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Background: Tuberculous meningitis (TBM) is a severe central nervous system (CNS) infection with a challenging diagnosis due to inadequate detection methods. This study evaluated current clinical detection methods and their applicability., Methods: A cohort of 514 CNS infection patients from 2018 to 2020 was studied. Data on general demographics, Cerebrospinal Fluid (CSF) analysis, epidemiology, and clinical outcomes were collected. TBM patients were identified, and the sensitivities of mmetagenomic next-generation sequencing (NGS), GeneXpert, and microbial culture were compared. Kappa statistic assessed the consistency between methods., Results: Among the patients involved, TBM (29%) and neurosyphilis (25%) were the two most prevalent CNS infections. CSF analysis indicated that 76% of patients had leukocytosis, suggesting a potential CNS inflammation. In TBM cases, 92.5% had elevated CSF protein and leukocyte counts. Moreover, the percentage of positive mNGS results was 55.6%. GeneXpert and MTB cultures alone had lower sensitivity, but combined use resulted in a 53.4% positive rate., Conclusions: This study highlights the high sensitivity of mNGS, comparable to GeneXpert and MTB culture. The combined methods are cost-effective and straightforward, and can partially substitute for mNGS, offering valuable alternatives for TBM diagnosis and providing insights into multiple diagnostic strategies in clinical practice., (© 2024. The Author(s).)

Macroscopic hematuria (MH)-associated acute kidney injury (AKI) is a rare condition that causes acute tubular damage due to severe glomerular bleeding with MH. A 66-year-old Japanese woman with no significant past medical history was referred for severe kidney injury with oliguric MH. Her prior medical checkup results showed no occult blood in her urine. Seven days earlier, she had experienced transient severe acute right lumbar back pain. On admission, her serum urea nitrogen was 147 mg/dL, serum creatinine (sCr) 18.3 mg/dL, urinary red blood cells (RBCs) > 100/hpf, urinary protein 28.8 g/gCr, with no hydronephrosis in either kidney, but two stones were found in the right kidney and right ureteropelvic junction. At the start of her hemodialysis, the patient was treated with high-dose steroids because of suspected rapidly progressive glomerulonephritis. A renal biopsy of the left kidney showed acute tubular injury with massive RBC casts filling the tubular lumen. Glomerulitis was not detected, but electron microscopy revealed diffuse glomerular thin basement membrane (TBM). Despite immediate steroid discontinuation, the patient's renal function and MH improved, and she was weaned from hemodialysis. The stones resolved 2 months after onset, but microscopic hematuria persisted for 7 months post-onset. The sCr level was fixed at 1.1 mg/dL 20 months post-onset. This is the first report of MH-AKI in a TBM without the risk of MH-AKI development, such as bleeding tendency or iron overload. In this TBM, a colic attack of the renal urinary tract induced glomerular bleeding, and intolerance to hematuria may have caused severe tubular damage., (© 2024. The Author(s), under exclusive licence to Japanese Society of Nephrology.)

Brittleness is an important mechanical property of rock. Accurately evaluating rock brittleness and its influence on the TBM tunnelling performance is necessary. In this work, via two practical engineering cases, with the aim of overcoming the difficulty of penetrating extremely hard rock (breccia fused tuff) in the Z huxi project, the influence of rock brittleness on the TBM tunnelling performance was studied via comparative analysis with that Nabang project. Seven commonly used rock brittleness indices based on stress‒strain curves were summarized, and a brittleness evaluation method suitable for extremely hard rock was determined by introducing the normalized specific energy to obtain brittleness indices for two lithologies (breccia fused tuff and biotite hornblende plagioclase gneiss) in two projects. The influences of rock brittleness on penetration and the specific energy were compared and analysed. The results showed that the brittleness indices B 3 and B 5 were more suitable for evaluating rock brittleness. Rock brittleness influenced the TBM tunnelling performance, but this influence gradually decreased with decreasing uniaxial compressive strength ( UCS ), which is obviously less than that of the rock strength. When the UCS was lower than 150 MPa, the TBM tunnelling parameters could be adjusted within a significant margin to eliminate the influence of rock brittleness, which could be ignored when predicting the tunnelling performance. When the UCS was greater than 150 MPa, rock brittleness imposed a notable influence on the tunnelling performance, which must be considered when predicting the tunnelling performance. This research could provide reference data for evaluating the hard rock brittleness index and accurately predicting the TBM tunnelling performance in engineering practice., (© 2024. The Author(s).)

Tracheobronchomalacia (TBM) is a frequently under-recognized condition that often coexists with other chronic respiratory diseases. The diagnosis of excessive central airway collapse requires consideration by the physician. Dynamic computed tomography scan of the chest and awake dynamic bronchoscopy are critical to establishing a diagnosis of TBM. Patients with severe TBM are candidates for tracheobronchoplasty. Multidisciplinary evaluation of patients with TBM has the potential benefit derived from shared decision-making to ensure patient optimization, prehabilitation, periprocedural care and posttreatment recovery, rehabilitation, and follow-up. Robotic tracheobronchoplasty is safe and improves pulmonary function tests and quality of life in patients with severe TBM., Competing Interests: Disclosure The authors have no disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The thermal hazards generated during the tunnel boring machine construction process significantly impact the physical and mental health of personnel. A field test was conducted on the tunnel of Metro Line 1 in Changsha, China, where the average temperature in the work zone reached up to 33.16 °C, and the air velocity was generally below 0.2 m/s. These conditions were unfavorable for ventilation and heat dissipation. In this paper, a full-scale CFD simulation model was established to simulate the construction environment and analyze the cooling demand. The results indicated that increasing the fresh air velocity could lower the temperature in the work zone; however, this effect was limited. When the fresh air temperature exceeded a certain threshold, it actually raised the average temperature of the work zone. Consequently, there is a need for supplementary cooling of the fresh air during the hot summer months. At a fresh air velocity of 15 m/s, the maximum temperature in the work zone was recorded at 27.8 °C when the fresh air was cooled down to 22.5 °C through auxiliary cooling measures. This approach effectively controlled the temperature in the work zone, reduced flow dead zones, and significantly improved air distribution and heat dissipation. Additionally, it ensured the physical and mental well-being of the construction workers and the safe operation of the equipment. This study provides valuable guidance for managing thermal environments in underground tunnel construction., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Su huan reports financial support was provided by 10.13039/501100004735Natural Science Foundation of Hunan Province China (2022JJ30194). Yang Zihan reports financial support was provided by Science and technology research and development project of China Construction Corporation (CSCEC-2022-Q-47). Yang Zihan reports financial support was provided by Science and technology research and development project of China Construction Fifth Bureau (cscec5b-2020-19). Li Xiaohua reports financial support was provided by Xiangtan Science And Technology Innovation Project (GX-YB20221005). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Introduction: Patients presenting with head and neck squamous cell carcinoma of unknown primary (HNSCCUP) remain challenging clinical scenarios as large variation exists in practices used to locate the primary., Objective: The objective of this systematic review is to review of the literature and offer recommendations for oropharyngeal biopsies in HNSCCUP., Method: Pubmed, Medline and Embase were searched to identify studies from inception to October 2021. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed., Results: A total of 483 articles were included and screened, 41 studies met the inclusion criteria, including over 3400 patients from the original articles (122 of these patients were reported on in two sequential articles by a single author - table 1) and 4 large metaanalyses including 1852 patients. The primary site identification rate following random biopsies or deep tissue biopsies is less than 5% in most studies. The mean detection rate following ipsilateral tonsillectomy is 34%; two pooled analyses indicate that the mean detection rate following tongue base mucosectomy is 64%, with this figure rising when the tonsils are negative., Conclusions: High level evidence is lacking, with heterogeneity in the reported studies. Published meta-analyses are based on retrospective data. There is little evidence supporting the practice of random/non-directed oropharyngeal biopsies. Available evidence supports palatine tonsillectomy and tongue base mucosectomy compared to deep tissue biopsies., (© 2024 John Wiley & Sons Ltd.)

