Chronic infection and concomitant airway inflammation is the leading cause of morbidity and mortality for people living with cystic fibrosis (CF). Although chronic infection in CF is undeniably ...polymicrobial, involving a lung microbiota, infection surveillance and control approaches remain underpinned by classical aerobic culture-based microbiology. How to use microbiomics to direct clinical management of CF airway infections remains a crucial challenge. A pivotal step towards leveraging microbiome approaches in CF clinical care is to understand the ecology of the CF lung microbiome and identify ecological patterns of CF microbiota across a wide spectrum of lung disease. Assessing sputum samples from 299 patients attending 13 CF centres in Europe and the USA, we determined whether the emerging relationship of decreasing microbiota diversity with worsening lung function could be considered a generalised pattern of CF lung microbiota and explored its potential as an informative indicator of lung disease state in CF.
We tested and found decreasing microbiota diversity with a reduction in lung function to be a significant ecological pattern. Moreover, the loss of diversity was accompanied by an increase in microbiota dominance. Subsequently, we stratified patients into lung disease categories of increasing disease severity to further investigate relationships between microbiota characteristics and lung function, and the factors contributing to microbiota variance. Core taxa group composition became highly conserved within the severe disease category, while the rarer satellite taxa underpinned the high variability observed in the microbiota diversity. Further, the lung microbiota of individual patient were increasingly dominated by recognised CF pathogens as lung function decreased. Conversely, other bacteria, especially obligate anaerobes, increasingly dominated in those with better lung function. Ordination analyses revealed lung function and antibiotics to be main explanators of compositional variance in the microbiota and the core and satellite taxa. Biogeography was found to influence acquisition of the rarer satellite taxa.
Our findings demonstrate that microbiota diversity and dominance, as well as the identity of the dominant bacterial species, in combination with measures of lung function, can be used as informative indicators of disease state in CF. Video Abstract.
In contrast to infections with human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques, SIV infection of a natural host, sooty mangabeys (Cercocebus atys), is ...non-pathogenic despite high viraemia. Here we sequenced and assembled the genome of a captive sooty mangabey. We conducted genome-wide comparative analyses of transcript assemblies from C. atys and AIDS-susceptible species, such as humans and macaques, to identify candidates for host genetic factors that influence susceptibility. We identified several immune-related genes in the genome of C. atys that show substantial sequence divergence from macaques or humans. One of these sequence divergences, a C-terminal frameshift in the toll-like receptor-4 (TLR4) gene of C. atys, is associated with a blunted in vitro response to TLR-4 ligands. In addition, we found a major structural change in exons 3-4 of the immune-regulatory protein intercellular adhesion molecule 2 (ICAM-2); expression of this variant leads to reduced cell surface expression of ICAM-2. These data provide a resource for comparative genomic studies of HIV and/or SIV pathogenesis and may help to elucidate the mechanisms by which SIV-infected sooty mangabeys avoid AIDS.
Therapies to prevent maternal Zika virus (ZIKV) infection and its subsequent fetal developmental complications are urgently required. We isolated three potent ZIKV-neutralizing monoclonal antibodies ...(nmAbs) from the plasmablasts of a ZIKV-infected patient-SMZAb1, SMZAb2, and SMZAb5-directed against two different domains of the virus. We engineered these nmAbs with Fc LALA mutations that abrogate Fcγ receptor binding, thus eliminating potential therapy-mediated antibody-dependent enhancement. We administered a cocktail of these three nmAbs to nonhuman primates 1 day before challenge with ZIKV and demonstrated that the nmAbs completely prevented viremia in serum after challenge. Given that numerous antibodies have exceptional safety profiles in humans, the cocktail described here could be rapidly developed to protect uninfected pregnant women and their fetuses.
Background:
Arthroscopic debridement for osteochondritis dissecans (OCD) lesions of the capitellum is a relatively common and straightforward surgical option for failure of nonoperative management. ...However, the long-term outcomes of this procedure remain unknown.
Hypothesis:
Arthroscopic debridement of capitellar OCD would provide satisfactory long-term improvement in patient-reported outcomes.
