Rapid intra-host diversification and evolution of SARS-CoV-2 in advanced HIV infection.

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions, but the processes responsible for these observations are incompletely understood. Here we use high-throughput, single-genome amplification and sequencing (HT-SGS) to sequence SARS-CoV-2 spike genes from people with HIV (PWH, n = 22) and people without HIV (PWOH, n = 25). In PWOH and PWH with CD4 T cell counts (i.e., CD4 counts) ≥ 200 cells/µL, we find that most SARS-CoV-2 genomes sampled in each person share one spike sequence. By contrast, in people with advanced HIV infection (i.e., CD4 counts < 200 cells/µL), HT-SGS reveals a median of 46 distinct linked groupings of spike mutations per person. Elevated intra-host spike diversity in people with advanced HIV infection is detected immediately after COVID-19 symptom onset, and early intra-host spike diversity predicts SARS-CoV-2 shedding duration among PWH. Analysis of longitudinal timepoints reveals rapid fluctuations in spike sequence populations, replacement of founder sequences by groups of new haplotypes, and positive selection at functionally important residues. These findings demonstrate remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern.

Administration of anti-HIV-1 broadly neutralizing monoclonal antibodies with increased affinity to Fcγ receptors during acute SHIVAD8-EO infection.

Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. Here, we investigate the effects of administering in acute SHIVAD8-EO infection either wild-type (WT) bNAbs or bNAbs carrying the S239D/I332E/A330L (DEL) mutation, which increases binding to FcγRs. Emergence of virus in plasma and lymph nodes (LNs) was delayed by bNAb treatment and occurred earlier in monkeys given DEL bNAbs than in those given WT bNAbs, consistent with faster clearance of DEL bNAbs from plasma. DEL bNAb-treated monkeys had higher levels of circulating virus-specific IFNγ single-producing CD8+ CD69+ T cells than the other groups. In LNs, WT bNAbs were evenly distributed between follicular and extrafollicular areas, but DEL bNAbs predominated in the latter. At week 8 post-challenge, LN monocytes and NK cells from DEL bNAb-treated monkeys upregulated proinflammatory signaling pathways and LN T cells downregulated TNF signaling via NF-κB. Overall, bNAbs with increased affinity to FcγRs shape innate and adaptive cellular immunity, which may be important to consider in future strategies of passive bNAb therapy.

An Anaphylactic Encounter With Ferric Gluconate Infusion: A Case Report.

Iron deficiency anemia (IDA) is a prevalent condition globally, often necessitating intravenous iron therapy. We present a case of a 71-year-old female with IDA who experienced a severe anaphylactic reaction shortly after commencing a sodium ferric gluconate complex infusion. Prompt cessation of the infusion and administration of epinephrine with steroids led to rapid recovery. This case underscores the importance of recognizing and managing rare yet potentially life-threatening hypersensitivity reactions to intravenous iron formulations, highlighting the need for vigilance among healthcare providers.

FIND-seq: high-throughput nucleic acid cytometry for rare single-cell transcriptomics.

Rare cells have an important role in development and disease, and methods for isolating and studying cell subsets are therefore an essential part of biology research. Such methods traditionally rely on labeled antibodies targeted to cell surface proteins, but large public databases and sophisticated computational approaches increasingly define cell subsets on the basis of genomic, epigenomic and transcriptomic sequencing data. Methods for isolating cells on the basis of nucleic acid sequences powerfully complement these approaches by providing experimental access to cell subsets discovered in cell atlases, as well as those that cannot be otherwise isolated, including cells infected with pathogens, with specific DNA mutations or with unique transcriptional or splicing signatures. We recently developed a nucleic acid cytometry platform called 'focused interrogation of cells by nucleic acid detection and sequencing' (FIND-seq), capable of isolating rare cells on the basis of RNA or DNA markers, followed by bulk or single-cell transcriptomic analysis. This platform has previously been used to characterize the splicing-dependent activation of the transcription factor XBP1 in astrocytes and HIV persistence in memory CD4 T cells from people on long-term antiretroviral therapy. Here, we outline the molecular and microfluidic steps involved in performing FIND-seq, including protocol updates that allow detection and whole transcriptome sequencing of rare HIV-infected cells that harbor genetically intact virus genomes. FIND-seq requires knowledge of microfluidics, optics and molecular biology. We expect that FIND-seq, and this comprehensive protocol, will enable mechanistic studies of rare HIV+ cells, as well as other cell subsets that were previously difficult to recover and sequence.

Cardiac Arrest Following GoLytely Consumption: A Potential Trigger for Hypovolemic Shock.

