bluuebunny/crossref_metadata_2025_split huggingface dataset:
Monogenic, polygenic, and oligogenic familial hypercholesterolemia
Authors: Tada Hayato , Nohara Atsushi , Kawashiri Masa-aki 
Published: November 2019

Purpose of review
Familial hypercholesterolemia has long been considered a monogenic disorder. However, recent advances in genetic analyses have revealed various forms of this disorder, including polygenic and oligogenic familial hypercholesterolemia. We review the current understanding of the genetic background of this disease.

Recent findings
Mutations in multiple alleles responsible for low-density lipoprotein regulation could contribute to the development of familial hypercholesterolemia, especially among patients with mutation-negative familial hypercholesterolemia. In oligogenic familial hypercholesterolemia, multiple rare genetic variations contributed to more severe familial hypercholesterolemia.

Summary
Familial hypercholesterolemia is a relatively common ‘genetic’ disorder associated with an extremely high risk of developing coronary artery disease. In addition to monogenic familial hypercholesterolemia, different types of familial hypercholesterolemia, including polygenic and oligogenic familial hypercholesterolemia, exist and have varying degrees of severity. Clinical and genetic assessments for familial hypercholesterolemia and clinical risk stratifications should be performed for accurate diagnosis, as should cascade screening and risk stratification for the offspring of affected patients.
The Relationship Between Prematurity, Method of Delivery, and Functional Gastrointestinal Disorders in Children
Authors: Velasco‐Benitez Carlos A. , Axelrod Cara H. , Gutierrez Susan , Saps Miguel 
Published: November 2019

ABSTRACTObjective:The pathogenesis of functional gastrointestinal disorders (FGIDs) remains unknown. Early life events including method of delivery and length of gestation may be risk factors for FGIDs. Data from studies on early life events and the development of FGIDs are scarce and contradictory.Objective:The aim of the study was to assess the association between mode of delivery, length of gestation, and FGIDs in children. We hypothesized that delivery via Cesarean section and prematurity would be associated with an increased prevalence of FGIDs.Methods:Questionnaires were mailed to families from 3 cities in Colombia. Parents provided information on mode of delivery, demographics, and medical history. School children completed the Spanish version of the Questionnaire of Pediatric Gastrointestinal Symptoms Rome IV. Categorical data were analyzed using Fisher exact tests. Calculation of odds ratio with 95% confidence interval was performed.Results:A total of 1497 children (535 preadolescents 10–12 years, 962 adolescents 13–18 years) participated. For participants born via Cesarean delivery, there was no significant increase in prevalence of any of the Rome IV FGIDs compared with vaginal delivery. There was a significant association between prematurity and FGIDs for those born between 28 and 32 weeks (confidence interval 0.99–3.37; P = 0.03). In this group, functional nausea was the only category of FGID to reach significance (0.16–112.23) (P = 0.02). However, statistical significance was lost when gestational ages were grouped together with multivariate analysis.Conclusions:Our findings provide evidence that Cesarean delivery and prematurity are not risk factors for the development of FGIDs. Future studies are indicated to further evaluate the relationship between early life events and FGIDs.
Liver Failure Among Young Saudi Infants
Authors: Lone Khurram Sadiq , AlSaleem Badr , Asery Ali , Bashir Muhammed Salman , Al‐Hussaini Abdulrahman 
Published: November 2019

ABSTRACTObjectives:The published data on early infantile liver failure (EILF) are scarce and limited to Caucasians. We conducted this study to describe the etiology and outcome of EILF among Arabs and identify prognostic factors.Methods:We retrospectively reviewed our database of 524 infants presenting with liver impairment from 2008 to 2018, and identified cases of EILF defined as presence of biochemical pattern of liver disease and INR ≥2 (unresponsive to vitamin K) with onset before 3 months of life. Primary outcomes included death or liver transplantation (LT) (poor outcome group) and survival with native liver (good outcome group).Results:Forty‐two cases of EILF (22 girls) were identified (8%). The etiology was indeterminate in 14 (33.3%) and established in 27 (64.3%): galactosemia (7 cases, 16.6%), tyrosinemia (5, 12%), neonatal hemochromatosis (NH), and hemophagocytic lymphohistiocytosis (HLH) (4 each, 9.5%]) mitochondrial hepatopathy (3, 7%), and miscellaneous (5, 12%). LF resolved in 15 cases (35.7%), either spontaneously or in response to specific therapy, 23 (54.7%) died, and 4 underwent LT (9.5%). ROC analysis for the best cut‐off value of serum total bilirubin for prediction of study outcomes was 120 μmol/L (sensitivity 81.5%, specificity 80%). Among the diagnostic groups, galactosemia and tyrosinemia predicted good outcome, whereas the idiopathic diagnosis predicted poor outcome (OR = 13).Conclusions:Similar to Western countries, galactosemia, tyrosinemia, NH, HLH, and mitochondrial hepatopathy are the main players in EILF in Saudi Arabia. Galactosemia and tyrosinemia predict good prognosis and idiopathic diagnosis predicts poor prognosis.
Clinical Implications of Fetal Heart Rate Interpretation Based on Underlying Physiology
Authors: O'Brien-Abel Nancy 
Published: November 2019

