bluuebunny/crossref_metadata_2025_split huggingface dataset:
Older age at Initiation of Antiretroviral Therapy Predicts Low Bone Mineral Density in Children with perinatally-infected HIV in Zimbabwe
Authors: Gregson Celia L , Hartley April , Majonga Edith , Mchugh Grace , Crabtree Nicola , Rukuni Ruramayi , Bandason Tsitsi , Mukwasi-Kahari Cynthia , Ward Kate A , Mujuru Hilda , Ferrand Rashida A 
Published: March 2019

AbstractBackgroundPerinatally-acquired HIV infection commonly causes stunting in children, but how this affects bone and muscle development is unclear. We investigated differences in bone and muscle mass and muscle function between children with HIV (CWH) and uninfected children.SettingCross-sectional study of CWH (6–16 years) receiving antiretroviral therapy (ART) for >6 months and children in the same age-group testing HIV-negative at primary health clinics in Zimbabwe.MethodsFrom Dual-energy X-ray Absorptiometry (DXA) we calculated total-body less-head (TBLH) Bone Mineral Content (BMC) for lean mass adjusted-for-height (TBLH-BMCLBM) Z-scores, and lumbar spine (LS) Bone Mineral Apparent Density (BMAD) Z-scores.ResultsThe 97 CWH were older (mean age 12.7vs. 10.0 years) and therefore taller (mean height 142cmvs. 134cm) than those 77 uninfected. However, stunting (height-for-age Z-score≤-2) was more prevalent in CWH (35%vs. 5%,p<0.001). Amongst CWH, 15% had low LS-BMAD (Z-score ≤-2) and 13% had low TBLH-BMCLBM, vs. 1% and 3% respectively in those uninfected (bothp≤0.02). After age, sex, height and puberty adjustment, LS-BMAD was 0.33 SDs (95%CI −0.01, 0.67;p=0.06) lower in CWH, with no differences in TBLH-BMCLBM, lean mass or grip strength by HIV status. However, there was a strong relationship between age at ART initiation and both LS-BMAD Z-score (r=-0.33,p=0.001) and TBLH-BMCLBMZ-score (r=-0.23,p=0.027); for each year ART initiation was delayed a 0.13 SD reduction in LS-BMAD was seen.ConclusionSize-adjusted low bone density is common in CWH. Delay in initiating ART adversely affects bone density. Findings support immediate ART initiation at HIV diagnosis.
Comparative analysis, applications, and interpretation of electronic health record-based stroke phenotyping methods
Authors: Thangaraj Phyllis M. , Kummer Benjamin R. , Lorberbaum Tal , Elkind Mitchell V. S. , Tatonetti Nicholas P. 
Published: March 2019

Background and PurposeAccurate identification of acute ischemic stroke (AIS) patient cohorts is essential for a wide range of clinical investigations. Automated phenotyping methods that leverage electronic health records (EHRs) represent a fundamentally new approach cohort identification. Unfortunately, the current generation of these algorithms is laborious to develop, poorly generalize between institutions, and rely on incomplete information. We systematically compared and evaluated the ability of several machine learning algorithms and case-control combinations to phenotype acute ischemic stroke patients using data from an EHR.MethodsUsing structured patient data from the EHR at a tertiary-care hospital system, we built machine learning models to identify patients with AIS based on 75 different case-control and classifier combinations. We then determined the models’ classification ability for AIS on an internal validation set, and estimated the prevalence of AIS patients across the EHR. Finally, we externally validated the ability of the models to detect self-reported AIS patients without AIS diagnosis codes using the UK Biobank.ResultsAcross all models, we found that the mean area under the receiver operating curve for detecting AIS was 0.963±0.0520 and average precision score 0.790±0.196 with minimal feature processing. Logistic regression classifiers with L1 penalty gave the best performance. Classifiers trained with cases with AIS diagnosis codes and controls with no cerebrovascular disease diagnosis codes had the best average F1 score (0.832±0.0383). In the external validation, we found that the top probabilities from a model-predicted AIS cohort were significantly enriched for self-reported AIS patients without AIS diagnosis codes (65-250 fold over expected).ConclusionsOur findings support machine learning algorithms as a way to accurately identify AIS patients without relying on diagnosis codes or using process-intensive manual feature curation. When a set of AIS patients is unavailable, diagnosis codes may be used to train classifier models. Our approach is potentially generalizable to other academic institutions and further external validation is needed.
Estimating the effect of the 2005 change in BCG policy in England: A retrospective cohort study
Authors: Abbott Sam , Christensen Hannah , Welton Nicky , Brooks-Pollock Ellen 
Published: March 2019

