bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and effectiveness of neoadjuvant PD-1 inhibitor (toripalimab) plus chemotherapy in stage II–III NSCLC (LungMate 002): an open-label, single-arm, phase 2 trial
Authors: Zhu Xinsheng , Sun Liangdong , Song Nan , He Wenxin , Xie Boxiong , Hu Junjie , Zhang Jing , Yang Jie , Dai Jie , Bian Dongliang , Xia Haoran , Sun Fenghuan , Xiong Anwen , Luo Jie , Zhang Lele , Yu Huansha , Liu Ming , Liu Hongcheng , Wang Haifeng , Zhang Haiping , Chen Chang , Wu Chunyan , Duan Liang , Zhu Yuming , Zhang Peng , Jiang Gening 
Published: December 2022

Abstract
Background
This trial aimed to analyse the safety, effectiveness and transcriptomic characteristics of neoadjuvant toripalimab plus chemotherapy in II–III non-small-cell lung cancer (NSCLC).

Methods
Patient eligibility mainly involved treatment-naive, clinical stage II–III and wild-type EGFR/ALK NSCLC. The patients received 2–4 cycles of toripalimab (240 mg q3w) plus carboplatin-based chemotherapy. After the second treatment cycle, all patients were re-evaluated by a multidisciplinary team. Candidates eligible for surgery underwent surgery; otherwise, patients received the remaining treatment cycles. The primary endpoints were safety and major pathological response (MPR). Secondary endpoints were R0 resection rate, progression-free survival (PFS) and overall survival (OS). RNA sequencing of baseline and post-treatment samples was conducted to explore the transcriptomic characteristics of the therapeutic response.

Results
In total, 50 eligible patients were enrolled, including 12 (24.0%) with resectable disease (RD) and 38 (76.0%) with potentially resectable disease (PRD). Treatment-related adverse events (TRAEs) were recorded in 48 cases (96.0%). Severe TRAEs occurred in 3 (6.0%) cases, including myelosuppression, drug-induced liver injury and death related to haemoptysis. The objective response rate (ORR) was 76.0%, with 8 (16.0%) patients having a complete response (CR), 30 (60.0%) partial response (PR), 10 (20.0%) stable disease (SD) and 2 (4.0%) progressive disease (PD). Surgery could be achieved in 12 (100%) patients with RD and 25 (65.8%) with PRD; 1 (2.0%) with PRD refused surgery. Therefore, R0 resection was performed for all 36 (100%) patients who underwent surgery; 20 (55.6%) achieved MPR, including 10 (27.8%) with a complete pathological response (pCR). The CHI3L1 (chitinase-3-like protein 1) immunohistochemistry (IHC) expression of baseline tumour samples could predict the therapeutic response (AUC=0.732), OS (P=0.017) and PFS (P=0.001). Increased PD-1 expression, T cell abundance and immune-related pathway enrichment were observed in post-treatment samples compared to baseline in the response group (CR+PR) but not in the non-response group (SD+PD).

Conclusions
Neoadjuvant toripalimab plus chemotherapy was safe and effective, with a high MPR and manageable TRAEs for II–III NSCLC, even converting initially PRD to RD. Disparate transcriptomic characteristics of therapeutic efficiency were observed, and CHI3L1 expression predicted therapeutic response and survival.

Trial registration
ChiCTR1900024014, June 22, 2019.
Subannular repair for functional mitral regurgitation with reduced systolic ventricle function: rationale and design of REFORM-MR registry
Authors: Girdauskas Evaldas , Pausch Jonas , Reichenspurner Hermann , Kempfert Jörg , Kuntze Thomas , Owais Tamer , Holubec Tomas , Krane Markus , Vitanova Keti , Borger Michael , Eden Matthias , Hachaturyan Violetta , Bramlage Peter , Falk Volkmar 
Published: December 2022

Abstract
Background
Functional mitral regurgitation (FMR) is one of the most common heart valve diseases that is a sequel of left ventricular remodelling. Although mitral valve annuloplasty is a standard treatment of FMR, the recurrence of FMR is a major drawback and occurs in 10–50% of patients. The REFORM-MR registry aims to investigate the effectiveness of standardized papillary muscle relocation and ring annuloplasty and to identify the risk factors associated with recurrent FMR.