Abstract
Understanding the physiology of fetal oxygenation and various influences on fetal heart rate control supports nurses, midwives, and physicians in interpreting and managing electronic fetal heart rate tracings during labor and birth. Maternal oxygenation, placental circulation and exchange, umbilical blood flow and fetal circulation affect fetal oxygenation, which is reflected in observed fetal heart rate patterns. Fetal heart control is further influenced by the central and autonomic nervous systems, baroreceptors, chemoreceptors, humoral factors, sleep–wake patterns, breathing movements, medications, painful stimuli, sound and vibrations, and temperature. Knowledge of the physiologic basis for fetal heart rate pattern characteristics guides interventions to improve fetal oxygenation when indicated. A review and update on clinical implications of fetal heart rate pattern interpretation based on underlying physiology is presented.
Effects of Different Exercise Intensities on Headache
Authors: Machado-Oliveira Luciano , da Silva Gauto Yumie Okuyama , de Santana Neto Fernando José , da Silva Magno Gomes , Germano-Soares Antonio Henrique , Diniz Paula Rejane Beserra 
Published: November 2019

The benefits of the regular exercise on quality of life of individuals living with a headache are well known. However, whether the benefits of the exercise training on headache parameters (i.e., intensity, frequency, and pain duration) occur in an intensity-dependent fashion remains unknown.

Objective
The aim of the study was to investigate the effects of different exercise intensities on headache parameters.

Design
A systematic review of clinical trials that analyzed the effect of physical exercise on headache, without time or language restriction. The TESTEX scale was used to evaluate the methodological quality of the articles.

Results
Sixteen (16) articles were included with interventions with aerobic training and resistance training. Primary results are positive effects of exercise on migraine symptoms, tension-type headache among others, and a decrease in the use of headache-related medications. On the other hand, the studies did not provide information on exercise intensity, especially studies with aerobic exercises. The intensities used for aerobic training was mostly controlled subjectively and the resistance training ranged from 10% to 80% of maximum repetition.

Conclusions
Exercise had a positive influence on the frequency and severity of headache crises, although the studies presented inconclusive data regarding the exercise parameters.
Deep Learning Analysis of Cerebral Blood Flow to Identify Cognitive Impairment and Frailty in Persons Living With HIV
Authors: Luckett Patrick , Paul Robert H. , Navid Jaimie , Cooley Sarah A. , Wisch Julie K. , Boerwinkle Anna H. , Tomov Dimitre , Ances Beau M. 
Published: November 2019

Background:
Deep learning algorithms of cerebral blood flow were used to classify cognitive impairment and frailty in people living with HIV (PLWH). Feature extraction techniques identified brain regions that were the strongest predictors.

Setting:
Virologically suppressed (<50 copies/mL) PLWH (n = 125) on combination antiretroviral therapy were enrolled. Participants averaged 51.4 (11.4) years of age and 13.7 (2.8) years of education. Participants were administered a neuropsychological battery, assessed for frailty, and completed structural neuroimaging.

Methods:
Deep neural network (DNN) models were trained to classify PLWH as cognitively unimpaired or impaired based on neuropsychological tests (Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised, Trail making, Letter-Number Sequencing, Verbal Fluency, and Color Word Interference), as well as frail, prefrail, or nonfrail based on the Fried phenotype criteria (at least 3 of the following 5: weight loss, physical inactivity, exhaustion, grip strength, walking time).

Results:
DNNs classified individuals with cognitive impairment in the learning, memory, and executive domains with 82%–86% accuracy (0.81–0.87 AUC). Our model classified nonfrail, prefrail, and frail PLWH with 75% accuracy. The strongest predictors of cognitive impairment were cortical (parietal, occipital, and temporal) and subcortical (amygdala, caudate, and hippocampus) regions, whereas the strongest predictors of frailty were subcortical (amygdala, caudate, hippocampus, thalamus, pallidum, and cerebellum).

