Miracle-dz/UniFAR-FTUs huggingface dataset:
Critical Questions Regarding Gadolinium Deposition in the Brain and Body After Injections of the Gadolinium-Based Contrast Agents, Safety, and Clinical Recommendations in Consideration of the EMA's Pharmacovigilance and Risk Assessment Committee Recommendation for Suspension of the Marketing Authori

Abstract For magnetic resonance, the established class of intravenous contrast media is the gadolinium-based contrast agents. In the 3 decades since initial approval, these have proven in general to be very safe for human administration. However, in 2006, a devastating late adverse reaction to administration of the less stable gadolinium-based contrast agents was identified, nephrogenic systemic fibrosis. The result of actions taken by the European Medicines Agency and the US Food and Drug Administration, stratifying the agents by risk and contraindicating specific agents in severe renal dysfunction, has led to no new cases being identified in North America or Europe. Subsequently, in 2014, long-term deposition in the brain of gadolinium was first shown, after administration of 2 nonionic linear chelates, gadodiamide, and gadopentetate dimeglumine. This has led to an intense focus on the question of in vivo distribution, possible dechelation, and subsequent deposition of gadolinium, together with substantial clarification of the phenomenon as well as stratification of the agents on this basis. This review focuses on 8 critical questions regarding gadolinium deposition in the brain and body, with the answers and discussion therein important for future regulatory decisions and clinical practice. It is now clear that dechelation of gadolinium occurs in vivo with the linear agents and is responsible for this phenomenon, with key experts in the field recommending, except where there is no suitable alternative, a shift in clinical practice from the linear to macrocyclic agents. In addition, on March 10, 2017, the Pharmacovigilance and Risk Assessment Committee of the European Medicines Agency recommended suspension of the marketing authorization for 4 linear gadolinium contrast agents—specifically Omniscan, Optimark, Magnevist, and MultiHance (gadodiamide, gadoversetamide, gadopentetate dimeglumine, and gadobenate dimeglumine)—for intravenous injection. Cited in the report was convincing evidence of gadolinium deposition in the brain months after injection of these linear agents. Primovist/Eovist (gadoxetic acid disodium) will remain available, being used at a lower dose for liver imaging, because it meets an important diagnostic need. In addition, a formulation of Magnevist for intra-articular injection will remain available because of its very low gadolinium concentration.
Evolution of the mass, size, and star formation rate in high redshift merging galaxies - MIRAGE – A new sample of simulations with detailed stellar feedback

We aim at addressing the questions related to galaxy mass assembly through major and minor wet merging processes in the redshift range 1<z<2. A consequent fraction of Milky Way like galaxies are thought to have undergone an unstable clumpy phase at this early stage. Using the adaptive mesh refinement code RAMSES, with a recent physically-motivated implementation of stellar feedback, we build the Merging and Isolated high-Redshift Adaptive mesh refinement Galaxies (MIRAGE) sample. It is composed of 20 mergers and 3 isolated idealized disks simulations with global physical properties in accordance with the 1<z<2 mass complete sample MASSIV. The numerical hydrodynamical resolution reaches 7 parsecs in the smallest Eulerian cells. Our simulations include: star formation, metal line cooling, metallicity advection, and a recent implementation of stellar feedback which encompasses OB-type stars radiative pressure, photo-ionization heating, and supernovae. The initial conditions are set to match the z~2 observations, thanks to a new public code DICE. The numerical resolution allows us to follow the formation and evolution of giant clumps formed in-situ from Jeans instabilities triggered by high initial gas fraction. The star formation history of isolated disks shows stochastic star formation rate, which proceeds from the complex behavior of the giant clumps. Our minor and major gas-rich merger simulations do not trigger starbursts, suggesting a saturation of the star formation in a turbulent and clumpy interstellar medium fed by substantial accretion from the circum-galactic medium. Our simulations are close to the normal regime of the disk-like star formation on a Schmidt-Kennicutt diagram. The mass-size relation and its rate of evolution matches observations, suggesting that the inside-out growth mechanisms of the stellar disk do not necessarily require to be achieved through a cold accretion.
Novel reproductive technologies to prevent mitochondrial disease

