SETTING: Tuberculosis (TB) program, Damien Foundation Projects, Bangladesh.OBJECTIVE: To summarize the outcome and its determinants of the first treatment for multidrug-resistant TB using a ...standardized regimen consisting of a minimum 9 months.DESIGN: This was a prospective,
observational study of a gatifloxacin (GFX) based directly observed regimen, mainly with initial hospitalization. The 4-month intensive phase was extended until sputum smear conversion. Patients were monitored using culture for up to 2 years after treatment completion.RESULTS: Of the 515
patients who met the study inclusion criteria and were successively enrolled from 2005 to 2011, 84.4% had a bacteriologically favorable outcome. Due to extensive disease with delayed sputum conversion, only half of the patients completed treatment within 9 months; however, 95% were able to
complete treatment within 12 months. Eleven patients failed or relapsed, and 93.1% of the 435 patients who were successfully treated completed at least 12 months post-treatment follow-up. The strongest risk factor for a bacteriologically unfavorable outcome was high-level fluoroquinolone (FQ)
resistance, particularly when compounded by initial pyrazinamide (PZA) resistance. Low-level FQ resistance had no unfavorable effect on treatment outcome. Amplification of drug resistance occurred only once, in a patient strain that was initially only susceptible to kanamycin and clofazimine.CONCLUSION:
The excellent outcome of the Bangladesh regimen was largely maintained. Bacteriological treatment failures and relapses were rare, except among patients with high-level GFX resistance, notably in the presence of PZA resistance.
Objectives
Evidence of premature cognitive ageing amongst people living with HIV (PLHIV) remains controversial due to previous research limitations including underpowered studies, samples with ...suboptimal antiretroviral access, varying rate of virological control, high rate of AIDS, over‐representation of non‐community samples, and inclusion of inappropriate controls. The current study addresses these limitations, while also considering mental health and non‐HIV comorbidity burden to determine whether PLHIV showed premature cognitive ageing compared with closely comparable HIV‐negative controls.
Methods
This study enrolled 254 PLHIV 92% on antiretroviral therapy; 84% with HIV RNA < 50 copies/mL; 15% with AIDS) and 72 HIV‐negative gay and bisexual men mean (SD) age = 49 (10.2) years from a single primary care clinic in Sydney, Australia. Neurocognitive function was evaluated with the Cogstate Computerized Battery (CCB) at baseline and 6 months after. Linear mixed‐effects (LME) models examined main and interaction effects of HIV status and chronological age on the CCB demographically uncorrected global neurocognitive z‐score (GZS), adjusting for repeated testing, and then adjusting sequentially for HIV disease markers, mental health and comorbidities.
Results
HIV status and age interacted with a lower GZS (β = −0.43, P < 0.05). Higher level of anxiety symptoms (β = −0.11, P < 0.01), historical AIDS (β = −0.12, P < 0.05) and historical HIV brain involvement (β = −0.12, P < 0.05) were associated with lower GZS.
Conclusions
We found a robust medium‐sized premature ageing effect on cognition in a community sample with optimal HIV care. Our study supports routine screening of cognitive and mental health among PLHIV aged ≥ 50 years.
SETTING: Data were collected from patients starting one of the shorter treatment regimens (STRs) for multidrug-resistant tuberculosis (MDR-TB) in Bangladesh, Niger or Cameroon.OBJECTIVE: To estimate ...the effect of either a gatifloxacin (GFX), moxifloxacin (MFX) or levofloxacin
(LVX) based STR on bacteriological effectiveness.DESIGN: Retrospective study of prospectively collected data.RESULTS: Among 1530 patients, bacteriological effectiveness was 96.7% overall. Stratified by treatment with a GFX-, LVX- or MFX-based regimen effectiveness was
respectively 97.5%, 95.5% and 94.7%. Compared to those on a GFX-based regimen, the estimated summary odds ratio of having an adverse outcome was more than double (OR 2.05, 95% CI 1.09-3.90) in patients treated with either an LVX-based or MFX-based regimen. After adjusting for initial
resistance, patients treated with an LVX-based regimen and MFX-based regimen had respectively a 4.5- and 8.4-fold times larger odds of an adverse bacteriological outcome. None among 859 patients at risk treated with a GFX-based compared to at least 4 of 228 among those on an MFX-based regimen
acquired fluoroquinolone resistance.CONCLUSION: GFX-based regimens had superior bacteriological effectiveness than MFX-based or LVX-based regimens. As GFX is currently unavailable in most MDR-TB programs, its reintroduction should be prioritised.
