bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoantigens and the tumor microenvironment play important roles in the prognosis of high-grade serous ovarian cancer
Authors: Yang Hua , Yu Mei , Zhong Sen , You Yan , Feng Fengzhi 
Published: January 2022

Abstract
Background
Despite the consistency of patient age, disease stage and treatment options, the prognosis of different high-grade serous ovarian carcinoma (HGSOC) patients is different. Here, we sought to measure predictive biomarkers for distinct responses to platinum-based chemotherapy and immunotherapy benefits.

Methods
Sixteen HGSOC patients receiving debulking surgery and adjuvant first-line combination chemotherapy at Peking Union Medical College Hospital (PUMCH) were enrolled. Whole exome sequencing (WES) and RNA-seq were performed on tumor and normal tissues of these patients.

Results
The tumor mutational burden (TMB) and intratumoral heterogeneity (ITH) of the platinum-resistant group were significantly higher than those of the platinum-sensitive group (P=0.0321 and P=0.0452, respectively). TMB, neoantigen and ITH had certain predictive value according to the area under the receiver operating characteristic (ROC) curve (AUC 0.7778 for TMB, 0.7619 for neoantigen, 0.7778 for ITH). The infiltration of other immune cells in tumor tissues was different between the two groups, but the difference was not significant. Univariate Cox proportional hazard analysis revealed poorer progression-free survival (PFS) for those patients who carried a higher number of neoantigens (P =0.0069), higher TMB (P =0.0083), and higher ITH (P =0.0249). Further Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis indicated the Differentially expressed genes (DEGs) in platinum-resistant and platinum-sensitive patients were mainly enriched in the phosphatidylinositol 3-kinase-Akt (PI3K-Akt) signaling pathway and focal adhesion pathway, which are associated with platinum resistance.

Conclusions
Higher TMB, neoantigen and ITH may account for the worse prognosis of patients with platinum-based chemotherapy and higher TMB was observed in the platinum-resistant group, which could make the patients in the platinum-resistant group to be the better candidates for immunotherapy.
Impact of receiving recorded mental health recovery narratives on quality of life in people experiencing non-psychosis mental health problems (NEON-O Trial): updated randomised controlled trial protocol
Authors: Rennick-Egglestone Stefan , Elliott Rachel , Newby Chris , Robinson Clare , Slade Mike 
Published: January 2022

Abstract
Background
Mental health recovery narratives are first-person lived experience accounts of recovery from mental health problems, which refer to events or actions over a period of time, and which include elements of adversity or struggle, and also self-defined or observable strengths, successes, or survival. Recorded recovery narratives are those presented in invariant form, including text, audio, or video. In a previous publication, we presented a protocol for three pragmatic trials of the Narrative Experiences Online (NEON) Intervention, a web application recommending recorded recovery narratives to participants. The aim of the definitive NEON Trial was to understand whether the NEON Intervention benefitted people with experience of psychosis. The aim of the smaller NEON-O and NEON-C trials was to evaluate the feasibility of conducting definitive trials of the NEON Intervention with people (1) experiencing non-psychosis mental health problems and (2) who informally care for others experiencing mental health problems.
An open recruitment strategy with a 60-week recruitment period was developed. Recruitment for the NEON Trial and NEON-O Trial targeted mental health service users and people not using mental health services. The NEON Trial recruited to time and target. The NEON-O Trial achieved its target in 10 weeks. Analysis considered by a Programme Steering Committee after the target was achieved demonstrated a definitive result could be obtained if the trial was adapted for recruitment to continue. The UK Health Research Authority approved all needed amendments following ethical review.

Purpose of this article
To describe the decision-making process for amending the NEON-O Trial and to describe amendments made to the NEON-O Trial to enable a definitive result. The article describes amendments to the aims, objectives, design, power calculation, recruitment rate, process evaluation design, and informed consent documents. The extended NEON-O Trial adopts analysis principles previously specified for the NEON Trial. The article provides a model for other studies adapting feasibility trials into definitive trials.

Trial registration
All trials prospectively registered. NEON Trial: ISRCTN11152837. Registered on 13th August 2018. NEON-C Trial: ISRCTN76355273. Registered on 9th January 2020. NEON-O Trial: ISRCTN63197153. Registered on 9th January 2020. The NEON-O Trial ISRCTN was updated when amendments were approved. Amendment details: NOSA2, 30th October 2020.
Making sense of the linear genome, gene function and TADs
Authors: Long Helen S. , Greenaway Simon , Powell George , Mallon Ann-Marie , Lindgren Cecilia M. , Simon Michelle M. 
Published: January 2022

Abstract
Background
Topologically associating domains (TADs) are thought to act as functional units in the genome. TADs co-localise genes and their regulatory elements as well as forming the unit of genome switching between active and inactive compartments. This has led to the speculation that genes which are required for similar processes may fall within the same TADs, allowing them to share regulatory programs and efficiently switch between chromatin compartments. However, evidence to link genes within TADs to the same regulatory program is limited.

