Stratifying asthma severity in children using cough sound analytic technology.

Introduction: Asthma is a common childhood respiratory disorder characterized by wheeze, cough and respiratory distress responsive to bronchodilator therapy. Asthma severity can be determined by subjective, manual scoring systems such as the Pulmonary Score (PS). These systems require significant medical training and expertise to rate clinical findings such as wheeze characteristics, and work of breathing. In this study, we report the development of an objective method of assessing acute asthma severity based on the automated analysis of cough sounds.Methods: We collected a cough sound dataset from 224 children; 103 without acute asthma and 121 with acute asthma. Using this database coupled with clinical diagnoses and PS determined by a clinical panel, we developed a machine classifier algorithm to characterize the severity of airway constriction. The performance of our algorithm was then evaluated against the PS from a separate set of patients, independent of the training set.Results: The cough-only model discriminated no/mild disease (PS 0-1) from severe disease (PS 5,6) but required a modified respiratory rate calculation to separate very severe disease (PS > 6). Asymptomatic children (PS 0) were separated from moderate asthma (PS 2-4) by the cough-only model without the need for clinical inputs.Conclusions: The PS provides information in managing childhood asthma but is not readily usable by non-medical personnel. Our method offers an objective measurement of asthma severity which does not rely on clinician-dependent inputs. It holds potential for use in clinical settings including improving the performance of existing asthma-rating scales and in community-management programs.AbbreviationsAMaccessory muscleBIbreathing indexCIconfidence intervalFEV1forced expiratory volume in one secondLRlogistic regressionPEFRpeak expiratory flow ratePSpulmonary scoreRRrespiratory rateSDstandard deviationSEstandard errorWAWestern Australia.

A prospective multicentre study testing the diagnostic accuracy of an automated cough sound centred analytic system for the identification of common respiratory disorders in children.

BACKGROUND: The differential diagnosis of paediatric respiratory conditions is difficult and suboptimal. Existing diagnostic algorithms are associated with significant error rates, resulting in misdiagnoses, inappropriate use of antibiotics and unacceptable morbidity and mortality. Recent advances in acoustic engineering and artificial intelligence have shown promise in the identification of respiratory conditions based on sound analysis, reducing dependence on diagnostic support services and clinical expertise. We present the results of a diagnostic accuracy study for paediatric respiratory disease using an automated cough-sound analyser. METHODS: We recorded cough sounds in typical clinical environments and the first five coughs were used in analyses. Analyses were performed using cough data and up to five-symptom input derived from patient/parent-reported history. Comparison was made between the automated cough analyser diagnoses and consensus clinical diagnoses reached by a panel of paediatricians after review of hospital charts and all available investigations. RESULTS: A total of 585 subjects aged 29 days to 12 years were included for analysis. The Positive Percent and Negative Percent Agreement values between the automated analyser and the clinical reference were as follows: asthma (97, 91%); pneumonia (87, 85%); lower respiratory tract disease (83, 82%); croup (85, 82%); bronchiolitis (84, 81%). CONCLUSION: The results indicate that this technology has a role as a high-level diagnostic aid in the assessment of common childhood respiratory disorders. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry (retrospective) - ACTRN12618001521213 : 11.09.2018.

Singapore tuberculosis (TB) clinical management guidelines 2024: A modified Delphi adaptation of international guidelines for drug-susceptible TB infection and pulmonary disease.

Introduction: Tuberculosis (TB) remains endemic in Singapore. Singapore's clinical practice guidelines for the management of tuberculosis were first published in 2016. Since then, there have been major new advances in the clinical management of TB, ranging from diagnostics to new drugs and treatment regimens. The National TB Programme convened a multidisciplinary panel to update guidelines for the clinical management of drug-susceptible TB infection and disease in Singapore, contextualising current evidence for local practice. Method: Following the ADAPTE framework, the panel systematically reviewed, scored and synthesised English-language national and international TB clinical guidelines published from 2016, adapting recommendations for a prioritised list of clinical decisions. For questions related to more recent advances, an additional primary literature review was conducted via a targeted search approach. A 2-round modified Delphi process was implemented to achieve consensus for each recommendation, with a final round of edits after consultation with external stakeholders. Results: Recommendations for 25 clinical questions spanning screening, diagnosis, selection of drug regimen, monitoring and follow-up of TB infection and disease were formulated. The availability of results from recent clinical trials led to the inclusion of shorter treatment regimens for TB infection and disease, as well as consensus positions on the role of newer technologies, such as computer-aided detection-artificial intelligence products for radiological screening of TB disease, next-generation sequencing for drug-susceptibility testing, and video observation of treatment. Conclusion: The panel updated recommendations on the management of drug-susceptible TB infection and disease in Singapore.

