bluuebunny/crossref_metadata_2025_split huggingface dataset:
Facilitators and barriers to the implementation of prehabilitation for frail patients into routine health care: a realist review
Authors: Sontag Anna Frederike , Kiselev Jörn , Schaller Stefan J , Spies Claudia , Rombey Tanja 
Published: February 2024

Abstract
Background
Despite evidence supporting the effectiveness of prehabilitation as a new preoperative care pathway to optimise perioperative outcomes, its implementation into routine health care is widely pending. Frail patients might particularly benefit from prehabilitation interventions, but facilitating and hindering factors need to be considered in the implementation process. Thus, our aim was to derive a programme theory on what prehabilitation programmes work for frail patients in what circumstances and why.

Methods
Following Pawson’s realist review approach, preliminary programme theories on facilitators and barriers were established. General and topic-specific databases were searched systematically for facilitators and barriers to the implementation of prehabilitation for frail patients. Articles were included if they dealt with multimodal prehabilitation programmes prior to surgery in a frail population and if they contained information on facilitators and barriers during the implementation process in the full text. Based on these articles, refined programme theories were generated.

Results
From 2,609 unique titles, 34 were retained for the realist synthesis. Facilitating factors included the individualisation of prehabilitation programmes to meet the patients’ needs and abilities, multimodality, adaption to the local setting and health care system, endorsement by an ambassador and sharing of responsibilities among a multidisciplinary team. Central barriers for frail patients were transportation, lack of social support, and inadequate, overwhelming information provision.

Conclusions
Implementing prehabilitation as a new care pathway for frail patients requires organisational readiness and adaptability to the local setting. On an individual level, a clear understanding of responsibilities and of the intervention’s goal among patients and providers are necessary. Added attention must be paid to the individualisation to fit the needs and restrictions of frail patients. This makes prehabilitation a resource-intense, but promising intervention for frail surgery patients.

Trial registration
PROSPERO (CRD42022335282).
Germline mutations of homologous recombination genes and clinical outcomes in pancreatic cancer: a multicenter study in Taiwan
Authors: Cheng Siao Muk , Su Yung-Yeh , Chiang Nai-Jung , Wang Chih-Jung , Chao Ying-Jui , Huang Chien-Jui , Tsai Hui-Jen , Chen Shang-Hung , Chang Chi-Yen , Tsai Chia-Rung , Li Yi-Jie , Yen Chia-Jui , Chuang Shih-Chang , Chang Jeffrey Shu-Ming , Shan Yan-Shen , Hwang Daw-Yang , Chen Li-Tzong 
Published: February 2024

Abstract
Background
Cancer susceptibility germline mutations are associated with pancreatic ductal adenocarcinoma (PDAC). However, the hereditary status of PDAC and its impact on survival is largely unknown in the Asian population.

Methods
Exome sequencing was performed on 527 blood samples from PDAC individuals and analyzed for mutations in 80 oncogenic genes. Pathogenic and likely pathogenic (P/LP) germline variants were diagnosed according to the ACMG variant classification categories. The association between germline homologous recombination gene mutations (gHRmut, including BAP1, BRCA1, BRCA2, PALB2, ATM, BLM, BRIP1, CHEK2, NBN, MUTYH, FANCA and FANCC) and the treatment outcomes was explored in patients with stage III/IV diseases treated with first-line (1L) platinum-based versus platinum-free chemotherapy.

Results
Overall, 104 of 527 (19.7%) patients carried germline P/LP variants. The most common mutated genes were BRCA2 (3.60%), followed by ATR (2.66%) and ATM (1.9%). After a median follow-up duration of 38.3-months (95% confidence interval, 95% CI 35.0–43.7), the median overall survival (OS) was not significantly different among patients with gHRmut, non-HR germline mutations, or no mutation (P = 0.43). Among the 320 patients with stage III/IV disease who received 1L combination chemotherapy, 32 (10%) had gHRmut. Of them, patients receiving 1L platinum-based chemotherapy exhibited a significantly longer median OS compared to those with platinum-free chemotherapy, 26.1 months (95% CI 12.7–33.7) versus 9.6 months (95% CI 5.9–17.6), P = 0.001. However, the median OS of patients without gHRmut was 14.5 months (95% CI 13.2–16.9) and 12.6 months (95% CI 10.8–14.7) for patients receiving 1L platinum-based and platinum-free chemotherapy, respectively (P = 0.22). These results were consistent after adjusting for potential confounding factors including age, tumor stage, performance status, and baseline CA 19.9 in the multivariate Cox regression analysis.

