The ability of a 3-gene host signature in blood to distinguish tuberculous meningitis from other brain infections.

BACKGROUND: Tuberculous meningitis (TBM) is difficult to diagnose. We investigated whether a 3-gene host response signature in blood can distinguish TBM from other brain infections. METHODS: The expression of 3 genes (Dual specificity phosphatase 3- DUSP3, Guanylate-binding protein- GBP5, Krupple-like factor 2- KLF2) was analysed by RNA sequencing of archived whole blood from four cohorts of Vietnamese adults: 281 with TBM; 279 with pulmonary tuberculosis; 50 with other brain infections; and 30 healthy controls. 'TB scores' (combined 3-gene expression) were calculated following published methodology and discriminatory performance compared using area under a receiver operator characteristic curve (AUC). RESULTS: GBP5 was upregulated in TBM compared to other brain infections (p < 0.001), with no difference in DUSP3 and KLF2 expression. The diagnostic performance of GBP5 alone (AUC 0.74 (95% CI 0.67-0.81)) was slightly better than the 3-gene TB score (AUC 0.66, 95% CI 0.58-0.73) in TBM. Both GBP5 expression and TB score were higher in HIV-positive participants (P < 0.001), with good diagnostic performance of GBP5 alone (AUC 0.86, 95% CI 0.80-0.93). CONCLUSION: The 3-gene host signature in whole blood has the ability to discriminate TBM from other brain infections, including in HIV-positive individuals. Validation in large prospective diagnostic study is now required.

USP19 deubiquitinase inactivation regulates α-synuclein ubiquitination and inhibits accumulation of Lewy body-like aggregates in mice.

The USP19 deubiquitinase is found in a locus associated with Parkinson's Disease (PD), interacts with chaperonins, and promotes secretion of α-synuclein (α-syn) through the misfolding-associated protein secretion (MAPS) pathway. Since these processes might modulate the processing of α-syn aggregates in PD, we inactivated USP19 (KO) in mice expressing the A53T mutation of α-syn and in whom α-syn preformed fibrils (PFF) had been injected in the striatum. Compared to WT, KO brains showed decreased accumulation of phospho-synuclein (pSyn) positive aggregates. This improvement was associated with less activation of microglia and improved performance in a tail-suspension test. Exposure of primary neurons from WT and KO mice to PFF in vitro also led to decreased accumulation of pSyn aggregates. KO did not affect uptake of PFF nor propagation of aggregates in the cultured neurons. We conclude that USP19 instead modulates intracellular dynamics of aggregates. At an early time following PFF injection when the number of pSyn-positive neurons were similar in WT and KO brains, the KO neurons contained less aggregates. KO brain aggregates stained more intensely with anti-ubiquitin antibodies. Immunoprecipitation of soluble proteins from WT and KO brains with antibodies to pSyn showed higher levels of ubiquitinated oligomeric species in the KO samples. We propose that the improved pathology in USP19 KO brains may arise from decreased formation or enhanced clearance of the more ubiquitinated aggregates and/or enhanced disassembly towards more soluble oligomeric species. USP19 inhibition may represent a novel therapeutic approach that targets the intracellular dynamics of α-syn complexes.

Development of treatment-decision algorithms for children evaluated for pulmonary tuberculosis: an individual participant data meta-analysis.

