Aminoglycoside heteroresistance in Enterobacter cloacae is driven by the cell envelope stress response.

Enterobacter cloacae is a Gram-negative nosocomial pathogen of the ESKAPE (Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, and Enterobacter spp.) priority group with increasing multi-drug resistance via the acquisition of resistance plasmids. However, E. cloacae can also display forms of antibiotic refractoriness, such as heteroresistance and tolerance. Here, we report that E. cloacae displays transient heteroresistance to aminoglycosides, which is accompanied with the formation of small colony variants (SCVs) with increased minimum inhibitor concentration (MIC) of gentamicin and other aminoglycosides used in the clinic, but not other antibiotic classes. To explore the underlying mechanisms, we performed RNA sequencing of heteroresistant bacteria, which revealed global gene expression changes and a signature of the CpxRA cell envelope stress response. Deletion of the cpxRA two-component system abrogated aminoglycoside heteroresistance and SCV formation, pointing to its indispensable role in these processes. The introduction of a constitutively active allele of cpxA led to high aminoglycoside MICs, consistent with cell envelope stress response driving these behaviors in E. cloacae. Cell envelope stress can be caused by environmental cues, including heavy metals. Indeed, bacterial exposure to copper increased gentamicin MIC in the wild-type but not in the ΔcpxRA mutant. Moreover, copper exposure also elevated the gentamicin MICs of clinical isolates from bloodstream infections, suggesting that CpxRA- and copper-dependent aminoglycoside resistance is broadly conserved in E. cloacae strains. Altogether, we establish that E. cloacae relies on transcriptional reprogramming via the envelope stress response pathway for transient resistance to a major class of frontline antibiotic.IMPORTANCEEnterobacter cloacae is a bacterium that belongs to the WHO high-priority group and an increasing threat worldwide due its multi-drug resistance. E. cloacae can also display heteroresistance, which has been linked to treatment failure. We report that E. cloacae shows heteroresistance to aminoglycoside antibiotics. These are important frontline microbicidal drugs used against Gram-negative bacterial infections; therefore, understanding how resistance develops among sensitive strains is important. We show that aminoglycoside resistance is driven by the activation of the cell envelope stress response and transcriptional reprogramming via the CpxRA two-component system. Furthermore, heterologous activation of envelope stress via copper, typically a heavy metal with antimicrobial actions, also increased aminoglycoside MICs of the E. cloacae type strain and clinical strains isolated from bloodstream infections. Our study suggests aminoglycoside recalcitrance in E. cloacae could be broadly conserved and cautions against the undesirable effects of copper.

Psychosocial predictors of return to alcohol use after liver transplant: A multicenter cohort study.

BACKGROUND: Alcohol use after liver transplant (LT) is associated with higher rates of graft loss and increased mortality; however, there are limited data evaluating predictors of return to alcohol use using biochemical markers like phosphatidylethanol (PEth). METHODS: This multicenter retrospective cohort study evaluated psychosocial predictors of return to alcohol use using PEth testing in patients transplanted for alcohol-associated liver disease (ALD). The study included 223 patients at three centers who had received a LT for ALD and had at least one PEth measurement post-LT. RESULTS: The rate of return to alcohol use was 6.9 cases per 100 person-years (26 patients total) over a median 555 days of follow-up after transplant. Younger age (HR 0.96; 95% CI 0.92-0.99, p = 0.02), mental health comorbidities (HR 2.83; 95% CI 1.25-6.39, p = 0.01), and non-Hispanic White race (HR 3.79; 95% CI 1.42-10.15, p = 0.01) were associated with return to alcohol use post-LT. There was no difference between post-LT return to alcohol use rates or short-term survival among patients with less than 6 months of sobriety prior to listing compared with those with more than 6 months. Patients with sustained alcohol use post-LT had increased odds of history of illicit substance use (OR 5.20; 95% CI 1.01-26.83, p = 0.04) but no significant difference in time from the last drink to listing (OR 1.03; 95% CI 0.18-5.80, p = 0.97). CONCLUSIONS: These findings emphasize the importance of mental health comorbidities rather than period of sobriety in predicting post-LT return to alcohol use. Furthermore, the higher risk of return to alcohol use in non-Hispanic White patients suggests a potential disparity with referral and selection of higher risk White patients.