Conclusions
Our study showed that nearly 20% of Taiwanese PDAC patients carried germline P/LP variants. The longer survival observed in gHRmut patients treated with 1L platinum-based chemotherapy highlights the importance of germline testing for all patients with advanced PDAC at diagnosis.
DNA methylation risk score for type 2 diabetes is associated with gestational diabetes
Authors: Linares-Pineda Teresa M. , Fragoso-Bargas Nicolas , Picón María José , Molina-Vega Maria , Jenum Anne Karen , Sletner Line , Lee-Ødegård Sindre , Opsahl Julia O. , Moen Gunn-Helen , Qvigstad Elisabeth , Prasad Rashmi B. , Birkeland Kåre I. , Morcillo Sonsoles , Sommer Christine 
Published: February 2024

Abstract
Background
Gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share many pathophysiological factors including genetics, but whether epigenetic marks are shared is unknown. We aimed to test whether a DNA methylation risk score (MRS) for T2DM was associated with GDM across ancestry and GDM criteria.

Methods
In two independent pregnancy cohorts, EPIPREG (n = 480) and EPIDG (n = 32), DNA methylation in peripheral blood leukocytes was measured at a gestational age of 28 ± 2. We constructed an MRS in EPIPREG and EPIDG based on CpG hits from a published epigenome-wide association study (EWAS) of T2DM.

Results
With mixed models logistic regression of EPIPREG and EPIDG, MRS for T2DM was associated with GDM: odd ratio (OR)[95% CI]: 1.3 [1.1–1.8], P = 0.002 for the unadjusted model, and 1.4 [1.1–1.7], P = 0.00014 for a model adjusted by age, pre-pregnant BMI, family history of diabetes and smoking status. Also, we found 6 CpGs through a meta-analysis (cg14020176, cg22650271, cg14870271, cg27243685, cg06378491, cg25130381) associated with GDM, and some of their methylation quantitative loci (mQTLs) were related to T2DM and GDM.

Conclusion
For the first time, we show that DNA methylation marks for T2DM are also associated with GDM, suggesting shared epigenetic mechanisms between GDM and T2DM.
Diversity in randomized clinical trials for peripheral artery disease: a systematic review
Authors: Long Chandler , Williams Abimbola O. , McGovern Alysha M. , Jacobsen Caroline M. , Hargens Liesl M. , Duval Sue , Jaff Michael R. 
Published: February 2024

Abstract
Background
Significant race and sex disparities exist in the prevalence, diagnosis, and outcomes of peripheral artery disease (PAD). However, clinical trials evaluating treatments for PAD often lack representative patient populations. This systematic review aims to summarize the demographic representation and enrollment strategies in clinical trials of lower-extremity endovascular interventions for PAD.

Methods
Following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched multiple sources (Medline, EMBASE, Cochrane, Clinicaltrials.gov, WHO clinical trial registry) for randomized controlled trials (RCTs), RCT protocols, and peer-reviewed journal publications of RCTs conducted between January 2012 and December 2022. Descriptive analysis was used to summarize trial characteristics, publication or study protocol characteristics, and the reporting of demographic characteristics. Meta-regression was used to explore associations between demographic characteristics and certain trial characteristics.

Results
A total of 2,374 records were identified. Of these, 59 met the inclusion criteria, consisting of 35 trials, 14 publications, and 10 protocols. Information regarding demographic representation was frequently missing. While all 14 trial publications reported age and sex, only 4 reported race/ethnicity, and none reported socioeconomic or marital status. Additionally, only 4 publications reported clinical outcomes by demographic characteristics. Meta-regression analysis revealed that 6% more women were enrolled in non-European trials (36%) than in European trials (30%).

Conclusions
The findings of this review highlight potential issues that may compromise the reliability and external validity of study findings in lower-extremity PAD RCTs when applied to the real-world population. Addressing these issues is crucial to enhance the generalizability and impact of clinical trial results in the field of PAD, ultimately leading to improved clinical outcomes for patients in underrepresented populations.

