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Summary: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease originating from the pilosebaceous unit, in which patients develop painful abscesses, sinus tracts, nodules and scarring, typically in intertriginous areas. Major gaps in our understanding of HS exist, and these may be partially due to the lack of an animal model for experimental studies. We developed an HS xenograft mouse model using human HS lesions grafted onto immunocompromised mice. Although the model had its limitations, several informative lessons were learned, which may contribute to future attempts at an HS animal model. [ABSTRACT FROM AUTHOR]

Clustering is commonly used in single-cell RNA-sequencing (scRNA-seq) pipelines to characterize cellular heterogeneity. However, current methods face two main limitations. First, they require user-specified heuristics which add time and complexity to bioinformatic workflows; second, they rely on post-selective differential expression analyses to identify marker genes driving cluster differences, which has been shown to be subject to inflated false discovery rates. We address these challenges by introducing nonparametric clustering of single-cell populations (NCLUSION): an infinite mixture model that leverages Bayesian sparse priors to identify marker genes while simultaneously performing clustering on single-cell expression data. NCLUSION uses a scalable variational inference algorithm to perform these analyses on datasets with up to millions of cells. By analyzing publicly available scRNA-seq studies, we demonstrate that NCLUSION (i) matches the performance of other state-of-the-art clustering techniques with significantly reduced runtime and (ii) provides statistically robust and biologically relevant transcriptomic signatures for each of the clusters it identifies. Overall, NCLUSION represents a reliable hypothesis-generating tool for understanding patterns of expression variation present in single-cell populations., Competing Interests: SR holds equity in Amgen and receives research funding from Microsoft. All other authors have declared that no competing interests exist.

Background: The clinical implications of obesity differ, depending on race, ethnicity, and sexual orientation., Methods: This roundtable discussion included 4 obesity specialists with expertise in the clinical management of obesity among diverse populations including Blacks, Hispanics/Latinos, Lesbian-Gay-Bisexual-Transgender-Questioning (LGBTQ) individuals, and Native-Americans., Results: One of the first obstacles towards overcoming disparities in managing obesity and its complications among diverse populations is understanding applicable terminology. This includes categorization terminology relative to Native Americans (for the purpose of assessing culture and possibly genetic predispositions), understanding the differences between Black African Americans and Black Africans, understanding the differences between the terms Hispanic and Latinx, and basic concepts behind different pronouns applicable to Lesbian-Gay-Bisexual-Transgender-Questioning (LGBTQ) individuals. After being better able to grasp the input from patients with diverse backgrounds, universal obesity assessment and management principles can be then tailored utilizing a patient-centered approach., Conclusion: Understanding the unique genetic, culture, and terminology regarding patients of different races, ethnicities, and sexual orientation may help clinicians better engage patients in managing obesity via utilizing a more patient-centered approach., (© 2022 The Author(s).)