This case report presents a rare but severe complication of polyethylene glycol (PEG) used for colonoscopic bowel preparation. A 71-year-old male developed cardiac arrest secondary to hypovolemic shock following consumption of GoLytely. Despite being hemodynamically stable prior to ingestion, the patient experienced extreme weakness, dizziness, and orthostatic hypotension post-consumption. Evaluation ruled out other causes of arrest. While serious complications from PEG are rare, this case underscores the importance of vigilance. Further investigation is warranted to elucidate the relationship between PEG use and cardiac events and to identify potential risk factors for adverse outcomes associated with bowel preparation regimens.

A Case of an Unusual Bleeder: Small Bowel Lymphoma.

This case report highlights an uncommon presentation of small bowel lymphoma as gastrointestinal bleeding in an 87-year-old female with a history of ulcerative colitis. Despite non-specific symptoms and negative findings on upper endoscopy and colonoscopy, ileoscopy revealed a distal ileal mass with a solitary non-bleeding ulcer, confirmed by biopsy as diffuse large B-cell lymphoma (DLBCL). The patient opted for palliative management. Small intestinal lymphomas, particularly DLBCL, pose diagnostic challenges due to their varied presentations. Timely detection is crucial for optimal outcomes, emphasizing the importance of prompt utilization of diagnostic methods in suspected cases.

Microscopic Colitis Secondary to Leflunomide: A Case Report.

Microscopic colitis (MC) is characterized by chronic watery diarrhea that requires histological examination for diagnosis. Here, we present a case of a 63-year-old female with rheumatoid arthritis who developed persistent diarrhea following leflunomide initiation. Despite a normal colonoscopy, random colonic biopsies confirmed MC. Discontinuation of leflunomide led to symptom resolution, implicating it as the causative agent. Leflunomide-induced MC is exceedingly rare, with limited documented cases. Understanding its variability in presentation and timely recognition is crucial. This case underscores the importance of thorough medication history assessment and consideration of drug-induced colitis in patients presenting with unexplained diarrhea, facilitating prompt management and resolution.

Bigger Than a Hen's Egg: A Case of Bouveret Syndrome.

Bouveret syndrome, a rare complication of cholelithiasis resulting in gallstone ileus, presents diagnostic and therapeutic challenges due to its low incidence and nonspecific symptoms. We report a case of Bouveret syndrome in a middle-aged male without significant medical history, emphasizing the need for heightened clinical suspicion. Diagnostic imaging, including computed tomography and upper endoscopy, revealed gastric outlet obstruction and a cholecystoduodenal fistula. Treatment involved unsuccessful endoscopic lithotripsy followed by surgical intervention. This case underscores the importance of interdisciplinary collaboration for successful management. With no standardized approach, individualized treatment strategies, including endoscopic and surgical interventions, are crucial for favorable outcomes in Bouveret syndrome.

Duodenal Carcinosarcoma: An Apple-Core Lesion Causing Gastric Outlet Obstruction.

We present a case of a 58-year-old male with a rare duodenal carcinosarcoma causing gastric outlet obstruction. Despite its aggressive nature and poor prognosis, with only 12 documented cases in the literature, this report sheds light on the clinical presentation and challenges in diagnosis and treatment. Carcinosarcoma, characterized by both carcinomatous and sarcomatous elements, poses difficulties in management due to its diverse tissue characteristics. Surgical resection remains the primary treatment, although the prognosis remains grim, emphasizing the need for further research into advanced therapeutic strategies to improve patient outcomes. This case underscores the rarity and clinical complexities associated with duodenal carcinosarcomas.

The Hepatic Imposter: Solitary Necrotic Nodules Masquerading as Hepatic Metastasis.

Solitary necrotic nodules in the liver present a diagnostic challenge due to their rarity and resemblance to metastatic tumors. We report a case where imaging revealed multiple hepatic lesions suggestive of malignancy, prompting a needle biopsy. Histopathology confirmed necrosis without malignancy. Despite advancements in imaging modalities, distinguishing solitary necrotic nodules from metastases remains difficult. Recognition of characteristic imaging features and consideration of biopsy are crucial for accurate diagnosis and management. This case underscores the importance of thorough evaluation and differential diagnosis in liver lesions to prevent unnecessary surgical interventions and ensure appropriate clinical care.

Non-cirrhotic Ascites: A Case of Severe Alcoholic Hepatitis.

This case report presents a unique instance of ascites in acute alcoholic hepatitis (AH) occurring in a non-cirrhotic patient. Comprehensive diagnostic evaluation excluded alternative etiologies, pinpointing sinusoidal non-cirrhotic portal hypertension. Present therapeutic modalities for AH, including steroids and pentoxifylline, offer limited efficacy, necessitating ongoing investigation. Liver transplantation may be contemplated in refractory cases. This case underscores the intricate nature of AH presentations and the challenges in their management, emphasizing the imperative need for continued research to delineate optimal therapeutic strategies. Early intervention remains pivotal in addressing AH complications, underscoring the need for heightened clinical vigilance and proactive treatment approaches in such cases.

