Miracle-dz/UniFAR-FTUs huggingface dataset:
Statistical Modelling of Mutations in Cancer Genomes

This PhD dissertation presents my work in statistical modelling of mutations in cancer genomes. In accordance with GSST rules, parts of this thesis were also used in the progress report for the qualifying examination. Cancer is one of the major health problems to human society nowadays. With a rapidly aging population, cancer is becoming one of the leading causes of death all over the world. Many studies have shown that cancer is primarily a genetic disease. Thus, the key to understand cancer is to study the genomic changes during cancer development. Thanks to the next generation sequencing (NGS) technology, we are now able to collect whole-genome DNA sequencing data quickly at a low cost. The increasing availability of whole-genome sequencing data from cancer cells, paired with the data obtained from normal tissues, provides opportunities to study the somatic mutations aroused during cancer process. The neutral somatic mutational process in the cancer genome is very complex. The mutation rate differs between patients, cancer types and also along the genome. In order to identify potential cancer drivers, it is crucial to model the neutral mutational process in the cancer genome. In the first part of this thesis, I will present my work of a multinomial logistic regression framework to model the somatic mutation rates in cancer genomes. Many studies have shown that cancer results from both external factors (smoking, radiation, UV lights etc) and internal factors (inherited mutations, immune conditions etc). Both external and internal factors trigger mutation processes and leave traits in the DNA sequence, e.g., mutational signatures. In the second part of this thesis, I will present my work to identify cancer signatures using non-negative matrix factorization (NMF).
Effects of Pridopidine on Functional Capacity in Early-Stage Participants from the PRIDE-HD Study

Background: No pharmacological treatment has been demonstrated to provide a functional benefit for persons with Huntington’s disease (HD). Pridopidine is a sigma-1-receptor agonist shown to have beneficial effects in preclinical models of HD. Objective: To further explore the effect of pridopidine on Total Functional Capacity (TFC) in the recent double-blind, placebo-controlled PRIDE-HD study. Methods: We performed post-hoc analyses to evaluate the effect of pridopidine on TFC at 26 and 52 weeks. Participants were stratified according to baseline TFC score and analyzed using repeated measures (MMRM) and multiple imputation assuming missing not-at-random (MNAR) and worst-case scenarios. Results: The pridopidine 45 mg bid dosage demonstrated a beneficial effect on TFC for the entire population at week 52 of 0.87 (nominal p = 0.0032). The effect was more pronounced for early HD participants (HD1/HD2, TFC = 7–13), with a change from placebo of 1.16 (nominal p = 0.0003). This effect remained nominally significant using multiple imputation with missing not at random assumption as a sensitivity analysis. Responder analyses showed pridopidine 45 mg bid reduced the probability of TFC decline in early HD patients at Week 52 (nominal p = 0.02). Conclusion: Pridopidine 45 mg bid results in a nominally significant reduction in TFC decline at 52 weeks compared to placebo, particularly in patients with early-stage HD.
Here's how compressibility and temperature affect bottom-hole mud pressure

This study presents graphical results showing how bottom-hole pressures and mud weights vary with depth for various oil and water muds and different temperature profiles. The model can be adjusted to handle not only constant temperature gradients, but any arbitrary temperature profile. In particular, a wellbore thermal simulator code has been used to generate circulating mud temperature profiles. Results from this model have been used to predict hydrostatic bottom-hole pressures for muds containing various amounts of oil, water, chlorides, and solids. 11 refs.
Growth, body composition, and endocrine issues in Williams syndrome.

PURPOSE OF REVIEW Williams syndrome is a multisystem disorder caused by a microdeletion on chromosome 7q. Throughout infancy, childhood, and adulthood, abnormalities in body composition and in multiple endocrine axes may arise for individuals with Williams syndrome. This review describes the current literature regarding growth, body composition, and endocrine issues in Williams syndrome with recommendations for surveillance and management by the endocrinologist, geneticist, or primary care physician. RECENT FINDINGS In addition to known abnormalities in stature, calcium metabolism, and thyroid function, individuals with Williams syndrome are increasingly recognized to have low bone mineral density, increased body fat, and decreased muscle mass. Furthermore, recent literature identifies a high prevalence of diabetes and obesity starting in adolescence, and, less commonly, a lipedema phenotype in both male and female individuals. Understanding of the mechanisms by which haploinsufficiency of genes in the Williams syndrome-deleted region contributes to the multisystem phenotype of Williams syndrome continues to evolve. SUMMARY Multiple abnormalities in growth, body composition, and endocrine axes may manifest in individuals with Williams syndrome. Individuals with Williams syndrome should have routine surveillance for these issues in either the primary care setting or by an endocrinologist or geneticist.
Neuromorphic Engineering: From Biological to Spike‐Based Hardware Nervous Systems

