bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk and benefit for umbrella trials in oncology: a systematic review and meta-analysis
Authors: Strzebonska Karolina , Blukacz Mateusz , Wasylewski Mateusz T. , Polak Maciej , Gyawali Bishal , Waligora Marcin 
Published: July 2022

Abstract
Background
Umbrella clinical trials in precision oncology are designed to tailor therapies to the specific genetic changes within a tumor. Little is known about the risk/benefit ratio for umbrella clinical trials. The aim of our systematic review with meta-analysis was to evaluate the efficacy and safety profiles in cancer umbrella trials testing targeted drugs or a combination of targeted therapy with chemotherapy.

Methods
Our study was prospectively registered in PROSPERO (CRD42020171494). We searched Embase and PubMed for cancer umbrella trials testing targeted agents or a combination of targeted therapies with chemotherapy. We included solid tumor studies published between 1 January 2006 and 7 October 2019. We measured the risk using drug-related grade 3 or higher adverse events (AEs), and the benefit by objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). When possible, data were meta-analyzed.

Results
Of the 6207 records identified, we included 31 sub-trials or arms of nine umbrella trials (N = 1637). The pooled overall ORR was 17.7% (95% confidence interval [CI] 9.5–25.9). The ORR for targeted therapies in the experimental arms was significantly lower than the ORR for a combination of targeted therapy drugs with chemotherapy: 13.3% vs 39.0%; p = 0.005. The median PFS was 2.4 months (95% CI 1.9–2.9), and the median OS was 7.1 months (95% CI 6.1–8.4). The overall drug-related death rate (drug-related grade 5 AEs rate) was 0.8% (95% CI 0.3–1.4), and the average drug-related grade 3/4 AE rate per person was 0.45 (95% CI 0.40–0.50).

Conclusions
Our findings suggest that, on average, one in five cancer patients in umbrella trials published between 1 January 2006 and 7 October 2019 responded to a given therapy, while one in 125 died due to drug toxicity. Our findings do not support the expectation of increased patient benefit in cancer umbrella trials. Further studies should investigate whether umbrella trial design and the precision oncology approach improve patient outcomes.
Exome sequencing contributes to identify comorbidities in a rare case of infant ARDS induced by the CD40LG mutation
Authors: Gong Xue , He Yunru , Lu Guoyan , Zhang Yulin , Qiu Yu , Qiao Lina , Li Yifei 
Published: July 2022

Abstract
Background
Acute respiratory distress syndrome (ARDS) causes significant mortality in young children with certain diseases. Early diagnosis and treatment can reduce infant mortality. Here, we report a rare case of exome sequencing in the early diagnosis of immunodeficiency in an infant.

Case presentation
A four-month-old full-term male infant presented with severe shortness of breath, hypoxemia, and unexplained parenchymal lung lesions. A series of examinations were performed to search for potential culprit viruses but negative results were obtained with the only exception being the rhinovirus that tested positive. The child’s family history revealed he had a brother who died of severe infection at the age of two years. We performed an exome sequencing analysis and a mutation analysis of CD40LG to obtain genetic data on the patient. Besides, we used flow cytometry to measure the CD40LG expression levels of activated T cells. A retrospective review of all the CD40LG mutant-induced X-linked hyper IgM syndromes (XHIGM) had been conducted to assess the differences between clinical and genetic molecular features. Finally, a regular intravenous immunoglobulin (IVIG) regimen led to steady breathing, the correction of hypoxemia, and a progressive improvement of lung CT scans. During follow-up, the patient received an IVIG regimen and his CT images improved. Moreover, his parents took advantage of pre-implantation genetic testing with in vitro fertilization to have a healthy twin offspring who did not carry such a mutation according to the early exome sequencing for the proband. Compared with other CD40LG mutant cases in our center, this proband displayed a normal plasma immunoglobulin level and he should be the youngest infant to have a molecular diagnosis of XHIGM.