Tunnel boring machines (TBMs) are used to excavate tunnels in a manner where the rock is constantly penetrated with rotating cutter heads. Fine particles of the rock minerals are thereby generated. Workers on and in the vicinity of the TBM are exposed to particulate matter (PM) consisting of bedrock minerals including α-quartz. Exposure to respirable α-quartz remains a concern because of the respiratory diseases associated with this exposure. The particle size distribution of PM and α-quartz is of special importance because of its influence on adverse health effects, monitoring and control strategies as well as accurate quantification of α-quartz concentrations. The major aim of our study was therefore to investigate the particle size distribution of airborne PM and α-quartz generated during tunnel excavation using TBMs in an area dominated by gneiss, a metamorphic type of rock. Sioutas cascade impactors were used to collect personal samples on 3 separate days. The impactor fractionates the dust in 5 size fractions, from 10 µm down to below 0.25 µm. The filters were weighted, and the α-quartz concentrations were quantified using X-ray diffraction (XRD) analysis and the NIOSH 7500 method on the 5 size fractions. Other minerals were determined using Rietveld refinement XRD analysis. The size and elemental composition of individual particles were investigated by scanning electron microscopy. The majority of PM mass was collected on the first 3 stages (aerodynamic diameter = 10 to 0.5 µm) of the Sioutas cascade impactor. No observable differences were found for the size distribution of the collected PM and α-quartz for the 3 sampling days nor the various work tasks. However, the α-quartz proportion varied for the 3 sampling days demonstrating a dependence on geology. The collected α-quartz consisted of more particles with sizes below 1 µm than the calibration material, which most likely affected the accuracy of the measured respirable α-quartz concentrations. This potential systematic error is important to keep in mind when analyzing α-quartz from occupational samples. Knowledge of the particle size distribution is also important for control measures, which should target particle sizes that efficiently capture the respirable α-quartz concentration., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Introduction: Tubercular meningitis (TBM) is a serious public health problem in developing countries as it leads to significant mortality and residual neurological sequelae. The estimated mortality due to TBM in India is 1.5 per 100,000 population. In resource-limited settings, only the Ziehl-Neelsen (ZN) stain, which has very little sensitivity, is available. The World Health Organization recommended the Loop Mediated Isothermal Amplification (TB LAMP) assay for pulmonary tuberculosis only. We evaluated this test for tubercular meningitis as well., Methodology: In a cross-sectional study of 2-year duration, we have taken 239 cerebrospinal fluid samples from suspected cases of tubercular meningitis patients. ZN staining along with Mycobacteria Growth Indicator Tube (MGIT) TB culture, Xpert MTB/RIF Ultra assay, and commercial TB LAMP assay were performed for each sample., Results: Out of 239 samples, 40 samples (16.73%) were found TB LAMP assay positive, 48 samples (20.08%) were found Xpert ultra-assay positive, 12 samples (5.02%) were MGIT TB culture positive and acid-fast bacillus smear positive in ten samples (4.18 %). Out of 12 MGIT-positive samples, all samples (100%) were TB LAMP and Xpert ultra positive and one sample (8.33%) was ZN smear positive. In 199 negative samples from the TB LAMP assay, eight samples were positive by Xpert, none by MGIT TB culture and AFB smear. Sensitivity and specificity were found as 100% and 87.66%, respectively, for the TB LAMP assay., Conclusion: TB LAMP assay is a rapid, cost-effective, sensitive, and specific test for tubercular meningitis infection in resource-limited settings., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2024 Vineeta Mittal, Manoj Kumar, Ajay Kumar Singh.)

The vibration of tunnel boring machine (TBM) is very difficult to monitor on sites, and related research on prediction methods is rare. Based on the field tunnelling test of a TBM in the Xinjiang Ehe project, the vibration information of the main beam of the TBM under different surrounding rock conditions is collected. The relationships among the tunnelling parameters, surrounding rock parameters and vibration parameters were studied. The results show that the penetration, cutter head speed, torque and thrust are important parameters affecting TBM vibration. In addition, the field penetration index and cutter head driving power index are significantly related to the root mean square of acceleration. Based on this, a multiple regression prediction model of TBM vibration is established. The model was verified and analysed via field projects, and the relative prediction error was less than 12%. This method can be used to predict the vibration of a TBM in real time through characteristic parameters without the use of a traditional monitoring system. This approach is highly important for determining the status of TBM equipment in real time., (© 2024. The Author(s).)

