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1.
Cancer Research ; 82(12), 2022.
Article in English | EMBASE | ID: covidwho-1986481

ABSTRACT

Purpose: The estrogen receptor (ER) is expressed in over 80% of breast tumors and has been shown to be a significant driver of breast cancer (BC) pathogenesis and therefore a target of effective first-line therapies. While both ionizing radiation (RT) and endocrine therapies (ET) are used for the treatment of ER+ BC, the effect of ET on tumor radiosensitization remains unclear, with concerns it may be radioprotective based on G1 cell arrest with ET treatment. Here we assessed the efficacy and mechanism of ER-mediated radiosensitization using various pharmacologic approaches in ER+ BC. Methods: Radiosensitization with ER inhibitors (tamoxifen [TAM], fulvestrant [FULV], AZD9496) was assessed using clonogenic survival assays. DNA damage was assessed by the neutral comet assay. Efficiency of homologous recombination (HR) or non-homologous end joining (NHEJ) as well as changes in cell cycle, apoptosis, and senescence were assessed. The efficacy of TAM with RT in vivo was assessed with an MCF-7 xenograft model. Results: The selective estrogen receptor modulator TAM radiosensitized ER+ MCF-7 (enhancement ratio [enhR]: 1.14-1.50) and T47D (enhR: 1.33-1.60) cells but not ER-negative SUM-159 cells (enhR: 0.99-1.02). The selective estrogen receptor degrader (SERD) FULV had similar radiosensitization effects in MCF-7 (enhR: 1.33-1.76) and T47D cells (enhR: 0.97-2.81) with no radiosensitization observed in SUM-159 cells (enhR: 1.01-1.03). The novel oral SERD AZD9496 radiosensitized MCF-7 cells (enhR: 1.36-1.56). MCF-7 cells treated with TAM and RT had an increase in dsDNA breaks compared to RT alone as measured by the comet assay (p<0.05) and a decrease in NHEJ-mediated repair with TAM (p<0.05). No changes were observed in HR-mediated repair by Rad51 foci or a reporter (p=NS). RT alone and in combination with TAM or FULV induced similar levels of cell cycle arrest, suggesting that radiosensitization with the combination therapy is cell-cycle independent. There were no significant changes in apoptosis with TAM, FULV, RT, or the combination (p=NS). Although TAM or FULV did induce senescence, ET with RT increased senescence induction (p<0.05). In vivo, combination RT and TAM led to a significant delay in days to tumor doubling (control: 17, TAM: 40, RT: 32, TAM+RT: undefined;p<0.0001), and a significant difference in tumor growth between mice treated with TAM or RT alone compared combination treatment, with no increased toxicities or skin lesions from the combination treatment. Conclusion: Our data suggest that TAM, FULV, or AZD9496 can radiosensitize ER+ breast tumors, and these agents with RT may be more effective for radiosensitization. This work also supports further clinical investigation of the timing of RT for patients receiving ET, including using ET during RT, especially as initiating ET prior to RT has been increasingly utilized as a bridging therapy followed by concurrent ET+RT during the COVID-19 pandemic.

2.
Revista De Ciencia Politica ; 42(2):24, 2022.
Article in English | Web of Science | ID: covidwho-1981100

ABSTRACT

The year 2021 marked the 25th anniversary of the signing of Guatemala's landmark peace accords. Yet celebrations of this historic achievement stood in sharp contrast to the year's alarming trends in the deterioration of democracy and the rule of law. Reviewing the events of 2021, this article uncovers two key patterns in Guatemalan politics, both evidence of democratic decline: 1) open assaults on judicial independence and breaches of the constitutional order, and 2) an escalation in the criminalization of government critics, particularly those on the frontlines of the anti-corruption struggle. It also takes stock of the most pernicious consequences of these patterns, including the abysmal Covid-19 response and the new opportunities for corruption amid resurgent impunity. Combined, these dynamics have also increased tensions within US-Guatemala relations as the Biden White House increasingly perceived the Guatemalan government as an unreliable partner in tackling the root causes of migration. In sum, 2021 was an inflection point in Guatemala's 25-year trajectory of peace-one that has steadily sent the country down an authoritarian path like many of its neighbors in the Western Hemisphere.

