bluuebunny/crossref_metadata_2025_split huggingface dataset:
The influence of immortal time bias in observational studies examining associations of antifibrotic therapy with survival in idiopathic pulmonary fibrosis: A simulation study
Authors: Zheng Qiang , Otahal Petr , Cox Ingrid A. , de Graaff Barbara , Campbell Julie A. , Ahmad Hasnat , Walters E. Haydn , Palmer Andrew J. 
Published: April 2023

BackgroundImmortal time bias (ITB) has been overlooked in idiopathic pulmonary fibrosis (IPF). We aimed to identify the presence of ITB in observational studies examining associations between antifibrotic therapy and survival in patients with IPF and illustrate how ITB may affect effect size estimates of those associations.MethodsImmortal time bias was identified in observational studies using the ITB Study Assessment Checklist. We used a simulation study to illustrate how ITB may affect effect size estimates of antifibrotic therapy on survival in patients with IPF based on four statistical techniques including time-fixed, exclusion, time-dependent and landmark methods.ResultsOf the 16 included IPF studies, ITB was detected in 14 studies, while there were insufficient data for assessment in two others. Our simulation study showed that use of time–fixed [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.47–0.64] and exclusion methods (HR 0.79, 95% CI 0.67–0.92) overestimated the effectiveness of antifibrotic therapy on survival in simulated subjects with IPF, in comparison of the time–dependent method (HR 0.93, 95% CI 0.79–1.09). The influence of ITB was mitigated using the 1 year landmark method (HR 0.69, 95% CI 0.58–0.81), compared to the time–fixed method.ConclusionThe effectiveness of antifibrotic therapy on survival in IPF can be overestimated in observational studies, if ITB is mishandled. This study adds to the evidence for addressing the influence of ITB in IPF and provides several recommendations to minimize ITB. Identifying the presence of ITB should be routinely considered in future IPF studies, with the time–dependent method being an optimal approach to minimize ITB.
Cold stress induces colitis-like phenotypes in mice by altering gut microbiota and metabolites
Authors: Sun Lijuan , Wang Xueying , Zou Yuankang , He Yixuan , Liang Changting , Li Juan , Li Pu , Zhang Jianbin 
Published: April 2023

IntroductionThe modernized lifestyle has been paralleled by an epidemic of inflammatory bowel disease (IBD). Excessive consumption of cold beverages is especially common among the modern humans. However, whether cold stress contributes directly to the gut barrier and gut–brain axis is not clear.MethodsWe conducted a cold stress model induced by cold water. The mice were treated with 14 consecutive days of intragastric cold or common water administration. We observed changes in gut transit and gut barrier in the colon. We also employed RNA sequencing-based transcriptomic analysis to identify the genes potentially driving gut injury, and simultaneously examined the gut microbiota and metabolites in the feces.ResultsWe found that cold stress disturbed the intestinal function and increased gut permeability. A set of core genes related to immune responses were consistently overexpressed in the cold stress group. Additionally, cold stress induced decreased bacterial diversity, ecological network, and increased pathogens mainly belonging to Proteobacteria. The dopamine signaling pathway-related metabolites were largely reduced in the cold stress group.ConclusionThis study revealed that cold stress could trigger an IBD-like phenotype in mice, implying that cold stress is a possible risk factor for IBD development.
A single relapse induces worsening of disability and health-related quality of life in patients with neuromyelitis optica spectrum disorder
Authors: Berthele Achim , Levy Michael , Wingerchuk Dean M. , Pittock Sean J. , Shang Shulian , Kielhorn Adrian , Royston Minying , Sabatella Guido , Palace Jacqueline 
Published: April 2023

