bluuebunny/crossref_metadata_2025_split huggingface dataset:
Handling intercurrent events and missing data in non-inferiority trials using the estimand framework: A tuberculosis case study
Authors: Rehal Sunita , Cro Suzie , Phillips Patrick PJ , Fielding Katherine , Carpenter James R 
Published: June 2023

IntroductionThe ICH E9 addendum outlining the estimand framework for clinical trials was published in 2019 but provides limited guidance around how to handle intercurrent events for non-inferiority studies. Once an estimand is defined, it is also unclear how to deal with missing values using principled analyses for non-inferiority studies.MethodsUsing a tuberculosis clinical trial as a case study, we propose a primary estimand, and an additional estimand suitable for non-inferiority studies. For estimation, multiple imputation methods that align with the estimands for both primary and sensitivity analysis are proposed. We demonstrate estimation methods using the twofold fully conditional specification multiple imputation algorithm and then extend and use reference-based multiple imputation for a binary outcome to target the relevant estimands, proposing sensitivity analyses under each. We compare the results from using these multiple imputation methods with those from the original study.ResultsConsistent with the ICH E9 addendum, estimands can be constructed for a non-inferiority trial which improves on the per-protocol/intention-to-treat-type analysis population previously advocated, involving respectively a hypothetical or treatment policy strategy to handle relevant intercurrent events. Results from using the ‘twofold’ multiple imputation approach to estimate the primary hypothetical estimand, and using reference-based methods for an additional treatment policy estimand, including sensitivity analyses to handle the missing data, were consistent with the original study’s reported per-protocol and intention-to-treat analysis in failing to demonstrate non-inferiority.ConclusionsUsing carefully constructed estimands and appropriate primary and sensitivity estimators, using all the information available, results in a more principled and statistically rigorous approach to analysis. Doing so provides an accurate interpretation of the estimand.
Defining Operative Indications in Lisfranc Injuries: A Systematic Review
Authors: Pearsall Christian , Arciero Emily , Gupta Puneet , Bäcker Henrik , Tantigate Direk , Trofa David P. , Vosseller J. Turner 
Published: June 2023

Objective The aim of this review was to determine operative indications for Lisfranc injuries. Methods A systematic review using a MEDLINE literature search was performed using the index “Lisfranc Injury” from 1980 onward using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines where applicable. Inclusion criteria were all clinical studies reporting on the management of Lisfranc injuries obtained via the search index, including case reports, review articles, cohort studies, and randomized trials. Non-English-language articles, inaccessible articles, those not relevant to the management of Lisfranc injuries (biomechanical, cadaveric, and technique articles), and those that did not explicitly state operative indications (vague or absent indications) were excluded. Results After identifying 737 studies, the full text of 391 studies was reviewed, and 58 reports providing explicit operative indications were included in the final analysis. Fifty-one (81.1%) studies provided diastasis cutoffs varying ≥2 mm (35/58; 60.4%), ≥ 1 mm (13; 22.4%), and ≥3 mm (3; 5.2%); the diastasis location was most commonly unspecified (31/58; 53.5%) or varied between combinations of metatarsal, tarsal, cuboid, and cuneiform bones (20/58; 27.6%). Specific imaging criteria for surgery included an avulsion fracture or fleck sign (3/58; 5.2%), arch height loss (3/58; 5.2%), and a tear on magnetic resonance imaging (5; 8.6%). The 11 (19%) studies defining operative indications in terms of classification schemes used the Nunley and Vertullo (8/58; 13.8%), Myerson (2; 3.5%), and Buehren (1; 1.7%) systems. Twenty-one (36.2%) studies provided multiple operative indications. Conclusion The most common Lisfranc operative indications among the limited reporting studies varied from a 1- to 3-mm diastasis across several locations. It is imperative for operative indications to be reported with an increased frequency and in a homogenous fashion to guide the clinical management of these subtle injuries. Levels of Evidence: Level IV; systematic Review
Air pollution and mortality in patients with chronic obstructive pulmonary disease: a cohort study in South Korea
Authors: Kang Suna , Hong Yun Soo , Park Jihwan , Kang Danbee , Kim Hyunsoo , Lee Jin , Kim Woojin , Kang Sung-Won , Guallar Eliseo , Cho Juhee , Park Hye Yun 
Published: June 2023