3.
Int J Retina Vitreous ; 8(1): 33, 2022 Jun 07.
Article in English | MEDLINE | ID: covidwho-1879264

ABSTRACT

Tertiary outpatient ophthalmology clinics are high-risk environments for COVID-19 transmission, especially retina clinics, where regular follow-up is needed for elderly patients with multiple comorbidities. Intravitreal injection therapy (IVT) for chronic macular diseases, is one of the most common procedures performed, associated with a significant burden of care because of the vigorous treatment regimen associated with multiple investigations. While minimizing the risk of COVID-19 infection transmission is a priority, this must be balanced against the continued provision of sight-saving ophthalmic care to patients at risk of permanent vision loss. This review aims to give evidence-based guidelines on managing IVT during the COVID-19 pandemic in common macular diseases such as age-related macular degeneration, diabetic macula edema and retinal vascular disease and to report on how the COVID-19 pandemic has affected IVT practices worldwide.To illustrate some real-world examples, 18 participants in the International Retina Collaborative, from 15 countries and across four continents, were surveyed regarding pre- and during- COVID-19 pandemic IVT practices in tertiary ophthalmic centers. The majority of centers reported a reduction in the number of appointments to reduce the risk of the spread of COVID-19 with varying changes to their IVT regimen to treat various macula diseases. Due to the constantly evolving nature of the COVID-19 pandemic, and the uncertainty about the normal resumption of health services, we suggest that new solutions for eye healthcare provision, like telemedicine, may be adopted in the future when we consider new long-term adaptations required to cope with the COVID-19 pandemic.

4.
Journal of Investigative Medicine ; 70(4):1056-1057, 2022.
Article in English | EMBASE | ID: covidwho-1868753

ABSTRACT

Purpose of Study To investigate potential evidence of in utero transmission of SARS-CoV-2 in the stool of newborns born to mothers with COVID-19 infection during pregnancy. Methods Used We investigated stool from 1 day to 2 months of age from 14 newborns born at 25-41 weeks whose mothers had COVID-19 during pregnancy. Newborns were admitted at delivery to the NICU or newborn nursery of our urban academic hospital from July 2020 to May 2021. A comparison group of 30 newborns had similar GAs and were born to mothers without COVID-19 during pregnancy. SARS-CoV-2 RNA was quantified with quantitative PCR using primers against SARS-CoV-2 envelope protein and non-structural protein 14 (NSP-14), spike protein with enzyme-linked immunosorbent assay (ELISA), and inflammatory cytokines interleukin- 6 (IL-6) and interferon-g (IFN-γ) elicited by stool homogenates in mouse bone marrow macrophages. This study was IRB approved with parental consent. Summary of Results Despite negative nasal PCRs from all newborns, viral RNAs and spike protein were detected in the stool of 11 out of 14 newborns as early as the first day of life (range 0-2 months, figure 2A and 2B). Stool RNA and spike protein levels increased over time in 2 and 4 newborns, respectively. Stool homogenates from all newborns elicited elevated inflammatory cytokines, IL-6 and IFN-γ, from mouse macrophages (figure 1). Most newborns were clinically well except for one death from gestational autoimmune liver disease and one with necrotizing enterocolitis. Conclusions These novel findings suggest risk of in utero SARS-CoV-2 transmission to the premature and term fetal intestine during gestation despite negative postnatal nasal PCRs. It is unclear if the presence of viral RNA and protein within the gut microbiome represents active virus in newborns with clinical hospital courses typical of their gestational age in 12 out of 14 cases. However, increasing levels of viral RNA and protein over time suggest replication in some infants, and their gut microbiome induced inflammation in mouse models. The presence of SARS-CoV-2 RNA and spike protein in the intestines of newborns may potentially impact development of the gut microbiome and the immune system and should be further investigated. (Figure Presented).

