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In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are ~330 fold higher in persons above 85 years of age compared to those 18-39 years old.To understand age-specific immune pathobiology of COVID-19 we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naïve T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.

HIV type 1 is associated with pulmonary dysfunction that is exacerbated by cigarette smoke. Alveolar macrophages (AM) are the most prominent immune cell in the alveolar space. These cells play an important role in clearing inhaled pathogens and regulating the inflammatory environment; however, how HIV infection impacts AM phenotype and function is not well understood, in part because of their autofluorescence and the absence of well-defined surface markers. The main aim of this study was to evaluate the impact of HIV infection on human AM and to compare the effect of smoking on their phenotype and function. Time-of-flight mass cytometry and RNA sequencing were used to characterize macrophages from human bronchoalveolar lavage of HIV-infected and -uninfected smokers and nonsmokers. We found that the frequency of CD163+ anti-inflammatory AM was decreased, whereas CD163−CCR7+ proinflammatory AM were increased in HIV infection. HIV-mediated proinflammatory polarization was associated with increased levels of inflammatory cytokines and macrophage activation. Conversely, smoking heightened the inflammatory response evident by change in the expression of CXCR4 and TLR4. Altogether, these findings suggest that HIV infection, along with cigarette smoke, favors a proinflammatory macrophage phenotype associated with enhanced expression of inflammatory molecules. Further, this study highlights time-of-flight mass cytometry as a reliable method for immunophenotyping the highly autofluorescent cells present in the bronchoalveolar lavage of cigarette smokers.

The sudden onset of the coronavirus pandemic has challenged many scholars of the social sciences to proceed in the absence of a robust theoretical research foundation upon which to build. This article seeks to help scholars meet this challenge, particularly as it pertains to Eurasia, through bringing together a multinational group of scholars in order to develop the roadmap for a new pandemic politics research subfield. It begins with a discussion of how states are responding to COVID-19 before moving into an exploration of reciprocal interactions between the pandemic and society, political economy, regime type, center-periphery relations, and international security. Finally, it discusses the potential novel contributions of a theoretical foundation rooted in the Foucauldian concept of “biopolitics.” Ultimately, we hope to spark an ongoing conversation regarding how political science and the social sciences more broadly can be used to understand the impacts of the pandemic and inform policymaking amidst the current and potential future pandemics.

Objectives Both delirium duration and delirium severity are associated with adverse patient outcomes. Serum biomarkers associated with delirium duration and delirium severity in ICU patients have not been reliably identified. We conducted our study to identify peripheral biomarkers representing systemic inflammation, impaired neuroprotection, and astrocyte activation associated with delirium duration, delirium severity, and in-hospital mortality. Design Observational study. Setting Three Indianapolis hospitals. Patients Three-hundred twenty-one critically ill delirious patients. Interventions None. Measurements and main results We analyzed the associations between biomarkers collected at delirium onset and delirium-/coma-free days assessed through Richmond Agitation-Sedation Scale/Confusion Assessment Method for the ICU, delirium severity assessed through Confusion Assessment Method for the ICU-7, and in-hospital mortality. After adjusting for age, gender, Acute Physiology and Chronic Health Evaluation II score, Charlson comorbidity score, sepsis diagnosis and study intervention group, interleukin-6, -8, and -10, tumor necrosis factor-α, C-reactive protein, and S-100β levels in quartile 4 were negatively associated with delirium-/coma-free days by 1 week and 30 days post enrollment. Insulin-like growth factor-1 levels in quartile 4 were not associated with delirium-/coma-free days at both time points. Interleukin-6, -8, and -10, tumor necrosis factor-α, C-reactive protein, and S-100β levels in quartile 4 were also associated with delirium severity by 1 week. At hospital discharge, interleukin-6, -8, and -10 retained the association but tumor necrosis factor-α, C-reactive protein, and S-100β lost their associations with delirium severity. Insulin-like growth factor-1 levels in quartile 4 were not associated with delirium severity at both time points. Interleukin-8 and S-100β levels in quartile 4 were also associated with higher in-hospital mortality. Interleukin-6 and -10, tumor necrosis factor-α, and insulin-like growth factor-1 were not found to be associated with in-hospital mortality. Conclusions Biomarkers of systemic inflammation and those for astrocyte and glial activation were associated with longer delirium duration, higher delirium severity, and in-hospital mortality. Utility of these biomarkers early in delirium onset to identify patients at a higher risk of severe and prolonged delirium, and delirium related complications during hospitalization needs to be explored in future studies.

Introduction Undiagnosed obstructive sleep apnoea (OSA) is increasingly recognized as a serious post-operative risk with bariatric surgery, hence increasing demand for pre-operative screening and a need for simpler ways for screening than the clinical standard, respiratory polygraphy, to mitigate strain on sleep services. WatchPAT 300 (WP) is a finger-mounted sensor that uses peripheral arterial tonometry to estimate the apnoea hyponoea index (AHI). While its use is increasing it has not yet been validated in patients with a BMI >35, the target population in bariatric surgery. Aims To validate WP against polygraphy in pre-bariatric surgery patients with clinically suspected OSA and a BMI>35 and to assess patient acceptability of WP. Methods AHI was measured simultaneously with WP and Embletta. Outcome measures were 1) autoscored AHI from WP and 2) manually re-scored AHI from Embletta. Agreement between AHI from Embletta and WP was assessed using intra-class correlation coefficient (ICC), bland Altman and ROC plots. Results 28 patients (22 female/6 male, mean ± SD age 44.1 ± 11.6, BMI 45.7 ± 7.5) participated. One study failed due to the patient removing the WP probe prematurely. AHI was higher in WP than Embletta (28.1± 17.9 versus 15.0 ±13.4; p 15 (Area under the curve 0.917; p Discussion WP accurately estimates the AHI in pre bariatric surgery patients, has a low failure rate and is clinically acceptable in this group. Further larger scale studies are needed to confirm these findings before incorporating into clinical guidelines.