Unraveling the Narrow Alley: A Case Report of Groove Pancreatitis.

Groove pancreatitis, a rare subtype of chronic pancreatitis, predominantly affects middle-aged men with a history of alcohol abuse. We present a unique case of a 31-year-old female with minimal alcohol consumption. Imaging revealed characteristic findings consistent with groove pancreatitis. Despite its rarity in young females, clinical suspicion led to the appropriate diagnosis and conservative management, resulting in symptomatic resolution. This case underscores the importance of recognizing atypical presentations of groove pancreatitis, emphasizing the necessity of tailored diagnostic approaches, and highlighting the efficacy of conservative management in achieving favorable outcomes, particularly in non-typical demographics.

Association Between Chronic Liver Disease and Adverse In-Hospital Outcomes in Patients Undergoing CABG: A Propensity Score-Matched Analysis.

Despite a 30% decrease in the rate over the last decade, coronary artery bypass graft (CABG) surgery remains a common major surgical procedure with significant morbidity and mortality. Chronic liver disease (CLD) patients, with increased survival rates because of medical advancements, are now frequently being considered for CABG, bearing higher perioperative risks. This study investigates the association between CLD and in-hospital outcomes in CABG patients using retrospective data from the National Inpatient Sample database (2016 to 2020) including 7,945 CLD patients who underwent CABG that were propensity score-matched with an equivalent number of patients without CLD who underwent CABG. Clinical variables were extracted using corresponding International Classification of Diseases, Tenth Revision codes, and multivariable logistic and linear regression models were used to assess in-hospital mortality, complications, and length of stay. The overall mortality rate was 5.5% (8.6% in the CLD group with cirrhosis, 5.9% CLD group without cirrhosis, and 2.8% in the non-CLD group, p <0.001). CLD with cirrhosis was associated with higher odds of mortality (adjusted odds ratio = 4.21, 95% confidence interval 3.61 to 4.94) and length of stay (ß = 1.03, 95% confidence interval 1.01 to 1.05). CLD patients with cirrhosis demonstrated higher odds of perioperative cardiac complications (cardiac arrest, ventricular arrhythmias, tamponade, and shock), thromboembolic events, gastrointestinal bleeding, bowel ischemia, acute kidney injury, pneumonia, and sepsis. This study reveals a substantial impact of CLD on adverse outcomes in CABG patients, emphasizing the need for tailored preoperative assessments and postoperative care.

Chest Pain Redefined: Atypical Presentation of Superior Mesenteric Artery Syndrome.

Superior mesenteric artery (SMA) syndrome is a rare cause of small bowel obstruction characterized by duodenal compression due to the narrowing of the SMA-aorta angle. We present a case of a 43-year-old male with postprandial chest pain, severe weight loss, and a narrowed aortomesenteric angle evident on computed tomography. Conservative management, including hydration, positioning, and weight gain, was initiated, leading to symptom resolution. SMA syndrome diagnosis requires clinical suspicion and radiological confirmation. Understanding this syndrome's varied presentations, diagnostic challenges, and therapeutic approaches is crucial for prompt management, especially when atypical symptoms like chest pain manifest, as seen in our case.

The Impact of an Intern's Clinical Guidebook on Easing the Transition of New Interns Into the United States Healthcare System.

This study explores the efficacy of an intern's clinical guidebook in facilitating the transition of categorical internal medicine interns into the United States healthcare system. New interns, particularly foreign medical graduates, face multifaceted challenges during their initial year of residency. The research, conducted at Ascension Saint Joseph Hospital in Chicago, employed a quasi-experimental pre-post design involving 20 interns. Participants were provided with an intern's clinical guidebook, and their knowledge was assessed through pre and post exams. Results demonstrated a statistically significant improvement in overall knowledge, with mean scores increasing from 65% to 77.37%. Subgroup analysis revealed similar improvements among both male and female interns. Data confidentiality and ethical considerations were prioritized, with participant data anonymized and stored securely. Despite limitations, this study highlights the guidebook's potential to enhance intern education and improve the quality of care provided during the crucial transition period. Further research is recommended to validate and extend these findings.

Rapid Emergence and Evolution of SARS-CoV-2 Variants in Advanced HIV Infection.