BACKGROUND: Many children with pulmonary tuberculosis remain undiagnosed and untreated with related high morbidity and mortality. Recent advances in childhood tuberculosis algorithm development have incorporated prediction modelling, but studies so far have been small and localised, with limited generalisability. We aimed to evaluate the performance of currently used diagnostic algorithms and to use prediction modelling to develop evidence-based algorithms to assist in tuberculosis treatment decision making for children presenting to primary health-care centres. METHODS: For this meta-analysis, we identified individual participant data from a WHO public call for data on the management of tuberculosis in children and adolescents and referral from childhood tuberculosis experts. We included studies that prospectively recruited consecutive participants younger than 10 years attending health-care centres in countries with a high tuberculosis incidence for clinical evaluation of pulmonary tuberculosis. We collated individual participant data including clinical, bacteriological, and radiological information and a standardised reference classification of pulmonary tuberculosis. Using this dataset, we first retrospectively evaluated the performance of several existing treatment-decision algorithms. We then used the data to develop two multivariable prediction models that included features used in clinical evaluation of pulmonary tuberculosis-one with chest x-ray features and one without-and we investigated each model's generalisability using internal-external cross-validation. The parameter coefficient estimates of the two models were scaled into two scoring systems to classify tuberculosis with a prespecified sensitivity target. The two scoring systems were used to develop two pragmatic, treatment-decision algorithms for use in primary health-care settings. FINDINGS: Of 4718 children from 13 studies from 12 countries, 1811 (38·4%) were classified as having pulmonary tuberculosis: 541 (29·9%) bacteriologically confirmed and 1270 (70·1%) unconfirmed. Existing treatment-decision algorithms had highly variable diagnostic performance. The scoring system derived from the prediction model that included clinical features and features from chest x-ray had a combined sensitivity of 0·86 [95% CI 0·68-0·94] and specificity of 0·37 [0·15-0·66] against a composite reference standard. The scoring system derived from the model that included only clinical features had a combined sensitivity of 0·84 [95% CI 0·66-0·93] and specificity of 0·30 [0·13-0·56] against a composite reference standard. The scoring system from each model was placed after triage steps, including assessment of illness acuity and risk of poor tuberculosis-related outcomes, to develop treatment-decision algorithms. INTERPRETATION: We adopted an evidence-based approach to develop pragmatic algorithms to guide tuberculosis treatment decisions in children, irrespective of the resources locally available. This approach will empower health workers in primary health-care settings with high tuberculosis incidence and limited resources to initiate tuberculosis treatment in children to improve access to care and reduce tuberculosis-related mortality. These algorithms have been included in the operational handbook accompanying the latest WHO guidelines on the management of tuberculosis in children and adolescents. Future prospective evaluation of algorithms, including those developed in this work, is necessary to investigate clinical performance. FUNDING: WHO, US National Institutes of Health.

An observational pragmatic quality-of-life study on paediatric tonsillectomy and waiting for surgery.

PURPOSE: To investigate parental perceptions of the effects of tonsillectomy on their child's quality of life while awaiting and following surgery in an Australian public health system. METHODS: An observational pragmatic study was undertaken at a tertiary Australian hospital. Parents of paediatric patients (2-16 years of age) listed for tonsillectomy completed a validated quality-of-life questionnaire (T-14 Paediatric Throat Disorders Outcome Test) at the initial consultation, on day of surgery, 6 weeks post-operatively and 6 months post-operatively. T-14 scores were compared using the Related-Samples Wilcoxon Signed Rank Test. RESULTS: Parents of 167 children participated in this study. There was a median wait time of 174 days (IQR 108-347) from the initial consultation until the day of surgery, with no significant change in median T-14 scores (35 [IQR 22-42] vs 36 [IQR 22-42]; n = 63; p > 0.05). There was a significant decrease from pre-operative T-14 scores to 6 weeks post-operatively (33.5 [IQR 22-42] vs 2 [IQR 0-5]; n = 160; p < 0.001), and this was sustained with a minor improvement at 6 months post-operatively (6 weeks 2 [IQR 0-5] vs 6 months 0 [IQR 0-2]; n = 148; p < 0.001). CONCLUSIONS: Paediatric tonsillectomy improves quality of life with a sustained benefit in the long term. There is no improvement to the patient's quality of life while awaiting tonsillectomy, thus patient welfare can be improved through reducing waiting times for surgery.

Outpatient parenteral antimicrobial therapy: how young is too young?