Sepsis is a significant cause of mortality in hospitalized patients. Concomitant development of acute kidney injury (AKI) increases sepsis mortality through unclear mechanisms. While electrolyte disturbances and toxic metabolite buildup during AKI could be important, it is possible that the kidney produces a protective molecule lost during sepsis with AKI. We previously demonstrated that systemic Tamm-Horsfall Protein (THP, uromodulin), a kidney-derived protein with immunomodulatory properties, falls in AKI. Using a mouse sepsis model without severe kidney injury, we show that the kidney increases circulating THP by enhancing basolateral release of THP from medullary thick ascending limb cells. In sepsis patients, changes in circulating THP are positively associated with critical illness. THP is also found de novo in injured lungs. Genetic ablation of THP in mice leads to increased mortality and bacterial burden during sepsis. Consistent with the increased bacterial burden, the presence of THP in vitro and in vivo leads macrophages and monocytes to upregulate a transcriptional program promoting cell migration, phagocytosis and chemotaxis and treatment of macrophages with purified THP increases phagocytosis. Rescue of septic THP-/- mice with exogenous systemic THP improves survival. Together, these findings suggest that through releasing THP, the kidney modulates the immune response in sepsis by enhancing mononuclear phagocyte function and systemic THP has therapeutic potential in sepsis.Significance StatementSepsis is a significant contributor to kidney injury as well as morbidity and mortality worldwide. Specific therapies to improve outcomes in sepsis with kidney injury have largely been limited to symptom management and infectious agent control, in part because it is unclear how kidney injury increases sepsis mortality. This paper describes the identification of Tamm-Horsfall protein, previously known to protect in ischemic models of AKI, as protective in preclinical models of sepsis. It demonstrates how the loss of THP leads to decreased mononuclear phagocyte function and diversity, increased pathogen burden and decreased survival. THP also increases in sepsis without severe kidney injury and concentrates in injured organs. Further study of THP in sepsis could lead to novel sepsis therapeutics.

Background: Delirium is a common post-operative complication for patients who undergo esophagectomy. The pathophysiology of delirium is poorly understood, limiting therapeutic options. To advance our pathophysiologic understanding, we conducted this study to evaluate the association of protein expression with postoperative delirium. Methods: A case-control study was performed using blood samples from the PEPOD randomized clinical control trial (NCT02213900). 52 patients (26 cases with delirium, 26 control) who were >18 years old, spoke English, and underwent esophagectomy were included, while those with schizophrenia, Parkinson’s, alcohol abuse, neuroleptic malignant syndrome, haloperidol allergy, and severe dementia were excluded. Samples were from pre-op and post-op day 1. Delirium was assessed for using the Confusion Assessment Method for the Intensive Care Unit and Richmond Agitation Sedation Scale, while the severity was assessed using DRS-R-68. Proteomic analysis was performed using TMT 10ples isobaric labels. Proteome Discoverer and STRING web-based tools were used for bioinformatic analyses, and the Wilcoxon-Mann-Whitney Odds (WMWodds) test was used to report between-group differences in protein abundance ratios. Results: 52 samples (26 cases, 26 controls) were analyzed for this study. Elevated protein abundance ratios of Coagulation factor IX (Median (IQR): 1.18 (1.08-1.28) p=0.047) and Mannosyl-oligosaccharide 1,2-alpha-mannosidase (Median (IQR): 1.50 (1.35-1.60) p=0.049) were noted in patients that developed delirium. Elevated protein abundance ratios of angiotensinogen (Median (IQR): 1.19 (1.14-1.23) p=0.038), ceruloplasmin (Median (IQR): 1.02 (0.98-1.08) p=0.038), and Complement C2 (Median (IQR): 1.01 (0.96-1.08) p=0.016) were noted in control patients. Protein abundance ratios for Complement C2 (Spearman rs=0.31, 95%CI [-0.55, -0.02]) and Mannosyl-oligosaccharide 1,2-alpha-mannosidase (rs=0.61, 95%CI [0.29, 0.81]) were associated with the severity of delirium in case patients. Conclusions: Changes in proteins associated with coagulation, inflammation, and protein handling were identified. These could be evaluated in future studies to develop tools for predicting onset and severity of post-operative delirium.

Background: Evidence linking microbiome and human health is rapidly growing. Microbiome profile can be a novel predictive biomarker for many diseases. However, bacteria count tables are typically sparse and bacteria are classified at a hierarchy of taxonomic levels, ranging from species to phylum. Existing analysis tools focus on identifying microbiome associations either at the community level or at a specific pre-defined taxonomic level. They fail to incorporate the evolutionary relationship between bacteria and cannot learn from the data to aggregate microbiome contribution, thus leading to less accurate and less interpretable results in prediction, classification or selection. Results: We present DeepBiome, a phylogney-informed neural network architecture for predicting phenotypes from microbiome counts and uncovering the microbiome-phenotype association network. It takes microbiome abundance as the input and let the phylogenetic taxonomy guide the neural network architecture. Commonly used neural network architectures are targeted towards image and text analysis and typically require huge amount of training data, which is scarce in biomedical applications. By leveraging the phylogenetic information, DeepBiome relieves the heavy burden of tuning for the optimal deep learning architecture, avoids overfitting, and more importantly enables visualizing the path from microbiome counts to disease. It is applicable to both regression and classification problems. The simulation study and real-life data analysis demonstrate that DeepBiome is highly accurate and efficient and and provides a deep understanding of complex microbiome-phenotype associations even using small to moderate training sample sizes. Conclusions: In practice, it is unknown at which taxonomic level that microbiome clusters tag the association. Therefore, the central advantage of the presented method over other analytical methods is that it offers an ecological and evolutionary understanding of host-microbe interactions which is important for microbiome-based medicine. DeepBiome is implemented using Python packages Keras and the Tensorflow. It is an open-source tool available at (https://github.com/Young-won/DeepBiome).

The National Heart, Lung, and Blood Institute (NHLBI) AIDS Program's goal is to provide direction and support for research and training programs in areas of HIV-related heart, lung, blood, and sleep (HLBS) diseases. To better define NHLBI current HIV-related scientific priorities and with the goal of identifying new scientific priorities and gaps in HIV-related HLBS research, a wide group of investigators gathered for a scientific NHLBI HIV Working Group on December 14–15, 2015, in Bethesda, MD. The core objectives of the Working Group included discussions on: (1) HIV-related HLBS comorbidities in the antiretroviral era; (2) HIV cure; (3) HIV prevention; and (4) mechanisms to implement new scientific discoveries in an efficient and timely manner so as to have the most impact on people living with HIV. The 2015 Working Group represented an opportunity for the NHLBI to obtain expert advice on HIV/AIDS scientific priorities and approaches over the next decade.