Background: Evidence on whether long-term exposure to air pollution increases the mortality risk in patients with chronic obstructive pulmonary disease (COPD) is limited. Objectives: We aimed to investigate the associations of long-term exposure to particulate matter with diameter <10 µm (PM10) and nitrogen dioxide (NO2) with overall and disease-specific mortality in COPD patients. Design: We conducted a nationwide retrospective cohort study of 121,423 adults ⩾40 years diagnosed with COPD during 1 January to 31 December 2009. Methods: Exposure to PM10 and NO2 was estimated for residential location using the ordinary kriging method. We estimated the risk of overall mortality associated with 1-, 3-, and 5-years average concentrations of PM10 and NO2 using Cox proportional hazards models and disease-specific mortality using the Fine and Gray method adjusted for age, sex, income, body mass index, smoking, comorbidities, and exacerbation history. Results: The adjusted hazard ratios (HRs) for overall mortality associated with a 10 µg/m3 increase in 1-year PM10 and NO2 exposures were 1.004 [95% confidence interval (CI) = 0.985, 1.023] and 0.993 (95% CI = 0.984, 1.002), respectively. The results were similar for 3- and 5-year exposures. For a 10-µg/m3 increase in 1-year PM10 and NO2 exposures, the adjusted HRs for chronic lower airway disease mortality were 1.068 (95% CI = 1.024, 1.113) and 1.029 (95% CI = 1.009, 1.050), respectively. In stratified analyses, exposures to PM10 and NO2 were associated with overall mortality in patients who were underweight and had a history of severe exacerbation. Conclusion: In this large population-based study of patients with COPD, long-term PM10 and NO2 exposures were not associated with overall mortality but were associated with chronic lower airway disease mortality. PM10 and NO2 exposures were both associated with an increased risk of overall mortality in underweight individuals and those with a history of severe exacerbation.
Prediction of mortality risk and duration of hospitalization of COVID-19 patients with chronic comorbidities based on machine learning algorithms
Authors: Amiri Parastoo , Montazeri Mahdieh , Ghasemian Fahimeh , Asadi Fatemeh , Niksaz Saeed , Sarafzadeh Farhad , Khajouei Reza 
Published: June 2023

Background The severity of coronavirus (COVID-19) in patients with chronic comorbidities is much higher than in other patients, which can lead to their death. Machine learning (ML) algorithms as a potential solution for rapid and early clinical evaluation of the severity of the disease can help in allocating and prioritizing resources to reduce mortality. Objective The objective of this study was to predict the mortality risk and length of stay (LoS) of patients with COVID-19 and history of chronic comorbidities using ML algorithms. Methods This retrospective study was conducted by reviewing the medical records of COVID-19 patients with a history of chronic comorbidities from March 2020 to January 2021 in Afzalipour Hospital in Kerman, Iran. The outcome of patients, hospitalization was recorded as discharge or death. The filtering technique used to score the features and well-known ML algorithms were applied to predict the risk of mortality and LoS of patients. Ensemble Learning methods is also used. To evaluate the performance of the models, different measures including F1, precision, recall, and accuracy were calculated. The TRIPOD guideline assessed transparent reporting. Results This study was performed on 1291 patients, including 900 alive and 391 dead patients. Shortness of breath (53.6%), fever (30.1%), and cough (25.3%) were the three most common symptoms in patients. Diabetes mellitus(DM) (31.3%), hypertension (HTN) (27.3%), and ischemic heart disease (IHD) (14.2%) were the three most common chronic comorbidities of patients. Twenty-six important factors were extracted from each patient's record. Gradient boosting model with 84.15% accuracy was the best model for predicting mortality risk and multilayer perceptron (MLP) with rectified linear unit function (MSE = 38.96) was the best model for predicting the LoS. The most common chronic comorbidities among these patients were DM (31.3%), HTN (27.3%), and IHD (14.2%). The most important factors in predicting the risk of mortality were hyperlipidemia, diabetes, asthma, and cancer, and in predicting LoS was shortness of breath. Conclusion The results of this study showed that the use of ML algorithms can be a good tool to predict the risk of mortality and LoS of patients with COVID-19 and chronic comorbidities based on physiological conditions, symptoms, and demographic information of patients. The Gradient boosting and MLP algorithms can quickly identify patients at risk of death or long-term hospitalization and notify physicians to do appropriate interventions.
Design and assessment of amblyopia, strabismus, and myopia treatment and vision training using virtual reality
Authors: Chan Hoi Sze , Tang Yuk Ming , Do Chi Wai , Ho Yin Wong Horace , Chan Lily YL , To Suet 
Published: June 2023

