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The redirection of the qiblahto the Kaʿbah (Q 2:142-5) is redated from 622, very soon after the hijrahwhere it is placed in the sīrah, to 628 on the eve of the Prophet’s negotiations with the leaders of Mecca at al-Ḥudaybiyah. It is interpreted as a compromise forced on the Prophet, if he was to reach a settlement with the Quraysh. A corollary was God’s authorisation of pilgrimage in pagan fashion and of animal sacrifice at the Kaʿbah (Q 22: 23-38, Q 5: 2-4). The Kaʿbah was redesignated a monotheist sanctuary, on the grounds of its foundation by Abraham (Q 2:125-7, Q 3:96-8, Q 22:28-9). These sūrahs(and an anomalous late passage in Q 14:35-7) are all late. No earlier sūrahassociates Abraham with the Kaʿbah.

The field of global neurosurgery seeks to improve access to neurosurgery and reduce health disparities worldwide. This process depends on intensive collaboration between partners in high-income and low-to-middle income country (LMIC) settings. Several such collaborations have propelled global neurosurgery forward, and long-standing partnerships in particular have brought subspecialty care and training to new locations. Recently, there have been more reports of collaborations between LMICs themselves. In this narrative study, we summarize the state of collaboration in global neurosurgery and discuss how the field is likely to change moving forward.

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 Gatewaylunar space station. Our proposed ultra-low-field GatewayMRI 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 Gatewaycan 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.

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.

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 15.7-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.

IMPORTANCE: The US Food and Drug Administration (FDA) and Centers for Medicare & Medicaid Services (CMS) have different statutory authorities; FDA evaluates safety and effectiveness for market authorization of medical devices while CMS determines whether coverage is “reasonable and necessary” for its beneficiaries. CMS has recently enacted policies automatically providing supplemental reimbursement for new, costly devices authorized after designation in FDA’s Breakthrough Devices Program (BDP) and in June 2023 issued notice for a new Transitional Coverage for Emerging Technologies pathway, accelerating coverage for Breakthrough devices. OBSERVATIONS: Aiming to incentivize innovation, FDA awards Breakthrough designations early in device development to expedite market authorization and can accept greater uncertainty in benefit and risk, contingent on postmarket evidence generation. Since 2020, Breakthrough designation has effectively automatically qualified devices to receive supplemental Medicare reimbursement after CMS waived a long-standing requirement that devices demonstrate “substantial clinical improvement” for beneficiaries. Using publicly available information, 3 examples of cardiovascular devices illustrate that the BDP may allow for FDA authorization based on less rigorous evidence, such as single-arm trials focused on surrogate end points with short-term follow-up whose participants are often not representative of Medicare beneficiaries. In 1 case, Breakthrough designation allowed a 30% decrease in enrollment of a trial used to support approval. Initial positive findings for some devices have remained unverified, and in 1 case even partially nullified, by postmarket studies. Manufacturers have also used Breakthrough designations to set the price of devices to facilitate additional pass-through payments, leading to higher short-term and long-term costs to CMS and health care systems. CONCLUSIONS AND RELEVANCE: The BDP may qualify new, costly devices for higher and automatic Medicare reimbursement despite evidence not being representative of CMS beneficiaries and persistent uncertainty of benefit and risk. To ensure the best evidence is generated to inform clinical care, FDA could apply more selectivity to BDP eligibility, specify objective criteria for revoking Breakthrough designation when appropriate, and ensure timely postmarket evidence generation, whereas CMS could independently review clinical evidence, advise manufacturers about standards for coverage review, and make supplemental payments and long-term device reimbursement contingent on clinical outcome benefit and postmarket evidence generation.

POINTS CLÉSLa prise en charge de la tuberculose (TB) chez les personnes âgées, enceintes ou aux prises avec des maladies concomitantes ou des troubles liés à la consommation de substances présente des défis; on recommande donc de consulter un expert en tuberculose.Les événements indésirables et les interruptions de traitement sont plus fréquents dans ces populations particulières que dans la population générale; une surveillance étroite et un soutien additionnel sont souvent nécessaires.Étant donné les modifications de la pharmacocinétique des médicaments antituberculeux et le potentiel de graves interactions médicament-médicament chez les patients présentant des maladies concomitantes, nous recommandons de consulter un pharmacien expérimenté.La TB active et ses traitements ont d’importantes répercussions sur la prise en charge des maladies concomitantes; une étroite collaboration avec des médecins spécialistes et des professionnels paramédicaux est souvent requise.La durée prolongée du traitement antituberculeux est une bonne occasion de dépister des maladies concomitantes et de faciliter l’orientation et les liens vers les soins pertinents.

