A global research priority agenda to advance public health responses to fatty liver disease

Background & aims An estimated 38% of adults worldwide have non-alcoholic fatty liver disease (NAFLD). From individual impacts to widespread public health and economic consequences, the implications of this disease are profound. This study aimed to develop an aligned, prioritised fatty liver disease research agenda for the global health community. Methods Nine co-chairs drafted initial research priorities, subsequently reviewed by 40 core authors and debated during a three-day in-person meeting. Following a Delphi methodology, over two rounds, a large panel (R1 n = 344, R2 n = 288) reviewed the priorities, via Qualtrics XM, indicating agreement using a four-point Likert-scale and providing written feedback. The core group revised the draft priorities between rounds. In R2, panellists also ranked the priorities within six domains: epidemiology, models of care, treatment and care, education and awareness, patient and community perspectives, and leadership and public health policy. Results The consensus-built fatty liver disease research agenda encompasses 28 priorities. The mean percentage of ‘agree’ responses increased from 78.3 in R1 to 81.1 in R2. Five priorities received unanimous combined agreement (‘agree’ + ‘somewhat agree’); the remaining 23 priorities had >90% combined agreement. While all but one of the priorities exhibited at least a super-majority of agreement (>66.7% ‘agree’), 13 priorities had 90% combined agreement. Conclusions Adopting this multidisciplinary consensus-built research priorities agenda can deliver a step-change in addressing fatty liver disease, mitigating against its individual and societal harms and proactively altering its natural history through prevention, identification, treatment, and care. This agenda should catalyse the global health community’s efforts to advance and accelerate responses to this widespread and fast-growing public health threat. Impact and implications An estimated 38% of adults and 13% of children and adolescents worldwide have fatty liver disease, making it the most prevalent liver disease in history. Despite substantial scientific progress in the past three decades, the burden continues to grow, with an urgent need to advance understanding of how to prevent, manage, and treat the disease. Through a global consensus process, a multidisciplinary group agreed on 28 research priorities covering a broad range of themes, from disease burden, treatment, and health system responses to awareness and policy. The findings have relevance for clinical and non-clinical researchers as well as funders working on fatty liver disease and non-communicable diseases more broadly, setting out a prioritised, ranked research agenda for turning the tide on this fast-growing public health threat

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Tunneled catheters' outcome optimization among diabetics on dialysis through antibiotic-lock placement

Efficacy and safety of antibiotic ‘locks’, in prevention of thrombotic and infectious complication-related morbidity and mortality, among diabetics dialyzed through tunneled-cuffed catheters (TCCs) has not been effectively investigated. This trial was designed to investigate the outcome of TCCs (n=109), inserted among 96 diabetic end-stage renal disease patients (March 2002–February 2003), by comparing the catheter thrombosis, catheter-related bloodstream infections (CRBSI), catheter survival, and mortality rates, between the cohorts of 49 patients who had TCCs (n=51) ‘locked’ with cefotaxime/heparin (group I) and 47 patients with TCCs (n=58) filled with standard heparin (group II). Thrombosis was defined as the inability to use catheter at a blood flow of 200ml/min despite intraluminal thrombolysis. Primary end points were catheter thrombosis and CRBSI; elective catheter removal and CRBSI-related death led to sensor of TCCs follow-up. Patients with intraluminal cefotaxime/heparin lock, on cumulative survival analysis, showed a superior thrombosis-free (86.3 vs 63.8%, P=0.023, log rank), infection-free (72.9 vs 27.1%, P=0.004, log rank), and thrombosis- and infection-free TCC survival (78.4 vs 37.9%, P=0.001, log rank) at 365 days, besides having significantly lower incidence of CRBSI (1.56 vs 3.68 episodes/1000 catheter days, P<0.0001) and CRBSI-related mortality (9.8 vs 23.4%, P=0.015), compared with the heparin-alone group. Deployment of cefotaxime–heparin ‘lock’ enhances catheter survival; reduces thrombotic and infectious complications and ensuing mortality, among diabetics on dialysis. However, further studies are needed to define the long-term implications of antibiotic locks in terms of the risk of emergence of antimicrobial resistance