Motoric cognitive risk syndrome as a predictive factor of cognitive impairment and dementia - A systematic review and meta-analysis.

BACKGROUND: Motoric cognitive risk syndrome (MCR) is defined as the presence of slow gait-speed and subjective cognitive decline in older individuals without mobility disability or dementia. While some studies suggest that MCR is a pre-dementia syndrome and may help predict the risk of cognitive impairment and dementia, not all studies concur. The objective of this study is to comprehensively summarize and synthesize evidence to assess the association between MCR and cognitive impairment and dementia. METHODS: Following a pre-specified protocol, two authors systematically searched PubMed, Embase, and The Cochrane Library from inception to 19 August 2024 for observational or randomized studies pertaining to the association between MCR and cognitive impairment and dementia. We favoured maximally adjusted hazards and odds ratios to determine the longitudinal and cross-sectional risk of cognitive impairment and dementia. We investigated for potential sources of heterogeneity and also conducted sensitivity and subgroup analyses by continent and the type of cognitive outcome. The quality of evidence was assessed using the Newcastle-Ottawa Scale (NOS) and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. RESULTS: We included 20 studies comprising a combined cohort of 1206,782 participants, of which 17 studies were included in the quantitative analysis. The pooled analysis outlined that individuals with MCR exhibited 2.20-fold higher risk of cognitive impairment and dementia, compared to controls (RR=2.20; 95 %CI=1.91-2.53). These findings remained robust across all subgroup analyses, sensitivity analyses and assessments of publication bias. CONCLUSION: MCR may be considered a predictive factor for long-term cognitive impairment and dementia. This should be taken into consideration when clinically evaluating the risk of cognitive impairment and dementia but further research is required to lend greater clarity to this association.

The rise of multidisciplinary clinics in hepatology: A practical, how-to-guide, and review of the literature.

Multidisciplinary clinics (MDCs) are gaining momentum throughout the medical field, having initially been pioneered in oncology clinics due to their inherent ability to streamline complex care and improve both patient outcomes and the patient care experience. Liver transplant and hepatobiliary tumor clinics are examples of established MDCs in hepatology. With the changing landscape of liver disease in regard to etiology and patient complexity and acuity, there is a clear need for efficient, highly coordinated care. These changes highlight opportunities for hepatology MDCs in alcohol-associated liver disease, metabolic dysfunction-associated steatotic liver disease, and palliative care. This review provides practical advice in navigating the complex logistics of establishing and maintaining a hepatology MDC while also reviewing the emerging evidence on clinical outcomes for patients seen in these MDCs. As hepatology looks to the future, establishment of MDCs in key clinical areas will be the cornerstone of patient care.

Sustained aviremia despite anti-retroviral therapy non-adherence in male children after in utero HIV transmission.

After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3-10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = -0.51 versus r = -0.07 for IFN-α). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero-acquired HIV infection after early cART initiation and may be associated with innate immune sex differences.

The landscape of liver transplantation for patients with alcohol-associated liver disease in the United States.

Indications for liver transplants have expanded to include patients with alcohol-associated liver disease (ALD) over the last decade. Concurrently, the liver allocation policy was updated in February 2020 replacing the Donor Service Area with Acuity Circles (ACs). The aim is to compare the transplantation rate, waitlist outcomes, and posttransplant survival of candidates with ALD to non-ALD and assess differences in that effect after the implementation of the AC policy. Scientific Registry for Transplant Recipients data for adult candidates for liver transplant were reviewed from the post-AC era (February 4, 2020-March 1, 2022) and compared with an equivalent length of time before ACs were implemented. The adjusted transplant rates were significantly higher for those with ALD before AC, and this difference increased after AC implementation (transplant rate ratio comparing ALD to non-ALD = 1.20, 1.13, 1.61, and 1.32 for the Model for End-Stage Liver Disease categories 37-40, 33-36, 29-32, and 25-28, respectively, in the post-AC era, p < 0.05 for all). The adjusted likelihood of death/removal from the waitlist was lower for patients with ALD across all lower Model for End-Stage Liver Disease categories (adjusted subdistribution hazard ratio = 0.70, 0.81, 0.84, and 0.70 for the Model for End-Stage Liver Disease categories 25-28, 20-24, 15-19, 6-14, respectively, p < 0.05). Adjusted posttransplant survival was better for those with ALD (adjusted hazard ratio = 0.81, p < 0.05). Waiting list and posttransplant mortality tended to improve more for those with ALD since the implementation of AC but not significantly. ALD is a growing indication for liver transplantation. Although patients with ALD continue to have excellent posttransplant outcomes and lower waitlist mortality, candidates with ALD have higher adjusted transplant rates, and these differences have increased after AC implementation.

