Miracle-dz/UniFAR-FTUs huggingface dataset:
New Diagnostic Approaches for Undiagnosed Rare Genetic Diseases.

Accurate diagnosis is the cornerstone of medicine; it is essential for informed care and promoting patient and family well-being. However, families with a rare genetic disease (RGD) often spend more than five years on a diagnostic odyssey of specialist visits and invasive testing that is lengthy, costly, and often futile, as 50% of patients do not receive a molecular diagnosis. The current diagnostic paradigm is not well designed for RGDs, especially for patients who remain undiagnosed after the initial set of investigations, and thus requires an expansion of approaches in the clinic. Leveraging opportunities to participate in research programs that utilize new technologies to understand RGDs is an important path forward for patients seeking a diagnosis. Given recent advancements in such technologies and international initiatives, the prospect of identifying a molecular diagnosis for all patients with RGDs has never been so attainable, but achieving this goal will require global cooperation at an unprecedented scale. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 21 is August 31, 2020. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Understanding risk communication for prevention and control of vector-borne diseases: A mixed-method study in Curaçao

Background Risk communication (RC) is an essential tool for the prevention and control of diseases as it impacts risk perception, increases awareness and might change behaviour. It is the interactive exchange of information about risks among experts and people. Effective RC can minimize the impact that diseases such as dengue, chikungunya and Zika have on populations. This study aimed to understand RC regarding vector-borne diseases in its social context and from the viewpoint of the audience to strengthen RC strategies in Curaçao. Methods In 2015, a cross-sectional mixed-method study applying focus group discussions (n = 7), in-depth interviews (n = 20) and a structured survey questionnaire (n = 339) was done in Curaçao. The study was designed based on the Health Belief Model and the Theory of Planned Behaviour. In addition, the Social Amplification of Risk Framework and the theory of cultural schemas were applied to understand RC in the social context. Results Television, radio and newspapers were the most important channels of information regarding dengue and chikungunya. Moreover, individuals also reported receiving information via social media, the internet and family/friends. Interestingly, the use of internet to obtain information diminished with age, while females were more likely to use internet compared to men. These key findings were statistically significant. An important outcome was that the risk perception towards chikungunya at the beginning of the outbreak was attenuated. This might be due to the (perceived) lack of RC before the epidemic. This same risk perception was amplified later during the outbreak by the increased exposure to information. Lastly, we show how cultural schemas influence people’s perception regarding preventive measures and treatment of chikungunya and dengue. Conclusions Data obtained emphasise the importance of understanding the user of media platforms and sharing information in a timely fashion through a transparent process with the content that convinces people of the seriousness of the matter.
The effect of the presence of epileptic attacks on the clinical duration of supratentorial brain meningiomas.

OBJECTIVE The aim: To study the effect of epileptic seizures in patients with supratentorial brain meningiomas on the clinical course of meningiomas in the early and late postoperative period. PATIENTS AND METHODS Materials and methods: A retrospective analysis of the course of the disease was performed in 242 patients with total removed supratentorial meningioma of the brain (general group). Long-term outcome of the disease was estimated in 176 people (a catamnesis group). RESULTS Results: The occurrence of a new neurological deficit was observed in 18 (18.0±3.8 %) patients out of 100 among patients with epileptic seizures before surgery and in 19 (13.4±2.9 %) out of 142 among those who had no seizures. The mortality rate was 1 (1.0±1.0 %) in the group of patients with seizures and 3 (2.8±1.4 %) in the group of patients without seizures before surgery. The prevalence of new neurological deficits in the catamnesis group is 14 (19.2±4.6 %) of 73 patients with epileptic seizures before surgery and 17 (16.5±3.7 %) of 103 patients without seizures. Mortality was 3 cases (4.1±2.3 %) in patients with seizures and 9 cases (8.7±2.8 %) among patients without seizures. CONCLUSION Conclusions: No data have been obtained that the presence of epileptic seizures affects the incidence of new neurological deficits, complications and mortality after surgical treatment of meningiomas in the early and late postoperative period.
Efficacy of Neuraminidase Inhibitors against H5N6 Highly Pathogenic Avian Influenza Virus in a Nonhuman Primate Model