Aerated Static Pile Composting for Industrial Biowastes: From Engineering to Microbiology.

This work demonstrated the feasibility of an industrial-scale aerated static pile composting system for treating one of the common biowastes-soybean curd residue. The mixing ratios of the feedstock were optimized to achieve a carbon-nitrogen ratio and a moisture level in the ranges of 25-35 and 60-70%, respectively. This open-air composting system required 6-7 months to obtain a mature compost. Solvita and seed germination tests further confirmed the maturity of the compost, with 25% compost extract concentration yielding the best germination index in the absence of phytotoxicity. The bacterial and fungal compositions of the compost piles were further examined with metagenomic analysis. Thermoactinomyces spp., Oceanobacillus spp., and Kroppenstedtia spp. were among the unique bacteria found, and Diutina rugosa, Thermomyces dupontii, and Candida taylorii were among the unique fungi found in the compost piles, suggesting the presence of good microorganisms for degrading the organic biowastes.

Sugar transporter Slc37a2 regulates bone metabolism in mice via a tubular lysosomal network in osteoclasts.

Osteoclasts are giant bone-digesting cells that harbor specialized lysosome-related organelles termed secretory lysosomes (SLs). SLs store cathepsin K and serve as a membrane precursor to the ruffled border, the osteoclast's 'resorptive apparatus'. Yet, the molecular composition and spatiotemporal organization of SLs remains incompletely understood. Here, using organelle-resolution proteomics, we identify member a2 of the solute carrier 37 family (Slc37a2) as a SL sugar transporter. We demonstrate in mice that Slc37a2 localizes to the SL limiting membrane and that these organelles adopt a hitherto unnoticed but dynamic tubular network in living osteoclasts that is required for bone digestion. Accordingly, mice lacking Slc37a2 accrue high bone mass owing to uncoupled bone metabolism and disturbances in SL export of monosaccharide sugars, a prerequisite for SL delivery to the bone-lining osteoclast plasma membrane. Thus, Slc37a2 is a physiological component of the osteoclast's unique secretory organelle and a potential therapeutic target for metabolic bone diseases.

Diagnostic Errors Are Common in Acute Pediatric Respiratory Disease: A Prospective, Single-Blinded Multicenter Diagnostic Accuracy Study in Australian Emergency Departments.

Background: Diagnostic errors are a global health priority and a common cause of preventable harm. There is limited data available for the prevalence of misdiagnosis in pediatric acute-care settings. Respiratory illnesses, which are particularly challenging to diagnose, are the most frequent reason for presentation to pediatric emergency departments. Objective: To evaluate the diagnostic accuracy of emergency department clinicians in diagnosing acute childhood respiratory diseases, as compared with expert panel consensus (reference standard). Methods: Prospective, multicenter, single-blinded, diagnostic accuracy study in two well-resourced pediatric emergency departments in a large Australian city. Between September 2016 and August 2018, a convenience sample of children aged 29 days to 12 years who presented with respiratory symptoms was enrolled. The emergency department discharge diagnoses were reported by clinicians based upon standard clinical diagnostic definitions. These diagnoses were compared against consensus diagnoses given by an expert panel of pediatric specialists using standardized disease definitions after they reviewed all medical records. Results: For 620 participants, the sensitivity and specificity (%, [95% CI]) of the emergency department compared with the expert panel diagnoses were generally poor: isolated upper respiratory tract disease (64.9 [54.6, 74.4], 91.0 [88.2, 93.3]), croup (76.8 [66.2, 85.4], 97.9 [96.2, 98.9]), lower respiratory tract disease (86.6 [83.1, 89.6], 92.9 [87.6, 96.4]), bronchiolitis (66.9 [58.6, 74.5], 94.3 [80.8, 99.3]), asthma/reactive airway disease (91.0 [85.8, 94.8], 93.0 [90.1, 95.3]), clinical pneumonia (63·9 [50.6, 75·8], 95·0 [92·8, 96·7]), focal (consolidative) pneumonia (54·8 [38·7, 70·2], 86.2 [79.3, 91.5]). Only 59% of chest x-rays with consolidation were correctly identified. Between 6.9 and 14.5% of children were inappropriately prescribed based on their eventual diagnosis. Conclusion: In well-resourced emergency departments, we have identified a previously unrecognized high diagnostic error rate for acute childhood respiratory disorders, particularly in pneumonia and bronchiolitis. These errors lead to the potential of avoidable harm and the administration of inappropriate treatment.