5.
Cancer Research ; 82(4 SUPPL), 2022.
Article in English | EMBASE | ID: covidwho-1779476

ABSTRACT

Purpose: Estrogen receptor (ER) expression is present in over 80% of breast tumors and has been shown to be a significant driver of breast cancer (BC) pathogenesis and therefore a target of first-line therapies for ER-positive (ER+) BC patients. While both ionizing radiation (RT) and endocrine therapies (ET) are used for the treatment of ER+ BC, the sequencing of therapy and the effect of ET on tumor radiosensitization remain unclear. Recently, this question has become much more clinically relevant when many physicians started offering ET as a bridging strategy to surgery and RT during the COVID-19 pandemic. Here we assessed the efficacy and mechanism of ER inhibition in ER+ BC in combination with RT in preclinical models. Methods: Clonogenic survival assays were used to assess radiosensitization. Inhibition of ER signaling was accomplished by treating ER+ MCF-7 and T47D cells with the selective ER modulator (SERM), tamoxifen, or the selective ER degrader (SERD), fulvestrant. The ER-negative SUM-159 cells were used as a negative control. DNA damage was assessed by the neutral comet assay. Efficiency of homologous recombination (HR) was measured by Rad51 foci or a GFP reporter system. Non-homologous end joining (NHEJ) efficiency was assessed with a pEYFP reporter. Cell cycle effects were measured using flow cytometry with propidium iodide (PI) staining. Apoptosis was assessed by annexin V/PI via flow Scytometry. Senescence was measured using β-galactosidase staining. Western blotting was used to quantify expression of proteins and phospho-proteins involved in cell cycle and apoptosis. An MCF-7 xenograft model was used to assess the efficacy of tamoxifen with RT in vivo. Synergy was determined using the fractional tumor volume (FTV) method. Results: ER inhibition with tamoxifen radiosensitized ER+ MCF-7 (10-250 nM, enhR: 1.14-1.50) and T47D (500 nM-2.0 μ M, enhR: 1.33-1.60) cells but not ER-negative SUM-159 cells (500 nM-2.0 μ M, enhR: 0.99-1.02). ER degradation with fulvestrant had similar radiosensitization effects in MCF-7 (1-25 nM, enhR: 1.33-1.76) and T47D cells (0.5-5 nM, enhR: 0.97-2.81) with no radiosensitization observed in SUM-159 cells (1-25 nM, enhR: 1.01-1.03). MCF-7 cells treated with 500 nM tamoxifen and 4 Gy RT had an increase in dsDNA breaks compared to RT alone as measured by the comet assay (p<0.05), and there was a decrease in NHEJ-mediated repair with tamoxifen treatment (p<0.05). No changes were observed in HR-mediated repair by Rad51 foci or an HR reporter (p=NS). RT alone and in combination with tamoxifen and fulvestrant induced similar levels of cell cycle arrest, suggesting that radiosensitization with the combination therapy is a cell-cycle independent effect. In addition, there were no significant changes in apoptosis in MCF-7 or T47D cells with endocrine therapy, RT, or the combination (p=NS). Although treatment with ET did induce senescence in ER+ MCF-7 and T47D cells, the combination treatment of ET with RT induced senescence to a much greater level suggesting this mechanism may contribute to radiosensitization (p<0.05). In vivo, combination RT and tamoxifen led to a significant delay in time to tumor doubling (17 days in control, 40 days with tamoxifen alone, 32 days with RT alone, and undefined with combination;p<0.0001) and a significant difference in tumor growth between mice treated with tamoxifen or RT alone compared to mice treated with tamoxifen and RT with synergy noted with combination treatment (FTV 1.297). Conclusion: Our data suggest that ET can radiosensitize ER+ breast tumors, and ET with RT may be more effective for radiosensitization. Ongoing studies will address concurrent versus sequential ET with RT. This work also supports further clinical investigation of the timing of RT for patients receiving ET, especially as ET prior to RT is increasingly used as a bridging therapy during the COVID-19 pandemic.

