λ Light Chain Bias Associated With Enhanced Binding and Function of Anti-HIV Env Glycoprotein Antibodies.

The humoral response to human immunodeficiency virus (HIV) remains incompletely understood. In this report, we describe biased λ light chain use during the HIV Env glycoprotein (Env) response in HIV infection and vaccination. We examined HIV Env binding (and neutralization) in the context of light chain use in subjects with acute HIV infection, chronic HIV infection, and among HIV vaccinees. In all populations tested, there was a λ chain bias for HIV Env binding antibodies, compared with other HIV antigens (such as p24) or tetanus toxoid. In subjects with chronic HIV infection, a λ bias was noted for neutralization, with λ antibodies accounting for up to 90% of all neutralization activity observed. This is the first report of antibody function in a human infection being tied to light chain use. In HIV infection, antibodies expressing λ light chains tended to have longer CDRL3s, increased light chain contact with HIV Env, and less hypermutation in the heavy chain, compared with antibodies using the κ light chain. These data also support an evolutionary model for the understanding the various κ to λ light chain ratios observed across species and suggest that the λ light chain bias against HIV provides the host an advantage in developing a more efficient humoral response.

JWA inhibits melanoma angiogenesis by suppressing ILK signaling and is an independent prognostic biomarker for melanoma.

Melanoma is the deadliest cutaneous malignancy because of its high incidence of metastasis. Melanoma growth and metastasis relies on sustained angiogenesis; therefore, inhibiting angiogenesis is a promising approach to treat metastatic melanoma. JWA is a novel microtubule-associated protein and our previous work revealed that JWA inhibited melanoma cell invasion and metastasis. However, the role of JWA in melanoma angiogenesis and the prognostic value are still unknown. Here, we report that JWA in melanoma cells significantly inhibited the tube formation of endothelial cells. In addition, JWA regulated integrin-linked kinase (ILK) through integrin αVß3 and such regulation was achieved through the transcription factor Sp1. Notably, both in vitro and in vivo angiogenesis assays revealed that JWA dramatically suppressed melanoma angiogenesis by inhibiting ILK signaling. Furthermore, we examined the expression of JWA protein in a large set of melanocytic lesions (n = 505) at different stages by tissue microarray and found an inverse correlation between JWA expression and melanoma progression (P = 5 × 10(-6)). Importantly, reduced JWA expression was correlated with a poorer overall, and disease-specific 5 year survival of patients (P = 0.001 and 0.007, respectively). Multivariate Cox regression analyses indicated that JWA was an independent prognostic marker for melanoma patients. Moreover, we found a significant negative correlation between JWA and ILK in melanoma biopsies, and their concomitant expression was closely correlated with melanoma patient survival (P = 0.004), further indicating the regulation of ILK expression by JWA is critical in melanoma. Taken together, our data highlight the function of JWA in melanoma angiogenesis and reveal the clinical prognostic value of JWA.

Immune Checkpoint Inhibitors Induced Hepatotoxicity; Gastroenterologists' Perspectives.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have promising clinical activity and are essential medications for patients with several malignancies. However, by deranging the immune system, these novel agents could lead to immune-related adverse events (IRAEs). Hepatotoxicity with checkpoint inhibitors usually results in acute hepatitis or drug-induced liver injury. METHODS: This review article discusses the recent clinical evidence available regarding checkpoint inhibitor-induced hepatitis and reviews an approach to their diagnosis and management. CONCLUSION: ICIs have improved patients' outcomes with different forms of malignancy; however, ICIs-related liver damage is a clinically significant entity in these patients. All patients should be monitored carefully for IRAEs while undergoing treatment with ICIs.

The clinical value of angiopoietin-2 in liver diseases.

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Myeloid-derived suppressor cells in gastrointestinal cancers: A systemic review.

Gastrointestinal (GI) cancers are one of the most common malignancies worldwide, with high rates of morbidity and mortality. Myeloid-derived suppressor cells (MDSCs) are major components of the tumor microenvironment (TME). MDSCs facilitate the transformation of premalignant cells and play roles in tumor growth and metastasis. Moreover, in patients with GI malignancies, MDSCs can lead to the suppression of T cells and natural killer cells. Accordingly, a better understanding of the role and mechanism of action of MDSCs in the TME will aid in the development of novel immune-targeted therapies.

A brief review of liver injury in patients with Corona Virus Disease-19 during the pandemic.

The novel coronavirus Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) infection has been mostly leading to respiratory distress syndrome, but liver injury has also been documented. The mechanism of liver injury is limited and poorly understood. However, the hepatic injury could be due to a consequence of systemic inflammatory response, viral infection of hepatocytes, or as a result of intensive care treatment or drug toxicity. Based on the current studies, this review article emphasizes on the demographic and potential mechanisms of Corona Virus Disease (COVID)-19-related liver dysfunction.