Background: Tuberculosis (TB) is a common infection in people living with HIV. However, the risk factors for HIV/TB co-infection in second-line HIV therapy are poorly understood. We aimed to determine the incidence and risk factors for TB co-infection in SECOND-LINE, an international randomized clinical trial of second-line HIV therapy., Methods: We did a cohort analysis of TB cases in SECOND-LINE. TB cases included any clinical or laboratory-confirmed diagnoses and/or commencement of treatment for TB after randomization. Baseline factors associated with TB were analyzed using Cox regression stratified by site., Results: TB cases occurred at sites in Argentina, India, Malaysia, Nigeria, South Africa, and Thailand, in a cohort of 355 of the 541 SECOND-LINE participants. Overall, 20 cases of TB occurred, an incidence rate of 3.4 per 100 person-years (95% CI: 2.1 to 5.1). Increased TB risk was associated with a low CD4+-cell count (≤200 cells/μL), high viral load (>200 copies/mL), low platelet count (<150 ×109/L), and low total serum cholesterol (≤4.5 mmol/L) at baseline. An increased risk of death was associated with TB, adjusted for CD4, platelets, and cholesterol. A low CD4+-cell count was significantly associated with incident TB, mortality, other AIDS diagnoses, and virologic failure., Discussion: The risk of TB remains elevated in PLHIV in the setting of second-line HIV therapy in TB endemic regions. TB was associated with a greater risk of death. Finding that low CD4+ T-cell count was significantly associated with poor outcomes in this population supports the value of CD4+ monitoring in HIV clinical management., Competing Interests: R.T.H. is supported by an Australian Government Research Training Program (RTP) Scholarship; M.N.P. is supported by fellowships from the Cancer Institute NSW and National Health and Medical Research Council; M. Law is supported by an investigator grant from the National Health and Medical Research Council. The other authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: The purpose of this study was to systematically review and quantitatively analyze outcomes in operative versus nonoperative management of displaced midshaft clavicle fractures in pediatric and adolescent patients., Data Sources: Using the Preferred Reporting items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, systematic searches of PubMed and EMBASE were conducted to identify English-language studies reporting outcomes in displaced pediatric midshaft clavicle fractures from 1997 to 2018., Study Selection: Studies that reported on outcomes of operative and/or nonoperative treatment of displaced midshaft clavicle fractures in patients younger than 19 years were included., Data Extraction: Patient and treatment characteristics, union rates, time to union, time to return to activity, patient-reported outcome measures, and complications were extracted., Data Synthesis: All extracted data were recorded and qualitatively compared. QuickDASH (Quick Disabilities of the Arm, Shoulder, and Hand) scores and Constant scores were pooled using random-effects modeling and compared among studies, which adequately reported data for hypothesis testing., Conclusions: Three thousand eight hundred ten articles were identified, and 12 met inclusion criteria. These studies encompassed 497 patients with an average age of 14.1 years (8-18 years, range). Both operative and nonoperative management of displaced midshaft clavicle fractures in this population provide excellent rates of union and patient-reported outcome measures. Compared with nonoperative management, operative management yielded faster return to activity, superior Constant scores, and equal QuickDASH scores. Operative management had higher complication rates and complications that required secondary operative treatment (mostly related to implant prominence)., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

When studying purified hematopoietic stem cells, the urge for mechanisms and reductionist approaches appears to be overwhelming. The prime focus of the field has recently been on the study of highly purified hematopoietic stem cells using various lineage and stem cell-specific markers, all of which adequately and conveniently fit the established hierarchical stem cell model. This methodology is tainted with bias and has led to incomplete conclusions. Much of our own work has shown that the purified hematopoietic stem cell, which has been so heavily studied, is not representative of the total population of hematopoietic stem cells and that rather than functioning within a hierarchical model of expansion the true hematopoietic stem cell is one that is actively cycling through various differentiation potentials within a dynamic continuum. Additional work with increased emphasis on studying whole populations and direct mechanistic studies to these populations is needed. Furthermore, the most productive studies may well be mechanistic at the cellular or tissue levels. Lastly, the application of robust machine learning algorithms may provide insight into the dynamic variability and flux of stem cell fate and differentiation potential.

Many different subpopulations of subcellular extracellular vesicles (EVs) have been described. EVs are released from all cell types and have been shown to regulate normal physiological homeostasis, as well as pathological states by influencing cell proliferation, differentiation, organ homing, injury and recovery, as well as disease progression. In this review, we focus on the bidirectional actions of vesicles from normal and diseased cells on normal or leukemic target cells; and on the leukemic microenvironment as a whole. EVs from human bone marrow mesenchymal stem cells (MSC) can have a healing effect, reversing the malignant phenotype in prostate and colorectal cancer, as well as mitigating radiation damage to marrow. The role of EVs in leukemia and their bimodal cross talk with the encompassing microenvironment remains to be fully characterized. This may provide insight for clinical advances via the application of EVs as potential therapy and the employment of statistical and machine learning models to capture the pleiotropic effects EVs endow to a dynamic microenvironment, possibly allowing for precise therapeutic intervention.

