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Complications of hematopoietic stem cell transplant (HSCT) include acute graft-versus-host disease (aGVHD). Severe cutaneous aGVHD can present with generalized erythroderma, desquamation, and bullae which can mimic toxic epidermal necrolysis (TEN). TEN occurs in response to a culprit medication. Transplant patients are often on many medications, making it difficult to distinguish between the two conditions. Given that TEN-like aGVHD is rare, we describe a case series of pediatric patients and review the literature.This is a multi-institutional case series of children who developed TEN-like aGVHD following bone marrow transplantation. Demographic, clinical, and treatment information was collected.Ten patients were identified. Median age at transplantation was 8.5 years (range 0.12-17 years). Median time from transplant to first skin symptoms was 35 days (range 6-110 days) and to first TEN-like symptoms was 40 days (range 16-116 days). 7/10 had other organ GVHD involvement. All patients were on concurrent medications at time of first skin symptoms including immunosuppression for GVHD prophylaxis, infection prophylaxis or treatment, and pain medication. Treatments for TEN-like aGVHD included immunosuppression.We observe that patients withor equal to 50% BSA involvement of their skin with TEN-like aGVHD, extracutaneous GVHD, and lack of reepithelization tend to have poor outcomes. Given the rarity of this condition, multidisciplinary care of these patients is important for accurate and timely diagnosis and treatment.

Several pieces of evidence have shown the neurotrophic effect of erythropoietin (EPO) and its introduction in the therapeutic practice of neurological diseases. However, its usefulness in the treatment of spinocerebellar ataxia type 2 (SCA2) has not been proven despite the fact that it is endogenously reduced in these patients.The study aims to investigate the safety, tolerability, and clinical effects of a nasally administered recombinant EPO in SCA2 patients.Thirty-four patients were enrolled in this double-blind, randomized, placebo-controlled, phase I-II clinical trial of the nasally administered human-recombinant EPO (NeuroEPO) for 6 months. The primary outcome was the change in the spinocerebellar ataxia functional index (SCAFI), while other motor, neuropsychological, and oculomotor measures were assessed.The 6-month changes in SCAFI score were slightly higher in the patients allocated to NeuroEPO treatment than placebo in spite of the important placebo effect observed for this parameter. However, saccade latency was significantly decreased in the NeuroEPO group but not in placebo. The frequency and severity of adverse events were similar between both groups, without evidences of hematopoietic activity of the drug.This study demonstrated the safety and tolerability of NeuroEPO in SCA2 patients after 6 months of treatments and suggested a small clinical effect of this drug on motor and cognitive abnormalities, but confirmatory studies are warranted. © 2022 International Parkinson and Movement Disorder Society.

The association between alcohol intake and cognitive decline has been widely studied. Sex differences and cognitive domains affected by alcohol intake patterns make this topic complex. The objective of this study was to investigate the effect of alcohol intake on cognition in middle-aged participants in the Brazilian Longitudinal Study of Adult Health by sex during 4 years of follow-up.A total of 7595 participants (55% women) aged between 50 and 75 years at baseline were assessed. Semantic and phonemic fluency, memory, and executive functions were assessed at baseline (2008-2010) and repeated during Visit 2. Linear mixed models were used to investigate the association between cognition and current abstainers, never drinkers, light drinkers, moderate drinkers, and heavy drinkers.Heavy alcohol intake accentuated the decline in executive functions for men (β = -0.01, p 0.05), and in semantic fluency (β = -0.02, p 0.05) and memory (β = -0.02, p 0.05) for women. Never drinker men also showed an accentuated decline in semantic fluency (β = -0.02, p 0.01). Moderate alcohol intake slowed cognitive decline in phonemic fluency for men (β = 0.02, p 0.01) and women (β = 0.01, p 0.01), and in executive functions (β = 0.01, p 0.05) for women.Having more than 14 drinks per week can impact executive functions in men and memory in women. In addition, alcohol consumption of seven to 14 drinks per week may have a protective effect on gender-specific cognitive functions. These findings should be considered in public health policies and guidelines on alcohol and cognitive aging.