Conclusion
Usually, XHIGM would not be suspected with a normal plasma immunoglobulin concentration. However, as we could not identify a potential comorbidity or risk factor, exome sequencing helps target this patient's real facts. Thus, this case report calls for exome sequencing to be performed in the case of unexplained infections when immunodeficiency is suspected after general immunological tests, especially for cases with a contributive family history among infants as the maternal transfused immunoglobulin might mask immune deficiency.
A signature of immune-related gene pairs (IRGPs) for risk stratification and prognosis of oral cancer patients
Authors: Yu Yanling , Tian Jing , Hou Yanni , Zhang Xinxin , Li Linhua , Cong Peifu , Ji Lei , Wang Xuri 
Published: July 2022

Abstract
Background
With low response to present immunotherapy, it is imperative to identify new immune-related biomarkers for more effective immunotherapies for oral cancer.

Methods
RNA profiles for 390 oral cancer patients and 32 normal samples were downloaded from The Cancer Genome Atlas (TCGA) database and differentially expressed genes (DEGs) were analyzed. Immune genesets from ImmPort repository were overlapped with DEGs. After implementing univariate Cox analysis and the least absolute shrinkage and selection operator (LASSO) Cox regression analysis, key immune-related gene pairs (IRGPs) among the overlapped DEGs for predicting the survival risk were obtained. Then, the cutoff of risk score was calculated by the receiver operating characteristic (ROC) curve to stratify oral cancer patients into high and low-risk groups. Multivariate Cox analysis was used to analyze independent prognostic indicators for oral cancer. Besides, infiltration of immune cells, functional annotation, and mutation analysis of IRGPs were conducted. Biological functions correlated with IRGPs were enriched by Gene Set Enrichment Analysis (GSEA) method.

Results
We identified 698 differentially expressed genes (DEGs) in response to oral cancer. 17 IRGPs among the DEGs were identified and integrated into a risk score model. Patients in the high-risk group have a significantly worse prognosis than those in the low-risk group in both training (P<0.001) and test (P=0.019) cohorts. Meanwhile, the IRGP model was identified as an independent prognostic factor for oral cancer. Different infiltration patterns of immune cells were found between the high- and low-risk groups that more types of T and B cells were enriched in the low-risk group. More immune-related signaling pathways were highly enriched in the low-risk group and Tenascin C (TNC) was the most frequently mutated gene. We have developed a novel 17-IRGPs signature for risk stratification and prognostic prediction of oral cancer.

Conclusion
Our study provides a foundation for improved immunotherapy and prognosis and is beneficial to the individualized management of oral cancer patients.
Barriers and enablers for deprescribing benzodiazepine receptor agonists in older adults: a systematic review of qualitative and quantitative studies using the theoretical domains framework
Authors: Evrard Perrine , Pétein Catherine , Beuscart Jean-Baptiste , Spinewine Anne 
Published: July 2022

AbstractBackgroundMany strategies aimed at deprescribing benzodiazepine receptor agonists (BZRA) in older adults have already been evaluated with various success rates. There is so far no consensus on which strategy components increase deprescribing the most. Yet, despite an unfavourable benefit-to-risk ratio, BZRA use among older adults remains high. We systematically reviewed barriers and enablers for BZRA deprescribing in older adults.MethodsTwo reviewers independently screened records identified from five electronic databases—Medline, Embase, PsycINFO, CINAHL and the Cochrane library—and published before October 2020. They searched for grey literature using Google Scholar. Qualitative and quantitative records reporting data on the attitudes of older adults, caregivers and healthcare providers towards BZRA deprescribing were included. Populations at the end of life or with specific psychiatric illness, except for dementia, were excluded. The two reviewers independently assessed the quality of the included studies using the mixed-methods appraisal tool. Barriers and enablers were identified and then coded into domains of the theoretical domains framework (TDF) using a combination of deductive and inductive qualitative analysis. The most relevant TDF domains for BZRA deprescribing were then identified.ResultsTwenty-three studies were included 13 quantitative, 8 qualitative and 2 mixed-method studies. The points of view of older adults, general practitioners and nurses were reported in 19, 9 and 3 records, respectively. We identified barriers and enablers in the majority of TDF domains and in two additional themes: “patient characteristics” and “BZRA prescribing patterns”. Overall, the most relevant TDF domains were “beliefs about capabilities”, “beliefs about consequences”, “environmental context and resources”, “intention”, “goals”, “social influences”, “memory, attention and decision processes”. Perceived barriers and enablers within domains differed across settings and across stakeholders.ConclusionThe relevant TDF domains we identified can now be linked to behavioural change techniques to help in the design of future strategies and health policies. Future studies should also assess barriers and enablers perceived by under-evaluated stakeholders (such as pharmacists, psychiatrists and health care professionals in the hospital setting).Trial registrationThis work was registered on PROSPERO under the title “Barriers and enablers to benzodiazepine receptor agonists deprescribing”. Registration number:CRD42020213035
Hypertensive disorders in pregnancy complicated by liver rupture or hematoma: a systematic review of 391 reported cases
Authors: Augustin Goran , Hadzic Matija , Juras Josip , Oreskovic Slavko 
Published: July 2022

