bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neutral theory: applicability and neutrality of clinical study endpoints where a disease-specific instrument is available
Authors: Jandhyala Ravi 
Published: May 2023

Abstract
Background
There is a pressing need to improve the accuracy of rare disease clinical study endpoints. Neutral theory, first described here, can be used to assess the accuracy of endpoints and improve their selection in rare disease clinical studies, reducing the risk of patient misclassification.

Methods
Neutral theory was used to assess the accuracy of rare disease clinical study endpoints and the resulting probability of false positive and false negative classifications at different disease prevalence rates. Search strings were extracted from the Orphanet Register of Rare Diseases using a proprietary algorithm to conduct a systematic review of studies published until January 2021. Overall, 11 rare diseases with one disease-specific disease severity scale (133 studies) and 12 rare diseases with more than one disease-specific disease severity scale (483 studies) were included. All indicators from clinical studies were extracted, and Neutral theory was used to calculate their match to disease-specific disease severity scales, which were used as surrogates for the disease phenotype. For those with more than one disease-severity scale, endpoints were compared with the first disease-specific disease severity scale and a composite of all later scales. A Neutrality score of > 1.50 was considered acceptable.

Results
Around half the clinical studies for half the rare diseases with one disease-specific disease severity score (palmoplantar psoriasis, achalasia, systemic lupus erythematosus, systemic sclerosis and Fournier’s gangrene) met the threshold for an acceptable match to the disease phenotype, one rare disease (Guillain-Barré syndrome) had one study with an acceptable match, and four diseases (Behcet’s syndrome, Creutzfeldt-Jakob disease, atypical hemolytic uremic syndrome and Prader-Willi syndrome) had no studies. Clinical study endpoints in almost half the rare diseases with more than one disease-specific DSS (acromegaly, amyotrophic lateral sclerosis, cystic fibrosis, Fabry disease and juvenile rheumatoid arthritis) were a better match to the composite, while endpoints in the remaining rare diseases (Charcot Marie Tooth disease, Gaucher disease Type I, Huntington’s disease, Sjogren’s syndrome and Tourette syndrome) were a worse match. Misclassifications varied with increasing disease prevalence.

Conclusions
Neutral theory confirmed that disease-severity measurement needs improvement in rare disease clinical studies, especially for some diseases, and suggested that the potential for accuracy increases as the body of knowledge on a disease increases. Using Neutral theory to benchmark disease-severity measurement in rare disease clinical studies may reduce the risk of misclassification, ensuring that recruitment and treatment effect assessment optimise medicine adoption and benefit patients.
Peripheral CD4+CD25hiCD127low regulatory T cells are increased in patients with gastrointestinal cancer
Authors: Qiu Junlan , Shi Weiqiang , Zhang Jin , Gao Qinqin , Feng Lin , Zhuang Zhixiang 
Published: May 2023

Abstract
Background
Regulatory T cells (Tregs) play an important role in regulation of immune response and immunologic tolerance in cancer. Gastrointestinal cancer is still a leading cause of cancer-related death in the world. This study aimed to detect Tregs in patients with gastrointestinal cancer.

Methods
In this study, 45 gastric cancer patients, 50 colorectal cancer patients and 50 healthy controls were enrolled. Flow cytometry was used to detect CD4+CD25hiCD127low Tregs, CD4+CD25hi, and CD4+ cells in peripheral blood. Cytokine interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) in peripheral blood and in the supernatant of Tregs cultures were measured by enzyme linked immunosorbent assay.

Results
Compared with healthy controls, the levels of CD4+CD25hiCD127low Tregs and CD4+CD25hi cells increased significantly in patients with gastrointestinal cancer. Patients with gastrointestinal cancer also showed a significantly increased levels of IL-10 and TGF-β1 in both peripheral blood and CD4+CD25hiCD127low Tregs culture medium.

Conclusion
The present study firstly demonstrated that gastrointestinal patients have a compromised immune status where the CD4+CD25hiCD127low Tregs, as well as levels of IL-10 and TGF-β1 are elevated. The data offered new information for understanding the immunological features of gastrointestinal patients, as well as provided new insights into approaches to develop new immunotherapies for patients with gastrointestinal cancer.
Salmonella Durban meningitis: case report and genomics study
Authors: Diasi Christelle Nanga , Ceyssens Pieter-Jan , Vodolazkaia Alexandra , Mukovnikova Marina , Dorval Sarah , Bauraind Olivia , Mattheus Wesley 
Published: May 2023

Abstract
Background
Bacterial meningitis caused by non-typhoid Salmonella can be a fatal condition which is more common in low and middle-income countries.