ABSTRACTBackgroundIn 2005, England changed from universal Bacillus Calmette–Guérin (BCG) vaccination of school-age children to targeted BCG vaccination of high-risk children at birth.MethodsWe combined notification data from the Enhanced Tuberculosis Surveillance system, with demographic data from the Labour Force Survey to construct retrospective cohorts of individuals in England relevant to both the universal, and targeted vaccination programmes between Jan 1, 2000 and Dec 31, 2010. For each cohort, we estimated incidence rates over a 5 year follow-up period and used Poisson and Negative Binomial regression models in order to estimate the impact of the change in policy on TB.ResultsIn the non-UK born, we found evidence for an association between a reduction in incidence rates and the change in BCG policy (school-age IRR: 0.74 (95%CI 0.61, 0.88), neonatal IRR: 0.62 (95%CI 0.44, 0.88)). We found some evidence that the change in BCG policy was associated with a increase in incidence rates in the UK born school-age population (IRR: 1.08 (95%CI 0.97, 1.19)) and weaker evidence of an association with a reduction in incidence rates in UK born neonates (IRR: 0.96 (95%CI 0.82, 1.14)). Overall, we found that the change in BCG policy was associated with directly preventing 385 (95% CI −105, 881) TB cases.ConclusionsWithdrawing universal vaccination at school-age and targeting BCG vaccination towards high-risk neonates was associated with reduced incidence of TB in England. This was largely driven by reductions in the non-UK born. There was a slight increase in UK born school-age cases.Key MessagesThere is little existing literature on the impact of withdrawing universal school-age BCG vaccination and introducing high-risk neonatal BCG vaccination on TB incidence rates in the populations directly affected by the vaccination programmes.There was strong evidence that the change in policy was associated with a decrease in TB incidence rates in non-UK born neonates and school-age children. In the UK born individuals, there was some evidence that the change in policy was associated with an increase in TB incidence rates in those relevant to the universal school-age scheme, with little evidence of a decrease in incidence rates in those relevant to the high-risk neonatal vaccination scheme.Overall the change in vaccination policy was associated with preventing TB cases, mainly in the non-UK born.These results provide an important evaluation of the direct effects of both withdrawing and implementing a BCG vaccination programme in a low incidence, high income, country and are relevant to several other countries that have made similar changes to their vaccination programmes.
Reducing RSV hospitalisation in a lower-income country by vaccinating mothers-to-be and their households
Authors: Brand Samuel P. C. , Munywoki Patrick , Walumbe David , Keeling Matt J. , Nokes D. James 
Published: March 2019

AbstractRespiratory syncytial virus is the leading cause of lower respiratory tract infection among infants. RSV is a priority for vaccine development. In this study, we investigate the potential effectiveness of a two-vaccine strategy aimed at mothers-to-be, thereby boosting maternally acquired antibodies of infants, and their household cohabitants, further cocooning infants against infection. We use a dynamic RSV transmission model which captures transmission both within households and communities, adapted to the changing demographics and RSV seasonality of a low-income country. Model parameters were inferred from past RSV hospitalisations, and forecasts made over a 10-year horizon. We find that a 50% reduction in RSV hospitalisations is possible if the maternal vaccine effectiveness can achieve 75 days of additional protection for newborns combined with a 75% coverage of their birth household co-inhabitants (∼7.5% population coverage).
Expression patterns of PD-L1 and PD-1 provide rationales for immune checkpoint inhibition in soft tissue sarcomas
Authors: Orth Martin F. , Buecklein Veit L. , Kampmann Eric , Subklewe Marion , Noessner Elfriede , Cidre-Aranaz Florencia , Romero-Pérez Laura , Wehweck Fabienne S. , Lindner Lars , Issels Rolf , Kirchner Thomas , Altendorf-Hofmann Annelore , Grünewald Thomas G. P. , Knösel Thomas 
Published: March 2019