BACKGROUND The use of nuclear transfer (NT) has been proposed as a novel reproductive treatment to overcome the transmission of maternally-inherited mitochondrial DNA (mtDNA) mutations. Pathogenic mutations in mtDNA can cause a wide-spectrum of life-limiting disorders, collectively known as mtDNA disease, for which there are currently few effective treatments and no known cures. The many unique features of mtDNA make genetic counselling challenging for women harbouring pathogenic mtDNA mutations but reproductive options that involve medical intervention are available that will minimize the risk of mtDNA disease in their offspring. This includes PGD, which is currently offered as a clinical treatment but will not be suitable for all. The potential for NT to reduce transmission of mtDNA mutations has been demonstrated in both animal and human models, and has recently been clinically applied not only to prevent mtDNA disease but also for some infertility cases. In this review, we will interrogate the different NT techniques, including a discussion on the available safety and efficacy data of these technologies for mtDNA disease prevention. In addition, we appraise the evidence for the translational use of NT technologies in infertility. OBJECTIVE AND RATIONALE We propose to review the current scientific evidence regarding the clinical use of NT to prevent mitochondrial disease. SEARCH METHODS The scientific literature was investigated by searching PubMed database until Jan 2017. Relevant documents from Human Fertilisation and Embryology Authority as well as reports from both the scientific and popular media were also implemented. The above searches were based on the following key words: 'mitochondria', 'mitochondrial DNA'; 'mitochondrial DNA disease', 'fertility'; 'preimplantation genetic diagnosis', 'nuclear transfer', 'mitochondrial replacement' and 'mitochondrial donation'. OUTCOMES While NT techniques have been shown to effectively reduce the transmission of heteroplasmic mtDNA variants in animal models, and increasing evidence supports their use to prevent the transmission of human mtDNA disease, the need for robust, long-term evaluation is still warranted. Moreover, prenatal screening would still be strongly advocated in combination with the use of these IVF-based technologies. Scientific evidence to support the use of NT and other novel reproductive techniques for infertility is currently lacking. WIDER IMPLICATIONS It is mandatory that any new ART treatments are first adequately assessed in both animal and human models before the cautious implementation of these new therapeutic approaches is clinically undertaken. There is growing evidence to suggest that the translation of these innovative technologies into clinical practice should be cautiously adopted only in highly selected patients. Indeed, given the limited safety and efficacy data, close monitoring of any offspring remains paramount.
Risk for poor performance on a language screening measure for bilingual preschoolers and kindergarteners.

PURPOSE This study documents the risk for language impairment in Latino children who had different levels of exposure to English and Spanish. METHOD A total of 1,029 preschool- and kindergarten-age children were screened in the domains of semantics and morphosyntax in both Spanish and English. Parent report was used to document current exposure to and use of Spanish and English, as well as year of first exposure to English. Risk for language impairment was compared for language group, year of first English exposure, age, and mother's education. RESULTS While bilingual children's scores on each subtest were significantly lower compared to their functional monolingual peers, they were no more likely to fall in the at-risk range based on a combination of all 4 subtests. Maternal education and year of first English exposure were weakly associated with risk for language impairment but not with language group (via 5 levels of first and second language exposure). CONCLUSIONS Prevalence of risk for language impairment when both languages are tested is not related to language group.
Predictors of Micrometastases in Patients with Barcelona Clinic Liver Cancer Classification B Hepatocellular Carcinoma