Case presentation
We report the case of a Salmonella meningitis in a Belgian six-month old male infant. The first clinical examination was reassuring, but after a few hours, his general state deteriorated. A blood test and a lumbar puncture were therefore performed. The cerebrospinal fluid analysis was compatible with a bacterial meningitis which was later identified by the NRC (National Reference Center) as Salmonella enterica serovar Durban.

Conclusions
In this paper, we present the clinical presentation, genomic typing, and probable sources of infection for an unusually rare serovar of Salmonella. Through an extended genomic analysis, we established its relationship to historical cases with links to Guinea.
Effect of appropriate empirical antimicrobial therapy on mortality of patients with Gram-negative bloodstream infections: a retrospective cohort study
Authors: Xu Shanshan , Song Zhihui , Han Furong , Zhang Chao 
Published: May 2023

Abstract
Background
Little evidence exists regarding the prevalence of pathogens in bloodstream infections (BSIs), the mortality risk, and the benefit of combination therapy over monotherapy. This study aims to describe patterns of empiric antimicrobial therapy, and the epidemiology of Gram-negative pathogens, and to investigate the effect of appropriate therapy and appropriate combination therapy on the mortality of patients with BSIs.

Methods
This was a retrospective cohort study including all patients with BSIs of Gram-negative pathogens from January 2017 to December 2022 in a Chinese general hospital. The in-hospital mortality was compared between appropriate and inappropriate therapy, and between monotherapy and combination therapy for patients receiving appropriate therapy. We used Cox regression analysis to identify factors independently associated with in-hospital mortality.

Results
We included 205 patients in the study, of whom 147 (71.71%) patients received appropriate therapy compared with 58 (28.29%) who received inappropriate therapy. The most common Gram-negative pathogen was Escherichia coli (37.56%). 131 (63.90%) patients received monotherapy and 74 (36.10%) patients received combination therapy. The in-hospital mortality was significantly lower in patients administered appropriate therapy than inappropriate therapy (16.33% vs. 48.28%, p = 0.004); adjusted hazard ratio [HR] 0.55 [95% CI 0.35–0.84], p = 0.006). In-hospital mortality was also not different in combination therapy and monotherapy in the multivariate Cox regression analyses (adjusted HR 0.42 [95% CI 0.15–1.17], p = 0.096). However, combination therapy was associated with lower mortality than monotherapy in patients with sepsis or septic shock (adjusted HR 0.94 [95% CI 0.86–1.02], p = 0.047).

Conclusions
Appropriate therapy was associated with a protective effect on mortality among patients with BSIs due to Gram-negative pathogens. Combination therapy was associated with improved survival in patients with sepsis or septic shock. Clinicians need to choose optical empirical antimicrobials to improve survival outcomes in patients with BSIs.
Relationship between key continuous glucose monitoring-derived metrics and specific cognitive domains in patients with type 2 diabetes mellitus
Authors: Dong Shanshan , Wang Lina , Zhao Chenxu , Zhang Rui , Gao Zhaoyu , Jiang Lei , Guo Yingying , Zhou Huimin , Xu Shunjiang 
Published: May 2023

Abstract
Background
Continuous glucose monitoring (CGM)-derived time in range (TIR) is closely associated with micro- and macrovascular complications in type 2 diabetes mellitus (T2DM). This study was performed to investigate the relationship between key CGM-derived metrics and specific cognitive domains in patients with T2DM.

Methods
Outpatients with T2DM who were otherwise healthy were recruited for this study. A battery of neuropsychological tests was performed to evaluate cognitive function, including memory, executive functioning, visuospatial ability, attention, and language. Participants wore a blinded flash continuous glucose monitoring (FGM) system for 72 h. The key FGM-derived metrics were calculated, including TIR, time below range (TBR), time above range (TAR), glucose coefficient of variation (CV), and mean amplitude of glycemic excursions (MAGE). Furthermore, the glycemia risk index (GRI) was also calculated by the GRI formula. Binary logistic regression was used to assess risk factors for TBR, and we further analysed the associations between neuropsychological test results and key FGM-derived metrics with multiple linear regressions.

