Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular dynamics simulation on the allosteric analysis of the c‐di‐GMP class I riboswitch induced by ligand binding

Riboswitches are RNA molecules that regulate gene expression using conformation change, affected by binding of small molecule ligands. Although a number of ligand‐bound aptamer complex structures have been solved, it is important to know ligand‐free conformations of the aptamers in order to understand the mechanism of specific binding by ligands. In this paper, we use dynamics simulations on a series of models to characterize the ligand‐free and ligand‐bound aptamer domain of the c‐di‐GMP class I (GEMM‐I) riboswitch. The results revealed that the ligand‐free aptamer has a stable state with a folded P2 and P3 helix, an unfolded P1 helix and open binding pocket. The first Mg ions binding to the aptamer is structurally favorable for the successive c‐di‐GMP binding. The P1 helix forms when c‐di‐GMP is successive bound. Three key junctions J1/2, J2/3 and J1/3 in the GEMM‐I riboswitch contributing to the formation of P1 helix have been found. The binding of the c‐di‐GMP ligand to the GEMM‐I riboswitch induces the riboswitch's regulation through the direct allosteric communication network in GEMM‐I riboswitch from the c‐di‐GMP binding sites in the J1/2 and J1/3 junctions to the P1 helix, the indirect ones from those in the J2/3 and P2 communicating to P1 helix via the J1/2 and J1/3 media.
Epidemiology of chronic rhinosinusitis in Bushehr, southwestern region of Iran: a GA2LEN study.

BACKGROUND Population-based studies using the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) criteria for the assessment of the chronic rhinosinusitis (CRS) prevalence play important roles in the development and promotion of public health policies. METHODS A multistage, stratified cluster, random sampling method was used to select the study participants from individuals living in Bushehr, which is in the southwestern part of Iran. The standardized Global Allergy and Asthma European Network (GA2LEN) questionnaire was completed by 5,201 participants, and the CRS prevalence were compared among different groups of related factors using chi-squared tests. RESULTS The overall CRS prevalence was 28.4% based on the EPOS criteria, while the self-reported physician-diagnosed CRS prevalence was 20.0%. There was no gender difference; however, CRS was more prevalent in smokers, individuals aged 25 - 34 years old, non-educated persons, and healthcare workers. CRS was also associated with asthma and allergic rhinitis. CONCLUSIONS The present study showed that the CRS prevalence in Iran was relatively high. These results support the idea that CRS is a major public health problem in Iran.
Assessing the efficacy of asynchronous telehealth-based hearing screening and diagnostic services using automated audiometry in a rural South African school

Background Asynchronous automated telehealth-based hearing screening and diagnostic testing can be used within the rural school context to identify and confirm hearing loss. Objective The aims of the study were to evaluate the efficacy of an asynchronous telehealth-based service delivery model using automated technology for screening and diagnostic testing as well as to describe the prevalence, type and degree of hearing loss. Method A comparative within-subject design was used. Frequency distributions, sensitivity, specificity scores as well as the positive and negative predictive values were calculated. Testing was conducted in a non-sound-treated classroom within a school environment on 73 participants (146 ears). The sensitivity and specificity rates were 65.2% and 100%, respectively. Diagnostic accuracy was 91.7% and the negative predictive values (NPV) and positive predictive values (PPV) were 93.8% and 100%, respectively. Results Results revealed that 23 ears of 20 participants (16%) presented with hearing loss. Twelve per cent of ears presented with unilateral hearing impairment and 4% with bilateral hearing loss. Mild hearing loss was identified as most prevalent (8% of ears). Eight ears obtained false-negative results and presented with mild low- to mid-frequency hearing loss. The sensitivity rate for the study was low and was attributed to plausible reasons relating to test accuracy, child-related variables and mild low-frequency sensory-neural hearing loss. Conclusion The study demonstrates that asynchronous telehealth-based automated hearing testing within the school context can be used to facilitate early identification of hearing loss; however, further research and development into protocol formulation, ongoing device monitoring and facilitator training is required to improve test sensitivity and ensure accuracy of results.
Clinical and pre-clinical utility of genomics in medulloblastoma