6.
Blood ; 138:1, 2021.
Article in English | EMBASE | ID: covidwho-1582278

ABSTRACT

Severe SARS-CoV-2 infection is complicated by dysregulation of the blood coagulation system and high rates of thrombosis, but virus-intrinsic mechanisms underlying this phenomenon are poorly understood. Increased intracellular calcium concentrations promote externalization of phosphatidylserine (PS), the membrane anionic phospholipid required for assembly and activation of the tenase and prothrombinase complexes to drive blood coagulation. TMEM16F is a ubiquitous phospholipid scramblase that mediates externalization of PS in a calcium-dependent manner. As SARS-CoV-2 ORF3a encodes a presumed cation channel with the ability to transport calcium, we hypothesized that ORF3a expression by infected host cells perturbs the cellular calcium rheostat, driving TMEM16F-dependent externalization of PS and enhancing procoagulant activity. Using a doxycycline-inducible system, synchronized expression of ORF3a in A549 pulmonary epithelial cells resulted in a time-dependent augmentation of tissue factor (TF) procoagulant activity exceeding 9-fold by 48 hours (p < 0.0001), with no change in TF cell-surface expression. This enhancement was dependent upon PS as determined by inhibition with the PS-binding protein lactadherin. Over 2-fold enhancement of prothrombinase activity (p < 0.0001) was also observed by 48 hours. ORF3a increased intracellular calcium levels by 18-fold at 48 hours (p < 0.0001), as determined by the intracellular calcium indicator fluo-4. After 16 hours of ORF3a expression, more than 60% of cells had externalized PS (p < 0.001) without increased cell death, as quantified by flow cytometry following annexin V binding. Immunofluorescence microscopy staining for ORF3a, annexin V, and nuclei confirmed ORF3a expression within internal and cell surface membranes and increased PS externalization. PS externalization was insensitive to the pan-caspase inhibitor z-VAD-FMK, and there was no evidence of apoptotic activation as determined by caspase-3 cleavage. By contrast, ORF3a expression did not augment coagulation in cells deficient in the calcium-dependent phospholipid scramblase TMEM16F. Similarly, ORF3a-enhanced TF procoagulant activity (p < 0.01) and prothrombinase activity (p<0.05) was completely abrogated using TMEM16 inhibitors, including the uricosuric agent benzbromarone that has been registered for human use in over 20 countries. Live SARS-CoV-2 infection of A549-ACE2 cells increased cell surface factor Xa generation at MOI 0.1 (p < 0.01) but not MOI 0.01 or following heat inactivation of the virus, and RNA sequencing confirmed ORF3a induction without increased F3 expression. RNA sequencing of human SARS-CoV-2 infected lung autopsy and control tissue (n= 53) confirmed these findings in vivo. Immunofluorescence staining for ORF3a and KRT8/18 and CD31 in SARS-CoV-2 infected human lung autopsy specimens demonstrated ORF3a expression in pulmonary epithelium and endothelial cells, highlighting the potential pathologic relevance of this mechanism. Here we demonstrate that expression of the SARS-CoV-2 accessory protein ORF3a increases the intracellular calcium concentration and TMEM16F-dependent PS scrambling to augment procoagulant activity of the tenase and prothrombinase complexes. Our studies of human cells and tissues infected with SARS-CoV-2 support the pathologic relevance of this mechanism. We highlight the therapeutic potential to target the ORF3a-TMEM16F axis as with benzbromarone to mitigate dysregulation of coagulation and thrombosis during severe SARS-CoV-2 infection. Disclosures: Schwartz: Miromatrix Inc: Membership on an entity's Board of Directors or advisory committees;Alnylam Inc.: Consultancy, Speakers Bureau. Schulman: CSL Behring: Consultancy, Research Funding.

