Impact of prophylactic and 'rescue pack' antibiotics on the airway microbiome in chronic lung disease

The management of many chronic lung diseases involves multiple antibiotic prescriptions either to treat acute exacerbations or as prophylactic therapy to reduce the frequency of exacerbations and improve patients’ quality of life. AIM: To investigate the effects of antibiotics on the homeostasis of bacterial communities in the airways, and how this may contribute to antimicrobial resistance (AMR) among respiratory pathogens and microbiota. METHODS: Within an observational cohort study, sputum was collected from 84 patients with chronic obstructive pulmonary disease and/or bronchiectasis at stable state: 47 were receiving antibiotic prophylaxis therapy. V3-V4 16S-rRNA sequencing on Illumina MiSeq, quantitative PCR for typical respiratory pathogens, bacteriology cultures and antimicrobial susceptibility testing of sputum isolates, resistome analysis on a subset of 17 sputum samples using MinION metagenomics sequencing were performed. FINDINGS: The phylogenetic α-diversity and the total bacterial density in sputum were significantly lower in patients receiving prophylactic antibiotics (p=0.014 and 0.029, respectively). Antibiotic prophylaxis was associated with significantly lower relative abundance of respiratory pathogens such as Pseudomonas aeruginosa, Moraxella catarrhalis and members of family Enterobacteriaceae in the airway microbiome, but not Haemophilus influenzae and Streptococcus pneumoniae. No major definite directional shifts in the microbiota composition were identified with prophylactic antibiotic use at the cohort level. Surveillance of AMR and resistome analysis revealed a high frequency of resistance to macrolide and tetracycline in the cohort. AMR expressed by pathogenic bacterial isolates was associated with antibiotics prescribed as ‘rescue packs’ for prompt initiation of self-treatment of exacerbations (Spearman’s rho=0.408, p=0.02). CONCLUSIONS: Antibiotic prophylactic therapy suppresses recognised pathogenic bacteria in the sputum of patients with chronic lung disease. The use of antibiotic rescue packs may be driving AMR in this cohort rather than prophylactic antibiotics

Baseline and acquired resistance to bedaquiline, linezolid and pretomanid, and impact on treatment outcomes in four tuberculosis clinical trials containing pretomanid

Bedaquiline (B), pretomanid (Pa) and linezolid (L) are key components of new regimens for treating rifampicin-resistant tuberculosis (TB). However, there is limited information on the global prevalence of resistance to these drugs and the impact of resistance on treatment outcomes. Mycobacterium tuberculosis (MTB) phenotypic drug susceptibility and whole-genome sequence (WGS) data, as well as patient profiles from 4 pretomanid-containing trials–STAND, Nix-TB, ZeNix and SimpliciTB–were used to investigate the rates of baseline resistance (BR) and acquired resistance (AR) to BPaL drugs, as well as their genetic basis, risk factors and impact on treatment outcomes. Data from >1,000 TB patients enrolled from 2015 to 2020 in 12 countries was assessed. We identified 2 (0.3%) participants with linezolid BR. Pretomanid BR was also rare, with similar rates across TB drug resistance types (0–2.1%). In contrast, bedaquiline BR was more prevalent among participants with highly resistant TB or longer prior treatment histories than those with newly diagnosed disease (5.2–6.3% vs. 0–0.3%). Bedaquiline BR was a risk factor for bacteriological failure or relapse in Nix-TB/ZeNix; 3/12 (25%, 95% CI 5–57%) participants with vs. 6/185 (3.2%, 1.2–6.9%) without bedaquiline BR. Across trials, we observed no linezolid AR, and only 3 cases of bedaquiline AR, including 2 participants with poor adherence. Overall, pretomanid AR was also rare, except in ZeNix patients with bedaquiline BR. WGS analyses revealed novel mutations in canonical resistant genes and, in 7 MTB isolates, the genetic determinants could not be identified. The overall low rates of BR to linezolid and pretomanid, and to a lesser extent to bedaquiline, observed in the pretomanid trials are in support of the worldwide implementation of BPaL-based regimens. Similarly, the overall low AR rates observed suggest BPaL drugs are better protected in the regimens trialed here than in other regimens combining bedaquiline with more, but less effective drugs

The widespread use of topical antimicrobials enriches for resistance in Staphylococcus aureus isolated from patients with atopic dermatitis.