Methods
REFORM-MR is a prospective, multicenter registry that enrols consecutive FMR patients across five sites in Germany. All patients with FMR and restricted movement of leaflets during systole (i.e., type IIIb mitral regurgitation) undergoing standardized subannular repair in combination with mitral valve annuloplasty are included in the study. The primary objective is to examine the effect of combined papillary muscle relocation and ring annuloplasty on the recurrence of FMR at 2 years postoperatively. The secondary objectives are MACCE rate, reinterventions on the mitral valve and cardiac-related mortality in the study cohort. Echocardiography core-lab and MRI core-lab will provide anonymized analysis of the imaging data in the REFORM-MR registry. Student’s t-test or Mann–Whitney U test for continuous variables and the Chi-Square or Fisher exact test for categorical variables are used for group comparisons. Kaplan–Meier analyses is performed for survival and safety outcomes.

Results
As of May 2021, a total of 97 patients were enrolled across five sites in Germany.

Conclusions
The results of this study will help define the outcomes of combined papillary muscle relocation and ring annuloplasty in the FMR treatment in a multicentre setting and to improve the understanding of the limitations of subannular repair procedures while treating patients with type III FMR.
Trial registration clinicaltrials.gov Identifier: NCT03470155.
The impact of a postoperative multimodal analgesia pathway on opioid use and outcomes after cardiothoracic surgery
Authors: Ward Ceressa T. , Moll Vanessa , Boorman David W. , Ooroth Lijo , Groff Robert F. , Gillingham Trent D. , Pyronneau Laura , Prabhakar Amit 
Published: December 2022

Abstract
Objective
The Enhanced Recovery after Surgery Cardiac Society recommends using multimodal analgesia (MMA) for postoperative pain however, evidence-based guidelines have yet to be established. This study examines the impact of a standardized postoperative MMA pathway in reducing opioid consumption and related complications after cardiothoracic surgery (CTS).

Methods
Within a multicenter healthcare system, a postoperative MMA pathway was developed and implemented at two CTS intensive care units (ICU) while the other CTS ICU opted to maintain the existing opioid-based pathway. A retrospective chart review was conducted on patients admitted to a CTS ICU within this healthcare system after conventional coronary artery bypass grafting and/or valve surgery from September 1, 2018, to June 30, 2019. Comparative analysis was conducted on patients prescribed MMA versus those managed with an opioid-based pathway. The primary outcome was total opioid consumption, converted to morphine milligram equivalents, 72-h post-surgery. Secondary outcomes included mobility within one-day post-surgery, ICU length of stay (LOS), time to first bowel movement (BM), and time to first zero Richmond Agitation-Sedation Scale (RASS).

Results
Seven hundred sixty-two adults were included for final analysis. The MMA group had a higher body mass index, higher percentage of females, were more likely classified as African American and had higher scores for risk-adjusted complications. General Linear Model analysis revealed higher opioid consumption in the MMA group (Est. 0.22, p < 0.0009); however, this was not statistically significant after adjusting for differences in fentanyl usage. The MMA group was more likely to have mobility within one-day post-surgery (OR 0.44, p < 0.0001), have longer time to first BM (OR 1.93, p = 0.0011), and longer time to first zero RASS (OR 1.62, p = 0.0071). The analgesia groups were not a predictor for ICU LOS.

Conclusions
Opioid consumption was not reduced secondary to this postoperative MMA pathway. The MMA group was more likely to have mobility within one-day post-surgery. Patients in the MMA group were also more likely to have prolonged time to first BM and first zero RASS. Development and evaluation of a perioperative MMA pathway should be considered.
Copy number variation analysis in 189 Romanian patients with global developmental delay/intellectual disability
Authors: Miclea Diana , Osan Sergiu , Bucerzan Simona , Stefan Delia , Popp Radu , Mager Monica , Puiu Maria , Zimbru Cristian , Chirita-Emandi Adela , Alkhzouz Camelia 
Published: December 2022

Abstract
Background
Developmental delay and intellectual disability represent a common pathology in general population, involving about 3% of the pediatric age population, the genetic etiology being often involved. The aim of this study was to determine the clinically relevant copy number variants in patients diagnosed with global developmental delay/intellectual disability in our population, using the chromosomal microarray analysis.

Methods
We analyzed 189 patients diagnosed with global developmental delay/intellectual disability, presented in Clinical Emergency Hospital for Children, Cluj-Napoca. The patients were completely clinically investigated, including dysmorphic and internal malformations evaluation, psychiatric, neuropsychological and metabolic evaluation, standard karyotyping. Genomic analysis was done using chromosomal microarray analysis.

