Research on the treatment of rifampin-susceptible tuberculosis-Time for a new approach.

In the Perspective, William Burman and colleagues advocate improving the safety and acceptability of treatment, rather than treatment-shortening, of rifampin-susceptible tuberculosis.

Musculoskeletal perturbations of deep space radiation: Assessment using a Gateway MRI.

Human space exploration expansion from Low-Earth Orbit to deep space is accelerating the need to monitor and address the known health concerns related to deep space radiation. The human musculoskeletal system is vulnerable to these risks (alongside microgravity) and its health reflects the well-being of other body systems. Multiparametric magnetic resonance imaging (MRI) is an important approach for assessing temporal physiological changes in the musculoskeletal system. We propose that ultra-low-field MRI provides an optimal low Size Weight and Power (SwaP) solution for non-invasively monitoring muscle and bone changes on the planned Gateway lunar space station. Our proposed ultra-low-field Gateway MRI meets low SWaP design specifications mandated by limited room in the lunar space station. This review summarizes the current state of our knowledge on musculoskeletal consequences of spaceflight, especially with respect to radiation, and then elaborates how MRI can be used to monitor the deleterious effects of space travel and the efficacy of putative countermeasures. We argue that an ultra-low-field MRI in cis-lunar space on the Gateway can provide valuable research and medical insights into the effects of deep space radiation exposure on astronauts. Such an MRI would also allow the development of imaging protocols that would facilitate Earth-bound teams to monitor space personnel musculoskeletal changes during future interplanetary spaceflight. It will especially have a role in monitoring countermeasures, such as the use of melanin, in protecting space explorers.

Indications for cerebral revascularization for moyamoya syndrome in pediatric sickle cell disease determined by Delphi methodology.

OBJECTIVE: Cerebral revascularization surgery (CRS) has been used to prevent stroke in children with sickle cell disease (SCD) and cerebral vasculopathy (e.g., moyamoya syndrome). While results suggest that it may be an effective treatment, surgical indications have not been well defined. This study sought to determine indications for offering revascularization surgery in centers with established sickle cell programs in the US. METHODS: Three sequential surveys utilizing the Delphi methodology were administered to neurosurgeons participating in the Stroke in Sickle Cell Revascularization Surgery study. Respondents were presented with clinical scenarios of patients with SCD and varying degrees of ischemic presentation and vasculopathy, and the group's agreement to offer surgical revascularization was measured. Consensus was defined as ≥ 75% similar responses. RESULTS: The response rate to all 3 surveys was 100%. Seventeen neurosurgeons from 16 different centers participated. The presence of moyamoya collaterals (MMCs) and arterial stenosis matching an ischemic distribution yielded the strongest recommendations to offer surgery. There was consensus to offer revascularization in the presence of MMCs and at least 50% arterial stenosis matching an ischemic distribution. In contrast, there was no consensus to offer revascularization with 50%-70% stenosis not matching an ischemic presentation in the absence of MMCs. The presence of the ivy sign in the distribution of the stenotic artery also contributed to the consensus to offer surgery in certain scenarios. CONCLUSIONS: There were several clinical scenarios that attained consensus to offer surgery; the strongest was moderate to severe arterial stenosis that matched the distribution of ischemic presentation in the presence of MMCs. Radiological findings of decreased cerebral flow or perfusion also facilitated attaining consensus to offer surgery. The findings of this study reflect expert opinion about questions that deserve prospective clinical research. Determination of indications for CRS can guide clinical practice and aid the design of prospective studies.

Bone and muscle differences in children and adolescents with type 1 diabetes: The mediating role of physical activity.

