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Daniel T Gildea,1 Stephanie M Woo,2 Corinne E O’Connor,3 Amol S Rangnekar4 1Department of Internal Medicine, MedStar Georgetown University Hospital, Washington, DC, USA; 2Department of Gastroenterology, MedStar Georgetown University Hospital, Washington, DC, USA; 3Georgetown University School of Medicine, Washington, DC, USA; 4MedStar Georgetown Transplant Institute, MedStar Georgetown University Hospital, Washington, DC, USACorrespondence: Daniel T Gildea, Tel +1 302-985-7777, Email daniel.gildea@medstar.netAbstract: This review analyzes data regarding liver injury associated with COVID-19 infection. We discuss reported effects on the liver from both COVID-19 and COVID-19 treatment as well as pathophysiology, review the potential role of drug-induced liver injury as an etiology of COVID-19-associated liver injury, and touch on other reports of significant outcomes including COVID-19 cholangiopathy and autoimmune hepatitis. Finally, we review the implications of COVID-19 infection in liver transplant recipients.Keywords: COVID-19, cholangiopathy, DILI, hepatitis, transplant, liver

Indigenous peoples have experienced higher rates of loss and death compared to the general population, partly due to historical loss. This qualitative inquiry focused on understanding Indigenous women's experiences of loss, grief, and death during the COVID-19 pandemic, involving 31 head-of-household Native American women from a southeastern US tribe. Reconstructive analysis of data from a community-based critical ethnography identified the following themes spanning the ecological levels of the FHORT: (a) loss of finances, (b) loss of structure and loss of self, (c) death due to COVID-19, (d) disrupted mourning and burial rituals, and (e) grief and extensive losses. Results indicate that the pandemic not only exacerbated historical loss, but interventions and models for working through grief and loss should not only be culturally tailored and promote healing across all ecological domains and include physical, mental, emotional, and spiritual aspects, but should also address historical trauma, collectivist values, and traditional ways., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Introduction:  Acute pancreatitis is a serious condition that has numerous etiologies and often requires hospital admission due to its high mortality rates. Statins are used worldwide to reduce the risk of cardiovascular disease. Some studies have shown an association between long-term statin use and acute pancreatitis. However, other studies have shown no effect or even postulated a mild protective effect. Due to conflicting information in the medical literature, the relationship between statins and acute pancreatitis remains unclear. The current study uses the TriNetX global research database to further investigate the impact of statin use on the development of acute pancreatitis over a five-year period., Methods:  Two cohorts were created using the TriNetX global research database. One group consisted of patients not taking statins, while the other group included patients taking any statins. Patients in both groups were required to be between the ages of 40 and 75 and had normal low-density lipoprotein cholesterol (LDL) (≤200 mg/dl) and triglyceride (≤150 mg/dl) levels. Patients were matched for age, gender, race, and comorbidities. The statin group was then compared to the no-statin group and measured for the outcome of the incidence of acute pancreatitis and the frequency of episodes within the first five years of statin use. Patients who experienced any acute pancreatitis episode before starting statin therapy or before meeting inclusion criteria were excluded from the study., Results:  Patients on statin therapy were significantly more likely to develop acute pancreatitis compared to patients not taking statin therapy (risk ratio 1.332, 95% CI: 1.242-1.429, P<0.0001). However, the statin group had a lower mean number of pancreatitis episodes than the no-statin group (4.6 vs. 5.3, P=0.043)., Conclusion:  The results from this large global dataset support the previously established idea that prolonged use of statins is associated with an increased risk of pancreatitis. Clinicians should strongly consider statin-induced pancreatitis when other common etiologies have been ruled out., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, O'Connor et al.)