HIV cure strategies aim to eliminate viral reservoirs that persist despite successful antiretroviral therapy (ART). We have previously described that 9% of HIV-infected individuals who receive ART harbor low levels of provirus (LoViReTs).We selected 22 LoViReTs matched with 22 controls ART suppressed for more than 3 years with fewer than 100 and more than 100 HIV-DNA copies/10We found that LoViReTs harbored not only lower levels of total HIV-DNA, but also significantly lower intact HIV-DNA, cell-associated HIV-RNA, and ultrasensitive viral load than controls. The proportion of intact versus total proviruses was similar in both groups. We found no differences in the percentage of host factors. In peripheral blood, 71% of LoViReTs had undetectable replication-competent virus. Minimum levels of total HIV-DNA were found in rectal and lymph node biopsies compared with HIV-infected individuals receiving ART. The main contributors to the reservoir were short-lived transitional memory and effector memory T cells (47% and 29%, respectively), indicating an altered distribution of the HIV reservoir in the peripheral T-cell subpopulations of LoViReTs.In conclusion, LoViReTs are characterized by low levels of viral reservoir in peripheral blood and secondary lymphoid tissues, which might be explained by an altered distribution of the proviral HIV-DNA towards more short-lived memory T cells. LoViReTs can be considered exceptional candidates for future interventions aimed at curing HIV.

Objectives: (1) To evaluate clinical and molecular cardiovascular disease (CVD) signs and their relationship with psoriatic arthritis (PsA) features and (2) to identify a clinical patient profile susceptible to benefit from methotrexate (MTX) and/or apremilast regarding CVD risk. Methods: This cross-sectional study included 100 patients with PsA and 100 age-matched healthy donors. In addition, an exploratory cohort of 45 biologically naïve patients treated for 6 months with apremilast, MTX or combined therapy according to routine clinical practice was recruited. Extensive clinical and metabolic profiles were obtained. Ninety-nine surrogate CVD-related molecules were analysed in plasma and peripheral blood mononuclear cells (PBMCs). Hard cluster analysis was performed to identify the clinical and molecular phenotypes. Mechanistic studies were performed on adipocytes. Results: Cardiometabolic comorbidities were associated with disease activity and long-term inflammatory status. Thirty-five CVD-related proteins were altered in the plasma and PBMCs of PsA patients and were associated with the key clinical features of the disease. Plasma levels of some of the CVD-related molecules might distinguish insulin-resistant patients (MMP-3, CD163, FABP-4), high disease activity (GAL-3 and FABP-4) and poor therapy outcomes (CD-163, LTBR and CNTN-1). Hard cluster analysis identified two phenotypes of patients according to the rates of cardiometabolic comorbidities with distinctive clinical and molecular responses to each treatment. Conclusions: (1) Novel CVD-related proteins associated with clinical features could be emerging therapeutic targets in the context of PsA and (2) the pleiotropic action of apremilast could make it an excellent choice for the management of PsA patients with high CVD risk, targeting metabolic alterations and CVD-related molecules.

The best approach to tuberculosis (TB) treatment in transplanted patients is still unknown. Current guidelines are based on evidence either extrapolated from other populations or observational. Rifampin-containing regimens have strong pharmacokinetic interactions with immunosuppressive regimens, with high rates of organ dysfunction and ∼20% mortality. This report describes the results obtained using non-rifampin-containing regimens to treat confirmed TB in adult patients with kidney/kidney-pancreas transplantation.Retrospective data analysis from confirmed TB cases in adult kidney/kidney-pancreas transplant recipients (2006-2019), treated "de novo" with non-rifampin-containing regimens.Fifty-seven patients had confirmed TB. Thirty patients were treated "de novo" with non-rifampin-containing regimens. These patients' mean age was 49.24 (±11.50) years. Induction immunosuppression was used in 22 patients. Maintenance immunosuppression was tacrolimus-mycophenolate-steroids in 13 (43%), sirolimus-mycophenolate-steroids in 6 (20%), and other immunosuppressive regimens in 11 (36%). Belatacept was used in four patients. TB localizations: pulmonary 43%; disseminated 23%; extrapulmonary 33%. Twenty-seven (90%) patients completed treatment with isoniazid, ethambutol, and levofloxacin (12 months, 23; 9 months, 3; 6 months, 1); 12 of these patients also received pyrazinamide for the first 2 months and were cured with functioning grafts. One patient (3%) lost the graft while on treatment. Two patients (7%) died while on TB treatment. Median (range) follow-up after completion of TB treatment was 32 (8-150) months. No TB relapses were observed.Results with non-rifampin-containing TB treatments in this case series were better (in terms of mortality and graft dysfunction) than those previously described with rifampin-containing regimens in transplanted patients.