BackgroundCumulative damage from multiple relapses in neuromyelitis optica spectrum disorder (NMOSD) is associated with poor health-related quality of life (HRQoL) and long-term disability in patients positive for anti-aquaporin 4 antibodies (AQP4+). This study assessed the effect of an individual relapse on HRQoL and disability outcomes in AQP4+ NMOSD.MethodsPost hoc analyses of data pooled from the PREVENT study and its open-label extension, which evaluated the efficacy and safety of eculizumab in AQP4+ NMOSD, examined the effect of a single relapse on 3 disability and 4 HRQoL outcome measures. Assuming the effect of 1 relapse extends to multiple relapses, an extrapolation was done to assess the effect of 2 relapses on these outcomes.ResultsIn 27 patients (placebo: n = 20; eculizumab: n = 7) experiencing an independently adjudicated relapse, 1 relapse led to significantly worse disability (modified Rankin Scale and Expanded Disability Status Scale [EDSS]) and HRQoL (36-item Short-Form Health Survey mental and physical component summaries; European Quality of Life 5-Dimension questionnaire 3-Level visual analogue scale and utility index) scores. In 4 of 7 outcomes, clinically meaningful worsening was more likely for relapsing versus non-relapsing patients (n = 116). Extrapolating the effect of 2 relapses predicted that clinically meaningful worsening was more likely in 6 out of 7 outcomes, including EDSS, for patients experiencing multiple relapses versus patients experiencing no relapses.ConclusionFindings from these clinical trial data demonstrate that a single NMOSD relapse can worsen disability and HRQoL, underscoring the role of relapse prevention in improving long-term outcomes in patients with AQP4+ NMOSD.
Variables associated with cortical motor mapping thresholds: A retrospective data review with a unique case of interlimb motor facilitation
Authors: Song Yinchen , Surgenor James V. , Leeds Zachary T. , Kanter John H. , Martinez-Camblor Pablo , Smith William J. , Boone M. Dustin , Abess Alexander T. , Evans Linton T. , Kobylarz Erik J. 
Published: April 2023

IntroductionIntraoperative neuromonitoring (IONM) is crucial to preserve eloquent neurological functions during brain tumor resections. We observed a rare interlimb cortical motor facilitation phenomenon in a patient with recurrent high-grade glioma undergoing craniotomy for tumor resection; the patient’s upper arm motor evoked potentials (MEPs) increased in amplitude significantly (up to 44.52 times larger, p &lt; 0.001) following stimulation of the ipsilateral posterior tibial nerve at 2.79 Hz. With the facilitation effect, the cortical MEP stimulation threshold was reduced by 6 mA to maintain appropriate continuous motor monitoring. It likely has the benefit of reducing the occurrence of stimulation-induced seizures and other adverse events associated with excessive stimulation.MethodsWe conducted a retrospective data review including 120 patients who underwent brain tumor resection with IONM at our center from 2018 to 2022. A broad range of variables collected pre-and intraoperatively were reviewed. The review aimed to determine: (1) whether we overlooked this facilitation phenomenon in the past, (2) whether this unique finding is related to any specific demographic information, clinical presentation, stimulation parameter (s) or anesthesia management, and (3) whether it is necessary to develop new techniques (such as facilitation methods) to reduce cortical stimulation intensity during intraoperative functional mapping.ResultsThere is no evidence suggesting that clinical presentation, stimulation configuration, or intraoperative anesthesia management of the patient with the facilitation effect were significantly different from our general patient cohort. Even though we did not identify the same facilitation effect in any of these patients, we were able to determine that stimulation thresholds for motor mapping are significantly associated with the location of stimulation (p = 0.003) and the burst suppression ratio (BSR) (p &lt; 0.001). Stimulation-induced seizures, although infrequent (4.05%), could occur unexpectedly even when the BSR was 70%.DiscussionWe postulated that functional reorganization and neuronal hyperexcitability induced by glioma progression and repeated surgeries were probable underlying mechanisms of the interlimb facilitation phenomenon. Our retrospective review also provided a practical guide to cortical motor mapping in brain tumor patients under general anesthesia. We also underscored the need for developing new techniques to reduce the stimulation intensity and, hence, seizure occurrence.
Sex hormones and risk of epilepsy: A bidirectional Mendelian randomization study
Authors: Ke Bin , Li Chunyu , Shang Huifang 
Published: April 2023

BackgroundMultiple evidence has suggested complex interaction between sex hormones and epilepsy. However, whether there exists a causal association and the effect direction remains controversial. Here we aimed to examine the causative role of hormones in the risk of epilepsy and vice versa.MethodsWe conducted a bidirectional two-sample Mendelian randomization analysis using summary statistics from genome-wide association studies of major sex hormones including testosterone (N = 425,097), estradiol (N = 311,675) and progesterone (N = 2,619), together with epilepsy (N = 44,889). We further performed sex-stratified analysis, and verified the significant results using summary statistics from another study on estradiol in males (N = 206,927).ResultsGenetically determined higher estradiol was associated with a reduced risk of epilepsy (OR: 0.90, 95% CI: 0.83–0.98, P = 9.51E-03). In the sex-stratified analysis, the protective effect was detected in males (OR: 0.92, 95% CI: 0.88–0.97, P = 9.18E-04), but not in females. Such association was further verified in the replication stage (OR: 0.44, 95% CI: 0.23–0.87, P = 0.017). In contrast, no association was identified between testosterone, progesterone and the risk of epilepsy. In the opposite direction, epilepsy was not causally associated with sex hormones.ConclusionThese results demonstrated higher estradiol could reduce the risk of epilepsy, especially in males. Future development of preventive or therapeutic interventions in clinical trials could attach importance to this.
Association of serum folate with prevalence of non-alcoholic fatty liver disease among adults (NHANES 2011–2018)
Authors: Yao Baodong , Lu Xiaojing , Xu Lai , Jiang Yun 
Published: April 2023