7.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-296897

ABSTRACT

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus has infected over 115 million people and caused over 2.5 million deaths worldwide. Yet, the molecular mechanisms underlying the clinical manifestations of COVID-19, as well as what distinguishes them from common seasonal influenza virus and other lung injury states such as Acute Respiratory Distress Syndrome (ARDS), remains poorly understood. To address these challenges, we combined transcriptional profiling of 646 clinical nasopharyngeal swabs and 39 patient autopsy tissues, matched with spatial protein and expression profiling (GeoMx) across 357 tissue sections. These results define both body-wide and tissue-specific (heart, liver, lung, kidney, and lymph nodes) damage wrought by the SARS-CoV-2 infection, evident as a function of varying viral load (high vs. low) during the course of infection and specific, transcriptional dysregulation in splicing isoforms, T cell receptor expression, and cellular expression states. In particular, cardiac and lung tissues revealed the largest degree of splicing isoform switching and cell expression state loss. Overall, these findings reveal a systemic disruption of cellular and transcriptional pathways from COVID-19 across all tissues, which can inform subsequent studies to combat the mortality of COVID-19, as well to better understand the molecular dynamics of lethal SARS-CoV-2 infection and other viruses.

8.
International Journal of Radiation Oncology Biology Physics ; 111(3):e253, 2021.
Article in English | EMBASE | ID: covidwho-1466397

ABSTRACT

Purpose/Objective(s): Estrogen receptor (ER) expression is present in over 80% of breast tumors and has been shown to be a significant driver of tumor initiation and progression and therefore a target of first-line therapies for ER-positive (ER+) breast cancer (BC) patients. While both ionizing radiation (RT) and endocrine therapies (ET) are used for the treatment of women with ER+ BC, the sequencing of therapy and the effect of ET on tumor radiosensitization remains unclear. Here we assessed the efficacy and mechanism of ER inhibition in ER+ BC in combination with RT in multiple preclinical models. Materials/Methods: Clonogenic survival assays were used to assess radiosensitization. ER inhibition was accomplished with tamoxifen and the selective ER degrader (SERD), fulvestrant, in ER+ MCF-7 and T47D cells or ER-negative (ER-) SUM-159 cells. DNA damage was assessed by yH2AX foci. Efficiency of homologous recombination (HR) or non-homologous end joining (NHEJ) was measured by RAD51 foci or using a pYFP reporter, respectively. Cell cycle effects were measured using flow cytometry with propidium iodide (PI) staining. Apoptosis was assessed by annexin V/PI via flow cytometry. Western blotting was used to quantify protein expression. An MCF-7 xenograft model was used to assess the efficacy of tamoxifen with RT in vivo where mice were pretreated with tamoxifen for one or six days prior to starting RT. Synergy was determined using the fractional tumor volume method. Results: One-hour pretreatment with tamoxifen prior to RT resulted in radiosensitization of ER+ MCF-7 (enhR: 1.14-1.50) and T47D (enhR: 1.33-1.60) cells but not ER- SUM-159 cells (enhR: 0.99-1.02). MCF-7 and T47D cells treated with tamoxifen and RT did not alter the kinetics of dsDNA break repair as measured by yH2AX foci (P > 0.05) but demonstrated a decrease in NHEJ-mediated repair (P < 0.05). No changes were observed in HR-mediated repair by Rad51 foci (P > 0.05). While cell cycle arrest was induced at 24 hours after RT, no changes were observed with tamoxifen treatment in combination with RT. In addition, there were no significant changes in apoptosis in MCF-7 or T47D cells with treatment of tamoxifen, RT, or the combination (P > 0.05). In vivo, an MCF-7 xenograft study demonstrated a significant delay in time to tumor doubling (17 days in control, 40 days with tamoxifen, 32 days with RT, and undefined with combination;P < 0.0001) and a significant difference in tumor growth between mice treated with tamoxifen or RT alone compared to mice treated with tamoxifen and RT with synergy noted with combination treatment. Conclusion: Our data suggest that endocrine therapies may be effectively used to radiosensitize ER+ breast tumors. This work also supports further clinical investigation of the timing of RT for patients receiving ET as concurrent use may be more effective than sequential, especially as ET prior to RT is increasingly used as a bridging therapy during the COVID pandemic.