Multitargeted agents provide tumor selectivity with reduced drug resistance and dose-limiting toxicities. We previously described the multitargeted 6-substituted pyrrolo[3,2- d ]pyrimidine antifolate 1 with activity against early- and late-stage pancreatic tumors with limited tumor selectivity. Structure-based design with our human serine hydroxymethyl transferase (SHMT) 2 and glycinamide ribonucleotide formyltransferase (GARFTase) structures, and published X-ray crystal structures of 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (ATIC), SHMT1, and folate receptor (FR) α and β afforded 11 analogues. Multitargeted inhibition and selective tumor transport were designed by providing promiscuous conformational flexibility in the molecules. Metabolite rescue identified mitochondrial C1 metabolism along with de novo purine biosynthesis as the targeted pathways. We identified analogues with tumor-selective transport via FRs and increased SHMT2, SHMT1, and GARFTase inhibition (28-, 21-, and 11-fold, respectively) compared to 1 . These multitargeted agents represent an exciting new structural motif for targeted cancer therapy with substantial advantages of selectivity and potency over clinically used antifolates.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain problematic due to high mortality rates and lack of effective treatments. Neutrophilic injury contributes to mortality in ALI/ARDS. Here, technology for rapid ARDS intervention is developed and evaluated, where intravenous salicylic acid-based polymer microparticles, i.e., Poly-Aspirin (Poly-A), interfere with neutrophils in blood, reducing lung neutrophil infiltration and injury in vivo in mouse models of ALI/ARDS. Importantly, Poly-A particles reduce multiple inflammatory cytokines in the airway and bacterial load in the bloodstream in a live bacteria lung infection model of ARDS, drastically improving survival. It is observed that phagocytosis of the Poly-A microparticles, with salicylic acid in the polymer backbone, alters the neutrophil surface expression of adhesion molecules, potentially contributing to their added therapeutic benefits. Given the proven safety profile of the microparticle degradation products-salicylic acid and adipic acid-it is anticipated that the Poly-A particles represent a therapeutic strategy in ARDS with a rare opportunity for rapid clinical translation., (© 2021 Wiley-VCH GmbH.)

This study aimed to examine the convergence among interpretation bias measures and their associations with depressive symptom severity. Research into interpretation biases employs measures of interpretation bias interchangeably, however, little is known about the relationship between these measures. Participants (N = 82 unselected undergraduate students; 59 female) completed four computer-based interpretation bias tasks in a cross-sectional design study. Indirect measures, based on participants' reaction times, were not correlated with each other and had poor split-half reliability. Direct measures were more strongly correlated with depressive symptoms than indirect measures, but only the Scrambled Sentences Task explained a reliable unique portion of the variance in depressive symptoms. Interpretation bias tasks may not measure the same cognitive process and may differ in the extent to which they are a cognitive marker of depression-linked interpretation bias. These findings help to improve the measurement of and theory underlying interpretation bias and depressive symptoms., (© 2021 Wiley Periodicals LLC.)

Objective: Although yoga shows promise as a treatment for posttraumatic stress disorder (PTSD), there are few randomized controlled trials that demonstrate significant benefits for individuals with PTSD. The present study addresses this need by comparing the effects of a holistic yoga program (HYP) to that of a wellness lifestyle program (WLP) on PTSD symptom severity with a randomized clinical trial., Method: The sample consisted of 209 participants (91.4% veterans; 66% male; 61.7% White) who met diagnostic criteria for PTSD at baseline. Participants were randomly assigned to attend one of the 2 weekly interventions for 16 weeks. The HYP consisted of yoga instruction, while the WLP consisted of didactics, discussions, and walking. PTSD severity was measured using the Clinician Administered PTSD Scale (CAPS-5) and the PTSD Checklist (PCL-5)., Results: Analyses revealed that the HYP reduced PTSD severity measured by the CAPS-5 significantly more than the WLP at treatment end (mean difference = -5.4, effect size = 0.46, p < .001), but not at 7-month follow up (mean difference = -0.9, p = .603). Similarly, the HYP reduced PTSD severity measured by the PCL-5 significantly more than the WLP at treatment end (difference = -6.0, p = .001), but not at 7-month follow up (mean difference = -1.0, p = .682)., Conclusion: Yoga may be an effective intervention for PTSD in addition to standard treatments. Future yoga trials should consider adding a social component to interventions or booster classes to maintain effects long term. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Aims: Recurrent hypoglycemia is understudied. This study evaluates recurrent hypoglycemia, fragmentation of care and mortality in a large urban center., Methods: The Chicago HealthLNK Data Repository (CHDR), a de-identified electronic health record data set from institutions across Chicago, identified 9741 patients with diabetes (DM) who had hypoglycemia (emergency department (ED) or inpatient admission (IA)) from 2006 to 2012. Recurrence was defined as more than one hypoglycemia encounter, and fragmentation of health care was defined as an ED visit or IA for hypoglycemia at >1 site., Results: 187,644 patients were identified with DM; of 9741 patients with hypoglycemia, 2857 (29.3%) had recurrence. Patients with ≥4 hypoglycemic encounters (n = 1035) represented 10.6%, but accounted for 40.3% hypoglycemic encounters. Of 2857 patients with recurrence, 304 patients (10.6%) had fragmented care. In those with high hypoglycemic encounters (≥4), 22% (N = 226) had ≥10 encounters; race and insurance status differences were associated with number of hypoglycemic encounters. Having hypoglycemia was associated with increased mortality compared to no hypoglycemia (n = 2696, 27.7% vs n = 20,188, 11.4%; p < 0.00001 by chi-square)., Conclusion: A small subset of patients with hypoglycemia accounted for a large subset of hypoglycemia encounters. Targeted interventions in this high-risk, high mortality group are needed., Competing Interests: Declaration of competing interest, (Copyright © 2020 Elsevier Inc. All rights reserved.)