Background: Characterizing viral response to lopinavir/ritonavir (LPV/r) monotherapy as second-line treatment may guide recommendations for resource-limited settings (RLS)., Methods: We conducted a 48-week prospective, single-arm study of LPV/r monotherapy in patients failing first-line therapy in Nigeria. The primary outcome was sustained HIV-1 viral load (VL) <400 copies/mL at 48 weeks., Results: Of 30 enrolled patients, 28 (93%) achieved viral suppression on LPV/r, while 29 (96%) experienced low-level viremia. At 48 weeks, 9 (30%) met the primary outcome of sustained viral suppression; 14 (47%) patients were suppressed on LPV/r in a snapshot analysis. Detectable VLs at 12 and 24 weeks were strongly associated with treatment failure at 48 weeks. New resistance mutations were not detected. The trial was stopped early due to treatment failure., Conclusion: In this study, the rate of virologic failure among patients on a second-line lopinavir monotherapy regimen was relatively high and predicted by early detectable viremia. However, no LPV/r-associated resistance mutations were detected despite fluctuating low-level viremia, demonstrating the high genetic barrier to resistance of the protease inhibitor class which could be useful in RLS.

Objective: Worldwide, HIV-associated cryptococcal meningitis affects approximately 1 million persons and causes 600,000 deaths each year mostly in sub-Saharan Africa. Limited data exist on cryptococcal meningitis and antigenemia in Nigeria, and most studies are geographically restricted. We determined the prevalence of cryptococcal antigenemia (CrAg) among HIV-infected, treatment-naive individuals in Nigeria., Design/methods: This was a retrospective, cross-sectional study across 4 geographic regions in Nigeria. We performed CrAg testing using a lateral flow immunoassay on archived whole-blood samples collected from HIV-infected participants at US President's Emergency Plan for AIDS Relief (PEPFAR)-supported sites selected to represent the major geographical and ethnic diversity in Nigeria. Eligible samples were collected from consenting patients (>15 years) naive to antiretroviral therapy with CD4 count less than 200 cells per cubic millimeter and were stored in an -80°C freezer., Results: A total of 2752 stored blood samples were retrospectively screened for CrAg. Most of the samples were from participants aged 30-44 years (57.6%), and 1570 (57.1%) were from women. The prevalence of CrAg positivity in specimens with CD4 <200 cells per cubic millimeter was 2.3% (95% confidence interval: 1.8% to 3.0%) and varied significantly across the 4 regions (P < 0.001). At 4.4% (3.2% to 5.9%), the South East contained the highest prevalence., Conclusions: The significant regional variation in CrAg prevalence found in Nigeria should be taken into consideration as plans are made to integrate routine screening into clinical care for HIV-infected patients.

We investigate mutations and correlates according to HIV-1 subtype after virological failure (VF) of standard first-line antiretroviral therapy (ART) (non-nucleoside/nucleotide reverse transcriptase inhibitor [NNRTI] +2 nucleoside/nucleotide reverse transcriptase inhibitor [N(t)RTI]). SECOND-LINE study participants were assessed at baseline for HIV-1 subtype, demographics, HIV-1 history, ART exposure, viral load (VL), CD4(+) count, and genotypic ART resistance. We used backward stepwise multivariate regression (MVR) to assess associations between baseline variables and presence of ≥3 N(t)RTI mutations, ≥1 NNRTI mutation, ≥3 thymidine analog-N(t)RTI [ta-N(t)RTI] mutations (TAMs), the K65/K70 mutation, and predicted etravirine (ETV)/rilpivirine (RPV) activity. The inclusion p-value for MVR was p < .2. The exclusion p-value from stepwise elimination was p > .05. Of 541 participants, 491 (91%) had successfully characterized baseline viral isolates. Subtype distribution: B (n = 123, 25%), C (n = 202, 41%), CRF01&#95;AE (n = 109, 22%), G (n = 25, 5%), and CRF02&#95;AG (n = 27, 5%). Baseline CD4(+) 200-394 cells/mm(3) were associated with <3 N(t)RTI mutations (OR = 0.47; 95% CI 0.29-0.77; p = .003), absence of the K65/K70 mutation (OR = 0.43; 95% CI 0.26-0.73; p = .002), and higher ETV sensitivity (OR = 0.52; 95% CI 0.35-0.78; p = .002). Recent tenofovir (TDF) use was associated with K65/K70 mutations (OR = 8.91; 95% CI 5.00-15.85; p < .001). Subtype CRF01&#95;AE was associated with ≥3 N(t)RTI mutations (OR = 2.34; 95% CI 1.31-4.17; p = .004) and higher RPV resistance (OR = 2.13; 95% CI 1.30-3.49; p = .003), and subtype C was associated with <3 TAMs (OR = 0.45; 95% CI 0.21-0.99; p = .015). Subtypes CRF01&#95;AE (OR = 2.46; 95% CI 1.26-4.78; p = .008) and G (OR = 4.77; 95% CI 1.44-15.76; p = .01) were associated with K65/K70 mutations. Higher VL at confirmed first-line VF was associated with ≥3 N(t)RTI mutations (OR = 1.39; 95% CI 1.07-1.78; p = .013) and ≥3 TAMs (OR = 1.62; 95% CI 1.15-2.29; p = .006). The associations of first-line resistance mutations across the HIV-1 subtypes in this study are consistent with knowledge derived from subtype B, with some exceptions. Patterns of resistance after failure of a first-line ta-N(t)RTI regimen support using TDF in N(t)RTI-containing second-line regimens, or using N(t)RTI-sparing regimens.