OBJECTIVE: To report the use, and assess the efficacy and outcomes of outpatient parenteral antimicrobial therapy (OPAT) in neonates (≤28 days of age), compared with older infants (1-12 months of age). DESIGN: A prospective 8-year observational study from September 2012 to September 2020. SETTING: The Hospital-in-the-Home (HITH) programme of the Royal Children's Hospital Melbourne. PATIENTS: Neonatal patients (≤28 days of age) were compared with older infants (1-12 months of age) receiving OPAT. INTERVENTIONS: Data were collected including demographics, diagnosis, type of venous access and antibiotic choice. MAIN OUTCOME MEASURES: Success of OPAT, antibiotic appropriateness, complications and readmission rate. RESULTS: There were 76 episodes for which neonates were admitted to HITH for OPAT, and 405 episodes for older infants. Meningitis was the most common diagnosis in both groups (59% and 35%, respectively); the most frequently prescribed antibiotic was ceftriaxone for both groups (61% and 49%). A positive bacterial culture was less frequent in neonates (38% vs 53%, p=0.02). Vascular access complication rate was 19% in neonates compared with 13% in older infants (p=0.2) with no central line-associated bloodstream infection in either group. Rates of appropriate antibiotic prescribing were similarly high between groups (93% vs 90%, p=0.3). The OPAT course was successfully completed in 74 of 74 (100%) neonates and 380 of 396 (96%) older infants (p=0.09). The unplanned readmission rate was low: 4 of 76 (5%) neonates and 27 of 405 (7%) older infants. CONCLUSIONS: OPAT is a safe and effective way of providing antibiotics to selected clinically stable neonatal patients. While appropriate antibiotic use was common, improvements can still be made.

Tuberculous meningitis: progress and remaining questions.

Tuberculous meningitis is a devastating brain infection that is caused by Mycobacterium tuberculosis and is notoriously difficult to diagnose and treat. New technologies characterising the transcriptome, proteome, and metabolome have identified new molecules and pathways associated with tuberculous meningitis severity and poor outcomes that could offer novel diagnostic and therapeutic targets. The next-generation GeneXpert MTB/RIF Ultra assay, when used on CSF, offers diagnostic sensitivity for tuberculous meningitis of approximately 70%, although it is not widely available and a negative result cannot rule out tuberculous meningitis. Small trials indicate that clinical outcomes might be improved with increased doses of rifampicin, the addition of linezolid or fluoroquinolones to standard antituberculosis therapy, or treatment with adjunctive aspirin combined with corticosteroids. Large phase 3 clinical trials are underway worldwide to address these and other questions concerning the optimal management of tuberculous meningitis; these studies also form a platform for studying pathogenesis and identifying novel diagnostic and treatment strategies, by allowing the implementation of new genomic, transcriptomic, proteomic, and metabolomic technologies in nested substudies.

Wearable devices for remote monitoring of hospitalized patients with COVID-19 in Vietnam.

Patients with severe COVID-19 disease require monitoring with pulse oximetry as a minimal requirement. In many low- and middle- income countries, this has been challenging due to lack of staff and equipment. Wearable pulse oximeters potentially offer an attractive means to address this need, due to their low cost, battery operability and capacity for remote monitoring. Between July and October 2021, Ho Chi Minh City experienced its first major wave of SARS-CoV-2 infection, leading to an unprecedented demand for monitoring in hospitalized patients. We assess the feasibility of a continuous remote monitoring system for patients with COVID-19 under these circumstances as we implemented 2 different systems using wearable pulse oximeter devices in a stepwise manner across 4 departments.

The role of Kingella kingae in pre-school aged children with bone and joint infections.

OBJECTIVES: The Pre-school Osteoarticular Infection (POI) study aimed to describe the burden of disease, epidemiology, microbiology and treatment of acute osteoarticular infections (OAI) and the role of Kingella kingae in these infections. METHODS: Information about children 3-60 months of age who were hospitalized with an OAI to 11 different hospitals across Australia and New Zealand between January 2012 and December 2016 was collected retrospectively. RESULTS: A total of 907 cases (73%) were included. Blood cultures grew a likely pathogen in only 18% (140/781). The peak age of presentation was 12 to 24 months (466/907, 51%) and Kingella kingae was the most frequently detected microorganism in this age group (60/466, 13%). In the majority of cases, no microorganism was detected (517/907, 57%). Addition of PCR to culture increased detection rates of K. kingae. However, PCR was performed infrequently (63/907, 7%). CONCLUSIONS: This large multi-national study highlights the need for more widespread use of molecular diagnostic techniques for accurate microbiological diagnosis of OAI in pre-school aged children. The data from this study supports the hypothesis that a substantial proportion of pre-school aged children with OAI and no organism identified may in fact have undiagnosed K. kingae infection. Improved detection of Kingella cases is likely to reduce the average length of antimicrobial treatment.