ABSTRACT Introduction: Integrated genomics has significantly advanced our understanding of medulloblastoma heterogeneity. It is now clear that it actually comprises at least four distinct molecular subgroups termed Wnt/Wingless (WNT), Sonic Hedgehog (SHH), Group 3, and Group 4 with stark clinical and biological differences. Areas covered: This paper reviews advances in the classification and risk stratification of medulloblastoma, specifically integrating subgroup with clinical and cytogenetic risk factors, with a summary of the potential to lead to more precise therapies. Moreover, the current state of preclinical modeling is summarized with respect to their utility in generating new treatments and correlation with genomic discoveries. Opportunities and challenges in developing new treatment paradigms are summarized and discussed, specifically new therapies for very high-risk metastatic/MYC-amplified Group 3 and TP53-mutant SHH and reductions in therapy for lower risk groups. Expert commentary: Survival across medulloblastoma has been stagnant for over 30 years, and new treatment paradigms are urgently required. Current therapy significantly over treats a high proportion of patients leaving them with lifelong side effects; while many patients still succumb to their disease. Applying biological advances could improve quality of life for a significant proportion of patients while offering new upfront approaches to the highest risk patients.
Hyaluronan antagonizes the differentiation effect of TGF-β1 on nasal epithelial cells through down-regulation of TGF-β type I receptor

Abstract Although hyaluronan (HA)-based biomaterials have been proposed to promote mucociliary differentiation of nasal epithelial cells (NECs), the mechanism by which HA affects the growth and differentiation of NECs has not been thoroughly explored. This study investigates the effect and mechanism of HA on the differentiation of NECs. The experiment cultures human NECs in four conditions, namely controls, transforming growth factor (TGF)-β1, TGF-β1 + HA and HA groups. In the TGF group, the NECs become irregular shape without formation of tight junction and mucociliary differentiation of NECs is inhibited. Epithelial–mesenchymal transition (EMT) of NECs also occurs in the TGF group. However, with addition of HA in TGF groups, NECs reveal the mucociliary phenotypes of epithelial cells with tight junction expression. Incubation of TGF-β1 in an NEC culture leads to an increase in phosphorylated type 1 TGF-β receptors (p-TβRI). This increase is attenuated when NECs are cultured in the presence of HA. Similar expressions are observed in phosphorylated smad2/smad3. Additionally, HA-dependent inhibition of TGF-β1 signalling is inhibited by co-incubation with a blocking antibody to CD44. Experimental results indicate that HA can antagonize TGF-β1 effect on EMT and mucociliary differentiation of NECs by down-regulation of TβR I, which is via CD44.
Deliberate Self-harm among Young People Begins to Increase at the Very Early Age: a Nationwide Study

Background Suicide in young people is one of most common cause of death; and deliberate self-harm (DSH) is important indicator of suicide. It is currently unclear how old the rate begins to increase or when it reaches to the same level with adults. The purpose of this study was to find beginning age of DSH and compare their characteristics with adults. Methods This study retrospectively reviewed 5 years of nationwide prospective registry named Emergency Department-based Injury In-depth Surveillance (EDIIS) registry composed of all injured patients who were admitted to twenty tertiary university hospital emergency departments. Injured patients aged 29 years or younger from January 1, 2011 to December 31, 2015 were included. Incidence rate of DSH in all age was described. Patients were stratified by age: early teenage (11–15 years), late teenage (16–19 years), and early adulthood (20–29 years). Data of early teenage group were compared to those of other groups for examining their characteristics. Results Among 588,549 injury patients, 8,400 patients reported DSH. The rate began to rise at age 11 and reach at age 16 which was equivalent to that of age 20 to 29. Early teenage had significantly higher excess mortality ratio based injury severity score (EMR-ISS) and had almost same level without significant difference in operation incidence or mortality compared to late teenage and early adulthood. Conclusion DSH rate began to rise at age 11, reaching adulthood level at age 16 in Korea.
Neurovascular coupling response to cognitive examination in healthy controls: a multivariate analysis