Context: Pain management (PM) has not been routinely incorporated into HIV/AIDS care and treatment in resource-constrained settings., Objectives: We describe training for multidisciplinary teams tasked with integrating care management into HIV clinics to address pain for persons living with HIV in Nigeria., Methods: Education on PM was provided to mixed-disciplinary teams including didactic and iterative sessions following home and hospital visits. Participants identified challenges and performed group problem solving., Results: HIV trainers identified barriers to introducing PM reflecting views of the patient, providers, culture, and the health environment. Implementation strategies included (1) building upon existing relationships; (2) preliminary advocacy; (3) attention to staff needs; and (4) structured data review., Conclusion: Implementing PM in Nigerian HIV clinics requires recognition of cultural beliefs., (© The Author(s) 2014.)

There is limited information on efficacy and durability of second-line antiretroviral therapy (2NL) beyond 12 months in resource-limited settings. A total of 73 patients were enrolled into a prospective 2NL observational cohort in Nigeria. Second-line antiretroviral therapy consisted of lopinavir/ritonavir plus nucleoside reverse transcriptase inhibitors. Time on 2NL ranged from 15 to 31 months. Genotypes were retrospectively done and not available to guide second-line regimen choice. At enrollment, median CD4 count was 121 cells/mm3, and median time on first-line antiretroviral therapy (ISL) was 24 months. At 6 to 9 months on 2NL, 72.6% (intention to treat [ITT]) and 88.3% (on treatment [OT]) had an undetectable viral load (UDVL). At 12 months, 65.8% (ITT) and 90.57% (OT) had UDVL. At >12 to 24 months and at >24 months, 57.5% (ITT) and 91.3% (OT) had UDVL. No statistically significant association was observed between CD4 at 2NL start, sex, genotypic sensitivity score of 2NL, or tenofovir (TDF) use in ISL and viral suppression. Two patients developed major protease inhibitor mutations while on 2NL. We observed a high degree of viral suppression at 12 months and little loss of viral suppression thereafter.