Improving immunization strategies in patients with inflammatory bowel disease.

Patients with inflammatory bowel disease (IBD) are susceptible to varieties of opportunistic infections due to immunological changes in the setting of their disease and drug-induced immunosuppression. Even though numerous infections can be prevented by vaccine, vaccination in IBD patients is inadequate. Data showed only 9% were vaccinated against pneumococcal infection and 28% described commonly receiving influenza vaccine. This review article discusses the recent immunizations against influenza virus; pneumococcal infection; human papilloma virus; tetanus, diphtheria and pertussis; measles, mumps and rubella; varicella zoster; and herpes zoster for individuals diagnosed with IBD and those patients with drug-related immunosuppression. In addition, this review discusses concerns about IBD patients planning to travel abroad. Immunization status and screening for opportunistic infection need to be addressed in IBD patients at the time of diagnosis and they should be vaccinated accordingly. Generally, standard vaccination strategies should be pursued in IBD patients, although live vaccines should be avoided while they are not immunocompetent.

Immune checkpoint inhibitor-induced colitis: A comprehensive review.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target down-regulators of the anti-cancer immune response: Cytotoxic T-lymphocyte antigen-4, programmed cell death protein-1, and its ligand programmed death-ligand 1. ICIs have revolutionized the treatment of a variety of malignancies. However, many immune-related adverse events have also been described which mainly occurs as the immune system becomes less suppressed, affecting various organs including the gastrointestinal tract and causing diarrhea and colitis. The incidence of immune-mediated colitis (IMC) ranges from 1%-25% depending on the type of ICI and if used in combination. Endoscopically and histologically there is a significant overlap between IMC and inflammatory bowel disease, however more neutrophilic inflammation without chronic inflammation is usually present in IMC. Corticosteroids are recommended for grade 2 or more severe colitis while holding the immunotherapy. About one third to two thirds of patients are steroid refractory and benefit from infliximab. Recently vedolizumab has been found to be efficacious in steroid and infliximab refractory cases. While in grade 4 colitis, the immunotherapy is permanently discontinued, the decision is controversial in grade 3 colitis.

Diagnosing active and latent tuberculosis among Iranian HIV-infected patients.

OBJECTIVE: To screen for Tuberculosis (TB) in human immunodeficiency virus (HIV) people in an effort to improve early TB diagnosis and reduce TB transmission. METHODS: A prospective study was conducted on adult HIV people from 2008 to 2011. Three samples of sputum, cell blood count, tuberculin skin test (TST) and chest X-ray were obtained from all patients. The characteristics of HIV patients with TB and HIV patients without TB were compared to each other. RESULTS: Of the 154 HIV patients included, 58 (38%) had tuberculosis with a mean CD4 cell count of 68 cells/mm3 . Active TB was found in 56 (47%) patients with a history of intravenous drug use. Cough (OR = 3.1, 95% CI 1.2-7.79), positive TST (OR = 8.15, 95% CI 3.28-20.25) and an abnormal chest X-ray (OR = 5.1, 95% CI 1.84-14.2) were the predicting factors for detecting active TB among HIV patients. The sensitivity and specificity of a combination of any symptoms with chest X-ray, smear, TST or all of these were 96.5% and 86.5%, respectively. CD4 cell count <100 (OR = 2.67; 95% CI 1.23-5.78) and smoking (OR = 13.4; 95% CI 3.04-59.4) remained independently associated with TB in a multivariate analysis. CONCLUSION: There was a high prevalence of TB within the HIV population. Screening for TB among these patients can be carried out at every clinic or health facility using a combination of symptoms, TST, chest X-ray and smear sample.

A Resident Initiative Improves Hepatitis C Screening Rates in Primary Care Clinics.

BACKGROUND: Electronic reminders for clinical patient counseling have proven to be an effective response to national recommendations to increase risk factor and birth cohort hepatitis C virus (HCV) screening. It is not known whether a resident-led educational intervention alone could increase screening rates where support for electronic intervention may be limited. OBJECTIVE: We determined whether a resident-designed and resident-implemented educational intervention would significantly improve HCV screening rates in primary care clinics. METHODS: The baseline HCV screening rate was determined retrospectively in our resident community-based primary care clinics. We then implemented an educational intervention that included presenting during resident conference, posting signs in resident work areas, and providing educational pamphlets to patients. We collected screening rate data at 3 and 6 months postintervention. The screening rate was defined as patients screened in clinic divided by the number of patients eligible for screening. RESULTS: The screening rate increased significantly from preintervention (6%, 64 of 1023) to 3 months (35%, 363 of 1026) and 6 months (41%, 443 of 1070) and between 3 and 6 months (P < .001). The percentage of screened patients who pursued testing increased significantly between preintervention (62%, 16 of 26) and 6 months (81%, 105 of 130), and between 3 months (67%, 95 of 141) and 6 months (P = .019). CONCLUSIONS: An educational intervention designed and implemented by residents significantly increased the screening and testing rates for HCV in community-based resident clinics.