BackgroundFolate was involved in oxidative stress, hepatic lipid metabolism and chronic hepatic inflammation. However, evidence about the association between serum folate level and non-alcoholic fatty liver disease (NAFLD) in general population is scarce. This study aimed to explore the relationship between serum folate level and NAFLD among adults.Methods7,146 adult participants aged 20 years and over who have complete data of serum folate level and liver function biomarkers in NHANES 2011–2018 were included. Serum folate level was measured by isotope-dilution high-performance liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). And suspected NAFLD was defined according to the United States fatty liver index (USFLI). Logistic regression and the restricted cubic spline models were performed.ResultsSerum folate level was inversely associated with the presence of NAFLD. When comparing the second, third and fourth quartiles of serum folate level to the lowest quartile, the adjusted ORs of the presence of NAFLD were 0.62 (0.49–0.78), 0.65 (0.51–0.84), and 0.43 (0.32–0.56) respectively (p for trend&lt;0.001). The non-linear and L-shaped relationship was found between serum folate level and the presence of NAFLD in the restricted cubic spline regression (p for non-linearity &lt;0.01). Consistent with serum total folate, serum 5-Methyltetrahydrofolate level was also inversely associated with the presence of NAFLD.ConclusionHigher serum folate level may be negatively associated with NAFLD.
Clinical significance of the controlling nutritional status (CONUT) score in gastric cancer patients: A meta-analysis of 9,764 participants
Authors: Liu Hui , Yang Xiao-Chuan , Liu Ding-Cheng , Tong Chao , Wen Wen , Chen Ri-Hui 
Published: April 2023

BackgroundThe clinical value of the controlling nutritional status (CONUT) score has been widely reported in multiple malignancies. The aim of this study is to investigate the association between the CONUT score and clinical outcomes in patients with gastric cancer.MethodsA comprehensive literature search of electronic databases including PubMed, Embase, and Web of Science was performed up to December 2022. The primary endpoints were survival outcomes and postoperative complications. Subgroup analysis and sensitivity analysis were performed during the pooled analysis.ResultsNineteen studies including 9,764 patients were included. The pooled results indicated that patients in the high CONUT group had a worse overall survival (HR = 1.70 95%CI: 1.54–1.87; P &lt; 0.0001; I2 = 33%) and recurrence-free survival (HR = 1.57; 95%CI: 1.36–1.82; P &lt; 0.0001; I2 = 30%), and a higher risk of complications (OR = 1.96; 95%CI: 1.50–2.57; P &lt; 0.0001; I2 = 69%). In addition, a high CONUT score was significantly associated with larger tumor size, higher percentage of microvascular invasion, later TNM stage and fewer patients receiving adjuvant chemotherapy, but not with tumor differentiation.ConclusionBased on existing evidence, the CONUT score could act as a valuable biomarker to predict clinical outcomes in patients with gastric cancer. Clinicians could use this useful indicator to stratify patients and formulate individual treatment plans.
Impact of donor age on short-term outcomes after pediatric split liver transplantation
Authors: Xu Min , Dong Chong , Sun Chao , Wang Kai , Zhang Wei , Qin Hong , Han Chao , Yang Yang , Zhang Fubo , Wang Zhen , Zheng Weiping , Wei Xinzhe , Gao Wei , Shen Zhongyang 
Published: April 2023