Background: Uncertainty exists about the best treatment for people with HIV-1 who have virological failure with first-line combination antiretroviral therapy of a non-nucleoside analogue (NNRTI) plus two nucleoside or nucleotide analogue reverse transcriptase inhibitors (NtRTI). We compared a second-line regimen combining two new classes of drug with a WHO-recommended regimen., Methods: We did this 96-week, phase 3b/4, randomised, open-label non-inferiority trial at 37 sites worldwide. Adults with HIV-1 who had confirmed virological failure (plasma viral load >500 copies per mL) after 24 weeks or more of first-line treatment were randomly assigned (1:1) to receive ritonavir-boosted lopinavir plus two or three NtRTIs (control group) or ritonavir-boosted lopinavir plus raltegravir (raltegravir group). The randomisation sequence was computer generated with block randomisation (block size four). Neither participants nor investigators were masked to allocation. The primary endpoint was the proportion of participants with plasma viral load less than 200 copies per mL at 48 weeks in the modified intention-to-treat population, with a non-inferiority margin of 12%. This study is registered with ClinicalTrials.gov, number NCT00931463., Findings: We enrolled 558 patients, of whom 541 (271 in the control group, 270 in the raltegravir group) were included in the primary analysis. At 48 weeks, 219 (81%) patients in the control group compared with 223 (83%) in the raltegravir group met the primary endpoint (difference 1·8%, 95% CI -4·7 to 8·3), fulfilling the criterion for non-inferiority. 993 adverse events occurred in 271 participants in the control group versus 895 in 270 participants in the raltegravir group, the most common being gastrointestinal., Interpretation: The raltegravir regimen was no less efficacious than the standard of care and was safe and well tolerated. This simple NtRTI-free treatment strategy might extend the successful public health approach to management of HIV by providing simple, easy to administer, effective, safe, and tolerable second-line combination antiretroviral therapy., Funding: University of New South Wales, Merck, AbbVie, the Foundation for AIDS Research., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: There is an urgent need to improve the evidence base for provision of second-line antiretroviral therapy (ART) following first-line virological failure. This is particularly the case in Sub-Saharan Africa where 70% of all people living with HIV/AIDS (PHA) reside. The aim of this study was to simulate the potential risks and benefits of treatment simplification in second-line therapy compared to the current standard of care (SOC) in a lower-middle income and an upper-middle income country in Sub-Saharan Africa., Methods: We developed a microsimulation model to compare outcomes associated with reducing treatment discontinuations between current SOC for second-line therapy in South Africa and Nigeria and an alternative regimen: ritonavir-boosted lopinavir (LPV/r) combined with raltegravir (RAL). We used published studies and collaborating sites to estimate efficacy, adverse effect and cost. Model outcomes were reported as incremental cost effectiveness ratios (ICERs) in 2011 USD per quality adjusted life year ($/QALY) gained., Results: Reducing treatment discontinuations with LPV/r+RAL resulted in an additional 0.4 discounted QALYs and increased the undiscounted life expectancy by 0.8 years per person compared to the current SOC. The average incremental cost was $6,525 per treated patient in Nigeria and $4,409 per treated patient in South Africa. The cost-effectiveness ratios were $16,302/QALY gained and $11,085/QALY gained for Nigeria and South Africa, respectively. Our results were sensitive to the probability of ART discontinuation and the unit cost for RAL., Conclusions: The combination of raltegravir and ritonavir-boosted lopinavir was projected to be cost-effective in South Africa. However, at its current price, it is unlikely to be cost-effective in Nigeria.

We report a case of acute fulminant myocarditis presenting with cardiac tamponade and shock. The patient was managed in the coronary care unit with emergency pericardiotomy, invasive hemodynamic monitoring, and supportive therapy for cardiac failure. Pleural effusion and pneumonia complicated her clinical course. She responded well to therapy with normalization of left ventricular systolic function. This case demonstrates the potential for complete recovery with appropriate management in acute myocarditis even with a fulminant course.

It was found that if large quantities of both exogenous RNA and Mg-2+ were present during gentle tissue homogenization, the subsequent addition of deoxycholate to the whole homogenate produced a viscous mass from which polysomes could be isolated in large yields. These polysomes were substantially less degraded than those isolated by previous methods. In the case of rat liver, 15 ribosomes per mRNA was the species present in highest concentration. The parameters of this method were investigated and optimized. About 80 percent of the rRNA in the homogenates was recovered in the polysomes. Omission of deoxycholate permitted the isolation of less-degraded free polysomes as well. In the liver of fed rats these represented one-fourth of the total polysomes, in good agreement with results obtained by an independent approach. Using the method to isolate polysomes from the liver of starving rats, it was found that only about one percent of the large amount of monomers and dimers present resulted from polysome breakdown during isolation. It was further shown that random RNAase hydrolysis of polysomes could not produce the patterns of liver polysomes seen during starvation. Polysomes isolated by this procedure were quite stable in solution and were very active in cell-free protein synthesis. Application of this method without adaptation to eight other tissues also permitted the isolation of large polysomes in high yields.