This paper assesses the viability of providing down and up spinning reserves by renewable energy resources (RES) in island power systems. The process consists of evaluating the impact of providing spinning reserve on the system operation costs of different islands by simulating the unit commitment problem. The assessment is carried out for La Palma (small size) and Tenerife (medium size) island power systems, and by considering different wind source availability scenarios for sample weeks of different seasons in current and future years. This paper differentiates between up and down reserves and studies their impacts separately. Results show that enabling RES to provide just down spinning reserve has economic benefits for all scenarios, by reducing over 40% the amount of thermal generation and over 30% the systems costs for high wind scenarios. It also confirms that employing variable deloading of wind energy as a source of up reserve is advisable, mainly in scenarios with high share of wind sources. In some scenarios, using RES as reserve provider, reduces the amount of thermal generation more than 50%, compared to when RES does not participate as a source of reserve, and can even lead to a full RES coverage of demand.

Matrix metalloproteinase-13 (MMP-13) is a uniquely important collagenase that promotes the irreversible destruction of cartilage collagen in osteoarthritis (OA). Collagenase activation is a key control point for cartilage breakdown to occur, yet our understanding of the proteinases involved in this process is limited. Neutrophil elastase (NE) is a well-described proteoglycan-degrading enzyme which is historically associated with inflammatory arthritis, but more recent evidence suggests a potential role in OA. In this study, we investigated the effect of neutrophil elastase on OA cartilage collagen destruction and collagenase activation. Neutrophil elastase induced significant collagen destruction from human OA cartilage ex vivo, in an MMP-dependent manner. In vitro, neutrophil elastase directly and robustly activated pro-MMP-13, and N-terminal sequencing identified cleavage close to the cysteine switch at 72 MKKPR, ultimately resulting in the fully active form with the neo-N terminus of 85 YNVFP. Mole-per-mole, activation was more potent than by MMP-3, a classical collagenase activator. Elastase was detectable in human OA synovial fluid and OA synovia which displayed histologically graded evidence of synovitis. Bioinformatic analyses demonstrated that, compared with other tissues, control cartilage exhibited remarkably high transcript levels of the major elastase inhibitor, (AAT) alpha-1 antitrypsin (gene name SERPINA1), but these were reduced in OA. AAT was located predominantly in superficial cartilage zones, and staining enhanced in regions of cartilage damage. Finally, active MMP-13 specifically inactivated AAT by removal of the serine proteinase cleavage/inhibition site. Taken together, this study identifies elastase as a novel activator of pro-MMP-13 that has relevance for cartilage collagen destruction in OA patients with synovitis.