Efficacy and Safety of Cell-based Immunotherapy in The Treatment of Recurrent or Metastatic Nasopharyngeal Carcinoma - A Systematic Review and Meta-analysis.

BACKGROUND: Recurrent/Metastatic Nasopharyngeal Carcinoma (RM-NPC) remains difficult to treat and contributes to considerable mortality. The first-line treatment for RM-NPC is Gemcitabine and Cisplatin and second-line treatment options differ. The endemic variant of NPC is associated with Epstein-Barr Virus (EBV). Therefore, Cell-based Immunotherapy (CBI) targeting EBV-specific RM-NPC may be effective. METHODS: We systematically searched PubMed, Embase and the Cochrane Library for randomised or observational studies investigating the efficacy and safety of CBI in the treatment of RM-NPC. We performed all meta-analyses using the random-effects model. Studies were further stratified by endemicity, nature of disease and drug type to investigate for potential between-study heterogeneity and additional pre-specified tests were employed to assess for publication bias. RESULTS: We screened 1,671 studies and included 13 studies with 403 participants in the systematic review, of which nine studies were eligible for meta-analysis. The use of CBI monotherapy as second or subsequent line treatment for EBV-positive RM-NPC revealed an ORR of 10 % (95 %CI = 3 %-29 %), median PFS of 2.37 months (95 %CI = 1.23-3.51) and median OS of 10.16 months (95 %CI = 0.67-19.65). For EBV-specific Cytotoxic T-Lymphocyte monotherapy, the pooled PD rate was 54 % (95 %CI = 9 %-93 %), SD rate was 22 % (95 %CI = 2 %-75 %) and incidence rate of any grade adverse events was 45 %. For Dendritic Cell monotherapy, a PD rate of 80 % (95 % CI = 29 %-98 %), SD rate of 11 % (95 % CI = 0 %-82 %) and incidence rate of any grade adverse events of 29 % was achieved. CONCLUSION: CBI monotherapy demonstrates some activity in pre-treated RM-NPC. More trials are needed to better understand how to integrate CBI into RM-NPC care.

Management of alcohol-associated liver disease and alcohol use disorder in liver transplant candidates and recipients: Challenges and opportunities.

Alcohol-associated liver disease poses a significant global health burden, with rising alcohol consumption and prevalence of alcohol use disorder (AUD) contributing to increased morbidity and mortality. This review examines the challenges and opportunities in the care of candidates and recipients of liver transplant (LT) with AUD. Despite advancements in posttransplant patient survival, the risk of disease recurrence and alcohol relapse remains substantial. Several challenges have been identified, including (1) rising disease burden of alcohol-associated liver disease, variable transplant practices, and systemic barriers; (2) disparities in mental health therapy access and the impact on transplant; (3) variable definitions, underdiagnosis, and stigma affecting access to care; and (4) post-LT relapse, its risk factors, and consequential harm. The review focuses on the opportunities to improve AUD care for candidates and recipients of LT through effective biochemical monitoring, behavioral and pharmacologic approaches, creating Centers of Excellence for post-LT AUD care, advocating for policy reforms, and ensuring insurance coverage for necessary services as essential steps toward improving patient outcomes. The review also highlights unmet needs, such as the scarcity of addiction specialists, and calls for further research on personalized behavioral treatments, digital health, and value-based care models to optimize AUD care in the LT setting.