Background Early antibiotic initiation is considered a cornerstone in the management of ventilator-associated pneumonia (VAP). However, recent data suggests that early antibiotic initiation may not be necessary in all cases. Additionally, the benefits of early antibiotic administration for infection have not been studied in a dedicated trauma population. This study’s aim was to evaluate the impact of antibiotic administration timing on in-hospital mortality in trauma patients with VAP.Methods This retrospective case-control study identified all trauma patients at a single level 1 academic trauma center from 2016 to 2020. Patients with a TQIP-defined VAP were included and stratified into 2 subgroups by in-hospital mortality. Time interval between airway culture and antibiotic initiation was gathered. Baseline measures of injury and illness severity were collected. Univariate analysis of the data was performed.Results Forty-five patients met inclusion criteria. Overall, 80% of patients survived admission (n = 36) and 20% of patients did not survive admission (n = 9). There were no significant differences in baseline characteristics or cultured organism between survivors and non-survivors. The median time interval between airway culture and antibiotic initiation was 2 hours (IQR 0-4.5) for survivors, and 0 hours (IQR 0-0) for non-survivors (P= .07). Antibiotics were administered within 1 hour of airway culture for 33.3% of survivors, and 77.8% of non-survivors (P= .02).Conclusions In a population of trauma patients with VAP, survivors had antibiotics initiated in more delayed fashion than non-survivors. These findings question the primacy of early antibiotic administration for suspected infection.

ABSTRACTIntroductionMany pediatric patients with malignant tumors continue to suffer poor outcomes. The current standard of care includes maximum safe surgical resection followed by chemotherapy and radiation which may be associated with considerable long-term morbidity. The emergence of oncolytic virotherapy (OVT) may provide an alternative or adjuvant treatment for pediatric oncology patients.Areas coveredWe reviewed seven virus types that have been investigated in past or ongoing pediatric tumor clinical trials: adenovirus (AdV-tk, Celyvir, DNX-2401, VCN-01, Ad-TD-nsIL-12), herpes simplex virus (G207, HSV-1716), vaccinia (JX-594), reovirus (pelareorep), poliovirus (PVSRIPO), measles virus (MV-NIS), and Senecavirus A (SVV-001). For each virus, we discuss the mechanism of tumor-specific replication and cytotoxicity as well as key findings of preclinical and clinical studies.Expert opinionSubstantial progress has been made in the past 10 years regarding the clinical use of OVT. From our review, OVT has favorable safety profiles compared to chemotherapy and radiation treatment. However, the antitumor effects of OVT remain variable depending on tumor type and viral agent used. Although the widespread adoption of OVT faces many challenges, we are optimistic that OVT will play an important role alongside standard chemotherapy and radiotherapy for the treatment of malignant pediatric solid tumors in the future.

This chapter highlights the most frequently encountered neurological malpractice claims. The format is designed to provide a rudimentary understanding of how lawsuits arise and thereby focus discussion on adapting practice patterns to improve patient care and minimize liability risk.