Study Design:
Case series; Level of evidence, 4.
Methods:
Patients aged ≤18 years who underwent arthroscopic debridement procedures for OCD lesions (International Cartilage Repair Society grades 3 and 4) were identified. Procedures included loose body removal when needed and direct debridement of the lesion; marrow stimulation with drilling or microfracture was added at the discretion of each surgeon. The cohort consisted of 53 elbows. Patient evaluation included visual analog scale for pain; motion; subjective satisfaction; Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) scores; reoperation; and rate of return to sports.
Results:
At a mean 11 years of follow-up (range, 5-23 years), the median visual analog scale score for pain was 0, and 96% of patients reported being improved as compared with how they were before surgery. The mean ± SD QuickDASH score was 4 ± 9 points (range, 0-52 points), and 80% of patients returned to their sports of interest. The arc of motion significantly improved from 115°± 28° preoperatively to 130°± 17° at latest follow-up (P = .026). Seven elbows (13%) required revision surgery for OCD lesions, resulting in high rates of overall survivorship free of revision surgery: 90% (95% CI, 80%-96%) at 5 years and 88% (95% CI, 76%-94%) at 10 years. At final follow-up, 7 all-cause reoperations were performed without revision surgery on the OCD lesion.
Conclusion:
Arthroscopic debridement of grade 3 or 4 OCD lesions of the capitellum produced satisfactory patient-reported outcomes in a majority of elbows, although a subset of patients experienced residual symptoms. The inherent selection bias of our cohort should be considered when applying these results to the overall population with OCD lesions, as we do not recommend this procedure for all patients.
Summary Background Sickle-cell anaemia is associated with substantial morbidity from acute complications and organ dysfunction beginning in the first year of life. Hydroxycarbamide substantially ...reduces episodes of pain and acute chest syndrome, admissions to hospital, and transfusions in adults with sickle-cell anaemia. We assessed the effect of hydroxycarbamide therapy on organ dysfunction and clinical complications, and examined laboratory findings and toxic effects. Methods This randomised trial was undertaken in 13 centres in the USA between October, 2003, and September, 2009. Eligible participants had haemoglobin SS (HbSS) or haemoglobin Sβ0 thalassaemia, were aged 9–18 months at randomisation, and were not selected for clinical severity. Participants received liquid hydroxycarbamide, 20 mg/kg per day, or placebo for 2 years. Randomisation assignments were generated by the medical coordinating centre by a pre-decided schedule. Identical appearing and tasting formulations were used for hydroxycarbamide and placebo. Patients, caregivers, and coordinating centre staff were masked to treatment allocation. Primary study endpoints were splenic function (qualitative uptake on99 Tc spleen scan) and renal function (glomerular filtration rate by99m Tc-DTPA clearance). Additional assessments included blood counts, fetal haemoglobin concentration, chemistry profiles, spleen function biomarkers, urine osmolality, neurodevelopment, transcranial Doppler ultrasonography, growth, and mutagenicity. Study visits occurred every 2–4 weeks. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov , number NCT00006400. Findings 96 patients received hydroxycarbamide and 97 placebo, of whom 83 patients in the hydroxycarbamide group and 84 in the placebo group completed the study. Significant differences were not seen between groups for the primary endpoints (19 of 70 patients with decreased spleen function at exit in the hydroxycarbamide group vs 28 of 74 patients in the placebo group, p=0·21; and a difference in the mean increase in DTPA glomerular filtration rate in the hydroxycarbamide group versus the placebo group of 2 mL/min per 1·73 m2 , p=0·84). Hydroxycarbamide significantly decreased pain (177 events in 62 patients vs 375 events in 75 patients in the placebo group, p=0·002) and dactylitis (24 events in 14 patients vs 123 events in 42 patients in the placebo group, p<0·0001), with some evidence for decreased acute chest syndrome, hospitalisation rates, and transfusion. Hydroxyurea increased haemoglobin and fetal haemoglobin, and decreased white blood-cell count. Toxicity was limited to mild-to-moderate neutropenia. Interpretation On the basis of the safety and efficacy data from this trial, hydroxycarbamide can now be considered for all very young children with sickle-cell anaemia. Funding The US National Heart, Lung, and Blood Institute; and the National Institute of Child Health and Human Development.