Children with type 1 diabetes (T1D) experience an increased risk of fracture, which may be related to altered bone development. We aimed to assess differences in bone, muscle and physical activity (PA), and explore if better muscle and PA measures would mitigate bone differences between children and adolescents with T1D and typically developing peers (TDP). We matched 56 children and adolescents with T1D (mean age 11.9 yrs) and 56 TDP (11.5 yrs) by sex and maturity from 171 participants with T1D and 66 TDP (6-17 yrs). We assessed the distal radius and tibia with high-resolution peripheral quantitative computed tomography (HR-pQCT), and the radius and tibia shaft bone and muscle with pQCT. We also measured muscle function from force-related measures in neuromuscular performance tests (push-up, grip test, countermovement and long jump). We compared PA based on questionnaire scores and accelerometers between groups. Bone, muscle, and neuromuscular performance measures were compared using MANOVA. We used mediation to explore the role of PA and muscle in bone differences. Children and adolescents with T1D had 6-10 % lower trabecular density, bone volume fraction, thickness and number at both distal radius and tibia, and 11 % higher trabecular separation at the distal radius than TDP. They also had 3-16 % higher cortical and tissue mineral density, and cortical thickness at the distal radius, 5-7 % higher cortical density and 1-3 % higher muscle density at both shaft sites compared to TDP. PA mediated the between-group difference in trabecular number (indirect effect -0.04) at the distal radius. Children and adolescents with T1D had lower trabecular bone density and deficits in trabecular micro-architecture, but higher cortical bone density and thickness at the radius and tibia compared to TDP. They engaged in less PA but had comparable muscle measures to those of TDP. PA participation may assist in mitigating deficit in trabecular number observed in children and adolescents with T1D.

Neurosurgical management of Myelomeningocele in premature infants: a case series.

INTRODUCTION: Myelomeningocele (MMC) is the most common neural tube defect, but rarely seen in premature infants. Most centers advocate for closure of MMC within 24 h of birth. However, this is not always possible in severely premature infants. Given the rarity of this patient population, we aimed to share our institutional experience and outcomes of severely premature infants with MMC. METHODS: We performed a retrospective, observational review of premature infants (≤ 32 weeks gestational age) identified through our multidisciplinary spina bifida clinic (1995-2021) and surgical logs. Descriptive statistics were compiled about this sample including timing of MMC closure and incidence of adverse events such as sepsis, CSF diversion, meningitis, and death. RESULTS: Eight patients were identified (50% male) with MMC who were born ≤ 32 weeks gestational age. Mean gestational age of the population was 27.3 weeks (SD 3.5). Median time to MMC closure was 1.5 days (IQR = 1-80.8). Five patients were taken for surgery within the recommended 48 h of birth; 2 patients underwent significantly delayed closure (107 and 139 days); and one patient's defect epithelized without surgical intervention. Six of eight patients required permanent cerebrospinal fluid (CSF) diversion (2 patients were treated with ventriculoperitoneal shunting (VPS), three were treated with endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) and 1 patient treated with ETV; mean of 3 years after birth, ranging from 1 day to 16 years). Two patients required more than one permanent CSF diversion procedure. Two patients developed sepsis (defined as meeting at least 2/4 SIRS criteria). In both cases of sepsis, patients developed signs and symptoms more than 72 h after birth. Notably, both instances of sepsis occurred unrelated to operative intervention as they occurred before permanent MMC closure. Two patients had intraventricular hemorrhage (both grade III). No patients developed meningitis (defined as positive CSF cultures) prior to MMC closure. Median follow up duration was 9.7 years. During this time epoch, 3 patients died: Two before 2 years of age of causes unrelated to surgical intervention. One of the two patients with grade III IVH died within 24 h of MMC closure. CONCLUSIONS: In our institutional experience with premature infants with MMC, some patients underwent delayed MMC closure. The overall rate of meningitis, sepsis, and mortality for preterm children with MMC was similar to MMC patients born at term.

Lysosome-Disrupting Agents in Combination with Venetoclax Increase Apoptotic Response in Primary Chronic Lymphocytic Leukemia (CLL) Cells Mediated by Lysosomal Cathepsin D Release and Inhibition of Autophagy.