The human brain is a sophisticated, high‐performance biocomputer that processes multiple complex tasks in parallel with high efficiency and remarkably low power consumption. Scientists have long been pursuing an artificial intelligence (AI) that can rival the human brain. Spiking neural networks based on neuromorphic computing platforms simulate the architecture and information processing of the intelligent brain, providing new insights for building AIs. The rapid development of materials engineering, device physics, chip integration, and neuroscience has led to exciting progress in neuromorphic computing with the goal of overcoming the von Neumann bottleneck. Herein, fundamental knowledge related to the structures and working principles of neurons and synapses of the biological nervous system is reviewed. An overview is then provided on the development of neuromorphic hardware systems, from artificial synapses and neurons to spike‐based neuromorphic computing platforms. It is hoped that this review will shed new light on the evolution of brain‐like computing.
Epigenetic regulation of replication origin assembly: A role for histone H1 and chromatin remodeling factors

During early embryonic development in several metazoans, accurate DNA replication is ensured by high number of replication origins. This guarantees rapid genome duplication coordinated with fast cell divisions. In Xenopus laevis embryos this program switches to one with a lower number of origins at a developmental stage known as mid‐blastula transition (MBT) when cell cycle length increases and gene transcription starts. Consistent with this regulation, somatic nuclei replicate poorly when transferred to eggs, suggesting the existence of an epigenetic memory suppressing replication assembly origins at all available sites. Recently, it was shown that histone H1 imposes a non‐permissive chromatin configuration preventing replication origin assembly on somatic nuclei. This somatic state can be erased by SSRP1, a subunit of the FACT complex. Here, we further develop the hypothesis that this novel form of epigenetic memory might impact on different areas of vertebrate biology going from nuclear reprogramming to cancer development.
Subcutaneous Sarilumab in Patients With Rheumatoid Arthritis who Previously Received Subcutaneous Sarilumab or Intravenous Tocilizumab: An Open‐Label Extension of a Randomized Clinical Trial

This post hoc analysis evaluated the safety and efficacy of open‐label sarilumab in patients with rheumatoid arthritis (RA) who completed the phase III double‐blind ASCERTAIN study (NCT01768572) and switched from intravenous (IV) tocilizumab to subcutaneous (SC) sarilumab, or who continued SC sarilumab in the open‐label extension (OLE) study EXTEND (NCT01146652).
Determination of total flavonoids content in Hemiphragma heterophyllum Wall.

[Objective] To detect the total flavonoids in Hemiphragma heterophyllum Wall. [Method] Total flavonoids were extracted from H.heterophyllum by ultrasound assisted method.With rutin as the reference substance,relative percentage content was detected by UV-Vis spectrophotometry at 510 nm. [Result] Rutin reference substance showed good linear relationship within the range of 0 and 0.22 mg/ml(R2=0.999 7);and RSD value was 0.425%. The mean value of total flavonoids in H.heterophyllum was 9.335%. [Conclusion] Detecting the total flavonoids content in H.heterophyllum by UV-Vis spectrophotometry was simple and reliable,which provided scientific references for the development of medicinal value.
Suboptimal Outcome with Endovascular Thrombectomy: Will Acute Stroke Unit Help?