Results
A total of 96 outpatients with T2DM were recruited for this study, with 45.8% experiencing hypoglycemia (TBR< 3.9 mmol/L). Spearman analysis results revealed that a higher TBR< 3.9 mmol/L was correlated with worse performance on the Trail Making Test A (TMTA), Clock Drawing Test (CDT), and cued recall scores (P < 0.05). Logistic regression analysis results indicated that the TMTA (OR = 1.010, P = 0.036) and CDT (OR = 0.429, P = 0.016) scores were significant factors influencing the occurrence of TBR< 3.9 mmol/L. Multiple linear regressions further demonstrated that TBR< 3.9 mmol/L (β = -0.214, P = 0.033), TAR> 13.9 mmol/L (β = -0.216, P = 0.030) and TAR10.1–13.9 mmol/L (β = 0.206, P = 0.042) were significantly correlated with cued recall scores after adjusting for confounding factors. However, TIR, GRI, CV and MAGE showed no significant correlation with the results of neuropsychological tests (P > 0.05).

Conclusions
A higher TBR< 3.9 mmol/L and TAR> 13.9 mmol/L were associated with worse cognitive functions (memory, visuospatial ability, and executive functioning). Conversely, a higher TAR of 10.1–13.9 mmol/L was associated with better memory performance in memory tasks.
Association of chorioamnionitis with infertility treatment and subsequent neonatal outcomes in the US: a population-based cohort study
Authors: Ni Meng , Li Lijuan , Zhang Qianqian , Zhao Jiuru , Li Wei , Shen Qianwen , Yao Dongting , Wang Tao , Li Baihe , Ding Xiya , Qi Sudong , Liu Zhiwei 
Published: May 2023

Abstract
Background
Chorioamnionitis (CAM) is a common risk factor for preterm births, resulting in several adverse outcomes. The association between infertility treatment and CAM is unclear. Therefore, this study examined the association between infertility treatment and CAM and described subsequent neonatal outcomes.

Methods
This population-based cohort study used data from the National Vital Statistics System Database. We included women who had a singleton live birth from January 1, 2016 to December 31, 2018. Women-infant pairs were stratified by infertility treatment, and the main outcome was a reported diagnosis of CAM in a checkbox format: clinical CAM or maternal temperature of > 38 °C. Multivariate logistic regression was used to examine the association between infertility treatment and CAM and the effect of infertility treatment on neonatal outcomes in women diagnosed with CAM.

Results
The final sample comprised 10,900,495 woman-infant pairs, and 1.4% received infertility treatment. Compared with the natural conception group, women receiving infertility treatment had a significantly higher risk of CAM (adjusted odds ratio [aOR] 1.772 [95% confidence interval {CI}, 1.718–1.827]). Furthermore, newborns exposed to CAM had a higher risk of very low birth weight (VLBW) (aOR, 2.083 [95% CI, 1.664–2.606], P < .001), preterm birth (aOR, 1.497 [95% CI, 1.324–1.693]; P < .001), neonatal intensive care unit admission (aOR, 1.234 [95% CI, 1.156–1.317]; P < .001), and other adverse neonatal outcomes in the infertility treatment group compared with ones conceived naturally.

Conclusions
This study found that women who received infertility treatment had a higher risk of CAM. And CAM deteriorated neonatal outcomes in the infertility treatment group.
Real-world practice of conversion surgery for unresectable hepatocellular carcinoma - a single center data of 26 consecutive patients
Authors: Zhang Bo , Shi Xuetao , Cui Kai , Li Zhongchao , Li Lei , Liu Zhaogang , Zhang Chengsheng , Sun Pengfei , Zhong Jingtao , Sun Zhicheng , Chang Zhibin , Ma Zhao , Gordon-Weeks Alex , Li Mingming , Zhao Lei 
Published: May 2023

Abstract
Aim
To understand the proportion of uHCC (unresectable hepatocellular carcinoma) patients who achieve successful conversion resection in a high-volume setting with state of the art treatment options.

Methods
We retrospectively reviewed all HCC patients hospitalized to our center from June 1st, 2019 to June 1st, 2022. Conversion rate, clinicopathological features, response to systemic and/or loco-regional therapy and surgical outcomes were analyzed.