Background and aims Non-alcoholic fatty liver (NAFLD) and its more serious form non-alcoholic steatohepatitis increase risk of hepatocellular carcinoma (HCC). Lipid metabolic alterations and its role in HCC development remain unclear. SPARC (Secreted Protein, Acidic and Rich in Cysteine) is involved in lipid metabolism, NAFLD and diabetes, but the effects on hepatic lipid metabolism and HCC development is unknown. The aim of this study was to evaluate the role of SPARC in HCC development in the context of NAFLD. Methods Primary hepatocyte cultures from knockout (SPARC-/- ) or wild-type (SPARC+/+ ) mice, and HepG2 cells were used to assess the effects of free fatty acids on lipid accumulation, expression of lipogenic genes and de novo triglyceride (TG) synthesis. A NAFLD-HCC model was stabilized on SPARC-/- or SPARC+/+ mice. Correlations among SPARC, lipid metabolism-related gene expression patterns and clinical prognosis were studied using HCC gene expression dataset. Results SPARC-/- mice increases hepatic lipid deposits over time. Hepatocytes from SPARC-/- mice or inhibition of SPARC by an antisense adenovirus in HepG2 cells resulted in increased TG deposit, expression of lipid-related genes and nuclear translocation of SREBP1c. Human HCC database analysis revealed that SPARC negatively correlated with genes involved in lipid metabolism, and with poor survival. In NAFLD-HCC murine model, the absence of SPARC accelerates HCC development. RNA-seq study revealed that pathways related to lipid metabolism, cellular detoxification and proliferation were upregulated in SPARC-/- tumour-bearing mice. Conclusions The absence of SPARC is associated with an altered hepatic lipid metabolism, and an accelerated NAFLD-related HCC development.

Here we show that by adjusting the concentration of tetrabutyl ammonium and phosphonium salts in water (approximate to 1.5-2.0 m), hydrophobic solvation triggers the formation of a unique, highly incompressible supramolecular liquid, with a dynamic structure similar to clathrates, involving essentially all H2O molecules of the solvent. Despite the increasing local order, the thermal diffusivity, and compressibility of these supramolecular liquids is strongly decreased with respect to bulk water due to slower relaxation dynamics. The results presented in this paper open an avenue to design a new family of supramolecular fluids, stable under atmospheric conditions, which can find important technological applications in energy storage and conversion.

Background Information on the characteristics of patients with nosocomial influenza and associated complications is scarce. This study compared epidemiological and clinical characteristics of patients admitted with hospital‐acquired influenza (HAI) to those with community‐acquired influenza (CAI) and analyzed risk factors associated with complications. Methods This retrospective, observational study included all adult patients with confirmed influenza virus infection admitted to Son Espases University Hospital during the influenza season in Spain (October to May) from 2012‐2013 to 2015‐2016. Symptom onset before admission was included as CAI, and 2 days after admission or within 48 hours after previous discharge were considered as HAI. Results Overall, 666 patients with laboratory‐confirmed influenza were included; 590 (88.6%) and 76 (11.4%) had CAI and HAI, respectively. Baseline characteristics and vaccination rates were similar in both groups. Patients with HAI had significantly fewer symptoms, less radiological alterations, and earlier microbiological diagnosis than those with CAI. Eighty‐five (14.4%) and 20 (27.6%) CAI and HAI patients, respectively, experienced at least one complication, including septic shock, admission to the intensive care unit, mechanical ventilation or evolution to death (any one, P = .003). Univariate and multivariate binary logistic regression was performed to assess independent risk factors associated with the occurrence of complications: nosocomial infection, diabetes, oseltamivir treatment, having received no vaccination, microbiological delay, dyspnea, and the state of confusion were the most important significant factors. Conclusions Our study shows the need to implement microbiological diagnostic measures in the first 48 hours to reduce HAI frequency and associated complications.

Aims Among renal cell carcinoma (RCC) the tumour immune microenvironment has been best characterised in clear cell RCC. In this study we investigated the expression of several immune markers, including PD-L1, FoxP3 and CD8 in primary and metastatic papillary RCC. Methods and results Three tissue microarrays were constructed from 78 cases with primary papillary RCC and paired metastatic tumour (24 cases) from 78 patients treated between 1982 and 2014. Immunohistochemistry analysis was performed using commercially available antibodies for PD-L1 (clone E1L3N), FoxP3, CD8 and Ki-67. Markers expression level in tumour and/or associated immune cells was analysed by tissue type (non-tumour versus primary tumour versus metastatic tumour) and correlated to clinicopathological features and outcome. Conclusion We found PD-L1 expression in up to one-quarter of primary and metastatic papillary RCC. On univariate analysis, CD8/FoxP3 ratio >1 was associated with favourable outcome, whereas papillary RCCs with high numbers of dual CD8/Ki-67-positive lymphocytes showed an increased likelihood for tumour progression and overall and cancer-related mortality. The association of CD8/FoxP3 ratio >1 and high count of CD8/Ki-67 with outcome remained significant on multivariate analysis when adjusting for stage, grade and patient's age.