Background and Aims: South Asian countries, including Pakistan, Afghanistan, India, and Bangladesh, have a high prevalence of pulmonary and extra-pulmonary tuberculosis (EPTB). This prevalence is influenced by various risk factors such as ethnicity, nutrition, socioeconomic disparities, high out-of-pocket healthcare expenses, and specific Mycobacterium Tuberculosis (TB) lineages. The COVID-19 pandemic has likely hindered access to healthcare and led to under-reporting of EPTB cases nationally and internationally. This rapid review aimed to summarize the literature on the prevalence and disease outcomes of EPTB in the mentioned countries, compare the situations across countries, and provide recommendations for future action., Methods: The review utilized PubMed and Google Scholar databases to search for literature on EPTB in South Asian countries. The search string included keywords related to different forms of EPTB and the countries of interest while excluding pulmonary tuberculosis., Results: The results showed that both TB, including drug-resistant TB, and EPTB are prevalent and burdensome in South Asia. In Pakistan, pleural TB was the most commonly reported form of EPTB, followed by lymph node TB, abdominal TB, osteoarticular TB, Central Nervous System TB, and miliary TB. In India, lymph node TB(LNTB) was more common among EPTB cases. Bangladesh reported a high prevalence of EPTB involving lymph node, pleura, and abdomen, while Afghanistan had a higher prevalence of forms such as LNTB and tuberculous meningitis., Conclusion: In conclusion, the prevalence of EPTB in Pakistan, Afghanistan, India, and Bangladesh is alarmingly high and negatively impacts population health. Effective measures are needed for treatment and management of this condition, along with addressing current and future challenges. Strengthening the evidence base through surveillance and research is crucial to understand the patterns and significant factors related to EPTB, requiring investment in these areas., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Objectives: This study aimed to assess the exposure to a selection of aerosols and gases in the work environment for workers performing tunnel construction using tunnel boring machines (TBMs), to identify determinants of exposure based on the information available and to calculate robust estimates of exposure using a statistical model. The focus was particulate matter (PM) and respirable crystalline silica (RCS). In addition, concentrations of nitrogen dioxide (NO2), elemental carbon (EC), and oil mist were assessed., Methods: Personal sampling was conducted from February 2017 to February 2019. PM in the thoracic and the respirable aerosol fractions was collected, and RCS was determined in the respirable aerosol fraction. Context information was collected on questionnaires. Because the workers could participate in the sampling more than once and multiple measurements were performed on the same date a mixed model was used in the analysis. Concentrations of PM and RCS are presented as estimated and measured geometric means (GMest and GMmea) and estimated arithmetic mean (AMest) in addition to the median. Measured concentrations of NO2, EC, and oil mist are presented as geometric means., Results: A total of 290 and 289 personal samples of PM in the thoracic and respirable aerosol fractions were available for analysis, respectively. Work title/work location, type of work (production, maintenance, or a combination of the two), and date of sampling were identified as determinants of exposure. Workers in the front of the TBMs had the highest exposure to PM and RCS. The GMest of RCS exposure varied from 35 to 413 μg m-3 depending on the work title. The geometric standard deviations for measured RCS concentrations by work title ranged from 1.6 to 3.5. A total of 16 samples of NO2 and EC and 12 samples of oil mist were collected. Maximum values of NO2 and EC were 54 µg m-3 and 23 µg m-3, respectively. The maximum measured value of oil mist was 0.08 mg m-3., Conclusions: All TBM workers were exposed to PM and RCS. Exposure to RCS may be substantial, and workers in front of the TBM were exposed to the highest concentrations of both PM and RCS. A day-to-day variation was found, probably caused by differences in drilling activities. Preventive measures are warranted to keep the exposure to PM and consequently the exposure to RCS as low as possible to protect the health of workers in tunnel construction., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Occupational Hygiene Society.)

Purpose  The purpose of this study is to evaluate magnetic resonance (MR) angiography (MRA) and venography (MRV) findings in tuberculous meningitis (TBM). Methods  Thirty consecutive patients of clinically diagnosed TBM were enrolled. Apart from T2-weighted imaging, T1-weighted imaging (T1WI), diffusion-weighted imaging, susceptibility-weighted imaging, fluid-attenuated inversion recovery, and postcontrast T1WI, time-of-flight (TOF) MRA and postcontrast MRV were done in all the patients. MRV was done after intravenous administration of gadolinium-based contrast agent followed by postcontrast T1WI. MRA and MRV findings were analyzed. Results  Mean age of the patients was 33.13 ± 14.93 years. Duration of symptom was 34.90 ± 33.82 (range: 10-150) days. Out of 30 patients, 11 were categorized as definite TBM and 19 probable TBM. Eighteen (60%) were grade I, 7 (23%) grade II, and 5 (16%) grade III TBM based on severity. MR abnormalities were in varying combinations of leptomeningeal enhancement in 24 (80%), pachymeningeal in 2, both in 3, tuberculomas in 13 (43.3%), ventriculitis in 1, hydrocephalus in 16 (53.3%), and infarcts in 10 (33.3%) patients out of which the tubercular zone infarct in 9 patients. TOF MRA showed arterial abnormality in 13 patients. Anterior cerebral artery and middle cerebral artery have commonly involved vessels. Dural sinus thrombosis was noted in two patients. Both were female. One patient had subacute thrombus in the posterior part of superior sagittal sinus, left transverse sinus, and proximal right transverse sinus. The second patient had a filling defect in the transverse sinus. Conclusion  In TBM, there is predominant arterial involvement causing infarcts which are usually seen in the tubercular zone. However, occasionally, there may be venous involvement causing cerebral venous sinus thrombosis., Competing Interests: Conflict of Interest None declared., (Association for Helping Neurosurgical Sick People. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

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.

Background: High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in human immunodeficiency virus (HIV) coinfection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity., Methods: In this phase II open-label trial, Ugandan adults with suspected TBM were randomized to standard-of-care control (PO-10, rifampicin 10 mg/kg/day), intravenous rifampicin (IV-20, 20 mg/kg/day), or high-dose oral rifampicin (PO-35, 35 mg/kg/day). We performed PK sampling on days 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration, and grade 3-5 adverse events., Results: We enrolled 61 adults, 92% were living with HIV, median CD4 count was 50 cells/µL (interquartile range [IQR] 46-56). On day 2, geometric mean plasma AUC0-24hr was 42.9·h mg/L with standard-of-care 10 mg/kg dosing, 249·h mg/L for IV-20 and 327·h mg/L for PO-35 (P < .001). In CSF, standard of care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27 mg/L, compared with 1.74 mg/L (95% confidence interval [CI] 1.2-2.5) for IV-20 and 2.17 mg/L (1.6-2.9) for PO-35 regimens (P < .001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (P = .34)., Conclusions: Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe and respectively resulted in exposures ~6- and ~8-fold higher than standard of care, and CSF levels above the MIC., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Introduction: Tubercular bacterial meningitis continues to be an important cause of morbidity (especially neurologic handicap) in children from resource-poor countries. The present study was planned to assess the clinical and radiological presentation in cases of tubercular meningitis as well as to study the factors associated with mortality., Methodology: This study was done over a period of 12 months on children between 5 years and 13 years with suspected TBM. Staging of tubercular meningitis was done according to RNTCP Pediatric TB guideline 2019., Result: The study was conducted on a total of 47 pediatric patients with TBM. Mean age of children in present study was 8.77 ± 2.5 years. Our study documented male preponderance for TBM. Severe thinness was observed in 38.3% patients with TBM. Only 59.6% patients were immunized against tuberculosis and history of contact was documented in 40.5% patients. Maximum children belonged to stage I of TBM (59.6%) followed by stage III and stage II in 34% and 6.4% patients respectively. Montoux test positivity was observed in 14.9% patients only. CSF CBNAAT was positive in 6.4% patients. The most common finding was meningeal enhancement seen in 27.7% of patients followed by tuberculomas in 10.6%.Chest X ray was abnormal in 44.7% patients. In present study mortality was observed in 11 (23.4%) cases. Out of various risk factors, mortality was significantly associated with nutritional status and stage of TBM (p < 0.01)., Conclusion: TBM is associated with high morbidity and mortality in children especially in India where Burden of TB is high. Our study emphasized on the risk factors associated with mortality in children with TBM and need for early diagnosis and appropriate treatment., Competing Interests: Conflict of interest All authors have none to declare., (Copyright © 2021 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

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.

The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of <150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts > 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a "one-size-fits-all" approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Cresswell FV et al.)