Tuberculosis (TB) is a major global health threat, infecting one-third of the world's population. Despite this prominence, the age, origin and spread of the disease have been topics of contentious ...debate. Molecular studies suggest that
Mycobacterium tuberculosis ‘sensu stricto’
, the most common strain of TB infecting humans today, originated in Africa and from there spread into Europe and Asia. The
M. tuberculosis
strains most commonly found across the Pacific and the Americas today are most closely related to European strains, supporting a hypothesis that the disease only reached these regions relatively recently via European sailors or settlers. However, this hypothesis is inconsistent with palaeopathological evidence of TB-like lesions in human remains from across the Pacific that predate European contact. Similarly, genetic evidence from pre-European South American mummies challenges the notion of a European introduction of the disease into the Pacific. Here, we review the complex evidence for the age and origin of TB in the Pacific, and discuss key gaps in our knowledge and how these may be addressed.
This article is part of the theme issue ‘Insights into health and disease from ancient biomolecules’.
The technologies for maintaining high recording density to suppress mechanical vibration and media flutter for ultrahigh TPI hard disk drive (HDD) require advance spindle motor design and technology ...against the traditional norms. To realize multimagnetic poles with limited stator slots, spindle motors generally use concentrated windings which offer small end winding and simple structure suitable for mass production. There is a variety of ways to construct a motor with different winding structures based on different pole/slot combinations. Winding structures directly affect the producing of motor back-emf and torque which determine motor capacity, reliability and efficiency. In this work, detailed analysis is carried out to identify the optimal winding structures of the high speed spindle motor and analyze their effect on the motor performances by using magneto-motive force harmonics analysis and electromagnetic magnetic field analysis. Results are useful in preliminary and final optimal designs of the high speed spindle motors.
To assess whether the 3-dimensional (3D) structural configuration of the central retinal vessel trunk and its branches (CRVT&B) could be used as a diagnostic marker for glaucoma.
Retrospective, ...deep-learning approach diagnosis study.
We trained a deep learning network to automatically segment the CRVT&B from the B-scans of the optical coherence tomography (OCT) volume of the optic nerve head. Subsequently, 2 different approaches were used for glaucoma diagnosis using the structural configuration of the CRVT&B as extracted from the OCT volumes. In the first approach, we aimed to provide a diagnosis using only 3D convolutional neural networks and the 3D structure of the CRVT&B. For the second approach, we projected the 3D structure of the CRVT&B orthographically onto sagittal, frontal, and transverse planes to obtain 3 two-dimensional (2D) images, and then a 2D convolutional neural network was used for diagnosis. The segmentation accuracy was evaluated using the Dice coefficient, whereas the diagnostic accuracy was assessed using the area under the receiver operating characteristic curves (AUCs). The diagnostic performance of the CRVT&B was also compared with that of retinal nerve fiber layer (RNFL) thickness (calculated in the same cohorts).
Our segmentation network was able to efficiently segment retinal blood vessels from OCT scans. On a test set, we achieved a Dice coefficient of 0.81 ± 0.07. The 3D and 2D diagnostic networks were able to differentiate glaucoma from nonglaucoma subjects with accuracies of 82.7% and 83.3%, respectively. The corresponding AUCs for the CRVT&B were 0.89 and 0.90, higher than those obtained with RNFL thickness alone (AUCs ranging from 0.74 to 0.80).
Our work demonstrated that the diagnostic power of the CRVT&B is superior to that of a gold-standard glaucoma parameter, that is, RNFL thickness. Our work also suggested that the major retinal blood vessels form a “skeleton”—the configuration of which may be representative of major optic nerve head structural changes as typically observed with the development and progression of glaucoma.