BackgroundDonor shortage is an important limitation of liver transplantation (LT). Split liver transplantation (SLT) may increase the sources of donors and reduce the problem of organ shortage. However, there are no standard criteria of the selection of SLT donor, especially regarding the donor age.MethodsWe retrospectively analyzed the clinical data of children who received initial SLT between January 2015 and December 2021. Based on the age of donors, the patients were divided into groups A (1–10 years old; n = 26), B (10–45 years old; n = 87), and C (45–55 years old; n = 27). The short-term (&lt;1 year after SLT) outcomes of the recipients were analyzed.ResultsA total of 140 patients received SLT from 122 donors. The 1-, 3- and 12-month patient survival rates in group A were 100.0%, and the graft survival rates were 92.3%. The 1-, 3- and 12-month survival rates of patient and graft in group B were 97.7%, 96.6%, and 95.0%, respectively, and in group C were 85.2%, 85.2%, and 81.1%, respectively. The patient survival rate was significantly lower in group C than in groups A and B (p = 0.0082). There was no significant difference in graft survival between the three groups (p = 0.0545).ConclusionsSimilar results were obtained for pediatric SLT with donors &lt;10 years old and 10–45 years old. Pediatric SLT can be performed with older donors (45–55 years) after strict donor selection and selection of appropriate recipients.
Higher ETCOc predicts longer phototherapy treatment in neonatal hyperbilirubinemia
Authors: Zhan Yuan-Li , Peng Hai-Bo , Jin Zhen-Chao , Su Jin-Feng , Tan Xiang-Yu , Zhao Lu , Zhang Lian 
Published: April 2023

ObjectiveThis study aimed to evaluate the predictive performance of end-tidal carbon monoxide corrected to ambient carbon monoxide (ETCOc) values phototherapy in neonates with significant hyperbilirubinemia.MethodsA prospective study was conducted on neonates with significant hyperbilirubinemia who received phototherapy between 3 and 7 days of life. The breath ETCOc and serum total bilirubin of the recruited infants were measured on admission.ResultsThe mean ETCOc at admission in 103 neonates with significant hyperbilirubinemia was 1.70 ppm. The neonates were categorized into two groups: phototherapy duration ≤72 h (n = 87) and &gt;72 h (n = 16) groups. Infants who received phototherapy for &gt;72 h had significantly higher ETCOc (2.45 vs. 1.60, P = 0.001). The cutoff value of ETCOc on admission for predicting longer phototherapy duration was 2.4 ppm, with a sensitivity of 62.5% and specificity of 88.5%, yielding a 50% positive predictive value and a 92.7% negative predictive value.ConclusionETCOc on admission can help predict the duration of phototherapy in neonates with hyperbilirubinemia, facilitate clinicians to judge disease severity, and make clinical communication easier and more efficient.
The effect of CFTR modulators on structural lung disease in cystic fibrosis
Authors: Mok L. Clara , Garcia-Uceda Antonio , Cooper Matthew N. , Kemner-Van De Corput Mariette , De Bruijne Marleen , Feyaerts Nathalie , Rosenow Tim , De Boeck Kris , Stick Stephen , Tiddens Harm A. W. M. 
Published: April 2023

Background: Newly developed quantitative chest computed tomography (CT) outcomes designed specifically to assess structural abnormalities related to cystic fibrosis (CF) lung disease are now available. CFTR modulators potentially can reduce some structural lung abnormalities. We aimed to investigate the effect of CFTR modulators on structural lung disease progression using different quantitative CT analysis methods specific for people with CF (PwCF).Methods: PwCF with a gating mutation (Ivacaftor) or two Phe508del alleles (lumacaftor-ivacaftor) provided clinical data and underwent chest CT scans. Chest CTs were performed before and after initiation of CFTR modulator treatment. Structural lung abnormalities on CT were assessed using the Perth Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF), airway-artery dimensions (AA), and CF-CT methods. Lung disease progression (0–3 years) in exposed and matched unexposed subjects was compared using analysis of covariance. To investigate the effect of treatment in early lung disease, subgroup analyses were performed on data of children and adolescents aged &lt;18 years.Results: We included 16 modulator exposed PwCF and 25 unexposed PwCF. Median (range) age at the baseline visit was 12.55 (4.25–36.49) years and 8.34 (3.47–38.29) years, respectively. The change in PRAGMA-CF %Airway disease (-2.88 (−4.46, −1.30), p = 0.001) and %Bronchiectasis extent (-2.07 (−3.13, −1.02), p &lt; 0.001) improved in exposed PwCF compared to unexposed. Subgroup analysis of paediatric data showed that only PRAGMA-CF %Bronchiectasis (-0.88 (−1.70, −0.07), p = 0.035) improved in exposed PwCF compared to unexposed.Conclusion: In this preliminary real-life retrospective study CFTR modulators improve several quantitative CT outcomes. A follow-up study with a large cohort and standardization of CT scanning is needed to confirm our findings.
Effects of dexmedetomidine on oxidative stress, programmed cell death, liver function, and expression of peripheral immune cells in patients with primary liver cancer undergoing hepatectomy
Authors: Li WenYing , Chen MingHao , Gong YuXin , Lin Feng , Sun Chen 
Published: April 2023