BACKGROUND: Carriage rates of Staphylococcus aureus on affected skin in atopic dermatitis (AD) are approximately 70%. Increasing disease severity during flares and overall disease severity correlate with increased burden of S. aureus. Treatment in AD therefore often targets S. aureus with topical and systemic antimicrobials. OBJECTIVES: To determine whether antimicrobial sensitivities and genetic determinants of resistance differed in S. aureus isolates from the skin of children with AD and healthy child nasal carriers. METHODS: In this case-control study, we compared S. aureus isolates from children with AD (n = 50) attending a hospital dermatology department against nasal carriage isolates from children without skin disease (n = 49) attending a hospital emergency department for noninfective conditions. Using whole genome sequencing we generated a phylogenetic framework for the isolates based on variation in the core genome, then compared antimicrobial resistance phenotypes and genotypes between disease groups. RESULTS: Staphylococcus aureus from cases and controls had on average similar numbers of phenotypic resistances per isolate. Case isolates differed in their resistance patterns, with fusidic acid resistance (FusR ) being significantly more frequent in AD (P = 0·009). The genetic basis of FusR also differentiated the populations, with chromosomal mutations in fusA predominating in AD (P = 0·049). Analysis revealed that FusR evolved multiple times and via multiple mechanism in the population. Carriage of plasmid-derived qac genes, which have been associated with reduced susceptibility to antiseptics, was eight times more frequent in AD (P = 0·016). CONCLUSIONS: The results suggest that strong selective pressure drives the emergence and maintenance of specific resistances in AD

Ears of the Armadillo: Global Health Research and Neglected Diseases in Texas

Neglected tropical diseases (NTDs) have\ud been recently identified as significant public\ud health problems in Texas and elsewhere in\ud the American South. A one-day forum on the\ud landscape of research and development and\ud the hidden burden of NTDs in Texas\ud explored the next steps to coordinate advocacy,\ud public health, and research into a\ud cogent health policy framework for the\ud American NTDs. It also highlighted how\ud U.S.-funded global health research can serve\ud to combat these health disparities in the\ud United States, in addition to benefiting\ud communities abroad

The effect of resistance training interventions on weight status in youth:a meta-analysis

Abstract Background There has been a rise in research into obesity prevention and treatment programmes in youth, including the effectiveness of resistance-based exercise. The purpose of this meta-analysis was to examine the effect of resistance training interventions on weight status in youth. Methods Meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered on PROSPERO (registration number CRD42016038365). Eligible studies were from English language peer-reviewed published articles. Searches were conducted in seven databases between May 2016 and June 2017. Studies were included that examined the effect of resistance training on weight status in youth, with participants of school age (5–18 years). Results There were 24 complete sets of data from 18 controlled trials (CTs) which explored 8 outcomes related to weight status. Significant, small effect sizes were identified for body fat% (Hedges’ g = 0.215, 95% CI 0.059 to 0.371, P = 0.007) and skinfolds (Hedges’ g = 0.274, 95% CI 0.066 to 0.483, P = 0.01). Effect sizes were not significant for: body mass (Hedges’ g = 0.043, 95% CI − 0.103 to 0.189, P = 0.564), body mass index (Hedges’ g = 0.024, 95% CI − 0.205 to 0.253, P = 0.838), fat-free mass (Hedges’ g = 0.073, 95% CI − 0.169 to 0.316, P = 0.554), fat mass (Hedges’ g = 0.180, 95% CI − 0.090 to 0.451, P = 0.192), lean mass (Hedges’ g = 0.089, 95% CI − 0.122 to 0.301, P = 0.408) or waist circumference (Hedges’ g = 0.209, 95% CI − 0.075 to 0.494, P = 0.149). Conclusions The results of this meta-analysis suggest that an isolated resistance training intervention may have an effect on weight status in youth. Overall, more quality research should be undertaken to investigate the impact of resistance training in youth as it could have a role to play in the treatment and prevention of obesity

Sensitivity of the UK clinical practice research datalink to detect neurodevelopmental effects of medicine exposure in utero:comparative analysis of an antiepileptic drug-exposed cohort

Introduction: Electronic healthcare data have several advantages over prospective observational studies, but the sensitivity of data on neurodevelopmental outcomes and its comparability with data generated through other methodologies is unknown. Objectives: The objectives of this study were to determine whether data from the UK Clinical Practice Research Datalink (CPRD) produces similar risk estimates to a prospective cohort study in relation to the risk of neurodevelopmental disorders (NDDs) following prenatal antiepileptic drug (AED) exposure. Methods: A cohort of mother–child pairs of women with epilepsy (WWE) was identified in the CPRD and matched to a cohort without epilepsy. The study period ran from 1 January 2000 to 31 March 2007 and children were required to be in the CPRD at age 6 years. AED exposure during pregnancy was determined from prescription data and children with an NDD diagnosis by 6 years were identified from Read clinical codes. The prevalence and risk of NDDs was calculated for mother–child pairs in WWE stratified by AED regimen and for those without epilepsy. Comparisons were made with the results of the prospective Liverpool and Manchester Neurodevelopment Group study which completed assessment on 201 WWE and 214 without epilepsy at age 6 years. Results: In the CPRD, 1018 mother–child pairs to WWE and 6048 to women without epilepsy were identified. The CPRD identified a lower prevalence of NDDs than the prospective study. In both studies, NDDs were more frequently reported in children of WWE than women without epilepsy, although the CPRD risk estimate was lower (2.16 vs. 0.96%, p < 0.001 and 7.46 vs. 1.87%, p = 0.0128). NDD prevalence differed across AED regimens but the CPRD data did not replicate the significantly higher risk of NDDs following in utero monotherapy valproate exposure (adjusted odds ratio [ORadj] 2.02, 95% confidence interval [CI] 0.52–7.86) observed in the prospective study (ORadj 6.05, 95% CI 1.65–24.53). Conclusion: It was possible to identify NDDs in the CPRD; however, the CPRD appears to under-record these outcomes. Larger studies are required to investigate further