Abstract
Background
Spontaneous liver rupture in pregnancy is often unrecognized, highly lethal, and not completely understood. The goal was to summarize and define the etiology, risk factors, clinical presentation, appropriate diagnostic methods, and therapeutic options for spontaneous hepatic rupture during pregnancy/puerperium (SHRP) complicated by the hypertensive disorder.

Methods
Literature search of all full-text articles included PubMed (1946–2021), PubMed Central (1900–2021), and Google Scholar. Case reports of a spontaneous hepatic rupture or liver hematoma during pregnancy or puerperium as a complication of hypertensive disorders (preeclampsia, eclampsia, HELLP syndrome) were searched. There was no restriction of language to collect the cases. Additional cases were identified by reviewing references of retrieved studies. PRISMA guidelines for the data extraction and quality assessment were applied.

Results
Three hundred and ninety-one cases were collected. The median maternal age was 31 (range 17–48) years; 36.6% were nulliparous. Most (83.4%) occurred in the third trimester. Maternal and fetal mortality was 22.1% and 37.2%, respectively. Maternal and fetal mortality was significantly higher 1) before the year 1990, 2) with maternal hemodynamic instability, and 3) eclampsia. The most important risk factors for SHRP were preeclampsia and HELLP syndrome. Most women had right lobe affected (70.9%), followed by both lobes in 22.1% and left lobe in 6.9%. The most common surgical procedure was liver packing. Liver transplantation was performed in 4.7% with 100% survival. Maternal mortality with liver embolization was 3.0%. Higher gestational age increases fetal survival.

Conclusion
The diagnosis and treatment of SHRP are often delayed, leading to high maternal and fetal mortality. SHRP should be excluded in hemodynamically unstable patients with preeclampsia/eclampsia or HELLP syndrome and right upper abdominal pain. Liver embolization and liver transplantation contribute to maternal survival. Maternal and fetal mortality was significantly higher before the year 1990. Hemodynamic instability, preeclampsia, and eclampsia have a significant negative influence on maternal survival.

Level of evidence
Level V
Program characteristics of cardiothoracic surgery departments versus divisions
Authors: Soler Lisa M. , Lopez Raymond A. , Hornbuckle Kyle J. , Dabal Robert J. , Chen Herbert , Xie Rongbing , Vardas Panos N. 
Published: July 2022

Abstract
Background
The organizational structure of cardiothoracic surgery practices varies among different programs throughout the United States (U.S.). We aimed to investigate the characteristics of the top ranked programs within the specialty and the surgeons practicing within each.

Methods
The top 50 hospitals for adult cardiology and heart surgery were identified using the US News and World Report 2019–20 ranking. There were 590 hospitals reported on, with 50 top rated programs. Data was collected from each hospital’s website, analyses conducted using SAS 9.4 with statistical significance set at p ≤ 0.05.

Results
When comparing cardiothoracic surgery program organizational structures, 21 of the top 50 ranked programs were departments and 24 were divisions within their respective Department of Surgery. Mean number of surgeons was 11 with no statistical difference when analyzed by division versus department. Overall, 9% of practicing cardiothoracic surgeons were female. Between programs that are a department versus division, general thoracic surgery was included in 58% of divisions and 52% of departments (p = ns). Among programs that were departments, approximately 6% of surgeons had attained a Ph.D., while in divisions approximately 4% of surgeons had attained a Ph.D.