Background Virtual reality is a relatively new intervention that has the potential to be used in the treatment of eye and vision problems. This article reviews the use of virtual reality-related interventions in amblyopia, strabismus, and myopia research. Methods Sources covered in the review included 48 peer-reviewed research published between January 2000 and January 2023 from five electronic databases (ACM Digital Library, IEEE Xplore, PubMed, ScienceDirect and Web of Science). To prevent any missing relevant articles, the keywords, and terms used in the search included “VR”, “virtual reality”, “amblyopia”, “strabismus,” and “myopia”. Quality assessment and data extraction were performed independently by two authors to form a narrative synthesis to summarize findings from the included research. Results Total number of 48 references were reviewed. There were 31 studies published on amblyopia, 18 on strabismus, and 6 on myopia, with 7 studies overlapping amblyopia and strabismus. In terms of technology, smartphone-based virtual reality headset viewers were utilized more often in amblyopia research, but commercial standalone virtual reality headsets were used more frequently in myopia and strabismus-related research. The software and virtual environment were mostly developed based on vision therapy and dichoptic training paradigms. Conclusion It has been suggested that virtual reality technology offers a potentially effective tool for amblyopia, strabismus, and myopia studies. Nonetheless, a variety of factors, especially the virtual environment and systems employed in the data presented, must be explored before determining whether virtual reality can be effectively applied in clinical settings. This review is significant as the technology in virtual reality software and application design features have been investigated and considered for future reference.
Rehabilitation after Hip Fracture Surgery Improves Physical and Cognitive Function in Patients with or Without Sarcopenia
Authors: Kanaya Yuji , Inoue Hirokazu , Sawamura Hideaki , Hoshino Yuichi , Takeshita Katsushi 
Published: June 2023

Introduction Sarcopenia is a prevalent risk factor for falls and fractures, and it affects the physical function and mortality of older people. The present study was performed to assess the prevalence of sarcopenia in patients who underwent rehabilitation after hip fracture surgery and to examine the association of sarcopenia with physical and cognitive function outcomes. Methods This case–control study involved 132 patients who were admitted to a convalescent rehabilitation ward at a single hospital after surgical treatment of hip fractures from April 2018 to March 2020. The skeletal muscle mass index was examined using whole-body dual-energy X-ray absorptiometry. The Asian Working Group for Sarcopenia 2019 diagnostic criteria were applied on admission. We compared the walking speed, Mini-Mental State Examination (MMSE) score, and Functional Independence Measure (FIM) score between the sarcopenia group and non-sarcopenia group on admission and on discharge. Results The prevalence of sarcopenia was 59.8%. In the non-sarcopenia group, the walking speed, MMSE score, FIM total score, FIM motor score, and FIM cognitive score were significantly lower on admission than those on discharge ( P < .05). In the sarcopenia group, the walking speed, MMSE score, FIM total score, and FIM motor score were significantly lower on admission than those on discharge ( P < .05); there was no significant difference in the FIM cognitive score between admission and discharge. On both admission and discharge, the MMSE score, FIM total score, FIM motor score, and FIM cognitive score were significantly better in the non-sarcopenia group than those in the sarcopenia group. Conclusions After postoperative rehabilitation of hip fractures in patients with and without sarcopenia, physical and cognitive function outcomes on discharge were significantly better than those on admission. Patients with sarcopenia had significantly worse physical and cognitive function outcomes than patients without sarcopenia both on admission and on discharge.
DYNLT1 promotes mitochondrial metabolism to fuel breast cancer development by inhibiting ubiquitination degradation of VDAC1
Authors: Huang Ling , Wei Bo , Zhao Yuran , Gong Xue , Chen Liming 
Published: June 2023

Abstract
Background
Mitochondrial metabolism has been proposed as an attractive target for breast cancer therapy. The discovery of new mechanisms underlying mitochondrial dysfunction will facilitate the development of new metabolic inhibitors to improve the clinical treatment of breast cancer patients. DYNLT1 (Dynein Light Chain Tctex-Type 1) is a key component of the motor complex that transports cellular cargo along microtubules in the cell, but whether and how DYNLT1 affects mitochondrial metabolism and breast cancer has not been reported.

