Hemophagocytic Lymphohistiocytosis: A Rare Complication of Acute Hepatitis E Infection.

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive hematological disorder caused by uncontrolled activation of cytotoxic T-cells (CTL), natural killer (NK) cells, and macrophages leading to hyperinflammation and cytokine storm. The clinical course is characterized by high-grade fever, cytopenia, and multiorgan dysfunction. HLH is classified as either primary/familial or secondary, the latter being most often triggered by infections, malignancies, and autoimmune disorders. Viral infections are commonly known to cause HLH with Epstein-Barr virus (EBV), cytomegalovirus (CMV), influenza virus, adenovirus, and parvovirus being most often implicated. Hepatitis E virus (HEV) has infrequently been reported to cause HLH with less than five cases being reported in the literature. We report a case of a young man who presented with hepatitis E-associated HLH.

High-Grade Atrioventricular Block Reveals Rare Transthyretin Cardiac Amyloidosis With Unique Hemodynamics.

Atrioventricular (AV) block is a common cardiac conduction disorder that is frequently encountered in clinical practice; however, the association with rare systemic conditions such as transthyretin amyloidosis (ATTR) is heavily underdiagnosed. ATTR amyloidosis is a systemic disorder characterized by the deposition of abnormal transthyretin protein fibrosis in various organs including the heart and vasculature, resulting in progressive organ dysfunction. We present a rare case of high-grade AV block unveiling ATTR cardiac amyloidosis with unusual hemodynamics, specifically severe supine hypertension with severe orthostatic hypotension. These findings posed a diagnostic challenge, underscoring the importance of a comprehensive diagnostic approach and meticulous review of medical history. Following pacemaker placement and the diagnosis of ATTR cardiac amyloidosis, our patient was started on a Tafamidis regimen.

A Single-Stage Medial Opening Wedge High Tibial Osteotomy for Varus Alignment Correction With Revision Arthroscopic Anterior Cruciate Ligament (ACL) Reconstruction.

Anterior cruciate ligament (ACL) injuries are a common clinical entity among people involved in contact sports activities. With the number of primary ACL reconstructions increasing, there has been a proportional increase in the revision of failed ACL reconstruction surgeries. As our understanding of knee kinematics improves over time, there has been evidence that alignment of the lower limb weight-bearing axis also plays an important part in ACL functioning. Medial opening wedge high tibial osteotomy (MOWHTO) is one such procedure that has been used extensively worldwide to correct the varus lower limb alignment. This procedure is usually reserved for young active patients with varus lower limb weight-bearing alignment. The technical dilemma for the surgeon arises when there is a need to revise a failed ACL reconstruction while at the same time correcting the axis malalignment. The general dictum says that alignment correction is done first followed by ligament reconstruction in a dual-stage procedure. However, single-stage surgery is possible in certain indications. In this case report, we present the case of a 31-year-old male involved in recreational sports who sustained a repeat ACL tear five years post the index surgery. He also had a significant varus alignment of the lower limb weight-bearing axis which was considered to be one of the causes of index surgery failure. In this report, we would like to highlight the problems we encountered in a single-stage procedure and certain surgical facets of a single-stage alignment surgery with arthroscopic revision ACL reconstruction.

Asymptomatic paroxysmal ventricular standstill in an elderly male following revascularization of multivessel coronary disease: A case report and literature review.

Ventricular standstill is a dangerous arrhythmia that requires prompt diagnosis and intervention, especially in patients with structural heart disease. Clinicians should recognize ventricular standstill as a complication of cardiac revascularization and be cognizant of asymptomatic cases necessitating intervention. Early evaluation to facilitate pacemaker implantation portends good outcomes in this patient subgroup.

Axonal self-sorting without target guidance in Drosophila visual map formation.

The idea of guidance toward a target is central to axon pathfinding and brain wiring in general. In this work, we show how several thousand axonal growth cones self-pattern without target-dependent guidance during neural superposition wiring in Drosophila. Ablation of all target lamina neurons or loss of target adhesion prevents the stabilization but not the development of the pattern. Intravital imaging at the spatiotemporal resolution of growth cone dynamics in intact pupae and data-driven dynamics simulations reveal a mechanism by which >30,000 filopodia do not explore potential targets, but instead simultaneously generate and navigate a dynamic filopodial meshwork that steers growth directions. Hence, a guidance mechanism can emerge from the interactions of the axons being guided, suggesting self-organization as a more general feature of brain wiring.