Conclusions
The top 50 Cardiothoracic Surgery programs in the U.S. have approximately the same number of surgeons within the group and are organized similarly. This study group had a slightly higher percentage of female surgeons than has previously been noted in cardiothoracic surgery, with general thoracic surgery trending toward higher gender diversity. The presence of physician scientists was low, though similar amongst the study groups.
HTA decision-making for drugs for rare diseases: comparison of processes across countries
Authors: Stafinski Tania , Glennie Judith , Young Andrea , Menon Devidas 
Published: July 2022

Abstract
Introduction
Drugs for rare diseases (DRDs) offer important health benefits, but challenge traditional health technology assessment, reimbursement, and pricing processes due to limited effectiveness evidence. Recently, modified processes to address these challenges while improving patient access have been proposed in Canada. This review examined processes in 12 jurisdictions to develop recommendations for consideration during formal government-led multi-sectoral discussions currently taking place in Canada.

Methods
(i) A scoping review of DRD reimbursement processes, (ii) key informant interviews, (iii) a case study of evaluations for and the reimbursement status of a set of 7 DRDs, and (iv) a virtual, multi-stakeholder consultation retreat were conducted.

Results
Only NHS England has a process specifically for DRDs, while Italy, Scotland, and Australia have modified processes for eligible DRDs. Almost all consider economic evaluations, budget impact analyses, and patient-reported outcomes; but less than half accept surrogate measures. Disease severity, lack of alternatives, therapeutic value, quality of evidence, and value for money are factors used in all decision-making process; only NICE England uses a cost-effectiveness threshold. Budget impact is considered in all jurisdictions except Sweden. In Italy, France, Germany, Spain, and the United Kingdom, specific factors are considered for DRDs. However, in all jurisdictions opportunities for clinician/patient input are the same as those for other drugs. Of the 7 DRDs included in the case study, the number that received a positive reimbursement recommendation was highest in Germany and France, followed by Spain and Italy. No relationship between recommendation type and specific elements of the pricing and reimbursement process was found.

Conclusions
Based on the collective findings from all components of the project, seven recommendations for possible action in Canada are proposed. These focus on defining “appropriate access”, determining when a “full” HTA may not be needed, improving coordination among stakeholder groups, developing a Canadian framework for Managed Access Plans, creating a pan-Canadian DRD/rare disease data infrastructure, genuine and continued engagement of patient groups and clinicians, and further research on different decision and financing options, including MAPs.
A characterization of trauma laparotomies in a scandinavian setting: an observational study
Authors: Bentin Jakob Mejdahl , Possfelt-Møller Emma , Svenningsen Peter , Rudolph Søren Steemann , Sillesen Martin 
Published: July 2022

AbstractBackgroundDespite treatment advances, trauma laparotomy continuous to be associated with significant morbidity and mortality. Most of the literature originates from high volume centers, whereas patient characteristics and outcomes in a Scandinavian setting is not well described. The objective of this study is to characterize treatments and outcomes of patients undergoing trauma laparotomy in a Scandinavian setting and compare this to international reports.MethodsA retrospective study was performed in the Copenhagen University Hospital, Rigshospitalet (CUHR). All patients undergoing a trauma laparotomy within the first 24 h of admission between January 1st 2019 and December 31st 2020 were included. Collected data included demographics, trauma mechanism, injuries, procedures performed and outcomes.ResultsA total of 1713 trauma patients were admitted to CUHR of which 98 patients underwent trauma laparotomy. Penetrating trauma accounted for 16.6% of the trauma population and 66.3% of trauma laparotomies. Median time to surgery after arrival at the trauma center (TC) was 12 min for surgeries performed in the Emergency Department (ED) and 103 min for surgeries performed in the operating room (OR). A total of 14.3% of the procedures were performed in the ED. A damage control strategy (DCS) approach was chosen in 18.4% of cases. Our rate of negative laparotomies was 17.3%. We found a mortality rate of 8.2%. The total median length of stay was 6.1 days.ConclusionThe overall rates, findings, and outcomes of trauma laparotomies in this Danish cohort is comparable to reports from similar Western European trauma systems.
Evaluation of a mobile mammography unit: concepts and randomized cluster trial protocol of a population health intervention research to reduce breast cancer screening inequalities
Authors: Guillaume Elodie , Rollet Quentin , Launay Ludivine , Beuriot Séverine , Dejardin Olivier , Notari Annick , Crevel Elodie , Benhammouda Ahmed , Verzaux Laurent , Quertier Marie-Christine , Launoy Guy 
Published: July 2022

Abstract
Background
Breast cancer is the leading cancer in women in France both in incidence and mortality. Organized breast cancer screening (OBCS) has been implemented nationwide since 2004, but the participation rate remains low (48%) and inequalities in participation have been reported. Facilities such as mobile mammography units could be effective to increase participation in OBCS and reduce inequalities, especially areas underserved in screening. Our main objective is to evaluate the impact of a mobile unit and to establish how it could be used to tackle territorial inequalities in OBCS participation.