Registration
The systematic review methodology was published in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42022378304).
Factors of success, barriers, and the role of frontline workers in Indigenous maternal-child health programs: a scoping review
Authors: Thompson Charlene , Million Tara , Tchir Devan , Bowen Angela , Szafron Michael 
Published: February 2024

Abstract
Background
Despite considerable investment in maternal-child programs in Canada, there has been little positive impact on the health of Indigenous mothers and their children. The reasons for this are unclear and there is a need to identify how such programs can be successfully implemented. Community input is essential for successful programs; however, it is unclear what the contributions of frontline workers have been in the health program process, i.e., program development, delivery, and evaluation. Based on these identified gaps, this scoping review aimed to: (1) identify factors of success and barriers to successful Indigenous maternal-child community health programs for mothers and their children aged 0–6 years; and (2) explore how frontline workers are included in the program process.

Methods
This scoping review was completed using the Arksey and O’Malley framework, informed by Levac et al. Four data bases (Medline, CINAHL, Embase, and Scopus), grey literature, and reference lists were searched for relevant materials from 1990–2019. Data was extracted from included articles and analysed using descriptive statistics, thematic analysis with the Braun and Clarke framework, and a Principal Component Analysis.

Results
Forty-five peer-reviewed and grey articles were included in the review. Factors of program success included: relationship building; cultural inclusion; knowledge transmission styles; community collaboration; client-centred approaches; Indigenous staff; and operational considerations. Barriers included: impacts of colonization; power structure and governance; client and community barriers to program access; physical and geographical challenges; lack of staff; and operational deficits. Frontline workers were found to have a role in program delivery (n = 45) and development (n = 25). Few (n = 6) had a role in program evaluation.

Conclusion
Although a better understanding of the frontline worker role in maternal-child health programs was obtained from the review, in a large proportion of literature the authors could not determine if the role went beyond program delivery. In addition, no direct input from frontline workers and their perspectives on program success or barriers were identified, suggesting areas to explore in future research. This review's findings have been applied to inform a community-based participatory research project and may also help improve the development, delivery, and evaluation of Indigenous maternal-child health programs.
‘Intracytoplasmic sperm injection (ICSI) paradox’ and ‘andrological ignorance’: AI in the era of fourth industrial revolution to navigate the blind spots
Authors: Sengupta Pallav , Dutta Sulagna , Jegasothy Ravindran , Slama Petr , Cho Chak-Lam , Roychoudhury Shubhadeep 
Published: February 2024

AbstractThe quandary known as the Intracytoplasmic Sperm Injection (ICSI) paradox is found at the juncture of Assisted Reproductive Technology (ART) and ‘andrological ignorance’ – a term coined to denote the undervalued treatment and comprehension of male infertility. The prevalent use of ICSI as a solution for severe male infertility, despite its potential to propagate genetically defective sperm, consequently posing a threat to progeny health, illuminates this paradox. We posit that the meteoric rise in Industrial Revolution 4.0 (IR 4.0) and Artificial Intelligence (AI) technologies holds the potential for a transformative shift in addressing male infertility, specifically by mitigating the limitations engendered by ‘andrological ignorance.’ We advocate for the urgent need to transcend andrological ignorance, envisaging AI as a cornerstone in the precise diagnosis and treatment of the root causes of male infertility. This approach also incorporates the identification of potential genetic defects in descendants, the establishment of knowledge platforms dedicated to male reproductive health, and the optimization of therapeutic outcomes. Our hypothesis suggests that the assimilation of AI could streamline ICSI implementation, leading to an overall enhancement in the realm of male fertility treatments. However, it is essential to conduct further investigations to substantiate the efficacy of AI applications in a clinical setting. This article emphasizes the significance of harnessing AI technologies to optimize patient outcomes in the fast-paced domain of reproductive medicine, thereby fostering the well-being of upcoming generations.
Association of inherited thrombophilia mutations and their combinations among palestinian women with unexplained recurrent miscarriage
Authors: Najjar Ayman A. , Hassouna Imam , Srour Mahmoud A. , Ibrahim Hany M. , Assi Randa Y. , Abd El Latif Heba M. 
Published: February 2024

Abstract
Background
Inherited thrombophilia (IT) has a complex pathophysiology and is associated with recurrent miscarriage (RM) by causing placental insufficiency and inhibiting fetal development. However, thrombophilia screening in unexplained RM cases is still questionable. This study aimed to investigate the association between the common eight IT mutations and their combinations among Palestinian women with unexplained RM.