Inhibition of polyamine biosynthesis preserves ß cell function in type 1 diabetes.

In preclinical models, α-difluoromethylornithine (DFMO), an ornithine decarboxylase (ODC) inhibitor, delays the onset of type 1 diabetes (T1D) by reducing ß cell stress. However, the mechanism of DFMO action and its human tolerability remain unclear. In this study, we show that mice with ß cell ODC deletion are protected against toxin-induced diabetes, suggesting a cell-autonomous role of ODC during ß cell stress. In a randomized controlled trial (ClinicalTrials.gov: NCT02384889) involving 41 recent-onset T1D subjects (3:1 drug:placebo) over a 3-month treatment period with a 3-month follow-up, DFMO (125-1,000 mg/m2) is shown to meet its primary outcome of safety and tolerability. DFMO dose-dependently reduces urinary putrescine levels and, at higher doses, preserves C-peptide area under the curve without apparent immunomodulation. Transcriptomics and proteomics of DFMO-treated human islets exposed to cytokine stress reveal alterations in mRNA translation, nascent protein transport, and protein secretion. These findings suggest that DFMO may preserve ß cell function in T1D through islet cell-autonomous effects.

Safety outcomes of sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes and other risk factors for cardiovascular disease: a systematic review and meta-analysis.

Sodium-glucose cotransporter-2 inhibitors (SGLT2-Is) have emerged as standard therapy for heart failure. We aim to assess the safety of SGLT2-Is in patients with a high risk of cardiovascular disease. Areas covered: An electronic database search was conducted for randomized control trials comparing SGLT2-Is to placebo in patients with a high risk of cardiac disease or heart failure. Data were pooled for outcomes using random-effect models. The odds ratio (OR) and 95% confidence interval (CI) were used to compare eight safety outcomes between the two groups. The analysis included ten studies with 71 553 participants, among whom 39 053 received SGLT2-Is; 28 809 were male and 15 655 were female (mean age, 65.2 years). The mean follow-up period was 2.3 years with the range being 0.8-4.2 years. The SGLT2-Is group had a significant reduction in AKI (OR = 0.8;95% CI 0.74-0.90) and serious adverse effects (OR = 0.9; 95% CI 0.83-0.96) as compared to placebo. No difference was found in fracture (OR = 1.1; 95% CI 0.91-1.24), amputation (OR = 1.1; 95% CI 1.00-1.29), hypoglycemia (OR 0.98;95% CI 0.83-1.15), and UTI (OR = 1.1; 95% CI 1.00-1.22). In contrast, DKA (OR = 2.4; 95% CI 1.65-3.60) and volume depletion (OR = 1.2; 95% CI 1.07-1.41) were higher in SGLT2-Is group. Expert opinion/commentary: The benefits of SLGT2-Is outweigh the risk of adverse events. They may reduce the risk of AKI but are associated with an increased risk of DKA and volume depletion. Further studies are warranted to monitor a wider range of safety outcomes of SGLT2-Is.

Biallelic Mutations in P4HTM Cause Syndromic Obesity.

We previously demonstrated that 50% of children with obesity from consanguineous families from Pakistan carry pathogenic variants in known monogenic obesity genes. Here, we have discovered a novel monogenetic recessive form of severe childhood obesity using an in-house computational staged approach. The analysis included whole-exome sequencing data of 366 children with severe obesity, 1,000 individuals of the Pakistan Risk of Myocardial Infarction Study (PROMIS) study, and 200,000 participants of the UK Biobank to prioritize genes harboring rare homozygous variants with putative effect on human obesity. We identified five rare or novel homozygous missense mutations predicted deleterious in five consanguineous families in P4HTM encoding prolyl 4-hydroxylase transmembrane (P4H-TM). We further found two additional homozygous missense mutations in children with severe obesity of Indian and Moroccan origin. Molecular dynamics simulation suggested that these mutations destabilized the active conformation of the substrate binding domain. Most carriers also presented with hypotonia, cognitive impairment, and/or developmental delay. Three of the five probands died of pneumonia during the first 2 years of the follow-up. P4HTM deficiency is a novel form of syndromic obesity, affecting 1.5% of our children with obesity associated with high mortality. P4H-TM is a hypoxia-inducible factor that is necessary for survival and adaptation under oxygen deprivation, but the role of this pathway in energy homeostasis and obesity pathophysiology remains to be elucidated.