Mutations within the TNF-like core domain of RANKL impair osteoclast differentiation and activation.

Receptor activator of nuclear factor-kappaB ligand (RANKL) is a key factor necessary for osteoclast differentiation and activation. Mutations within the TNF-like core domain of RANKL have been recently reported in patients with osteoclast-poor autosomal recessive osteopetrosis. However, the functional consequence owing to RANKL mutations has not been well characterized. Here we describe the functional propensity of RANKL mutants in osteoclast differentiation and their impact on RANKL-mediated signaling cascades. Recombinant RANKL (rRANKL) mutants within the TNF-like core domain exhibited diminished osteoclastogenic potential as compared with wild-type rRANKL1 encoding the full TNF-like core domain [amino acids (aa) 160-318]. Consistent with the insufficient activities on osteoclastogenesis, rRANKL mutants showed reduced activation of nuclear factor-kappaB, IkappaBalpha degradation, and ERK phosphorylation. In addition, we found that rRANKL mutants interfered with wild-type rRANKL-induced osteoclastogenesis with deletion mutant rRANKL5 (aa 246-318) exhibiting the greatest inhibitory effect. The same mutant also significantly reduced wild-type rRANKL1 (aa 160-318)-induced osteoclastic bone resorption in vitro. BIAcore assays demonstrated that rRANKL5 alone, lacking the AA'' and CD loops, weakly binds to receptor activator of nuclear factor-kappaB (RANK). Intriguingly, preincubation of mutant rRANKL5 with rRANKL1 before exposure to RANK enhanced the maximal binding level to RANK, indicating that rRANKL5 forms hybrid trimeric complexes with rRANKL1. Furthermore, RANKL mutant mimicking human RANKL V277 mutation in patients, impairs osteoclast differentiation and signaling. Taken together, these data lend support to the notion that the TNF-like core domain of RANKL contains structural determinants that are crucial for osteoclast differentiation and activation, thus providing a possible mechanistic explanation for the observed phenotype in osteopetrotic patients harboring RANKL mutations.

Introducing the ORIGINS project: a community-based interventional birth cohort.

Objectives Non-communicable diseases (NCDs) pose the greatest threat to human health globally. The dramatic rise in early onset NCDs - such as childhood obesity, the allergy epidemic and an increasing burden of mental ill health in children and youth - reflect the profound early impact of modern environments on developing systems. The ORIGINS Project is a research platform enabling world class investigation of early antecedent pathways to NCDs, and how to curtail these. As well as facilitating strategic long-term research capacity, ORIGINS is a pipeline for short-term productivity through a series of clinical trials, early interventions, mechanistic studies, and targeted research questions to improve maternal and paternal health and the early environment. Methods ORIGINS is a decade-long collaborative initiative between the Joondalup Health Campus (JHC) and the Telethon Kids Institute (TKI) to establish a Western Australian (WA) birth cohort of 10,000 families, enrolled during pregnancy. It is currently funded to follow up participating children and their families to five years of age. Comprehensive data and biological samples are collected from participants at up to 15 different timepoints, from the first antenatal clinic visit. In the process, ORIGINS is creating a major research platform, consisting of an extensive, world class biobank and databank. Of key strength and novelty, ORIGINS includes a series of harmonised nested sub-projects integrated with clinical and diagnostic services and providing real-time feedback to improve the health of individuals and the community. Conclusions At its core, ORIGINS aims to improve the health and quality of life of the next generation through improved pathways to optimise the early environment and reduce adversity by promoting primary prevention, early detection and early intervention. This dynamic, interactive, community-based project not only provides novel research capacity, productivity, collaboration and translational impact on future generations - it is also anticipated to have flow on benefits for community engagement, cohesion and purpose. This will provide a sentinel example for tailored replication in other communities around the world as part of interconnected grass root strategies to improve planetary health.

