Metformin as adjuvant treatment in hepatitis C virus infections and associated complications.

Hepatitis C virus is an important global cause of hepatitis and subsequently cirrhosis and hepatocellular carcinoma. These infections may also cause extrahepatic manifestations, including insulin resistance and type 2 diabetes mellitus. These two complications can potentially reduce sustained virologic responses (SVR) in some drug regimens for this infection. Metformin has important biochemical effects that can limit viral replication in cellular cultures and can improve the response to antiviral drug therapy based on ribavirin and interferon. Clinical studies comparing treatment regimens with interferon, ribavirin, metformin with these regimens without metformin have demonstrated that metformin increases viral clearance, establishes higher rates of SVRs, and increases insulin sensitivity. Metformin also reduces the frequency of hepatocellular carcinoma in patients who have had SVRs. Larger treatment trials are needed to determine metformin's short-term and long-term treatment effects in patients with diabetes using newer antiviral drugs. In particular, if metformin reduces the frequency of cirrhosis and hepatocellular carcinoma, this would significantly reduce the morbidity and mortality associated with this infection.

A Case of Trueperella bernardiae Bacteremia due to a PICC-Associated Infection in a Paraplegic Patient.

Trueperella bernardiae is a Gram-positive bacterium known to cause a wide variety of opportunistic infections in humans. We report a novel case of T. bernardiae bacteremia in a paraplegic patient due to a peripherally inserted central catheter- (PICC-) associated infection that was treated successfully with piperacillin/tazobactam.

A Case of Myroides odoratimimus Bacteremia due to a Tunneled Dialysis Catheter-Associated Infection in a Paraplegic Patient.

Myroides odoratimimus is a Gram-negative opportunistic pathogen known to rarely cause a wide range of opportunistic infections in humans. We report a novel case of M. odoratimimus bacteremia in a paraplegic patient with an extensive medical history likely due to a tunneled dialysis catheter infection that was successfully treated with levofloxacin.

Upper Respiratory Infection Drives Clinical Signs and Inflammatory Responses Following Heterologous Challenge of SARS-CoV-2 Variants of Concern in K18 Mice.

The evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in the emergence of several variants of concern (VOC) with increased immune evasion and transmissibility. This has motivated studies to assess protection conferred by earlier strains following infection or vaccination to each new VOC. We hypothesized that while NAbs play a major role in protection against infection and disease, a heterologous reinfection or challenge may gain a foothold in the upper respiratory tract (URT) and result in a self-limited viral infection accompanied by an inflammatory response. To test this hypothesis, we infected K18-hACE2 mice with SARS-CoV-2 USA-WA1/2020 (WA1) and, after 24 days, challenged with WA1, Alpha, or Delta. While NAb titers against each virus were similar across all cohorts prior to challenge, the mice challenged with Alpha and Delta showed weight loss and upregulation of proinflammatory cytokines in the URT and lower RT (LRT). Mice challenged with WA1 showed complete protection. We noted increased levels of viral RNA transcripts only in the URT of mice challenged with Alpha and Delta. In conclusion, our results suggested self-limiting breakthrough infections of Alpha or Delta in the URT, which correlated with clinical signs and a significant inflammatory response in mice.

Disseminated coccidioidomycosis in a patient on mycophenolate.

Disseminated coccidioidomycosis is a rare but serious complication of fungal illness, with immunocompromised patients more susceptible to severe illness. Here we report a unique case of disseminated coccidioidomycosis in a patient on mycophenolate for treatment of polymyositis.

A possible case of bictegravir-associated severe unconjugated hyperbilirubinemia.

BACKGROUND: Bictegravir (BIC) co-formulated with emtricitabine (FTC) and tenofovir alafenamide (TAF) is approved by Federal Food and Drug Administration in 2018 for both treatment-naïve and experienced persons living with HIV (PLWH). CASE PRESENTATION: A young man with recently diagnosed human immunodeficiency virus (HIV) infection presented with jaundice. Blood work was significant for mild anemia and grade 4 unconjugated hyperbilirubinemia. A comprehensive evaluation for hemolytic anemia failed to reveal any etiology. Other causes of hyperbilirubinemia were negative. Four months prior, patient was started on antiretroviral therapy with a single tablet regimen containing bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), brand name Biktarvy®, and the medication was suspected to be the cause. The medication was held, and the hyperbilirubinemia improved. CONCLUSION: Severe hyperbilirubinemia can be found in the patient using BIC/FTC/TAF. The data for this adverse reaction is scarce, and more studies are needed on this possible side effect. The mechanism of unconjugated hyperbilirubinemia by INSTI remains undefined.