Methods
This is an unmatched case-control study with 200 women (100 unexplained RM cases, 100 controls). Eight common IT mutations namely Factor V Leiden (FVL), prothrombin gene (FII) G202120A, Methylenetetrahydrofolate Reductase (MTHFR) gene (C677T and A1298C), B-fibrinogen gene − 455G > A, FV HR2 A4070G, Plasminogen activator inhibitor 1 (PAI1) 5G/4G and Factor XIIIA (FXIIIA) V34L; were analyzed. The first five mutations were analyzed by Restriction Fragment Length Polymorphism PCR and the other three mutations were analyzed using Amplification Refractory Mutation System PCR.

Results
The prevalence of the eight IT mutations among the control group was in the order PAI1 5G/4G (69%), MTHFR C677T (53%) and A1298C (47%), BFG − 455G > A (35%), FVL and FV HR2 (each 18%), FXIIIA V34L (16%) and FII G20210A (3%). Patients had a higher percentage of MTHFR A1298C (heterozygotes and mutant homozygote) compared to controls (p = 0.016). Frequencies of mutant alleles MTHFR A1298C (p < 0.001) and FXIIIA V34L (p = 0.009) were higher among patients compared to controls. No significant differences were observed for all other mutations or mutant alleles. Most patients (75%) and controls (75%) have 2–4 mutant alleles out of 8 mutant alleles studied, while 1% of patients and 2% of controls have zero mutant alleles. None of the combinations of the most often studied mutations (FVL, FII G20210A, MTHFR C1677T, and MTHFR A1298C) showed a significant difference between patients and controls.

Conclusions
There was a significant association between unexplained RM and the mutant alleles of MTHFR A1298C and FXIIIA V34L. No significant association was observed between unexplained RM and the combination of both mutant alleles for the mutations studied. This study is the first Palestinian report that evaluates eight inherited thrombophilia mutations and their alleles’ combinations in unexplained RM cases.
IGFBP5 is released by senescent cells and is internalized by healthy cells, promoting their senescence through interaction with retinoic receptors
Authors: Alessio Nicola , Aprile Domenico , Peluso Gianfranco , Mazzone Valeria , Patrone Deanira , Di Bernardo Giovanni , Galderisi Umberto 
Published: February 2024

AbstractCells that are exposed to harmful genetic damage, either from internal or external sources, may undergo senescence if they are unable to repair their DNA. Senescence, characterized by a state of irreversible growth arrest, can spread to neighboring cells through a process known as the senescence-associated secretory phenotype (SASP). This phenomenon contributes to both aging and the development of cancer. The SASP comprises a variety of factors that regulate numerous functions, including the induction of secondary senescence, modulation of immune system activity, remodeling of the extracellular matrix, alteration of tissue structure, and promotion of cancer progression. Identifying key factors within the SASP is crucial for understanding the underlying mechanisms of senescence and developing effective strategies to counteract cellular senescence. Our research has specifically focused on investigating the role of IGFBP5, a component of the SASP observed in various experimental models and conditions.Through our studies, we have demonstrated that IGFBP5 actively contributes to promoting senescence and can induce senescence in neighboring cells. We have gained valuable insights into the mechanisms through which IGFBP5 exerts its pro-senescence effects. These mechanisms include its release following genotoxic stress, involvement in signaling pathways mediated by reactive oxygen species and prostaglandins, internalization via specialized structures called caveolae, and interaction with a specific protein known as RARα. By uncovering these mechanisms, we have advanced our understanding of the intricate role of IGFBP5 in the senescence process. The significance of IGFBP5 as a pro-aging factor stems from an in vivo study we conducted on patients undergoing Computer Tomography analysis. In these patients, we observed an elevation in circulating IGFBP5 levels in response to radiation-induced organismal stress.Globally, our findings highlight the potential of IGFBP5 as a promising therapeutic target for age-related diseases and cancer.
From the identification of actionable molecular targets to the generation of faithful neuroblastoma patient-derived preclinical models
Authors: Capasso Mario , Brignole Chiara , Lasorsa Vito A. , Bensa Veronica , Cantalupo Sueva , Sebastiani Enrico , Quattrone Alessandro , Ciampi Eleonora , Avitabile Marianna , Sementa Angela R. , Mazzocco Katia , Cafferata Barbara , Gaggero Gabriele , Vellone Valerio G. , Cilli Michele , Calarco Enzo , Giusto Elena , Perri Patrizia , Aveic Sanja , Fruci Doriana , Tondo Annalisa , Luksch Roberto , Mura Rossella , Rabusin Marco , De Leonardis Francesco , Cellini Monica , Coccia Paola , Iolascon Achille , Corrias Maria V. , Conte Massimo , Garaventa Alberto , Amoroso Loredana , Ponzoni Mirco , Pastorino Fabio 
Published: February 2024

