Acute Hepatitis due to Primary Human Immunodeficiency Virus Infection.

The acute retroviral syndrome may present with diverse systemic manifestations and laboratory abnormalities. Here we present a rare case of primary human immunodeficiency virus (HIV) infection causing severe acute hepatitis. Liver histopathology demonstrated a pattern of lymphocytic inflammation consistent with acute hepatitis, high levels of HIV proviral DNA were detected within liver tissue, and immunofluorescence showed HIV p24 antigen within immune and parenchymal cells including hepatocytes. We review the literature pertaining to HIV infection of cell compartments within the liver and discuss the implications for HIV-associated acute liver disease.

Legionella pneumophila and Staphylococcus aureus co-infections in a patient with SARS-CoV-2.

A man fully mRNA-vaccinated against COVID-19 presented to our hospital with an acute febrile illness, respiratory symptoms and a positive test for SARS-CoV-2. He was later found early into hospitalisation to have two morbid bacterial co-infections: Legionella pneumophila serogroup 1 and methicillin-resistant Staphylococcus aureus (MRSA). Although this patient was initially admitted for COVID-19 management, his initial presentation was remarkable for lobar pneumonia, hyponatraemia and rhabdomyolysis more compatible with Legionnaire's disease than severe COVID-19. On discovery of MRSA pneumonia as a second bacterial infection, immunosuppressive COVID-19 therapies were discontinued and targeted antibiotics towards both bacterial co-infections were initiated. The patient's successful recovery highlighted the need to have high suspicion for bacterial co-infections in patients presenting with community-acquired pneumonia and a positive SARS-CoV-2 test, as patients with serious bacterial co-infections may have worse outcomes with use of immunosuppressive COVID-19 therapies.

Interferon gamma runs interference on persistent COVID-19.

COVID-19 represents a collection of disease endotypes stemming from infection with SARS-CoV-2 and thus requires precision medicine approaches to target specific viral variants and stages of illness. In this issue, van Laarhoven et al.1 describe five immunocompromised patients with prolonged COVID-19 successfully treated with interferon gamma (IFNγ).

A Pilot Trial Evaluating Stereotactic Body Radiation Therapy to Induce Hyperemia in Combination With Transarterial Chemoembolization for Hepatocellular Carcinoma.

PURPOSE: Despite the survival benefit of transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC), a majority of tumors recur, attributed to hypovascularity and treatment resistance. Preclinical studies show that moderate radiation doses induce changes in tumor permeability and perfusion, suggesting an opportunity for TACE sensitization by radiation. In this prospective phase 1 trial, we evaluated the feasibility, safety, tolerability, response, and functional magnetic resonance imaging (MRI) changes associated with single-fraction stereotactic body radiation therapy (SBRT) followed by TACE within 24 hours. METHODS AND MATERIALS: Patients with HCC, 1 to 3 lesions, Childs-Pugh A/B liver function, and no major vascular invasion were enrolled. The primary objective was to establish the feasibility of single-dose SBRT (7.5 or 10 Gy) followed by TACE within 24 hours. Secondary endpoints included safety, tolerability, perfusional changes via functional MRI, overall response rate (ORR), clinical benefit rate (CBR), freedom from local progression, progression-free survival, and overall survival. RESULTS: Sixteen patients were enrolled, and 13 received SBRT and TACE. Median follow-up was 15.3 months. Best overall ORR and CBR were 76.9% and 92.3%, respectively. The 1- and 3-month ORR was 76.9% and 69.2%, respectively, and 1- and 3-month CBR was 92.3% and 69.2%, respectively. Median overall survival, progression-free survival, and freedom from local progression were 14.0, 5.2, and 5.9 months, respectively. Crude rates of grade 1+ and grade 2+ toxicity were 85% and 38%, respectively. No grade 3 to 4 toxicities were recorded. One grade 5 toxicity occurred due to hemorrhage 4 days after TACE. On dynamic contrast-enhanced MRI, the transfer rate constant from blood plasma to extracellular extravascular space (kpe) increased within 6 hours post-SBRT but decreased by 24 hours. CONCLUSIONS: We hypothesized a strategy of SBRT preceding TACE for the purpose of enhancing TACE delivery and efficacy and tested this strategy in a small pilot study. We found that single-dose SBRT followed by TACE within 24 hours is feasible and tolerable. Dynamic contrast-enhanced MRI revealed acute changes in tumor permeability/perfusion after SBRT. Additional studies are needed to establish the safety and efficacy of this combination and the effects of SBRT on the HCC microenvironment.