G protein-coupled receptors (GPCRs) comprise the largest group of membrane receptors in eukaryotic genomes and collectively they regulate nearly all cellular processes. Despite the widely recognized importance of this class of proteins, many GPCRs remain understudied. G protein-coupled receptor 27 (Gpr27) is an orphan GPCR that displays high conservation during vertebrate evolution. Although, GPR27 is known to be expressed in tissues that regulate metabolism including the pancreas, skeletal muscle, and adipose tissue, its functions are poorly characterized. Therefore, to investigate the potential roles of Gpr27 in energy metabolism, we generated a whole body gpr27 knockout zebrafish line. Loss of gpr27 potentiated the elevation in glucose levels induced by pharmacological or nutritional perturbations. We next leveraged a mass spectrometry metabolite profiling platform to identify other potential metabolic functions of Gpr27. Notably, genetic deletion of gpr27 elevated medium-chain acylcarnitines, in particular C6-hexanoylcarnitine, C8-octanoylcarnitine, C9-nonanoylcarnitine, and C10-decanoylcarnitine, lipid species known to be associated with insulin resistance in humans. Concordantly, gpr27 deletion in zebrafish abrogated insulin-dependent Akt phosphorylation and glucose utilization. Finally, loss of gpr27 increased the expression of key enzymes in carnitine shuttle complex, in particular the homolog to the brain-specific isoform of CPT1C which functions as a hypothalamic energy senor. In summary, our findings shed light on the biochemical functions of Gpr27 by illuminating its role in lipid metabolism, insulin signaling, and glucose homeostasis.

BACKGROUND Drug-induced maculopapular exanthemas (MPEs) are mediated by Th1 CD4+ T cells. One of the mechanisms of control of Th1 cells in homeostasis is the interaction between the checkpoint inhibitor Tim3 and its physiological ligand galectin-9 (Gal9). Disorders affecting this axis may be responsible for various autoimmune and immunological diseases. The aim of this study was to determinate the influence of the Tim3-Gal9 axis on the development of MPE induced by drugs. METHODS Frequencies of different cell subsets and the expression of Tim3 and Gal9 were measured in peripheral blood by flow cytometry and in skin biopsies by immunohistochemistry. Gal9 expression was assessed by RT-qPCR; its release was measured by multiplex assay. The effects of blocking or enhancing the Tim3-Gal9 axis on monocyte-derived dendritic cell (moDC) maturation and T-cell proliferation were determined by flow cytometry. RESULTS The expression of Tim3 was significantly reduced in peripheral blood Th1 cells and in the skin of MPE patients vs controls. Gal9 expression and release were significantly reduced in patient peripheral blood and moDCs, respectively. The addition of exogenous Gal9 significantly reduced Tim3+ Th1 proliferation, although Treg proliferation increased. CONCLUSION This study showed the involvement of the Tim3-Gal9 axis in MPE. The reduced expression of Tim3 in Th1 cells together with the impaired expression of Gal9 in PBMCs and DCs appears to have a role in the development of the disease. The potential of Gal9 to suppress Th1 and enhance Treg proliferation makes it a promising tool for treating these reactions.

Marine environments face acute pressures from human impacts, often resulting in substantial changes in community structure. On the inshore Great Barrier Reef (GBR), palaeoecological studies show the collapse of the previously dominant coral Acropora from the impacts of degraded water quality associated with European colonization. Even more dramatic impacts can result in the replacement of corals by fleshy macroalgae on modern reefs, but their past distribution is unknown because they leave no fossil record. Here, we apply DNA metabarcoding and high-throughput sequencing of the 18S rDNA gene on palaeoenvironmental DNA (aeDNA) derived from sediment cores at two sites on Pandora Reef (GBR), to enhance palaeoecological studies by incorporating key soft-bodied taxa, including macroalgae. We compared temporal trends in this aeDNA record with those of coral genera derived from macrofossils. Multivariate analysis of 12 eukaryotic groups from the aeDNA community showed wide variability over the past 750 years. The occurrence of brown macroalgae was negatively correlated only with the dominant coral at both sites. The occurrence of coralline and green macroalgae was positively correlated with only the dominant coral at one of the sites, where we also observed a significant association between the whole coral community and the occurrence of each of the three macroalgae groups. Our results demonstrate that reef sediments can provide a valuable archive for understanding the past distribution and occurrence of important soft-bodied reef dwellers. Combining information from fossils and aeDNA provides an enhanced understanding of temporal changes of reefs ecosystems at decadal to millennial timescales.