Background
The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Masters Program designated bariatric surgery as a clinical pathway. Among the tiers of the Masters Program, ...revisional bariatric surgery is the highest tier of “mastery” within the pathway. This article presents the top 10 seminal studies representing the current landscape of revisional bariatrics.
Methods
The literature was systematically searched and seminal articles designated by consensus agreement of the SAGES Metabolic and Bariatric Surgery committee using multiple criteria, including impact on the field, citation frequency, and expert opinion. Articles were reviewed by committee members and presented in summarized fashion.
Results
The top 10 papers are presented in grouped thematic categories covering the early evolution of revisional bariatrics, changing criteria for reoperative bariatric surgery, divergence of revision versus conversion bariatric surgery, and recent technologic innovations in revisional bariatric surgery. Each summary is presented with expert appraisal and commentary.
Conclusion
These seminal papers represent a snapshot of the dynamic field of revisional bariatric surgery and emphasize the need to not only remain current with contemporary trends but also keep a patient-oriented perspective on patient and intervention selection for optimal success.
Hypoxia inducible factors (HIFs) are heterodimeric transcription factors induced in a variety of pathophysiological settings, including cancer. We describe the first detailed structure–activity ...relationship study of small molecules designed to inhibit HIF-2α–ARNT heterodimerization by binding an internal cavity of the HIF-2α PAS-B domain. Through a series of biophysical characterizations of inhibitor–protein interactions (NMR and X-ray crystallography), we have established the structural requirements for artificial inhibitors of the HIF-2α–ARNT PAS-B interaction. These results may serve as a foundation for discovering therapeutic agents that function by a novel mode of action.
The adenosine diphosphate (ADP) receptor P2RY12 (purinergic receptor P2Y, G protein coupled, 12) plays a critical role in platelet aggregation, and P2RY12 inhibitors are used clinically to prevent ...cardiac and cerebral thrombotic events. Extracellular ADP has also been shown to increase osteoclast (OC) activity, but the role of P2RY12 in OC biology is unknown. Here, we examined the role of mouse P2RY12 in OC function. Mice lacking P2ry12 had decreased OC activity and were partially protected from age-associated bone loss. P2ry12-/- OCs exhibited intact differentiation markers, but diminished resorptive function. Extracellular ADP enhanced OC adhesion and resorptive activity of WT, but not P2ry12-/-, OCs. In platelets, ADP stimulation of P2RY12 resulted in GTPase Ras-related protein (RAP1) activation and subsequent αIIbβ3 integrin activation. Likewise, we found that ADP stimulation induced RAP1 activation in WT and integrin β3 gene knockout (Itgb3-/-) OCs, but its effects were substantially blunted in P2ry12-/- OCs. In vivo, P2ry12-/- mice were partially protected from pathologic bone loss associated with serum transfer arthritis, tumor growth in bone, and ovariectomy-induced osteoporosis: all conditions associated with increased extracellular ADP. Finally, mice treated with the clinical inhibitor of P2RY12, clopidogrel, were protected from pathologic osteolysis. These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss.
Objective: This study evaluated health care worker exposure to antineoplastic drugs. Methods: A cross-sectional study examined environmental samples from pharmacy and nursing areas. A 6-week diary ...documented tasks involving those drugs. Urine was analyzed for two specific drugs, and blood samples were analyzed by the comet assay. Results: Sixty-eight exposed and 53 nonexposed workers were studied. Exposed workers recorded 10,000 drug-handling events during the 6-week period. Sixty percent of wipe samples were positive for at least one of the five drugs measured. Cyclophosphamide was most commonly detected, followed by 5-fluorouracil. Three of the 68 urine samples were positive for one drug. No genetic damage was detected in exposed workers using the comet assay. Conclusions: Despite following recommended safehandling practices, workplace contamination with antineoplastic drugs in pharmacy and nursing areas continues at these locations.
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