Kupffer cell diversity maintains liver function in alcohol-associated liver disease.

BACKGROUND AND AIMS: Liver macrophages are heterogeneous and play an important role in alcohol-associated liver disease (ALD) but there is limited understanding of the functions of specific macrophage subsets in the disease. We used a Western diet alcohol (WDA) mouse model of ALD to examine the hepatic myeloid cell compartment by single cell RNAseq and targeted KC ablation to understand the diversity and function of liver macrophages in ALD. APPROACH AND RESULTS: In the WDA liver, KCs and infiltrating monocytes/macrophages each represented about 50% of the myeloid pool. Five major KC clusters all expressed genes associated with receptor-mediated endocytosis and lipid metabolism, but most were predicted to be noninflammatory and antifibrotic with 1 minor KC cluster having a proinflammatory and extracellular matrix degradation gene signature. Infiltrating monocyte/macrophage clusters, in contrast, were predicted to be proinflammatory and profibrotic. In vivo, diphtheria toxin-based selective KC ablation during alcohol exposure resulted in a liver failure phenotype with increases in PT/INR and bilirubin, loss of differentiated hepatocyte gene expression, and an increase in expression of hepatocyte progenitor markers such as EpCAM, CK7, and Igf2bp3. Gene set enrichment analysis of whole-liver RNAseq from the KC-ablated WDA mice showed a similar pattern as seen in human alcoholic hepatitis. CONCLUSIONS: In this ALD model, KCs are anti-inflammatory and are critical for the maintenance of hepatocyte differentiation. Infiltrating monocytes/macrophages are largely proinflammatory and contribute more to liver fibrosis. Future targeting of specific macrophage subsets may provide new approaches to the treatment of liver failure and fibrosis in ALD.

Outcomes following Lower Extremity Amputation in Patients with Diabetes Mellitus and Peripheral Arterial Disease.

BACKGROUND: Lower extremity amputations (LEAs) are projected to increase drastically in the United States. The potential effects of diabetes mellitus (DM) and peripheral arterial disease (PAD) on LEA outcomes have not been well-explored. We sought to investigate the clinical outcomes of LEA in patients with DM alone, PAD alone, and patients with concurrent DM and PAD (DM + PAD) from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample. METHODS: Adult patients (≥18 years) undergoing LEA in 2007-2011 based on ICD-9 procedure codes were selected. Patient morbidity, and mortality were assessed utilizing logistic and linear regression. Multivariable analyses adjusted for additional patient and hospital characteristics. RESULTS: A total of 62,291 LEAs were identified between 2007 and 2011. The mean (SD) age was 66.4 (13.7) years. Patients were predominantly Caucasian (56.4%), male (62.9%), and admitted as an emergency admission (44.1%). A higher incidence of LEA was observed in patients with DM + PAD (47.3%) than those with either DM alone (26.4%) or PAD alone (26.3%). On adjustment for patient characteristics, PAD alone was associated with significantly higher mortality and complications postoperatively (OR 1.71; P < 0.001, and 1.28; P < 0.001, respectively), but concurrent DM + PAD was not associated with these outcomes. CONCLUSION: Outcomes were significantly affected by presence of PAD as a comorbidity in patients undergoing LEA. It is imperative to understand and enhance preventive measures and screening guidelines for such comorbidities to optimize postoperative outcomes to ensure best-practice care in this patient population.

Concomitant Achalasia and Barrett's Esophagus: A Rare Coincidence.

The pathophysiologies of achalasia and gastroesophageal reflux disease with Barrett's esophagus are highly distinct, though the clinical signs and symptoms of both are highly overlapped. The concomitant development of both achalasia and Barrett's esophagus is rare. We describe a case of a patient with a concomitant diagnosis of both pathologies and further explain the epidemiology of carrying both diseases simultaneously.

Persistent Apoptotic Enteropathy in an Individual With Marginal Cell Lymphoma.