Gonadal androgens are associated with decreased type I interferon production by plasmacytoid dendritic cells and increased IgG titres to BNT162b2 following co-vaccination with live attenuated influenza vaccine in adolescents.

mRNA vaccine technologies introduced following the SARS-CoV-2 pandemic have highlighted the need to better understand the interaction of adjuvants and the early innate immune response. Type I interferon (IFN-I) is an integral part of this early innate response that primes several components of the adaptive immune response. Women are widely reported to respond better than men to tri- and quadrivalent influenza vaccines. Plasmacytoid dendritic cells (pDCs) are the primary cell type responsible for IFN-I production, and female pDCs produce more IFN-I than male pDCs since the upstream pattern recognition receptor Toll-like receptor 7 (TLR7) is encoded by X chromosome and is biallelically expressed by up to 30% of female immune cells. Additionally, the TLR7 promoter contains several putative androgen response elements, and androgens have been reported to suppress pDC IFN-I in vitro. Unexpectedly, therefore, we recently observed that male adolescents mount stronger antibody responses to the Pfizer BNT162b2 mRNA vaccine than female adolescents after controlling for natural SARS-CoV-2 infection. We here examined pDC behaviour in this same cohort to determine the impact of IFN-I on anti-spike and anti-receptor-binding domain IgG titres to BNT162b2. Through flow cytometry and least absolute shrinkage and selection operator (LASSO) modelling, we determined that serum-free testosterone was associated with reduced pDC IFN-I, but contrary to the well-described immunosuppressive role for androgens, the most bioactive androgen dihydrotestosterone was associated with increased IgG titres to BNT162b2. Also unexpectedly, we observed that co-vaccination with live attenuated influenza vaccine boosted the magnitude of IgG responses to BNT162b2. Together, these data support a model where systemic IFN-I increases vaccine-mediated immune responses, yet for vaccines with intracellular stages, modulation of the local IFN-I response may alter antigen longevity and consequently improve vaccine-driven immunity.

Macrophage activation syndrome with acute hepatitis in a patient with adult-onset immunodeficiency with anti-interferon gamma antibodies: a case report.

BACKGROUND: Macrophage activation syndrome is a rare disorder leading to unregulated immune activity manifesting with nonspecific constitutional symptoms, laboratory abnormalities, and multiorgan involvement. We report the case of a patient who presented with acute hepatitis secondary to macrophage activation syndrome diagnosed by liver biopsy and successfully treated with intravenous immune globulin, anakinra, and rituximab. CASE PRESENTATION: A 42-year-old Laotian woman with adult-onset immunodeficiency with anti-interferon gamma antibodies presented with a fever, headache, generalized myalgia, dark urine, and reduced appetite in the setting of family members at home with similar symptoms. Her laboratory workup was notable for evidence of acute hepatitis without acute liver failure. After an unrevealing comprehensive infectious and noninvasive rheumatologic workup was completed, a liver biopsy was performed ultimately revealing the diagnosis of macrophage activation syndrome. She was successfully treated with intravenous immune globulin, anakinra, and rituximab. CONCLUSION: This case highlights the importance of maintaining macrophage activation syndrome on the differential of a patient with acute hepatitis of unknown etiology in the correct clinical context and the value of a liver biopsy in making a diagnosis when noninvasive testing is unrevealing.

Laboratory-adapted and wild-type black soldier flies express differential plasticity in bioconversion and nutrition when reared on urban food waste streams.