ABSTRACTSoft tissue sarcomas (STS) are highly malignant cancers with mesenchymal origin. In many instances, clinical outcome is poor due to high rates of local recurrence and metastasis.The programmed death receptor ligand 1 (PD-L1) is expressed in several cancers. PD-L1 interacts with its receptor, PD-1, on the surface of tumor infiltrating lymphocytes (TILs), thereby attenuating anti-cancer immune response. Immune checkpoint inhibitors targeting this interaction are promising new anti-cancer drugs. However, present studies on the PD-L1 and PD-1 expression status in STS are limited either by small sample size, analysis of single STS subtypes, or lack of combinatorial assessment of PD-L1, PD-1 and TILs.To overcome these limitations, we evaluated the expression patterns of intratumoral PD-L1, the amount of TILs and their PD-1 expression status, as well as associations with clinicopathological parameters in a large and comprehensive cohort of 274 samples comprising more than six STS subtypes.We found that nearly all STS subtypes showed partial PD-L1 expression, albeit with a broad range of PD-L1 positivity across subtypes (50% angiosarcomas, 23% UPS, 13% leiomyosarcomas, 12% dedifferentiated liposarcomas, 3% synovial sarcomas, 0 MPNST, and 18% mixed sarcomas). Co-expression and correlation analyses uncovered that expression of PD-L1 was associated with more PD-1 positive TILs (P< 0.001), higher tumor grading (P= 0.022) and worse patients’ 5-year overall survival (P= 0.016).In sum, the substantial portion of STS showing PD-L1 expression, the simultaneous presence of PD-1 positive TILs, and the association of PD-L1 with unfavorable clinical outcome provide a rationale for immune checkpoint inhibition in patients with PD-L1-positive STS.
The Anaerobic Efflux Pump MdtEF-TolC Confers Resistance to Cationic Biocides
Authors: Novoa Diego , Conroy-Ben Otakuye 
Published: March 2019

AbstractTheE. coliRND transporter MdtEF-TolC is a tri-partite efflux pump that exports toxic substances. Little is known of the full range of substrate specificity of the anaerobic efflux pump, but MdtF shares similar homology and substrate specificity to the major RND efflux protein AcrB. To determine the substrate range of the anaerobic efflux pump MdtEF-TolC,E. colimutants were exposed to 210 different biocides, and growth was monitored. This approach was used to validate AcrAB-TolC substrates and discover new chemicals transported by the major antibiotic efflux protein. Results showed that overexpression of MdtEF conferred resistance to the same substrates as AcrAB-TolC, but were limited to cationic amino-based biocides. Alignment of the amino acids lining the distal pocket of MdtF and AcrB revealed a more acidic isoelectric point (pI) of an order of magnitude in MdtF, whereas the proximal pocket and external cleft were homologous and displayed identical pIs. This analysis suggests that pH, which determines acid-base speciation, and the distal pocket surface proteins play a role in MdtF substrate specificity.ImportanceHigh-throughput screening ofE. colimutants revealed that the substrates of the anaerobic efflux pump MdtEF-TolC are the same cationic biocides exported by AcrAB-TolC. Comparison of the protein sequences of the distal pocket, proximal pocket, and external cleft of the two RND proteins showed homology in amino acid surface charge and isoelectric point. Residue differences within the distal pocket are responsible for a more acidic pI and greater negative charge of the inner membrane protein MdtF surface, and support the findings of transport of cationic substances.
Resistance Rate Distribution of MDR-TB Among Pulmonary Tuberculosis Patients Attending Nnamdi Azikiwe University Teaching Hospital Nnewi and ST Patrick’S Hospital Mile 4 Abakiliki in Southeast Nigeria
Authors: Okoro Chinenye Esther , Akujobi Confort Nnenna , Udoh Iniekong Philip , Ibhawaegbele Stellamaris Ojiuzor , Ezema Charles Ikechukwu , Ezeugwu Uchechukwu Anthonia , Dozie-Nwakile Ogechukwu Calista , Okpe Aaron Chukwuemeka 
Published: March 2019