Direct recordings of grid-like neuronal activity in human spatial navigation

Grid cells in the entorhinal cortex appear to represent spatial location via a triangular coordinate system. Such cells, which have been identified in rats, bats and monkeys, are believed to support a wide range of spatial behaviors. Recording neuronal activity from neurosurgical patients performing a virtual-navigation task, we identified cells exhibiting grid-like spiking patterns in the human brain, suggesting that humans and simpler animals rely on homologous spatial-coding schemes

Radiation-induced cancer after radiotherapy for non-Hodgkin's lymphoma of the head and neck: a retrospective study

<p>Abstract</p> <p>Background</p> <p>survivors of non-Hodgkin's lymphoma (NHL) are well known to be at an increased risk of second malignancies. In this study, we evaluated the incidence and clinical features of head and neck cancer (HNC) occurring after radiotherapy (RT) for NHL.</p> <p>Materials and methods</p> <p>We investigated the clinical records of 322 patients who had received RT for early-stage NHL of the head and neck at our institute between 1952 and 2000.</p> <p>Results</p> <p>There were 4 patients with a second HNC developing in the irradiated field, consisting of 2 patients with gum cancer, 1 case with tongue cancer and 1 case with maxillary sinus cancer. The pathological diagnosis in all the 4 patients was squamous cell carcinoma (SCC). Two of the patients (one with gum cancer and one with maxillary sinus cancer) died of the second HNC, while the remaining 2 patients are still living at the time of writing after therapy for the second HNC, with neither recurrence of the second tumor nor relapse of the primary tumor. The ratio of the observed to the expected number (O/E ratio) of a second HNC was calculated to be 12.7 (95%CI, 4.07–35.0), and the absolute excess risk (AER) per 10,000 person-years was 13.3. The median interval between the RT and the diagnosis of the second HNC was 17.0 years (range, 8.7 to 22.7 years).</p> <p>Conlusion</p> <p>The risk of HNC significantly increased after RT for early-stage NHL. These results suggest that second HNC can be regarded as one of the late complications of RT for NHL of the head and neck.</p

Revisions to the International Neuroblastoma Response Criteria: A Consensus Statement From the National Cancer Institute Clinical Trials Planning Meeting

Purpose More than two decades ago, an international working group established the International Neuroblastoma Response Criteria (INRC) to assess treatment response in children with neuroblastoma. However, this system requires modification to incorporate modern imaging techniques and new methods for quantifying bone marrow disease that were not previously widely available. The National Cancer Institute sponsored a clinical trials planning meeting in 2012 to update and refine response criteria for patients with neuroblastoma. Methods Multidisciplinary investigators from 13 countries reviewed data from published trials performed through cooperative groups, consortia, and single institutions. Data from both prospective and retrospective trials were used to refine the INRC. Monthly international conference calls were held from 2011 to 2015, and consensus was reached through review by working group leadership and the National Cancer Institute Clinical Trials Planning Meeting leadership council. Results Overall response in the revised INRC will integrate tumor response in the primary tumor, soft tissue and bone metastases, and bone marrow. Primary and metastatic soft tissue sites will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) and iodine-123 (123I) –metaiodobenzylguanidine (MIBG) scans or [18F]fluorodeoxyglucose–positron emission tomography scans if the tumor is MIBG nonavid. 123I-MIBG scans, or [18F]fluorodeoxyglucose–positron emission tomography scans for MIBG-nonavid disease, replace technetium-99m diphosphonate bone scintigraphy for osteomedullary metastasis assessment. Bone marrow will be assessed by histology or immunohistochemistry and cytology or immunocytology. Bone marrow with ≤ 5% tumor involvement will be classified as minimal disease. Urinary catecholamine levels will not be included in response assessment. Overall response will be defined as complete response, partial response, minor response, stable disease, or progressive disease. Conclusion These revised criteria will provide a uniform assessment of disease response, improve the interpretability of clinical trial results, and facilitate collaborative trial designs