Cognitive testing with transcranial Doppler ultrasonography (TCD) has been used to assess neurovascular coupling (NVC), but few studies address its multiple contributions. Subcomponent analysis considers the relative myogenic (resistance area product, RAP) and metabolic (critical closing pressure (CrCP)) contributors. The aim of this study was to investigate the changes in subcomponents that occur with cognitive stimulation with the Addenbrooke's Cognitive Examination (ACE‐III) in healthy controls. Healthy volunteers underwent continuous recording of bilateral TCD, heart rate (HR, three‐lead ECG), end‐tidal CO2 (ETCO2, capnography), and mean arterial pressure (MAP, Finometer). The study comprised a 5‐min baseline recording, followed by all 20 paradigms from the ACE‐III. The cerebral blood flow velocity (CBFv) response was decomposed into the relative contributions (subcomponents); VBP (MAP), VCrCP (CrCP), and VRAP (RAP). Data are presented as peak population normalized mean changes from baseline, and median area under the curve (AUC). Forty bilateral datasets were obtained (27 female, 37 right hand dominant). VBP increased at task initiation in all paradigms but differed between tasks (range (SD): 4.06 (8.92)–16.04 (12.23) %, P < 0.05). HR, but not ETCO2, also differed significantly (P < 0.05). Changes in VRAP reflected changes in MAP, but in some paradigms atypical responses were seen. VCrCP AUC varied significantly within paradigm sections (range [SD]: 18.4 [24.17] to 244.21 [243.21] %*s, P < 0.05). All paradigms demonstrated changes in subcomponents with cognitive stimulation, and can be ranked based on their relative presumed metabolic demand. The integrity of NVC requires further investigation in patient populations.
Illustrating where spatial perception versus memory-based representation: spatial neglect in a distinguished artist; a case report

ABSTRACT Spatial neglect is a disorder of attention, perception, and processing of stimuli in contralesional space. The heterogeneous behaviors involve diverse neuroanatomical mechanisms. Anecdotal evidence suggests that neural circuitry of active spatial perception may differ from that used to encode spatial memory. These differences can escape detection by conventional assessments, thereby leading to missed diagnoses. We present a case, in an artist who demonstrates selective impairment in a contralesional space during active Where spatial perception. His performance is better when asked to draw entirely from memory. This case highlights the variability in neglect, importance for comprehensive testing, and encourages further investigation.
A 10-Year Prospective Study of Bone Mineral Density and Bone Turnover in Males and Females With Type 1 Diabetes

Context In a previous community-based, cross-sectional study, males with type 1 diabetes (T1D) had lower bone mineral density (BMD) than did matched people without diabetes but females with T1D had normal BMD. Objective To determine whether BMD in the males continued to decline, the neutral effect of T1D on BMD in females persisted, and whether temporal BMD changes reflected changes in bone turnover markers. Design Longitudinal observational study. Setting Urban community. Patients Forty-eight of the original 102 original cross-sectional study participants (20 males, 28 females) of mean age 42.0 years and median diabetes duration 14.6 years at baseline who were restudied a mean of 10.3 years later. Main Outcome Measures BMD at total hip, femoral neck, lumbar spine (L1 to L4), and distal forearm. Biochemical bone turnover markers. Results After adjustment for age, body mass index (BMI), and renal function, there was no temporal change in BMD at the hip or forearm in the males (P ≥ 0.12), but lumbar spine BMD increased (P = 0.009). Females exhibited no statistically significant change in BMD in similar multivariable models that also included postmenopausal status, except a mild increase at the forearm (P = 0.046). Age- and sex-related changes in bone turnover markers paralleled those in general population studies. Conclusions There is a reduction in BMD in males with T1D that occurs early in the course of the disease but then stabilizes. BMD in females with T1D remains similar to that expected for age, BMI, and postmenopausal status.
Bounded, efficient and multiply robust estimation of average treatment effects using instrumental variables

Instrumental variables are widely used for estimating causal effects in the presence of unmeasured confounding. Under the standard instrumental variable model, however, the average treatment effect is only partially identifiable. To address this, we propose novel assumptions that enable identification of the average treatment effect. Our identification assumptions are clearly separated from model assumptions that are needed for estimation, so researchers are not required to commit to a specific observed data model in establishing identification. We then construct multiple estimators that are consistent under three different observed data models, and multiply robust estimators that are consistent in the union of these observed data models. We pay special attention to the case of binary outcomes, for which we obtain bounded estimators of the average treatment effect that are guaranteed to lie between −1 and 1. Our approaches are illustrated with simulations and a data analysis evaluating the causal effect of education on earnings.
Prophylaxis for aspergillosis in patients with haematological malignancies: pros and cons