Rationale: Few data have been published regarding scoring tools for selection of postgraduate medical trainee candidates that have wide applicability.Objectives: The authors present a novel scoring tool developed to assist postgraduate programs in generating an institution-specific rank list derived from selected elements of the U.S. Electronic Residency Application System (ERAS) application.Methods: The authors developed and validated an ERAS and interview day scoring tool at five pulmonary and critical care fellowship programs: the ERAS Application Scoring Tool–Interview Scoring Tool. This scoring tool was then tested for intrarater correlation versus subjective rankings of ERAS applications. The process for development of the tool was performed at four other institutions, and it was performed alongside and compared with the “traditional” ranking methods at the five programs and compared with the submitted National Residency Match Program rank list.Results: The ERAS Application Scoring Tool correlated h...

Objectives The aim of the present study was to determine the efficacy and safety of the ultrasonic surgical aspiration (Sonopet®) in the treatment of anogenital intraepithelial neoplasia. Methods We conducted a retrospective chart review of patients who underwent treatment of anogenital intraepithelial neoplasia between 2011 and 2018 with the ultrasonic surgical aspirator (Sonopet®). Results 256 patients underwent treatment with the ultrasonic surgical aspirator. The most frequent pathologic entities treated were VIN 2 (41.79%) and VAIN 2 (40.62%). Anal disease including both condyloma and anal intraepithelial lesions were found and treated in 10.56% of patients. Overall recurrence for patients treated with Sonopet was 10.54%. For patients previously treated with other modalities such as laser, the recurrence rate was even lower (2.34%). The median time to recurrence was 12.2 months. No surgical complications were recorded, and only minor post-operative complications were reported by patients. Conclusions The ultrasonic surgical aspiration (Sonopet®) is effective and safe surgical procedure for treatment of anogenital intraepithelial neoplasia. It was effective in both dermal and mucosal pathologies.

In metagenomic studies, testing the association of microbiome composition and clinical outcomes translates to testing the nullity of variance components. Motivated by a lung HIV (human immunodeficiency virus) microbiome project, we study longitudinal microbiome data by variance component models with more than two variance components. Current testing strategies only apply to the models with exactly two variance components and when sample sizes are large. Therefore, they are not applicable to longitudinal microbiome studies. In this paper, we propose exact tests (score test, likelihood ratio test, and restricted likelihood ratio test) to (1) test the association of the overall microbiome composition in a longitudinal design and (2) detect the association of one specific microbiome cluster while adjusting for the effects from related clusters. Our approach combines the exact tests for null hypothesis with a single variance component with a strategy of reducing multiple variance components to a single one. Simulation studies demonstrate that our method has correct type I error rate and superior power compared to existing methods at small sample sizes and weak signals. Finally, we apply our method to a longitudinal pulmonary microbiome study of human immunodeficiency virus (HIV) infected patients and reveal two interesting genera Prevotella and Veillonella associated with forced vital capacity. Our findings shed lights on the impact of lung microbiome to HIV complexities. The method is implemented in the open source, high-performance computing language Julia and is freely available at https://github.com/JingZhai63/VCmicrobiome.

Nachdem sich HIV/Aids in Russland Ende der 1990er Jahre unter Personen, die intravenös Drogen konsumieren, explosionsartig ausgebreitet hatte, stellt die Krankheit nun ein ernstes Problem für Gesellschaft und öffentliche Gesundheit dar. Die Gefahr wurde anfangs durch ein energisches Eingreifen der Zivilgesellschaft gemildert, das zu großen Teilen von der Weltgemeinschaft im Gesundheitswesen finanziert wurde. Dadurch sollten die bewährtesten Präventions- und Behandlungsstrategien eingeführt werden. Die dritte Amtszeit von Präsident Putin mit der konsequenten Demontage der meisten internationalen Partnerschaften fiel mit einer erneuten Beschleunigung der Epidemie zusammen. Aggressive Botschaften, die Drogenkonsum sowie sexuelle Handlungen/Identitäten, die jenseits tradierter Normen liegen, als unmoralisch darstellen, erwiesen sich als machtvolles Instrument für die Kampagne des Kreml, mit der Verachtung für und Angst vor westlichen Ideen und Verhaltensmustern geschürt werden. Diese Strategie manifestiert sich unter anderem in der deutlichen Weigerung, Programme zum Spritzentausch, Opioid-Agonisten-Therapie (etwa mit Methadon) oder selbst den Gebrauch von Kondomen zu fördern. Diese stellen allesamt zentrale Elemente des Harm Reduction-Ansatzes dar, der allgemein als grundlegendes Instrument zur Verhinderung von Neuinfizierungen mit HIV anerkannt wird. Ohne einen umfassenden Wandel in ihrer Haltung und Taktik wird sich die russische Regierung weiterhin einer kostspieligen und wachsenden Belastung durch HIV/Aids gegenübersehen, die ihrem Anspruch auf einen Weltmachtstatus Hohn spricht.

Rationale: Previous work found the lung microbiome in healthy subjects infected with HIV was similar to that in uninfected subjects. We hypothesized the lung microbiome from subjects infected with HIV with more advanced disease would differ from that of an uninfected control population.Objectives: To measure the lung microbiome in an HIV-infected population with advanced disease.Methods: 16s RNA gene sequencing was performed on acellular bronchoalveolar lavage (BAL) fluid from 30 subjects infected with HIV with advanced disease (baseline mean CD4 count, 262 cells/mm3) before and up to 3 years after starting highly active antiretroviral therapy (HAART) and compared with 22 uninfected control subjects.Measurements and Main Results: The lung microbiome in subjects infected with HIV with advanced disease demonstrated decreased alpha diversity (richness and diversity) and greater beta diversity compared with uninfected BAL. Differences improved with HAART, but still persisted up to 3 years after starting thera...

Improved understanding of the lung microbiome in HIV-infected individuals could lead to better strategies for diagnosis, therapy, and prophylaxis of HIV-associated pneumonias. Differences in the oral and lung microbiomes in HIV-infected and HIV-uninfected individuals are not well defined. Whether highly active antiretroviral therapy influences these microbiomes is unclear.We determined whether oral and lung microbiomes differed in clinically healthy groups of HIV-infected and HIV-uninfected subjects.Participating sites in the Lung HIV Microbiome Project contributed bacterial 16S rRNA sequencing data from oral washes and bronchoalveolar lavages (BALs) obtained from HIV-uninfected individuals (n = 86), HIV-infected individuals who were treatment naive (n = 18), and HIV-infected individuals receiving antiretroviral therapy (n = 38).Microbial populations differed in the oral washes among the subject groups (Streptococcus, Actinomyces, Rothia, and Atopobium), but there were no individual taxa that differed among the BALs. Comparison of oral washes and BALs demonstrated similar patterns from HIV-uninfected individuals and HIV-infected individuals receiving antiretroviral therapy, with multiple taxa differing in abundance. The pattern observed from HIV-infected individuals who were treatment naive differed from the other two groups, with differences limited to Veillonella, Rothia, and Granulicatella. CD4 cell counts did not influence the oral or BAL microbiome in these relatively healthy, HIV-infected subjects.The overall similarity of the microbiomes in participants with and without HIV infection was unexpected, because HIV-infected individuals with relatively preserved CD4 cell counts are at higher risk for lower respiratory tract infections, indicating impaired local immune function.