Attention has been paid to H5N6 highly pathogenic avian influenza virus (HPAIV) because of its heavy burden on the poultry industry and human mortality. Since an influenza A virus carrying N6 neuraminidase (NA) has never spread in humans, the potential for H5N6 HPAIV to cause disease in humans and the efficacy of antiviral drugs against the virus need to be urgently assessed. We used nonhuman primates to elucidate the pathogenesis of H5N6 HPAIV as well as to determine the efficacy of antiviral drugs against the virus. ABSTRACT Attention has been paid to H5N6 highly pathogenic avian influenza virus (HPAIV) because of its heavy burden on the poultry industry and human mortality. Since an influenza A virus carrying N6 neuraminidase (NA) has never spread in humans, the potential for H5N6 HPAIV to cause disease in humans and the efficacy of antiviral drugs against the virus need to be urgently assessed. We used nonhuman primates to elucidate the pathogenesis of H5N6 HPAIV as well as to determine the efficacy of antiviral drugs against the virus. H5N6 HPAIV infection led to high fever in cynomolgus macaques. The lung injury caused by the virus was severe, with diffuse alveolar damage and neutrophil infiltration. In addition, an increase in interferon alpha (IFN-α) showed an inverse correlation with virus titers during the infection process. Oseltamivir was effective for reducing H5N6 HPAIV propagation, and continuous treatment with peramivir reduced virus propagation and the severity of symptoms in the early stage. This study also showed pathologically severe lung injury states in cynomolgus macaques infected with H5N6 HPAIV, even in those that received early antiviral drug treatments, indicating the need for close monitoring and further studies on virus pathogenicity and new antiviral therapies.
ENO1‐targeted superparamagnetic iron oxide nanoparticles for detecting pancreatic cancer by magnetic resonance imaging

The aim of this study was to investigate in vitro magnetic resonance imaging (MRI) of PDAC using ENO1‐targeted superparamagnetic iron oxide nanoparticles and xenograft models. Expression level and location of ENO1 protein in pancreatic cancer cell lines of CFPAC‐1 and MiaPaCa‐2 were detected by Western blotting, flow cytometry and confocal microscopy. Dex‐g‐PCL/SPIO nanoparticles targeting ENO1 were constructed with ENO1 antibody and characterized by MRI. In addition, ENO1‐Dex‐g‐PCL/SPIO nanoparticles were tested to assess their efficacy on the detection of PDAC using in vitro and in vivo MRI. The results showed that ENO1 was expressed in both human PDAC cell lines of CFPAC‐1 and MiaPaCa‐2, demonstrating that the localization of cytoplasm and membrane was dominant. It was confirmed that ENO1 antibody was connected to the SPIO surface in ENO1‐Dex‐g‐PCL/SPIO nanoparticles. The nanoparticles had satisfactory superparamagnetism and significantly enhance the detection of PDAC by in vivo and in vitro MRI. In conclusion, ENO1 can serve as a membrane protein expressed on human PDAC cell lines. ENO1‐targeted SPIO nanoparticles using ENO1 antibody can increase the efficiency of detection of PDAC by in vitro and in vivo MRI.
BRAF mutational status as a prognostic marker for survival in malignant melanoma: a systematic review and meta-analysis

Abstract Background: The analysis of the BRAF mutational status has been established as a standard procedure during diagnosis of advanced malignant melanoma due to the fact that BRAF inhibitors constitute a cornerstone in the treatment of metastatic disease. However, the general impact of BRAF mutational status on survival remains unclear. Our study aimed to assess the underlying prognostic significance of BRAF mutant versus wild type (WT) malignant melanoma on overall survival (OS), disease-free survival (DFS) and progression-free survival (PFS). Material and methods: A systematic literature search in EMBASE, Medline and Cochrane CENTRAL was performed. Studies were included if they reported survival outcomes for BRAF mutant versus WT patients as hazard ratios (HR) or in Kaplan-Meier (KM) curves. Random-effects meta-analysis models were used to pool HRs across the studies. Results: Data from 52 studies, representing 7519 patients, were pooled for analysis of OS. The presence of a BRAF mutation was statistically significantly associated with a reduced OS (HR [95% confidence interval (CI)]: 1.23 [1.09–1.38]), however, with substantial heterogeneity between the studies (I2: 58.0%). Meta-regression and sensitivity analyses showed that age, sex and BRAF mutation testing method did not have a significant effect on the OS HR. BRAF mutant melanoma showed comparable effect on DFS to non-BRAF mutant melanoma in stage I–III melanoma (combined HR: 1.16, 95% CI: 0.92–1.46), and on PFS in stage III–IV (HR: 0.98 (95% CI: 0.68−1.40)). Conclusion: Although there was substantial heterogeneity between the studies, the overall results demonstrated a poorer prognosis and OS in patients harbouring BRAF mutations. Future studies should take this into account when evaluating epidemiological data and treatment effects of new interventions in patients with malignant melanoma.
WHO infant and young child feeding indicators in relation to anthropometric measurements