ABSTRACT Introduction: Along with new diagnostic options, comes the recent development of novel antifungal agents that expanded the spectrum of activity over traditional treatments contributing to the successful management of fungal diseases. Nevertheless, invasive fungal infections (IFI) represent a major hindrance to the favorable outcome of patients with hematologic malignancies. According to these observations, an appropriate prevention of IFI occurring in hematologic patients should be considered of paramount importance. However, the wide use of antifungal agents may facilitate the emergence of resistance and may be associated to the occurrence of severe adverse events and eventually may significantly increase the cost of therapeutic procedures. Areas covered: The aim of present review is to analyze advantages and disadvantages of primary antifungal prophylaxis (PAP) in hematologic patients. Expert commentary: Patients with AML/MDS undergoing intensive chemotherapy and patients receiving stem cell transplantation are at high risk of IFI, and therefore may benefit form PAP, although several additional factors should be carefully evaluated in our decision-making approach, including the local epidemiology and the prompt availability of diagnostic facilities. The advent of new treatment options for hematologic patients such as target therapies might facilitate the rise of new risk categories so far underestimated.
Pheochromocytoma and paraganglioma in Fontan patients: Common more than expected

OBJECTIVE Pheochromocytoma and paraganglioma (extra-adrenal pheochromocytoma) are rare neuroendocrine tumors that arise from the neuroendocrine cells. Chronic hypoxia is known as a possible cause, and a strong link between cyanotic congenital heart disease and these tumors has been reported. However, reports of phechromocytoma/paraganglioma in Fontan patients were scarce. We herein report seven cases of phechromocytoma/paraganglioma after Fontan operation at a single tertiary center. METHODS We retrospectively reviewed medical records and imaging studies who diagnosed as phechromocytoma/paraganglioma after Fontan operation in Seoul National University Children's Hospital. RESULTS Seven patients were identified during follow-up after Fontan operation, and the prevalence was 2.5% among Fontan patients greater than 10 years old on active follow-up. Three patients were diagnosed as phechromocytoma and 4 patients as paraganglioma. Median time interval between Fontan operation and diagnosis of pheochromocytoma/paraganglioma was 21.4 years (range, 10.4-29.7 years). Resting percutaneous oxygen saturation varied from 77% to 94%. All patients underwent complete tumor resection. Phechromocytoma recurred in two patients, of whom one patient died at the age of 18 years due to the tumor progression with multiple metastasis and aggravation of heart failure with profound cyanosis. Pheochromocytoma/paraganglioma developed after hepatocellular carcinoma in two patients. CONCLUSION Phechromocytoma/paraganglioma could occur in Fontan patients more than expected. Because it is curable by tumor resection during its early phase, early diagnosis and treatment of pheochromocytoma are crucial in Fontan patients not to make hemodynamic deterioration and aggravation of heart failure.
A framework for meta-analysis of prediction model studies with binary and time-to-event outcomes

It is widely recommended that any developed—diagnostic or prognostic—prediction model is externally validated in terms of its predictive performance measured by calibration and discrimination. When multiple validations have been performed, a systematic review followed by a formal meta-analysis helps to summarize overall performance across multiple settings, and reveals under which circumstances the model performs suboptimal (alternative poorer) and may need adjustment. We discuss how to undertake meta-analysis of the performance of prediction models with either a binary or a time-to-event outcome. We address how to deal with incomplete availability of study-specific results (performance estimates and their precision), and how to produce summary estimates of the c-statistic, the observed:expected ratio and the calibration slope. Furthermore, we discuss the implementation of frequentist and Bayesian meta-analysis methods, and propose novel empirically-based prior distributions to improve estimation of between-study heterogeneity in small samples. Finally, we illustrate all methods using two examples: meta-analysis of the predictive performance of EuroSCORE II and of the Framingham Risk Score. All examples and meta-analysis models have been implemented in our newly developed R package “metamisc”.
4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)†