Supplemental Digital Content is available in the text., Objectives: Differences in mortality rates previously reported in critically ill patients with coronavirus disease 2019 have increased the need for additional data on mortality and risk factors for death. We conducted this study to describe length of stay, mortality, and risk factors associated with in-hospital mortality in mechanically ventilated patients with coronavirus disease 2019. Design: Observational study. Setting: Two urban, academic referral hospitals in Indianapolis, Indiana. Patients or Subjects: Participants were critically ill patients 18 years old and older, admitted with coronavirus disease 2019 between March 1, 2020, and April 27, 2020. Interventions: None. Measurements and Main Results: Outcomes included in-hospital mortality, duration of mechanical ventilation, and length of stay. A total of 242 patients were included with mean age of 59.6 years (sd, 15.5 yr), 41.7% female and 45% African American. Mortality in the overall cohort was 19.8% and 20.5% in the mechanically ventilated subset. Patients who died were older compared with those that survived (deceased: mean age, 72.8 yr [sd, 10.6 yr] vs patients discharged alive: 54.3 yr [sd, 14.8 yr]; p < 0.001 vs still hospitalized: 59.5 yr [sd, 14.4 yr]; p < 0.001) and had more comorbidities compared with those that survived (deceased: 2 [0.5–3] vs survived: 1 [interquartile range, 0–1]; p = 0.001 vs still hospitalized: 1 [interquartile range, 0–2]; p = 0.015). Older age and end-stage renal disease were associated with increased hazard of in-hospital mortality: age 65–74 years (hazard ratio, 3.1 yr; 95% CI, 1.2–7.9 yr), age 75+ (hazard ratio, 4.1 yr; 95% CI, 1.6–10.5 yr), and end-stage renal disease (hazard ratio, 5.9 yr; 95% CI, 1.3–26.9 yr). The overall median duration of mechanical ventilation was 9.3 days (interquartile range, 5.7–13.7 d), and median ICU length of stay in those that died was 8.7 days (interquartile range, 4.0–14.9 d), compared with 9.2 days (interquartile range, 4.0–14.0 d) in those discharged alive, and 12.7 days (interquartile range, 7.2–20.3 d) in those still remaining hospitalized. Conclusions: We found mortality rates in mechanically ventilated patients with coronavirus disease 2019 to be lower than some previously reported with longer lengths of stay.

HIV-1 is associated with infectious and noninfectious lung disease, both of which are exacerbated by cigarette smoke. Alveolar macrophages (AMs) are the most prominent immune cell in the alveolar space. These cells play an important role in clearing inhaled pathogens and regulating the inflammatory environment, however, how HIV infection impacts AM function is not well understood, in part due to their autofluorescent properties. The aim of this study was to evaluate the impact of HIV infection on AMs. Utilizing Time of Flight Mass Cytometry (CyTOF) and RNAseq we characterized macrophages from bronchoalveolar lavage (BAL) of HIV-infected and uninfected smokers and nonsmokers. We found that the frequency of alternatively activated AMs, defined by expression of CD163 and CD206, was decreased, while CD163-CCR7+ AM were increased in HIV infection. This phenotype was associated with increased levels of inflammatory cytokines and macrophage activation. While the inflammatory state of macrophages was not impacted by cigarette smoke, other markers such as TLR4 and CXCR4, which are associated with heightened inflammatory response to bacterial products and HIV infection, were altered with smoking. These findings suggest that HIV infection is associated with an increase in pro-inflammatory and depletion of anti-inflammatory AMs, which along with cigarette smoke-induced TLR4 and CXCR4 expression contributes to increased inflammation in the lung. Furthermore, this study demonstrates that CyTOF is a reliable method for immunophenotyping highly autofluorescent cells isolated from the bronchoalveolar lavage of cigarette smokers.

It remains a mystery why HIV-associated end-organ pathologies persist in the era of combined antiretroviral therapy (ART). One possible mechanism is the continued production of HIV-encoded proteins in latently HIV-infected T cells and macrophages. The proapoptotic protein HIV-Nef persists in the blood of ART-treated patients within extracellular vesicles (EVs) and peripheral blood mononuclear cells. Here we demonstrate that HIV-Nef is present in cells and EVs isolated from BAL of patients on ART. We hypothesize that HIV-Nef persistence in the lung induces endothelial apoptosis leading to endothelial dysfunction and further pulmonary vascular pathologies. The presence of HIV-Nef in patients with HIV correlates with the surface expression of the proapoptotic endothelial-monocyte-activating polypeptide II (EMAPII), which was implicated in progression of pulmonary emphysema via mechanisms involving endothelial cell death. HIV-Nef protein induces EMAPII surface expression in human embryonic kidney 293T cells, T cells, and human and mouse lung endothelial cells. HIV-Nef packages itself into EVs and increases the amount of EVs secreted from Nef-expressing T cells and Nef-transfected human embryonic kidney 293T cells. EVs from BAL of HIV+ patients and Nef-transfected cells induce apoptosis in lung microvascular endothelial cells by upregulating EMAPII surface expression in a PAK2-dependent fashion. Transgenic expression of HIV-Nef in vascular endothelial-cadherin+ endothelial cells leads to lung rarefaction, characterized by reduced alveoli and overall increase in lung inspiratory capacity. These changes occur concomitantly with lung endothelial cell apoptosis. Together, these data suggest that HIV-Nef induces endothelial cell apoptosis via an EMAPII-dependent mechanism that is sufficient to cause pulmonary vascular pathologies even in the absence of inflammation.