BACKGROUND: The black soldier fly (BSF) offers a potential solution to address shortages of feed and food sources; however, selecting effective rearing substrates remains a major hurdle in BSF farming. In an urban area like Singapore, current practice is based on rearing BSF on homogeneous waste streams (e.g., spent brewery grains or okara) because heterogeneous food wastes (e.g., mixed kitchen/canteen waste or surplus cooked food) present several operational challenges with respect to the standardization of development, nutritional content, and harvesting. RESULTS: In this study, we compared two genetic strains of BSF larvae (wild-type and laboratory-adapted line) in a bioconversion experiment with diverse types of food waste (homogeneous/heterogeneous; plant/meat) and we quantified the phenotypic plasticity. Our results demonstrate different plasticity in bioconversion performance, larval growth and larval nutrition between the two BSF lines. This difference may be attributed to the selective breeding the laboratory-adapted line has experienced. Notably, larval lipid content displayed little to no genetic variation for plasticity compared with larval protein and carbohydrate content. Despite variation in larval development, heterogeneous food wastes can produce better performance in bioconversion, larval growth, and larval nutrient content than homogeneous food waste. All-meat diets result in high larvae mortality but larval survival could be rescued by mixing meat with plant-based food wastes. CONCLUSION: Overall, we suggest using mixed meals for BSF larvae feeding. Targeted breeding may be a promising strategy for the BSF industry but it is important to consider the selection effects on plasticity in larval nutrition carefully. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Association of Benign Paroxysmal Positional Vertigo with Depression and Anxiety-A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the extent to which Benign Paroxysmal Positional Vertigo (BPPV) is associated with a higher prevalence of depression and anxiety in patients. DATA SOURCES: Three databases including PubMed, Embase, and The Cochrane Library were searched by two independent authors from inception to June 12, 2022 for observational studies and randomized controlled trials investigating the association between BPPV and depression and anxiety. We included studies published as full-length articles in peer-reviewed journals with an adult population aged at least 18 years who have BPPV, detected through validated clinical methods like clinical diagnosis, interview and Dix-Hallpike test. RESULTS: A total of 23 articles met the final inclusion criteria and 19 articles were included in the meta-analysis. BPPV was associated with a 3.19 increased risk of anxiety compared to controls, and 27% (17%-39%) of BPPV patients suffered from anxiety. Furthermore, the weighted average Beck's Anxiety Inventory score was 18.38 (12.57; 24.18), while the weighted average State-Trait Anxiety Index score was 43.08 (37.57; 48.60). CONCLUSION: There appears to be some association between BPPV and anxiety, but further studies are required to confirm these associations. Laryngoscope, 134:526-534, 2024.

Pre-existing Hepatic Encephalopathy: Really a Contraindication to Elective TIPS?

PURPOSE: To evaluate the impact of pre-transjugular intrahepatic portosystemic shunt (TIPS) hepatic encephalopathy (HE) on developing post-TIPS HE. MATERIALS AND METHODS: In this retrospective, single center observational study, all patients who underwent successful TIPS placement between January 2005 and May 2020 with data pertaining to HE in their chart were included. Patient demographics and procedural details were recorded. Clinical outcomes post-TIPS, were collected and compared across patients with and without pre-TIPS HE. RESULTS: Of 326 included patients, 159 (159/326, 48.8%) had a history of pre-TIPS HE. In total those without a history of HE were more likely to develop HE during follow up (136 (136/167, 81.4%) vs 107 (107/159, 67.3%), p = 0.001). When evaluating for predictors of developing HE within 3 months of TIPS placement, no significant variables were found on logistic regression, including prior history of HE (HR 1.16 (95% CI 0.73-1.84), p = 0.529). Univariate and multivariate regression analysis, however, showed that a history of HE was predictive of developing HE at any point in the follow-up period (p = 0.002 and p = 0.008, respectively). However, on Kaplan-Meier analysis no significant difference in the development of HE (p = 0.574) or hospital admission for HE (p = 0.554) post-TIPS was seen between patients with and without pre-TIPS HE. Additionally, there was no difference in 3-month survival (p = 0.412) or overall survival post-TIPS survival (p = 0.798). CONCLUSION: Pre-TIPS HE did not predict the development of HE within 3 months of TIPS. Outcomes such as hospital admission and survivability were not different between patients with and without prior HE.

Low screening rates and high prevalence of osteoporosis in cirrhosis: A real-world retrospective analysis.

