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We previously created a mandatory, inpatient, hepatology resident curriculum that immediately improved comfort, knowledge, and career interest in chronic liver disease (CLD). The durability of these effects needs to be known to use this intervention to address the hepatologist shortage. Thus, we aimed to assess this curriculum’s long‐term outcomes on internal medicine (IM) residents’ CLD comfort, knowledge, and career interest. From 2015 to 2019 at a single institution, one IM resident was always assigned to the rotation. Similar anonymous assessments were administered to incoming postgraduate year (PGY)‐1 residents and graduating PGY‐3 residents, including a historic control cohort that graduated in June 2015. At residency completion, the intervention cohort (n = 61) had significantly higher comfort (1, not at all comfortable/strongly disagree; 5, very comfortable/strongly agree) with both hepatology (e.g., hepatitis C, 2.5 vs. 3.3, P

The prevalence of chronic liver disease (CLD) is rising, but it remains unclear if medical school curricula are emphasizing CLD to reflect its growing epidemiology. To assess comfort levels and knowledge of CLD among recently graduated medical students An anonymous survey was distributed to incoming categorical Internal Medicine (IM) interns at a single academic institution during a 2-year period. The survey consisted of 38 Likert-like questions evaluating comfort levels and self-assessed knowledge for several general medicine and liver diseases, as well as 12 multiple-choice questions to objectively test knowledge. Wilcoxon ranked sum and Fisher’s exact test were then used. There was a 100% (n = 65) completion rate. Only 14 (22%) of those surveyed reported exposure to a hepatology rotation in medical school. Highest mean comfort levels (1 = not at all comfortable, 5 = very comfortable) were for managing congestive heart failure (3.59) and chronic obstructive pulmonary disease (3.77). Mean comfort levels for various liver diseases were significantly lower (2.22–3.03, all p

Long COVID, a type of Post-Acute Sequelae of SARS CoV-2 infection (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the pathophysiological mechanisms that drive this inflammation remain unknown. Inflammation during acute Coronavirus Disease 2019 (COVID-19) could be exacerbated by microbial translocation (from the gut and/or lung) to the blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We found higher levels of fungal translocation – measured as β-glucan, a fungal cell wall polysaccharide – in the plasma of individuals experiencing PASC compared to those without PASC or SARS-CoV-2 negative controls. The higher β-glucan correlated with higher levels of markers of inflammation and elevated levels of host metabolites involved in activating N-Methyl-D-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neuro-toxic properties. Mechanistically, β-glucan can directly induce inflammation by binding to myeloid cells (via the Dectin-1 receptor) and activating Syk/NF-κB signaling. Using an in vitro Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared to plasma from SARS-CoV-2 negative controls. This higher NF-κB signaling was abrogated by the Syk inhibitor Piceatannol. These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

Beyond neutralization, antibodies binding to their Fc receptors elicit several innate immune functions including antibody-dependent complement deposition (ADCD), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). These functions are beneficial, as they contribute to pathogen clearance; however, they also can induce inflammation. We tested the possibility that qualitative differences in SARS-CoV-2-specific antibody-mediated innate immune functions contribute to coronavirus disease 2019 (COVID-19) severity. We found that anti-S1 and anti-RBD antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from nonhospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation, whereas higher ADCP was associated with lower systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 specific antibodies as potential contributors to COVID-19 severity. Understanding these qualitative features of natural and vaccine-induced antibodies will be important in achieving optimal efficacy and safety of SARS-CoV-2 vaccines and/or COVID-19 therapeutics.IMPORTANCE A state of hyperinflammation and increased complement activation has been associated with coronavirus disease 2019 (COVID-19) severity. However, the pathophysiological mechanisms that contribute to this phenomenon remain mostly unknown. Our data point to a qualitative, rather than quantitative, difference in SARS-CoV-2-specific antibodies' ability to elicit Fc-mediated innate immune functions as a potential contributor to COVID-19 severity and associated inflammation. These data highlight the need for further studies to understand these qualitative features and their potential contribution to COVID-19 severity. This understanding could be essential to develop antibody-based COVID-19 therapeutics and SARS-CoV-2 vaccines with an optimal balance between efficacy and safety.

