Lipotoxicity and immunometabolism in ischemic acute kidney injury: current perspectives and future directions.

Dysregulated lipid metabolism is implicated in the pathophysiology of a range of kidney diseases. The specific mechanisms through which lipotoxicity contributes to acute kidney injury (AKI) remain poorly understood. Herein we review the cardinal features of lipotoxic injury in ischemic kidney injury; lipid accumulation and mitochondrial lipotoxicity. We then explore a new mechanism of lipotoxicity, what we define as "immunometabolic" lipotoxicity, and discuss the potential therapeutic implications of targeting this lipotoxicity using lipid lowering medications.

HLA matching between donors and recipients improves clinical liver transplant graft survival.

BACKGROUND AND AIMS: The importance of human leukocyte antigen (HLA) matching between liver transplant donors and recipients on graft survival remains unclear and is not a clinical consideration in liver transplantation. This study aimed to determine the relationship between HLA matching and liver graft survival using a large-scale multi-centre database (UNOS/OPTN) and multivariate logistic analysis. The secondary aim was to determine whether this relationship was influenced by transplant indication and donor status. METHODS: This retrospective observational analysis was performed using 22 702 liver transplant recipients from the UNOS/OPTN database. Patients were divided into two groups based on number of HLA mismatches (0-3 mismatches vs. 4-6 mismatches) and then subcategorized by indication and donor status. Risk-adjusted outcomes were assessed by multivariate Cox analysis adjusting for donor and recipient characteristics and visualized using Kaplan-Meier survival curves. RESULTS: Allograft survival and risk of acute rejection were associated with degree of HLA mismatch. This association between HLA mismatch and graft survival persisted in individuals who underwent transplant for hepatitis, metabolic, drug toxicity, and congenital indications. Donor status also influenced the relationship between HLA mismatch and graft survival. Graft survival in DBD recipients was longer than in DCD in the 4-6 HLA mismatch group, whereas no significant difference was found in the 0-3 HLA mismatch group. CONCLUSION: HLA mismatch significantly reduced graft survival and increased risk of acute rejection. This association was noted only in specific indications. These findings are of potential clinical relevance to organ allocation, allograft matching algorithms, immunosuppression protocols, and transplant surveillance.

Clinical trials of pharmacological interventions for SARS-CoV-2 published in leading medical journals report adherence but not how it was assessed.

AIMS: Adherence to pharmacological interventions in clinical trials is crucial for accurate identification of beneficial and adverse outcomes. The ways in which adherence to interventions should be reported in trial publications are described in the Template for Intervention Description and Replication (TIDieR), a 12-item extension of the Consolidated Standards of Reporting Trials reporting guidelines. The objective of this study was to assess compliance with TIDieR Items 11 and 12 of randomized controlled trials (RCTs) of interventions in SARS-CoV-2 infection published in 5 selected journals during 2021. METHODS: We assessed pharmacological interventions for SARS-CoV-2 infection reported in RCTs published in 2021 in the Annals of Internal Medicine, The BMJ, JAMA, The Lancet and The New England Journal for Medicine for compliance with TIDieR items addressing intervention adherence (Items 11 and 12). We calculated proportional adherence for pharmacological and comparator interventions where available. RESULTS: We found 75 eligible RCTs. Twenty-eight (37%) reported results of SARS-CoV-2 vaccinations. Compliance with Items 11 and 12 could be assessed in 71 of these 75. Of the 71 RCTs, 37 (52%) reported how adherence was assessed (Item 11), and 70 reported adherence rates (Item 12). Only 1 of the 71 RCTs (1.4%, 0-7.6%) fully complied with TIDieR Items 11 and 12. CONCLUSION: Half of RCTs of SARS-CoV-2 pharmacological interventions published in leading medical journals in 2021 complied with reporting of how adherence assessments were made and almost none complied with both TIDieR Items 11 and 12. The implications for interpretation, application and replication of findings based on these publications warrant consideration.

Symptomatic atherosclerotic vascular disease and graft survival in primary kidney transplant recipients - Observational analysis of the united network of organ sharing database.

OBJECTIVES: The aim of this study was to investigate whether symptomatic atherosclerotic vascular disease (SAVD) was associated with graft survival in primary kidney transplant recipients. SUMMARY BACKGROUND DATA: Recipient atherosclerotic vascular disease is associated with increased mortality rates amongst renal transplant patients. However, its relationship with graft survival has not been well studied. METHODS: This retrospective observational analysis was performed using data for adult kidney transplant recipients between 11/09/2000 and 28/02/2020 extracted from the UNOS national organ transplantation database. Patients were divided into two groups based on recipient history of symptomatic atherosclerotic disease (angina or peripheral vascular disease). Risk-adjusted outcomes were assessed by multivariate Cox regression analysis adjusting for both donor and recipient characteristics. RESULTS: 11,771 adult kidney transplant recipients from the UNOS database were eligible for analysis (1543 had a history of SAVD, 10,228 did not have a history of SAVD). After adjusting for confounders, positive SAVD status was associated with an adverse effect on graft survival at both 1 year (HR 1.35, p < 0.001) and 10 years (HR 1.15, p < 0.001). CONCLUSIONS: SAVD should be considered an independent risk factor for poor prognosis in patients undergoing kidney transplant.