Health Related Quality of Life T-14 Outcomes for Pediatric Bizact Tonsillectomy.

Objectives: The objective of this study was to assess the T-14 outcomes of the BizactTM device for tonsillectomy in a pediatric population. Methods: A case series chart review was undertaken at a public tertiary teaching hospital and private otolaryngology practice, with data collected from pediatric patients who underwent a BizactTM tonsillectomy between July 2016 and October 2019 for any indication, whose parents consented to completing the T-14 questionnaire providing a parental perspective of the child's quality of life. Primary outcomes were T-14 scores recorded preoperatively and 6 weeks post-operatively. Secondary outcome measures were postoperative complications, including hemorrhage and readmission. Results: 146 patients were identified. There was a significant improvement in T-14 scores from a median of 24 (Interquartile range (IQR) 18-33) prior to surgery to 2 (IQR 0-4) at 6 weeks postoperatively (p < 0.001). The post-tonsillectomy hemorrhage rate was 6.1% (9/146 participants). Conclusions: Pediatric BizactTM tonsillectomy is effective in treating common indications for pediatric tonsillectomy, reflected by improved parent-reported health-related quality of life T-14 scores postoperatively.

Defeating Paediatric Tuberculous Meningitis: Applying the WHO "Defeating Meningitis by 2030: Global Roadmap".

Children affected by tuberculous meningitis (TBM), as well as their families, have needs that lie at the intersections between the tuberculosis and meningitis clinical, research, and policy spheres. There is therefore a substantial risk that these needs are not fully met by either programme. In this narrative review article, we use the World Health Organization (WHO) "Defeating Meningitis by 2030: global roadmap" as a starting point to consider key goals and activities to specifically defeat TBM in children. We apply the five pillars outlined in the roadmap to describe how this approach can be adapted to serve children affected by TBM. The pillars are (i) prevention; (ii) diagnosis and treatment; (iii) surveillance; (iv) support and care for people affected by meningitis; and (v) advocacy and engagement. We conclude by calling for greater integration between meningitis and TB programmes at WHO and at national levels.

Subtle differences in autonomic symptoms in people diagnosed with hypermobile Ehlers-Danlos syndrome and hypermobility spectrum disorders.

The hypermobile Ehlers-Danlos syndrome (hEDS) GENE study is a multicenter, cohort study with the goal to identify genes associated with hypermobile EDS. Of the 148 people enrolled in the hEDS GENE study, 98 meet the 2017 hEDS criteria, 27 have a hypermobility spectrum disorder (HSD) and 23 are asymptomatic family members. More than 80% of participants are female with an average age of 41 years. Each participant has completed seven questionnaires to quantify disease-related symptomatology. People with hypermobility experience a variety of physical and somatic symptoms, especially in the areas of fatigue, kinesiophobia, gastrointestinal, and autonomic function. These cause a significant decrease in health-related quality of life. The frequency and severity of most symptoms were indistinguishable between participants with hEDS and HSD; however, there were significant differences in autonomic symptoms. Less than 20% of participants had autoantibodies known to be associated with dysautonomia. Subtle symptomatic differences in people meeting the 2017 diagnostic criteria suggest focusing further etiologic studies on autonomic pathways.

Tuberculous Meningitis in Children: Reducing the Burden of Death and Disability.

Tuberculous meningitis disproportionately affects young children. As the most devastating form of tuberculosis, it is associated with unacceptably high rates of mortality and morbidity even if treated. Challenging to diagnose and treat, tuberculous meningitis commonly causes long-term neurodisability in those who do survive. There remains an urgent need for strengthened surveillance, improved rapid diagnostics technology, optimised anti-tuberculosis drug therapy, investigation of new host-directed therapy, and further research on long-term functional and neurodevelopmental outcomes to allow targeted intervention. This review focuses on the neglected field of paediatric tuberculous meningitis and bridges current clinical gaps with research questions to improve outcomes from this crippling disease.