Protein structural information is essential for the detailed mapping of a functional protein network. For a higher modelling accuracy and quicker implementation, template-based algorithms have been extensively deployed and redefined. The methods only assess the predicted structure against its native state/template and do not estimate the accuracy for each modelling step. A divergence measure is therefore postulated to estimate the modelling accuracy against its theoretical optimal benchmark. By freezing the domain boundaries, the divergence measures are predicted for the most crucial steps of a modelling algorithm. To precisely refine the score using weighting constants, big data analysis could further be deployed.

Human Immunodeficiency Virus (HIV)-infected persons are at a higher risk of developing Tuberculous Meningitis (TBM). We aimed to estimate the prevalence of TBM-HIV co-infection. We systematically searched Pubmed/Medline, Embase and Cochrane library databases from January 1, 2000, to January 31, 2017, to find relevant studies. We employed the random-effects meta-analysis model to estimate the pooled prevalence of TBM-HIV co-infection. Twenty-six eligible studies showed the prevalence of HIV in TBM patients. In the pooled analyses, the prevalence of HIV was 30% (95% CI: 12-47) in patients with confirmed TBM, and 12.1% (95% CI: 7.3-19.2) in patients with suspected TBM. This study shows a high prevalence of TBM-HIV co-infection. Establishing proper diagnostic criteria and preventive measures for TBM infections could assist in the prevention and management of TBM infection, particularly TBM-HIV co-infection., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Tuberculosis (TB) is the most prevalent infectious disease in the world. In recent years there has been a significant increase in the incidence of TB due to the emergence of multidrug resistant strains of Mycobacterium tuberculosis ( M. tuberculosis ) and the increased numbers of highly susceptible immuno-compromised individuals. Central nervous system TB, includes TB meningitis (TBM-the most common presentation), intracranial tuberculomas, and spinal tuberculous arachnoiditis. Individuals with TBM have an initial phase of malaise, headache, fever, or personality change, followed by protracted headache, stroke, meningismus, vomiting, confusion, and focal neurologic findings in two to three weeks. If untreated, mental status deteriorates into stupor or coma. Delay in the treatment of TBM results in, either death or substantial neurological morbidity. This review provides latest developments in the biomedical research on TB meningitis mainly in the areas of host immune responses, pathogenesis, diagnosis, and treatment of this disease.

The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of <150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts > 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a "one-size-fits-all" approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Cresswell FV et al.)

Introduction. Childhood tuberculosis meningitis is a severe form of tuberculosis with high morbidity and mortality. The diagnosis is frequently missed and delayed due to lack of sensitive tests like acid-fast bacilli (AFB) smear and delayed results by culture. Aims. To compare the role of IS6110 and protein antigen b PCR in cerebrospinal fluid (CSF) for rapid diagnosis of tuberculous meningitis (TBM) in children. Methodology. Forty-five cases of TBM and 20 controls were enrolled in this prospective study. Results. The mean ages of cases and controls were 4.2±0.5 years and 4.5±0.7 years, respectively. In the TBM group, two-thirds of the children were <4 years of age, and 62 % were males. Sensitivities of AFB smear examination, Löwenstein-Jensen (LJ) medium and bactenecin (BACTEC) culture in cases were 4.4, 0 and 2.2%, respectively. The protein antigen b PCR was most sensitive as it was positive in 35 (77.8 %) of TBM patients; IS6110 PCR was positive in 27 (60 %) patients. Both PCR-based tests had higher positivity than conventional tests and BACTEC culture. No significant difference was seen between the PCR tests. Excellent agreement was observed between both PCR-based tests as they were concordant for 26 positive samples and 35 negative samples. Conclusion. Protein b PCR is a sensitive and rapid method for the diagnosis of TBM (sensitivity 77.8 %). Both PCRs were more sensitive than smear, LJ and BACTEC. The specificity of both PCR was 100 %.

Checklists are pivotal in the systematic assessment of critically ill patients, pre-operative assessments and for patients with multisystem involvements. Management of tuberculous meningitis is challenging due to prolonged hospital stay, multiple neurological complications like seizures, stroke, raised intracranial tension, stroke, neurosurgical interventions, multiple invasive procedures, health-care-associated sepsis, and ventilation. All these complications are managed by separate checklists to avoid treatment-related errors. The current manuscript aims to ensure completeness of inpatient care addressing issues addressing diagnostic issues, supportive care, and intensive care related issues., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Behl A and Dhawan S.)

Objective: To determine the utility of CSF Xpert MTB/RIF (GeneXpert) in diagnosis of tubercular meningitis in children in the age group of 2 mo to 12 y., Methods: This hospital based prospective observational study was conducted at Department of Pediatrics, Karnataka Institute of Medical Sciences (KIMS), Hubli from December 2015 through November 2016. All children with clinically suspected tuberculous meningitis (TBM) were included in the study. These children underwent a detailed history taking, clinical examination, blood investigations, lumbar puncture and CT brain. Cerebrospinal fluid (CSF) samples were sent for CSF GeneXpert examination. Statistical analysis was done using IBM SPSS Statistics Version 20., Results: A total of 28 children were enrolled in the study. Six (21.4%), 4 (14.3%) and 18 (64.3%) cases were definite, probable and possible TBM cases respectively. Most common age group affected was <5 y (83.33%) with median age 2.5 y (IQR 4.875). Male:female ratio was 1.5:1. CSF GeneXpert was tested positive in 6 cases (21.4%). The sensitivity of the test against the clinical scoring (>/=10) was 46.15% (95% CI, 19.22-74.87) and specificity was 100% (95% CI, 78.20-100). There was a significant association between CSF GeneXpert and Mantoux test (P = 0.002), CSF cell type >50% lymphocytes (P = 0.005) and CSF protein >100 mg/dl (P = 0.025) along with CT hydrocephalus (P = 0.021), granuloma (P = 0.009) and basal exudates (P = 0.025). None of the cases were tested smear positive for acid-fast bacilli (AFB)., Conclusions: CSF GeneXpert is superior to smear for AFB in TBM.

Tuberculous meningitis (TBM) results from dissemination of M. tuberculosis to the cerebrospinal fluid (CSF) and meninges. Ischaemia, hydrocephalus and raised intracranial pressure frequently result, leading to extensive brain injury and neurodisability. The global burden of TBM is unclear and it is likely that many cases are undiagnosed, with many treated cases unreported. Untreated, TBM is uniformly fatal, and even if treated, mortality and morbidity are high. Young age and human immunodeficiency virus (HIV) infection are potent risk factors for TBM, while Bacillus Calmette-Guérin (BCG) vaccination is protective, particularly in young children. Diagnosis of TBM usually relies on characteristic clinical symptoms and signs, together with consistent neuroimaging and CSF parameters. The ability to confirm the TBM diagnosis via CSF isolation of M. tuberculosis depends on the type of diagnostic tests available. In most cases, the diagnosis remains unconfirmed. GeneXpert MTB/RIF and the next generation Xpert Ultra offer improved sensitivity and rapid turnaround times, and while roll-out has scaled up, availability remains limited. Many locations rely only on acid fast bacilli smear, which is insensitive. Treatment regimens for TBM are based on evidence for pulmonary tuberculosis treatment, with little consideration to CSF penetration or mode of drug action required. The World Health Organization recommends a 12-month treatment course, although data on which to base this duration is lacking. New treatment regimens and drug dosages are under evaluation, with much higher dosages of rifampicin and the inclusion of fluoroquinolones and linezolid identified as promising innovations. The inclusion of corticosteroids at the start of treatment has been demonstrated to reduce mortality in HIV-negative individuals but whether they are universally beneficial is unclear. Other host-directed therapies show promise but evidence for widespread use is lacking. Finally, the management of TBM within health systems is sub-optimal, with drop-offs at every stage in the care cascade., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Seddon JA et al.)