Neoadjuvant and adjuvant treatment strategies for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common liver malignancy worldwide and a major cause of cancer-related mortality for which liver resection is an important curative-intent treatment option. However, many patients present with advanced disease and with underlying chronic liver disease and/or cirrhosis, limiting the proportion of patients who are surgical candidates. In addition, the development of recurrent or de novo cancers following surgical resection is common. These issues have led investigators to evaluate the benefit of neoadjuvant and adjuvant treatment strategies aimed at improving resectability rates and decreasing recurrence rates. While high-level evidence to guide treatment decision making is lacking, recent advances in locoregional and systemic therapies, including antiviral treatment and immunotherapy, raise the prospect of novel approaches that may improve the outcomes of patients with HCC. In this review, we evaluate the evidence for various neoadjuvant and adjuvant therapies and discuss opportunities for future clinical and translational research.

Primary Care Provider Awareness of IR: A Single-Center Analysis.

PURPOSE: To evaluate primary care provider awareness of interventional radiology (IR) services at a tertiary care academic medical center to identify areas of IR practice that require additional education and awareness initiatives. MATERIAL AND METHODS: An internet-based survey was distributed via email to primary care providers, including internal medicine (IM), family medicine (FM), obstetrics and gynecology (OBGYN), and hospital medicine (HM) physicians in the region. The survey consisted of 17 questions regarding provider demographics, experiences with IR in their practice, awareness of IR training, and awareness of IR procedures and services. RESULTS: A total of 234 of 533 invited physicians completed the survey (40% IM, 22% FM, 22% HM, and 16% OBGYN). Providers rated their knowledge of IR as poor (49, 20.3%), adequate (137, 56.9%), good (49, 20.3%), and excellent (6, 2.5%). Although 235 (97.5%) had consulted IR previously, only 141 (58.5%) had referred a patient directly to IR for an elective procedure. IR was offered as an alternative to surgical procedures never (42, 17.6%), a quarter of the time (101, 42.3%), half of the time (61, 25.5%), three-quarters of the time (27, 11.3%), and every time (8, 3.35%). Most respondents (161, 67.4%) learned the most about IR procedures during residency. Most (180, 75.3%) indicated that they would like to learn more about IR. CONCLUSIONS: These findings indicate that more can be done to educate providers about the potential role of IR in patient care. Provider awareness is limited regarding procedures that are increasingly popular in the IR community. This study helps to identify specific areas of IR in which awareness of can be increased.

Nationwide Trends in Use of Catheter-Directed Therapy for Treatment of Pulmonary Embolism in Medicare Beneficiaries from 2004 to 2016.

PURPOSE: To evaluate changes in the use of catheter-directed therapy (CDT) for pulmonary embolism (PE) treatment with attention to primary operator specialty in the Medicare population. METHODS: Using a 5% national sample of Medicare claims data from 2004 to 2016, all claims associated with PE were identified. The annual volume of 2 billable CDT services-arterial mechanical thrombectomy and transcatheter arterial infusion for thrombolysis-were determined to evaluate changes in CDT use and primary CDT operator specialty over time. RESULTS: The total number of CDT procedures increased over the course of the study period, representing 0.457 and 5.057 service counts per 100,000 Medicare beneficiaries in 2004 and 2016, respectively. The proportion of PEs treated with CDT increased 10-fold from 2004 to 2016, increasing from 0.1% to 1.0%. Interventional radiologists performed most CDT therapies each year, with the exception of 2010 when vascular surgeons performed more. In 2016, interventional radiologists performed 3.54 CDT services for PE per 100,000 Medicare beneficiaries, which was 70% of total CDT for PE procedures, followed by interventional cardiologists and vascular surgeons performing 0.92 services (18%) and 0.60 services (12%), respectively. CONCLUSIONS: CDT is an increasingly used treatment for PE, with a 10-fold increase from 2004 to 2016. Interventional radiologists are the dominant providers of these services, followed by interventional cardiologists and vascular surgeons.