Impact of expanding a paediatric OPAT programme with an antimicrobial stewardship intervention.

BACKGROUND: As treatment out of hospital with outpatient parenteral antimicrobial therapy (OPAT) increases, so too does the risk for patients of being less visible, with potential for suboptimal care. OBJECTIVES: We aimed to compare pre-expansion and post-expansion (1) successful completion, complications and (2) the impact of an OPAT-specific antimicrobial stewardship (AMS) intervention to mitigate inappropriate antibiotic prescribing. DESIGN: A prospective longitudinal study during two consecutive 12-month periods: period A (1 August 2012 to 31 July 2013) and period B (1 August 2013 to 31 July 2014). SETTING: The Hospital-in-the-Home (HITH) programme at The Royal Children's Hospital Melbourne. PARTICIPANTS: All patients who received OPAT during the study period. INTERVENTIONS: Between the two periods, the programme expanded from 16 to 32 patients/day. To coincide with this, a combined AMS intervention was introduced: (1) OPAT-specific guidelines and (2) active review of OPAT prescriptions and input by Paediatric Infectious Diseases. MAIN OUTCOMES: Successful completion of OPAT, OPAT-related complications, readmission, length of stay and antibiotic appropriateness. RESULTS: Over 2 years, 646 patients (47% female, median age 7 years) were treated via OPAT for 754 episodes. Patient episodes increased from 254 in period A to 500 in period B, with proportional increases in infants under 1 month and immunocompromised patients. OPAT was successfully completed in 245/251 (98%) versus 473/482 (98%) (OR 1.8, 95% CI 0.7 to 4.5, p=0.3). OPAT-related complications remained low: intravenous catheter-associated complications 16/138 (12%) versus 41/414 (10%), and antibiotic-associated complications 0/254 (0%) versus 2/500 (0.4%). Despite the increase in activity, with the AMS intervention, overall appropriate antibiotic prescribing remained high: 71% versus 76%. Inappropriately long durations reduced from 30/312 (10%) to 37/617 (6%) (OR 0.6, 95% CI 0.4 to 0.99, p=0.04), and median number of days on broad-spectrum antibiotics from 11 (IQR 8-24.5) to 8 (IQR 5-11). CONCLUSION: During a period of substantial expansion, we maintained clinical outcomes. A modest AMS intervention reduced some but not all aspects of inappropriate antibiotic prescribing.

Tuberculous meningitis: where to from here?

PURPOSE OF REVIEW: Tuberculous meningitis (TBM) is associated with significant mortality and morbidity yet is difficult to diagnose and treat. We reviewed original research published in the last 2 years, since 1 January 2018, which we considered to have a major impact in advancing diagnosis, treatment and understanding of the pathophysiology of TBM meningitis in children and adults. RECENT FINDINGS: Studies have sought to identify a high sensitivity diagnostic test for TBM, with new data on modified Ziehl--Neelsen staining, urinary and cerebrospinal fluid (CSF) lipoarabinomannan and GeneXpert Ultra. Recent studies on CSF biomarkers provide a better understanding of the detrimental inflammatory cascade and neuromarkers of brain damage and suggest potential for novel host-directed therapy. Tryptophan metabolism appears to affect outcome and requires further study. Increased clinical trials activity in TBM focuses on optimizing antituberculosis drug regimens and adjuvant therapy; however, there are few planned paediatric trials. SUMMARY: Tuberculous meningitis still kills or disables around half of sufferers. Although some progress has been made, there remains a need for more sensitive diagnostic tests, better drug therapy, improved management of complications and understanding of host-directed therapy if outcomes are to improve.

Tuberculosis treatment in children: The changing landscape.

Traditionally children have been treated for tuberculosis (TB) based on data extrapolated from adults. However, we know that children present unique challenges that deserve special focus. New data on optimal drug selection and dosing are emerging with the inclusion of children in clinical trials and ongoing research on age-related pharmacokinetics and pharmacodynamics. We discuss the changing treatment landscape for drug-susceptible and drug-resistant paediatric tuberculosis in both the most common (intrathoracic) and most severe (central nervous system) forms of disease, and address the current knowledge gaps for improving patient outcomes.