β‐catenin is a multifunctional protein that not only acts in the canonical Wnt/β‐catenin pathway to regulate gene expression but also binds to cadherin proteins in adherens junctions, where it plays ...a key role in regulating cytoskeleton linked with these junctions. Recently, evidence has been presented indicating an essential role for β‐catenin in regulating the trafficking of insulin vesicles in β‐cells and showing that changes in nutrient levels rapidly alter levels of β‐catenin in these cells. Given the importance of neuroendocrine hormone secretion in the regulation of whole body glucose homeostasis, the present study aimed to investigate whether β‐catenin signalling is regulated in the hypothalamus during the normal physiological response to food intake. Rats were subjected to a fasting/re‐feeding paradigm, and then samples were collected at specific timepoints for analysis of β‐catenin expression by immunohistochemistry and western blotting. Changes in gene expression were assessed by a quantitative reverse transcriptase‐polymerase chain reaction. Using immunohistochemistry, feeding acutely increased detectable cytoplasmic levels of β‐catenin (‘stabilised β‐catenin’) in neurones in specific regions of the hypothalamus involved in metabolic regulation, including the arcuate, dorsomedial and paraventricular nuclei of the hypothalamus. Feeding‐induced elevations in β‐catenin in these nuclei were associated with an increased transcription of several genes known to be responsive to Wnt/β‐catenin signalling. The effect of feeding was mimicked by administration of the GLP‐1 agonist exendin‐4 and was also characterised by cAMP‐dependent phosphorylation of β‐catenin at serine residues 552 and 675. These data suggest that β‐catenin/T cell factor signalling is involved in metabolic sensing in the hypothalamus.
Mutations of the PIK3CA gene may predict response to phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors. Concomitant mutations in the mitogen-activated protein ...kinase (MAPK) pathway may mediate resistance.
Tumors from patients with breast, cervical, endometrial, and ovarian cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA, KRAS, NRAS, and BRAF mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway.
Of 140 patients analyzed, 25 (18%) had PIK3CA mutations, including five of 14 patients with squamous cell cervical, seven of 29 patients with endometrial, six of 29 patients with breast, and seven of 60 patients with ovarian cancers. Of the 25 patients with PIK3CA mutations, 23 (median of two prior therapies) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Two (9%) of 23 patients had stable disease for more than 6 months, and seven patients (30%) had a partial response. In comparison, only seven (10%) of 70 patients with the same disease types but with wild-type PIK3CA treated on the same protocols responded (P = .04). Seven patients (30%) with PIK3CA mutations had coexisting MAPK pathway (KRAS, NRAS, BRAF) mutations (ovarian cancer, n = 5; endometrial cancer, n = 2), and two of these patients (ovarian cancer) achieved a response.
PIK3CA mutations were detected in 18% of tested patients. Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors demonstrated a higher response rate than patients without mutations. A subset of patients with ovarian cancer with simultaneous PIK3CA and MAPK mutations responded to PI3K/AKT/mTOR inhibitors, suggesting that not all patients demonstrate resistance when the MAPK pathway is concomitantly activated.
Objectives
This study aimed to assess the oral health and the prevalence of pre‐existing oral colonization with respiratory pathogens in dependent elderly, and whether these factors influence ...pneumonia development.
Materials and Methods
Participants residing in a long‐term care facility received bedside oral examinations, and information on their oral health (caries status, calculus index and debris index) was obtained. Samples from the tongue and teeth were collected at baseline and at time of pneumonia development. Sputum was collected at the time of pneumonia diagnosis. Samples were assessed for Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus and Streptococcus pneumoniae by polymerase chain reaction.
Results
This was a 1‐year longitudinal study of 60 dependent elderly (mean age: 64.2 ± 14.1 years). Seventeen patients (28.3%) developed pneumonia. The mean Decayed, Missing and Filled Teeth and Simplified Oral Hygiene Index were 22.8 ± 9.2 and 4.0 ± 1.0, respectively. At baseline, 48.3% were orally colonized with ≥1 respiratory pathogens. The presence of H. influenzae (P = .002) and P. aeruginosa (P = .049) in the sputum was significantly associated with their colonization on the tongue at baseline. In the bivariate analyses, pneumonia development was associated with naso‐gastric feeding tube (P = .0001), H. influenzae (P = .015) and P. aeruginosa (P = .003) tongue colonization at baseline and calculus index (P = .002). Multivariate analyses revealed that calculus index (P = .09) and the presence of tracheostomy (P = .037) were associated with pneumonia.
Conclusions
The calculus amount and tongue colonization with respiratory pathogens are risk factors for pneumonia development. Oral hygiene measures to remove tongue biofilm and calculus may reduce pneumonia development.
CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed ...to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication.
Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti-CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts).
Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 95% CI, 0.38 to 0.90;
= .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 95% CI, 0.42 to 1.30;
= .29), with 5-year adjusted risk difference of 1.6% (95% CI, -1.5 to 4.4; all-pts) and 1.4% (95% CI, -1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup.
In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression.
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