Objectives: Multimorbidity is the presence of two or more chronic health conditions. Tuberculosis (TB) survivors are known to have higher prevalence of multimorbidity, although prevalence estimates from high-income low-TB incidence jurisdictions are not available and potential differences in the patterns of chronic disease among TB survivors with multimorbidity are poorly understood. In this study, we aimed to (1) compare the prevalence of multimorbidity among TB survivors with matched non-TB controls in a high-income setting; (2) assess the robustness of aim 1 analyses to different modelling strategies, unmeasured confounding, and misclassification bias; and (3) among people with multimorbidity, elucidate chronic disease patterns specific to TB survivors. Methods: A population-based cohort study of people immigrating to British Columbia, Canada, 1985–2015, using health administrative data. Participants were divided into two groups: people diagnosed with TB (TB survivors) and people not diagnosed with TB (non-TB controls) in British Columbia. Coarsened exact matching (CEM) balanced demographic, immigration, and socioeconomic covariates between TB survivors and matched non-TB controls. Our primary outcome was multimorbidity, defined as ≥2 chronic diseases from the Elixhauser comorbidity index. Results: In the CEM-matched sample (n=1962 TB survivors; n=1962 non-TB controls), we estimated that 21.2% of TB survivors (n=416), compared with 12% of non-TB controls (n=236), had multimorbidity. In our primary analysis, we found a double-adjusted prevalence ratio of 1.74 (95% CI: 1.49–2.05) between TB survivors and matched non-TB controls for multimorbidity. Among people with multimorbidity, differences were observed in chronic disease frequencies between TB survivors and matched controls. Conclusion: TB survivors had a 74% higher prevalence of multimorbidity compared with CEM-matched non-TB controls. TB-specific multimorbidity patterns were observed through differences in chronic disease frequencies between the matched samples. These findings suggest a need for TB-specific multimorbidity interventions in high-income settings such as Canada. We suggest TB survivorship as a framework for developing person-centred interventions for multimorbidity among TB survivors.

Background:The prevalence of tuberculosis infection is critical to the design of tuberculosis prevention strategies, yet is unknown in Canada. We estimated the prevalence of tuberculosis infection among Canadian residents born abroad.Methods:We estimated the prevalence of tuberculosis infection by age and year of migration to Canada for people from each of 168 countries by constructing country-specific and calendar year–specific trends for annual risk of infection using a previously developed model. We combined country-specific prevalence estimates with Canadian Census data from 2001, 2006, 2011, 2016 and 2021 to estimate the overall prevalence of tuberculosis infection among foreign-born Canadian residents.Results:The estimated overall prevalence of tuberculosis infection among foreign-born people in Canada was 25% (95% uncertainty interval [UI] 20%–35%) for census year 2001, 24% (95% UI 20%–33%) for 2006, 23% (95% UI 19%–30%) for 2011, 22% (95% UI 19%–28%) for 2016 and 22% (95% UI 19%–27%) for 2021. The prevalence increased with age at migration and incidence of tuberculosis in the country of origin. In 2021, the estimated prevalence of infection among foreign-born residents was lowest in Quebec (19%, 95% UI 16%–24%) and highest in Alberta (24%, 95% UI 21%–28%) and British Columbia (24%, 95% UI 20%–30%). Among all foreign-born Canadian residents with tuberculosis infection in 2021, we estimated that only 1 in 488 (95% UI 185–1039) had become infected within the 2 preceding years.Interpretation:About 1 in 4 foreign-born Canadian residents has tuberculosis infection, but very few were infected within the 2 preceding years (the highest risk period for progression to tuberculosis disease). These data may inform future tuberculosis infection screening policies.

Extracellular vesicles (EVs) are lipid-based particles naturally released from cells and recognized as promising drug delivery vehicles for improving therapeutic outcomes. Efficient manufacturing of therapeutic EVs have been challenging for their clinical translations. Three-dimensional (3D) cell cultures enabled by biomaterial scaffolds have been used as a platform for improving EV manufacturing compared to conventional methods such as isolation from bodily fluids and standard Petri-dish cell culture. Recent studies on 3D culture derived EV production prove it to enhance the EV yield, functional cargos, and therapeutic efficacies. However, there are still challenges with scaling up 3D cell culture production platforms for industrial use. Hence, there is a high demand for designing, optimizing, and implementing large scale EV manufacturing platforms derived from 3D cell cultures. We will first review the current advances of biomaterial-enabled 3D cell cultures in EV manufacturing, followed by the effect of these 3D cell culture platforms on the EV yield, the EV quality, and therapeutic efficacies. Lastly, we will discuss the key challenges and potential for implementing biomaterial-enabled 3D culture in EV manufacturing for large scale processes in the industrial use.

