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"Brown, Robert S"
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Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease
Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality
1
–
3
. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice
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, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin—a two-subunit exotoxin that is secreted by
Enterococcus faecalis
5
,
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—as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of
E. faecalis
. The presence of cytolysin-positive (cytolytic)
E. faecalis
correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic
E. faecalis
. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic
E. faecalis
with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic
E. faecalis
, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.
In patients with alcoholic hepatitis, cytolysin-positive
Enterococcus faecalis
strains are correlated with liver disease severity and increased mortality, and in mouse models these strains can be specifically targeted by bacteriophages.
Journal Article
Hepatitis C and liver transplantation
Liver transplantation is a life-saving therapy to correct liver failure, portal hypertension and hepatocellular carcinoma arising from hepatitis C infection. But despite the successful use of living donors and improvements in immunosuppression and antiviral therapy, organ demand continues to outstrip supply and recurrent hepatitis C with accelerated progression to cirrhosis of the graft is a frequent cause of graft loss and the need for retransplantation. Appropriate selection of candidates and timing of transplantation, coupled with better pre- and post-transplant antiviral therapy, are needed to improve outcomes.
Journal Article
Development and external validation of a prediction risk model for short-term mortality among hospitalized U.S. COVID-19 patients: A proposal for the COVID-AID risk tool
The 2019 novel coronavirus disease (COVID-19) has created unprecedented medical challenges. There remains a need for validated risk prediction models to assess short-term mortality risk among hospitalized patients with COVID-19. The objective of this study was to develop and validate a 7-day and 14-day mortality risk prediction model for patients hospitalized with COVID-19.
We performed a multicenter retrospective cohort study with a separate multicenter cohort for external validation using two hospitals in New York, NY, and 9 hospitals in Massachusetts, respectively. A total of 664 patients in NY and 265 patients with COVID-19 in Massachusetts, hospitalized from March to April 2020.
We developed a risk model consisting of patient age, hypoxia severity, mean arterial pressure and presence of kidney dysfunction at hospital presentation. Multivariable regression model was based on risk factors selected from univariable and Chi-squared automatic interaction detection analyses. Validation was by receiver operating characteristic curve (discrimination) and Hosmer-Lemeshow goodness of fit (GOF) test (calibration). In internal cross-validation, prediction of 7-day mortality had an AUC of 0.86 (95%CI 0.74-0.98; GOF p = 0.744); while 14-day had an AUC of 0.83 (95%CI 0.69-0.97; GOF p = 0.588). External validation was achieved using 265 patients from an outside cohort and confirmed 7- and 14-day mortality prediction performance with an AUC of 0.85 (95%CI 0.78-0.92; GOF p = 0.340) and 0.83 (95%CI 0.76-0.89; GOF p = 0.471) respectively, along with excellent calibration. Retrospective data collection, short follow-up time, and development in COVID-19 epicenter may limit model generalizability.
The COVID-AID risk tool is a well-calibrated model that demonstrates accuracy in the prediction of both 7-day and 14-day mortality risk among patients hospitalized with COVID-19. This prediction score could assist with resource utilization, patient and caregiver education, and provide a risk stratification instrument for future research trials.
Journal Article
Management of Thrombocytopenia in Patients with Chronic Liver Disease
BackgroundThrombocytopenia is the most common hematologic complication associated with chronic liver disease (CLD) with important clinical implications. While the mechanisms for thrombocytopenia are multifactorial, platelet sequestration in the spleen and decreased thrombopoietin (TPO) production are the main mechanisms in patients with CLD.AimThis review outlines the current treatment options for thrombocytopenia in patients with CLD, explores their limitations, and proposes a revised treatment algorithm for the management of thrombocytopenia in this patient group.MethodsA PubMed search of the literature was undertaken with search terms focused on CLD and thrombocytopenia.ResultsUntil now, the standard-of-care treatment in these patients has been the use of platelet transfusions either prophylactically or periprocedurally to control bleeding. Treatment options, such as splenic artery embolization and splenectomy, are invasive, and their utility is limited by significant complications. The US Food and Drug Administration recently approved 2 s-generation TPO-receptor agonists, avatrombopag and lusutrombopag, as safe and effective therapies for the treatment of thrombocytopenia in patients with CLD scheduled to undergo a procedure.ConclusionsThe addition of avatrombopag and lusutrombopag offers physicians an alternative to platelet transfusions in patients with CLD who have to undergo medical/dental procedures that could potentially put them at an increased risk of bleeding. There are several other drugs in the research pipeline at various stages of development, including a new class of monoclonal antibodies that can bind to and activate TPO-receptor agonists. The outlook for treatment choices for thrombocytopenia in patients with liver disease is promising.