Results
Pathogenic findings (including uniparental disomy) and variants of unknown significance were detected in 53 of 189 patients (28.04%). Pathogenic copy number variants and uniparental disomy were observed in 35 of 189 patients (18.51%). Two patients presented uniparental disomy for chromosome 15, one with clinical phenotype of Prader-Willi syndrome and the other with clinical phenotype with Angelman syndrome. Within the category of pathogenic findings, the recurrent copy number variants were seen in 21 of 35 patients (60%).

Conclusions
The increased percentage of pathogenic structural variants observed in patients with global developmental delay/intellectual disability analyzed by chromosomal microarray technique supports its use in patients with a non-specific phenotype such as these neurodevelopmental disorders. The high percentage of recurrent pathogenic variants between these findings is a finding that support their initial evaluation when a genetic testing algorithm could be a useful option.
A one-year genomic investigation of Escherichia coli epidemiology and nosocomial spread at a large US healthcare network
Authors: Mills Emma G. , Martin Melissa J. , Luo Ting L. , Ong Ana C. , Maybank Rosslyn , Corey Brendan W. , Harless Casey , Preston Lan N. , Rosado-Mendez Joshua A. , Preston Scott B. , Kwak Yoon I. , Backlund Michael G. , Bennett Jason W. , Mc Gann Patrick T. , Lebreton Francois 
Published: December 2022

AbstractBackgroundExtra-intestinal pathogenicEscherichia coli(ExPEC) are a leading cause of bloodstream and urinary tract infections worldwide. Over the last two decades, increased rates of antibiotic resistance inE. colihave been reported, further complicating treatment. Worryingly, specific lineages expressing extended-spectrumβ-lactamases (ESBLs) and fluoroquinolone resistance have proliferated and are now considered a serious threat. Obtaining contemporary information on the epidemiology and prevalence of these circulating lineages is critical for containing their spread globally and within the clinic.MethodsWhole-genome sequencing (WGS), phylogenetic analysis, and antibiotic susceptibility testing were performed for a complete set of 2075E. coliclinical isolates collected from 1776 patients at a large tertiary healthcare network in the USA between October 2019 and September 2020.ResultsThe isolates represented two main phylogenetic groups, B2 and D, with six lineages accounting for 53% of strains: ST-69, ST-73, ST-95, ST-131, ST-127, and ST-1193. Twenty-seven percent of the primary isolates were multidrug resistant (MDR) and 5% carried an ESBL gene. Importantly, 74% of the ESBL-E.coliwere co-resistant to fluoroquinolones and mostly belonged to pandemic ST-131 and emerging ST-1193. SNP-based detection of possible outbreaks identified 95 potential transmission clusters totaling 258 isolates (12% of the whole population) from ≥ 2 patients. While the proportion of MDR isolates was enriched in the set of putative transmission isolates compared to sporadic infections (35 vs 27%,p= 0.007), a large fraction (61%) of the predicted outbreaks (including the largest cluster grouping isolates from 12 patients) were caused by the transmission of non-MDR clones.ConclusionBy coupling in-depth genomic characterization with a complete sampling of clinical isolates for a full year, this study provides a rare and contemporary survey on the epidemiology and spread ofE. coliin a large US healthcare network. While surveillance and infection control efforts often focus on ESBL and MDR lineages, our findings reveal that non-MDR isolates represent a large burden of infections, including those of predicted nosocomial origins. This increased awareness is key for implementing effective WGS-based surveillance as a routine technology for infection control.
Genome-wide placental DNA methylations in fetal overgrowth and associations with leptin, adiponectin and fetal growth factors
Authors: Yang Meng-Nan , Huang Rong , Zheng Tao , Dong Yu , Wang Wen-Juan , Xu Ya-Jie , Mehra Vrati , Zhou Guang-Di , Liu Xin , He Hua , Fang Fang , Li Fei , Fan Jian-Gao , Zhang Jun , Ouyang Fengxiu , Briollais Laurent , Li Jiong , Luo Zhong-Cheng ,   for the Shanghai Birth Cohort
Published: December 2022

Abstract
Background
Fetal overgrowth “programs” an elevated risk of type 2 diabetes in adulthood. Epigenetic alterations may be a mechanism in programming the vulnerability. We sought to characterize genome-wide alterations in placental gene methylations in fetal overgrowth and the associations with metabolic health biomarkers including leptin, adiponectin and fetal growth factors.