AbstractRATIONALE: The long-term trajectory of people recovering from COVID-19 and the cause of persistent symptoms remains poorly understood.OBJECTIVE: We sought to determine how pulmonary function tests (PFTs), patient-reported outcome measures (PROMs) and radiologic features change over 12 months in people hospitalized with COVID-19.METHODS: A prospective, consecutive cohort of patients hospitalized with PCR-confirmed SARS-CoV-2 were recruited. Longitudinal clinical data, PROMs, PFTs and computed tomography (CT) chests were collected at 3, 6 and/or 12 months after symptom onset. Repeated analysis of variance (ANOVA) and Friedman tests were used to compare changes in outcomes over time.MEASUREMENT AND MAIN RESULTS: Eighty-one patients were enrolled with 70 completing the 12-month visit. At 3 months, the mean diffusing capacity of the lung for carbon monoxide was reduced at 76 ± 16%-predicted and improved to 80 ± 16%-predicted at 6 months (p < 0.001). The median values for dyspnea, cough, sleep and quality of life (QoL) were abnormal at 3 months, with QoL being the only PROM that significantly improved at 6 months. There was no further statistically significant change in PFT parameters or PROMs between 6 and 12 months. The percentages of lung affected by ground glass and reticulation at 3 months were 11.3% (IQR 5.6–19.6) and 4.4% (IQR 1.6–7.9), respectively. These improved at 12 months with ground glass being 0% (IQR 0-3.3) and reticulation 1.7% (IQR 0–3.3).CONCLUSIONS: PFTs improve between 3 and 6 months, with no change over the subsequent 6 months in patients hospitalized with COVID-19. Despite improved and nearly normal physiologic and radiologic results in most patients, 60% report abnormal PROMs at 12 months.

The USDA Forest Service is working closely with collaborative stakeholder groups to accelerate the pace and scale of restoration in fire-prone mixed conifer forests of eastern Oregon. Collaboratively planned restoration projects are typically designed to conserve older trees established before fire exclusion policies and other management practices began to alter forest landscapes beginning in the late 1800s. Tools exist for accurately estimating the age of common species including ponderosa pine, Douglas-fir, and western larch. There are no existing tools available for aging grand/white fir, although an important objective of many restoration projects in mixed conifer stands is to retain older grand/white fir while removing younger individuals that have infilled into stands in the absence of fire to enhance resilience of stands to future climate and disturbance regimes. This article describes the development of tools to age grand fir on the Malheur National Forest by taking simple field measurements of morphological characteristics. Bark fissure depth, height to live foliage, and diameter at breast height were the strongest noncorrelated tree morphological characteristics associated with tree age. Crown class had no predictive power for estimating tree age. A variety of methods are presented that can estimate the age of grand fir with reasonable accuracy and are appropriate for different management objectives. Additional field testing and continued experimentation with different tree aging methods within an adaptive management framework is recommended.Study Implications: Shade tolerant grand fir has expanded dramatically in mixed conifer stands of eastern Oregon in the absence of frequent fire. Collaboratively designed restoration projects in mixed conifer stands usually call for the removal of younger grand fir while maintaining older grand fir that contribute to stand- and landscape-scale biodiversity. It can be difficult to estimate the age of grand fir based on morphological clues because of highly variable growth forms in this species. However, several easy-to-use grand fir aging tools promise to facilitate restoration by making reasonably accurate estimates of tree age.

BackgroundThere is growing interest in using high-dose rifamycin (HDR) regimens in TB treatment, but the safety and efficacy of HDR regimens remain uncertain. We performed a systematic review and meta-analysis comparing HDR to standard-dose rifamycin (SDR) regimens.MethodsWe searched MEDLINE, Embase, CENTRAL, Cochrane Database of Systematic Reviews and clinicaltrials.gov for prospective studies comparing daily therapy with HDRs to SDRs. Rifamycins included rifampicin, rifapentine and rifabutin. Our primary outcome was the rate of severe adverse events (SAEs), with secondary outcomes of death, all adverse events, SAE by organ and efficacy outcomes of 2-month culture conversion and relapse. This study was prospectively registered in the International Prospective Register of Systematic Reviews (CRD42020142519).ResultsWe identified 9057 articles and included 13 studies with 6168 participants contributing 7930 person-years (PY) of follow-up (HDR: 3535 participants, 4387 PY; SDR: 2633 participants, 3543 PY). We found no significant difference in the pooled incidence rate ratio (IRR) of SAE between HDR and SDR (IRR 1.00, 95% CI 0.82 to 1.23, I2=41%). There was no significant difference when analysis was limited to SAE possibly, probably or likely medication-related (IRR 1.07, 95% CI 0.82 to 1.41, I2=0%); studies with low risk of bias (IRR 0.98, 95% CI 0.79 to 1.20, I2=44%); or studies using rifampicin (IRR 1.00, 95% CI 0. 0.75–1.32, I2=38%). No significant differences were noted in pooled outcomes of death, 2-month culture conversion and relapse.ConclusionsHDRs were not associated with a significant difference in SAEs, 2-month culture conversion or death. Further studies are required to identify specific groups who may benefit from HDR.