Inside the ß Cell: Molecular Stress Response Pathways in Diabetes Pathogenesis.

The pathogeneses of the 2 major forms of diabetes, type 1 and type 2, differ with respect to their major molecular insults (loss of immune tolerance and onset of tissue insulin resistance, respectively). However, evidence suggests that dysfunction and/or death of insulin-producing ß-cells is common to virtually all forms of diabetes. Although the mechanisms underlying ß-cell dysfunction remain incompletely characterized, recent years have witnessed major advances in our understanding of the molecular pathways that contribute to the demise of the ß-cell. Cellular and environmental factors contribute to ß-cell dysfunction/loss through the activation of molecular pathways that exacerbate endoplasmic reticulum stress, the integrated stress response, oxidative stress, and impaired autophagy. Whereas many of these stress responsive pathways are interconnected, their individual contributions to glucose homeostasis and ß-cell health have been elucidated through the development and interrogation of animal models. In these studies, genetic models and pharmacological compounds have enabled the identification of genes and proteins specifically involved in ß-cell dysfunction during diabetes pathogenesis. Here, we review the critical stress response pathways that are activated in ß cells in the context of the animal models.

Outcomes of Heart Failure in COVID-19 Patients: An Appalachian Experience.

Background: The Southeastern rural areas of the USA have a higher prevalence of heart failure (HF). Coronavirus disease 2019 (COVID-19) infection is associated with poor outcomes in patients with HF. Our study aimed to compare the outcomes of hospitalized HF patients with and without COVID-19 infection specifically in rural parts of the USA. Methods: We conducted a retrospective cohort study of HF patients with and without COVID-19 hospitalized in Southeastern rural parts of the USA by using the Appalachian Regional Healthcare System. Analyses were stratified by waves from April 1, 2020 to May 31, 2021, and from June 1, 2021 to October 19, 2021. Results: Of the 14,379 patients hospitalized with HF, 6% had concomitant COVID-19 infection. We found that HF patients with COVID-19 had higher mortality rate compared to those without COVID-19 (21.8% versus 3.8%, respectively, P < 0.01). Additionally, hospital resource utilization was significantly higher in HF patients with COVID-19 compared to HF patients without COVID-19 with intensive care unit (ICU) utilization of 21.6% versus 13.8%, P < 0.01, mechanical ventilation use of 17.3% versus 6.2%, P < 0.01, and vasopressor/inotrope use of 16.8% versus 7.9%, P < 0.01. A lower percentage of those with COVID-19 were discharged home compared to those without a COVID-19 diagnosis (63.4% versus 72.0%, respectively). There was a six-fold greater odds of dying in the first wave and seven-fold greater odds of dying in the second wave. Conclusions: Our study confirms previous findings of poor outcome in HF patients with COVID-19. There is a need for review of healthcare resources in rural hospitals which already face numerous healthcare challenges.

Loperamide-Induced Ventricular Tachycardia Storm.

Loperamide is an over-the-counter antilaxative medication with minor opioid properties. For this reason, it has recently become a drug of concern for the Food and Drug Administration due to its potential for abuse. In addition, further apprehension pertaining to its over-the-counter availability has developed due to the recent increase in reported cases of loperamide overdose or prolonged use leading to arrhythmias. We described a rare case of loperamide-induced ventricular tachycardia storm.

Extracellular vesicles in ß cell biology: Role of lipids in vesicle biogenesis, cargo, and intercellular signaling.