ABSTRACT: Endovascular thrombectomy (EVT) has revolutionized the care of patients with acute ischemic stroke. The efficacy of EVT is dependent on the optimal setup of a stroke system. Extrapolating the results of clinical trials to any individual stroke center should be done with caution. This is more important for centers with suboptimal stroke systems of care. The Canadian registry has helped highlight the suboptimal outcome post EVT in Manitoba. This could potentially be optimized with the addition of an acute stroke unit in the near future. Our study will serve as a baseline for future improvement in acute stroke care.
Progress report on new antiepileptic drugs: A summary of the Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV). II. Drugs in more advanced clinical development

The Fifteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XV) was held as a fully virtual conference from July 27 to July 30, 2020 for the sessions on drugs, and on August 3, 2020 for the sessions on devices. A total of 534 delegates from 63 countries attended lectures and interactive discussions, representing a broad range of disciplines from basic science, clinical research, and clinical care. This progress report provides summaries of recent findings on investigational compounds for which preclinical data as well as data from patient studies were presented. The report includes the following five compounds: anakinra, cenobamate, CVL‐865, fenfluramine, and ganaxolone, all with novel modes of action compared to more established antiepileptic drugs. Some of these compounds demonstrated promising results in placebo‐controlled phase 3 trials, and two have recently received approval from the US Food and Drug Administration (FDA). These include cenobamate, which was approved by the FDA on November 21, 2019 for the treatment of partial onset (focal) seizures in adults, and fenfluramine oral solution, which was approved by the FDA on June 25, 2020 for the treatment of seizures associated with Dravet syndrome in patients 2 years and older.
Umbrella systematic review of systematic reviews and meta-analyses on comorbid physical conditions in people with autism spectrum disorder

Background Comorbid physical conditions may be more common in people with autism spectrum disorder (ASD) than other people. Aims To identify what is and what is not known about comorbid physical conditions in people with ASD. Method We undertook an umbrella systematic review of systematic reviews and meta-analyses on comorbid physical conditions in people with ASD. Five databases were searched. There were strict inclusion/exclusion criteria. We undertook double reviewing for eligibility, systematic data extraction and quality assessment. Prospective PROSPERO registration: CRD42015020896. Results In total, 24 of 5552 retrieved articles were included, 15 on children, 1 on adults, and 8 both on children and adults. Although the quality of included reviews was good, most reported several limitations in the studies they included and considerable heterogeneity. Comorbid physical conditions are common, and some are more prevalent than in the general population: sleep problems, epilepsy, sensory impairments, atopy, autoimmune disorders and obesity. Asthma is not. However, there are substantial gaps in the evidence base. Fewer studies have been undertaken on other conditions and some findings are inconsistent. Conclusions Comorbid physical conditions occur more commonly in people with ASD, but the evidence base is slim and more research is needed. Some comorbidities compound care if clinicians are unaware, for example sensory impairments, given the communication needs of people with ASD. Others, such as obesity, can lead to an array of other conditions, disadvantages and early mortality. It is essential that potentially modifiable physical conditions are identified to ensure people with ASD achieve their best outcomes. Heightening clinicians’ awareness is important to aid in assessments and differential diagnoses, and to improve healthcare.
-Heart Failure with Preserved Ejection Fraction Diminishes Peripheral Hemodynamics and Accelerates Exercise-Induced Neuromuscular Fatigue.

This study investigated the impact of heart failure with a preserved ejection fraction (HFpEF) on neuromuscular fatigue and peripheral hemodynamics during small muscle mass exercise not limited by cardiac output. Eight HFpEF patients (ejection-fraction: 61±2%, NYHA II-III) and eight healthy-controls performed dynamic single-leg knee-extension exercise [80% peak workload] to task-failure and maximal intermittent isometric quadriceps contractions (8×15-s, 20-s rest). Controls repeated knee-extension at the same absolute workload as the HFpEF. During knee-extension, leg blood flow was quantified using Doppler ultrasound. Pre- to post-exercise changes in quadriceps twitch-torque (ΔQtw, peripheral fatigue), voluntary-activation (ΔVA, central fatigue), and corticospinal excitability were quantified. At the same relative intensity, HFpEF (24±5W) and controls (42±6W) had a similar time to task-failure (~10min), ΔQtw (~50%), and ΔVA (~6%) (P>0.3). This resulted in a greater exercise-induced change in neuromuscular function per unit work in HFpEF, which was significantly correlated with a slower leg blood flow response time (r=0.77). Knee-extension exercise at the same absolute workload resulted in a ~40% lower leg blood flow and greater ΔQtw (56±15 vs 11±10%) and ΔVA (5±3 vs 0±2%) in HFpEF than controls (P<0.05). Corticospinal excitability remained unaltered during exercise in both groups. Finally, despite a similar ΔVA, ΔQtw was larger in HFpEF compared to controls during isometric exercise (-49±9 vs -23±2%, P<0.05). In conclusion, HFpEF are characterized by a greater susceptibility to neuromuscular fatigue during exercise not limited by cardiac output. The patients' compromised peripheral hemodynamic response to exercise likely accounts, at least partly, for the attenuated fatigue resistance in this population.
Saccades along spatial neural circuit discontinuities