Results
A total of 1,904 HCC patients were identified, with 1672 patients receiving anti-HCC treatment. 328 patients were considered up-front resectable. Of the remaining 1344 uHCC patients, 311 received loco-regional treatment, 224 received systemic treatment, and the remainder (809) received combination systemic plus loco-regional treatment. Following treatment, one patient from the systemic group and 25 patients from the combination group were considered to have resectable disease. A high objective response rate (ORR) was observed in these converted patients (42.3% under RECIST v1.1 and 76.9% under mRECIST criteria). The disease control rate (DCR) reached 100%. 23 patients underwent curative hepatectomy. Major post-operative morbidity was equivalent in the both groups (P=0.76). Pathologic complete response (pCR) was 39.1%. During conversion treatment, grade 3 or higher treatment-related adverse events (TRAEs) were observed in 50% of patients. The median follow-up time was 12.9 months (range, 3.9~40.6) from index diagnosis and 11.4 months (range, 0.9~26.9) from resection. Three patients experienced disease recurrence following conversion surgery.

Conclusions
By intensive treatment, a small sub-group of uHCC patients (2%) may potentially be converted to curative resection. Loco-regional combined with systemic modality was relative safe and effective in the conversion therapy. Short-term outcomes are encouraging, but long-term follow-up in a larger patient population are required to fully understand the utility of this approach.
Long-term effectiveness and safety of lacosamide as adjunctive therapy in children and adolescents with refractory epilepsy: a real-world study
Authors: Zhao Ting , Yu Lu-hai , Zhang Hui-lan , Yu Jing , Feng Jie , Wang Ting-ting , Sun Yan , Li Hong-jian 
Published: May 2023

Abstract
Purpose
The effectiveness and tolerability of lacosamide (LCM) among Chinese children and adolescents with refractory epilepsy has not yet been established. Therefore, the objective of this study was to assess the effectiveness and tolerability of LCM among children and adolescents with refractory epilepsy in Xinjiang, Northwest China.

Methods
Effectiveness was assessed by measuring changes in seizure frequency at 3, 6 and 12 months compared with baseline. Patients that achieved ≥ 50% reduction in the frequency of all seizures per month, relative to baseline, were considered to be responders.

Results
105 children and adolescents with refractory epilepsy were enrolled in the study. The responder rates were 47.6%, 39.2%, and 31.9%, respectively at 3, 6, and 12 months. Seizure freedom rates were 32.4%, 28.9%, and 23.6% at 3, 6, and 12 months, respectively. The retention rates at 3, 6, and 12 months were 92.4%, 78.1%, and 69.5%, respectively. The maintenance dose of LCM within the responder group (8.2 ± 4.5 mg·kg− 1·d− 1) was significantly higher compared to the non-responder group (7.3 ± 2.3 mg·kg− 1·d− 1) (p < 0.05). At first follow-up, 44 patients (41.9%) reported experiencing at least one treatment-emergent adverse events.

Conclusion
This real-world study of children and adolescents validated that LCM was both an effective and well-tolerated treatment option for the treatment of refractory epilepsy.
Improved access to HIV diagnosis and linkage to antiretroviral therapy among children in Southern Nigeria: a before-after study
Authors: Nwanja Esther , Nwaokoro Pius , Akpan Uduak , Toyo Otoyo , Ezeh Golda , Elechi Iheanyichukwu , Idiong Helen , Badru Titilope , Sanwo Olusola , Idemudia Augustine , Pandey Satish Raj , Khamofu Hadiza , Bateganya Moses 
Published: May 2023

Abstract
Background
Globally, two out of five children living with HIV (CLHIV) are unaware of their HIV status, and a little more than 50% are receiving antiretroviral therapy (ART). This paper describes case-finding strategies and their contribution to identifying CLHIV and linking them to ART in Nigeria.

Methods
This before-after study used program data abstracted during the implementation of different paediatric-focused strategies (provider-initiated testing and counselling, orphans and vulnerable children testing, family-based index testing, early infant diagnosis (EID), community-driven EID, and community-based testing) delivered in health facilities and in communities to improve HIV case identification. Data were abstracted for children (0 to 14 years) who received HIV testing services and were initiated on ART in Akwa Ibom State, Nigeria during the pre-implementation period (April–June 2021) and during the implementation period (July–September 2021). Descriptive statistics were used to describe the testing coverage, positivity rate (proportion of tests that were positive for HIV), linkage to ART, and ART coverage, by age, sex, and testing modality. Interrupted time series analysis (ITSA) on STATA 14 was used to estimate the effect of the implementation of these strategies on HIV testing uptake and positivity rate at a 0.05 significance level.