Adolescent and young adult health in a children's hospital: Everybody's business.

BACKGROUND: To guide the development of adolescent health training and the planning of future services, accurate data describing health service use by adolescents and young adults are needed. AIM: To describe admission rates for adolescents (12-17 years) and young adults (age 18 years and over) attending a specialist children's hospital over an 8-year period. Specific objectives were to describe the (i) proportion of adolescents and young adults admitted under different specialties; (ii) age range, with emphasis on those 18 years and over; and (iii) proportion of patients admitted to the general adolescent ward. METHODS: Data on adolescent and young adult admissions to Princess Margaret Hospital (PMH) were collected prospectively from July 2000 to June 2008. RESULTS: Adolescents and young adults accounted for one fifth (range 18-22%) of all admissions to PMH. Over the 8-year period, the number of adolescent and young adult admissions increased from 3935 (54% males) to 4967 (56% males) per year. The proportion admitted to the general adolescent ward ranged from 22% to 36%. The three specialties admitting the most adolescents and young adults were General Surgery (11-13%), Orthopaedics (11-13%) and Oncology/Haematology (10-14%). The age range was: 12-14 years (57-67%); 15-17 (30-39%); 18+ (2-5%). At least 15 patients aged 20 or over were admitted each year, mostly for Dental or Plastic Surgery. CONCLUSIONS: Adolescent and young adult health is part of the core business of paediatrics. This should be reflected in the planning of future paediatric services. All trainees require some basic training, regardless of heir specialty area.

Implementation of infection prevention and control in acute care hospitals in Mainland China - a systematic review.

Background: Healthcare-associated infections (HAIs) and antimicrobial resistance (AMR) affect patients in acute-care hospitals worldwide. No systematic review has been published on adoption and implementation of the infection prevention and control (IPC) key components. The objective of this systematic review was to assess adoption and implementation of the three areas issued by the "National Health Commission of the People's Republic of China" in acute-care hospitals in Mainland China, and to compare the findings with the key and core components on effective IPC, issued by the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO). Methods: We searched PubMed and the Chinese National Knowledge Infrastructure for reports on the areas "structure, organisation and management of IPC", "education and training in IPC", and "surveillance of outcome and process indicators in IPC" in acute-care facilities in Mainland China, published between January 2012 and October 2017. Results were stratified into primary care hospitals and secondary/tertiary care hospitals. Results: A total of 6580 publications were retrieved, of which 56 were eligible for final analysis. Most of them were survey reports (n = 27), followed by observational studies (n = 17), and interventional studies (n = 12), either on hand hygiene promotion and best practice interventions (n = 7), or by applying education and training programmes (n = 5). More elements on IPC were reported by secondary/tertiary care hospitals than by primary care hospitals. Gaps were identified in the lack of detailing on organisation and management of IPC, education and training activities, and targets of surveillance such as central line-associated bloodstream infections, ventilator associated pneumonia, catheter-associated urinary tract infections, and Clostridium difficile infections. Information was available on adoption and implementation of 7 out of the 10 ECDC key components, and 7 out of the 8 WHO core components. Conclusion: To variable degrees, there is evidence on implementation of all NHCPRC areas and of most of the ECDC key components and the WHO core components in acute care hospitals in Mainland China. The results are encouraging, but gaps in effective IPC were identified that may be used to guide future national policy-making in Mainland China.

A Case of Relapsing Peritoneal Dialysis-Associated Peritonitis by Dokdonella koreensis.

