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Background Chronic Obstructive Pulmonary Disease (COPD) poses significant public health and economic challenges and performant prognostic models may be useful to direct treatment. The purpose of this study was to develop predictive models, validate the DOSE and updated ADO predictive models, and identify predictors of future hospitalisation and mortality in contemporary Australian COPD patients. Methods Data from 8,578 inpatients and outpatients diagnosed with COPD (via post-bronchodilator spirometry) between 2006 and 2021 at a large South Australian tertiary public hospital were analysed. Multivariate logistic models and Cox regression, utilising penalised regularisation in multiply imputed data, were used to investigate predictors of hospitalisation due to COPD exacerbation at 1-, 3-, and 5-years post-diagnosis, and COPD-specific mortality at 3- and 5-years. Haemoglobin-corrected DLCO (DLCOc) was used to extend the DOSE and updated ADO models. Results Locally developed models could predict COPD-specific 1-year hospitalisation risk with AUCs 0.80 (95% CI = [0.76, 0.83]) in males and 0.82 (95% CI = [0.78, 0.86]) in females on a temporally distinct hold-out set, with 3- and 5-year AUCs falling within this range. COPD-specific mortality was predicted with AUCs of 0.90 (95% CI = [0.85, 0.94]) and 0.89 (95% CI = [0.84, 0.92]) at 3 and 5 years in females, and 0.90 (95% CI = [0.86, 0.93]) and 0.88 (95% CI = [0.84, 0.92]) in males. Cox regression models predicted survival well in the test set for both females (C-index = 0.88, 95% CI = [0.85, 0.90]) and males (C-index = 0.86, 95% CI = [0.82, 0.88]). Local model performance was superior to that of the DOSE and updated ADO models for all outcomes, although not always significantly. Among the selected predictors, reduced DLCOc was strongly predictive of all outcomes. and acts as a short-term survival risk for follow-up durations less than 10 years. There was no significant difference in performance between sex, and there were differences in selected features and feature strength between sexes. Extending the extant clinical models with DLCOc significantly improved updated ADO and DOSE model fit and improved discriminatory performance, with the extended ADO index achieving AUC of 0.77 (95% CI = [0.75, 0.79]) and 0.87 (95% CI = [0.84, 0.89]) for predicting 5-year hospitalisation and mortality respectively across the full cohort. The extended DOSE index performed similarly with AUCs 0.77 (95% CI = [0.75, 0.79]) and 0.87 (95% CI = 0.83, 0.89)) for 5-year hospitalisation and mortality. Conclusions Ours is the only large clinical cohort and prognostic study of Australian COPD patients to date. Locally developed models achieved greater discriminative performance than the original updated ADO and DOSE models within our cohort. Extending the ADO and DOSE models with DLCOc significantly improved model fit in our cohort. We recommend further research into the use of DLCOc as a prognostic index for COPD, and its inclusion in future modelling attempts. Trial registration Retrospectively registered. Clinical trial number: Not Applicable.

Background: Pleural effusions remain a common medical problem which often requires diagnostic pleurocentesis to determine the underlying cause. Pleurocentesis is a frequently performed procedure worldwide with improved safety using ultrasound (US) technology. Objectives: This prospective, single-center study evaluated the use of an ultraportable handheld (UPHH) US compared with standard point-of-care (SPOC) US in determining a safe site for pleurocentesis. In addition, US image quality and factors impacting on image quality were assessed using both UPHH and SPOC US. Methods: Paired US assessments were performed by thoracic physicians using UPHH and SPOC US on patients with unilateral pleural effusions to determine a safe site for pleurocentesis (defined as >2 cm of pleural fluid, >2 cm from a solid organ/diaphragm, and <7 cm chest wall depth). Distance measurements for key structures and image quality scores (using a 5-point Likert rating scale) were obtained at the time of US assessment. Factors affecting image quality were analyzed using univariate analysis. Results: In 52 of the 54 included patients (96.3%), UPHH US was able to identify a safe site for pleurocentesis. Distance measurements between UPHH and SPOC US were not statistically different (all <0.5 cm with values of p > 0.05), but image quality was reduced in UPHH compared with SPOC US by 1 point on a 5-point Likert rating scale (p < 0.002). Increasing body mass index was associated with a reduction in image quality in both UPHH and SPOC US (all p < 0.01). Conclusions: Although image quality was lower in UPHH than SPOC US, a safe site was found in 96.3% of patients, which suggests that UPHH US may be a useful tool for diagnostic pleuro­centesis when SPOC US is not available (http://www.anzctr.org.au/, Australia New Zealand Clinical Trials Registry, No. ACTRN12618001592235).