Venetoclax and obinutuzumab are becoming frontline therapies for chronic lymphocytic leukemia (CLL) patients. Unfortunately, drug resistance still occurs, and the combination could be immunosuppressive. Lysosomes have previously been identified as a target for obinutuzumab cytotoxicity in CLL cells, but the mechanism remains unclear. In addition, studies have shown that lysosomotropic agents can cause synergistic cell death in vitro when combined with the BTK inhibitor, ibrutinib, in primary CLL cells. This indicates that targeting lysosomes could be a treatment strategy for CLL. In this study, we have shown that obinutuzumab induces lysosome membrane permeabilization (LMP) and cathepsin D release in CLL cells. Inhibition of cathepsins reduced obinutuzumab-induced cell death in CLL cells. We further determined that the lysosomotropic agent siramesine in combination with venetoclax increased cell death in primary CLL cells through an increase in reactive oxygen species (ROS) and cathepsin release. Siramesine treatment also induced synergistic cytotoxicity when combined with venetoclax. Microenvironmental factors IL4 and CD40L or incubation with HS-5 stromal cells failed to significantly protect CLL cells from siramesine- and venetoclax-induced apoptosis. We also found that siramesine treatment inhibited autophagy through reduced autolysosomes. Finally, the autophagy inhibitor chloroquine failed to further increase siramesine-induced cell death. Taken together, lysosome-targeting drugs could be an effective strategy in combination with venetoclax to overcome drug resistance in CLL.

Case Presentation of a Neuroglial Cyst Causing Acute Hydrocephalus.

Neuroglial cysts are rare congenital cysts that seldom require surgical treatment. This case highlights a rare instance when a neurolglial cyst caused acute hydrocephalus in a 10-year old boy. Originally diagnosed and managed as pediatric-onset migraines, the patient presented to the emergency department with nausea, vomiting, and ataxia without clear pathology on neuroradiology. The neurosurgical team took him to the operating room based on his clinical picture and history and the cyst was discovered there. The pathology was benign, and he has had a complete resolution of symptoms.

Differential Inflammatory Cytokine Elaboration in Serum from Brick Kiln Workers in Bhaktapur, Nepal.

Previous studies involving workers at brick kilns in the Kathmandu Valley of Nepal have investigated chronic exposure to hazardous levels of fine particulate matter (PM2.5) common in ambient and occupational environments. Such exposures are known to cause and/or exacerbate chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD) and asthma. However, there is a paucity of data regarding the status of systemic inflammation observed in exposed workers at brick manufacturing facilities within the country. In the current study, we sought to elucidate systemic inflammatory responses by quantifying the molecular cytokine/chemokine profiles in serum from the study participants. A sample of participants were screened from a kiln in Bhaktapur, Nepal (n = 32; 53% female; mean ± standard deviation: 28.42 ± 11.47 years old) and grouped according to job category. Blood was procured from participants on-site, allowed to clot at room temperature, and centrifuged to obtain total serum. A human cytokine antibody array was used to screen the inflammatory mediators in serum samples from each of the participants. For the current study, four job categories were evaluated with n = 8 for each. Comparisons were generated between a control group of administration workers vs. fire master workers, administration workers vs. green brick hand molders, and administration workers vs. top loaders. We discovered significantly increased concentrations of eotaxin-1, eotaxin-2, GCSF, GM-CSF, IFN-γ, IL-1α, IL-1ß, IL-6, IL-8, TGF-ß1, TNF-α, and TIMP-2 in serum samples from fire master workers vs. administration workers (p < 0.05). Each of these molecules was also significantly elevated in serum from green brick hand molders compared to administration workers (p < 0.05). Further, each molecule in the inflammatory screening with the exception of TIMP-2 was significantly elevated in serum from top loaders compared to administration workers (p < 0.05). With few exceptions, the fire master workers expressed significantly more systemic inflammatory molecular abundance when compared to all other job categories. These results reveal an association between pulmonary exposure to PM2.5 and systemic inflammatory responses likely mediated by cytokine/chemokine elaboration. The additional characterization of a broader array of inflammatory molecules may provide valuable insight into the susceptibility to lung diseases among this population.

Endoluminal Biopsy for Vein of Galen Malformation.