BACKGROUND: Type 1 diabetes (T1D) is a complex autoimmune disorder whose pathogenesis involves an intricate interplay between ß cells of the pancreatic islet, other islet cells, and cells of the immune system. Direct intercellular communication within the islet occurs via cell surface proteins and indirect intercellular communication has traditionally been seen as occurring via secreted proteins (e.g., endocrine hormones and cytokines). However, recent literature suggests that extracellular vesicles (EVs) secreted by ß cells constitute an additional and biologically important mechanism for transmitting signals to within the islet. SCOPE OF REVIEW: This review summarizes the general mechanisms of EV formation, with a particular focus on how lipids and lipid signaling pathways influence their formation and cargo. We review the implications of EV release from ß cells for T1D pathogenesis, how EVs and their cargo might be leveraged as biomarkers of this process, and how EVs might be engineered as a therapeutic candidate to counter T1D outcomes. MAJOR CONCLUSIONS: Islet ß cells have been viewed as initiators and propagators of the cellular circuit giving rise to autoimmunity in T1D. In this context, emerging literature suggests that EVs may represent a conduit for communication that holds more comprehensive messaging about the ß cells from which they arise. As the field of EV biology advances, it opens the possibility that intervening with EV formation and cargo loading could be a novel disease-modifying approach in T1D.

Proinflammatory signaling in islet ß cells propagates invasion of pathogenic immune cells in autoimmune diabetes.

Type 1 diabetes is a disorder of immune tolerance that leads to death of insulin-producing islet ß cells. We hypothesize that inflammatory signaling within ß cells promotes progression of autoimmunity within the islet microenvironment. To test this hypothesis, we deleted the proinflammatory gene encoding 12/15-lipoxygenase (Alox15) in ß cells of non-obese diabetic mice at a pre-diabetic time point when islet inflammation is a feature. Deletion of Alox15 leads to preservation of ß cell mass, reduces populations of infiltrating T cells, and protects against spontaneous autoimmune diabetes in both sexes. Mice lacking Alox15 in ß cells exhibit an increase in a population of ß cells expressing the gene encoding the protein programmed death ligand 1 (PD-L1), which engages receptors on immune cells to suppress autoimmunity. Delivery of a monoclonal antibody against PD-L1 recovers the diabetes phenotype in knockout animals. Our results support the contention that inflammatory signaling in ß cells promotes autoimmunity during type 1 diabetes progression.

Role of Polyamines and Hypusine in ß Cells and Diabetes Pathogenesis.

The polyamines-putrescine, spermidine, and spermine-are polycationic, low molecular weight amines with cellular functions primarily related to mRNA translation and cell proliferation. Polyamines partly exert their effects via the hypusine pathway, wherein the polyamine spermidine provides the aminobutyl moiety to allow posttranslational modification of the translation factor eIF5A with the rare amino acid hypusine (hydroxy putrescine lysine). The "hypusinated" eIF5A (eIF5Ahyp) is considered to be the active form of the translation factor necessary for the translation of mRNAs associated with stress and inflammation. Recently, it has been demonstrated that activity of the polyamines-hypusine circuit in insulin-producing islet ß cells contributes to diabetes pathogenesis under conditions of inflammation. Elevated levels of polyamines are reported in both exocrine and endocrine cells of the pancreas, which may contribute to endoplasmic reticulum stress, oxidative stress, inflammatory response, and autophagy. In this review, we have summarized the existing research on polyamine-hypusine metabolism in the context of ß-cell function and diabetes pathogenesis.

A zebrafish tailfin injury assay protocol for quantifying immune cell migration and infiltration.

Myeloid cells, such as macrophages, are critical components of the inflammatory response, in which infected, injured, or necrotic tissues are targeted for resolution. A key aspect of the inflammatory response is migration of myeloid cells to target tissues. Although studying immune cell migration in mammalian models in vivo is challenging, zebrafish are more tractable owing to their optical transparency and rapidity in generating transgenic lines. Here, we present a tailfin injury assay protocol for quantifying immune infiltration at injury sites. For complete details on the use and execution of this profile, please refer to Anderson-Baucum et al. (2021) and Kulkarni et al. (2021).