Results
Comparing genome-wide placental gene DNA methylations in large-for-gestational-age (LGA, an indicator of fetal overgrowth, n = 30) versus optimal-for-gestational-age (OGA, control, n = 30) infants using the Illumina Infinium Human Methylation-EPIC BeadChip, we identified 543 differential methylation positions (DMPs; 397 hypermethylated, 146 hypomethylated) at false discovery rate < 5% and absolute methylation difference > 0.05 after adjusting for placental cell-type heterogeneity, maternal age, pre-pregnancy BMI and HbA1c levels during pregnancy. Twenty-five DMPs annotated to 20 genes (QSOX1, FCHSD2, LOC101928162, ADGRB3, GCNT1, TAP1, MYO16, NAV1, ATP8A2, LBXCOR1, EN2, INCA1, CAMTA2, SORCS2, SLC4A4, RPA3, UMAD1,USP53, OR2L13 and NR3C2) could explain 80% of the birth weight variations. Pathway analyses did not detect any statistically significant pathways after correcting for multiple tests. We validated a newly discovered differentially (hyper-)methylated gene-visual system homeobox 1 (VSX1) in an independent pyrosequencing study sample (LGA 47, OGA 47). Our data confirmed a hypermethylated gene—cadherin 13 (CDH13) reported in a previous epigenome-wide association study. Adiponectin in cord blood was correlated with its gene methylation in the placenta, while leptin and fetal growth factors (insulin, IGF-1, IGF-2) were not.

Conclusions
Fetal overgrowth may be associated with a large number of altered placental gene methylations. Placental VSX1 and CDH13 genes are hypermethylated in fetal overgrowth. Placental ADIPOQ gene methylations and fetal circulating adiponectin levels were correlated, suggesting the contribution of placenta-originated adiponectin to cord blood adiponectin.
Cerebrovascular complications and outcomes of critically ill adult patients with infective endocarditis
Authors: Rambaud Thomas , de Montmollin Etienne , Jaquet Pierre , Gaudemer Augustin , Mariotte Eric , Abid Sonia , Para Marylou , Cimadevilla Claire , Iung Bernard , Duval Xavier , Wolff Michel , Bouadma Lila , Timsit Jean-François , Sonneville Romain 
Published: December 2022

Abstract
Background
Neurological complications are associated with poor outcome in patients with infective endocarditis (IE). Although guidelines recommend systematic brain imaging in the evaluation of IE patients, the association between early brain imaging findings and outcomes has never been evaluated in critically ill patients. We aimed to assess the association of CT-defined neurological complications with functional outcomes of critically ill IE patients.

Methods
This retrospective cohort study included consecutive patients with severe, left-sided IE hospitalized in the medical ICU of a tertiary care hospital. Patients with no baseline brain CT were excluded. Baseline CT-scans were classified in five mutually exclusive categories (normal, moderate-to-severe ischemic stroke, minor ischemic stroke, intracranial hemorrhage, other abnormal CT). The primary endpoint was 1-year favorable outcome, defined by a modified Rankin Scale score of 0–3.

Results
Between 06/01/2011 and 07/31/2018, 156 patients were included. Among them, 87/156 (56%) had a CT-defined neurological complication, including moderate-to-severe ischemic stroke (n = 33/156, 21%), intracranial hemorrhage (n = 24/156, 15%), minor ischemic stroke (n = 29/156, 19%), other (n = 3/156, 2%). At one year, 69 (45%) patients had a favorable outcome. Factors negatively associated with favorable outcome in multivariable analysis were moderate-to-severe ischemic stroke (OR 0.37, 95%CI 0.14 − 0.95) and age (OR 0.94, 95%CI 0.91–0.97). By contrast, the score on the Glasgow Coma Scale was positively associated with favorable outcome (per 1-point increment, OR 1.23, 95%CI 1.08–1.42). Sensitivity analyses conducted in operated patients revealed similar findings. Compared to normal CT, only moderate-to-severe ischemic stroke was associated with more frequent post-operative neurological complications (n = 8/23 (35%) vs n = 1/46 (2%), p < 0.01).