ABSTRACTTuberculosis, one of the oldest recorded human afflictions, is still one of the biggest killers among the infectious diseases, despite the worldwide use of a live attenuated vaccine and several antibiotics. This study was designed to assess the resistance rate distribution of MDR-TB among pulmonary tuberculosis patients attending Nnamdi Azikiewe University Teaching Hospital (NAUTH) Nnewi and St Patrick’s Hospital Mile 4 Abakaliki in the Southeast Nigeria. Patients with persistent cough for over two weeks were screened by Ziehl-Neelsen (ZN) technique for the presence of acid fast bacilli (AFB) in their sputum and a total of 103 patients with AFB positive sputum samples were recruited. The positive sputum samples were subjected to Xpert MTB/RIF assay (GeneXpert®, Cepheid USA) and culture on Lowestein Jensen medium for 42days at 37°C. Drug susceptibility testing was done on the isolates using the nitrate reduction assay (NRA). Xpert MTB/RIF assay detected MTB in 83(80.6%) samples out of which 45(67.2%) were rifampicin resistant. Sixty-seven (80.7%) of the isolates were resistant to at least one of the first-line drugs. Primary resistance was 91% while 19.4%, 35.8%, 22.4% and 22.4% of the isolates were resistant to one, two, three and four drugs respectively. Isoniazid had the highest rate of resistance (57.8%) while Ethambutol had the least (34.9%) and 30(44.8%) of the resistant isolates were MDR. Smoking (P=.002), gender (P=.002) and history of TB treatment (P=.012) were significantly associated with drug resistance. Educational status was significantly associated with MDR-TB (P=.020). NAUTH and St Patrick’s hospital had MDR-TB rates of 38.9% and 46.9% respectively. The findings of this study indicate high prevalence of MDR-TB among patients with pulmonary TB in the study sites and this portrays a menace to adequate TB control. Prompt diagnosis of TB, adequate patient compliance to therapy and increased awareness and mass education is recommended
Development, characterization and standardization of a nose-only inhalation exposure system for exposure of rabbits to small particle aerosols containingFrancisella tularensis
Authors: O’ Malley Katherine J. , Bowling Jennifer D. , Barry Eileen M. , Hazlett Karsten R. O. , Reed Douglas S. 
Published: March 2019

ABSTRACTInhalation ofFrancisella tularensis(Ft) causes pneumonic tularemia in humans, a severe disease with a 30-60% mortality rate. Reproducible delivery of aerosolized virulent bacteria in relevant animal models is essential for evaluating medical countermeasures. Here we developed optimized protocols for infecting New Zealand White (NZW) rabbits with aerosols containingFt. We evaluated relative humidity, aerosol exposure technique, and bacterial culture conditions to optimize spray factor (SF), a central metric of aerosolization. This optimization reduced both inter-and intra-daily variability and were applicable to multiple isolates ofFt. Further improvements in the accuracy and precision of the inhaled pathogen dose were achieved through enhanced correlation of bacterial culture OD and CFU. Plethysmograph data collected during exposures found that respiratory function varied considerably between rabbits, was not a function of weight, and did not improve with acclimation to the system. Vaccine Strain (LVS)-vaccinated rabbits were challenged via aerosol with human-virulentFtSCHU S4 that had been cultivated in either Mueller Hinton Broth (MHB) or Brain Heart Infusion (BHI) broth. LVS-vaccinated animals challenged with MHB-SCHU S4 experienced short febrile periods (median: 3.2 days), limited weight loss (< 5%), and longer median survival times (~18 d) that were significantly different than unvaccinated controls. In contrast, LVS-vaccinated rabbits challenged with BHI SCHU S4 experienced longer febrile periods (median: 5.5 days), greater weight loss (> 10%), and median survival times that were not significantly different than unvaccinated controls. These studies highlight the importance of careful characterization and optimization of protocols for aerosol challenge with pathogenic agents.
Bioelectrical signaling via domain wall migration
Authors: McNamara Harold M. , Salegame Rajath , Tanoury Ziad Al , Xu Haitan , Begum Shahinoor , Ortiz Gloria , Pourquie Olivier , Cohen Adam E. 
Published: March 2019

AbstractElectrical signaling in biology is typically associated with action potentials, transient spikes in membrane voltage that return to baseline. The Hodgkin-Huxley equations of electrophysiology belong to a more general class of reaction-diffusion equations which could, in principle, support patterns of membrane voltage which are stable in time but structured in space. Here we show theoretically and experimentally that homogeneous or nearly homogeneous tissues can undergo spontaneous spatial symmetry breaking into domains with different resting potentials, separated by stable bioelectrical domain walls. Transitions from one resting potential to another can occur through long-range migration of these domain walls. We map bioelectrical domain wall motion using all-optical electrophysiology in an engineered stable cell line and in human iPSC-derived myoblasts. Bioelectrical domain wall migration may occur during embryonic development and during physiological signaling processes in polarized tissues. These results demonstrate a novel form of bioelectrical pattern formation and long-range signaling.
Modeling decision-making under uncertainty: a direct comparison study between human and mouse gambling data
Authors: Cabeza Lidia , Giustiniani Julie , Chabin Thibault , Ramadan Bahrie , Joucla Coralie , Nicolier Magali , Pazart Lionel , Haffen Emmanuel , Fellmann Dominique , Gabriel Damien , Peterschmitt Yvan 
Published: March 2019