Diseases at the crossroads: chronic myelogenous leukemia and tuberculosis.

Chronic myelogenous leukemia (CML) and tuberculosis (TB) are diseases with effective available therapy. Treating patients who are afflicted simultaneously with both of these conditions is challenging due to significant drug interactions and the requirement of strict adherence to the multi-agent treatment regimen. Here, we report a case of peritoneal tuberculosis which was successfully treated with a non-rifampin based regimen in tandem with ongoing administration of a tyrosine kinase inhibitor, dasatinib, for CML. We discuss treatment challenges and the strategy on how to circumvent them. As prevalence of CML increases worldwide, patients with concomitant CML and TB will be seen more often by physicians in all continents, and development of guidelines on simultaneous management of these conditions is imperative.

Mycobacterial infection and the impact of rifabutin treatment in organ transplant recipients: a single-center study.

Tuberculosis (TB) is a frequently encountered infection among organ transplant recipients in developing countries, and the incidence of infection after the first year of transplantation is considerably high. In this study, the impact of rifabutin treatment on organ transplant recipients with TB infection was evaluated with respect to the trend of infection, management and outcome. The medical records of 26 post-transplant patients who received an organ transplant between 2004 and 2012 and later diagnosed with TB of different organs were reviewed retrospectively. We retrieved data regarding clinical features as well as treatment and outcomes. The median time interval between transplantation and TB was 36 months (IQR 12-101 months). The most common form of infection was pulmonary/pleural TB. All our subjects received rifabutin instead of rifampin in the anti-TB treatment regime as rifabutin is a less-potent inducer of cytochrome P-450. All patients responded satisfactorily to the treatment and maintained excellent allograft function. Moreover, we did not have any mortality among our recipients. Drug-induced hepatitis was observed in nine (35%) patients. Rifabutin is an excellent alternative medication to rifampin in the setting of TB management. Hepatotoxicity is a potential risk for treatment because of the potential additive toxicity of immunosuppressive drugs.

Disseminated Kaposi's Sarcoma with the Involvement of Penis in the Setting of HIV Infection.

Kaposi's sarcoma (KS) is a malignant proliferation of the endothelial cells. It typically presents with several vascular nodules on the skin and other organs. The penile localization of KS, particularly on the shaft area, is exceptional. We report an HIV-positive 34-year-old man who had multiple purplish-black plaques on his extremities and several small violaceous macules on the glans and shaft of the penis. Kaposi's sarcoma was diagnosed by histopathology.

Conventional Laparoscopic vs Robotic Training: Which is Better for Naive Users? A Randomized Prospective Crossover Study.

OBJECTIVE: Robotic training (RT) using the da Vinci skills simulator and conventional training (CT) using a laparoscopic "training box" are both used to augment operative skills in minimally invasive surgery. The current study tests the hypothesis that skill acquisition is more rapid using RT than using CT among naive learners. DESIGN AND PARTICIPANTS: A total of 40 subjects without laparoscopic or robotic surgical experience were enrolled and randomized to begin with either RT or CT. Then, 2 specific RT tasks were reproduced for CT and repeated 5 times each with RT and CT. Time and quality indicators were measured quantitatively. A crossover technique was used to control for in-study experience bias. RESULTS: The tasks "pick and place jacks" (PP) and "thread the rings" (TR) were achieved faster with RT than with CT despite crossover (p < 0.0001). An RT-favoring difference was observed in speed for both tasks when changing modality. Percentage improvement with increasing trials was similar for RT and CT: RT completion time averaged 39 seconds and 211 seconds (PP and TR, respectively), compared with 65 seconds and 362 seconds when using CT (p < 0.0001); final improvement averaged 26% and 46% for RT (PP and TR, respectively) vs 31% and 47% for CT (p was 0.76 for PP and 0.20 for TR). Within the PP task, RT times averaged 41 seconds without previous CT experience vs 35 seconds with previous CT experience (p = 0.20); CT times averaged 61 seconds without and 69 seconds with previous RT experience (p = 0.48). Comparable times for the TR task were 212 seconds vs 216 seconds (p = 0.66) and 388 seconds vs 334 seconds (p = 0.17). Both instrument collisions and excessive force occurred more commonly for RT than for CT within the TR task (p < 0.0001). CONCLUSIONS: Speeds were faster overall with RT than with CT, but the percentage of speed improvement with trials was similar, suggesting similar learning curves, with minimal transfer effect appreciated.