Design, Synthesis, and Biological Evaluation of NAP Isosteres: A Switch from Peripheral to Central Nervous System Acting Mu-Opioid Receptor Antagonists.

The µ opioid receptor (MOR) has been an intrinsic target to develop treatment of opioid use disorders (OUD). Herein, we report our efforts on developing centrally acting MOR antagonists by structural modifications of 17-cyclopropylmethyl-3,14-dihydroxy-4,5α-epoxy-6ß-[(4'-pyridyl) carboxamido] morphinan (NAP), a peripherally acting MOR-selective antagonist. An isosteric replacement concept was applied and incorporated with physiochemical property predictions in the molecular design. Three analogs, namely, 25, 26, and 31, were identified as potent MOR antagonists in vivo with significantly fewer withdrawal symptoms than naloxone observed at similar doses. Furthermore, brain and plasma drug distribution studies supported the outcomes of our design strategy on these compounds. Taken together, our isosteric replacement of pyridine with pyrrole, furan, and thiophene provided insights into the structure-activity relationships of NAP and aided the understanding of physicochemical requirements of potential CNS acting opioids. These efforts resulted in potent, centrally efficacious MOR antagonists that may be pursued as leads to treat OUD.

A Novel 2-Hit Zebrafish Model to Study Early Pathogenesis of Non-Alcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases in adults. NAFLD progresses from benign liver fat accumulation to liver inflammation and cirrhosis, and ultimately leads to liver failure. Although several rodent models have been established for studying NAFLD, they have limitations that include cost, speed of disease development, key dissimilarities, and poor amenability to pharmacological screens. Here, we present a novel 2-hit zebrafish model to replicate aspects of NAFLD pathogenesis. We fed zebrafish larvae a high-fat diet (HFD) to drive liver fat accumulation (first hit). Next, we exacerbated liver-specific inflammation using a transgenic line (fabp10-CETI-PIC3) that induces the expression of proinflammatory cytokines following induction with doxycycline (second hit). These hits promoted fat accumulation and liver inflammation, as demonstrated by the high expression of inflammatory cytokines, macrophage infiltration, stress induction, and hepatic lipid droplet accumulation. Furthermore, zebrafish in this paradigm showed deranged glucose metabolism. To validate a small-molecule screening approach, we treated HFD-fed fish with pioglitazone, a drug shown to be beneficial for NAFLD in humans, and measured a sharp reduction in liver lipid accumulation. These results demonstrate new utility for zebrafish in modeling early NAFLD pathogenesis and demonstrate their feasibility for in vivo screening of new pharmacological interventions.

Association of Sodium-Glucose Cotransporter 2 Inhibitors With Cardiovascular Outcomes in Patients With Type 2 Diabetes and Other Risk Factors for Cardiovascular Disease: A Meta-analysis.