BACKGROUND: Patients with cirrhosis are at increased risk for osteoporosis, and those who suffer a fracture are at high risk for mortality. Despite this, osteoporosis is often overlooked and undertreated. This study aimed to evaluate osteoporosis screening, management, and adverse osteoporosis medication events in patients with cirrhosis. METHODS: We performed a retrospective chart review of adult outpatients with compensated and decompensated cirrhosis seen in single health system over a 6-year period. Patient demographics, liver and bone health comorbidities, DEXA scan results, and medications were abstracted. RESULTS: In total, 5398 patients met criteria. The cohort was predominately white (79.1%) and older (age 59). 44.4% were female. 64.6% had decompensated cirrhosis. Median MELD-Na score was 12.8. 23.5% had a DEXA scan ordered, approximately 50% completed this test. Patients who were older, female, white, with more severe liver disease, and other osteoporosis risk factors were more likely to have a DEXA scan ordered. 48.5% of patients had osteopenia and 30.2% had osteoporosis on DEXA scan. Only 22.6% of patients with osteoporosis received treatment, most commonly oral bisphosphonates. Oral bisphosphonate prescription was not associated with variceal bleeding (8.4% without vs. 4.8% with, p = 0.487). CONCLUSION: A minority of patients with cirrhosis were screened for osteoporosis. The majority screened had osteopenia or osteoporosis on DEXA scan. Less than a quarter of patients with osteoporosis were started on treatment. Real-world experience of oral bisphosphonate use did not reveal higher rates of gastrointestinal bleeding. There is room for improvement in all aspects of bone health care in cirrhosis.

Age- and sex-specific differences in immune responses to BNT162b2 COVID-19 and live-attenuated influenza vaccines in UK adolescents.

Introduction: The key to understanding the COVID-19 correlates of protection is assessing vaccine-induced immunity in different demographic groups. Young people are at a lower risk of COVID-19 mortality, females are at a lower risk than males, and females often generate stronger immune responses to vaccination. Methods: We studied immune responses to two doses of BNT162b2 Pfizer COVID-19 vaccine in an adolescent cohort (n = 34, ages 12-16), an age group previously shown to elicit significantly greater immune responses to the same vaccine than young adults. Adolescents were studied with the aim of comparing their response to BNT162b2 to that of adults; and to assess the impacts of other factors such as sex, ongoing SARS-CoV-2 infection in schools, and prior exposure to endemic coronaviruses that circulate at high levels in young people. At the same time, we were able to evaluate immune responses to the co-administered live attenuated influenza vaccine. Blood samples from 34 adolescents taken before and after vaccination with COVID-19 and influenza vaccines were assayed for SARS-CoV-2-specific IgG and neutralising antibodies and cellular immunity specific for SARS-CoV-2 and endemic betacoronaviruses. The IgG targeting influenza lineages contained in the influenza vaccine were also assessed. Results: Robust neutralising responses were identified in previously infected adolescents after one dose, and two doses were required in infection-naïve adolescents. As previously demonstrated, total IgG responses to SARS-CoV-2 Spike were significantly higher among vaccinated adolescents than among adults (aged 32-52) who received the BNT162b2 vaccine (comparing infection-naïve, 49,696 vs. 33,339; p = 0.03; comparing SARS-CoV-2 previously infected, 743,691 vs. 269,985; p <0.0001) by the MSD v-plex assay. There was no evidence of a stronger vaccine-induced immunity in females compared than in males. Discussion: These findings may result from the introduction of novel mRNA vaccination platforms, generating patterns of immunity divergent from established trends and providing new insights into what might be protective following COVID-19 vaccination.

Mortality and Cardiovascular Outcomes in Adult Non-Liver Solid Organ Transplant Patients With Nonalcoholic Steatohepatitis.

BACKGROUND: The effect of nonalcoholic steatohepatitis (NASH) on mortality or major adverse cardiovascular events (MACE) in non-liver solid organ transplant recipients (NL-SOT) is unknown. METHODS: Using a retrospective design, adult NL-SOT recipients who had biopsy-proven NASH were compared NL-SOT recipients with normal liver function tests and imaging; propensity matched at a 1:10 ratio on the following: age, sex, race, transplant year, transplant organ, smoking status, and diabetes status. Both deceased and living donor recipients were included; heart and liver transplant patients were excluded. Primary outcome was incidence of all-cause mortality and MACE (a composite outcome of coronary artery disease, ischemic stroke, and peripheral arterial disease). RESULTS: Seven patients (3 kidney and 4 lung transplants) had biopsy-proven NASH and 70 patients without NASH, both groups were predominantly male (53%-57%), White (86%-91%), and overweight (mean body mass index ∼ 26). The majority of patients were on calcineurin inhibitors (≥85%), antimetabolites (≥97%), and prednisone (≥50%). Survival analysis showed that NASH patients had a higher risk of death (hazard ratio [HR], 3.24; 95% confidence interval [CI], 1.26-8.33, P = 0.02). NASH did not affect the risk of death-censored graft failure (HR, 1.08; 95% CI, 0.14-8.67; P = .94) or the risk of MACE (HR, 1.03; 95% CI, 0.23-4.62; P = .97). CONCLUSIONS: In NL-SOT recipients, NASH is significantly associated with mortality but not with MACE.