The prevalence of chronic liver disease (CLD) is rising, but it remains unclear if medical school curricula are emphasizing CLD to reflect its growing epidemiology.To assess comfort levels and knowledge of CLD among recently graduated medical students METHODS: An anonymous survey was distributed to incoming categorical Internal Medicine (IM) interns at a single academic institution during a 2-year period. The survey consisted of 38 Likert-like questions evaluating comfort levels and self-assessed knowledge for several general medicine and liver diseases, as well as 12 multiple-choice questions to objectively test knowledge. Wilcoxon ranked sum and Fisher's exact test were then used.There was a 100% (n = 65) completion rate. Only 14 (22%) of those surveyed reported exposure to a hepatology rotation in medical school. Highest mean comfort levels (1 = not at all comfortable, 5 = very comfortable) were for managing congestive heart failure (3.59) and chronic obstructive pulmonary disease (3.77). Mean comfort levels for various liver diseases were significantly lower (2.22-3.03, all p 0.01). Mean self-rated knowledge (1 = no knowledge, 5 = strong knowledge) was also low (2.14-3.13). Although 98% agreed that hepatology is critical to IM training, only 42% agreed that their hepatology education during medical school was adequate.Recently graduated medical students are less comfortable managing liver diseases compared to other general medical conditions. Only a minority report satisfaction with hepatology education during medical school. These findings suggest that medical curricula need to be modified to better emphasize CLD.

Beyond neutralization, antibodies elicit several innate immune functions including complement deposition (ADCD), phagocytosis (ADCP), and cytotoxicity (ADCC). These functions can be both beneficial (by clearing pathogens) and/or detrimental (by inducing inflammation). We tested the possibility that qualitative differences in SARS-CoV-2 specific antibody-mediated innate immune functions contribute to Coronavirus disease 2019 (COVID-19) severity. We found that antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from non-hospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 antibodies as potential contributors to COVID-19 severity.

Background Elderly patients are exposed to increased number of medications, often with no proof of a positive benefit/risk ratio. Unfortunately, this trend does not spare those with limited life expectancy, including end-stage cancer patients who require only palliative treatment. For many medications in this subpopulation, the risk of adverse drug events outweighs the possible benefits and yet, many are still poly-medicated during their last year of life. Aim To describe the extent of polypharmacy among end-stage cancer patients, at the time of admission to homecare hospice. Methods A retrospective chart review of 202 patients admitted to Homecare Hospice of the Israel Cancer Association and died before January 2015. Results Average lifespan from admission until death was 39.2 ± 5.4 days. 63% died within the first month, 89% within 3 months. Excluding oncological treatments, 181 (90%) and 46 (23%) patients were treated with ≥ 6 and ≥ 12 drugs for chronic diseases, respectively. Two months before death, 32 (16%) patients were treated with ≥ 3 blood pressure lowering drugs, 62 (31%) with statins and 48 (23%) with aspirin. Conclusion Though not representative of the whole end-stage cancer patient population, our study demonstrates that these patients are exposed to extensive polypharmacy. Most of these medications could have probably been safely de-prescribed much earlier in the course of the malignant disease. Considering the prolonged trust-based relationship with their patients, the family physicians are those who should be encouraged to implement the palliative approach and reduce polypharmacy much before reaching hospice settings.

Reactive oxygen species (ROS) generation has been implicated in many pathologies including ischemia/reperfusion (I/R) injury. This led to multiple studies on antioxidant therapies to treat cardiovascular diseases but paradoxically, results have so far been mixed as ROS production can be beneficial as a signaling mechanism and in cardiac protection via preconditioning interventions. We investigated whether the differential impact of increased ROS in injury as well as in protection could be explained by their site of production on the mitochondrial electron transport chain. Using amplex red to measure ROS production, we found that mitochondria isolated from hearts after I/R produced more ROS than non-ischemic when complex I substrate (glutamate/malate) was used. Interestingly, the substrates of complex II (succinate) and ubiquinone (sn-glycerol 3-phosphate, G3P) produced less ROS in mitochondria from I/R hearts compared to normal healthy hearts. The inhibitors of complex I (rotenone) and complex III (antimycin A) increased ROS production when glutamate/malate and G3P were used; in contrast, they reduced ROS production when the complex II substrate was used. Mitochondrial calcium retention capacity required to induce mitochondrial permeability transition pore (mPTP) opening was measured using calcium green fluorescence and was found to be higher when mitochondria were treated with G3P and succinate compared to glutamate/malate. Furthermore, Langendorff hearts treated with glutamate/malate exhibited reduced cardiac functional recovery and increased myocardial infarct size compared to hearts treated with G3P. Thus, ROS production by the stimulated respiratory chain complexes I and III has opposite roles: cardio-deleterious when produced in complex I and cardio-protective when produced in complex III. The mechanism of these ROS involves the inhibition of the mPTP opening, a key event in cell death following ischemia/reperfusion injury.