Spatial patterns of gene expression in living organisms orchestrate cell decisions in development, homeostasis, and disease. However, most methods for reconstructing gene patterning in 3D cell culture and artificial tissues are restricted by patterning depth and scale. We introduce a depth- and scale-flexible method to direct volumetric gene expression patterning in 3D artificial tissues, which we call "heat exchangers for actuation of transcription" (HEAT). This approach leverages fluid-based heat transfer from printed networks in the tissues to activate heat-inducible transgenes expressed by embedded cells. We show that gene expression patterning can be tuned both spatially and dynamically by varying channel network architecture, fluid temperature, fluid flow direction, and stimulation timing in a user-defined manner and maintained in vivo. We apply this approach to activate the 3D positional expression of Wnt ligands and Wnt/β-catenin pathway regulators, which are major regulators of development, homeostasis, regeneration, and cancer throughout the animal kingdom., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Multidrug-resistant (MDR) clinical isolate-769, human immunodeficiency virus type-1 (HIV-1) protease (PDB ID: 1TW7), was shown to exhibit wide-open flaps and an expanded active site cavity, causing loss of contacts with protease inhibitors. In the current study, the expanded active site cavity of MDR769 HIV-1 protease was screened with a series of peptide-inhibitors that were designed to mimic the natural substrate cleavage site, capsid/p2. Scanning Ala/Phe chemical mutagenesis approach was incorporated into the design of the peptide series to mimic the substrate co-evolution. Among the peptides synthesized and evaluated, a lead peptide (6a) with potent activity (IC50: 4.4nM) was identified against the MDR769 HIV-1 protease. Isothermal titration calorimetry data showed favorable binding profile for 6a against both wild type and MDR769 HIV-1 protease variants. Nuclear magnetic resonance spectrum of (15)N-labeled MDR769 HIV-1 protease in complex with 6a showed some major perturbations in chemical shift, supporting the peptide induced conformational changes in protease. Modeling analysis revealed multiple contacts between 6a and MDR769 HIV-1 protease. The lead peptide-inhibitor, 6a, with high potency and good binding profile can be used as the basis for developing potent small molecule inhibitors against MDR variants of HIV., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Development of p-aminopropiophenone (PAPP) as a toxicant for pest predator management in New Zealand and Australia prompted investigation of its toxicity to potential nontarget species. Acute oral toxicity of PAPP in brushtail possums (Trichosurus vulpecula), dama wallabies (Macropus eugenii), and Mallards (Anas platyrhynchos) was estimated in pen trials, carried out between February 2000 and September 2001. The susceptibility of possums (LD50>or=500 mg kg(-1)) and wallabies (LD50 89 mg kg(-1)) to PAPP was low in comparison to noncarnivorous placental mammal species, but ducks (LD50 38 mg kg(-1)) were more susceptible than other bird species. These results suggest that the nontarget hazard to possums and wallabies from PAPP bait applied for pest predator control would be low. However, future development of PAPP as a vertebrate pest control agent should include rigorous assessments of the hazard posed by bait formulations to bird species and provision for delivery techniques that could mitigate exposure of nontarget birds.

There is increasing evidence that longevity and stress resistance are connected, but the mechanism is unclear. We report that mitochondria are regulated in response to oxidative stress and calorie restriction through a shared mechanism involving peroxisome proliferator-activated receptor-gamma co-activator 1alpha (PGC-1alpha). We demonstrate that PGC-1alpha subcellular distribution is regulated, and its transcriptional activity is promoted through SIRT1-dependent nuclear accumulation. In addition, the duration of PGC-1alpha activity is regulated by glycogen synthase kinase beta (GSK3beta), which targets PGC-1alpha for intranuclear proteasomal degradation. This mechanism of regulation permits the rapidity and persistence of PGC-1alpha activation to be independently controlled. We provide evidence that this pathway of PGC-1alpha regulation occurs in vivo in mice, both in the oxidative stress response and with calorie restriction. Our data show how mitochondrial function may be adapted in response to external stimuli, and support the concept that such adaptation is critically involved in cellular survival and in lifespan extension by calorie restriction.