9.
Cardiovascular Revascularization Medicine ; 28:S11, 2021.
Article in English | EMBASE | ID: covidwho-1368598

ABSTRACT

Background: Following a period of stability, the coronavirus disease 2019 (COVID-19) pandemic appears to be re-intensifying globally. As the pandemic continues to evolve, so does our understanding of its implications on ST-segment elevation myocardial infarction (STEMI). We sought to describe a single center STEMI experience at one of the epicenters of the COVID-19 pandemic. Methods: This was a retrospective observational study which included consecutive suspected STEMI patients from March 1 through August 31, 2019, (Cohort 1) compared to the same time period in 2020 (Cohort 2), at a tertiary referral center in Nassau County, New York. Results: Cohort 2 (n=93) saw a similar number of acute myocardial infarction (AMI) team activations compared to cohort 1 (n=90) (Figure 1). Infection control measures and additional investigation were required to clarify the diagnosis in cohort 2, resulting in longer door-to-balloon times (95.9 minutes vs. 74.4 minutes, p=0.0587). We observed similar inpatient length of stay (LOS) (3.6 days vs. 5.0 days, p=0.0901) and mortality (13.2% vs. 9.2%, p=0.5876). Conclusions: Our single-center study, located at one of the epicenters of the pandemic, demonstrated a similar number of AMI team activations, mimicking the seasonal variability seen in 2019, but with longer door-to-balloon times. Despite this, inpatient LOS and mortality remained unchanged. [Formula presented]

10.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-8946

ABSTRACT

COVID-19 patients commonly present with neurological signs of central nervous system (CNS) and/or peripheral nervous system dysfunction. However, which neural cells are permissive to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been controversial. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively permissive to SARS-CoV-2 infection both in vitro and upon transplantation in vivo, and that SARS-CoV-2 infection triggers a DA neuron inflammatory and cellular senescence response. A high-throughput screen in hPSC-derived DA neurons identified several FDA approved drugs, including riluzole, metformin, and imatinib, that can rescue the cellular senescence phenotype and prevent SARS-CoV-2 infection. RNA-seq analysis of human ventral midbrain tissue from COVID-19 patients, using formalin-fixed paraffin-embedded autopsy samples, confirmed the induction of an inflammatory and cellular senescence signature and identified low levels of SARS-CoV-2 transcripts. Our findings demonstrate that hPSC-derived DA neurons can serve as a disease model to study neuronal susceptibility to SARS-CoV-2 and to identify candidate neuroprotective drugs for COVID-19 patients. The susceptibility of hPSC-derived DA neurons to SARS-CoV-2 and the observed inflammatory and senescence transcriptional responses suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.

11.
Przeglad Dermatologiczny ; 107(6):608, 2020.
Article in English | EMBASE | ID: covidwho-1224306

ABSTRACT

The COVID-19 pandemic represents a systemic respiratory infection often with dermatologic signs and systemic sequelae, a public health challenge paralleling the two great influenza pandemics of the last century. COVID-19 have been cutaneous findings are grouped into 6 categories with three distinct indicative patterns: vesicular (varicella-like), vasculopathic, and chilblains-like (including ,COVID toes and ,COVID fingers) plus three less suggestive ones: dermatitic, maculopapular, and urticarial morphologies. Vasculopathic changes are the most concerning, in some patients reflecting a devastating blood clotting dysfunction. Other skin alterations represent adverse cutaneous drug reactions, such as generalized pustular figurate erythema from hydroxychloroquine, and other alterations associated with COVID-19 lifestyle modifications for patients and health care workers.

12.
Circulation ; 142:2, 2020.
Article in English | Web of Science | ID: covidwho-1090807
14.
Hepatology ; 72(1 SUPPL):1026A, 2020.
Article in English | EMBASE | ID: covidwho-986120