SummaryIn the metagenomics studies, testing the association of microbiome composition and clinical conditions translates to testing the nullity of variance components. Computationally efficient score tests have been the major tools. But they can only apply to the null hypothesis with a single variance component and when sample sizes are large. Therefore, they are not applicable to longitudinal microbiome studies. In this paper, we propose exact tests (score test, likelihood ratio test, and restricted likelihood ratio test) to solve the problems of (1) testing the association of the overall microbiome composition in a longitudinal design and (2) detecting the association of one specific microbiome cluster while adjusting for the effects from related clusters. Our approach combines the exact tests for null hypothesis with a single variance component with a strategy of reducing multiple variance components to a single one. Simulation studies demonstrate that our method has correct type I error rate and superior power compared to existing methods at small sample sizes and weak signals. Finally, we apply our method to a longitudinal pulmonary microbiome study of human immunodeficiency virus (HIV) infected patients and reveal two interesting genera Prevotella and Veillonella associated with forced vital capacity. Our findings shed lights on the impact of lung microbiome to HIV complexities. The method is implemented in the open source, high-performance computing language Julia and is freely available at https://github.com/JingZhai63/VCmicrobiome.

High-throughput sequencing technology has enabled population-based studies of the role of the human microbiome in disease etiology and exposure response. Microbiome data are summarized as counts or composition of the bacterial taxa at different taxonomic levels. An important problem is to identify the bacterial taxa that are associated with a response. One method is to test the association of specific taxon with phenotypes in a linear mixed effect model, which incorporates phylogenetic information among bacterial communities. Another type of approaches consider all taxa in a joint model and achieves selection via penalization method, which ignores phylogenetic information. In this paper, we consider regression analysis by treating bacterial taxa at different level as multiple random effects. For each taxon, a kernel matrix is calculated based on distance measures in the phylogenetic tree and acts as one variance component in the joint model. Then taxonomic selection is achieved by the lasso (least absolute shrinkage and selection operator) penalty on variance components. Our method integrates biological information into the variable selection problem and greatly improves selection accuracies. Simulation studies demonstrate the superiority of our methods versus existing methods, for example, group-lasso. Finally, we apply our method to a longitudinal microbiome study of Human Immunodeficiency Virus (HIV) infected patients. We implement our method using the high performance computing language Julia. Software and detailed documentation are freely available at https://github.com/JingZhai63/VCselection.

SIV DNA can be detected in lymphoid tissue–resident macrophages of chronically SIV-infected Asian macaques. These macrophages also contain evidence of recently phagocytosed SIV-infected CD4+ T cells. Here, we examine whether these macrophages contain replication-competent virus, whether viral DNA can be detected in tissue-resident macrophages from antiretroviral (ARV) therapy–treated animals and humans, and how the viral sequences amplified from macrophages and contemporaneous CD4+ T cells compare. In ARV-naive animals, we find that lymphoid tissue–resident macrophages contain replication-competent virus if they also contain viral DNA in ARV-naive Asian macaques. The genetic sequence of the virus within these macrophages is similar to those within CD4+ T cells from the same anatomic sites. In ARV-treated animals, we find that viral DNA can be amplified from lymphoid tissue–resident macrophages of SIV-infected Asian macaques that were treated with ARVs for at least 5 months, but we could not detect replication-competent virus from macrophages of animals treated with ARVs. Finally, we could not detect viral DNA in alveolar macrophages from HIV-infected individuals who received ARVs for 3 years and had undetectable viral loads. These data demonstrate that macrophages can contain replication-competent virus, but may not represent a significant reservoir for HIV in vivo.

Background: The increase in the use of monoclonal antibodies (mAB) as a targeted therapy for a variety of diseases has been accompanied by an increase in reports of interstitial lung abnormalities in treated patients. Objective: Bronchoalveolar lavage (BAL) is routinely performed in these patients to rule out infection, so we sought to determine the BAL cellular pattern in individuals with mAB-induced lung disease (mAB-ILD). Methods: We utilized a case-control study design. Among patients treated with mAB, cases were defined as those with otherwise-unexplained interstitial lung abnormalities, which resolved after cessation of treatment, while controls were defined as those with interstitial abnormalities clearly explained by other etiologies. Results: From 2000 to 2012, we identified 9 cases and 7 controls. The mean age of the cases was 62.6 ± 26 years and 6 were female. The most common radiographic finding was diffuse ground-glass opacities. The most common BAL cellular pattern was mixed inflammation with moderate lymphocytic and mild neutrophilic alveolitis. The cases had a higher mean lymphocyte count than the controls (40.1 ± 32.6 vs. 13.1 ± 25.5, p = 0.008). The rest of the BAL cellular analyses were similar between the 2 groups. The median CD4:CD8 ratio in 7 patients with >15% lymphocytes was 0.9 (0.6-3). There was no significant difference in the CD4:CD8 ratio between the 2 groups. Conclusions: Mixed inflammation with moderate lymphocytic and mild neutrophilic alveolitis is the most common BAL cellular pattern in patients with mAB-ILD. Such findings may be useful for the early identification of mAB-ILD.

Entrapment of the suprascapular nerve (SSN) at the spinoglenoid notch (SGN) specifically affects the infraspinatus, and isolated external rotation (ER) weakness can result. We describe the technique of open SSN decompression at the SGN for infraspinatus involvement and report the results of a consecutive series.Twenty-nine shoulders underwent SSN decompression at the SGN. The mean age was 44 years (range, 15-69 years), and the mean follow-up was 4.3 years (range, 1-7 years). On manual muscle testing, ER strength was abnormal in all patients: 2/5 in 3, 3/5 in 21, and 4/5 in 5. The mean preoperative American Shoulder and Elbow Surgeons (ASES) score was 48 (range, 23-83). Atrophy of the infraspinatus was visible or palpable in 72% of shoulders. Magnetic resonance imaging showed ganglion cysts at the SGN in only 20.7% of shoulders.Of the patients, 19 (66%) regained full ER strength, 9 (31%) improved to 4/5, and 1 (3%) had ER strength of 3/5. The mean ASES score improved to 75 (range, 60-100) (P.05). Of 29 shoulders, 23 (79%) showed improved ER strength within 1 week of surgery. All ganglion cyst cases regained full ER strength within a mean of 6 weeks. In all cases, ER strength improved by at least 1 full strength grade.A ganglion cyst is not necessary to produce SSN compression at the SGN. SSN compression at the SGN can present as an isolated entity or can occur in conjunction with rotator cuff pathology or a ganglion cyst. An index of suspicion, physical examination, magnetic resonance imaging, and electromyography confirm the diagnosis. The described operative approach detaches no muscle and allows rapid recovery, and in all cases, ER strength improved to normal or by 1 full grade.