Introduction: Estrogen effect can be mediated by three receptors: Classical estrogen receptors: alpha (ERa) and beta (ERb), and recently identified G protein-coupled estrogen receptor1 (GPER1). Hypothesis: We investigated the role of ERa, ERb and GPER1 in mediating rapid estrogen-induced cardioprotection in male mice hearts subjected to ischemia/reperfusion using wild type (WT) and gene specific knockout animals. Methods: Isolated hearts from wild type (WT: C57BL/6NCrL), ERa-/-, ERb-/- and GPER1-/- were perfused using Langendorff apparatus with Krebs Henseleit buffer (control) or with the addition of estrogen (40 nM). Hearts were subjected to 18 min global ischemia followed by 60 min reperfusion. Cardiac function was recorded during the entire experiment and myocardial infarct size measured by TTC staining at the end of the reperfusion. Mitochondria calcium retention capacity (CRC) required to induce the mitochondrial permeability transition pore (mPTP) opening was assessed after 10 min reperfusion. Protein levels were measured by Western Blot in whole heart lysates after 5 min treatment just before ischemia, and after 10 min reperfusion. LY294002, U0126 and Chelerythrin-Cl were used as inhibitor of PI-3K/Akt, MAPK/ERK and PKC translocation, respectively. Results: In WT, ERa-/- and ERb-/-, estrogen treatment significantly improved cardiac functional recovery, reduced infarct size and improved mitochondrial CRC. However, estrogen effects were completely absent in GPER1-/-. Estrogen treatment during 5 min before ischemia induced up-regulation of Akt, GSK-3b, and ERK1/2 phosphorylation in WT mouse as compared with control but not in GPER1-/-. However, after 10 min reperfusion estrogen effect was still oserved on GSK-3b, but not on Akt and ERK1/2. Chelerythrin-Cl prevented estrogen-induced cardioprotection effect and U126 abolished estrogen effect on mitochondrial CRC while LY294002 could not prevent estrogen effect on GSK-3b observed in WT. P Conclusion: Rapid activation of GPER1 induces cardioprotection effect against ischemia/reperfusion injury. Estrogen effects through GPER1 are associated with phosphorylation of Akt, GSK-3b and ERK1/2, translocation of PKC, and inhibition of the mPTP opening.

ROS generation has been implicated in cardiac damage during ischemia/reperfusion injury, and also in cardioprotection by preconditioning with a series of short ischemic pulses. In mitochondria, complex I produces ROS in the matrix, while, complex III mainly in the inter-membrane space. We hypothesized that the deleterious or protective action of ROS might depend by their site of production in the electron transfer chain (ETC).We measured in heart isolated mitochondria ROS production (H2O2) with Amplex Red and the calcium-retention-capacity (CRC) with Calcium Green. CRC provides an indication of mitochondria viability as it measures the Ca2+ required to induce the opening of the mitochondrial permeability transition pore (mPTP). Specific substrates for complex I (glutamate/malate), complex II (succinate) that leads to ROS production in complex III, ETC inhibitors (rotenone and antimycin-A, pro-apoptotic agents), and MnSOD (catalyzes the conversion of superoxide into oxygen and H2O2) were used.We found that CRC was much higher in mitochondria energized with succinate than with glutamate/malate. ROS production by glutamate/malate stimulation in mitochondria isolated 10 min after ischemia/reperfusion and mitochondria from non-ischemic heart is increased by ETC inhibitors. On the other hand, ROS production was diminished when in the same conditions were stimulated with succinate. MnSOD significantly increased ROS production when using glutamate/malate, while there was no significant effect with succinate.These data strongly suggest that ROS produced in the matrix by complex I stimulation (glutamate/malate) is cardio-deleterious while when produced by stimulation of complex II (succinate) within the mitochondrial intermembrane space is cardioprotective. Supported by NIH and AHA.