Bundling HIV and TB Care at a District-Level Center in Sierra Leone: A high-yield method for diagnosing co-infection with TB and antiretroviral treatment failure among people living with HIV.

BACKGROUND: Protocols for HIV care are widely accepted by all international organizations and are proven to reduce mortality and complications from living with HIV. Unfortunately, executing best practice recommendations in Sierra Leone is difficult due to shortages in staff, training, and medications. METHODS: From June 2016 to August 2016, we implemented both an HIV guideline-based clinical evaluation protocol and a patient-centered workflow for TB screening and CD4 testing in the HIV clinic at Koidu Government Hospital (KGH) in rural Sierra Leone. The primary outcome of interest was how often this service center resulted in a clinically significant change in the patients' HIV regimen. Reasons for changing regimen included diagnosis of co-infection with tuberculosis (TB), diagnosis of clinical or presumed immunologic treatment failure of antiretroviral (ART) medications and, need for adherence to weight-based dosing in pediatric patients. FINDINGS: A total of 188 patients with HIV were seen in the clinic; 49 (26%) of these patients had a clinically significant change in their HIV regimen. The most common reason for regimen change was TB co-infection diagnosis in 38 (20%) patients. The other reasons for HIV regimen changes included: eight children whose ART was adjusted to meet appropriate levels for weight-based guidelines, five patients diagnosed with presumed immunologic treatment failure (some also co-infected with tuberculosis), and two patients with a serious side effect to ART. INTERPRETATION: A comprehensive, patient-centric HIV clinic can result in high rates of case detection for tuberculosis and recognition of immunological ART failure.

Institutional Interventional Radiology Symposium Increases Medical Student Interest and Identifies Target Recruitment Candidates.

OBJECTIVES: To assess and raise medical student interest in interventional radiology (IR); and to evaluate student response across gender, level of training, and surgical vs nonsurgical specialty interest. MATERIALS AND METHODS: All Ohio medical students were invited to an IR Symposium held by a large academic medical center in central Ohio. The program encompassed didactic lectures, hands-on simulation models, and a networking luncheon with faculty, trainees, and industry partners. All attendees completed an anonymous, 5-point Likert scaled survey preattending and postattending the event to assess their awareness of IR as a specialty, understanding of the current training pathways, and level of interest. RESULTS: A total of 46 participants (M:F 60%:40%, MS1-53%, MS2-36%, and MS3-11%) attended the symposium. The cohort demonstrated increased interest in pursuing a career in IR following the symposium (4.12 vs 3.70, P < 0.001). Students with an interest in a nonsurgical specialty showed an increased interest in IR (4.20 vs 3.68, P < 0.001), whereas surgically oriented students did not demonstrate a significant increase (4.00 vs 3.71, P = 0.375). No statistically significant differences were noted across gender or level of training. The symposium experience significantly increased understanding of the IR training pathways (4.51 vs 2.94, P < 0.001). Students rated lectures (57%) and endovascular simulators (41%) as the most useful experiences. CONCLUSIONS: This study demonstrated the role of symposia in improving medical student awareness of IR and training pathways. Findings were validated across gender and training level, and identified the subset of students with nonsurgical interests as most responsive to such intervention and potential recruitment.

Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming.

The NLRP3 inflammasome is activated in response to microbial and danger signals, resulting in caspase-1-dependent secretion of the proinflammatory cytokines IL-1ß and IL-18. Canonical NLRP3 inflammasome activation is a two-step process requiring both priming and activation signals. During inflammasome activation, NLRP3 associates with mitochondria; however, the role for this interaction is unclear. In this article, we show that mouse NLRP3 and caspase-1 independently interact with the mitochondrial lipid cardiolipin, which is externalized to the outer mitochondrial membrane at priming in response to reactive oxygen species. An NLRP3 activation signal is then required for the calcium-dependent association of the adaptor molecule ASC with NLRP3 on the mitochondrial surface, resulting in inflammasome complex assembly and activation. These findings demonstrate a novel lipid interaction for caspase-1 and identify a role for mitochondria as supramolecular organizing centers in the assembly and activation of the NLRP3 inflammasome.

A consortium-driven framework to guide the implementation of ICH M7 Option 4 control strategies.