A biological control strategy relying on a self-disseminating agent may provide the only affordable long-term technique for reducing brushtail possum (Trichosurus vulpecula) numbers throughout New Zealand. The objective of this study was to determine the frequency and patterns of social interactions in single and mixed-sex groups of possums, in order to identify interactions that may assist in the dissemination of biocontrol agents. Thirty-two sexually mature wild-caught possums (16 female, 16 male) were housed in captive groups (of four) in enclosures during the breeding and non-breeding seasons. Groups consisted of either all females, females and males or all males. Four types of social interactions were defined: threats, fights, affiliative and sexual interactions. Interactions only occurred between two animals at one time and were most frequent in the non-breeding season. Within all female groups, possums readily engaged in interactions that had either an agonistic or affiliative nature. Mixed-sex groups interacted less frequently than females, but also engaged in both agonistic and affiliative interactions. In contrast, possums in all male groups rarely interacted, with only a few fights and no affiliative interactions observed. Some mixed-sex dyads appeared to 'associate' during the breeding period. Young were produced by three females that regularly associated with a male and one female that showed little associative behaviour. Given the different interaction patterns observed in each group type, biological control agents that rely on specific interaction patterns for dissemination, are likely to spread at different rates among different possum groups and in different seasons.

Aims: To describe the nature and incidence of metastatic mineralisation in brushtail possums (Trichosurus vulpecula) caught on Kawau Island., Methods: Wild-caught possums were individually housed in captivity over a 24-month period and fed a cereal-based mash diet. Possums that became debilitated were examined post mortem for evidence of metastatic mineralisation of the heart, major blood vessels and kidneys. Serum and aortic segments were collected from affected animals and were analysed for mineral composition. Non-debilitated animals and possums that were experimentally poisoned with cholecalciferol were examined as a comparison., Results: Fifteen of 42 possums (36%) captured on Kawau Island and housed in captivity were debilitated as a result of metastatic mineralisation of the walls of the aorta and/or of the kidney tubules, with four further possums having evidence of mineralisation when humanely killed. Phosphate and ammonium deposits were found in the aorta, and calcium deposits in the kidney tubules. Serum phosphorus and calcium levels were elevated in the debilitated animals. Similar lesions were found in only one of 288 possums captured from other North Island areas and housed in captivity over the same time period., Conclusion: Possums from Kawau Island appear to be more predisposed to metastatic mineralisation than possums from other areas of the North Island. The lesions observed in these possums were similar to those caused by cholecalciferol poisoning.

Leptospira interrogans serovar balcanica is a potential vector being investigated for spreading a biological control agent among introduced brushtail possums (Trichosurus vulpecula) in New Zealand. As previous studies have shown that possums are unlikely to contract leptospirosis through a contaminated environment alone, the objective was to determine whether L. interrogans serovar balcanica could be transmitted between sexually mature, socially housed possums. Possums were infected experimentally with L. interrogans serovar balcanica and housed in pairs or groups with uninfected possums for either 70 or 140 days, during the breeding or non-breeding seasons. No transmission occurred between any infected and uninfected possums during the non-breeding season. However, transmission occurred between females that had been socially housed in pairs or groups in the breeding season. Mixed sex transmission also occurred in pairs and groups, both from males to females and from females to males. Mixed sex transmission usually occurred rapidly (< 44 days) and was not associated with the production of offspring. No transmission occurred between males during the breeding or the non-breeding seasons. Transmission probably occurs as a result of affiliative or sexual behaviour, but is unlikely to occur through fighting. The social transmission pathways determined in this study suggest that L. interrogans serovar balcanica may have the transmission attributes desired in a vector for biological control.