Peritonitis is a common and serious complication of peritoneal dialysis (PD) with significant morbidity. We report the first case of relapsing Dokdonella koreensis peritonitis in a patient on peritoneal dialysis. A 63-year-old Chinese man, with history of renal failure on continuous ambulatory peritoneal dialysis, presented with cloudy peritoneal effluent and abdominal pain. There was no sign or symptom suggestive of exit-site/tunnel tract infection. Peritoneal effluent cultures yielded Dokdonella koreensis which was initially misidentified as Weeksella virosa and Brevundimonas species by the API® 20 NE and VITEK® 2 GN ID card, respectively. He was treated with intraperitoneal amikacin, but the infection relapsed within a few days upon completing each antibiotic course. He eventually required removal of catheter and was transferred to hemodialysis. Infections due to unusual organisms may pose a diagnostic issue as currently available commercial tests will not be able to identify them. There is a role for using 16S rRNA sequencing to help identify these organisms and guide patient management.

Streptococcus pneumoniae bacteraemia due to parotitis in a patient with systemic sclerosis and secondary Sjögren's syndrome.

INTRODUCTION: Invasive pneumococcal disease is an uncommon and notifiable disease in Singapore. It is often associated with significant morbidity and mortality. We report a rare case of invasive pneumococcal bacteraemia due to parotitis in a patient with systemic sclerosis and secondary Sjögren's syndrome. We also present a retrospective review of Streptococcus pneumoniae bacteraemia cases in Singapore General Hospital from January 2011 to April 2016. CASE PRESENTATION: A 59-year-old Malay lady with a history of systemic sclerosis with secondary Sjögren's syndrome presented with fever and left parotid gland swelling. Clinical examination revealed poor salivary pooling and left parotid swelling without fluctuance. Ultrasound of the left parotid gland confirmed acute parotitis without evidence of abscess or sialolithiasis. Blood cultures were positive for S. pneumoniae. She was diagnosed to have invasive pneumococcal bacteraemia secondary to acute parotitis, and treated with intravenous benzylpenicillin with clearance of bacteraemia after 3 days. Upon discharge, her antibiotics were changed to intravenous ceftriaxone to facilitate outpatient parenteral antibiotic therapy for another 2 weeks. She responded favourably to antibiotics at follow-up, with no complications from the bacteraemia. A review of the microbiological records of the Singapore General Hospital revealed 116 cases of pneumococcal bacteraemia, most (80.3 %) of which were due to pneumonia. None were due to parotitis. CONCLUSION: S. pneumoniae parotitis and subsequent bacteraemia is rare. Prompt recognition of the disease and appropriate use of antibiotics are important. This case highlights that close communication between healthcare workers (microbiologist, rheumatologist and infectious disease specialist) is essential in ensuring good clinical outcomes in patients with a potentially fatal disease.

CD4+ T cells in lymph nodes of UVB-irradiated mice suppress immune responses to new antigens both in vitro and in vivo.

The mechanisms by which erythemal UVB irradiation modulates systemic immune responses to antigens applied to non-irradiated sites are poorly understood. In this study, regulatory CD4+ T cells were identified in the skin-draining lymph nodes (SDLNs) of UVB-irradiated, but otherwise naive mice. A transgenic mouse strain (DO11.10) was utilized in which the majority of CD4+ T cells expressed the ovalbumin (OVA(323-339)) T-cell receptor. Thus, T-cell responses could be examined following erythemal UVB irradiation without further antigen sensitization. CD4+ T cells from the SDLNs of UVB-irradiated mice had significantly reduced capacity to respond to presentation of the OVA(323-339) peptide in vitro. Transfer of CD4+ T cells from the SDLNs of UVB-irradiated antigen-naive mice significantly reduced both OVA sensitization and contact hypersensitivity responses to an experimental hapten in the recipient mice. Depletion of CD4+CD25+ cells abrogated this UVB-suppressive effect in the in vitro proliferation assay. There was also a significant increase in the proportion of CD4+CD25+Foxp3+ cells in the SDLNs of UVB-irradiated mice. The potential of these regulatory cells poised to regulate responses to incoming antigens at distant non-irradiated sites broadens the biological impact of UVB irradiation of skin on immunity.

Calcium/calmodulin-dependent kinase activity is required for efficient induction of osteoclast differentiation and bone resorption by receptor activator of nuclear factor kappa B ligand (RANKL).