SARS-CoV-2 and HIV: Impact on Pulmonary Epithelial Cells.

The SARS-CoV-2 pandemic provides a natural opportunity for the collision of coronavirus disease-2019 (COVID-19) with chronic infections, which place numerous individuals at high risk of severe COVID-19. Infection with Human Immunodeficiency Virus (HIV), a global epidemic, remains a major public health concern. Whether prior HIV+ status exacerbates COVID-19 warrants investigation. Herein, we characterized the impact of SARS-CoV-2 in human bronchial epithelial cells (HBECs) previously exposed to HIV. We optimized the air-liquid interface (ALI) cell culture technique to allow for challenges with HIV at the basolateral cell surface and SARS-CoV-2 spike protein on the apical surface, followed by genetic analyses for cellular stress/toxicity and innate/adaptive immune responses. Our results suggest that the IL-10 pathway was consistently activated in HBECs treated with spike, HIV, or a combination. Recombinant spike protein elicited COVID-19 cytokine storms while HIV activated different signaling pathways. HIV-treated HBECs could no longer activate NF-kB, pro-inflammatory TRAF-6 ubiquitination nor RIP1 signaling. Combinations of HIV and SARS-CoV-2 spike increased gene expression for activation of endoplasmic reticulum-phagosome pathway and downregulated non-canonical NF-kB pathways that are key in functional regulatory T cells and RNA Polymerase II transcription. Our in vitro studies suggest that prior HIV infection may not exacerbate COVID-19. Further in vivo studies are warranted to advance this field.

A red herring colonization of Mycobacterium lentiflavum in cutaneous sporotrichosis lesions misleading the diagnosis.

A 42-year-old man presented with a sporotrichoid lymphocutaneous infection for 1 month. The histopathology of the lesions showed numerous intracellular mycobacteria within foamy histiocytes suggestive of nontuberculous mycobacteria and misled the empiric treatment. The final culture grew Sporothrix spp. and the lesions improved with antifungal treatment alone. This case report depicts a case of Mycobacterium lentiflavum colonization in cutaneous sporotrichosis lesions on histopathology to raise awareness among physicians about this rare coincidence that could mislead the diagnosis.

A case report of multi-system inflammatory syndrome in adults (MIS-A) associated with heart failure.

BACKGROUND: Multi-system inflammatory syndrome in children (MIS-C) is a systemic inflammatory condition where various body organs, such as the heart, kidney, gastrointestinal organs, become inflamed. Several cases have been reported in children linking MIS-C with novel corona virus disease-2019 (COVID-19); however, few cases have been reported in adults [multi-system inflammatory syndrome in adults (MIS-A)]. CASE SUMMARY: A case of a 20-year-old male patient with a history of COVID-19 infection 2 months before presentation who presented with fever and acute right lower quadrant pain. Workup revealed right-sided mesenteric lymphadenopathy and mild colitis that was non-responsive to antibiotics. The patient was found to have significantly elevated inflammatory markers. He also developed myocarditis resulting in acute systolic heart failure with reduced ejection fraction. The diagnosis of MIS-A was made by exclusion. The patient showed improvement with intravenous immunoglobulin and pulse steroids. Based on the available literature, MIS-C was defined till the age of 21; however, we think it is a misnomer for adults more than 18. Hence, we prefer to use MIS-A for our patient. CONCLUSION: It is essential to diagnose and treat patients with the multi-system inflammatory syndrome at an early stage; the management of these patients, especially with heart disease, should include immune-modulatory therapy as well as guideline-directed therapy.

Common Themes in Zoonotic Spillover and Disease Emergence: Lessons Learned from Bat- and Rodent-Borne RNA Viruses.

Rodents (order Rodentia), followed by bats (order Chiroptera), comprise the largest percentage of living mammals on earth. Thus, it is not surprising that these two orders account for many of the reservoirs of the zoonotic RNA viruses discovered to date. The spillover of these viruses from wildlife to human do not typically result in pandemics but rather geographically confined outbreaks of human infection and disease. While limited geographically, these viruses cause thousands of cases of human disease each year. In this review, we focus on three questions regarding zoonotic viruses that originate in bats and rodents. First, what biological strategies have evolved that allow RNA viruses to reside in bats and rodents? Second, what are the environmental and ecological causes that drive viral spillover? Third, how does virus spillover occur from bats and rodents to humans?

SARS-CoV-2 and Human Immunodeficiency Virus: Pathogen Pincer Attack.