The pathogenesis of Tuberculous meningitis (TBM) is poorly understood, but contemporary molecular biology technologies have allowed for recent improvements in our understanding of TBM. For instance, neutrophils appear to play a significant role in the immunopathogenesis of TBM, and either a paucity or an excess of inflammation can be detrimental in TBM. Further, severity of HIV-associated immunosuppression is an important determinant of inflammatory response; patients with the advanced immunosuppression (CD4+ T-cell count of <150 cells/μL) having higher CSF neutrophils, greater CSF cytokine concentrations and higher mortality than those with CD4+ T-cell counts > 150 cells/μL. Host genetics may also influence outcomes with LT4AH genotype predicting inflammatory phenotype, steroid responsiveness and survival in Vietnamese adults with TBM. Whist in Indonesia, CSF tryptophan level was a predictor of survival, suggesting tryptophan metabolism may be important in TBM pathogenesis. These varying responses mean that we must consider whether a "one-size-fits-all" approach to anti-bacillary or immunomodulatory treatment in TBM is truly the best way forward. Of course, to allow for proper treatment, early and rapid diagnosis of TBM must occur. Diagnosis has always been a challenge but the field of TB diagnosis is evolving, with sensitivities of at least 70% now possible in less than two hours with GeneXpert MTB/Rif Ultra. In addition, advanced molecular techniques such as CRISPR-MTB and metagenomic next generation sequencing may hold promise for TBM diagnosis. Host-based biomarkers and signatures are being further evaluated in childhood and adult TBM as adjunctive biomarkers as even with improved molecular assays, cases are still missed. A better grasp of host and pathogen behaviour may lead to improved diagnostics, targeted immunotherapy, and possibly biomarker-based, patient-specific treatment regimens., Competing Interests: No competing interests were disclosed., (Copyright: © 2019 Cresswell FV et al.)

Growing evidence points to persistent neurological injury in chronic HIV infection. It remains unclear whether chronically HIV-infected individuals on combined antiretroviral therapy (cART) develop progressive brain injury and impaired neurocognitive function despite successful viral suppression and immunological restoration. In a longitudinal neuroimaging study for the HIV Neuroimaging Consortium (HIVNC), we used tensor-based morphometry to map the annual rate of change of regional brain volumes (mean time interval 1.0 ± 0.5 yrs), in 155 chronically infected and treated HIV+ participants (mean age 48.0 ± 8.9 years; 83.9% male) . We tested for associations between rates of brain tissue loss and clinical measures of infection severity (nadir or baseline CD4+ cell count and baseline HIV plasma RNA concentration), HIV duration, cART CNS penetration-effectiveness scores, age, as well as change in AIDS Dementia Complex stage. We found significant brain tissue loss across HIV+ participants, including those neuro-asymptomatic with undetectable viral loads, largely localized to subcortical regions. Measures of disease severity, age, and neurocognitive decline were associated with greater atrophy. Chronically HIV-infected and treated individuals may undergo progressive brain tissue loss despite stable and effective cART, which may contribute to neurocognitive decline. Understanding neurological complications of chronic infection and identifying factors associated with atrophy may help inform strategies to maintain brain health in people living with HIV.

Stroke is common in tuberculous meningitis. Stroke commonly affects the tubercular zone, comprising the anterior part of the thalamus, caudate and the internal capsule (anterior limb and genu). Stroke, in tuberculous meningitis is predominantly arterial ischemic stroke, and is due to infiltrative, proliferative or necrotizing arteritis. Rarely, aneurysm formation and mycotic aneurysms have also been described. The authors describe the clinical and autopsy findings of a 27-mo-old boy with tuberculous meningitis whose course was complicated by arterial and venous strokes, and nonresponse to adequate and appropriate antitubercular therapy.

In contrast to ab-initio protein modeling methodologies, comparative modeling is considered as the most popular and reliable algorithm to model protein structure. However, the selection of the best set of templates is still a major challenge. An effective template-ranking algorithm is developed to efficiently select only the reliable hits for predicting the protein structures. The algorithm employs the pairwise as well as multiple sequence alignments of template hits to rank and select the best possible set of templates. It captures several key sequences and structural information of template hits and converts into scores to effectively rank them. This selected set of templates is used to model a target. Modeling accuracy of the algorithm is tested and evaluated on TBM-HA domain containing CASP8, CASP9 and CASP10 targets. On an average, this template ranking and selection algorithm improves GDT-TS, GDT-HA and TM&#95;Score by 3.531, 4.814 and 0.022, respectively. Further, it has been shown that the inclusion of structurally similar templates with ample conformational diversity is crucial for the modeling algorithm to maximally as well as reliably span the target sequence and construct its near-native model. The optimal model sampling also holds the key to predict the best possible target structure.