Blood pressure (BP) is a strong cardiovascular risk factor, predicting cardiovascular mortality in the general population. High salt consumption is a major contributor of increased BP and hypertension. However, there is a controversy on whether BP response to salt intake would be sex-specific. Thus, we aimed to verify the changes in BP according to different salt intake in men and women in a large sample of adults. The present analysis refers to 12 813 participants (from 35 to 64 years) with a validated 12-hour overnight urine collection in which salt intake was estimated. A set of questionnaires, clinical examination, and laboratory tests were carried out during a single visit to one of the six investigation centers involved. Salt intake was 12.9 ± 5.9 g/d in men and 9.3 ± 4.3 g/d in women. BP increases as salt intake increases, regardless of using BP-lowering medication. The slope of increase in BP elicited by salt intake was significantly higher in women than in men. Thus, the increase in BP by salt intake was stepper in women even after controlling for confounders, regardless of using BP-lowering medication or being hypertensive. In conclusion, salt intake is elevated in this large sample of Brazilian adults in which only a few participants are compliant with the recommendation. Also, women have a higher responsiveness of BP according to salt intake than men, and it is not associated with age, BP level, or the use of BP-lowering medication.

Identifying organisms that play an important role in maintaining ecosystem function is a key aspect of resilience‐based management. For Australia's Great Barrier Reef (GBR), we found that the recovery ability of shallow exposed fore‐reefs is more than 14 times higher when tabular Acropora are present. The disproportionate role that tabular Acropora play appears to be driven by a combination of traits including high recruitment, high growth rate and, importantly, large maximum colony sizes. Despite this key role, tabular Acropora are highly sensitive to most pressures. We compile evidence suggesting that if tabular corals were to decline or disappear on the GBR, the potential for reef recovery on exposed fore‐reefs would be considerably slowed. We then consider the merits of placing special emphasis on the protection of tabular Acropora within the management of the GBR. Importantly, we recognise that an analysis of costs and benefits of such recognition is vital before any change is implemented. Actions might include targeted crown‐of‐thorns starfish control, anchoring restrictions and protection for tabular corals on reefs identified as essential for their larval dispersal. In addition, targeted communications about the critical importance of these highly recognisable corals may boost community support and participation in their protection.

OBJECTIVE To estimate annual weight gain and the incidence of overweight and obesity, stratified according to gender and socioeconomic factors. METHODS From the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), we included 13 625 women and men aged 35-74 (2008-2010) who attended a follow-up visit after a mean 3.8-years. Standardized questionnaires were used to record sociodemographic data, and height and weight were measured on all participants during in-person visits at research centers. The incidence rate to overweight was calculated among those not having excess weight at baseline, and incident obesity among those not having this condition at baseline. We evaluated the incidence of overweight and obesity in men and women, adjusted by age, through Poisson regression with robust variance. Large annual weight gain by gender was being defined as ≥90th percentile in the cohort. RESULTS A global incidence of 7.7% for overweight and 10.6% for obesity was observed, with higher levels seen among black woman (28.5%), young men (21.1%) and woman with low educational level (35.0%). The proportions of overweight and obesity increased with age at both time points, more commonly among those with the lowest levels of per capita income and fewer years of schooling. Large annual weight gain was greater among participants with an intermediate level of education and those who self-identified as black. CONCLUSIONS A high overall risk of becoming overweight/obese was found, especially among women. The roles of race and education level are fundamental to understanding the effects produced by social inequalities in rates of excess weight.