The ICH M7 Option 4 control of (potentially) mutagenic impurities is based on the use of scientific principles in lieu of routine analytical testing. This approach can reduce the burden of analytical testing without compromising patient safety, provided a scientifically rigorous approach is taken which is backed up by sufficient theoretical and/or analytical data. This paper introduces a consortium-led initiative and offers a proposal on the supporting evidence that could be presented in regulatory submissions.

Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment.

The inbred mouse strain C57BL/6J is widely used in models of immunological and infectious diseases. Here we show that C57BL/6J mice have a defect in neutrophil recruitment to a range of inflammatory stimuli compared with the related C57BL/6N substrain. This immune perturbation is associated with a missense mutation in Nlrp12 in C57BL/6J mice. Both C57BL/6J and NLRP12-deficient mice have increased susceptibility to bacterial infection that correlates with defective neutrophil migration. C57BL/6J and NLRP12-deficient macrophages have impaired CXCL1 production and the neutrophil defect observed in C57BL/6J and NLRP12-deficient mice is rescued by restoration of macrophage NLRP12. These results demonstrate that C57BL/6J mice have a functional defect in NLRP12 and that macrophages require NLRP12 expression for effective recruitment of neutrophils to inflammatory sites.

Predictors of suboptimal bowel preparation in asymptomatic patients undergoing average-risk screening colonoscopy.

AIM: To identify risk factors for a suboptimal preparation among a population undergoing screening or surveillance colonoscopy. METHODS: Retrospective review of the University of Michigan and Veteran's Administration (VA) Hospital records from 2009 to identify patients age 50 and older who underwent screening or surveillance procedure and had resection of polyps less than 1 cm in size and no more than 2 polyps. Patients with inflammatory bowel disease or a family history of colorectal cancer were excluded. Suboptimal procedures were defined as procedure preparations categorized as fair, poor or inadequate by the endoscopist. Multivariable logistic regression was used to identify predictors of suboptimal preparation. RESULTS: Of 4427 colonoscopies reviewed, 2401 met our inclusion criteria and were analyzed. Of our population, 16% had a suboptimal preparation. African Americans were 70% more likely to have a suboptimal preparation (95%CI: 1.2-2.4). Univariable analysis revealed that narcotic and tricyclic antidepressants (TCA) use, diabetes, prep type, site (VA vs non-VA), and presence of a gastroenterology (GI) fellow were associated with suboptimal prep quality. In a multivariable model controlling for gender, age, ethnicity, procedure site and presence of a GI fellow, diabetes [odds ratio (OR) = 2.3; 95%CI: 1.6-3.2], TCA use (OR = 2.5; 95%CI: 1.3-4.9), narcotic use (OR = 1.7; 95%CI: 1.2-2.5) and Miralax-Gatorade prep vs 4L polyethylene glycol 3350 (OR = 0.6; 95%CI: 0.4-0.9) were associated with a suboptimal prep quality. CONCLUSION: Diabetes, narcotics use and TCA use were identified as predictors of poor preparation in screening colonoscopies while Miralax-Gatorade preps were associated with better bowel preparation.

Monocytes Take Their Own Path to IL-1ß.

Generally, two signals are required to activate the NLRP3 inflammasome. In this issue of Immunity, Hornung and colleagues (2016) describe an alternative inflammasome activation pathway in human monocytes triggering activation of the NLRP3 inflammasome in response to a single stimulus.

A Nitrogen-Assisted One-Pot Heteroaryl Ketone Synthesis from Carboxylic Acids and Heteroaryl Halides.

A practical and highly effective one-pot synthesis of versatile heteroaryl ketones directly from carboxylic acids and heteroaryl halides under mild conditions is reported. This method does not require derivatization of carboxylic acids (preparation of acid chlorides, Weinreb amides, etc.) or the use of any additives/catalysts. A wide substrate scope of carboxylic acids with high functional group tolerance has also been demonstrated. The results reveal that the presence of an α-nitrogen on the halide substrate greatly improves the desired ketone formation.

Radiofrequency Wire Recanalization of Chronically Thrombosed TIPS.

Radiofrequency (RF) guide wires have been applied to cardiac interventions, recanalization of central venous thromboses, and to cross biliary occlusions. Herein, the use of a RF wire technique to revise chronically occluded transjugular intrahepatic portosystemic shunts (TIPS) is described. In both cases, conventional TIPS revision techniques failed to revise the chronically thrombosed TIPS. RF wire recanalization was successfully performed through each of the chronically thrombosed TIPS, demonstrating initial safety and feasibility in this application.