Objective: Tracheobronchomalacia is a progressive, debilitating disease with limited treatment options. Open tracheobronchoplasty (TBP) is an accepted surgical option for management of severe tracheobronchomalacia. This study examined the outcomes of the first reported series of robot-assisted TBP (R-TBP)., Methods: We retrospectively reviewed the records of patients with clinical suspicion for tracheobronchomalacia who had dynamic computed tomography scan and subsequent R-TBP from May 2016 to December 2017., Results: Four hundred thirty-five patients underwent dynamic computed tomography scan for suspicion of tracheobronchomalacia. Of this group, 42 patients underwent R-TBP. In the surgery group, the median age was 66 years (interquartile range, 39-72 years) and there were 30 women (71%). Respiratory comorbidities included asthma (88%) and chronic obstructive pulmonary disease (52%). The median operative time was 249 minutes (interquartile range, 266-277 minutes). Median hospital length of stay was 3 days (interquartile range, 2-4.75 days), and there were 19 postoperative complications (11 minor and 8 major). There were no mortalities at 90 days. Comparison of preoperative and postoperative pulmonary function testing demonstrated improvement in forced expiratory volume at 1 second by 13.5% (P = .01), forced vital capacity by 14.5% (P < .0001), and peak expiratory flow rate by 21.0% (P < .0001). Quality of life questionnaires also showed improvement with 82% reporting overall satisfaction with the procedure., Conclusions: R-TBP can be performed with low morbidity and mortality. Early follow-up reveals significant improvement in pulmonary function testing and high patient satisfaction when compared with preoperative baseline. Long-term follow-up is needed to demonstrate the durability of R-TBP and substantiate its role in the management of patients with symptomatic, severe tracheobronchomalacia., (Copyright © 2018 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background : Tuberculous meningitis (TBM) has 44% (95%CI 35-52%) in-hospital mortality with standard therapy in Uganda. Rifampicin, the cornerstone of TB therapy, has 70% oral bioavailability and ~10-20% cerebrospinal fluid (CSF) penetration.  With current WHO-recommended TB treatment containing 8-12mg/kg rifampicin, CSF rifampicin exposures frequently fall below the minimal inhibitory concentration for M. tuberculosis . Two Indonesian phase II studies, the first investigating intravenous rifampicin 600mg and the second oral rifampicin ~30mg/kg, found the interventions were safe and resulted in significantly increased CSF rifampicin exposures and a reduction in 6-month mortality in the investigational arms. Whether such improvements can be replicated in an HIV-positive population remains to be determined. Protocol : We will perform a phase II, open-label randomised controlled trial, comparing higher-dose oral and intravenous rifampicin with current standard of care in a predominantly HIV-positive population. Participants will be allocated to one of three parallel arms (I:I:I): (i) intravenous rifampicin 20mg/kg for 2-weeks followed by oral rifampicin 35mg/kg for 6-weeks; (ii) oral rifampicin 35mg/kg for 8-weeks; (iii) standard of care, oral rifampicin 10mg/kg/day for 8-weeks. Primary endpoints will be: (i) pharmacokinetic parameters in plasma and CSF; (ii) safety. We will also examine the effect of higher-dose rifampicin on survival time, neurological outcomes and incidence of immune reconstitution inflammatory syndrome. We will enrol 60 adults with suspected TBM, from two hospitals in Uganda, with follow-up to 6 months post-enrolment. Discussion : HIV co-infection affects the bioavailability of rifampicin in the initial days of therapy, risk of drug toxicity and drug interactions, and ultimately mortality from TBM. Our study aims to demonstrate, in a predominantly HIV-positive population, the safety and pharmacokinetic superiority of one or both investigational arms compared to current standard of care. The most favourable dose may ultimately be taken forward into an adequately powered phase III trial. Trial registration : ISRCTN42218549 (24 th April 2018)., Competing Interests: Competing interests: Sanofi are donating IV and oral Rifidin for the purposes of the trial. Sanofi were not responsible for protocol design and will be independent from the analysis and reporting of the trial.

Background: Tuberculous meningitis (TBM) is the second most common cause of meningitis in sub-Saharan Africa and is notoriously difficult to diagnose. We describe the impact of improved TBM diagnostics over 6.5 years at two Ugandan referral hospitals. Methods: Cohort one received cerebrospinal fluid (CSF) smear microscopy only (2010-2013). Cohort two received smear microscopy and Xpert MTB/Rif (Xpert) on 1ml unprocessed CSF at physician discretion (2011-2013). Cohort three received smear microscopy, routine liquid-media culture and Xpert on large volume centrifuged CSF (2013-2017) for all meningitis suspects with a negative CSF cryptococcal antigen. We compared rates of microbiologically confirmed TBM and hospital outcomes over time. Results: 1672 HIV-infected adults presenting with suspected meningitis underwent lumbar puncture, of which 33% (558/1672) had negative CSF cryptococcal antigen and 12% (195/1672) were treated for TB meningitis. Over the study period, microbiological confirmation of TBM increased from 3% to 41% (P<0.01) and there was a decline in in-hospital mortality from 57% to 41% (P=0.27) amongst those with a known outcome. Adjusting for definite TBM diagnosis and antiretroviral therapy use, and using imputed data, assuming 50% of those with an unknown outcome died, the odds of dying were nearly twice as high in cohort one (adjusted odds ratio 1.7, 95% CI 0.7 to 4.4) compared to cohort three.  Sensitivity of Xpert was 63% (38/60) and culture was 65% (39/60) against a composite reference standard. Conclusions: As TBM diagnostics have improved, microbiologically-confirmed TBM diagnoses have increased and in-hospital mortality has declined. Yet, mortality due to TB meningitis remains unacceptably high and further measures are needed to improve outcomes from TBM in Uganda., Competing Interests: No competing interests were disclosed.

Background: Microbiological confirmation of tuberculous meningitis (TBM) remains problematic. We assessed the diagnostic performance of a modified Ziehl-Neelsen (MZN) staining method that showed promise in earlier studies. Methods: Patients evaluated for TBM in Shaanxi province, China, were prospectively enrolled from May, 2011 to April, 2013. Cerebrospinal fluid (CSF) specimens were evaluated using the Xpert MTB/RIF® assay, MZN staining, and standard biochemical and microbiological tests, together with detailed clinical and radiological assessment. Results: Among 316 patients included in the study, 38 had definite TBM, 66 probable TBM, 163 possible TBM and 49 "no TBM," using consensus uniform research case definition criteria. Comparing "definite or probable TBM" to "no TBM" MZN staining had higher sensitivity than Xpert MTB/RIF® (88.5 vs. 36.5%), but greatly reduced specificity (71.4 vs. 100.0%); 14/49 (28.6%) cases with "no TBM" tested positive on MZN. Mycobacterium tuberculosis culture was performed in 104/179 (58.1%) of MZN positive samples; 12.5% (13/104) were positive. Using Xpert MTB/RIF® as the reference standard, MZN had a sensitivity of 92.1% (95% CI 79.2-97.3) and specificity of 71.4% (95% CI 57.6-82.2). Conclusion: Xpert MTB/RIF® offered a rapid and specific TBM diagnosis, but sensitivity was poor. MZN was mainly hampered by false positives. Strategies to enhance the sensitivity of Xpert MTB/RIF® or improve the diagnostic accuracy of MZN should be explored.

Tuberculous meningitis (TBM) is one of those most serious manifestations of extra-pulmonary tuberculosis and prompt diagnosis and treatment is required for better clinical outcome. It is difficult to diagnose due to lack of rapid, sensitive, and specific tests. Newer methods, which are easy and reliable, are required to diagnose TBM at an early stage. Thus our aim was to evaluate the Multiplex polymerase chain reaction (PCR) technique, using primers directed against the insertion sequence IS6110 and MPB64 gene for the detection of Mycobacterium tuberculosis in Cerebrospinal fluid (CSF), for rapid diagnosis of TBM patients. 102 CSF samples were analyzed from patients suspected with TBM along with a control group of 10 patients having other neurological disorders. CSF sediments were analyzed individually for M. tuberculosis DNA by Multiplex PCR using two set of primers targeting insertion sequence IS6110 and gene MBp64, which is very specific for MTBC. Out of 37 patients diagnosed with TBM clinically, MPB64 PCR was positive in 22, IS6110 PCR was positive in 28, both PCR using Multiplex were positive in 34 and Microscopy was positive in one. Thus Sensitivity of MPB64 PCR, IS6110 PCR, Multiplex PCR and Microscopy were found to be 62.3%, 75.4%, 91.8% and 2.7% respectively. In non TBM group PCR was negative in all cases hence, the specificity was 100%. Multiplex PCR system using primers targeting IS6110 and MPB64, for the detection of M. tuberculosis DNA in CSF samples, has high sensitivity than any one of them alone, and could be used for the early detection of TBM in CSF samples., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Mycobacterium tuberculosis (M. tuberculosis) is the causative agent of tuberculosis (TB) that causes millions of death every year. We have sequenced the genome of M. tuberculosis isolated from cerebrospinal fluid (CSF) of a patient diagnosed with tuberculous meningitis (TBM). The isolated strain was referred as M. tuberculosis SB24. Genomic DNA of the M. tuberculosis SB24 was extracted and subjected to whole genome sequencing using PacBio platform. The draft genome size of M. tuberculosis SB24 was determined to be 4,452,489 bp with a G + C content of 65.6%. The whole genome shotgun project has been deposited in NCBI SRA under the accession number SRP076503.