Abstract
Background
Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor of infants. Although the overall survival of patients with NB has improved in the last years, more than 50% of high-risk patients still undergo a relapse. Thus, in the era of precision/personalized medicine, the need for high-risk NB patient-specific therapies is urgent.

Methods
Within the PeRsonalizEd Medicine (PREME) program, patient-derived NB tumors and bone marrow (BM)-infiltrating NB cells, derived from either iliac crests or tumor bone lesions, underwent to histological and to flow cytometry immunophenotyping, respectively. BM samples containing a NB cells infiltration from 1 to 50 percent, underwent to a subsequent NB cells enrichment using immune-magnetic manipulation. Then, NB samples were used for the identification of actionable targets and for the generation of 3D/tumor-spheres and Patient-Derived Xenografts (PDX) and Cell PDX (CPDX) preclinical models.

Results
Eighty-four percent of NB-patients showed potentially therapeutically targetable somatic alterations (including point mutations, copy number variations and mRNA over-expression). Sixty-six percent of samples showed alterations, graded as “very high priority”, that are validated to be directly targetable by an approved drug or an investigational agent. A molecular targeted therapy was applied for four patients, while a genetic counseling was suggested to two patients having one pathogenic germline variant in known cancer predisposition genes. Out of eleven samples implanted in mice, five gave rise to (C)PDX, all preserved in a local PDX Bio-bank. Interestingly, comparing all molecular alterations and histological and immunophenotypic features among the original patient’s tumors and PDX/CPDX up to second generation, a high grade of similarity was observed. Notably, also 3D models conserved immunophenotypic features and molecular alterations of the original tumors.

Conclusions
PREME confirms the possibility of identifying targetable genomic alterations in NB, indeed, a molecular targeted therapy was applied to four NB patients. PREME paves the way to the creation of clinically relevant repositories of faithful patient-derived (C)PDX and 3D models, on which testing precision, NB standard-of-care and experimental medicines.
Comparison of standard mismatch repair deficiency and microsatellite instability tests in a large cancer series
Authors: Nádorvári Maja L. , Kenessey István , Kiss András , Barbai Tamás , Kulka Janina , Rásó Erzsébet , Tímár József 
Published: February 2024

Abstract
Background
The tumor-agnostic indication of immune checkpoint inhibitors to treat cancers with mismatch repair deficiency (dMMR)/microsatellite instability (MSI) increased the demand for such tests beyond Lynch syndrome. International guideline recommendations accept immunohistochemistry (IHC) for dMMR or molecular techniques (PCR or NGS) for MSI status determinations considering the two tests are equal, although there are scattered reports contradicting to this presumption.

Materials and methods
Here we have directly compared four protein MMR immunohistochemistry (IHC) to MSI Pentaplex PCR test in a large cancer patient cohort (n = 1306) of our diagnostic center where the two tests have been run parallel in 703 cases.

Results
In this study we have found a high discrepancy rate (19.3%) of the two tests which was independent of the tumor types. The MSI PCR sensitivity for MMR IHC status was found to be very low resulting in a relatively low positive and negative predicting values. As a consequence, the correlation of the two tests was low (kappa < 0.7). During analysis of the possible contributing factors of this poor performance, we have excluded low tumor percentage of the samples, but identified dMMR phenotypes (classic versus non-classic or unusual) as possible contributors.

Conclusion
Although our cohort did not include samples with identified technical errors, our data strongly support previous reports that unidentified preanalytical factors might have the major influence on the poor performance of the MSI PCR and MMR IHC. Furthermore, the case is open whether the two test types are equally powerful predictive markers of immunotherapies.