Calcium/calmodulin-dependent protein kinase (CaMK) is a major down stream mediator of Ca(2+) signaling in a wide range of cellular functions, including ion channel and cell cycle regulation and neurotransmitter synthesis and release. Here we have investigated the role of the CaMK signaling pathway in osteoclast differentiation and bone resorption. We observed that the CaMKI, CaMKII gamma isoforms were present in both bone-marrow derived macrophages and RAW264.7 murine macrophage cell line, and that expression persisted during osteoclast differentiation in the presence of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL). RANKL-induced differentiation was accompanied by increased cyclic AMP response element transcriptional activity, and ERK phosphorylation, which are both downstream targets of CaMK. Two selective inhibitors of CaMKs, KN-93 and KN-62, inhibited osteoclastogenesis in a time and concentration-dependent manner. This was accompanied by suppression of cathepsin K expression and osteoclastic bone resorption, which are markers for differentiated osteoclast function. KN-93 and KN-62 both inhibited RANKL-induced ERK phosphorylation and CREB transcriptional activity. These findings imply a role for CaMK in osteoclast differentiation and bone resorption.

Effect of both ultraviolet B irradiation and histamine receptor function on allergic responses to an inhaled antigen.

Exposure of skin to UVB radiation (290-320 nm) modulates the immune system, with most studies showing a suppression of Th1-driven immune responses. This study investigated the effects of UVB on Th2-associated immune responses using a murine model of allergic respiratory inflammation. C57BL/6, histamine receptor-1 knockout (H1RKO), and histamine receptor-2 knockout (H2RKO) mice were exposed to a single 4 kJ/m(2) dose of UVB (twice a minimal edemal dose) on shaved dorsal skin 3 days before intranasal sensitization with papain, a cysteine protease homologue of the dust mite allergen Der p 1. H1RKO mice demonstrated enhanced papain-specific inflammatory responses in the lung-draining lymph nodes (LDLNs), whereas the responses of H2RKO mice closely mimicked those of C57BL/6 mice. UVB irradiation 3 days before sensitization reduced in vitro papain-specific proliferation of LDLN cells of C57BL/6 and H1RKO mice but not H2RKO mice 24 h after challenge. The regulatory effect of UVB was transferred by adoptive transfer of unfractionated LDLN cells from UVB-irradiated, papain-sensitized C57BL/6 and H1RKO donor mice in naive recipients of the corresponding strain that were subsequently sensitized and challenged with papain. Additionally, UVB exposure suppressed papain-induced IL-5 and IL-10 production in vitro by LDLN cells from H1RKO mice but not from C57BL/6 mice or H2RKO mice. The results of this study demonstrate systemic immunomodulation of responses to intranasally delivered Ag by UVB irradiation and implicate a role for the H2 receptor in UVB-induced suppression of Ag-specific responses in the draining lymph nodes.

Primary defect in UVB-induced systemic immunomodulation does not relate to immature or functionally impaired APCs in regional lymph nodes.

UVB irradiation of the shaved dorsal skin of mice can cause both local and systemic suppression of contact hypersensitivity responses; the former demonstrated by administration of the sensitizing Ag/hapten to the irradiated site and the latter by its administration at least 72 h later to distal unirradiated sites. The immunological basis of systemic immunomodulation is not clear. When haptens (trinitrochlorobenzene, FITC) were administered to the shaved ventral skin 4 days after irradiation (8 kJ/m(2)) to the shaved dorsum of BALB/c mice, CD11c(+)/FITC(+) cells in the skin-draining lymph nodes from control and irradiated mice produced on a per cell basis similar levels of IL-12 and PGE(2) were phenotypically mature and efficient at presenting FITC to lymphocytes from FITC-sensitized mice. Ag presentation by FACS-sorted CD11c(+) lymph node cells isolated 4 days after UVB irradiation was as efficient as were cells from unirradiated mice at presentation in vitro of an OVA peptide (OVA(323-339)) to CD4(+) cells from OVA-TCR-transgenic DO11.10 mice. Further, IFN-gamma levels were increased in the cultures containing CD11c(+) cells from UVB-irradiated mice, suggesting that inflammation may precede downstream immunosuppression. These results suggest that the primary cause of reduced contact hypersensitivity responses in mice in which UV irradiation and the sensitizing Ag are applied to different sites several days apart must originate from cells other than CD11c(+) APCs that directly or by production of soluble mediators (IL-12, PGE(2)) affect cellular responses in the nodes of UVB-irradiated mice.