Test Characteristics of Urinary Lipoarabinomannan and Predictors of Mortality among Hospitalized HIV-Infected Tuberculosis Suspects in Tanzania.

Tuberculosis is the most common cause of death among patients with HIV infection living in tuberculosis endemic countries, but many cases are not diagnosed pre-mortem. We assessed the test characteristics of urinary lipoarabinomannan (LAM) and predictors of mortality among HIV-associated tuberculosis suspects in Tanzania. We prospectively enrolled hospitalized HIV-infected patients in Dar es Salaam, with ≥2 weeks of cough or fever, or weight loss. Subjects gave 2 mLs of urine to test for LAM using a commercially available ELISA, ≥2 sputum specimens for concentrated AFB smear and solid media culture, and 40 mLs of blood for culture. Among 212 evaluable subjects, 143 (68%) were female; mean age was 36 years; and the median CD4 count 86 cells/mm(3). 69 subjects (33%) had culture confirmation of tuberculosis and 65 (31%) were LAM positive. For 69 cases of sputum or blood culture-confirmed tuberculosis, LAM sensitivity was 65% and specificity 86% compared to 36% and 98% for sputum smear. LAM test characteristics were not different in patients with bacteremia but showed higher sensitivity and lower specificity with decreasing CD4 cell count. Two month mortality was 64 (53%) of 121 with outcomes available. In multivariate analysis there was significant association of mortality with absence of anti-retroviral therapy (p = 0.004) and a trend toward association with a positive urine LAM (p = 0.16). Among culture-negative patients mortality was 9 (75%) of 12 in LAM positive patients and 27 (38%) of 71 in LAM negative patients (p = 0.02). Urine LAM is more sensitive than sputum smear and has utility for the rapid diagnosis of culture-confirmed tuberculosis in this high-risk population. Mortality data raise the possibility that urine LAM may also be a marker for culture-negative tuberculosis

Antibody recognizing 4-sulfated chondroitin sulfate proteoglycans restores memory in tauopathy-induced neurodegeneration

Chondroitin sulfate proteoglycans (CSPGs) are the main active component of perineuronal nets (PNNs). Digestion of the glycosaminoglycan chains of CSPGs with chondroitinase ABC or transgenic attenuation of PNNs leads to prolongation of object recognition memory and activation of various forms of plasticity in the adult central nervous system. The inhibitory properties of the CSPGs depend on the pattern of sulfation of their glycosaminoglycans, with chondroitin 4-sulfate (C4S) being the most inhibitory form. In this study, we tested a number of candidates for functional blocking of C4S, leading to selection of an antibody, Cat316, which specifically recognizes C4S and blocks its inhibitory effects on axon growth. It also partly blocks binding of semaphorin 3A to PNNs and attenuates PNN formation. We asked whether injection of Cat316 into the perirhinal cortex would have the same effects on memory as chondroitinase ABC treatment. We found that masking C4S with the Cat316 antibody extended long-term object recognition memory in normal wild-type mice to 24 hours, similarly to chondroitinase or transgenic PNN attenuation. We then tested Cat316 for restoration of memory in a neurodegeneration model. Mice expressing tau with the P301S mutation showed profound loss of object recognition memory at 4 months of age. Injection of Cat316 into the perirhinal cortex normalized object recognition at 3 hours in P301S mice. These data indicate that Cat316 binding to C4S in the extracellular matrix can restore plasticity and memory in the same way as chondroitinase ABC digestion. Our results suggest that antibodies to C4S could be a useful therapeutic to restore memory function in neurodegenerative disorders.This work was supported by the ERC advanced grant ECM Neuro (294502), by a fellowship to SY from Alzheimer's Research UK (ARUK-RF2016A-1), and by the NIHR Cambridge Biomedical Research Centre

Demographics and Medication Use of Patients with Late-Onset Alzheimer's Disease in Hong Kong