In its 2010 report, the World Health Organization estimates that 34 million people worldwide are living with HIV 1 Lung disease is a major source of morbidity and mortality in these patients and can be directly linked to progressive loss of pulmonary immunity. Typically, infections complications occur in an orderly fashion, with increased susceptibility to common pathogens occurring early in HIV infection and susceptibility to opportunistic pathogens appearing later after substantial losses of CD4+ T cells (Figure 1). The immunologic correlate of this progression is the loss of antigen-specific immune responses early in HIV infection, followed by the loss of alloantigen and finally mitogen responses. However, the development of combination antiretroviral therapy (ART) has greatly influenced the morbidity and mortality of HIV infection. This influence has generally been attributed to improvements in immunologic function, either by preventing the progressive loss of immunity in HIV infection or by actually promoting immune reconstitution. While the effects of ART are well described in the vascular compartment, their effects at the tissue level, including the lung, are just beginning to be understood. In this review, we will describe how ART has greatly improved the lung immunologic and inflammatory milieu in HIV-infected subjects. The consequences of this improvement will be discussed extensively by other authors contributing to this publication. 1 Progression of cellular immunodeficiency in HIV infection. There is early loss of antigen-specific immune responses and increased susceptibility to bacterial infections. Over time, there is progressive CD4+ T cell depletion, progressive loss of T cell ... Effect of HIV on Pulmonary Immune Responses The respiratory tract from the oropharynx to the alveoli serves as an interface between the host and the environment. Thus, pulmonary immune responses are felt to represent a form of mucosal immunity. Pulmonary immunity can be divided into innate and acquired responses. Most pathogens gaining access to the respiratory tract are phagocytized by alveolar macrophages (AM), the principal arm of innate immunity. Importantly, phagocytosis of most foreign material gaining access to the alveolar space does not result in an inflammatory response due to the general immunosuppressive properties of alveolar macrophages 2. This results in a generalized paucity of lung inflammation under normal conditions, allowing gas exchange to occur unimpeded. Failure of innate host defenses leads to persistence of antigen in the respiratory tract and initiation of specific acquired immune responses. This process, which typically occurs in regional lung lymphoid tissue, results in the production of antigen specific effector T and B cells which traffic back to the site of initial challenge, in this case the alveolar space, under the control of local chemokine production in the lung 3. During the initial antigenic response, memory B and T cells are also created that allow the host to respond more rapidly upon re-exposure to the same antigen. Importantly, memory cells make up the predominant resident lymphocyte population in the normal lung 4. HIV infection impacts all components of the pulmonary immune response and has been addressed in a prior chapter. Specifically, the alveolar environment in HIV infection is characterized by: Generalized alveolar macrophage activation 5,6. Generalized CD4 T cell and CD8 T cell activation 7,8. Preserved alveolar macrophage phagocytic function 6,9,10. Increased concentrations of most macrophage and lymphocyte cytokines studied to date 11. Mild decrease in absolute CD4 T cell counts and a large decrease in CD4:CD8 T cell ratio in the alveolar space 12,13. Early preferential loss of antigen-specific memory CD4 T cells 14-16. Increase in the number and percentage of CD8+ cells resulting in a lymphocytic alveolitis 17. High immunoglobulin concentrations 18,19, but poor opsonic activity 20,21. The end result of these changes is a generalized state of cellular activation and accumulation of immune cells and pro-inflammatory mediators in the alveolar space (Figure 2A). Since HIV is easily detectable in the lungs of HIV-infected individuals not on ART 22, it is reasonable to speculate that the virus itself can drive this response. In fact, very early studies recognized that HIV-infected individuals had an increase in lung CD8+ T cells consisting of HIV-specific cytotoxic T lymphocytes 17, a finding confirmed by later investigators 13. However, despite this apparent appropriate anti-HIV response and background “inflammatory” state, clearly defects in specific immunity are present as demonstrated by the increase in opportunistic infections. The challenge, and hope, of effective antiretroviral therapy is to return the alveolar compartment to a more “normal” state. 2 Effect of ART on the alveolar environment in HIV infection. A) In untreated patients, there is persistent HIV antigen in the lung leading to generalized cellular activation and augmented cytokine and chemokine secretion in response to pathogens and other ... Effects of ART on Pulmonary Immunity While there is extensive literature on effects of ART in controlling plasma viral load and improving immune responsiveness of peripheral blood mononuclear cells (PBMC), there is a paucity of data describing the effect of ART in tissue compartments, especially the lung. Much of the existing data on lung immunologic changes after starting ART pertain to IRIS which is a clinically recognized disease discussed later in this chapter. Less understood is the effect of ART on lung immune function and inflammation in individuals who are otherwise doing well after starting treatment. This type of analysis requires participation of HIV-infected individuals on ART in research protocols where studies such as bronchoscopy and chest imaging are performed in the absence of clinical symptoms. The existing literature on these types of studies is described here. A. Effects on lung HIV viral load If, as speculated above, the presence of HIV antigens in the lung drives the development of CD8+ lymphocytic alveolitis and induces generalized cellular activation in the pulmonary microenvironment, then control of the pulmonary viral load should return alveolar constituents towards a normal state. Thus, the first question to be addressed is whether ART can reduce the lung viral load. Cross-sectional studies had suggested that individuals on ART had decreased detection of HIV in BAL, compared with lavages obtained from individuals not on treatment 22. To address this question prospectively, a longitudinal study was conducted under the auspices of the Adult AIDS Clinical Trials Group in which blood and BAL were obtained from HIV-infected individuals starting ART and again after 4 weeks, and 24 weeks 23. At each time point, free virus (in plasma and acellular BAL fluid) as well as cellular HIV RNA and DNA (in PBMCs and alveolar cells) was measured. As expected, ART was associated with a significant decline in plasma viral load and a delayed, but significant decrease in the cellular viral load in peripheral blood cells. However, the decline in the lung viral load, both in the acellular compartment as well as in alveolar cells, was much more rapid and dramatic. At baseline, the ability to detect HIV in the lung and vascular compartments was similar. After four weeks of ART, the ability to detect HIV in BAL was significantly lower than the ability to detect HIV in plasma. After 6 months of therapy, the ability to detect HIV RNA in lung cells was significantly less than the ability to detect HIV RNA in PBMCs. Thus, the lung appears to respond to ART as well as, if not better, than the vascular compartment 23

