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Despite concerns that patients with liver transplants might be at increased risk of adverse outcomes from COVID-19 because of coexisting comorbidities and use of immunosuppressants, the effect of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on this patient group remains unclear. We aimed to assess the clinical outcomes in these patients.In this multicentre cohort study, we collected data on patients with laboratory-confirmed SARS-CoV-2 infection, who were older than 18 years, who had previously received a liver transplant, and for whom data had been submitted by clinicians to one of two international registries (COVID-Hep and SECURE-Cirrhosis) at the end of the patient's disease course. Patients without a known hospitalisation status or mortality outcome were excluded. For comparison, data from a contemporaneous cohort of consecutive patients with SARS-CoV-2 infection who had not received a liver transplant were collected from the electronic patient records of the Oxford University Hospitals National Health Service Foundation Trust. We compared the cohorts with regard to several outcomes (including death, hospitalisation, intensive care unit [ICU] admission, requirement for intensive care, and need for invasive ventilation). A propensity score-matched analysis was done to test for an association between liver transplant and death.Between March 25 and June 26, 2020, data were collected for 151 adult liver transplant recipients from 18 countries (median age 60 years [IQR 47-66], 102 [68%] men, 49 [32%] women) and 627 patients who had not undergone liver transplantation (median age 73 years [44-84], 329 [52%] men, 298 [48%] women). The groups did not differ with regard to the proportion of patients hospitalised (124 [82%] patients in the liver transplant cohort vs 474 [76%] in the comparison cohort, p=0·106), or who required intensive care (47 [31%] vs 185 [30%], p=0·837). However, ICU admission (43 [28%] vs 52 [8%], p0·0001) and invasive ventilation (30 [20%] vs 32 [5%], p0·0001) were more frequent in the liver transplant cohort. 28 (19%) patients in the liver transplant cohort died, compared with 167 (27%) in the comparison cohort (p=0·046). In the propensity score-matched analysis (adjusting for age, sex, creatinine concentration, obesity, hypertension, diabetes, and ethnicity), liver transplantation did not significantly increase the risk of death in patients with SARS-CoV-2 infection (absolute risk difference 1·4% [95% CI -7·7 to 10·4]). Multivariable logistic regression analysis showed that age (odds ratio 1·06 [95% CI 1·01 to 1·11] per 1 year increase), serum creatinine concentration (1·57 [1·05 to 2·36] per 1 mg/dL increase), and non-liver cancer (18·30 [1·96 to 170·75]) were associated with death among liver transplant recipients.Liver transplantation was not independently associated with death, whereas increased age and presence of comorbidities were. Factors other than transplantation should be preferentially considered in relation to physical distancing and provision of medical care for patients with liver transplants during the COVID-19 pandemic.European Association for the Study of the Liver, US National Institutes of Health, UK National Institute for Health Research.

Background Common variable immunodeficiency (CVID) is a rare primary B-cell immunodeficiency disorder associated with multisystem complications of impaired humoral immunity. CVID is characterized by impaired adaptive responses to pathogen challenge and a paradoxical predisposition to a wide range of autoimmune and neoplastic complications. Methods We present a case series describing our experience of liver transplantation in two patients with CVID and perform a comprehensive literature review of post-transplant complications and survival outcomes detailing the global experience of 30 reported cases of adult liver transplantation for common variable immunodeficiency-related liver disease (CVIDrLD). Results Liver transplantation in CVIDrLD is frequently complicated by atypical infections, autoimmune complications and graft recurrence and is associated with suboptimal long term survival outcomes post-transplantation in comparison to established listing indications for liver transplantation; this is further compounded (median survival 3 vs. 5 years) when removing patients with concomitant chronic hepatitis C infection from the survival analysis. Conclusions Liver transplantation is associated with poor overall survival outcomes and careful consideration should be given to the phenotype and severity of immunodeficiency, the presence of chronic pathogen colonisation and the extrahepatic burden of disease at the time of assessment. At present, despite careful patient selection, survival post-transplant outcomes fall below acceptable listing thresholds, necessitating a conservative approach to consideration of single organ listing in this context with current available treatments. Patients with a secondary aetiological factor for liver disease may perform better post-transplant.

In the absence of adequate compensatory regeneration, overwhelming liver damage can cause acute liver failure (ALF) and death without emergent liver transplantation (LT). Auxiliary LT produces satisfactory outcomes in this setting, with the prospect of native liver regeneration sustaining long-term survival. Since animal models only partially recapitulate human liver regeneration, we investigated the molecular mechanisms controlling it in this unique LT setting, as an exemplar of human liver regeneration. We demonstrate coordinated changes in expression of microRNA (miRNA) during regeneration that drive proliferation, innate immunity and angiogenesis. In contrast, failed regeneration in a similar cohort is associated with distinct miRNA enforcing cell cycle inhibition and DNA methylation. The miRNA expression associated with successful or failed regeneration when recapitulated in vitro, triggered expression of cardinal regeneration-linked genes promoting cell cycle entry or inhibition, respectively. Furthermore, inhibition of miRNA 150, 663 and 503, whose downregulation is associated with successful regeneration, induced cell proliferation which a key determinant of successful regeneration. Our data indicate that human liver regeneration may be orchestrated by distinct miRNA controlling key regeneration-linked processes including hepatocyte proliferation. To our knowledge this is the first characterization of molecular processes associated with human liver regeneration.

Gene expression profiling was used to explore the role of Nef in HIV. Nef induces a transcriptional program in T cells that is 97% identical to that of anti-CD3 T cell activation. This program is inhibited in the presence of cyclosporin. A requirement for TCRζ and ZAP-70 is demonstrated for formation of the complete profile. Among eight factors particular to the anti-CD3 activation profile are IL16 and YY1, negative regulators of HIV transcription. In contrast, Nef exclusively upregulates factors positively regulating HIV, including Tat-SF1, U1 SNRNP, and IRF-2. New genes associated with Nef include CDK9, the induction of which enhances Tat function. Thus, Nef acts as a master switch early in the viral life cycle, forcing an environment conducive to dynamic viral production.

A consumer-oriented approach to the delivery of health care and an understanding of the processes that influence clinical management decisions require the measurement of what patients seek when they consult their doctor. The present study completed the development of an instrument (the Patient Requests Form) that can quantify the intentions of patients attending their general practitioner. The Patient Requests Form was completed by 410 patients attending two general practices: one in an inner city area, the other in a small town. Principal components analysis revealed that the responses from each sample yielded identical components that described three distinct types of request: (i) for explanation and reassurance, (ii) for emotional support, and (iii) for investigation and treatment. Scales constructed to measure each type of request have high internal consistency while being sufficiently brief to be acceptable to general practice patients. The Patient Requests Form is a novel, convenient method to quantify the intentions of patients when they consult a general practitioner. It permits research into neglected aspects of consultation behaviour, including the factors that influence patients' intentions to seek different kinds of help and GPs' perceptions of these intentions.