Different neurodegenerative diseases can cause memory disorders and other cognitive impairments. The early detection and the stratification of patients according to the underlying disease are essential for an efficient approach to this healthcare challenge. This emphasizes the importance of differential diagnostics. Most studies compare patients and controls, or Alzheimer's disease with one other type of dementia. Such a bilateral comparison does not resemble clinical practice, where a clinician is faced with a number of different possible types of dementia. Here we studied which features in structural magnetic resonance imaging (MRI) scans could best distinguish four types of dementia, Alzheimer's disease, frontotemporal dementia, vascular dementia, and dementia with Lewy bodies, and control subjects. We extracted an extensive set of features quantifying volumetric and morphometric characteristics from T1 images, and vascular characteristics from FLAIR images. Classification was performed using a multi-class classifier based on Disease State Index methodology. The classifier provided continuous probability indices for each disease to support clinical decision making. A dataset of 504 individuals was used for evaluation. The cross-validated classification accuracy was 70.6% and balanced accuracy was 69.1% for the five disease groups using only automatically determined MRI features. Vascular dementia patients could be detected with high sensitivity (96%) using features from FLAIR images. Controls (sensitivity 82%) and Alzheimer's disease patients (sensitivity 74%) could be accurately classified using T1-based features, whereas the most difficult group was the dementia with Lewy bodies (sensitivity 32%). These results were notable better than the classification accuracies obtained with visual MRI ratings (accuracy 44.6%, balanced accuracy 51.6%). Different quantification methods provided complementary information, and consequently, the best results were obtained by utilizing several quantification methods. The results prove that automatic quantification methods and computerized decision support methods are feasible for clinical practice and provide comprehensive information that may help clinicians in the diagnosis making.

Tuberculous meningitis (TBM) is a serious form of disease of the central nervous system. Early and accurate diagnosis of the disease and effective treatment are key important factors to contain the disease. The disease presents as chronic meningitis where other partners such as fungal meningitis, neurosyphilis, cysticercal meningitis, carcinomatous meningitis and partially treated pyogenic meningitis share a similar clinical picture making the diagnosis complicated. Culturing of the pathogen Mycobacterium tuberculosis (MTB) from the cerebrospinal fluid (CSF) sample has shown a poor response. The main immunological method for the immunodiagnosis of TBM is the detection of an antibody response in the CSF. In the present study, total MTB sonicated extract antigen was used for ELISA and Western blot. ELISA shows overall immune response of the test sample, whereas Western blotting reveals the specific reactivity to a particular molecular weight antigen. This would also reveal the immunodominant antigen. A total of 300 CSF samples were analyzed by both ELISA and Western blotting. Of the 240 clinically suspected TBM cases, 111 samples were positive by ELISA and 81 samples by Western blot. A total of 76 CSF samples were positive by both ELISA and Western blot. None of the control samples showed positivity either by ELISA or by Western blot. TBM patients revealed major antibody reactivity to 30-40 kD region, followed by 14 kD region. ELISA is sensitive with mild non-specific binding, but Western blot is specific in detecting the immune response. The findings will be useful in definitive immunodiagnosis of TBM., (Copyright © 2015 Asian African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is characterized by cortical atrophy and disrupted anatomic connectivity, and leads to abnormal interactions between neural systems. Diffusion-weighted imaging (DWI) and graph theory can be used to evaluate major brain networks and detect signs of a breakdown in network connectivity. In a longitudinal study using both DWI and standard magnetic resonance imaging (MRI), we assessed baseline white-matter connectivity patterns in 30 subjects with mild cognitive impairment (MCI, mean age 71.8 ± 7.5 years, 18 males and 12 females) from the Alzheimer's Disease Neuroimaging Initiative. Using both standard MRI-based cortical parcellations and whole-brain tractography, we computed baseline connectivity maps from which we calculated global "small-world" architecture measures, including mean clustering coefficient and characteristic path length. We evaluated whether these baseline network measures predicted future volumetric brain atrophy in MCI subjects, who are at risk for developing AD, as determined by 3-dimensional Jacobian "expansion factor maps" between baseline and 6-month follow-up anatomic scans. This study suggests that DWI-based network measures may be a novel predictor of AD progression., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The presence of brain atrophy and its progression in early Parkinson's disease (PD) are still a matter of debate, particularly in patients without cognitive impairment. The aim of this longitudinal study was to assess whether PD patients who remain cognitively intact develop progressive atrophic changes in the early stages of the disease. For this purpose, we employed high-resolution T1-weighted MR imaging to compare 22 drug-naïve de novo PD patients without cognitive impairment to 17 age-matched control subjects, both at baseline and at three-year follow-up. We used tensor-based morphometry to explore the presence of atrophic changes at baseline and to compute yearly atrophy rates, after which we performed voxel-wise group comparisons using threshold-free cluster enhancement. At baseline, we did not observe significant differences in regional atrophy in PD patients with respect to control subjects. In contrast, PD patients showed significantly higher yearly atrophy rates in the prefrontal cortex, anterior cingulum, caudate nucleus, and thalamus when compared to control subjects. Our results indicate that even cognitively preserved PD patients show progressive cortical and subcortical atrophic changes in regions related to cognitive functions and that these changes are already detectable in the early stages of the disease., (Copyright © 2014 Wiley Periodicals, Inc.)

Great uncertainty exists in the global exchange of carbon between the atmosphere and the terrestrial biosphere. An important source of this uncertainty lies in the dependency of photosynthesis on the maximum rate of carboxylation (V cmax) and the maximum rate of electron transport (J max). Understanding and making accurate prediction of C fluxes thus requires accurate characterization of these rates and their relationship with plant nutrient status over large geographic scales. Plant nutrient status is indicated by the traits: leaf nitrogen (N), leaf phosphorus (P), and specific leaf area (SLA). Correlations between V cmax and J max and leaf nitrogen (N) are typically derived from local to global scales, while correlations with leaf phosphorus (P) and specific leaf area (SLA) have typically been derived at a local scale. Thus, there is no global-scale relationship between V cmax and J max and P or SLA limiting the ability of global-scale carbon flux models do not account for P or SLA. We gathered published data from 24 studies to reveal global relationships of V cmax and J max with leaf N, P, and SLA. V cmax was strongly related to leaf N, and increasing leaf P substantially increased the sensitivity of V cmax to leaf N. J max was strongly related to V cmax, and neither leaf N, P, or SLA had a substantial impact on the relationship. Although more data are needed to expand the applicability of the relationship, we show leaf P is a globally important determinant of photosynthetic rates. In a model of photosynthesis, we showed that at high leaf N (3 gm(-2)), increasing leaf P from 0.05 to 0.22 gm(-2) nearly doubled assimilation rates. Finally, we show that plants may employ a conservative strategy of J max to V cmax coordination that restricts photoinhibition when carboxylation is limiting at the expense of maximizing photosynthetic rates when light is limiting.