Conclusions:
DNN models achieved high accuracy in classifying cognitive impairment and frailty status in PLWH. Feature selection algorithms identified predictive regions in each domain and identified overlapping regions between cognitive impairment and frailty. Our results suggest frailty in HIV is primarily subcortical, whereas cognitive impairment in HIV involves subcortical and cortical brain regions.
Dual Analysis of Loss to Follow-up for Perinatally HIV-Infected Adolescents Receiving Combination Antiretroviral Therapy in Asia
Authors: Bartlett Adam W. , Lumbiganon Pagakrong , Jamal Mohamed Thahira A. , Lapphra Keswadee , Muktiarti Dina , Du Quy Tuan , Hansudewechakul Rawiwan , Ly Penh Sun , Truong Khanh Huu , Van Nguyen Lam , Puthanakit Thanyawee , Sudjaritruk Tavitiya , Chokephaibulkit Kulkanya , Do Viet Chau , Kumarasamy Nagalingeswaran , Nik Yusoff Nik Khairulddin , Kurniati Nia , Fong Moy Siew , Wati Dewi Kumara , Nallusamy Revathy , Sohn Annette H. , Kariminia Azar ,   for the TREAT Asia Pediatric HIV Observational Database of IeDEA Asia-Pacific
Published: November 2019

Background:
Perinatally HIV-infected adolescents (PHIVA) are an expanding population vulnerable to loss to follow-up (LTFU). Understanding the epidemiology and factors for LTFU is complicated by varying LTFU definitions.

Setting:
Asian regional cohort incorporating 16 pediatric HIV services across 6 countries.

Methods:
Data from PHIVA (aged 10–19 years) who received combination antiretroviral therapy 2007–2016 were used to analyze LTFU through (1) an International epidemiology Databases to Evaluate AIDS (IeDEA) method that determined LTFU as >90 days late for an estimated next scheduled appointment without returning to care and (2) the absence of patient-level data for >365 days before the last data transfer from clinic sites. Descriptive analyses and competing-risk survival and regression analyses were used to evaluate LTFU epidemiology and associated factors when analyzed using each method.

Results:
Of 3509 included PHIVA, 275 (7.8%) met IeDEA and 149 (4.3%) met 365-day absence LTFU criteria. Cumulative incidence of LTFU was 19.9% and 11.8% using IeDEA and 365-day absence criteria, respectively. Risk factors for LTFU across both criteria included the following: age at combination antiretroviral therapy initiation <5 years compared with age ≥5 years, rural clinic settings compared with urban clinic settings, and high viral loads compared with undetectable viral loads. Age 10–14 years compared with age 15–19 years was another risk factor identified using 365-day absence criteria but not IeDEA LTFU criteria.

Conclusions:
Between 12% and 20% of PHIVA were determined LTFU with treatment fatigue and rural treatment settings consistent risk factors. Better tracking of adolescents is required to provide a definitive understanding of LTFU and optimize evidence-based models of care.
Ectopic Corticotropin-Releasing Hormone–Secreting Pancreatic Neuroendocrine Tumor
Authors: Zhang Jingjing , Kulkarni Harshad R. , Baum Richard P. 
Published: November 2019

Abstract
Ectopic Cushing syndrome secondary to corticotropin releasing hormone (CRH)–secreting tumors or CRH and adrenocorticotropin hormone cosecreting tumors is extremely rare. We report here the case of a 54-year-old man who experienced CRH-secreting pancreatic neuroendocrine tumor causing Cushing syndrome, initially detected by SSTR (somatostatin receptor) scintigraphy, then significantly progressed with multiple liver metastases, demonstrating significantly increased SSTR expression on 68Ga-DOTATOC PET/CT and a “mismatch” imaging pattern on 18F-FDG PET/CT. The patient underwent peptide receptor radionuclide therapy with 177Lu/90Y-DOTATOC and demonstrated excellent response to the treatment.
Compartment Syndrome of the Temporal Muscle
Authors: Bottini Gian Battista , Tükel Hüseyin Can , Brandtner Christian , Wittig Jörn , Gaggl Alexander 
Published: November 2019

Abstract
The authors report a patient with masticator space abscess due to an ascending infection following a wisdom tooth extraction. They administered antibiotics and did an incision and drainage; however, osteomyelitis of the mandible and compartment syndrome of the temporal muscle complicated the course. The authors suggest a physiopathology and discuss the management of this study.
New Ileostomy Formation and Subsequent Community-onset Acute and Chronic Kidney Disease
Authors: Smith Stephen A. , Ronksley Paul E. , Tan Zhi , Dixon Elijah , Hemmelgarn Brenda R. , Buie W. Donald , Pannu Neesh , James Matthew T. 
Published: November 2019

Objective:
The aim of this study was to examine relationships between ileostomy formation and subsequent kidney disease.

