9.5], p = 0.036; maximal: 16.4 [9.5, 28.1] vs. 31.5 [20.6, 46.0] pmol/min/µg protein, p < 0.001). In DKA samples, basal and maximal OCRs were significantly increased when treated with thiamine, CoQ10, or both. In controls, basal and maximal OCR were significantly increased only with thiamine treatment.ConclusionMitochondrial metabolic profiles of patients with DKA demonstrated lower cellular oxygen consumption when compared to healthy controls. Oxygen consumption increased significantly in cells of patients with DKA treated with thiamine or CoQ10. These results suggest that thiamine and CoQ10 could potentially have therapeutic benefits in DKA via their metabolic effects on mitochondrial cellular respiration.

Experimental efforts searching for dark matter particles over the last few decades have ruled out many candidates led by the new generation of tonne-scale liquid xenon. For light dark matter, hydrogen could be a better target than xenon as it would offer a better kinematic match to the low mass particles. This article describes the HydroX concept, an idea to expand the dark matter sensitivity reach of large liquid xenon detectors by adding hydrogen to the liquid xenon. We discuss the nature of signal generation in liquid xenon to argue that the signal produced at the interaction site by a dark matter–hydrogen interaction could be significantly enhanced over the same interaction on xenon, increasing the sensitivity to the lightest particles. We discuss the technical implications of adding hydrogen to a xenon detector, as well as some background considerations. Finally, we make projections as to the potential sensitivity of a HydroX implementation and discuss next steps. Dark matter searches have faced challenges in detecting lighter particles with traditional xenon detectors. The authors propose the HydroX concept, integrating hydrogen into liquid xenon detectors, enhancing sensitivity to lighter dark matter particles and detection capabilities in the field.

BACKGROUNDPlasma heparan sulfate, a glycosaminoglycan released during endothelial glycocalyx degradation, predicts sepsis mortality. Chondroitin sulfate is a circulating glycosaminoglycan not specific to glycocalyx degradation; its relevance to sepsis is unknown.METHODSWe studied the associations of plasma chondroitin sulfate with (a) mortality in patients with sepsis-associated hypotension and (b) the relative effectiveness of a randomly assigned liberal versus restrictive intravenous fluid resuscitation strategy. We selected 574 patients enrolled in the Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis trial using an outcome-enriched sampling strategy. We used liquid chromatography-mass spectrometry to quantify plasma chondroitin sulfate. In comparison, we measured hyaluronic acid as a glycocalyx degradation marker and IL-6 as an inflammatory biomarker. We conducted Cox proportional hazards regression analyses to examine associations of baseline biomarker concentrations with mortality and resuscitation strategy effectiveness. We used inverse probability of selection weights and generalized raking to account for the nonrepresentative sampling design.RESULTSPlasma chondroitin sulfate, hyaluronic acid, and IL-6 were associated with mortality within 90 days. As baseline chondroitin sulfate increased, subsequent randomization to a restrictive strategy was increasingly beneficial (P = 0.022): treatment effect hazard ratio (restrictive versus liberal) for mortality was estimated as 1.49 (95% CI, 0.98-2.27), 1.30 (95% CI, 1.00-1.69), 1.09 (95% CI, 0.82-1.44), 0.88 (95% CI, 0.66-1.16), and 0.71 (95% CI, 0.52-0.97) for 10th, 25th, 50th, 75th, and 90th percentiles of baseline chondroitin sulfate.CONCLUSIONPlasma chondroitin sulfate predicts sepsis mortality and may modify the response to a subsequent liberal versus restrictive intravenous fluid resuscitation strategy.TRIAL REGISTRATIONClinicalTrials.gov NCT03434028.FUNDINGNIH grants R01HL149422 and R01HL094786.

We consider a problem motivated by issues in nutritional epidemiology, across diseases and populations. In this area, it is becoming increasingly common for diseases to be modeled by a single diet score, such as the Healthy Eating Index, the Mediterranean Diet Score, etc. For each disease and for each population, a partially linear single-index model is fit. The partially linear aspect of the problem is allowed to differ in each population and disease. However, and crucially, the single-index itself, having to do with the diet score, is common to all diseases and populations, and the nonparametrically estimated functions of the single-index are the same up to a scale parameter. Using B-splines with an increasing number of knots, we develop a method to solve the problem, and display its asymptotic theory. An application to the NIH-AARP Study of Diet and Health is described, where we show the advantages of using multiple diseases and populations simultaneously rather than one at a time in understanding the effect of increased Milk consumption. Simulations illustrate the properties of the methods. Supplementary materials for this article are available online.