BACKGROUND AND OBJECTIVES: Vein of Galen malformation (VOGM), the result of arteriovenous shunting between choroidal and/or subependymal arteries and the embryologic prosencephalic vein, is among the most severe cerebrovascular disorders of childhood. We hypothesized that in situ analysis of the VOGM lesion using endoluminal tissue sampling (ETS) is feasible and may advance our understanding of VOGM genetics, pathogenesis, and maintenance. METHODS: We collected germline DNA (cheek swab) from patients and their families for genetic analysis. In situ VOGM "endothelial" cells (ECs), defined as CD31+ and CD45-, were obtained from coils through ETS during routine endovascular treatment. Autologous peripheral femoral ECs were also collected from the access sheath. Single-cell RNA sequencing of both VOGM and peripheral ECs was performed to demonstrate feasibility to define the transcriptional architecture. Comparison was also made with a published normative cerebrovascular transcriptome atlas. A subset of VOGM ECs was reserved for future DNA sequencing to assess for somatic and second-hit mutations. RESULTS: Our cohort contains 6 patients who underwent 10 ETS procedures from arterial and/or venous access during routine VOGM treatment (aged 12 days to ∼6 years). No periprocedural complications attributable to ETS occurred. Six unique coil types were used. ETS captured 98 ± 88 (mean ± SD; range 17-256) experimental ECs (CD31+ and CD45-). There was no discernible correlation between cell yield and coil type or route of access. Single-cell RNA sequencing demonstrated hierarchical clustering and unique cell populations within the VOGM EC compartment compared with peripheral EC controls when annotated using a publicly available cerebrovascular cell atlas. CONCLUSION: ETS may supplement investigations aimed at development of a molecular-genetic taxonomic classification scheme for VOGM. Moreover, results may eventually inform the selection of personalized pharmacologic or genetic therapies for VOGM and cerebrovascular disorders more broadly.

Combination immunotherapy with vaccine and oncolytic HSV virotherapy is time dependent.

PURPOSE: Oncolytic virotherapy or immunovirotherapy is a strategy that utilizes viruses to selectively infect and kill tumor cells while also stimulating an immune response against the tumor. Early clinical trials in both pediatric and adult patients using oncolytic herpes simplex viruses (oHSVs) have demonstrated safety and promising efficacy; however, combinatorial strategies designed to enhance oncolysis while also promoting durable T cell responses for sustaining disease remission are likely required. We hypothesized that combining the direct tumor cell killing and innate immune stimulation by oHSV with a vaccine that promotes T cell mediated immunity may lead to more durable tumor regression. EXPERIMENTAL DESIGN: To this end, we investigated the preclinical efficacy and potential synergy of combining oHSV with a self-assembling nanoparticle vaccine co-delivering peptide antigens and Toll-like receptor-7 and -8 agonists (TLR-7/8a) (referred to as SNAPvax™), that induces robust tumor specific T cell immunity. We then assessed how timing of the treatments (i.e., vaccine before or after oHSV) impacts T cell responses, viral replication, and preclinical efficacy. RESULTS: The sequence of treatments was critical, as survival was significantly enhanced when the SNAPvax™ vaccine was given prior to oHSV. Increased clinical efficacy was associated with reduced tumour volume and increases in virus replication and tumor antigen specific CD8+ T cells. CONCLUSIONS: These findings substantiate the criticality of combination immunotherapy timing and provide preclinical support for combining SNAPvax with oHSV as a promising treatment approach for both pediatric and adult tumors.

The role of occipital condyle and atlas anomalies on occipital cervical fusion outcomes in Chiari malformation type I with syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.