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine. In phase 2b and 3 studies, tezepelumab significantly reduced exacerbations versus placebo in patients with severe uncontrolled asthma, irrespective of baseline levels of type 2 inflammatory biomarkers. We investigated the mechanism of action of tezepelumab by assessing its effects on airway inflammatory cells, airway remodelling, and airway hyperresponsiveness.

Conservation of old-growth forests has become an increasingly important objective of Forest Service managers over the last three decades. The US Forest Service recently made changes to policies that prohibit cutting of live trees >53 cm (the “21-inch rule”). We review the disturbance ecology of dry and mesic old-growth forests of Oregon and contrast conservation policies for these two forest types. We describe the development of age-based alternatives to the 21-inch rule on the Klamath Reservation and in the Malheur National Forest in eastern Oregon. We conclude by outlining an adaptive management strategy to conserve dry forest old growth that seeks to restore the ecological processes that perpetuate old tree populations over time. We argue that what is good for dry forest ecosystems is good for dry forest old growth, especially in the face of changing climate and disturbance regimes.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

Maintenance dialysis patients are at an increased risk for active tuberculosis (TB). In 2012, British Columbia, Canada, began systematically screening maintenance dialysis patients for latent TB infection (LTBI) and treating people with evidence of LTBI when appropriate. We examined LTBI treatment outcomes and compared treatment outcomes before and after rollout of the systematic screening program.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

Graphical Abstract

Objective: To compare non-tuberculosis (non-TB)-cause mortality risk overall and cause-specific mortality risks within the immigrant population of British Columbia (BC) with and without TB diagnosis through time-dependent Cox regressions. Methods: All people immigrating to BC during 1985–2015 (N?=?1,030,873) were included with n?=?2435 TB patients, and the remaining as non-TB controls. Outcomes were time-to-mortality for all non-TB causes, respiratory diseases, cardiovascular diseases, cancers, and injuries/poisonings, and were ascertained using ICD-coded vital statistics data. Cox regressions were used, with a time-varying exposure variable for TB diagnosis. Results: The non-TB-cause mortality hazard ratio (HR) was 4.01 (95% CI 3.57–4.51) with covariate-adjusted HR of 1.69 (95% CI 1.50–1.91). Cause-specific covariate-adjusted mortality risk was elevated for respiratory diseases (aHR?=?2.96; 95% CI 2.18–4.00), cardiovascular diseases (aHR?=?1.63; 95% CI 1.32–2.02), cancers (aHR?=?1.40; 95% CI 1.13–1.75), and injuries/poisonings (aHR?=?1.85; 95% CI 1.25–2.72). Conclusions: In any given year, if an immigrant to BC was diagnosed with TB, their risk of non-TB mortality was 69% higher than if they were not diagnosed with TB. Healthcare providers should consider multiple potential threats to the long-term health of TB patients during and after TB treatment. TB guidelines in high-income settings should address TB survivor health.

Occipital-cervical fusion (OCF) and ventral decompression (VD) may be used in the treatment of pediatric Chiari-1 malformation (CM-1) with syringomyelia (SM) as adjuncts to posterior fossa decompression (PFD) for complex craniovertebral junction pathology.

It remains unclear if participation in moderate-to-vigorous physical activity (MVPA) differs between children with ASD and typically developing children (TDC). We compared daily MVPA, time spent in MVPA during physical education (PE) and recess, and odds of not meeting MVPA recommendation (60 min/day) between children with ASD and TDC. Nine studies reporting accelerometer-measured MVPA were included in the meta-analyses. MVPA was 30 min lower/day, 12% and 8% lower during PE and recess, respectively, in children with ASD, and they had 4 times higher odds of not meeting MVPA recommendation when compared to TDC. Children with ASD engage in daily MVPA less than TDC and below the guidelines. Tailored interventions to increase MVPA in children with ASD are warranted.