Because of the plethora of exposure sources and routes through which humans are exposed to trihalomethanes (THM), the limitation of their short half-lives could be overcome, if a highly sensitive method was available to quantify urinary THM concentrations at sub-ppb levels. The objective of this study was to develop a fast and reliable method for the determination of the four THM analytes in human urine. A sensitive methodology was developed for THM in urine samples using gas chromatography coupled with triple quadrupole mass spectrometry (GC-QqQ-MS/MS) promoting its use in epidemiological and biomonitoring studies. The proposed methodology enjoys limits of detection similar to those reported in the literature (11-80 ng L(-1)) and the advantages of small initial urine volumes (15 mL) and fast analysis per sample (12 min) when compared with other methods. This is the first report using GC-QqQ-MS/MS for the determination of THM in urine samples. Because of its simplicity and less time-consuming nature, the proposed method could be incorporated into detailed (hundreds of participants' urine samples) exposure assessment protocols providing valuable insight into the dose-response relationship of THM and cancer or pregnancy anomalies., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: Tuberculous meningitis (TBM) frequently is complicated by hydrocephalus and cerebral infarction. Previous studies have shown radiologic evidence of cerebral infarction in TBM to be an indicator of poor outcome in both adults and children. Our objective was to assess short-term mortality in adult patients with TBM and hydrocephalus treated with an external ventricular drain and to assess the prognostic value of cerebral infarction on admission computed tomography imaging within this cohort., Methods: This was a retrospective case series based on an adult intensive care unit admissions database, analyzing demographic, clinical, diagnostic, and radiologic data against short-term mortality., Results: A total of 25 patients managed from 2005 to 2011 were identified. Three patients were excluded. Mean age was 31 years. British Medical Research Council clinical severity grading was grade I in 9.1%, grade II in 31.8%, and grade III in 59.1%. Short-term mortality was 68.2% overall. Cerebral infarction on admission scanning was seen in 10 patients (45.5%). Prevalence of infarcts was not significantly higher in HIV-positive patients (50.0% vs. 42.9%). Mortality in the group with infarcts was 100%, compared with 41.7% in the group without infarcts. Mortality in patients with an admission Glasgow Coma Scale of 8 or less was 91.7%. Mortality in the HIV-positive group was slightly greater, but this increase did not reach statistical significance (71.4% vs. 57.1% P = 0.6). Univariate analysis showed presence of infarcts at admission, Glasgow Coma Scale ≤8 at admission and age of 30 years or more to be significantly related to mortality. There was also a statistically significantly increased mortality according to British Medical Research Council grade., Conclusion: TBM with hydrocephalus requiring cerebrospinal diversion carries a significant short-term mortality. Within this cohort, the group of patients who have computed tomography-evident cerebral infarcts at admission has an even worse outcome, with a significantly greater short-term mortality prevalence., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Mounier-Kuhn syndrome or congenital tracheobronchomegaly is a chronic airway condition which for currently unknown reasons mostly affects males. It is commonly overlooked on conventional chest X-rays, and is considered to be rare, but the prevalence might be higher as commonly assumed. The hallmark of it is a dilatation of the main airways which frequently, but not always, causes marked, mainly respiratory, symptoms, and patients usually present with varying degrees of recurrent infections, breathlessness, haemoptysis, dyspnoea. Although at least 200 case reports have been published, there have been only a few attempts to review them, and none in the last 20 years. Due to the lack of clinical trials and wide variability of case-report format, a systematic review was deemed not feasible, therefore PubMed and Medline databases were searched using terms "Mounier-Kuhn syndrome", "tracheobronchomegaly", "tracheomegaly", and "bronchomegaly", without any time restrictions, to summarize currently known facts about the syndrome. To the authors' best knowledge, the result is currently the most comprehensive review of previously published literature about the congenital tracheobronchomegaly, and summarizes what's known about symptoms, prevalence, disease associations, and treatment options for this syndrome., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Obesity and major depressive disorder (MDD) are highly prevalent and often comorbid health conditions. Both are associated with differences in brain structure and are genetically influenced. Yet, little is known about how obesity, MDD, and known risk genotypes might interact in the brain. Subjects were 81 patients with MDD (mean age 48.6 years) and 69 matched healthy controls (mean age 51.2 years). Subjects underwent 1.5T magnetic resonance imaging, genotyping for the fat mass and obesity associated (FTO) gene rs3751812 polymorphism, and measurements for body mass index (BMI). We conducted a whole brain voxelwise analysis using tensor-based morphometry (TBM) to examine the main and interaction effects of diagnosis, BMI and FTO genotype. Significant effects of BMI were observed across widespread brain regions, indicating reductions in predominantly subcortical and white matter areas associated with increased BMI, but there was no influence of MDD or FTO rs3751812 genotype. There were no significant interaction effects. Within MDD patients, there was no effect of current depressive symptoms; however the use of antidepressant medication was associated with reductions in brain volume in the frontal lobe and cerebellum. Obesity affects brain structure in both healthy participants and MDD patients; this influence may account for some of the brain changes previously associated with MDD. BMI and the use of medication should ideally be measured and controlled for when conducting structural brain imaging research in MDD., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Heavy metals can accumulate in organisms via various pathways, including respiration, adsorption and ingestion. They are known to generate free radicals and induce oxidative and/or nitrosative stress with depletion of anti-oxidants. Tuna by-product meal (TBM) is rich in proteins and can, therefore, offer an attractive protein source for animals. This study was undertaken to assess the effects of metals present in TBM, namely cadmium (Cd), lead (Pb), and mercury (Hg), separately or in combination with oxidative stress, on cell viability. Three cell models: rat liver FTO2B, human hepatoma HepG2, and human hepatic WRL-68, were used. Cell viability was determined following exposure to various concentrations of the metals. Two antioxidant genes, catalase (CAT) and superoxide dismutase (SOD), were measured to obtain a better understanding of oxidative stress-associated gene expression. Among the metals present in TBM, only Cd at a concentration of 30μM was noted to exhibit cytotoxic effects. This cytotoxicity was even more pronounced after co-stimulation with H2O2, used to mimic systemic oxidative stress. At non-toxic concentrations, Hg and Pb were noted to aggravate oxidative stress toxicity. The results further revealed that exposure to Cd, Pb, and a co-stimulation of H2O2 with Hg resulted in the increased expression of antioxidant gene SOD. A risk assessment of toxic contaminants in TBM indicated that food safety objectives should consider the human health impacts of foods derived from animals fed on contaminated meal and that much care should be taken when TBM is used in animal diet., (Copyright © 2013 Elsevier GmbH. All rights reserved.)