Apoptotic enteropathy is a histological finding of increased crypt apoptosis that is commonly associated with diarrhea. Several etiologies for this disease state including immunodeficiency, autoimmune, infection, hereditary, checkpoint inhibitors, immunosuppressants, and immunomodulators have been previously described. We describe an extremely rare case of a patient with marginal cell lymphoma treated with bendamustine, rituximab, and obinutuzumab presenting with severe, relapsing, chronic diarrhea with persistent apoptotic enteropathy of unknown etiology, despite hematological remission and discontinuation of treatment for 1 year.

Cerebrospinal fluid AFB smear in adults with tuberculous meningitis: A systematic review and diagnostic test accuracy meta-analysis.

BACKGROUND: Cerebrospinal fluid (CSF) Ziehl-Neelsen acid-fast bacilli (AFB) smear is a rapid, cheap, widely available test for tuberculous meningitis (TBM). Yet, reported test sensitivity is highly variable. We performed a systematic review and meta-analysis for CSF AFB smear vs. other mycobacterial tests to diagnose TBM. METHODS: We searched MEDLINE and Embase for studies reporting sensitivity and specificity of AFB smear against mycobacterial tests (reference standard) in adults (≥15 years) with suspected TBM. We used the QUADAS-2 tool to assess risk of bias. We estimated pooled sensitivity and specificity of AFB smear versus the reference standard using random-effects bivariate modeling. We used the I2 statistic to assess heterogeneity between studies. RESULTS: Of 981 articles identified, 11 were eligible for inclusion with a total of 1713 participants. Seven studies were from high-TB burden settings and 4 from low-TB burden settings. The pooled sensitivity and specificity of CSF AFB smear were 8% (95%CI 3-21) and 100% (95%CI 90-100), with substantial heterogeneity in diagnostic performance (I2 >95% for both) and reference standards. CONCLUSION: CSF AFB smear has poor sensitivity in most settings. If other more sensitive tests are available, those should be used preferentially rather than CSF AFB smear.

Tuberculosis IRIS: Pathogenesis, Presentation, and Management across the Spectrum of Disease.

Antiretroviral therapy (ART), while essential in combatting tuberculosis (TB) and HIV coinfection, is often complicated by the TB-associated immune reconstitution inflammatory syndrome (TB-IRIS). Depending on the TB disease site and treatment status at ART initiation, this immune-mediated worsening of TB pathology can take the form of paradoxical TB-IRIS, unmasking TB-IRIS, or CNS TB-IRIS. Each form of TB-IRIS has unique implications for diagnosis and treatment. Recently published studies have emphasized the importance of neutrophils and T cell subtypes in TB-IRIS pathogenesis, alongside the recognized role of CD4 T cells and macrophages. Research has also refined our prognostic understanding, revealing how the disease can impact lung function. While corticosteroids remain the only trial-supported therapy for prevention and management of TB-IRIS, increasing interest has been given to biologic therapies directly targeting the immune pathology. TB-IRIS, especially its unmasking form, remains incompletely described and more data is needed to validate biomarkers for diagnosis. Management strategies remain suboptimal, especially in the highly morbid central nervous system (CNS) form of the disease, and further trials are necessary to refine treatment. In this review we will summarize the current understanding of the immunopathogenesis, the presentation of TB-IRIS and the evidence for management recommendations.

A Unique Presentation of a Large, Seven-segment, Spinal Epidural Abscess in a Patient with a Pleural Empyema.

Spinal epidural abscesses are insidious infections spread via hematologic, contiguous, or iatrogenic routes. On average, spinal epidural abscesses span two to four vertebral segments and are most commonly localized to the thoracic region. Fever, back pain, and neurological deficits are the most common clinical manifestations. However, the triad of these findings are not always detected. Patients may present with subtle symptoms leading to misdiagnosis and poor prognosis. We present a case of a large, anteriorly located, spinal epidural abscess in a patient originally admitted for dyspnea and confusion.