Summary and Background Data:
Colonic absorptive capacity loss from ileostomy formation can cause volume depletion and could result in kidney disease

Methods:
We conducted a population-based cohort study comparing patients who underwent ileostomy formation with or without bowel resection (ileostomy group) to patients who underwent bowel resection without ileostomy formation (reference group). Adjusted odds ratios (aORs) for community-onset acute kidney injury (AKI) within 3 months and new-onset chronic kidney disease (CKD) within 1 year following hospital discharge were determined.

Results:
Among 19,889 patients, 4136 comprised the ileostomy group and 15,753 comprised the reference group; 1350 patients experienced community-onset AKI and 464 developed new-onset CKD. The aOR for community-onset AKI with ileostomy formation was 4.08 [95% confidence interval (CI) = 3.62–4.61] for any stage AKI, 7.08 (95% CI = 5.66–8.85) for stage ≥2 injury, and 7.67 (95% CI = 5.06–11.63) for stage 3 injuries. Community-onset AKI modified associations between ileostomy formation and new-onset CKD (P = 0.002). Odds of new-onset CKD were increased in the ileostomy group relative to the reference group for patients both with (aOR = 4.99; 95% CI = 3.42–7.28) and without (aOR = 2.45; 95% CI = 1.85–2.23) previous community-onset AKI episodes. In analyses comparing patients that underwent ileostomy formation and subsequent reversal within 1 year to the reference group without ileostomy, the relationship with new-onset CKD was attenuated for patients both with (aOR = 2.49; 95% CI = 1.50–4.12) and without (aOR = 0.97; 95% CI = 0.67–1.40) previous community-onset AKI episodes.

Conclusions:
Ileostomy formation is strongly associated with subsequent kidney disease. Vigilance for this complication and new strategies for prevention and treatment are necessary.
Survival Advantage of Laparoscopic Versus Open Resection For Colorectal Liver Metastases
Authors: Syn Nicholas L. , Kabir Tousif , Koh Ye Xin , Tan Hwee Leong , Wang Louis Z. , Chin Brian Zhaojie , Wee Ian , Teo Jin Yao , Tai Bee Choo , Goh Brian K. P. 
Published: November 2019

Objective:
To perform an individual participant data meta-analysis using randomized trials and propensity-score matched (PSM) studies which compared laparoscopic versus open hepatectomy for patients with colorectal liver metastases (CLM).

Background:
Randomized trials and PSM studies constitute the highest level of evidence in addressing the long-term oncologic efficacy of laparoscopic versus open resection for CLM. However, individual studies are limited by the reporting of overall survival in ways not amenable to traditional methods of meta-analysis, and violation of the proportional hazards assumption.

Methods:
Survival information of individual patients was reconstructed from the published Kaplan-Meier curves with the aid of a computer vision program. Frequentist and Bayesian survival models (taking into account random-effects and nonproportional hazards) were fitted to compare overall survival of patients who underwent laparoscopic versus open surgery. To handle long plateaus in the tails of survival curves, we also exploited “cure models” to estimate the fraction of patients effectively “cured” of disease.

Results:
Individual patient data from 2 randomized trials and 13 PSM studies involving 3148 participants were reconstructed. Laparoscopic resection was associated with a lower hazard rate of death (stratified hazard ratio = 0.853, 95% confidence interval: 0.754–0.965, P = 0.0114), and there was evidence of time-varying effects (P = 0.0324) in which the magnitude of hazard ratios increased over time. The fractions of long-term cancer survivors were estimated to be 47.4% and 18.0% in the laparoscopy and open surgery groups, respectively. At 10-year follow-up, the restricted mean survival time was 8.6 months (or 12.1%) longer in the laparoscopy arm (P < 0.0001). In a subgroup analysis, elderly patients (≥65 years old) treated with laparoscopy experienced longer 3-year average life expectancy (+6.2%, P = 0.018), and those who live past the 5-year milestone (46.1%) seem to be cured of disease.