Conclusion
Moderate-to-severe ischemic stroke had an independent negative impact on 1-year functional outcome in critically ill IE patients; whereas other complications, including intracranial hemorrhage, had no such impact.
What drives mixed-species shoaling among wild zebrafish? The roles of predators, food access, abundance of conspecifics and familiarity
Authors: Mukherjee Ishani , Bhat Anuradha 
Published: December 2022

ABSTRACT
Mixed-species groups occur across a wide range of faunal communities and provide several benefits to members. While zebrafish have often been observed to form mixed-species shoals with coexisting species, the factors determining their occurrence are not yet fully understood. Shoals comprising zebrafish (Danio rerio), flying barbs (Esomus danricus), and whitespots (Aplocheilus panchax) were collected from a stagnant canal at Haringhata (West Bengal, India), and using laboratory-based experiments, we deciphered likely drivers of mixed-species shoaling among zebrafish. Experiments assessing foraging efficiency revealed that the amount of food consumed by individual zebrafish in mixed shoals was comparable to the amount consumed by these individuals in conspecific shoals. Within mixed-species shoals, zebrafish individuals, despite being smaller than the other species, consumed a comparable amount of food as the other species. Shoal choice experiments revealed that under predator risk, zebrafish associate more with mixed shoals and showed comparable associations to shoals differing in the abundance of conspecifics. Furthermore, zebrafish preferred associating with familiar conspecifics over unfamiliar mixed and unfamiliar conspecific shoals. Therefore, equitable food consumption in mixed shoals, greater association with mixed shoals in the presence of predators, and familiarity were important in driving zebrafish towards mixed-species shoaling.
This article has an associated First Person interview with the first author of the paper.
Exploring the spatial variation and associated factors of childhood febrile illness among under-five children in Ethiopia: Geographically weighted regression analysis
Authors: Gelaw Negalgn Byadgie , Tessema Getayeneh Antehunegn , Gelaye Kassahun Alemu , Tessema Zemenu Tadesse , Ferede Tigist Andargie , Tewelde Abebe W/Selassie 
Published: December 2022

Background
The global burden of febrile illness and the contribution of many fever inducing pathogens have been difficult to quantify and characterize. However, in sub-Saharan Africa it is clear that febrile illness is a common cause of hospital admission, illness and death including in Ethiopia. Therefore the major aim of this study is to explore the spatial variation and associated factors of childhood febrile illness among under-five children in Ethiopia.

Methods
This study were based on the 2016 Ethiopian Demographic health survey data. A total weighted sample of 10,127 under- five children was included. Data management was done using Stata version-14, Arc-GIS version—10.8 and SatsScan version- 9.6 statistical software. Multi-level log binomial model was fitted to identify factors associated with childhood febrile illness. Variables with a p-value < 0.2 in the bi-variable analysis were considered for the multivariable analysis. In the multivariable multilevel log binomial regression analysis p-value< 0.05, the APR with the 95% CI was reported. Global spatial autocorrelation was done to assess the spatial pattern of childhood febrile illness. Spatial regression was done to identify factors associated with the spatial variations of childhood febrile illness and model comparison was based on adjusted R2 and AICc.

Result
The prevalence of febrile illness among under-five children was 13.6% (95% CI: 12.6%, 14 .7%) with significant spatial variation across regions of Ethiopia with Moran’s I value of 0.148. The significant hotspot areas of childhood febrile illness were identified in the Tigray, Southeast of Amhara, and North SNPPR. In the GWR analysis, the proportion of PNC, children who had diarrhea, ARI, being 1st birth order, were significant explanatory variables. In the multilevel log binomial regression age of children 7–24 months(APR = 1.33, 95% CI: (1.03, 1.72)), maternal age 30–39 years (APR = 1.36 95% CI: 1.02, 1.80)), number of children (APR = 1.78, 95% CI: 0.96, 3.3), diarrhea(APR = 5.3% 95% CI: (4.09, 6.06)), ARI (APR = 11.5, 95% CI: (9.2, 14.2)) and stunting(APR = 1.21; 95% CI: (0.98, 1.49) were significantly associated with childhood febrile illness.

Conclusion
Childhood febrile illness remains public health problem in Ethiopia. On spatial regression analysis proportion of women who had PNC, proportion of children who had diarrhea, proportion of children who had ARI, and proportion of children who had being 1st birth order were associated factors. The detailed map of childhood febrile illness and its predictors could assist health program planners and policy makers to design targeted public health interventions for febrile illness.