Study Objectives: The use of opioid medication for chronic pain has been increasing. The main aim of this study was to assess how many patients on opioids for chronic pain had sleep disordered breathing (SDB) and the type of SDB. The impact of these medications on daytime arterial blood gas (ABG) measurements and psychomotor vigilance was also studied. Methods: Twenty-four patients (aged 18–75 years) on long-term opioids were prospectively recruited. Patients underwent home polysomnogram (PSG), psychomotor vigilance testing (PVT), and awake daytime ABG. Overnight PSG findings were compared to those of patients matched for age, sex, and BMI referred to our sleep service for evaluation of SDB. PVT results in the patient cohort were compared to PVT in healthy controls. Results: Forty-six percent of opioid patients had severe SDB as defined by an apnea hypopnea index (AHI) > 30/h. The severity of SDB was similar in opioid-treated pain clinic patients and sleep clinic patients (mean ± SD AHI: Opioid-treated patients 32.7 ± 25.6; Sleep Study comparator group 28.9 ± 24.6, p = 0.6). Opioid patients had a higher frequency of central apneas and a lower arousal index (CAI: 3.9 ± 8.3 vs. 0.3 ± 0.5 events/h; p = 0.004, AI 8.0 ± 4.1 vs. 20.1 ± 13.8, p < 0.001). Pain clinic patients had impaired gas exchange during sleep and wakefulness. Nine of 20 (45%) had daytime hypercapnia, indicating a surprising number were in chronic respiratory failure. Morphine equivalent doses correlated with the severity of SDB. PVT was impaired when compared to a healthy PVT comparator group (RT: Opioid-treated patients 0.43 ± 0.27: Healthy PVT comparator group 0.28 ± 0.03 sec; p < 0.001). Conclusions: Patients on long-term opioids frequently have severe SDB, which in part is central in origin. PVT was markedly impaired. Half of the patients studied have evidence of chronic ventilatory failure. Commentary: A commentary on this article appears in this issue on page 853. Citation: Rose AR, Catcheside PG, McEvoy RD, Paul D, Kapur D, Peak E, Vakulin A, Antic NA. Sleep disordered breathing and chronic respiratory failure in patients with chronic pain on long term opioid therapy. J Clin Sleep Med 2014;10(8):847–852.

A case of chylothorax following innominate vein thrombosis which developed as a late complication of transvenous pacemaker implantation is discussed. A 78-year-old man presented with a refractory left-sided pleural effusion, which turned out to be a chylothorax. He had undergone a transvenous pacemaker implantation 6 years earlier for sick sinus syndrome. Aetiological work-up showed occlusion of the innominate vein as the cause for the chylothorax. The chylothorax resolved following pleurodesis with talc slurry, and the innominate vein was recanalized by angioplasty. To our knowledge, this is the first report of a case of this nature.

A case of chylothorax following innominate vein thrombosis, which developed as a late complication of transvenous pacemaker implantation, is discussed. A 78-year-old man presented with a refractory left-sided pleural effusion, which turned out to be chylothorax. He had undergone a transvenous pacemaker implantation 6 years earlier for sick sinus syndrome. The aetiological workup showed occlusion of the innominate vein as the cause for the chylothorax. The chylothorax resolved following pleurodesis with talc slurry, and the innominate vein was recanalized by angioplasty. To our knowledge this is the first report of a case of this nature.

Holtzman and colleagues identify PARP9-DTX3L as an E3 ubiquitin ligase complex that interacts with STAT1 to modify chromatin accessibility for expression in interferon-stimulated genes and to target viral proteases for degradation. Enhancing the response to interferon could offer an immunological advantage to the host. In support of this concept, we used a modified form of the transcription factor STAT1 to achieve hyper-responsiveness to interferon without toxicity and markedly improve antiviral function in transgenic mice and transduced human cells. We found that the improvement depended on expression of a PARP9-DTX3L complex with distinct domains for interaction with STAT1 and for activity as an E3 ubiquitin ligase that acted on host histone H2BJ to promote interferon-stimulated gene expression and on viral 3C proteases to degrade these proteases via the immunoproteasome. Thus, PARP9-DTX3L acted on host and pathogen to achieve a double layer of immunity within a safe reserve in the interferon signaling pathway.