The risk of tuberculosis (TB) is variable among individuals with latent Mycobacterium tuberculosisinfection (LTBI), but validated estimates of personalized risk are lacking. In pooled data from 18 systematically identified cohort studies from 20 countries, including 80,468 individuals tested for LTBI, 5-year cumulative incident TB risk among people with untreated LTBI was 15.6% (95%?confidence interval (CI), 8.0–29.2%) among child contacts, 4.8% (95% CI, 3.0–7.7%) among adult contacts, 5.0% (95% CI, 1.6–14.5%) among migrants and 4.8% (95% CI, 1.5–14.3%) among immunocompromised groups. We confirmed highly variable estimates within risk groups, necessitating an individualized approach to risk stratification. Therefore, we developed a personalized risk predictor for incident TB (PERISKOPE-TB) that combines a quantitative measure of T cell sensitization and clinical covariates. Internal–external cross-validation of the model demonstrated a random effects meta-analysis C-statistic of 0.88 (95% CI, 0.82–0.93) for incident TB. In decision curve analysis, the model demonstrated clinical utility for targeting preventative treatment, compared to treating all, or no, people with LTBI. We challenge the current crude approach to TB risk estimation among people with LTBI in favor of our evidence-based and patient-centered method, in settings aiming for pre-elimination worldwide.

Deep learning-based radiological image analysis could facilitate use of chest x-rays as triage tests for pulmonary tuberculosis in resource-limited settings. We sought to determine whether commercially available chest x-ray analysis software meet WHO recommendations for minimal sensitivity and specificity as pulmonary tuberculosis triage tests.

Congenital hydrocephalus (CH), characterized by enlarged brain ventricles, is considered a disease of excessive cerebrospinal fluid (CSF) accumulation and thereby treated with neurosurgical CSF diversion with high morbidity and failure rates. The poor neurodevelopmental outcomes and persistence of ventriculomegaly in some post-surgical patients highlight our limited knowledge of disease mechanisms. Through whole-exome sequencing of 381 patients (232 trios) with sporadic, neurosurgically treated CH, we found that damaging de novo mutations account for >17% of cases, with five different genes exhibiting a significant de novo mutation burden. In all, rare, damaging mutations with large effect contributed to ~22% of sporadic CH cases. Multiple CH genes are key regulators of neural stem cell biology and converge in human transcriptional networks and cell types pertinent for fetal neuro-gliogenesis. These data implicate genetic disruption of early brain development, not impaired CSF dynamics, as the primary pathomechanism of a significant number of patients with sporadic CH.

ABSTRACTThis paper explores the comparative performance of two subject areas (Units of Assessment – UOAs) in the UK national Research Assessment Exercises of 1992, 1996, 2001, 2008 and the Research Excellence Framework of 2014. The Units of Assessment are Economics and Econometrics; and Business and Management Studies. Given the wide range of disciplines in the Business and Management Studies UOA universities have the choice of submitting their economics and econometrics research either to it or to the Economics and Econometrics UOA. Over the period 1992–2014 the number of universities entering the Economics and Econometrics UOA declined significantly in contrast to the growth in the number entering the Business and Management Studies UOA. The reasons for this include the finding that university managers were more likely to tolerate poor performance (measured by internal and external gaps) in Business and Management Studies than in Economics and Econometrics. Considerable differences were found between old (pre-1992) and new (post-1992) universities, with Economics and Econometrics now solely the domain of old universities as new ones have withdrawn. In sharp contrast, Business and Management Studies has a good balance of old and new universities.

We describe a screening approach to identify customized substrates for serum-free human mesenchymal stromal cell (hMSC) culture. In particular, we combine a biomaterials screening approach with design of experiments (DOE) and multivariate analysis (MVA) to understand the effects of substrate stiffness, substrate adhesivity, and media composition on hMSC behavior in vitro. This approach enabled identification of poly(ethylene glycol)-based and integrin binding hydrogel substrate compositions that supported functional hMSC expansion in multiple serum-containing and serum-free media, as well as the expansion of MSCs from multiple, distinct sources. The identified substrates were compatible with standard thaw, seed, and harvest protocols. Finally, we used MVA on the screening data to reveal the importance of serum and substrate stiffness on hMSC expansion, highlighting the need for customized cell culture substrates in optimal hMSC biomanufacturing processes.