Purpose Transarterial chemoembolization (TACE) is indicated for Barcelona Clinic Liver Cancer (BCLC) B hepatocellular carcinoma (HCC). Whether TACE provides any long-term survival benefits remains unclear. We aimed to investigate micrometastases predictors with which to identify patients who would benefit from surgical resection (SR). Materials and Methods First, we analyzed risk factors of micrometastases, microvascular invasion, and poor histologic grade in 38 patients with newly diagnosed resectable BCLC stage B HCC limited to one or two segments with well-preserved liver function and who underwent SR between January 2006 and December 2013. Second, we validated identified risk factors in 54 newly diagnosed resectable BCLC B HCC patients with well-preserved liver function who underwent TACE during the same period to determine their influence on survival. Results Risk factors of micrometastases in SR patients were α-fetoprotein (AFP) ≥110 [hazard ratio (HR)=5.166; 95% confidence interval (CI), 1.031–25.897; p=0.046] and prothrombin induced by vitamin K absence-II (PIVKA-II) ≥800 (HR=5.166; 95% CI, 1.031–25.897; p=0.046). The cumulative probability of tumor recurrence (p=0.009) after SR differed according to levels of AFP and PIVKA-II. After validation of these risk factors in the TACE group, patients with SR and AFP <110 and PIVKA-II <800 had superior survival outcomes than other patients (HR=0.116; 95% CI, 0.027–0.497; p=0.004). Conclusion AFP and PIVKA-II levels predict micrometastases and survival. Therefore, they should be considered when selecting SR for BCLC B HCC.
Echocardiographic reference ranges for normal left ventricular 2D strain: results from the EACVI NORRE study

Aims To obtain the normal ranges for 2D echocardiographic (2DE) measurements of left ventricular (LV) strain from a large group of healthy volunteers accounting for age and gender. Methods and results A total of 549 (mean age: 45.6 ± 13.3 years) healthy subjects were enrolled at 22 collaborating institutions of the Normal Reference Ranges for Echocardiography (NORRE) study. 2DE data sets have been analysed with a vendor-independent software package allowing homogeneous measurements irrespective of the echocardiographic equipment used to acquire the data sets. The lowest expected values of LV strains and twist calculated as ± 1.96 standard deviations from the mean were -16.7% in men and -17.8% in women for longitudinal strain, -22.3% and -23.6% for circumferential strain, 20.6% and 21.5% for radial strain, and 2.2 degrees and 1.9 degrees for twist, respectively. In multivariable analysis, longitudinal strain decreased with age whereas the opposite occurred with circumferential and radial strain. Male gender was associated with lower strain for longitudinal, circumferential, and radial strain. Inter-vendor differences were observed for circumferential and radial strain despite the use of vendor-independent software. Importantly, no intervendor differences were noted in longitudinal strain. Conclusion The NORRE study provides contemporary, applicable 2D echocardiographic reference ranges for LV longitudinal, radial, and circumferential strain. Our data highlight the importance of age- and gender-speciﬁc reference values for LV strain.
What Are the Characteristics of Primary Angle Closure With Longer Axial Length?

Purpose To compare biometric parameters between primary angle closure with longer axial length (AL) and those with medium or shorter AL. Methods We prospectively recruited 138 primary angle-closure patients. Low-coherence interferometry and ultrasound biomicroscopy examinations were performed before laser peripheral iridotomy and pilocarpine treatment. AL was categorized as shorter (<22.5 mm), medium (≥22.5 to <23.5 mm), or longer (≥23.5 mm). Anterior chamber depth and width (ACD and ACW), lens vault (LV), anterior vault (AV), relative AV (AV/AL), relative lens position (RLP, [ACD + 1/2 lens thickness]/AL), trabecular-ciliary angle (TCA), keratometry, and other biometric parameters were compared among different AL groups. Results Among 138 angle-closure patients, 15 (10.9%) patients had longer ALs, of which 11 (73.3%) were male. These angle-closure eyes with longer AL had flatter cornea (P = 0.006 and 0.022 for flat and steep keratometry) and larger ACW (P = 0.006), but smaller RLP (P = 0.019) than those with medium AL; similarly, they had flatter cornea (P < 0.001 for both flat and steep keratometry), and larger ACW (P < 0.001), AV (P = 0.004), and TCA (P = 0.024), but smaller relative AV (P = 0.040) and RLP (P = 0.005) than those with shorter AL. No significant differences were found in the other parameters. Conclusions Primary angle closure with longer AL was uncommon. Causes of angle closure in these atypical patients were manifold. These patients were predominantly male; they had smaller relative dimension of the anterior segment, flatter cornea, and more anterior RLP and less anteriorly rotated ciliary body compared with those angle-closure patients with relatively shorter AL.
Smoldyn: particle‐based simulation with rule‐based modeling, improved molecular interaction and a library interface