Paramount efforts worldwide are seeking to increase understanding of the basic virology of SARS-CoV-2, characterize the spectrum of complications associated with COVID-19, and develop vaccines that can protect from new and recurrent infections with SARS-CoV-2. While we continue learning about this new virus, it is clear that 1) the virus is spread via the respiratory route, primarily by droplets and contact with contaminated surfaces and fomites, as well as by aerosol formation during invasive respiratory procedures; 2) the airborne route is still controversial; and 3) that those infected can spread the virus without necessarily developing COVID-19 (ie, asymptomatic). With the number of SARS-CoV-2 infections increasing globally, the possibility of co-infections and/or co-morbidities is becoming more concerning. Co-infection with Human Immunodeficiency Virus (HIV) is one such example of polyparasitism of interest. This military-themed comparative review of SARS-CoV-2 and HIV details their virology and describes them figuratively as separate enemy armies. HIV, an old enemy dug into trenches in individuals already infected, and SARS-CoV-2 the new army, attempting to attack and capture territories, tissues and organs, in order to provide resources for their expansion. This analogy serves to aid in discussion of three main areas of focus and draw attention to how these viruses may cooperate to gain the upper hand in securing a host. Here we compare their target, the key receptors found on those tissues, viral lifecycles and tactics for immune response surveillance. The last focus is on the immune response to infection, addressing similarities in cytokines released. While the majority of HIV cases can be successfully managed with antiretroviral therapy nowadays, treatments for SARS-CoV-2 are still undergoing research given the novelty of this army.

Identification of Novel MeCP2 Cancer-Associated Target Genes and Post-Translational Modifications.

Abnormal regulation of DNA methylation and its readers has been associated with a wide range of cellular dysfunction. Disruption of the normal function of DNA methylation readers contributes to cancer progression, neurodevelopmental disorders, autoimmune disease and other pathologies. One reader of DNA methylation known to be especially important is MeCP2. It acts a bridge and connects DNA methylation with histone modifications and regulates many gene targets contributing to various diseases; however, much remains unknown about how it contributes to cancer malignancy. We and others previously described novel MeCP2 post-translational regulation. We set out to test the hypothesis that MeCP2 would regulate novel genes linked with tumorigenesis and that MeCP2 is subject to additional post-translational regulation not previously identified. Herein we report novel genes bound and regulated by MeCP2 through MeCP2 ChIP-seq and RNA-seq analyses in two breast cancer cell lines representing different breast cancer subtypes. Through genomics analyses, we localize MeCP2 to novel gene targets and further define the full range of gene targets within breast cancer cell lines. We also further examine the scope of clinical and pre-clinical lysine deacetylase inhibitors (KDACi) that regulate MeCP2 post-translationally. Through proteomics analyses, we identify many additional novel acetylation sites, nine of which are mutated in Rett Syndrome. Our study provides important new insight into downstream targets of MeCP2 and provide the first comprehensive map of novel sites of acetylation associated with both pre-clinical and FDA-approved KDACi used in the clinic. This report examines a critical reader of DNA methylation and has important implications for understanding MeCP2 regulation in cancer models and identifying novel molecular targets associated with epigenetic therapies.

Changes in neutrophil-to-lymphocyte ratios in postcardiac arrest patients treated with targeted temperature management.

OBJECTIVE: The prognostic value of changes in neutrophil-to-lymphocyte ratios (NLR) in cardiac arrest survivors receiving targeted temperature management (TTM) is unknown. The current study investigated NLR in postcardiac arrest (PCA) patients undergoing TTM. METHODS: This retrospective single-center study included 95 patients (59 males, age: 55.0±17.0 years) with in-hospital and out-of-hospital cardiac arrests who underwent TTM for PCA syndrome within 6 h of cardiac arrest. Hypothermia was maintained for 24 h at a target temperature of 33°C. NLR was calculated as the absolute neutrophil count divided by the absolute lymphocyte count. RESULTS: Of the 95 patients, 59 (62%) died during hospital stay. Fewer vasopressors were used in patients who survived. Out-of-hospital cardiac arrest was more frequent in decedents (p=0.005). Length of stay in the hospital and intensive care unit were significantly longer in patients who survived (p=0.0001 and p=0.001, respectively). NLR on admission and during rewarming did not differ between survivors and decedents. NLR during cooling was significantly higher in decedents (p=0.014). Delta NLR cut-off of 13.5 best separated survivors and decedents (AUC=0.68, 95% CI: 0.57-0.79, p=0.003 with a sensitivity and specificity of 64% and 67%, respectively). In multivariate logistic regression analysis, larger increase in NLR was significantly associated with decreased survival (OR: 0.96, 95% CI: 0.94-0.99, p=0.008). CONCLUSION: Changes in NLR are an independent determinant of survival in patients with return of spontaneous circulation PCA treated with TTM. An NLR change can be used to predict survival in these patients.