F. Cardoso*, E. Senkus, A. Costa, E. Papadopoulos, M. Aapro, F. André, N. Harbeck, B. Aguilar Lopez, C. H. Barrios, J. Bergh, L. Biganzoli, C. B. Boers-Doets, M. J. Cardoso, L. A. Carey, J. Cortés, G. Curigliano, V. Diéras, N. S. El Saghir, A. Eniu, L. Fallowfield, P. A. Francis, K. Gelmon, S. R. D. Johnston, B. Kaufman, S. Koppikar, I. E. Krop, M. Mayer, G. Nakigudde, B. V. Offersen, S. Ohno, O. Pagani, S. Paluch-Shimon, F. Penault-Llorca, A. Prat, H. S. Rugo, G. W. Sledge, D. Spence, C. Thomssen, D. A. Vorobiof, B. Xu, L. Norton & E. P. Winer
Pneumococcal Conjugate Vaccines Turning the Tide on Inequity: A Retrospective Cohort Study of New Zealand Children Born 2006–2015

BACKGROUND Hospitalization rates for infectious diseases in New Zealand (NZ) children have increased since 1989. The highest burden is among Māori and Pacific children, and the most socioeconomically deprived. New Zealand introduced pneumococcal conjugate vaccine (PCV)7 in June 2008, PCV10 in 2011, and PCV13 in 2014. METHODS A retrospective cohort study of NZ children aged <6 years between 2006 and 2015 was performed using administrative databases. Demographics and hospitalizations were linked to evaluate the impact of the PCV vaccination program on cases of invasive pneumococcal disease (IPD), all-cause pneumonia (ACP), and otitis media (OM), defined by ICD-10-AM codes, and to explore the effect by ethnicity and deprivation. RESULTS Between 2006 and 2015, there were 640 children hospitalized with IPD, 26589 for ACP, and 44545 for OM. IPD hospitalizations declined by 73% between 2005 and 2015 for children <6 years of age, whereas ACP and OM declined by 8% and 25%, respectively. The highest rates for all diseases were among Māori and Pacific children and those from high deprivation. However, the declines were highest among Māori and Pacific children and those from socioeconomically deprived areas. IPD hospitalizations declined by 79% and 67% for Māori and Pacific children, respectively, between 2006 and 2015. ACP declined by 12% in Māori and 21% in Pacific children. OM declined by 51% in Māori children. CONCLUSION In contrast to the increasing trend of hospitalization rates for infectious disease in New Zealand, the use of PCV appears associated with reductions in ethnic and socioeconomic disparities in hospitalization for IPD, ACP, and OM.
Survival analysis of the association between antenatal care attendance and neonatal mortality in 57 low- and middle-income countries

Abstract Background Neonatal mortality is unacceptably high in most low- and middle-income countries (LMICs). In these countries, where access to emergency obstetric services is limited, antenatal care (ANC) utilization offers improved maternal health and birth outcomes. However, evidence for this is scanty and mixed. We explored the association between attendance for ANC and survival of neonates in 57 LMICs. Methods Employing standardized protocols to ensure comparison across countries, we used nationally representative cross-sectional data from 57 LMICs (N = 464 728) to investigate the association between ANC visits and neonatal mortality. Cox proportional hazards multivariable regression models and meta-regression analysis were used to analyse pooled data from the countries. Kaplan-Meier survival curves were used to describe the patterns of neonatal survival in each region. Results After adjusting for potential confounding factors, we found 55% lower risk of neonatal mortality [hazard ratio (HR) 0.45, 95% confidence interval (CI) 0.42–0.48] among women who met both WHO recommendations for ANC (first visit within the first trimester and at least four visits during pregnancy) in pooled analysis. Furthermore, meta-analysis of country-level risk shows 32% lower risk of neonatal mortality (HR 0.68, 95% CI 0.61–0.75) among those who met at least one WHO recommendation. In addition, ANC attendance was associated with lower neonatal mortality in all the regions except in the Middle East and North Africa. Conclusions ANC attendance is protective against neonatal mortality in the LMICs studied, although differences exist across countries and regions. Increasing ANC visits, along with other known effective interventions, can improve neonatal survival in these countries.