Brain organoids offer unprecedented insights into brain development and disease modeling and hold promise for drug screening. Significant hindrances, however, are morphological and cellular heterogeneity, inter-organoid size differences, cellular stress, and poor reproducibility. Here, we describe a method that reproducibly generates thousands of organoids across multiple hiPSC lines. These High Quantity brain organoids (Hi-Q brain organoids) exhibit reproducible cytoarchitecture, cell diversity, and functionality, are free from ectopically active cellular stress pathways, and allow cryopreservation and re-culturing. Patient-derived Hi-Q brain organoids recapitulate distinct forms of developmental defects: primary microcephaly due to a mutation in CDK5RAP2 and progeria-associated defects of Cockayne syndrome. Hi-Q brain organoids displayed a reproducible invasion pattern for a given patient-derived glioma cell line. This enabled a medium-throughput drug screen to identify Selumetinib and Fulvestrant, as inhibitors of glioma invasion in vivo. Thus, the Hi-Q approach can easily be adapted to reliably harness brain organoids’ application for personalized neurogenetic disease modeling and drug discovery. Human brain organoids are plagued by heterogeneity and poor reproducibility, critical parameters for reliable disease modeling and drug testing. Here, the authors report on Hi-Q organoids which solve these limitations and can be cryopreserved in large quantities.

Microbes have central roles in ocean food webs and global biogeochemical processes, yet specific ecological relationships among these taxa are largely unknown. This is in part due to the dilute, microscopic nature of the planktonic microbial community, which prevents direct observation of their interactions. Here, we use a holistic (that is, microbial system-wide) approach to investigate time-dependent variations among taxa from all three domains of life in a marine microbial community. We investigated the community composition of bacteria, archaea and protists through cultivation-independent methods, along with total bacterial and viral abundance, and physico-chemical observations. Samples and observations were collected monthly over 3 years at a well-described ocean time-series site of southern California. To find associations among these organisms, we calculated time-dependent rank correlations (that is, local similarity correlations) among relative abundances of bacteria, archaea, protists, total abundance of bacteria and viruses and physico-chemical parameters. We used a network generated from these statistical correlations to visualize and identify time-dependent associations among ecologically important taxa, for example, the SAR11 cluster, stramenopiles, alveolates, cyanobacteria and ammonia-oxidizing archaea. Negative correlations, perhaps suggesting competition or predation, were also common. The analysis revealed a progression of microbial communities through time, and also a group of unknown eukaryotes that were highly correlated with dinoflagellates, indicating possible symbioses or parasitism. Possible ‘keystone’ species were evident. The network has statistical features similar to previously described ecological networks, and in network parlance has non-random, small world properties (that is, highly interconnected nodes). This approach provides new insights into the natural history of microbes.

IntroductionAir pollution is a significant global health concern, with studies from the USA and Europe linking long-term exposure to respiratory issues and poor school attendance in children. While Indian cities experience much higher pollution levels, the impact on lung development in Indian children remains unclear. This study aims to assess the burden of impaired lung function in Indian children and identify key factors contributing to pollution-induced lung injury.Methods and analysisThis longitudinal, prospective cohort study is conducted in four cities categorised by particulate matter 2.5 (PM2.5) levels: ‘very high’ (Delhi), ‘high’ (Mumbai, Bangalore) and ‘moderate’ (Mysore). A total of 4000 participants (1000 from each city) will be included in the study. Participants will complete a structured questionnaire covering sociodemographics, asthma and allergy history (International Study of Asthma and Allergies in Childhood core questionnaire), dietary intake (24-hour recall and Food Frequency Questionnaire), Physical Activity-C Questionnaire and air pollution exposure. Spirometry and Forced Oscillation Technique will be used to assess lung function. Blood samples will be collected for identification of biomarkers to predict lung impairment. After quality checks, data will be compiled, summarising pulmonary function parameters alongside covariates and confounders. Analysis of Variance (ANOVA) will assess between-city and within-city differences in lung function.We anticipate a higher prevalence of reduced lung function in children residing in cities with very high and high PM2.5 levels compared with the moderately polluted city. Findings from this study could establish normal age-appropriate lung function reference values for Indian urban children, aiding in clinical diagnosis.If a reliable biomarker for identifying children at risk of lung impairment is available, it could serve as an early predictor of poor lung health in asymptomatic children.Ethics and disseminationThe approval from individual site institutional review board (IRB) is obtained prior to initiation of the study from institutional ethics committee, St. John’s Medical College and Hospital, Bangalore; institutional ethics committee, JSS Medical College, Mysore; institute ethics committee, Indian Institute of Technology Bombay and institute ethics committee, All India Institute of Medical Sciences. Findings from this study will be disseminated through conference presentations, peer-reviewed publications and establishment of normal age-appropriate lung function reference values for children living in urban India.