OBJECTIVE: Congenital anomalies of the atlanto-occipital articulation may be present in patients with Chiari malformation type I (CM-I). However, it is unclear how these anomalies affect the biomechanical stability of the craniovertebral junction (CVJ) and whether they are associated with an increased incidence of occipitocervical fusion (OCF) following posterior fossa decompression (PFD). The objective of this study was to determine the prevalence of condylar hypoplasia and atlas anomalies in children with CM-I and syringomyelia. The authors also investigated the predictive contribution of these anomalies to the occurrence of OCF following PFD (PFD+OCF). METHODS: The authors analyzed the prevalence of condylar hypoplasia and atlas arch anomalies for patients in the Park-Reeves Syringomyelia Research Consortium database who underwent PFD+OCF. Condylar hypoplasia was defined by an atlanto-occipital joint axis angle (AOJAA) ≥ 130°. Atlas assimilation and arch anomalies were identified on presurgical radiographic imaging. This PFD+OCF cohort was compared with a control cohort of patients who underwent PFD alone. The control group was matched to the PFD+OCF cohort according to age, sex, and duration of symptoms at a 2:1 ratio. RESULTS: Clinical features and radiographic atlanto-occipital joint parameters were compared between 19 patients in the PFD+OCF cohort and 38 patients in the PFD-only cohort. Demographic data were not significantly different between cohorts (p > 0.05). The mean AOJAA was significantly higher in the PFD+OCF group than in the PFD group (144° ± 12° vs 127° ± 6°, p < 0.0001). In the PFD+OCF group, atlas assimilation and atlas arch anomalies were identified in 10 (53%) and 5 (26%) patients, respectively. These anomalies were absent (n = 0) in the PFD group (p < 0.001). Multivariate regression analysis identified the following 3 CVJ radiographic variables that were predictive of OCF occurrence after PFD: AOJAA ≥ 130° (p = 0.01), clivoaxial angle < 125° (p = 0.02), and occipital condyle-C2 sagittal vertical alignment (C-C2SVA) ≥ 5 mm (p = 0.01). A predictive model based on these 3 factors accurately predicted OCF following PFD (C-statistic 0.95). CONCLUSIONS: The authors' results indicate that the occipital condyle-atlas joint complex might affect the biomechanical integrity of the CVJ in children with CM-I and syringomyelia. They describe the role of the AOJAA metric as an independent predictive factor for occurrence of OCF following PFD. Preoperative identification of these skeletal abnormalities may be used to guide surgical planning and treatment of patients with complex CM-I and coexistent osseous pathology.

Neurosurgical Management of Myelomeningocele in Premature Infants: A Case Series.

Introduction: Myelomeningocele (MMC) is the most common neural tube defect, but rarely seen in premature infants. Most centers advocate for closure of MMC within 24 hours of birth. However, this is not always possible in severely premature infants. Given the rarity of this patient population, we aimed to share our institutional experience and outcomes of severely premature infants with MMC. Methods: We performed a retrospective, observational review of premature infants (≤ 32 weeks gestational age) identified through our multidisciplinary spina bifida clinic (1995-2021) and surgical logs. Descriptive statistics were compiled about this sample including timing of MMC closure and incidence of adverse events such as sepsis, CSF diversion, meningitis, and death. Results: Eight patients were identified (50% male) with MMC who were born ≤ 32 weeks gestational age. Mean gestational age of the population was 27.3 weeks (SD 3.5). Median time to MMC closure was 1.5 days (IQR = 1 -80.8). Five patients were taken for surgery within the recommended 48 hours of birth; 2 patients underwent significantly delayed closure (107 and 139 days); and one patient's defect epithelized without surgical intervention. Six of eight patients required permanent cerebrospinal fluid (CSF) diversion (2 patients were treated with ventriculoperitoneal shunting (VPS), three were treated with endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) and 1 patient treated with ETV; mean of 3 years after birth, ranging from 1 day to 16 years). Two patients required more than one permanent CSF diversion procedure. Two patients developed sepsis (defined as meeting at least 2/4 SIRS criteria), and 2 patients had intraventricular hemorrhage (both grade III). No patients developed meningitis (defined as positive CSF cultures) prior to MMC closure. Median follow up duration was 9.7 years. During this time epoch, 3 patients died: Two before 2 years of age of causes unrelated to surgical intervention. One of the two patients with grade III IVH died within 24 hours of MMC closure. Conclusions: In our institutional experience with premature infants with MMC, some patients underwent delayed MMC closure. The overall rate of meningitis, sepsis, and mortality for preterm children with MMC was similar to MMC patients born at term.

Evaluation of multidisciplinary high-risk pregnancy clinic for myelomeningocele.

INTRODUCTION: A cross-sectional study retrospectively evaluating the perceived usefulness of attending a multi-disciplinary, roundtable, educational prenatal clinic for mothers expecting children with myelomeningocele is presented. METHODS: Mothers who currently have children with SB completed a survey which evaluated their overall preparedness, spina bifida education, delivery plans, surgical expectations, and expectations in terms of quality of life and development. Open comments were also collected. Statistical analysis was performed to identify differences between those who attended prenatal counseling and those who did not. RESULTS: Approximately half of these mothers received some form of prenatal SB counseling. Mothers who attended prenatal counseling reported that they felt more informed and prepared throughout their pregnancy, during the delivery of their child and during their initial hospital stay than mothers who did not. They reported that the roundtable discussions were beneficial, and the education they received was useful in helping them form accurate expectations and feel more at ease. CONCLUSION: This suggests that prenatal counseling and the High-Risk Pregnancy Clinic (HRPC) provides perceived utility to families and mothers and that the HRPC is an effective method of providing prenatal counseling to mothers whose unborn children have been diagnosed with myelomeningocele.