Abstract Objective: This study aimed to report the WHO infant and young child feeding (IYCF) indicators from Kuwait and to investigate the associations between these indicators and anthropometric measurements. Design: The Kuwait Nutritional Surveillance System uses observational cross-sectional approach to collects data by face-to-face interviews with mothers or child guardians using a structured questionnaire that was developed based on the WHO IYCF indicators. The weight and height of infants and young children were measured using digital scales in a standardised manner. Setting: Vaccination centres in all governorates (provinces) of Kuwait. Participants: Infants and young Kuwaiti children aged 0–23 months (N 5839). Results: The prevalence of exclusive breastfeeding and age-appropriate breastfeeding were 8·0 and 7·4 %, respectively. The prevalence of stunting and wasting was 7·5 and 2·4 %, respectively, while the prevalence of overweight and obesity was 6·5 and 1·6 %, respectively. In the multivariable analysis, exclusive breastfeeding and age-appropriate breastfeeding were more common in children with stunted growth (AOR 1·71 (95 % CI 1·08, 2·70; P = 0·021) and 1·44 (95 % CI 1·01, 2·06; P = 0·046), respectively). The introduction of solid/semisolid or soft foods was inversely associated with stunting (AOR 0·52; 95 % CI 0·30, 0·90; P = 0·021). Only age-appropriate breastfeeding was inversely associated with overweight (AOR 0·62; 95 % CI 0·39, 0·98; P = 0·043). Conclusion: Our findings showed that indicators of breastfeeding are low in Kuwait. Our findings suggest that the associations between different WHO IYCF indicators and stunting as well as overweight is complex, which highlights the need for a better understanding of WHO IYCF indicators in both low- and high-income countries.
Nurse Staffing, the Clinical Work Environment, and Burn Patient Mortality.

The complexity of modern burn care requires an integrated team of specialty providers working together to achieve the best possible outcome for each burn survivor. Nurses are central to many aspects of a burn survivor's care, including physiologic monitoring, fluid resuscitation, pain management, infection prevention, complex wound care, and rehabilitation. Research suggests that in general, hospital nursing resources, defined as nurse staffing and the quality of the work environment, relate to patient mortality. Still, the relationship between those resources and burn mortality has not been previously examined. This study used a multivariable risk-adjusted regression model and a linked, cross-sectional claims database of over 14,000 adult (≥18 yrs.) thermal burn patients admitted to 653 hospitals to evaluate these relationships. Hospital nursing resources were independently reported by over 29,000 bedside nurses working in the study hospitals. In the high burn patient-volume hospitals (≥100/yr.) that care for the most severe burn injuries, each additional patient added to a nurse's workload is associated with 30% higher odds of mortality (p<0.05, 95% CI [1.02, 1.94]), and improving the work environment is associated with 28% lower odds of death (p<0.05, 95%CI [0.07, 0.99]). Nursing resources are vital in the care of burn patients and are a critical, yet previously omitted, variable in the evaluation of burn outcomes. Attention to nurse staffing and improvement to the nurse work environment is warranted to promote optimal recovery for burn survivors. Given the influence of nursing on mortality, future research evaluating burn patient outcomes should account for nursing resources.
Molybdenosis: a potential problem in ruminants grazing on coal mine spoils