Results
A total of 70,210 children were tested for HIV within the six-month period, and 1,012 CLHIV were identified. A total of 78% (n = 54,821) of the tests and 83.4% (n = 844) CLHIV were diagnosed during the implementation period. During implementation, the HIV positivity rate increased from 1.09% (168/15,389) to 1.54% (844/54,821), while linkage to ART increased from 99.4% (167/168) to 99.8% (842/844). The contribution from community-based modalities to CLHIV identified increased from 63% (106/168) to 84% (709/844) during the implementation, with the majority, 60.8% (431/709), from community-based index testing. Overall, ART coverage increased from 39.7 to 55.6% at the end of the intervention period.

Conclusion
The findings show that expanding differentiated HIV testing approaches provided mostly in the community significantly increased pediatric case identification. However, ART coverage remains low, especially for younger age groups, and requires further efforts.
Survival of children with trisomy 18 associated with the presence of congenital heart disease and intervention in the Republic of Korea
Authors: Song In Gyu , Shin Seung Han , Cho Yoon-Min , Lim Youna 
Published: May 2023

Abstract
Background
Trisomy 18 syndrome (T18) is the second most common autosomal trisomy and has a high risk of fetal loss and stillbirth. Aggressive surgical treatments for the respiratory, cardiac, or digestive systems of patients with T18 were previously futile, while the results of recent studies are controversial. Over the past decade, there have been approximately 300,000 to 400,000 births annually in the Republic of Korea; however, there have been no nationwide studies on T18. This nationwide retrospective cohort study aimed to determine the prevalence of T18 in Korea and its prognosis according to the presence of congenital heart disease and relevant interventions.

Methods
This study utilized NHIS-registered data between 2008 and 2017. A child was defined as having T18 if the ICD-10 revision code Q91.0–3 was reported. Subgroup analysis was performed for children with congenital heart diseases, and survival rates were compared based on the history of cardiac surgical or catheter interventions. The primary outcomes in this study were the survival rate during the first hospitalization period and the 1-year survival rate.

Results
Of the children born between 2008 and 2017, 193 were diagnosed with T18. Of these, 86 died, with a median survival of 127 days. The 1-year survival rate for children with T18 was 63.2%. The survival rate in the first admission of children with T18 who did and did not have congenital heart disease was 58.3% and 94.1%, respectively. Children with heart disease who underwent surgical or catheter intervention had a longer survival time than those who did not.

Conclusions
We suggest these data could be used in ante- and postnatal counseling. Ethical concerns about the prolonged survival of children with T18 remain; however, the potential benefits of interventions for congenital heart disease in this population need further study.
Vitamin D supplementation improved physical growth and neurologic development of Preterm Infants receiving Nesting Care in the neonatal Intensive Care Unit
Authors: Tang Wei-qin , Ma Ning , Meng Li-ying , Luo Ya-wen , Wang Ying-jie , Zhang Di 
Published: May 2023

Abstract
Objective
To study the effects of vitamin D supplementation on physical growth and neurologic development of very preterm infants receiving nesting intervention in the neonatal intensive care unit (NICU).

Methods
A total of 196 preterm infants had been hospitalized in NICU with the gestational age (GA) between 28 and 32 weeks. Among them, 98 preterm infants received nesting intervention, and the other 98 cases received both nesting and vitamin D supplementation (400 IU). The interventions were continued until 36 weeks postmenstrual age (PMA). The 25(OH)D serum levels, anthropometric parameters, and Premie-Neuro (PN) scores were compared at 36 weeks PMA.

Results
Higher median serum level of 25(OH)D was found in the nesting + vitamin D [38.40 ng/mL (IQR: 17.20 ~ 70.88) ng/mL] as compared to the nesting group [15.95 ng/mL (IQR: 10.80 ~ 24.30) ng/mL] at 36 weeks PMA. Besides, infants receiving combined nesting intervention and vitamin D supplementation had less proportion of vitamin D deficiency [VDD, 25(OH)D levels < 20 ng/mL] than those receiving nesting intervention alone. After intervention, the anthropometric parameters of infants, including weight, length, BMI and head circumference were improved in the nesting + vitamin D group as compared to the nesting group at 36 weeks PMA, with higher scores of neurological, movement and responsiveness.

Conclusions
Vitamin D supplementation effectively decreased the prevalence of VDD and led to higher concentrations of 25(OH)D at 36 weeks PMA. This was one more study that supported the necessity of vitamin D supplementation to improve physical growth and neurologic development of preterm-born newborns who received nesting intervention in the NICU.