Rationale: Lung infections caused by opportunistic or virulent pathogensare a principal cause of morbidityandmortality in HIVinfection. It is unknown whether HIV infection leads to changes in basal lung microflora, which may contribute to chronic pulmonary complications that increasingly are being recognized in individuals infected with HIV. Objectives: To determine whether the immunodeficiency associated with HIV infection resulted in alteration of the lung microbiota. Methods:We used 16S ribosomal RNA targeted pyrosequencing and shotgun metagenomic sequencing to analyze bacterial gene sequences in bronchoalveolar lavage (BAL) and mouths of 82 HIV-positive and 77 HIV-negative subjects. Measurements and Main Results: Sequences representing Tropheryma whipplei, the etiologic agent of Whipple's disease, were significantly more frequent in BAL of HIV-positive compared with HIV-negative individuals. T. whipplei dominated the community (>50% of sequence reads) in 11 HIV-positive subjects, but only 1 HIV-negative individual (13.4 versus 1.3%; P = 0.0018). In 30 HIV-positive individuals sampled longitudinally, antiretroviral therapy resulted in a significantly reduced relative abundance of T. whipplei in the lung. Shotgun metagenomic sequencing was performed on eight BAL samples dominated by T. whipplei 16S ribosomal RNA. Whole genome assembly of pooled reads showed that uncultured lungderived T. whipplei had similar gene content to two isolates obtained from subjects with Whipple's disease. Conclusions: Asymptomatic subjects with HIV infection have unexpected colonization of the lung by T. whipplei, which is reduced by effective antiretroviral therapy and merits further study for a potential pathogenic role in chronic pulmonary complications of HIV infection. Copyright © 2013 by the American Thoracic Society.

Pulmonary disease remains a primary source of morbidity and mortality in persons living with HIV (PLWH), although the advent of potent combination antiretroviral therapy has resulted in a shift from predominantly infectious to noninfectious pulmonary complications. PLWH are at high risk for COPD, pulmonary hypertension, and lung cancer even in the era of combination antiretroviral therapy. The underlying mechanisms of this are incompletely understood, but recent research in both human and animal models suggests that oxidative stress, expression of matrix metalloproteinases, and genetic instability may result in lung damage, which predisposes PLWH to these conditions. Some of the factors that drive these processes include tobacco and other substance use, direct HIV infection and expression of specific HIV proteins, inflammation, and shifts in the microbiome toward pathogenic and opportunistic organisms. Further studies are needed to understand the relative importance of these factors to the development of lung disease in PLWH.

Background\ud Domestic combustion of biomass fuels, such as wood, charcoal, crop residue and dung causes Household Air Pollution (HAP). These inhaled particulates affect more than half of the world’s population, causing respiratory problems such as infection and inflammatory lung disease. We examined whether the presence of black carbon in alveolar macrophages was associated with alterations in the lung microbiome in a Malawi population. \ud \ud Methods\ud Bronchoalveolar lavage samples from 44 healthy adults were sequenced using 16S rDNA amplification to assess microbial diversity, richness and relative taxa abundance. Individuals were classified as high or low particulate exposure as determined by questionnaire and the percentage of black carbon within their alveolar macrophages.\ud \ud Results\ud Subjects in the low and high particulate groups did not differ in terms of source of fuels used for cooking or lighting. There was no difference in alpha or beta diversity by particulate group. Neisseria and Streptococcus were significantly more abundant in samples from high particulate exposed individuals, and Tropheryma was found less abundant. Petrobacter abundance was higher in people using biomass fuel for household cooking and lighting, compared with exclusive use of electricity.\ud \ud Conclusions\ud Healthy adults in Malawi exposed to higher levels of particulates have higher abundances of potentially pathogenic bacteria (Streptococcus, Neisseria) within their lung microbiome. Domestic biomass fuel use was associated with an uncommon environmental bacterium (Petrobacter) associated with oil-rich niches.

The lung microbiome plays a significant role in normal lung function and disease. Because microbial colonization is likely influenced by immunodeficiency, one would speculate that infection with human immunodeficiency virus (HIV) alters the lung microbiome. Furthermore, how this alteration might impact pulmonary complications now seen in HIV-infected patients on antiretroviral therapy (ART), which has shifted from opportunistic infections to diseases associated with chronic inflammation, is not known. There have been limited publications on the lung microbiome in HIV infection, many of them emanating from the Lung HIV Microbiome Project. Current evidence suggests that the lung microbiome in healthy HIV-infected individuals with preserved CD4 counts is similar to uninfected individuals. However, in individuals with more advanced disease, there is an altered alveolar microbiome characterized by a loss of richness and evenness (alpha diversity) within individuals. Furthermore, as a group the taxa making up the HIV-infected and uninfected lung microbiome are different (differences in beta diversity), and the HIV-infected population is more spread out (greater dispersion) than the uninfected population. These differences decline with ART, but even after effective therapy the alveolar microbiome in HIV-infected individuals contains increased amounts of signature bacteria, some of which have previously been associated with chronic lung inflammation. Furthermore, more recent investigations into the lung virome in HIV infection suggest that perturbations in lung viral communities also exist in HIV infection, and that these too are associated with evidence of lung inflammation. Thus, it is likely both microbiome and virome alterations in HIV infection contribute to lung inflammation in these individuals, which has important implications on the changing spectrum of pulmonary complications in patients living with HIV.

Study Objectives:Understanding the etiologic mechanisms underlying impaired glucose tolerance in obstructive sleep apnea (OSA) would assist development of therapies against this comorbidity. We hyp...

Pulmonary emphysema is a disease characterized by alveolar cellular loss and inflammation. Recently, excessive apoptosis of structural alveolar cells has emerged as a major mechanism in the development of emphysema. Here, we investigated the proapoptotic and monocyte chemoattractant cytokine endothelial monocyte-activating protein 2 (EMAPII). Lung-specific overexpression of EMAPII in mice caused simplification of alveolar structures, apoptosis, and macrophage accumulation, compared with that in control transgenic mice. Additionally, in a mouse model of cigarette smoke-induced (CS-induced) emphysema, EMAPII levels were significantly increased in murine lungs. This upregulation was necessary for emphysema development, as neutralizing antibodies to EMAPII resulted in reduced alveolar cell apoptosis, inflammation, and emphysema-associated structural changes in alveoli and small airways and improved lung function. The mechanism of EMAPII upregulation involved an apoptosis-dependent feed-forward loop, since caspase-3 instillation in the lung markedly increased EMAPII expression, while caspase inhibition decreased its production, even in transgenic EMAPII mice. These findings may have clinical significance, as both current smokers and ex-smoker chronic obstructive pulmonary disease (COPD) patients had increased levels of secreted EMAPII in the bronchoalveolar lavage fluid compared with that of nonsmokers. In conclusion, we suggest that EMAPII perpetuates the mechanism of CS-induced lung emphysema in mice and, given its secretory nature, is a suitable target for neutralization antibody therapy.