Methods
The expression levels of DYNLT1 were analyzed in clinical samples and a panel of cell lines. The role of DYNLT1 in breast cancer development was investigated using in vivo mouse models and in vitro cell assays, including CCK-8, plate cloning and transwell assay. The role of DYNLT1 in regulating mitochondrial metabolism in breast cancer development is examined by measuring mitochondrial membrane potential and ATP levels. To investigate the underlying molecular mechanism, many methods, including but not limited to Co-IP and ubiquitination assay were used.

Results
First, we found that DYNLT1 was upregulated in breast tumors, especially in ER + and TNBC subtypes. DYNLT1 promotes the proliferation, migration, invasion and mitochondrial metabolism in breast cancer cells in vitro and breast tumor development in vivo. DYNLT1 colocalizes with voltage-dependent anion channel 1 (VDAC1) on mitochondria to regulate key metabolic and energy functions. Mechanistically, DYNLT1 stabilizes the voltage-dependent anion channel 1 (VDAC1) by hindering E3 ligase Parkin-mediated VDAC1 ubiquitination and degradation.

Conclusion
Our data demonstrate that DYNLT1 promotes mitochondrial metabolism to fuel breast cancer development by inhibiting Parkin-mediated ubiquitination degradation of VDAC1. This study suggests that mitochondrial metabolism can be exploited by targeting the DYNLT1-Parkin-VDAC1 axis to improve the ability of metabolic inhibitors to suppress cancers with limited treatment options, such as triple-negative breast cancer (TNBC).
Comprehensive analyses of a CD8+ T cell infiltration related gene signature with regard to the prediction of prognosis and immunotherapy response in lung squamous cell carcinoma
Authors: Chen Liang , Weng Yiming , Cui Xue , Li Qian , Peng Min , Song Qibin 
Published: June 2023

AbstractLung squamous cell carcinoma (LUSC) is associated with a worse prognosis than other histological subtypes of non-small cell lung cancer. Due to the vital role of CD8+ T cells in anti-tumor immunity, the characterization of CD8+ T cell infiltration-related (CTLIR) gene signature in LUSC is worthy of in-depth exploration. In our study, tumor tissues of LUSC patients from Renmin Hospital of Wuhan University were stained by multiplex immunohistochemistry to evaluate the density of infiltrated CD8+ T cells and explore the correlation with immunotherapy response. We found that the proportion of LUSC patients who responded to immunotherapy was higher in the high density of CD8+ T cell infiltration group than in the low density of CD8+ T cell infiltration group. Subsequently, we collected bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) database. The abundance of infiltrating immune cells in LUSC patients was analyzed by using CIBERSORT algorithm, and weighted correlation network analysis was performed to identify the co-expressed gene modules related to CD8+ T cells. We then developed a prognostic gene signature based on CD8+ T cell co-expressed genes and calculated the CTLIR risk score, which stratified LUSC patients into high-risk and low-risk groups. With univariate and multivariate analyses, the gene signature was identified as an independent prognostic factor in LUSC patients. The overall survival of LUSC patients in the high-risk group was significantly shorter than that of the low-risk group in the TCGA cohort, which was validated in Gene Expression Omnibus datasets. We analyzed immune cell infiltration in the tumor microenviroment and found fewer CD8+ T cells and more regulatory T cell infiltration in the high-risk group, which is characterized as an immunosuppressive phenotype. Furthermore, the LUSC patients in the high-risk group were predicted to have a better response to immunotherapy than those in the low-risk group when treated with PD-1 and CTLA4 inhibitors. In conclusion, we performed a comprehensive molecular analysis of the CTLIR gene signature in LUSC and constructed a risk model for LUSC patients to predict prognosis and immunotherapy response.
Genotype-degree of hemolysis correlation in hereditary spherocytosis
Authors: Shi Yimeng , Li Yuan , Yang Xiawan , Li Xiaoxia , Peng Guangxin , Zhao Xin , Liu Xu , Zhao Yufei , Hu Jing , Hu Xiangrong , Zhang Baohang , Zhou Kang , Yang Yang , Xiong Youzhen , Li Jianping , Fan Huihui , Yang Wenrui , Ye Lei , Jing Liping , Zhang Li , Zhang Fengkui 
Published: June 2023