ABSTRACT

Background: Modest weight loss (5-7%) remains the goldstandard of treatment for nonalcoholic fatty liver disease (NAFLD), though patients rarely achieve this independently The YMCA's Diabetes Prevention Program (DPP) is a nationwide structured lifestyle intervention program that has demonstrated weight loss within this range The goal of this study is to determine if the DPP can be repurposed to induce weight loss, decrease liver enzymes, and improve hepatic steatosis in NAFLD Methods: Eligible patients had NAFLD (defined by Fibroscan controlled attenuation parameter (CAP) score >238dB/m) and elevated liver enzymes (ALT>25U/L in females, >33U/L in males) without competing etiologies for liver disease Patients with cirrhosis were excluded A retrospective cohort that received standard of care recommendations was analyzed for change in ALT Two sequential prospective cohorts of 20 patients were enrolled in the experimental YMCA DPP Classroom sessions occurred weekly for 16 weeks, bi-weekly for 4 weeks, and then monthly for 48 weeks total Primary endpoints included change in BMI, ALT, and Fibroscan score. Completers were defined as those attending at least 9 of the first 16 weekly sessions. Changes in variables were analyzed using paired t-test End of study data was not completed for cohort 2 due to COVID19 and therefore aggregate data is presented for week 16 and end of study data (week 48) is presented for only cohort 1 Results: A total of 20 patients from both cohorts were completers 16% were female (n=12) 16 patients had interim study data and were included in the week 16 analysis All but one patient lost weight Baseline mean BMI was 34 3 and decreased to 33 6 by week 16 (p=0 02) Baseline mean ALT was 91 8U/L and decreased to 55 1U/L by week 16 (p=0 005) Mean Fibroscan fibrosis score improved from 6.7kPa to 5.5kPa and CAP score improved from 321dB/m to 291dB/m by week 16 (p=0 008 and p=0 12, respectively) 9 patients from cohort 1 were included in the week 48 analysis Mean BMI was 35 4 at baseline and decreased to 33 6 by week 48 (p=0 002) Mean ALT was 85 0U/L at baseline decreased to 41 6U/L (p=0 01) Mean Fibroscan score improved from 6 9kPa to 5 9kPa (p=0 07) Other metabolic parameters also trended towards significant improvement at week 16 and 48 (Table 1). The retrospective cohort (N=31) had a mean baseline ALT of 69U/L with no significant change at 6-month follow-up (mean ALT 60U/L, p=0 24) Conclusion: Standard of care lifestyle recommendations are ineffective in inducing weight loss and improvement in ALT in NAFLD The YMCA DPP repurposed to treat NAFLD resulted in statistically significant improvements in BMI and ALT in patients with NAFLD Fibroscan scores and other metabolic parameters also improved, though the sample size is likely too small to see a statistically significant improvement The existing infrastructure established by the YMCA throughout the U S could emerge as a leading treatment option for NAFLD patients.

15.
Hepatology ; 72(1 SUPPL):278A, 2020.
Article in English | EMBASE | ID: covidwho-986075

ABSTRACT

Background: COVID-19 was declared a pandemic by the World Health Organization, caused by severe acute respiratory syndrome corona-virus 2 (SARS-CoV-2) Respiratory failure is the most common mortality outcome in COVID-19 patients, yet serious and even fatal manifestations are seen across multiple organ systems Emerging clinical data from our own hospital revealed a high prevalence of initial presentations with GI manifestations Almost one third of patients presenting to our hospital reported at least one gastrointestinal manifestation including nausea, vomiting, diarrhea, or abdominal pain 62% of patients presented with biochemical evidence of liver injury Moreover, the presence of liver injury on presentation was associated with a significantly higher risk of ICU admission and death As this is a new and novel clinical entity, robust in vitro models that phenocopy SARS-CoV-2 infection and human COVID-19 disease are limited Current in vitro (e g Vero cells) and in vivo models (mouse models engineered with ACE2) are so distinct from human infection that they may not capture key components of viral infection or virus-host interactions Therefore, the development of robust human models of COVID-19 infection will be essential for the study of SARS-Cov-2 viral infection and to identify robust SARS-CoV-2 therapeutics Methods: Human pluripotent stem cells (hPSCs), including human embryonic stem cells hESCs) and induced pluripotent stem cells (hiPSCs), can be used to derive functional human cells/tissues/organoids for modeling human disease and drug discovery, including for infectious diseases Here we leveraged several stem cell platforms (e g endodermal lineages including hepatocyte and cholangiocyte) along with primary human hepatocytes and cholangiocyte organoid systems to study SARS-CoV-2 infection SARS-CoV-2 pseudoparticles were used to study SARS-CoV-2 viral entry SARS-CoV-2 (USA-WA1/2020) was used to validate viral infection and to study cellular response Autopsy liver samples from COVID-19 patients were obtained and compared to SARS-CoV-2 infected liver models Results: Adult hepatocyte and cholangiocyte organoids along with PSC derived hepatocytes and cholangiocytes are Permissive to SARS-CoV-2 virus infection and show similar transcriptome changes and chemokine responses for SARSCoV- 2 infection as seen in autopsy samples from COVID-19 Patients Conclusion: We report here the development of robust models of SARS-CoV-2 infection in primary and PSC derived hepatocyte and cholangiocytes which phenocopy COVID-19 hepatic disease These disease-relevant human cell/organoid-based platforms can be directly applied for drug screening and the evaluation of prospective antiviral therapeutics as well be used to delineate molecular mechanisms underlying COVID-19 disease.