Cellular immunity to SARS-CoV-2 following intrafamilial exposure in seronegative family members.

Introduction: Family studies of antiviral immunity provide an opportunity to assess virus-specific immunity in infected and highly exposed individuals, as well as to examine the dynamics of viral infection within families. Transmission of SARS-CoV-2 between family members represented a major route for viral spread during the early stages of the pandemic, due to the nature of SARS-CoV-2 transmission through close contacts. Methods: Here, humoral and cellular immunity is explored in 264 SARS-CoV-2 infected, exposed or unexposed individuals from 81 families in the United Kingdom sampled in the winter of 2020 before widespread vaccination and infection. Results: We describe robust cellular and humoral immunity into COVID-19 convalescence, albeit with marked heterogeneity between families and between individuals. T-cell response magnitude is associated with male sex and older age by multiple linear regression. SARS-CoV-2-specific T-cell responses in seronegative individuals are widespread, particularly in adults and in individuals exposed to SARS-CoV-2 through an infected family member. The magnitude of this response is associated with the number of seropositive family members, with a greater number of seropositive individuals within a family leading to stronger T-cell immunity in seronegative individuals. Discussion: These results support a model whereby exposure to SARS-CoV-2 promotes T-cell immunity in the absence of an antibody response. The source of these seronegative T-cell responses to SARS-CoV-2 has been suggested as cross-reactive immunity to endemic coronaviruses that is expanded upon SARS-CoV-2 exposure. However, in this study, no association between HCoV-specific immunity and seronegative T-cell immunity to SARS-CoV-2 is identified, suggesting that de novo T-cell immunity may be generated in seronegative SARS-CoV-2 exposed individuals.

Impact of Gastroenterology Consultation on the Clinical Outcomes of Patients Admitted With Hepatic Encephalopathy.

Introduction Hepatic encephalopathy (HE) is a common complication of cirrhosis and a common reason for hospital admission. We aimed to determine whether expert consultation from gastroenterology (GI) leads to better clinical outcomes for inpatients with HE. Methods A retrospective review was performed of all adult patients (age ≥ 18) admitted with HE to a tertiary care hospital between January 2013 and April 2018. Patients who received a GI consult were compared to patients who did not receive a GI consult (No consult group). The primary outcome was hospital length of stay (LOS); secondary outcomes were rates of 30-day hospital readmission and 90-day mortality. Multivariate analysis was conducted to adjust for known confounders.  Results Four hundred and twenty-five patients (814 encounters) were included in the study; of these, 236 patients had received a GI consultation for HE. Patients in the GI consult group were younger (mean age 55 vs 58 years, p= 0.02) and had higher Model For End-Stage Liver Disease-sodium (MELD-Na) score (mean MELD-Na 23.5 vs 17.5, p<0.01) compared to patients who did not receive GI consultation. The precipitants of HE were significantly different between the groups: there was more spontaneous bacterial peritonitis (SBP) and GI bleeding (GIB) in the GI consult group and more lactulose non-adherence in the no consult group. There was no difference in the etiology of liver disease between the two groups. Median LOS for the GI consult group was six days vs three days in the no consult group (p<0.01); the incidence rate ratio was 1.79 (95%CI 1.59-2.02, p<0.01) on multivariate analysis. There was no difference in 30-day readmission or 90-day mortality between the two groups.  Conclusion GI consultation for patients with HE admitted to a hospital medicine service may be associated with longer LOS. In selected patients admitted with HE, GI consultation may not be necessary to achieve good clinical outcomes.