The massive depletion of gastrointestinal-tract CD4 T cells is a hallmark of the acute phase of HIV infection. In contrast, the depletion of the lower-respiratory-tract mucosal CD4 T cells as measured in bronchoalveolar lavage (BAL) fluid is more moderate and similar to the depletion of CD4 T cells observed in peripheral blood (PB). To understand better the dynamics of disease pathogenesis and the potential for the reconstitution of CD4 T cells in the lung and PB following the administration of effective antiretroviral therapy, we studied cell-associated viral loads, CD4 T-cell frequencies, and phenotypic and functional profiles of antigen-specific CD4 T cells from BAL fluid and blood before and after the initiation of highly active antiretroviral therapy (HAART). The major findings to emerge were the following: (i) BAL CD4 T cells are not massively depleted or preferentially infected by HIV compared to levels for PB; (ii) BAL CD4 T cells reconstitute after the initiation of HAART, and their infection frequencies decrease; (iii) BAL CD4 T-cell reconstitution appears to occur via the local proliferation of resident BAL CD4 T cells rather than redistribution; and (iv) BAL CD4 T cells are more polyfunctional than CD4 T cells in blood, and their functional profile is relatively unchanged after the initiation of HAART. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might aid in the reconstitution of mucosal CD4 T cells.

Objective To determine if patients with autonomic failure have increased sleep disturbances and if multiple system atrophy (MSA) and pure autonomic failure (PAF) patients have frequent arousals from sleep associated with an attenuated heart rate (HR) response compared to healthy volunteers. Methods With informed consent, 10 autonomic failure patients and 10 healthy volunteers were studied. Sleep disturbances were scored using standard criteria. Arousals were identified from stage 2 sleep and differences in the R–R interval between groups were tested using a mixed-model regression analysis. Results Three MSA and one PAF patient had obstructive sleep apnoea compared to one volunteer. One MSA and three PAF patients had periodic limb movements. One MSA patient had REM behaviour disorder. The autonomic patients had significantly reduced total sleep time ( p = 0.007) and sleep efficiency ( p = 0.003). The HR response to arousal was smaller in autonomic failure patients compared to volunteers during the early phase of the arousal ( p = 0.047), but not the later phase ( p = 0.67). Conclusion Autonomic failure patients have increased sleep disturbances compared to healthy volunteers. The smaller HR response in autonomic failure patients suggests that an intact sympathetic nervous system is a key component of the HR response associated with arousal from sleep.

Chronic lung diseases are increasingly recognised complications of the human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome (AIDS). Of these, pulmonary emphysema, characterised by permanent destruction of the lung parenchyma distal to the terminal bronchioles accompanied by various degrees of inflammation, is emerging as a distinct source of morbidity for patients infected with HIV. Similarly, HIV is now frequently cited as a susceptibility factor for the development of emphysema, independent of cigarette smoking status. The presence of common coexistent confounding factors that may predispose patients to chronic lung injury such as drugs, opportunistic infections and malnutrition, limits the scope of studies of direct mechanisms involved in HIV associated emphysematous lung disease. We review the clinical studies supporting a direct association between HIV infection and emphysema. Recent developments in the basic understanding of HIV infection and emphysema are also reviewed, since they may aid in understanding the pathobiology of HIV associated emphysema. The authors emphasise how HIV infection may affect cytotoxic lymphocyte activation, lung capillary endothelial cell injury and apoptosis, sphingolipid imbalance and oxidative stress in the lung. A better understanding of the pathogenesis of HIV associated pulmonary emphysema may provide clues and therapeutic targets that have broader application in this disease, including cigarette smoke induced emphysema.

To avoid potential polyethylene problems in younger shoulders with degenerative joint disease (DJD) requiring arthroplasty, lateral meniscus allograft (LMA) was used as a biologic resurfacing of the glenoid. We report preliminary, short-term results of this technique in a younger, higher-demand population. The shoulders of 20 men and 10 women, with an average age of 42 years (range, 18 to 52 years), underwent total shoulder arthroplasty with a LMA. A metallic prosthesis was used on the humerus. Etiology of the DJD was osteoarthritis in 16, postinstability surgery in 8, traumatic in 4, and failed open reduction with internal fixation in 2. Twenty-two (73%) had previous shoulder surgery. Preoperative average scores were American Shoulder and Elbow Surgeons (ASES), 38; Simple Shoulder Test (SST), 3.3; and Visual Analogue Scale (VAS), 6.4. The average active forward elevation was 96 degrees and external rotation was 26 degrees . Average follow-up was 18 months (range, 12 to 48 months). Postoperative average scores were ASES, 69; SST, 7.8; and VAS, 2.3. Active forward elevation was 139 degrees and external rotation was 53 degrees . All were significant improvements (P.02). Most (94%) would have the surgery again. Radiologic evaluation at 1 year revealed an average joint space of 1.8 mm on anteroposterior views and 1.6 mm on axillary views. Five complications (17%) occurred within the first postoperative year, all of which required reoperation. Pain resulted in 2 conversions to a polyethylene glenoid. Polyethylene glenoids in young shoulders risk early failure. For young, high-demand shoulders with DJD requiring arthroplasty, the LMA shows promise. Most problems presented within the first year. Although not perfect, it provided significant pain relief, range-of-motion gains, and patient satisfaction without the risk of poly wear or loosening. Longer-term follow-up will be required to determine ultimate durability.

Highly active antiretroviral therapy (HAART) has dramatically altered the spectrum of morbidity and mortality in HIV-infected patients. This has been attributed to improvements in the lung microenvironment leading to enhanced pulmonary immunity, either by preventing the progressive loss of immune function or by actually promoting immune restoration. However, these changes have been accompanied by the recognition of new pulmonary complications in HIV-infected subjects, especially those associated with immune reconstitution. In this review, we will describe how HIV infection alters the normal pulmonary environment, highlight the effect of HAART on these perturbations and discuss potential complications of HAART in the lung, focusing on the pulmonary immune reconstitution inflammatory syndrome (IRIS).