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly population. However, epidemiological studies on the demographics of AD in Hong Kong population are lacking. OBJECTIVE: We investigated the demographics, comorbidities, mortality rates, and medication use of patients with AD in Hong Kong to understand how the disease has been managed locally. METHODS: This was a collaborative study of The Hong Kong University of Science and Technology and the Hospital Authority Data Collaboration Lab. We analyzed the demographic data, clinical records, diagnoses, and medication records of patients with AD under the care of the Hospital Authority between January 1, 2007 and December 31, 2017. RESULTS: We identified 23,467 patients diagnosed with AD. The median age at diagnosis was 84 years old, and 71% of patients were female. The most common comorbidity was hypertension (52.6%). 39.9% of patients received medications for dementia; of those, 68.4% had taken those medications for >  1 year. Compared to nonusers, long-term AD medication users had a significantly younger age of AD onset and were taking more lipid-regulating medication, diabetes medication, or antidepressants. Surprisingly, the use of antipsychotics in patients with AD was quite common; 50.7% of patients had received any type of antipsychotic during disease progression. CONCLUSION: This study provides detailed information on the demographics and medication use of patients with AD in Hong Kong. The data from this AD cohort will aid our future research aiming to identify potential AD risk factors and associations between AD and other diseases

The contribution of inherited genotype to breast cancer

The etiology of breast cancer is complex, and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. These inherited genotypes include those that affect the propensity to be exposed to breast carcinogens, and those associated with breast tumorigenesis directly. In addition, inherited genotypes may influence response to breast cancer chemoprevention and treatment. Studies relating inherited genotypes with breast cancer incidence and mortality should consider a broader spectrum of genes and their potential roles in multistage carcinogenesis than have been typically evaluated to date. Understanding the role of inherited genotype at different stages of carcinogenesis could improve our understanding of cancer biology, may identify specific exposures or events that correlate with carcinogenesis, or target relevant biochemical pathways for the development of preventive or therapeutic interventions

Deep learning-based polygenic risk analysis for Alzheimer's disease prediction

BACKGROUND: The polygenic nature of Alzheimer's disease (AD) suggests that multiple variants jointly contribute to disease susceptibility. As an individual's genetic variants are constant throughout life, evaluating the combined effects of multiple disease-associated genetic risks enables reliable AD risk prediction. Because of the complexity of genomic data, current statistical analyses cannot comprehensively capture the polygenic risk of AD, resulting in unsatisfactory disease risk prediction. However, deep learning methods, which capture nonlinearity within high-dimensional genomic data, may enable more accurate disease risk prediction and improve our understanding of AD etiology. Accordingly, we developed deep learning neural network models for modeling AD polygenic risk. METHODS: We constructed neural network models to model AD polygenic risk and compared them with the widely used weighted polygenic risk score and lasso models. We conducted robust linear regression analysis to investigate the relationship between the AD polygenic risk derived from deep learning methods and AD endophenotypes (i.e., plasma biomarkers and individual cognitive performance). We stratified individuals by applying unsupervised clustering to the outputs from the hidden layers of the neural network model. RESULTS: The deep learning models outperform other statistical models for modeling AD risk. Moreover, the polygenic risk derived from the deep learning models enables the identification of disease-associated biological pathways and the stratification of individuals according to distinct pathological mechanisms. CONCLUSION: Our results suggest that deep learning methods are effective for modeling the genetic risks of AD and other diseases, classifying disease risks, and uncovering disease mechanisms

An 84 microGauss Magnetic Field in a Galaxy at Redshift z=0.692

The magnetic field pervading our Galaxy is a crucial constituent of the interstellar medium: it mediates the dynamics of interstellar clouds, the energy density of cosmic rays, and the formation of stars. The field associated with ionized interstellar gas has been determined through observations of pulsars in our Galaxy. Radio-frequency measurements of pulse dispersion and the rotation of the plane of linear polarization, i.e., Faraday rotation, yield an average value B ~ 3 microGauss. The possible detection of Faraday rotation of linearly polarized photons emitted by high-redshift quasars suggests similar magnetic fields are present in foreground galaxies with redshifts z > 1. As Faraday rotation alone, however, determines neither the magnitude nor the redshift of the magnetic field, the strength of galactic magnetic fields at redshifts z > 0 remains uncertain. Here we report a measurement of a magnetic field of B ~ 84 microGauss in a galaxy at z =0.692, using the same Zeeman-splitting technique that revealed an average value of B = 6 microGauss in the neutral interstellar gas of our Galaxy. This is unexpected, as the leading theory of magnetic field generation, the mean-field dynamo model, predicts large-scale magnetic fields to be weaker in the past rather than stronger