Copper-to-molybdenum ratios in all but two sweetclover samples collected on spoil at eight coal mines in the Northern Great Plains ranged from 0.44:1 to 5:1. Ratios of 5:1 or less in forage are reported to cause molybdenosis, a nutritional disease occurring in molybdic regions of the world. Therefore, if the major forage on coal-mine spoils is sweetclover or other species with similar Cu:Mn ratios, molybdenosis may be expected to occur in cattle and sheep grazing in these areas.
Impact of Antimicrobial Stewardship Interventions on Appropriateness of Surgical Antibiotic Prophylaxis: How to Improve

Surgical site infections (SSIs) are the most common healthcare-associated infections. The appropriate use of Surgical Antibiotic Prophylaxis (SAP) is a key component to reduce SSIs, while its inappropriate application is a major cause of some emerging infections and selects for antibiotic resistance. We describe an Antimicrobial Stewardship (AMS) intervention on SAP appropriateness. The prospective study was conducted in an Italian hospital, in 12 main surgical units, and was organized in three subsequent phases, as follows. Phase 0: Definition of hospital evidence-based guidelines and a new workflow to optimize the process of ordering, dispensing, administering and documenting the SAP. Phase 1: We analysed 2059 elective surgical cases from January to June 2018 for three SAP parameters of appropriateness: indication, choice and dose. Phase 2: In July 2018, an audit was performed to analyse the results; we reviewed 1781 elective surgical procedures from July to December 2018 looking for the same three SAP appropriateness parameters. The comparative analysis between phases 1 and 2 demonstrated that the correct indication, the correct dose and the overall compliance significantly improved (p-value 0.00128, p-value < 2.2·1016 and p-value < 5.6·1012 respectively). Our prospective study demonstrates a model of successful antimicrobial stewardship intervention that improves appropriateness on SAP.
Infertility and ovarian cancer risk: Evidence from nine prospective cohort studies

Epidemiological studies have investigated the relationship between infertility and the risk of ovarian cancer (OC); however, the results have been inconsistent. We therefore conducted the first meta‐analysis to update and quantify the aforementioned association based on prospective cohort studies. Studies were identified by searching PubMed, EMBASE and Web of Science databases up to January 8, 2020. We extracted data from the studies and performed quality assessments. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using a random‐effects model. Publication bias, and subgroup, meta‐regression and sensitivity analyses were also conducted. Nine prospective cohort studies with a total of 10 383 OC cases and 6 278 830 participants were included in the present study. The summary RR of the association between infertility and the risk of OC was 1.51 (95% CI: 1.35‐1.69), with low heterogeneity. Positive associations were observed in most subgroup analyses stratified by predefined factors, including region, duration of follow‐up, study quality, causes of infertility, invasiveness of OC, infertility treatment status and adjustment of potential confounding parameters. No significant publication bias was detected. Our findings suggest that infertility in women were associated with an increased risk of OC.
MR-guided microwave ablation in hepatic malignancies: clinical experiences from 50 procedures

Abstract Purpose To investigate technical success, technique efficacy, safety and outcome of MR-guided microwave ablation (MWA) in hepatic malignancies. Material and methods In this prospective IRB-approved study, patients scheduled for percutaneous treatment of hepatic malignancies underwent MR-guided MWA in a closed-bore 1.5 T MR system. Technical success was assessed on post-procedural MR control imaging. Technique efficacy was evaluated 4 weeks after the procedure on multi-parametric MRI. Assessment of safety followed the Society of Interventional Radiology grading system. Kaplan–Meier survival estimates were calculated to evaluate overall survival (OS), time to local tumor progression (TLTP), and time to non-target progression (TNTP). Results Between 2015 and 2019, 47 patients (60.5 ± 12.2 years; 39 male) underwent 50 procedures for 58 hepatic tumors (21 hepatocellular carcinomas; 37 metastases). Mean target tumor size was 16 ± 7mm (range: 6–39 mm). Technical success and technique efficacy were 100% and 98%, respectively. Lesions were treated using 2.6 applicator positions (range: 1–6). Mean energy, ablation duration per tumor, and procedure duration were 43.2 ± 23.5 kJ, 26.7 ± 13.1 min and 211.2 ± 68.7 min, respectively. 10 minor (20%) and 3 major (6%) complications were observed. Median post-interventional hospital admission was 1 day (range: 1–19 days). Median OS was 41.6 (IQR: 26.4–) months. Local recurrence occurred after 4 procedures (8%) with TLTP ranging between 3.1 and 41.9 months. Non-target recurrence was observed in 64% of patients after a median TNTP of 13.8 (IQR 2.3–) months. Conclusion MR-guided MWA allows for safe and successful treatment of hepatic malignancies with a high technique efficacy however with relatively long procedure durations.
Antiproliferative Effects of Thymoquinone in MCF-7 Breast and HepG2 Liver Cancer Cells: Possible Role of Ceramide and ER Stress