The impact of the COVID-19 pandemic on glycaemic control in people with diabetes: A systematic review and meta-analysis.

AIM: To identify, appraise and synthesize the available evidence on the impact of the coronavirus disease 2019 (COVID-19) pandemic and lockdown (LD) on glycaemic control in people with diabetes. MATERIALS AND METHODS: We searched multiple databases up to 2 February 2021 for studies reporting HbA1c, time in range (TIR), average or fasting glucose, severe hypoglycaemia and diabetic ketoacidosis. Data were pooled using random effects meta-analysis and are presented as mean difference (MD) with 95% confidence intervals (CI). This review was preregistered on PROSPERO (CRD42020179319). RESULTS: We include 59 studies; 44 (n = 15 464) were included in quantitative syntheses and 15 were narratively synthesized. Pooled data were grouped by diabetes type. Results from 28 studies (n = 5048 type 1 diabetes [T1D] and combined diabetes participants) showed that TIR increased during LD compared with before LD (MD 2.74%, 95% CI 1.80% to 3.69%). Data from 10 studies (n = 1294 T1D participants) showed that TIR increased after LD compared with before LD (MD 5.14%, 95% CI 3.12% to 7.16%). Pooled results from 12 studies (n = 4810 T1D and type 2 diabetes participants) resulted in average glucose decreasing after LD compared with before LD (MD -6.86 mg/dl, 95% CI -8.54 to -5.18). Results for other outcomes, including HbA1c, were not statistically significantly different. CONCLUSIONS: The COVID-19 pandemic was associated with small improvements across multiple outcomes of glycaemic control, although there was insufficient evidence to suggest that this led to changes in HbA1c. Most evidence came from people with access to diabetes technologies in high-income countries; more research is needed in less advantaged populations.

The association of weight loss with changes in the gut microbiota diversity, composition, and intestinal permeability: a systematic review and meta-analysis.

The gut microbiome may be a mediator between obesity and health outcomes. However, it is unclear how intentional weight loss changes the gut microbiota and intestinal permeability. We aimed to systematically review and quantify this association. We searched Medline, Embase, CINAHL, Cochrane databases, and trial registries until June 2020 (PROSPERO: CRD42020205292). We included trials of weight loss interventions (energy-restricted diets, pharmacotherapy, bariatric surgery) reporting on the microbiome. Two reviewers independently completed screening, extraction, and risk assessment with the ROBINS-I tool. Pooled standardized mean differences (SMDs) were obtained from random-effects meta-analyses. Forty-seven trials with 1,916 participants (81% female) and a median follow-up of 6 months (range: 2-24) were included. Based on imprecise evidence but with fairly consistent direction of effect, weight loss was associated with a statistically significant increase in α-diversity [SMD: 0.4 (95% CI: 0.2, 0.6], p < .0001, I2 = 70%, n = 30 studies) and a statistically significant reduction in intestinal permeability [SMD: -0.7 (95% CI: -0.9, -0.4), p < .0001, I2 = 83%, n = 17 studies]. Each kg of weight loss was associated with a 0.012 (95% CI: 0.0003, 0.024, p = .045) increase in α-diversity and a -0.017 (95% CI: -0.034, -0.001, p = .038) reduction in intestinal permeability. There was clear evidence of increases in the relative abundance of Akkermansia, but no clear evidence of changes in individual phyla, species, or fecal short-chain fatty acids. Restricting the analyses to the studies with lower risk of bias did not materially alter the estimates. Increasing weight loss is positively associated with increases in gut microbiota α-diversity and reductions in intestinal permeability.

Risks of infection, hospital and ICU admission, and death from COVID-19 in people with asthma: systematic review and meta-analyses.

OBJECTIVES: To determine if and to what degree asthma may predispose to worse COVID-19 outcomes in order to inform treatment and prevention decisions, including shielding and vaccine prioritisation. DESIGN: Systematic review and meta-analysis. SETTING: Electronic databases were searched (October 2020) for clinical studies reporting at least one of the following stratified by asthma status: risk of infection with SARS-CoV-2; hospitalisation, intensive care unit (ICU) admission or mortality with COVID-19. PARTICIPANTS: Adults and children who tested positive for or were suspected to have COVID-19. MAIN OUTCOME MEASURES: Main outcome measures were the following stratified by asthma status: risk of infection with SARS-CoV-2; hospitalisation, ICU admission or mortality with COVID-19. We pooled odds ratios (ORs) and presented these with 95% confidence intervals (CI). Certainty was assessed using GRADE (Grading of Recommendations, Assessment, Development and Evaluations). RESULTS: 30 (n=112 420) studies were included (12 judged high quality, 15 medium, 3 low). Few provided indication of asthma severity. Point estimates indicated reduced risks in people with asthma for all outcomes, but in all cases the evidence was judged to be of very low certainty and 95% CIs all included no difference and the possibility of increased risk (death: OR 0.90, 95% CI 0.72 to 1.13, I2=58%; hospitalisation: OR 0.95, 95% CI 0.71 to 1.26; ICU admission: OR 0.96, 95% CI 0.75 to 1.24). Findings on hospitalisation are also limited by substantial unexplained statistical heterogeneity. Within people with asthma, allergic asthma was associated with less COVID-19 risk and concurrent chronic obstructive pulmonary disease was associated with increased risk. In some studies, corticosteroids were associated with increased risk, but this may reflect increased risk in people with more severe asthma. CONCLUSIONS: Though absence of evidence of a clear association between asthma and worse outcomes from COVID-19 should not be interpreted as evidence of absence, the data reviewed indicate that risks from COVID-19 in people with asthma, as a whole, may be less than originally anticipated.