Sustainability and impact of an intervention to improve initiation of tuberculosis preventive treatment: results from a follow-up study of the ACT4 randomized trial.

Background: In a cluster randomized trial (clinicaltrials.gov: NCT02810678) a flexible but comprehensive health system intervention significantly increased the number of household contacts (HHC) identified and started on tuberculosis preventive treatment (TPT). A follow-up study was conducted one year later to test the hypotheses that these effects were sustained, and were reproducible with a simplified intervention. Methods: We conducted a follow-up study from May 1, 2018 until April 30, 2019, as part of a multinational cluster randomized trial. Eight sites in 4 countries that had received the intervention in the original trial received no further intervention; eight other sites in the same countries that had not received the intervention (control sites in the original trial) now received a simplified version of the intervention. This consisted of repeated local evaluation of the Cascade of care for TB infection, and stakeholder decision making. The number of HHC identified and starting TPT were repeatedly measured at all 16 sites and expressed as rates per 100 newly diagnosed index TB patients. The sustained effect of the original intervention was estimated by comparing these rates after the intervention in the original trial with the last 6 months of the follow-up study. The reproducibility was estimated by comparing the pre-post intervention changes in rates at sites receiving the original intervention with the pre-post changes in rates at sites receiving the later, simplified intervention. Findings: With regard to the sustained impact of the original intervention, compared to the original post-intervention period, the number of HHC identified and treated per 100 newly diagnosed TB patients was 10 more (95% confidence interval: 84 fewer to 105 more), and 1 fewer (95% CI: 22 fewer to 20 more) respectively up to 14 months after the end of the original intervention. With regard to the reproducibility of the simplified intervention, at sites that had initially served as control sites, the number of HHC identified and treated per 100 TB patients increased by 33 (95% CI: -32, 97), and 16 (-69, 100) from 3 months before, to up to 6 months after receiving a streamlined intervention, although differences were larger, and significant if the post-intervention results were compared to all pre-intervention periods. Interpretation: Up to one year after it ended, a health system intervention resulted in sustained increases in the number of HHC identified and starting TPT. A simplified version of the intervention was associated with non-significant increases in the identification and treatment of HHC. Inferences are limited by potential bias due to other temporal effects, and the small number of study sites. Funding: Funded by the Canadian Institutes of Health Research (Grant number 143350).

Stimulative piezoelectric nanofibrous scaffolds for enhanced small extracellular vesicle production in 3D cultures.

Small extracellular vesicles (sEVs) have great promise as effective carriers for drug delivery. However, the challenges associated with the efficient production of sEVs hinder their clinical applications. Herein, we report a stimulative 3D culture platform for enhanced sEV production. The proposed platform consists of a piezoelectric nanofibrous scaffold (PES) coupled with acoustic stimulation to enhance sEV production of cells in a 3D biomimetic microenvironment. Combining cell stimulation with a 3D culture platform in this stimulative PES enables a 49 fold increase in the production rate per cell with minimal deviations in particle size and protein composition compared with standard 2D cultures. We find that the enhanced sEV production is attributable to the activation and upregulation of crucial sEV production steps through the synergistic effect of stimulation and the 3D microenvironment. Moreover, changes in cell morphology lead to cytoskeleton redistribution through cell matrix interactions in the 3D cultures. This in turn facilitates intracellular EV trafficking, which impacts the production rate. Overall, our work provides a promising 3D cell culture platform based on piezoelectric biomaterials for enhanced sEV production. This platform is expected to accelerate the potential use of sEVs for drug delivery and broad biomedical applications.

Paired qualitative and quantitative analysis of bacterial microcolonies in the tonsils of patients with tonsillar hyperplasia.