Journal Article
Opportunities to address gaps in early detection and improve outcomes of liver cancer
Abstract
Death rates from primary liver cancer (hepatocellular carcinoma [HCC]) have continued to rise in the United States over the recent decades despite the availability of an increasing range of treatment modalities, including new systemic therapies. Prognosis is strongly associated with tumor stage at diagnosis; however, most cases of HCC are diagnosed beyond an early stage. This lack of early detection has contributed to low survival rates. Professional society guidelines recommend semiannual ultrasound-based HCC screening for at-risk populations, yet HCC surveillance continues to be underused in clinical practice. On April 28, 2022, the Hepatitis B Foundation convened a workshop to discuss the most pressing challenges and barriers to early HCC detection and the need to better leverage existing and emerging tools and technologies that could improve HCC screening and early detection. In this commentary, we summarize technical, patient-level, provider-level, and system-level challenges and opportunities to improve processes and outcomes across the HCC screening continuum. We highlight promising approaches to HCC risk stratification and screening, including new biomarkers, advanced imaging incorporating artificial intelligence, and algorithms for risk stratification. Workshop participants emphasized that action to improve early detection and reduce HCC mortality is urgently needed, noting concern that many of the challenges we face today are the same or similar to those faced a decade ago and that HCC mortality rates have not meaningfully improved. Increasing the uptake of HCC screening was identified as a short-term priority while developing and validating better screening tests and risk-appropriate surveillance strategies.
Journal Article
Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis
In this phase 3 study involving patients with HCV genotype 1, 2, 3, 4, or 6 and decompensated cirrhosis, sofosbuvir–velpatasvir with or without ribavirin for 12 weeks or sofosbuvir–velpatasvir for 24 weeks resulted in high rates of sustained virologic response.
The number of patients with decompensated cirrhosis caused by chronic infection with the hepatitis C virus (HCV) is projected to rise in the coming decade.
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For many years, the only treatment option for such patients was liver transplantation. Recently, however, clinical trials of newly approved direct-acting antiviral agents have shown that it is possible to treat HCV infection safely and effectively in patients with decompensated cirrhosis and that successful treatment is associated with early improvement in liver function.
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–
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The possible long-term benefits of treatment on existing liver disease remain unknown. The only regimen that is currently approved for the . . .
Journal Article
A transgenic approach for controlling Lygus in cotton
Lygus
species of plant-feeding insects have emerged as economically important pests of cotton in the United States. These species are not controlled by commercial
Bacillus thuringiensis
(Bt) cotton varieties resulting in economic losses and increased application of insecticide. Previously, a Bt crystal protein (Cry51Aa2) was reported with insecticidal activity against
Lygus
spp. However, transgenic cotton plants expressing this protein did not exhibit effective protection from
Lygus
feeding damage. Here we employ various optimization strategies, informed in part by protein crystallography and modelling, to identify limited amino-acid substitutions in Cry51Aa2 that increase insecticidal activity towards
Lygus
spp. by >200-fold. Transgenic cotton expressing the variant protein, Cry51Aa2.834_16, reduce populations of
Lygus
spp. up to 30-fold in whole-plant caged field trials. One transgenic event, designated MON88702, has been selected for further development of cotton varieties that could potentially reduce or eliminate insecticide application for control of
Lygus
and the associated environmental impacts.
Plant-feeding insects of the
Lygus
genus have emerged as a major pest effecting cotton crops in the USA. Here the authors optimize the insecticidal activity of a
Bacillus thuringiensis
crystal protein and produce transgenic plants that are resistant to feeding damage by
Lygus
species.
Journal Article