Risks of and From SARS-CoV-2 Infection and COVID-19 in People With Diabetes: A Systematic Review of Reviews.

BACKGROUND: This review was commissioned by the World Health Organization and presents a summary of the latest research evidence on the impact of coronavirus disease 2019 (COVID-19) on people with diabetes (PWD). PURPOSE: To review the evidence regarding the extent to which PWD are at increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or of suffering its complications, including associated mortality. DATA SOURCES: We searched the Cochrane COVID-19 Study Register, Embase, MEDLINE, and LitCOVID on 3 December 2020. STUDY SELECTION: Systematic reviews synthesizing data on PWD exposed to SARS-CoV-2 infection, reporting data on confirmed SARS-CoV-2 infection, admission to hospital and/or to intensive care unit (ICU) with COVID-19, and death with COVID-19 were used. DATA EXTRACTION: One reviewer appraised and extracted data; data were checked by a second. DATA SYNTHESIS: Data from 112 systematic reviews were narratively synthesized and displayed using effect direction plots. Reviews provided consistent evidence that diabetes is a risk factor for severe disease and death from COVID-19. Fewer data were available on ICU admission, but where available, these data also signaled increased risk. Within PWD, higher blood glucose levels both prior to and during COVID-19 illness were associated with worse COVID-19 outcomes. Type 1 diabetes was associated with worse outcomes than type 2 diabetes. There were no appropriate data for discerning whether diabetes was a risk factor for acquiring SARS-CoV-2 infection. LIMITATIONS: Due to the nature of the review questions, the majority of data contributing to included reviews come from retrospective observational studies. Reviews varied in the extent to which they assessed risk of bias. CONCLUSIONS: There are no data on whether diabetes predisposes to infection with SARS-CoV-2. Data consistently show that diabetes increases risk of severe COVID-19. As both diabetes and worse COVID-19 outcomes are associated with socioeconomic disadvantage, their intersection warrants particular attention.

Asthma and COVID-19: review of evidence on risks and management considerations.

BACKGROUND: Respiratory illnesses typically present increased risks to people with asthma (PWA). However, data on the risks of COVID-19 to PWA have presented contradictory findings, with implications for asthma management. OBJECTIVE: To assess the risks and management considerations of COVID-19 in people with asthma (PWA). METHOD: We conducted a rapid literature review. We searched PubMed, medRxiv, LitCovid, TRIP, Google and Google Scholar for terms relating to asthma and COVID-19, and for systematic reviews related to specific management questions within our review, in April 2020. References were screened and data were extracted by one reviewer. RESULTS: We extracted data from 139 references. The evidence available is limited, with some sources suggesting an under-representation of PWA in hospitalised cases and others showing an increased risk of worse outcomes in PWA, which may be associated with disease severity. Consensus broadly holds that asthma medications should be continued as usual. Almost all aspects of asthma care will be disrupted during the pandemic due not only to limits in face-to-face care but also to the fact that many of the diagnostic tools used in asthma are considered aerosol-generating procedures. Self-management and remote interventions may be of benefit for asthma care during this time but have not been tested in this context. CONCLUSIONS: Evidence on COVID-19 and asthma is limited and continuing to emerge. More research is needed on the possible associations between asthma and COVID-19 infection and severity, as well as on interventions to support asthma care in light of constraints and disruptions to healthcare systems. We found no evidence regarding health inequalities, and this urgently needs to be addressed in the literature as the burdens of asthma and of COVID-19 are not equally distributed across the population.

Pilomatricoma on 18F-fluorodeoxyglucose positron emission tomography-computed tomography: Peripheral mimic of an aggressive soft-tissue malignancy.

Pilomatricoma, also known as calcifying epithelioma of Malherbe, is a rare skin tumor originating from the hair follicle matrix. We report a case of pilomatricoma in a 50-year-old woman, presenting as a rapidly growing pretibial mass. Malignant pilomatricoma is associated with potentially fatal metastases and are clinically and histologically indistinguishable from benign pilomatricoma. Thus, an 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) scan was requested for staging, revealing marked FDG uptake restricted to the primary lesion and no evidence of separate disease. The purpose of this report is to demonstrate the importance of PET/CT in the staging of this FDG-avid tumor; the malignancy of which is often first revealed by metastases. Our case also demonstrates that pilomatricoma should be included in the differential diagnosis of a rapidly growing peripheral soft-tissue mass; conventionally, the domain of sarcoma.