The discovery of bacterial microcolonies in tonsillar tissue of patients with tonsillar hyperplasia has raised the question of their role in provoking the local immune response. Tonsils collected from patients undergoing tonsillectomy were stained for three clinically relevant bacterial taxa and lymphocytes. The bacterial composition and abundance of microcolonies was investigated using a combination of laser-microdissection, amplicon sequencing and Droplet Digital polymerase chain reaction. Microcolonies were detected in most samples (32/35) with a high prevalence of Haemophilus influenzae (78% of samples). B and T cell lymphocytes were significantly higher in the epithelium adjacent to microcolonies compared to epithelium distal to microcolonies. Furthermore, significant positive and negative correlations were identified between bacterial taxa and lymphocytes. Genus Streptococcus, which includes Group A Streptococcus (traditionally described as the main pathogen of tonsillar hyperplasia), was found in low abundance in this study. These results suggest other potential pathogens may be involved in stimulating the local immune response leading to tonsillar hyperplasia.

High-dose, short-duration versus standard rifampicin for tuberculosis preventive treatment: a partially blinded, three-arm, non-inferiority, randomised, controlled trial.

BACKGROUND: Tuberculosis preventive treatment (TPT) is a key component of tuberculosis elimination. To improve completion and reduce the burden for people and health systems, short, safe, and effective TPT regimens are needed. We aimed to compare safety and treatment completion of various doses and durations of rifampicin in people who were recommended to receive TPT. METHODS: This partially blinded, parallel-arm, non-inferiority, randomised, controlled, phase 2b trial was done at seven university-affiliated clinics in Canada, Indonesia, and Viet Nam. Participants aged 10 years or older were included if they had an indication for TPT according to WHO guidelines for Indonesia and Viet Nam, or Canadian guidelines for Canadian sites, and a positive tuberculin skin test or interferon-γ release assay. Participants were randomly assigned (1:1:1) to receive oral rifampicin at 10 mg/kg once daily for 4 months (standard-dose group), 20 mg/kg daily for 2 months (20 mg/kg group), or 30 mg/kg daily for 2 months (30 mg/kg group). The randomisation sequence was computer generated with blocks of variable size (three, six, and nine) and stratified by country for Indonesia and Viet Nam, and by city within Canada. Participants and investigators were masked to dose in high-dose groups, but unmasked to duration in all groups. The two co-primary outcomes were safety (in the safety population, in which participants received at least one dose of the study drug) and treatment completion (in the modified intention-to-treat [mITT] population, excluding those ineligible after randomisation). Protocol-defined adverse events were defined as grade 3 or worse, or rash or allergy of any grade, judged by an independent and masked panel as possibly or probably related to the study. A margin of 4% was used to assess non-inferiority. This study is registered with ClinicalTrials.gov, NCT03988933 (active). FINDINGS: Between Sept 1, 2019, and Sept 30, 2022, 1692 people were assessed for eligibility, 1376 were randomly assigned, and eight were excluded after randomisation. 1368 participants were included in the mITT population (454 in the standard group, 461 in the 20 mg/kg group, and 453 in the 30 mg/kg group). 589 (43%) participants were male and 779 (57%) were female. 372 (82%) in the standard-dose group, 329 (71%) in the 20 mg/kg group, and 293 (65%) in the 30 mg/kg group completed treatment. No participants in the standard-dose group, one (<1%) of 441 participants in the 20 mg/kg group, and four (1%) of 423 in the 30 mg/kg group developed grade 3 hepatotoxicity. Risk of protocol-defined adverse events was higher in the 30 mg/kg group than in the standard-dose group (adjusted risk difference 4·6% [95% CI 1·8 to 7·4]) or the 20 mg/kg group (5·1% [2·3 to 7·8]). There was no difference in the risk of adverse events between the 20 mg/kg and standard-dose groups (-0·5% [95% CI -2·4 to 1·5]; non-inferiority met). Completion was lower in the 20 mg/kg group (-7·8% [95% CI -13·6 to -2·0]) and the 30 mg/kg group (-15·4% [-21·4 to -9·4]) than in the standard-dose group. INTERPRETATION: In this trial, 2 months of 30 mg/kg daily rifampicin had significantly worse safety and completion than 4 months of 10 mg/kg daily and 2 months of 20 mg/kg daily (the latter, a fully blinded comparison); we do not consider 30 mg/kg to be a good option for TPT. Rifampicin at 20 mg/kg daily for 2 months was as safe as standard treatment, but with lower completion. This difference remains unexplained. FUNDING: Canadian Institutes of Health Research.