Importance: The cardiovascular outcome in selected populations when sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) are emerging as standard therapy is not clearly understood. It is important to learn the magnitude of cardiovascular benefit using SGLT2-Is across the select subgroups that include both sexes and multiple age and racial and ethnic groups. Objectives: To evaluate the association between use of SGLT2-Is and cardiovascular benefits in a prespecified group in a larger sample size using data obtained from randomized clinical trials. Data Sources: Search of electronic databases PubMed, Google Scholar, Web of Science, and Cochrane from inception to January 10, 2021, with additional studies identified through conference papers and meeting presentations, ClinicalTrials.gov, and reference lists of published studies. Study Selection: Placebo-controlled randomized clinical trials in which participants had atherosclerotic cardiovascular disease (ASCVD) or risk factors for ASCVD, diabetes, or heart failure and which reported the primary outcome were included in this study. Multicenter observational and nonobservational studies and those with different outcomes of interest were excluded. Data Extraction and Synthesis: Medical Subject Heading search terms included SGLT2-I and multiple cardiovascular outcomes in different combinations. The study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The analysis of all outcomes was performed using a Mantel-Haenszel equation and the random-effects model. Main Outcomes and Measures: Six efficacy outcomes of SGLT2-I use (cardiovascular death and hospitalization for heart failure [HHF] as the primary outcome and major adverse cardiovascular event, HHF, cardiovascular death, acute myocardial infarction, and all-cause mortality as secondary outcomes), were evaluated. Subgroup analysis was performed for the primary outcome of cardiovascular death or HHF. Odds ratios (ORs) and 95% CIs were used to compare 2 interventions. Results: Ten studies with 71 553 participants were included, among whom 39 053 received SGLT2-Is; among studies that reported these data, 28 809 were men and 15 655 were women (mean age, 65.2 [range, 61.9-70.0] years). Race and ethnicity were defined in the original trials and were categorized as Asian, Black, or other (6900 participants) and White (26 646 participants) for the purposes of this analysis (the category "other" was not specified consistently). In terms of age, 16 793 were younger than 65 years and 17 087 were 65 years or older. At a mean follow-up 2.3 (range, 0.8-4.2) years, the SGLT2-I group favored reduction in primary outcome (3165 of 39 053 [8.10%] vs 3756 of 32 500 [11.56%]; OR, 0.67 [95% CI, 0.55-0.80]; P < .001). No difference was noted in the rate of acute myocardial infarction compared with the placebo group (1256 of 26 931 [4.66%] vs 958 of 20 373 [4.70%]; OR, 0.95 [95% CI, 0.87-1.03]; P = .22). Subgroup analysis favored SGLT2-I use for the primary outcome in both sexes, age groups, and racial and ethnic groups. Conclusions and Relevance: This meta-analysis supports that SGLT2-Is have emerged as an effective class of drugs for improving cardiovascular morbidity and mortality in selected patients. Sodium-glucose cotransporter 2 inhibitors were not associated with reduced risk of acute myocardial infarction. Future long-term prospective studies are warranted to understand the long-term cardiovascular benefits.

An assessment of race and gender-based biases among readmission predicting tools (HOSPITAL, LACE, and RAHF) in heart failure population.

BACKGROUND: The objective of our study is to retrospectively investigate if the HOSPITAL score, LACE index, and RAHF scale exhibit any bias based on gender and race in heart failure readmissions. METHODS: This is a retrospective cohort study with all adult medical patients discharged with congestive heart failure from 2016 to 2018 from Southern Illinois University School of Medicine Hospitalist service. The receiver operating characteristic (ROC) curve was constructed comparing prediction tools (HOSPITAL score, LACE index, and RAHF scale) performance based on gender and race by measuring the area under the curve (AUC). Absolute Between-ROC Area (ABROCA) values were calculated. All statistical analyses were performed using R version 3.6.2. RESULTS: The performance of the HOSPITAL score in the majority and minority population showed a statistically significant difference between AUCs (0.714 and 0.633, p = 0.029) and an ABROCA of 0.081 indicating superior performance in predicting hospital readmissions in the majority group vs. the minority. The performance of RAHF score in females and males showed statistically significant differences between AUCs (0.567 and 0.527, p = 0.04) and an ABROCA of 0.04 indicating the superior performance of the RAHF score in females compared with males. CONCLUSIONS: Our study demonstrated that the HOSPITAL score and the RAHF scale showed significant differences in predicting 30-day readmissions risk based on race and gender, respectively, in heart failure patients, whereas the LACE index did not show any significant difference.

An overview on mechanism, cause, prevention and multi-nation policy level interventions of dietary iron deficiency.

Iron deficiency anemia (IDA) is probably the most ignored situation in the world of malnutrition-largely due to its slow progression. Multiple reasons can be attributed as the cause of IDA, which is not limited to any specific region or population; therefore, making it a matter of global concern. Despite the human body's ability to absorb and conserve iron stores, the gradual loss due to various physiological conditions leads to net deficiency of iron. Countless commercial iron supplements are available, but at given physiological conditions, almost all of these "Bio-not-available" iron forms quite often become ineffective. World Health Organization and other government bodies have jointly developed health advisories and tried to developed nutrition supplements several times in the last two decades. IDA, when combined with other disease conditions, becomes a life-threatening situation. At the same time, an overdose of iron could also be very harmful to the body. Therefore, it is important to deal with this situation with caution. This article covers iron metabolism, available options for iron supplementation, regulatory aspects and strategies to prevent IDA.