Conclusions:
This patient-level meta-analysis of high-quality studies demonstrated an unexpected survival benefit in favor of laparoscopic over open resection for CLM in the long-term. From a conservative viewpoint, these results can be interpreted to indicate that laparoscopy is at least not inferior to the standard open approach.
Biochemical Modulation and Pathophysiology of Migraine
Authors: Chan Calvin , Wei Diana Y. , Goadsby Peter J. 
Published: November 2019

Background:
Migraine is a common disabling neurological disorder where attacks have been recognized to consist of more than headache. The premonitory, headache, and postdromal phases are the various phases of the migraine cycle, where aura can occur before, during, or after the onset of pain. Migraine is also associated with photosensitivity and cranial autonomic symptoms, which includes lacrimation, conjunctival injection, periorbital edema, ptosis, nasal congestion, and rhinorrhoea. This review will present the current understanding of migraine pathophysiology and the relationship to the observed symptoms.

Evidence Acquisition:
The literature was reviewed with specific focus on clinical, neurophysiological, functional imaging, and preclinical studies in migraine including the studies on the role of calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP).

Results:
The phases of the migraine cycle have been delineated by several studies. The observations of clinical symptoms help develop hypotheses of the key structures involved and the biochemical and neuronal pathways through which the effects are mediated. Preclinical studies and functional imaging studies have provided evidence for the role of multiple cortical areas, the diencephalon, especially the hypothalamus, and certain brainstem nuclei in the modulation of nociceptive processing, symptoms of the premonitory phase, aura, and photophobia. CGRP and PACAP have been found to be involved in nociceptive modulation and through exploration of CGRP mechanisms, new successful treatments have been developed.

Conclusions:
Migraine is a complex neural disorder and is important to understand when seeing patients who present to neuro-ophthalmology, especially with the successful translation from preclinical and clinical research leading to successful advances in migraine management.
Classification of clear cell renal cell carcinoma based onPKMalternative splicing
Authors: Li Xiangyu , Turanli Beste , Juszczak Kajetan , Kim Woonghee , Arif Muhammad , Sato Yusuke , Ogawa Seishi , Turkez Hasan , Nielsen Jens , Boren Jan , Uhlen Mathias , Zhang Cheng , Mardinoglu Adil 
Published: November 2019

SummaryClear cell renal cell carcinoma (ccRCC) accounts for 70–80% of kidney cancer diagnoses and displays high molecular and histologic heterogeneity. Hence, it is necessary to reveal the underlying molecular mechanisms involved in progression of ccRCC to better stratify the patients and design effective treatment strategies. Here, we analyzed the survival outcome of ccRCC patients as a consequence of the differential expression of four transcript isoforms of the pyruvate kinase muscle type (PKM). We first extracted a classification biomarker consisting of eight gene pairs whose within-sample relative expression orderings (REOs) could be used to robustly classify the patients into two groups with distinct molecular characteristics and survival outcomes. Next, we validated our findings in a validation cohort and an independent Japanese ccRCC cohort. We finally performed drug repositioning analysis based on transcriptomic expression profiles of drug-perturbed cancer cell lines and proposed that paracetamol, nizatidine, dimethadione and conessine can be repurposed to treat the patients in one of the subtype of ccRCC whereas chenodeoxycholic acid, fenoterol and hexylcaine can be repurposed to treat the patients in the other subtype.
scGAIN: Single Cell RNA-seq Data Imputation using Generative Adversarial Networks
Authors: Gunady Mohamed K. , Kancherla Jayaram , Bravo Héctor Corrada , Feizi Soheil 
Published: November 2019

AbstractSingle cell RNA sequencing (scRNA-seq) provides a rich view into the heterogeneity underlying a cell population. However single-cell data are usually noisy and very sparse due to the presence of dropout genes. In this work we propose an approach to impute missing gene expressions in single cell data using generative adversarial networks (GANs). By learning an approximate distribution of the data, our approach, scGAIN, can impute dropouts in simulated and real single cell data. The work in this paper discusses how to adopt GAIN training model into the domain of imputing single cell data. Experiments show that scGAIN gives competitive results compared to the state-of-the-art approaches while showing superiority in various aspects in simulation and real data. Imputation by scGAIN successfully recovers the underlying clustering of different subpopulations, provides sharp estimates around true mean expressions and increase the correspondence with matched bulk RNAseq experiments.