Respirable dust and crystalline silica concentrations among workers at a brick kiln in Bhaktapur, Nepal.

Exposure to respirable dust and crystalline silica (SiO2) has been linked to chronic obstructive pulmonary disease, silicosis, cancer, heart disease, and other respiratory diseases. Relatively few studies have measured respirable dust and SiO2 concentrations among workers at brick kilns in low- and middle-income countries. The purpose of this study was to measure personal breathing zone (PBZ) respirable dust and SiO2 concentrations among workers at one brick kiln in Bhaktapur, Nepal. A cross-sectional study was conducted among 49 workers in five job categories: administration, fire master, green (unfired) brick hand molder, green brick machine molder, and top loader. PBZ air samples were collected from each worker following Methods 0600 (respirable dust) and 7500 (respirable crystalline SiO2: cristobalite, quartz, tridymite) of the U.S. National Institute for Occupational Safety and Health. Eight-hour time-weighted average (TWA) respirable dust and quartz concentrations were also calculated. SiO2 percentage was measured in one bulk sample each of wet clay, the release agent used by green brick hand molders, and top coat soil at the brick kiln. The geometric mean (GM) sample and TWA respirable dust concentrations were 0.20 (95% confidence interval [CI]: 0.16, 0.27) and 0.12 (95% CI: 0.09, 0.16) mg/m3, respectively. GM sample and TWA quartz concentrations were 15.28 (95% CI: 11.11, 21.02) and 8.60 (95% CI: 5.99, 12.34) µg/m3, respectively. Job category was significantly associated with GM sample and TWA respirable dust and quartz concentrations (all p < 0.0001). Top loaders had the highest GM sample and TWA respirable dust concentrations of 1.49 and 0.99 mg/m3, respectively. Top loaders also had the highest GM sample and TWA quartz concentrations of 173.08 and 114.39 µg/m3, respectively. Quartz percentages in bulk samples were 16%-27%. Interventions including using wet methods to reduce dust generation, administrative controls, personal protective equipment, and education and training should be implemented to reduce brick kiln worker exposures to respirable dust and SiO2.

Pediatric non-galenic pial arteriovenous fistula's characteristics and outcomes: a systematic review.

INTRODUCTION: Pediatric non-galenic pial arteriovenous fistulas (pAVFs) are rare vascular malformations that are characterized by a pial arterial-venous connection without an intervening capillary bed. Outcomes and treatment strategies for pAVFs are highly individualized, owing to the rarity of the disease and lack of large-scale data guiding optimal treatment approaches. METHODS: We performed a systematic review of pediatric patients (< 18 years at diagnosis) diagnosed with a pAVF by digital subtraction angiogram (DSA). The demographics, treatment modalities, and outcomes were documented for each patient and clinical outcome data was collected. Descriptive information stratified by outcome scores were classified as follows: 1 = excellent (no deficit and full premorbid activity), 2 = good (mild deficit and full premorbid activity), 3 = fair (moderate deficit and impaired activity), 4 = poor (severe deficit and dependent on others), 5 = death. RESULTS: A total of 87 studies involving 231 patients were identified. Median age at diagnosis was 3 years (neonates to 18 years). There was slight male preponderance (55.4%), and 150 subjects (81.1%*) experienced excellent outcomes after treatment. Of the 189 patients treated using endovascular approaches, 80.3% experienced excellent outcomes and of the 15 patients surgically treated subjects 75% had an excellent outcome. The highest rate of excellent outcomes was achieved in patients treated with Onyx (95.2%) and other forms of EvOH (100%). High output heart failure and comorbid vascular lesions tended to result in worse outcomes, with only 54.2% and 68% of subjects experiencing an excellent outcome, respectively. *Outcomes were reported in only 185 patients. CONCLUSION: pAVFs are rare lesions, necessitating aggregation of patient data to inform natural history and optimal treatment strategies. This review summarizes the current literature on pAVF in children, where children presenting with heart failure as a result of high flow through the lesion were less likely to experience an excellent outcome. Prospective, large-scale studies would further characterize pediatric pAVFs and enable quantitative analysis of outcomes to inform best treatment practices.