Isolation of Mycobacterium branderi, an unusual species from an acute myelogenous leukemia patient.

We report a case of pulmonary infection caused by Mycobacterium branderi, a slow growing non-tuberculosis mycobacteria, in a patient with acute myelogenous leukemia. The pulmonary disease was treated successfully with the combination of Ciprofloxacin, Doxycycline and Clarithromycin. M. branderi may be considered as an opportunistic pathogen, especially among immunologically compromised patients.

Management of nontuberculous mycobacterial infection in the elderly.

The incidence of nontuberculous mycobacteria (NTM) has increased over the last decades. Elderly people are more susceptible to NTM and experience increased morbidities. NTM incidence is expected to rise due to an increasing elderly population at least up to 2050. Given the importance of NTM infection in the elderly, an increasing interest exists in studying NTM characteristics in the aged population. In this review, we summarize the characteristics of NTM infection among elderly patients. We focus on epidemiology, clinical presentation, and treatment options of NTM in this age group. We highlight the differences in the diagnosis and treatment between rapid and slow growing mycobacterial infections. The current recommendation for treatment of NTM is discussed. We debate if in vitro susceptibility testing has a role in the treatment of NTM. Drug-drug interaction between antibiotics used to treat NTM and other medications, particularly warfarin, is another important issue that we discuss. Finally, we review the prognosis of NTM disease in elderly patients.

Highlight on advances in nontuberculous mycobacterial disease in North America.

Nontuberculous mycobacteria (NTM) are ubiquitous in the environment and exist as an important cause of pulmonary infections in humans. Pulmonary involvement is the most common disease manifestation of NTM and the incidence of NTM is growing in North America. Susceptibility to NTM infection is incompletely understood; therefore preventative tools are not well defined. Treatment of pulmonary nontuberculous mycobacterial (NTM) infection is difficult and entails multiple antibiotics and an extended treatment course. Also, there is a considerable variation in treatment management that should be considered before initiating treatment. We highlight the new findings in the epidemiology diagnosis and treatment of mycobacterial infections. We debate new advances regarding NTM infection in cystic fibrosis patients and solid organ transplant recipients. Finally, we introduce a new epidemiologic model for NTM disease based on virulence-exposure-host factors.

Performance of QuantiFERON TB gold test compared with the tuberculin skin test for detecting latent tuberculosis infection in lung and heart transplant candidates.

OBJECTIVES: Evaluation for latent tuberculosis infection is advised before organ transplant. The interferon-gamma release assay has been shown to be more specific than the tuberculin skin test for screening for latent tuberculosis infection. We compared the tuberculin skin test and QuantiFERON-TB Gold In-Tube test for screening for latent tuberculosis infection and agreement between the tests in heart and lung transplant recipients before transplant. MATERIALS AND METHODS: Fifty-five adult patients who had been evaluated for heart and lung transplant between September 2011 and September 2012 at Masih Daneshvari Hospital in Iran were prospectively enrolled. We performed the tuberculin skin test and QuantiFERON-TB Gold In-Tube test. RESULTS: Of the 55 patients, 3 (5%) had positive tuberculin skin test results, and 11 (20%) had positive QuantiFERON-TB Gold In-Tube test results. Agreement between the tuberculin skin test and QuantiFERON-TB Gold In-Tube test was fair (Kappa=0.061; 95% CI: - 0.185-0.307) (P = .56). CONCLUSIONS: The positivity for QuantiFERON-TB Gold In-Tube test was greater than the positivity for the tuberculin skin test, and QuantiFERON-TB Gold In-Tube test more accurately determined the risk for latent tuberculosis infection. However, a further longitudinal study is necessary to verify that the QFT-G test would predict developing tuberculosis after heart and lung transplant.

Multidrug-resistant tuberculosis treatment with linezolid-containing regimen.

The following is a case of multidrug-resistant pulmonary tuberculosis (MDR-TB) that was treated successfully with a linezolid-containing regimen. It was found that linezolid is an efficient medicine for MDR-TB treatment with an acceptable side effect profile. Treatment was maintained for 18 months, and closely monitoring toxicities did not reveal evidence of any neurologic adverse effects. However, despite our expectation, thrombocytopenia was seen after 2 years follow-up.