Motivation: Smoldyn is a spatial and stochastic biochemical simulator. It treats each molecule of interest as an individual particle in continuous space, simulating molecular diffusion, molecule‐membrane interactions and chemical reactions, all with good accuracy. This article presents several new features. Results: Smoldyn now supports two types of rule‐based modeling. These are a wildcard method, which is very convenient, and the BioNetGen package with extensions for spatial simulation, which is better for complicated models. Smoldyn also includes new algorithms for simulating the diffusion of surface‐bound molecules and molecules with excluded volume. Both are exact in the limit of short time steps and reasonably good with longer steps. In addition, Smoldyn supports single‐molecule tracking simulations. Finally, the Smoldyn source code can be accessed through a C/C ++ language library interface. Availability and Implementation: Smoldyn software, documentation, code, and examples are at http://www.smoldyn. org. Contact: steven.s. andrews@gmail.com
Incidence of Chronic Hepatitis B and C Virus Infection in Damietta, Egypt

We investigated the incidence of Hepatitis B (HBV) and Hepatitis C (HCV) virus infection among patients with liver disease in Damietta Egypt from 2003 to 2005. Of the 146 liver patients studied, 25.3% had HCV and 8.9% had HBV. The incidence of HBV and HCV infection was greater in males than females, especially for HCV. There was a sharp increase in the number of cases of HCV in liver patients in 2005 compared with 2003 (2.2-fold higher in men and 2.3-fold higher in women). Over the years, the rate of HBV and HCV infection was higher in male than female patients (69.2 % versus 30.7% for HBV and 67.5% versus 32.4 % for HCV Alanine Amino-Transferase (ALT) α -glutathione-s- transferase were used a biomarker of Hepatocellular damage. IgG anti-HCV is related to the elevation of ALT levels and can be used as a serologic marker to indicate the presence of active HCV induced liver damage.
Exploiting mAb structure characteristics for a directed QbD implementation in early process development

Abstract In today’s biopharmaceutical industries, the lead time to develop and produce a new monoclonal antibody takes years before it can be launched commercially. The reasons lie in the complexity of the monoclonal antibodies and the need for high product quality to ensure clinical safety which has a significant impact on the process development time. Frameworks such as quality by design are becoming widely used by the pharmaceutical industries as they introduce a systematic approach for building quality into the product. However, full implementation of quality by design has still not been achieved due to attrition mainly from limited risk assessment of product properties as well as the large number of process factors affecting product quality that needs to be investigated during the process development. This has introduced a need for better methods and tools that can be used for early risk assessment and predictions of critical product properties and process factors to enhance process development and reduce costs. In this review, we investigate how the quantitative structure–activity relationships framework can be applied to an existing process development framework such as quality by design in order to increase product understanding based on the protein structure of monoclonal antibodies. Compared to quality by design, where the effect of process parameters on the drug product are explored, quantitative structure–activity relationships gives a reversed perspective which investigates how the protein structure can affect the performance in different unit operations. This provides valuable information that can be used during the early process development of new drug products where limited process understanding is available. Thus, quantitative structure–activity relationships methodology is explored and explained in detail and we investigate the means of directly linking the structural properties of monoclonal antibodies to process data. The resulting information as a decision tool can help to enhance the risk assessment to better aid process development and thereby overcome some of the limitations and challenges present in QbD implementation today.
The Use of Remotely Controlled Mandibular Positioner as a Predictive Screening Tool for Mandibular Advancement Device Therapy in Patients with Obstructive Sleep Apnea through Single-Night Progressive Titration of the Mandible: A Systematic Review.