Saccades are realized by six extraocular muscles that define the final reference frame for eyeball rotations. However, upstream of the nuclei innervating the eye muscles, eye movement commands are represented in two-dimensional retinocentric coordinates, as is the case in the superior colliculus (SC). In such spatial coordinates, the horizontal and vertical visual field meridians, relative to the line of sight, are associated with neural tissue discontinuities due to routing of binocular retinal outputs when forming retinotopic sensory-motor maps. At the level of the SC, a functional discontinuity along the horizontal meridian was additionally discovered, beyond the structural vertical discontinuity associated with hemifield lateralization. How do such neural circuit discontinuities influence purely cardinal saccades? Using thousands of saccades from 3 rhesus macaque monkeys and 14 human subjects, we show how the likelihood of purely horizontal or vertical saccades is infinitesimally small, nulling a discontinuity problem. This does not mean that saccades are sloppy. On the contrary, saccades exhibit remarkable direction and amplitude corrections to account for small initial eye position deviations due to fixational variability: “purely” cardinal saccades can deviate, with an orthogonal component of as little as 0.03 deg, to correct for tiny target position deviations from initial eye position. In humans, probing perceptual target localization additionally revealed that saccades show different biases from perception when targets deviate slightly from purely cardinal directions. These results demonstrate a new functional role for fixational eye movements in visually-guided behavior, and they motivate further neurophysiological investigations of saccade trajectory control in the brainstem. New and Noteworthy Purely cardinal saccades are often characterized as being straight. We show how a small amount of curvature is inevitable, alleviating an implementational problem of dealing with neural circuit discontinuities in the representations of the visual meridians. The small curvature functionally corrects for minute variability in initial eye position due to fixational eye movements. Saccades are far from sloppy; they deviate by as little as <1% of the total vector size to adjust their landing position.
Factors associated with the absence of cocaine craving in treatment-seeking individuals during inpatient cocaine detoxification

ABSTRACT Background Anecdotal evidence suggests a substantial proportion of individuals with cocaine use disorder do not report craving during inpatient detoxification. Objective To examine prevalence and clinical correlates of consistent absence of cocaine craving among inpatients during detoxification. We hypothesized that craving absence would be associated with less severity of cocaine use, depression, and anxiety. Alternative explanations were also explored. Methods Craving absence (i.e., non-cravers) was defined as a daily score of zero across two separate craving visual analogue scales in each of the inpatient days. Participants scoring ≥1 on ≥1 day were considered cravers. Severity of cocaine use disorder as well as in-treatment depression and anxiety were assessed. Alternative contributors included presence of cocaine and other substances in urine at admission, in-treatment prescription of psychotropic medications, treatment motivation, executive function, interoception, and social desirability. Results Eighty-seven participants (78.2% males) met criteria as either non-cravers (n = 29; 33.3%) or cravers (n = 58; 66.7%). Mean length of admission in non-cravers and cravers was, respectively, 10.83 and 13.16 days. Binary logistic regression model showed that non-cravers scored significantly lower than cravers on cocaine use during last month before treatment (OR, 95% CI; 0.902, 0.839–0.970), in-treatment depression (OR, 95% CI; 0.794, 0.659–0.956), and in-treatment prescribing of antipsychotics (OR, 95% CI; 0.109, 0.014–0.823). Model prediction accuracy was 88.9%. Conclusions One in three patients undergoing inpatient detoxification experienced absence of craving, linked to less pretreatment cocaine use, better mood, and decreased administration of antipsychotics. Findings may inform pretreatment strategies and improve treatment cost-effectiveness.
The first 6 months of HIV-SARS-CoV-2 coinfection: outcomes for 6947 individuals