Factors Associated with Advanced Inferior Vena Cava Filter Removals: A Single-Center Retrospective Study of 203 Patients Over 7 Years.

PURPOSE: To identify factors associated with advanced inferior vena cava filter (IVCF) retrieval to raise awareness on technical considerations, retrieval efficiency, and patient safety. MATERIALS AND METHODS: A single-center retrospective review was performed of 203 consecutive retrievable IVC filters placed between 2007 and 2014. Attempted retrievals were classified as advanced if the routine "snare and sheath" technique was initially unsuccessful after multiple attempts, or an alternate endovascular maneuver or access site was utilized. Patient and filter characteristics were recorded. RESULTS: 203 attempted retrievals were reviewed (48.7 % male, 51.2 % female, mean age 52.7 years, mean dwell time 109 days). Advanced retrievals were observed in 20 patients (9.8 %) (15 females, 5 males). Fluoroscopy time (p ≤ 0.01, 34.3 ± 21.1 and 5.3 ± 4.5 min for advanced retrievals and routine retrievals respectively, same below), gender (p = 0.031), and retrieval tilt angle (p ≤ 0.01, 5.7 ± 5.10° vs. 11.9 ± 11.03°) were associated with advanced retrievals. Females were 3.16 times more likely to have an advanced retrieval performed than males with a significantly higher tilt angle in those with advanced retrieval. History of cancer (p = 0.502), dwell time (p = 0.916), retrieval caval diameter (p = 0.053), placement caval diameter (p = 0.365), filter type (p = 0.710), strut perforation (p = 0.506), placement tilt angle (p = 0.311), and age (p = 0.558) were not found significantly associated with advanced retrievals. CONCLUSIONS: Women are at increased risk for advanced filter retrieval secondary to a significant change in filter tilt over time compared to men, independent of filter type or competing demographic or filter risks, likely placing them at increased risk for higher procedural fluoroscopy times.

Initiation and perpetuation of NLRP3 inflammasome activation and assembly.

The NLRP3 (NOD-like receptor family, pyrin domain containing 3) inflammasome is a multiprotein complex that orchestrates innate immune responses to infection and cell stress through activation of caspase-1 and maturation of inflammatory cytokines pro-interleukin-1ß (pro-IL-1ß) and pro-IL-18. Activation of the inflammasome during infection can be protective, but unregulated NLRP3 inflammasome activation in response to non-pathogenic endogenous or exogenous stimuli can lead to unintended pathology. NLRP3 associates with mitochondria and mitochondrial molecules, and activation of the NLRP3 inflammasome in response to diverse stimuli requires cation flux, mitochondrial Ca(2+) uptake, and mitochondrial reactive oxygen species accumulation. It remains uncertain whether NLRP3 surveys mitochondrial integrity and senses mitochondrial damage, or whether mitochondria simply serve as a physical platform for inflammasome assembly. The structure of the active, caspase-1-processing NLRP3 inflammasome also requires further clarification, but recent studies describing the prion-like properties of ASC have advanced the understanding of how inflammasome assembly and caspase-1 activation occur while raising new questions regarding the propagation and resolution of NLRP3 inflammasome activation. Here, we review the mechanisms and pathways regulating NLRP3 inflammasome activation, discuss emerging concepts in NLRP3 complex organization, and expose the knowledge gaps hindering a comprehensive understanding of NLRP3 activation.

Synthesis of isotope-labeled HSP90 inhibitor: [(13) CD3 ] and [(14) C]-TAK-459.

[(13) CD3 ]-TAK-459 (1A), an HSP90 inhibitor, was synthesized from [(13) CD3 ]-sodium methoxide in three steps in an overall yield of 29%. The key intermediate [(13) CD3 ]-2-methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine was synthesized in two steps from 2,6-dibromopyridine and stable isotope-labeled sodium methoxide. [(14) C]-TAK-459 (1B) was synthesized from [(14) C(U)]-guanidine hydrochloride in five steps in an overall radiochemical yield of 5.4%. The key intermediate, [(14) C]-(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one, was prepared by microwave-assisted condensation.