STUDY OBJECTIVES To perform a review of the current evidence regarding the use of a remotely controlled mandibular positioner (RCMP) and to analyze the efficacy of RCMP as a predictive selection tool in the treatment of obstructive sleep apnea (OSA) with oral appliances that protrude the mandible (OAm), exclusively relying on single-night RCMP titration. METHODS An extensive literature search is performed through PubMed.com, Thecochranelibrary.com (CENTRAL only), Embase.com, and recent conference meeting abstracts in the field. RESULTS A total of 254 OSA patients from four full-text articles and 5 conference meeting abstracts contribute data to the review. Criteria for successful RCMP test and success with OAm differed between studies. Study populations were not fully comparable due to range-difference in baseline apneahypopnea index (AHI). However, in all studies elimination of airway obstruction events during sleep by RCMP titration predicted OAm therapy success by the determination of the most effective target protrusive position (ETPP). A statistically significant association is found between mean AHI predicted outcome with RCMP and treatment outcome with OAm on polysomnographic or portable sleep monitoring evaluation (p < 0.05). CONCLUSIONS The existing evidence regarding the use of RCMP in patients with OSA indicates that it might be possible to protrude the mandible progressively during sleep under poly(somno)graphic observation by RCMP until respiratory events are eliminated without disturbing sleep or arousing the patient. ETPP as measured by the use of RCMP was significantly associated with success of OAm therapy in the reported studies. RCMP might be a promising instrument for predicting OAm treatment outcome and targeting the degree of mandibular advancement needed.
Characterization and Optimal Management of High-risk Pancreatic Anastomoses During Pancreatoduodenectomy

Objective: The aim of this study was to identify the optimal fistula mitigation strategy following pancreaticoduodenectomy. Background: The utility of technical strategies to prevent clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreatoduodenectomy (PD) may vary by the circumstances of the anastomosis. The Fistula Risk Score (FRS) identifies a distinct high-risk cohort (FRS 7 to 10) that demonstrates substantially worse clinical outcomes. The value of various fistula mitigation strategies in these particular high-stakes cases has not been previously explored. Methods: This multinational study included 5323 PDs performed by 62 surgeons at 17 institutions. Mitigation strategies, including both technique related (ie, pancreatogastrostomy reconstruction; dunking; tissue patches) and the use of adjuvant strategies (ie, intraperitoneal drains; anastomotic stents; prophylactic octreotide; tissue sealants), were evaluated using multivariable regression analysis and propensity score matching. Results: A total of 522 (9.8%) PDs met high-risk FRS criteria, with an observed CR-POPF rate of 29.1%. Pancreatogastrostomy, prophylactic octreotide, and omission of externalized stents were each associated with an increased rate of CR-POPF (all P < 0.001). In a multivariable model accounting for patient, surgeon, and institutional characteristics, the use of external stents [odds ratio (OR) 0.45, 95% confidence interval (95% CI) 0.25–0.81] and the omission of prophylactic octreotide (OR 0.49, 95% CI 0.30–0.78) were independently associated with decreased CR-POPF occurrence. In the propensity score matched cohort, an “optimal” mitigation strategy (ie, externalized stent and no prophylactic octreotide) was associated with a reduced rate of CR-POPF (13.2% vs 33.5%, P < 0.001). Conclusions: The scenarios identified by the high-risk FRS zone represent challenging anastomoses associated with markedly elevated rates of fistula. Externalized stents and omission of prophylactic octreotide, in the setting of intraperitoneal drainage and pancreaticojejunostomy reconstruction, provides optimal outcomes.