Abstract We aimed to investigate the impact of thymoquinone (TQ), on sphingolipid metabolites, ER stress and apoptotic pathways in MCF-7 and HepG2 cancer cells. Antiproliferative effect was exerted in cancer cells via TQ incubation at different doses and durations. Cell viability was measured by MTT assay. Levels of sphingosine-1-phosphate (S1P), C16-C24 sphingomyelins (SM) and C16-C24 ceramides (CER) were determined by LC-MS/MS. Neutral sphingomyelinase (N-SMase) enzyme activity was measured by colorimetric assay and ceramide-1-phosphate (C1P) levels were determined by immunoassay. Nuclear factor kappa-b subunit 1 (NFκB1) and glucose-regulated protein 78-kd (GRP78) gene expressions were evaluated by quantitative PCR analysis, while NF-κB p65, GRP 78 and cleaved caspase-3 protein levels were assesed by immunofluorescence and western blot analysis. Incubation with TQ significantly decreased cell viability, S1P, C1P, NF-κB1 mRNA and NF-κB p65 protein levels in cancer cells compared to controls. A significant increase was observed in N-SMase activity, cellular levels of C16-C24 CERs and cleaved caspase-3 levels in cancer cells treated with TQ. GRP78 mRNA and protein levels also increased in cancer cells treated with TQ. In conclusion, TQ-induced ceramide accumulation and ER stress in conjunction with decreased S1P, C1P and NF-κB mediated cell survival may promote cancer cell death by triggering apoptosis.
Phenylalanine and Tyrosine as Exogenous Precursors of Wheat (Triticum aestivum L.) Secondary Metabolism through PAL-Associated Pathways

Reacting to environmental exposure, most higher plants activate secondary metabolic pathways, such as the metabolism of phenylpropanoids. This pathway results in the formation of lignin, one of the most important polymers of the plant cell, as well as a wide range of phenolic secondary metabolites. Aromatic amino acids, such as phenylalanine and tyrosine, largely stimulate this process, determining two ways of lignification in plant tissues, varying in their efficiency. The current study analyzed the effect of phenylalanine and tyrosine, involved in plant metabolism through the phenylalanine ammonia-lyase (PAL) pathway, on the synthesis and accumulation of phenolic compounds, as well as lignin by means of the expression of a number of genes responsible for its biosynthesis, based on the example of common wheat (Triticum aestivum L.).
Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G‐protein‐coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families.
Validation of self-reported height and weight in a large, nationwide cohort of U.S. adults

Background Height and weight are commonly used metrics in epidemiologic studies to calculate body mass index. Large cohort studies generally assess height and weight by self-report rather than by measurement. The aim of this study was to assess the validity of self-reported height and weight in the Cancer Prevention Study-3 (CPS-3), a large, nationwide cohort recruited by the American Cancer Society between 2006–2013. Methods In a subset of CPS-3 participants (n = 2,643), weight and height were assessed at the same time via self-report and in-person measurement. BMI was calculated and classified underweight (<18.5 kg/m2), normal (18.5-<25 kg/m2), overweight (25-<30 kg/m2), or obese (≥30 kg/m2). Self-reported and measured height, weight, and BMI were compared using mean differences and Bland-Altman plots and examined by sex, race/ethnicity, education, marital status, age group, and BMI category. Results Men and women slightly overreported height and underreported weight. BMI calculated from self-reported data was lower than for measured data for men and women. In analyses stratified by race/ethnicity, age, education, and marital status, older women and women with less than a college degree overreported height. Approximately 13% of men and 7% of women were misclassified into a lower self-reported BMI category, with misclassification of BMI being greatest in obese men and women. Conclusions Overall, height, weight, and BMI were well-reported, and this study further suggests that BMI computed from self-reported weight and height is a valid measure in men and women across different socio-demographic groups.