16.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-3030

ABSTRACT

Dysfunctional immune responses contribute critically to the progression of Coronavirus Disease-2019 (COVID-19) from mild to severe stages including fatality, with pro-inflammatory macrophages as one of the main mediators of lung hyper-inflammation. Therefore, there is an urgent need to better understand the interactions among SARS-CoV-2 permissive cells, macrophage, and the SARS-CoV-2 virus, thereby offering important insights into new therapeutic strategies. Here, we used directed differentiation of human pluripotent stem cells (hPSCs) to establish a lung and macrophage co-culture system and model the host-pathogen interaction and immune response caused by SARS-CoV-2 infection. Among the hPSC-derived lung cells, alveolar type II and ciliated cells are the major cell populations expressing the viral receptor ACE2 and co-effector TMPRSS2, and both were highly permissive to viral infection. We found that alternatively polarized macrophages (M2) and classically polarized macrophages (M1) had similar inhibitory effects on SARS-CoV-2 infection. However, only M1 macrophages significantly up-regulated inflammatory factors including IL-6 and IL-18, inhibiting growth and enhancing apoptosis of lung cells. Inhibiting viral entry into target cells using an ACE2 blocking antibody enhanced the activity of M2 macrophages, resulting in nearly complete clearance of virus and protection of lung cells. These results suggest a potential therapeutic strategy, in that by blocking viral entrance to target cells while boosting anti-inflammatory action of macrophages at an early stage of infection, M2 macrophages can eliminate SARS-CoV-2, while sparing lung cells and suppressing the dysfunctional hyper-inflammatory response mediated by M1 macrophages.

17.
PubMed; 2020.
Preprint in English | PubMed | ID: ppcovidwho-2670

ABSTRACT

Heart injury has been reported in up to 20% of COVID-19 patients, yet the cause of myocardial histopathology remains unknown. In order to study the cause of myocardial pathology in COVID-19 patients, we used a hamster model to determine whether following infection SARS-CoV-2, the causative agent of COVID-19, can be detected in heart tissues. Here, we clearly demonstrate that viral RNA and nucleocapsid protein is present in cardiomyocytes in the hearts of infected hamsters. Interestingly, functional cardiomyocyte associated gene expression was decreased in infected hamster hearts, corresponding to an increase in reactive oxygen species (ROS). This data using an animal model was further validated using autopsy heart samples of COVID-19 patients. Moreover, we show that both human pluripotent stem cell-derived cardiomyocytes (hPSC-derived CMs) and adult cardiomyocytes (CMs) can be infected by SARS-CoV-2 and that CCL2 is secreted upon SARS-CoV-2 infection, leading to monocyte recruitment. Increased CCL2 expression and macrophage infiltration was also observed in the hearts of infected hamsters. Using single cell RNA-seq, we also show that macrophages are able to decrease SARS-CoV-2 infection of CMs. Overall, our study provides direct evidence that SARS-CoV-2 infects CMs in vivo and proposes a mechanism of immune-cell infiltration and pathology in heart tissue of COVID-19 patients.

18.
Pain Physician ; 23(4 Special Issue):S461-S462, 2020.
Article in English | EMBASE | ID: covidwho-762840
20.
Pain Physician ; 23(4 Special Issue):S455-S456, 2020.
Article in English | EMBASE | ID: covidwho-726238
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