AbstractDecision-making is a conserved evolutionary process enabling to choose one option among several alternatives, and relying on reward and cognitive control systems. The Iowa Gambling Task allows to assess human decision-making under uncertainty by presenting four cards decks with various cost-benefit probabilities. Participants seek to maximize their monetary gains by developing long-term optimal choice strategies. Animal versions have been adapted with nutritional rewards but interspecies data comparisons are still scarce. Our study directly compared physiological decision-making performances between humans and wild-type C57BL/6 mice. Human subjects fulfilled an electronic Iowa Gambling Task version while mice performed a maze-based adaptation with four arms baited in a probabilistic way. Our data show closely matching performances among species with similar patterns of choice behaviors. Moreover, both populations clustered into good, intermediate, and poor decision-making categories with similar proportions. Remarkably, mice good decision-makers behaved as humans of the same category, but slight differences among species have been evidenced for the other two subpopulations. Overall, our direct comparative study confirms the good face validity of the rodent gambling task. Extended behavioral characterization and pathological animal models should help strengthen its construct validity and disentangle determinants of decision-making in animals and humans.
The evolution of the 9aaTAD domain in Sp2 proteins: inactivation with valines and intron reservoirs
Authors: Piskacek Martin , Havelka Marek , Jendruchova Kristina , Knight Andrea , Keegan Liam P. 
Published: March 2019

AbstractThe Sp1 transcription factor has been defined as glutamine-rich activator. The Nine amino acid TransActivation Domains (9aaTAD) have been identified in numerous transcription activators. Here, we identified the conserved 9aaTAD motif in the Sp1 and in all nine members of SP family with broad natural 9aaTAD variations. We showed by the amino acid substitutions that the glutamine residues are completely dispensable for 9aaTADs function. We described the 9aaTAD domains’ origin and evolutionary history. The ancestral Sp2 gene with inactive 9aaTAD has duplicated in early chordates and created new paralogs Sp1, Sp3 and Sp4. We discovered that the accumulation of valines in the 9aaTADs correlated with the domain inactivation. The Sp2 activation domain, whose dormancy have lasted over 100 million years during chordate evolution, enabled later diversification in the Sp1-4 clade, including both repressors and activators. The new paralogs Sp1 and Sp3 activation domains have regained their original activator function by loss of valines in their 9aaTADs.
Simulations of the effect of diffusion on asymmetric spin echo based quantitative BOLD: An investigation of the origin of deoxygenated blood volume overestimation
Authors: Stone Alan J , Holland Naomi C , Berman Avery J L , Blockley Nicholas P 
Published: March 2019

AbstractQuantitative BOLD (qBOLD) is a technique for mapping oxygen extraction fraction (OEF) and deoxygenated blood volume (DBV) in the human brain. Recent measurements using an asymmetric spin echo (ASE) based qBOLD approach produced estimates of DBV which were systematically higher than measurements from other techniques. In this study, we investigate two hypotheses for the origin of this DBV overestimation using simulations and consider the implications for experimental measurements. Investigations were performed by combining Monte Carlo simulations of extravascular signal with an analytical model of the intravascular signal.Hypothesis 1DBV overestimation is due to the presence of intravascular signal which is not accounted for in the analysis model. Intravascular signal was found to have a weak effect on qBOLD parameter estimates.Hypothesis 2DBV overestimation is due to the effects of diffusion which are not accounted for in the analysis model. The effect of diffusion on the extravascular signal was found to result in a vessel radius dependent variation in qBOLD parameter estimates. In particular, DBV overestimation peaks for vessels with radii from 20 to 30 μm and is OEF dependent. This results in the systematic underestimation of OEF.ImplicationsThe impact on experimental qBOLD measurements was investigated by simulating a more physiologically realistic distribution of vessel sizes with a small number of discrete radii. Overestimation of DBV consistent with previous experiments was observed, which was also found to be OEF dependent. This results in the progressive underestimation of the measured OEF. Furthermore, the relationship between the measured OEF and the true OEF was found to be dependent on echo time and spin echo displacement time.The results of this study demonstrate the limitations of current ASE based qBOLD measurements and provide a foundation for the optimisation of future acquisition approaches.