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions1-4, but the evolutionary processes underlying these observations are incompletely understood. Here we used high-throughput, single-genome amplification and sequencing (HT-SGS) to obtain up to ~103 SARS-CoV-2 spike gene sequences in each of 184 respiratory samples from 22 people with HIV (PWH) and 25 people without HIV (PWOH). Twelve of 22 PWH had advanced HIV infection, defined by peripheral blood CD4 T cell counts (i.e., CD4 counts) <200 cells/µL. In PWOH and PWH with CD4 counts ≥200 cells/µL, most single-genome spike sequences in each person matched one haplotype that predominated throughout the infection. By contrast, people with advanced HIV showed elevated intra-host spike diversity with a median of 46 haplotypes per person (IQR 14-114). Higher intra-host spike diversity immediately after COVID-19 symptom onset predicted longer SARS-CoV-2 RNA shedding among PWH, and intra-host spike diversity at this timepoint was significantly higher in people with advanced HIV than in PWOH. Composition of spike sequence populations in people with advanced HIV fluctuated rapidly over time, with founder sequences often replaced by groups of new haplotypes. These population-level changes were associated with a high total burden of intra-host mutations and positive selection at functionally important residues. In several cases, delayed emergence of detectable serum binding to spike was associated with positive selection for presumptive antibody-escape mutations. Taken together, our findings show remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern (VOCs).

Safety and Efficacy of Highly Selective 5-Hydroxytryptamine Receptor 4 Agonists for Diabetic and Idiopathic Gastroparesis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Gastroparesis significantly affects quality of life and healthcare expenditure. Effective treatment options are limited, and the utility of current prokinetic agents is inhibited by serious adverse effects. There exists an unmet need for prokinetic agents demonstrating both efficacy and an acceptable adverse effect profile. Highly selective 5-Hydroxytryptamine receptor 4 (5-HT4) agonists have exhibited clinical efficacy and safety in randomized controlled trials (RCTs). Consequently, we conducted a meta-analysis to comprehensively assess the safety and efficacy of these highly selective agents. Multiple databases, including PubMed, Scopus, and Embase, were systematically screened from inception until September 2023. Only RCTs evaluating the efficacy and safety of highly selective 5-HT4 agonists for gastroparesis were included. Key outcomes of interest included the pooled rates of Gastroparesis Cardinal Symptom Index (GCSI) scores, gastric emptying time (GET), and adverse event rates in each group. We adhered to standard meta-analysis methodology utilizing the random-effects model, with heterogeneity assessed by I2 statistics. Our analysis identified six RCTs, comprising 570 patients with diabetic (48%) or idiopathic (51%) gastroparesis, with mean ages of 46 and 45.9 years in the intervention and placebo groups, respectively. In the meta-analysis, highly selective 5-HT4 agonists demonstrated significantly superior pooled GCSI scores compared to placebo (mean difference: 4.283, (1.380, 7.186), p<0.05). Pooled GET was also significantly improved with 5-HT4 agonists compared to placebo (mean difference: 2.534, (1.695, 3.373), p<0.05). Although pooled rates of total adverse events were higher with 5-HT4 agonists (mean difference: 6.975, (1.042, 46.684), p<0.05), rates of specific adverse events such as diarrhea, abdominal pain, and headaches were comparable. In conclusion, this meta-analysis underscores a statistically significant improvement in GET and GCSI scores among patients receiving highly selective 5-HT4 agonists (Velusetrag, Felcisetrag, Prucalopride) for both diabetic and idiopathic gastroparesis. While the overall adverse effect profile is deemed acceptable, larger studies with extended follow-up periods are needed to investigate rare and/or serious adverse events. Moreover, future high-quality RCTs comparing the efficacy and safety of these novel agents with currently available agents are essential to further validate these findings.

A Rare Association of Epstein-Barr Virus and Budd-Chiari Syndrome.

Budd-Chiari syndrome (BCS) is a rare hepatic venous outflow obstruction typically associated with hypercoagulable states. We present a unique case of a 29-year-old male with BCS triggered by a recent Epstein-Barr virus (EBV) infection. Workup unveiled antiphospholipid antibody syndrome as an underlying prothrombotic condition. Diagnostic challenges included inconclusive ultrasound findings, necessitating magnetic resonance imaging for confirmation. This case underscores the importance of considering infectious triggers for venous thromboembolism in BCS. Understanding the potential link between EBV and thrombosis warrants further investigation.

Reviewing the influence of positive leadership on worker well-being: A comprehensive analysis.

The study provides a review of existing empirical studies on the impact of positive leadership on worker well-being. The aim it to integrate current knowledge and provide directions for future research. The study analyses the content of 118 articles retrieved mainly from Google Scholar and Scopus database published between 2004 and 2022. Findings revealed that most of the studies are atheoretical with the dominant theory applied being conservation of resource theory. Furthermore, most of the studies were cross-sectionally designed, used convenient sampling and self-reported questionnaire. A conceptual framework is presented which synthesizes findings from prior works and shows the various dimensions of positive leadership practices and worker well-being. Additionally, a comprehensive future research agenda for theoretical and empirical advancement is suggested. The study offers a comprehensive framework that synthesizes and integrates the existing literature on positive leadership and worker well-being. The findings offer researchers in leadership a common platform for discourse.