Eye Size at Birth in Prosimian Primates: Life History Correlates and Growth Patterns

BACKGROUND: Primates have large eyes relative to head size, which profoundly influence the ontogenetic emergence of facial form. However, growth of the primate eye is only understood in a narrow taxonomic perspective, with information biased toward anthropoids.\ud \ud METHODOLOGY/PRINCIPAL FINDINGS: We measured eye and bony orbit size in perinatal prosimian primates (17 strepsirrhine taxa and Tarsius syrichta) to infer the extent of prenatal as compared to postnatal eye growth. In addition, multiple linear regression was used to detect relationships of relative eye and orbit diameter to life history variables. ANOVA was used to determine if eye size differed according to activity pattern. In most of the species, eye diameter at birth measures more than half of that for adults. Two exceptions include Nycticebus and Tarsius, in which more than half of eye diameter growth occurs postnatally. Ratios of neonate/adult eye and orbit diameters indicate prenatal growth of the eye is actually more rapid than that of the orbit. For example, mean neonatal transverse eye diameter is 57.5% of the adult value (excluding Nycticebus and Tarsius), compared to 50.8% for orbital diameter. If Nycticebus is excluded, relative gestation age has a significant positive correlation with relative eye diameter in strepsirrhines, explaining 59% of the variance in relative transverse eye diameter. No significant differences were found among species with different activity patterns.\ud \ud CONCLUSIONS/SIGNIFICANCE: The primate developmental strategy of relatively long gestations is probably tied to an extended period of neural development, and this principle appears to apply to eye growth as well. Our findings indicate that growth rates of the eye and bony orbit are disassociated, with eyes growing faster prenatally, and the growth rate of the bony orbit exceeding that of the eyes after birth. Some well-documented patterns of orbital morphology in adult primates, such as the enlarged orbits of nocturnal species, mainly emerge during postnatal development.\ud \u

In-home evaluation of efficacy and titration of a mandibular advancement device for obstructive sleep apnea

There is increasing evidence that mandibular advancement devices (MADs) can be an effective treatment for some patients with obstructive sleep apnea, a highly prevalent chronic disease. In this study, the objectives were to objectively assess the effectiveness of MAD therapy using a limited channel recorder, and to develop a model for identifying patients who may be appropriate for MAD therapy as the initial treatment option. Thirty patients were prospectively recruited and studied at two independent dentist offices and the participants’ homes. Subjects wore the ARES Unicorder for two nights before insertion of the MAD, and again when the dentist determined that the patient had reached the titration endpoint. Self-reported measures of depression, sleepiness, and quality of life were obtained pre- and posttreatment. The reviewer was blinded to the study status while the physiological signals were being visually inspected. Significant reductions in the apnea/hypopnea index (AHI), hypoxemia measures, and snoring level were observed posttreatment. Twenty-seven of the 30 (90%) patients had a posttreatment AHI (using a 4% desaturation for hypopneas) below a clinical cut-off of 10. All but one patient (97%) exhibited at least a 50% decrease in AHI or had a posttreatment AHI ≤ 10. Significant differences in body mass index, weight, and neck circumference in patients with posttreatment AHIs above and below a clinical cut-off of five were identified. The linear regression used to predict the posttreatment AHI using pretreatment data resulted in an R2 of 0.68. The model correctly predicted two patients who were unable to obtain a posttreatment AHI of 10 or less. This study was designed to demonstrate two models of collaboration between a dental sleep medicine specialist and a sleep medicine physician in the monitoring of a patient treated with a MAD. The outcome data suggest that the limited channel recording system can be used as an alternative to laboratory polysomnography to reduce the cost of MAD treatment, and to improve the quality and consistency of posttreatment patient care