Purpose of review The aim of this review is to summarize the clinical outcomes of people living with HIV (PWH) coinfected with SARS-CoV-2 during the first six months of the COVID-19 pandemic. Recent findings Several reports from single centers have described increased, decreased, or no difference in outcomes of COVID-19 in PWH. These studies have come from a range of locations, each with different underlying HIV prevalence and access to various antiretroviral therapy (ART) regimens. Differences in healthcare quality, access and policies may also affect reported outcomes in PWH across different locations, making interpretation of results more challenging. Meanwhile, different components of ART have been proposed to protect against SARS-CoV-2 acquisition or disease progression. Summary The current review considers 6 months of data across geographic regions with a range of healthcare quality and access and ART regimens to generate a wider view of COVID-19 outcomes in PWH. Taken together, these studies indicate that HIV infection may be associated with increased risk of COVID-19 diagnosis, but comorbidities appear to play a larger role than HIV-specific variables in outcomes of COVID-19 among PWH. ART does not appear to protect from COVID-19 disease acquisition, progression or death.
Assessment of haemostasis and impact of fibrinogen supplementation on clot properties using global haemostasis assays in patients on chronic dialysis

Background Multifactorial haemostasis disorders are typical of patients with end-stage renal disease (ESRD) on chronic haemodialysis (HD). Thromboelastometry and impedance aggregometry allow for a comprehensive assessment of clot formation, lysis, and platelet (PLT) function. This study aims to determine the haemostatic profile in a group of patients with ESRD on chronic, interrupted dialysis, especially in terms of PLT function and the impact of in vitro fibrinogen concentrate supplementation on clot properties. Methods A total of 22 patients on chronic HD and 22 healthy controls (HC) were enrolled in the prospective study with a control group. Global haemostasis assays (GHA) were used to describe the haemostasis profile and to assess the effect of fibrinogen concentrate supplementation on improving clot quality. Results Despite the lack of considerable differences in the number of PLTs, there was a significantly lower potential of PLT aggregation in the HD group (922 ±163 AU*min). A higher concentration of fibrinogen was also observed in this group which presented considerably higher maximum clot firmness (MCF) FIBTEM (22 ±5.3 mm). Clotting time (CT) EXTEM was also prolonged (72 ±23 s). No hyperfibrinolysis was reported. In vitro fibrinogen concentrate supplementation resulted in significant improvement in MCF FIBTEM (30 mm vs. 22 mm; P < 0.001). However, it also led to a deterioration in PLT aggregation as assessed by TRAPtest. Conclusions The haemostasis profile of ESRD patients demonstrates a limited potential of PLT aggregation, with no improvement after fibrinogen addition.
Enhancing the Performance of Organic Solar Cells by Prolonging the Lifetime of Photogenerated Excitons

Exciton lifetime (τ) is crucial for the migration of excitons to donor/acceptor interfaces for subsequent charge separation in organic solar cells (OSCs); however, obvious prolongation of τ has rarely been achieved. Here, by introducing a solid additive 9‐fluorenone‐1‐carboxylic acid (FCA) into the active layer, which comprises a nonfullerene acceptor, 3,9‐bis(2‐methylene‐((3‐(1,1‐dicyanomethylene)‐6/7‐methyl)‐indanone))‐5,5,11,11‐tetrakis(4‐hexylphenyl)‐dithieno[2,3‐d:2′,3′‐d′]‐s‐indaceno[1,2‐b:5,6‐b′]dithiophene (IT‐M), τ is substantially prolonged from 491 to 928 ps, together with obvious increases in fluorescence intensity and quantum yield. Time‐resolved transient infrared spectra indicate the presence of an intermolecular vibrational coupling between the electronic excited state of IT‐M and the electronic ground state of FCA, which is first observed here and which can suppress the internal conversion process. IT‐M‐based OSCs display an improved short‐circuit current and fill factor after the addition of FCA. Thus, the power conversion efficiency is increased, particularly for devices with a large donor/acceptor ratio of 1:4, whose efficiency is increased by 56%. This study describes a novel method, which is also applicable to other nonfullerene acceptors, for further improving the performance of OSCs without affecting their morphology and light absorption properties.