Abstract
Background
Hereditary spherocytosis (HS) is a common inherited hemolytic anemia, caused by mutations in five genes that encode erythrocyte membrane skeleton proteins. The red blood cell (RBC) lifespan could directly reflect the degree of hemolysis. In the present cohort of 23 patients with HS, we performed next-generation sequencing (NGS) and Levitt’s carbon monoxide (CO) breath test to investigate the potential genotype-degree of hemolysis correlation.

Results
In the present cohort, we identified 8 ANK1,9 SPTB,5 SLC4A1 and 1 SPTA1 mutations in 23 patients with HS, and the median RBC lifespan was 14(8–48) days. The median RBC lifespan of patients with ANK1, SPTB and SLC4A1 mutations was 13 (8–23), 13 (8–48) and 14 (12–39) days, respectively, with no statistically significant difference (P = 0.618). The median RBC lifespan of patients with missense, splice and nonsense/insertion/deletion mutations was 16.5 (8–48), 14 (11–40) and 13 (8–20) days, respectively, with no significant difference (P = 0.514). Similarly, we found no significant difference in the RBC lifespan of patients with mutations located in the spectrin-binding domain and the nonspectrin-binding domain [14 (8–18) vs. 12.5 (8–48) days, P = 0.959]. In terms of the composition of mutated genes, 25% of patients with mild hemolysis carried ANK1 or SPTA1 mutations, while 75% of patients with mild hemolysis carried SPTB or SLC4A1 mutations. In contrast, 46.7% of patients with severe hemolysis had ANK1 or SPTA1 mutations and 53.3% of patients with severe hemolysis had SPTB or SLC4A1 mutations. However, there was no statistically significant difference in the distribution of mutated genes between the two groups (P = 0.400).

Conclusion
The present study is the first to investigate the potential association between genotype and degree of hemolysis in HS. The present findings indicated that there is no significant correlation between genotype and degree of hemolysis in HS.
SUsPECT: a pipeline for variant effect prediction based on custom long-read transcriptomes for improved clinical variant annotation
Authors: Salz Renee , Saraiva-Agostinho Nuno , Vorsteveld Emil , van der Made Caspar I. , Kersten Simone , Stemerdink Merel , Allen Jamie , Volders Pieter-Jan , Hunt Sarah E. , Hoischen Alexander , ’t Hoen Peter A.C. 
Published: June 2023

AbstractOur incomplete knowledge of the human transcriptome impairs the detection of disease-causing variants, in particular if they affect transcripts only expressed under certain conditions. These transcripts are often lacking from reference transcript sets, such as Ensembl/GENCODE and RefSeq, and could be relevant for establishing genetic diagnoses. We present SUsPECT (Solving Unsolved Patient Exomes/gEnomes using Custom Transcriptomes), a pipeline based on the Ensembl Variant Effect Predictor (VEP) to predict variant impact on custom transcript sets, such as those generated by long-read RNA-sequencing, for downstream prioritization. Our pipeline predicts the functional consequence and likely deleteriousness scores for missense variants in the context of novel open reading frames predicted from any transcriptome. We demonstrate the utility of SUsPECT by uncovering potential mutational mechanisms of pathogenic variants in ClinVar that are not predicted to be pathogenic using the reference transcript annotation. In further support of SUsPECT’s utility, we identified an enrichment of immune-related variants predicted to have a more severe molecular consequence when annotating with a newly generated transcriptome from stimulated immune cells instead of the reference transcriptome. Our pipeline outputs crucial information for further prioritization of potentially disease-causing variants for any disease and will become increasingly useful as more long-read RNA sequencing datasets become available.