Study background: Primary liver cancer is a severe health issue that imposes a significant health burden on families. Oxidation and subsequent cell death impair liver function and provoke an immune response. The present article investigates the effect of Dexmedetomidine on oxidation, cell death, the expression of peripheral immune cells, and liver function. The clinical data will represent the facts and evidence of the effects of this intervention.Methods: We analyzed clinical data reporting various accounts of the effects of Dexmedetomidine on oxidation, cell death, the expression of peripheral immune cells, and liver function among patients who underwent hepatectomy. The surgical procedure reported the differences in cell death as procedural outcomes among pre- and post-treatment records were compared and contrasted.Results: We found decreased cell apoptosis in the treatment group: the number of incisions to remove dead cells was lower in the treatment group than in the pre-treatment group. Likewise, lower oxidation was reported in pre-treatment than in post-treatment records. The expression of peripheral immune cells was higher in the pre-treatment clinical data than in post-treatment, suggesting a reduction in oxidation following dexmedetomidine treatment. Liver function was a function of oxidation and cell death outcomes. In the pre-treatment clinical data, liver function was poor, whereas improved functions were reported in the post-treatment clinical data.Discussion: We found compelling evidence of Dexmedetomidine’s effects on oxidative stress and programmed cell death. The intervention suppresses the production of reactive oxygen species and the consequential apoptosis. Additionally, liver functions improve due to the decrease in hepatocyte apoptosis. Since the peripheral immune cells are expressed against tumors, a decrease in the progression of primary liver cancer decreased the expression of the peripheral immune cells.Conclusion: Dexmedetomidine’s positive effects stood out in the present research article. The intervention reduced oxidation by balancing the production of reactive oxygen species and the detoxification processes. Reduced oxidation induced reduced cell death through apoptosis, resulting in a low expression of peripheral immune cells and improved liver functions.
Etiology of anxious and fearful behavior in juvenile neuronal ceroid lipofuscinosis (CLN3 disease)
Authors: Ostergaard John R. 
Published: April 2023

BackgroundJuvenile neuronal ceroid lipofuscinosis (JNCL, CLN3) is a childhood-onset neurodegenerative disease with prominent symptoms comprising a pediatric dementia syndrome. As in adult dementia, behavioral symptoms like mood disturbances and anxiety are common. In contrast to in adult dementia, however, the anxious behavioral symptoms increase during the terminal phase of JNCL disease. In the present study, the current understanding of the neurobiological mechanisms of anxiety and anxious behavior in general is addressed as will a discussion of the mechanism of the anxious behavior seen in young JNCL patients. Based on developmental behavioral points of view, known neurobiological mechanisms, and the clinical presentation of the anxious behavior, a theory of its etiology is described.Result and discussionDuring the terminal phase, the cognitive developmental age of JNCL patients is below 2 years. At this stage of mental development individuals act primarily from a concrete world of consciousness and do not have the cognitive ability to encounter a normal anxiety response. Instead, they experience the evolutionary basic emotion of fear, and as the episodes typically are provoked when the adolescent JNCL patient is exposed to either loud sounds, is lifted from the ground, or separated from the mother/known caregiver, the fear can best be perceived as the developmental natural fear-response that appears in children 0-2 years of age. The efferent pathways of the neural fear circuits are mediated through autonomic, neuroendocrine, and skeletal-motor responses. The autonomic activation occurs early, is mediated through the sympathetic and parasympathetic neural systems, and as JNCL patients beyond puberty have an autonomic imbalance with a significant sympathetic hyperactivity, the activation of the autonomic nervous system results in a disproportionate high sympathetic activity resulting in tachycardia, tachypnea, excessive sweating, hyperthermia, and an increased atypical muscle activity. The episodes are thus phenotypically similar to what is seen as Paroxysmal Sympathetic Hyperactivity (PSH) following an acute traumatic brain injury. As in PSH, treatment is difficult and so far, no consensus of a treatment algorithm exists. Use of sedative and analgesic medication and minimizing or avoiding provocative stimuli may partly reduce the frequency and intensity of the attacks. Transcutaneous vagal nerve stimulation might be an option worth to investigate rebalancing the sympathetic-parasympathetic disproportion.