Learned aversions developed following sublethal ingestion of poisons are reported to be long-lived in many pest species. This study aimed to identify the duration of bait aversions following poisoning with a common poison (cyanide) used for possum control in New Zealand. Groups of possums with bait aversions (following cyanide poisoning) were reexposed to the bait (flavoured food) in a 2-choice test, at intervals of 1, 3, 6, 12, or 24 months. The relative intakes of the bait (used as the measure of bait aversion) did not differ between treatments (0.21, 0.21, 0.27, 0.32, and 0.20) for the 5 groups, respectively. The effect of repeated reexposures to the bait was also tested. The proportion of flavoured food eaten was 0.11, 0.19, 0.23, 0.33, and 0.36 for 1 to 5 reexposures, respectively. There was a significant increase in intake with repeated exposure. Thus, cyanide-induced aversions were strong and lasted for at least 24 months. The aversions weakened over several reexposures to the bait, but only for those individuals that had weaker initial aversions.

In New Zealand, the biological control of introduced brushtail possums (Trichosurus vulpecula) may be the only affordable option for achieving a significant long term reduction in pest numbers on a national scale. Leptospira interrogans serovar balcanica is among the potential biocontrol agents and vectors currently being investigated for this purpose. As the transmission pathways of L. interrogans serovar balcanica between possums are poorly understood, the objective of the study was to determine whether infection could result from exposure to contaminated environments. Sixteen individually housed, uninfected possums, in three groups, were regularly exposed over a period of 32 days to contaminated cages or grass enclosures of 16 other experimentally infected possums all shedding leptospires in their urine. None of the 16 challenged possums developed serological evidence of L. interrogans serovar balcancia infection. These results suggest that this organism is unlikely to be transmitted environmentally, supporting previous circumstantial evidence that social contact may be required for transmission of L. interrogans serovar balcanica between possums.

Data on changes in the condition and feeding behaviour of captive brushtail possums (Trichosurus vulpecula) following an experimental infection with Leptospira interrogans serovar balcanica are presented. The daily food intake of nine experimentally infected possums was recorded for 47 days before and 24 days after balcanica inoculation (0.5 ml intraperitoneally containing about 10(8) organisms). Body weight was recorded seven times between 42 days before and 96 days after inoculation. The mean daily food intake of infected possums decreased significantly throughout the 24-day recording period after infection with balcanica. The mean body weight of infected possums had decreased significantly by day 26 after inoculation but had fully recovered by day 96 after inoculation. Uninfected and control possums showed no significant changes in mean daily food intake or mean body weight over the experimental period. These data suggest that the health of possums is temporarily affected by infection with balcanica, but that overt disease caused by balcanica is unlikely. These findings support previous research suggesting that balcanica has only subclinical effects on possums.

Background: Endocavitary radiation therapy is an alternative to surgical therapy for some early rectal carcinomas. Careful patient selection is necessary to ensure good results. The purpose of this study was to examine the authors' experience with endocavitary radiation at their institution from 1984 to 1991 to determine which factors were associated with treatment failure to provide for better future patient selection., Methods: Thirty-two patients with carcinoma of the rectum, not apparently involving the muscle wall, underwent 75-120 Gy of endocavitary radiation as potentially curative therapy. Treatment was given as a series of 2-4 doses of 30 Gy at three weekly intervals. Twenty-two patients had polypoid tumors, 5 sessile, and 5 ulcerated., Results: After a mean follow-up of 43 months (range, 6-103 months), 4 of 5 patients (80%) with ulcerated tumors developed local recurrences, compared with only 4 of 27 (15%) with sessile or polypoid lesions. Not only was the incidence of local recurrence greater for patients with ulcerated tumors (P = 0.009), but the time to recurrence was shorter also (P = 0.0001). Tumor size, anterior or posterior location, and dose of radiation received did not affect the rate of recurrence., Conclusions: These results indicate that superficial polypoid and sessile rectal tumors can be managed successfully with endocavitary radiation. Ulcerating tumors are likely to recur locally within a short time and therefore should be considered for surgical treatment initially.

Possums (Trichosurus vulpecula) are New Zealand's main vertebrate pest. Control practices using poisons are likely to remain the most cost effective methods for the immediate future but poisons may be avoided in the field. A series of experiments were conducted to determine whether cyanide bait avoidance involved conditioned food aversions (CFA) induced by sublethal cyanide ingestion. Food aversions were conditioned in three experiments using intraperitoneal or oral routes of administration with three different cyanide formulations over a range of doses. Across all experiments there was a direct relationship between dose and the proportion of animals developing CFAs. When administered orally, doses greater than 5 mg/kg resulted in more than 50% of surviving animals developing aversions. Route of administration or formulation appeared to have no differential effect on development of CFA. Although there was considerable variation between individuals in the degree of aversion shown this may be one mechanism that could account for poor possum kill rates in some poisoning operations.