Methods
A collaborative project will be conducted as a randomized controlled cluster trial in 2022–2024 in remote areas of four French departments. Small geographic areas were constructed by clustering women eligible to OBCS, according to distance to the nearest radiology centre, until an expected sample of eligible women was attained, as determined by logistic and financial constraints. Intervention areas were then selected by randomization in parallel groups. The main intervention is to propose an appointment at the mobile unit in addition to current OBCS in these remote areas according to the principle of proportionate universalism. A few weeks before the intervention, OBCS will be promoted with a specific information campaign and corresponding tools, applying the principle of multilevel, intersectoral and community empowerment to tackle inequalities.

Discussion
This randomized controlled trial will provide a high level of evidence in assessing the effects of mobile unit on participation and inequalities. Contextual factors impacting the intervention will be a key focus in this evaluation. Quantitative analyses will be complemented by qualitative analyses to investigate the causal mechanisms affecting the effectiveness of the intervention and to establish how the findings can be applied at national level.

Trial registration
Registered on ClinicalTrials.gov, December 21, 2021: NCT05164874.
Eimeria falciformis secretes extracellular vesicles to modulate proinflammatory response during interaction with mouse intestinal epithelial cells
Authors: Olajide Joshua Seun , Xiong Ling , Yang Shunli , Qu Zigang , Xu Xiao , Yang Bin , Wang Jing , Liu Baohong , Ma Xueting , Cai Jianping 
Published: July 2022

Abstract
Background
Protozoan parasite secretions can be triggered by various modified media and diverse physicochemical stressors. Equally, host-parasite interactions are known to co-opt the exchange and secretion of soluble biochemical components. Analysis of Eimeria falciformis sporozoite secretions in response to interaction with mouse intestinal epithelial cells (MIECs) may reveal parasite secretory motifs, protein composition and inflammatory activities of E. falciformis extracellular vesicles (EVs).

Methods
Eimeria falciformis sporozoites were allowed to interact with inactivated MIECs. Parasite secretions were separated into EV and vesicle-free (VF) fractions by discontinuous centrifugation and ultracentrifugation. Secreted EVs were purified in an iodixanol density gradient medium and the protein composition of both EV and VF fractions were analyzed by liquid chromatoraphy-tandem mass spectroscopy. The inflammatory activities of E. falciformis sporozoite EV on MIECs were then investigated.

Results
During the interaction of E. falciformis sporozoites with inactivated MIECs, the parasite secreted VF and vesicle-bound molecules. Eimeria falciformis vesicles are typical pathogenic protozoan EVs with a mean diameter of 264 ± 2 nm, and enclosed heat shock protein (Hsp) 70 as classical EV marker. Refractile body-associated aspartyl proteinase (or eimepsin), GAP45 and aminopeptidase were the main components of E. falciformis sporozoite EVs, while VF proteins include Hsp90, actin, Vps54 and kinases, among others. Proteomic data revealed that E. falciformis EV and VF proteins are aggregates of bioactive, antigenic and immunogenic molecules which act in concert for E. falciformis sporozoite motility, pathogenesis and survival. Moreover, in MIECs, E. falciformis EVs induced upregulation of gene expression and secretion of IL-1β, IL-6, IL-17, IL-18, MCP1 as well as pyroptosis-dependent caspase 11 and NLRP6 inflammasomes with the concomitant secretion of lactate dehydrogenase.

Conclusions
Eimeria falciformis sporozoite interaction with MIECs triggered the secretion of immunogenic and antigenic proteins. In addition, E. falciformis sporozoite EVs constitute parasite-associated molecular pattern that induced inflammatory response and cell death. This study offers additional insight in the secretion and protein composition of E. falciformis secretomes as well as the proinflammatory functions of E. falciformis sporozoite EVs.

Graphical Abstract