Results
We investigated the functional similarity of genes which fall within the same TAD. To do this we developed a TAD randomisation algorithm to generate sets of “random TADs” to act as null distributions. We found that while pairs of paralogous genes are enriched in TADs overall, they are largely depleted in TADs with CCCTC-binding factor (CTCF) ChIP-seq peaks at both boundaries. By assessing gene constraint as a proxy for functional importance we found that genes which singly occupy a TAD have greater functional importance than genes which share a TAD, and these genes are enriched for developmental processes. We found little evidence that pairs of genes in CTCF bound TADs are more likely to be co-expressed or share functional annotations than can be explained by their linear proximity alone.

Conclusions
These results suggest that algorithmically defined TADs consist of two functionally different groups, those which are bound by CTCF and those which are not. We detected no association between genes sharing the same CTCF TADs and increased co-expression or functional similarity, other than that explained by linear genome proximity. We do, however, find that functionally important genes are more likely to fall within a TAD on their own suggesting that TADs play an important role in the insulation of these genes.
Obesity is not associated with adverse outcomes among hospitalized patients with Clostridioides difficile infection
Authors: Malick Alyyah , Wang Ying , Axelrad Jordan , Salmasian Hojjat , Freedberg Daniel 
Published: January 2022

Abstract
Background
Obesity is associated with increased risk for death in most infections but has not been studied as a risk factor for mortality in Clostridioides difficile infection (CDI). This study tested obesity as a risk factor for death in patients hospitalized with CDI. This was a three-center retrospective study that included hospitalized adults with CDI at Columbia University Irving Medical Center, Brigham and Women’s Hospital, and NYU Langone from 2010 to 2018. Multivariate logistic regression was used to assess the relationship between obesity, measured by body mass index, and death from any cause within 30 days after the index CDI test.

Results
Data for 3851 patients were analyzed, including 373 (9.7%) who died within 30 days following a diagnosis of CDI. After adjusting for other factors, BMI was not associated with increased risk for death in any BMI category [adjusted OR (aOR) 0.96, 95% CI 0.69 to 1.34 for BMI > 30 vs BMI 20–30; aOR 1.02, 95% CI 0.53 to 1.87 for BMI > 40 vs BMI 20–30]. After stratifying into three groups by age, there were trends towards increased mortality with obesity in the middle-aged (56–75 vs ≤ 55 years old) yet decreased mortality with obesity in the old (> 75 vs ≤ 55) (p = NS for all). Advanced age and low albumin were the factors most strongly associated with death.

Conclusions
We found no association between obesity and death among patients with CDI, in contrast to most other infections. Obesity is not likely to be useful for risk-stratifying hospitalized patients with CDI.
Repeated mild traumatic brain injury impairs fracture healing in male mice
Authors: Kesavan Chandrasekhar , Rundle Charles , Mohan Subburaman 
Published: January 2022

AbstractObjectivesThe goal of this study was to evaluate the long-term impact of repeated (r) mild traumatic brain injury (mTBI) on the healing of fractures in a mouse model. Ten week-old male mice were subjected to r-mTBI once per day for 4 days followed by closed femoral fracture using a three-point bending technique, 1 week post impact and fracture healing phenotype evaluated at 20 weeks of age.ResultsMicro-CT analysis of the fracture callus region at nine weeks post fracture revealed reduced bone volume (30%,p < 0.05) in the r-mTBI fracture group compared to the control-fracture group. The connectivity density of the fracture callus bone was reduced by 40% (p < 0.01)in the r-mTBI fracture group. Finite element analysis of the fracture callus region showed reduced failure load (p = 0.08) in the r-mTBI group compared to control group. There was no residual cartilage in the fracture callus region of either the r-mTBI or control fracture group. The reduced fracture callus bone volume and mechanical strength of fracture callus in r-mTBI mice 9 weeks post fracture are consistent with negative effects of r-mTBI on fracture healing over a long-term resulting in decreased mechanical strength of the fracture callus.
A proof-of-concept study of growth hormone in children with Phelan–McDermid syndrome
Authors: Sethuram S. , Levy T. , Foss-Feig J. , Halpern D. , Sandin S. , Siper P. M. , Walker H. , Buxbaum J. D. , Rapaport R. , Kolevzon A. 
Published: January 2022

Abstract
Background
Phelan–McDermid syndrome (PMS) is caused by 22q13 deletions including SHANK3 or pathogenic sequence variants in SHANK3 and is among the more common rare genetic findings in autism spectrum disorder (ASD). SHANK3 is critical for synaptic function, and preclinical and clinical studies suggest that insulin-like growth factor-1 (IGF-1) can reverse a range of deficits in PMS. IGF-1 release is stimulated by growth hormone secretion from the anterior pituitary gland, and this study sought to assess the feasibility of increasing IGF-1 levels through recombinant human growth hormone (rhGH) treatment, in addition to establishing safety and exploring efficacy of rhGH in children with PMS.

Methods
rhGH was administered once daily for 12 weeks to six children with PMS using an open-label design. IGF-1 levels, safety, and efficacy assessments were measured every 4 weeks throughout the study.

Results
rhGH administration increased levels of IGF-1 by at least 2 standard deviations and was well tolerated without serious adverse events. rhGH treatment was also associated with clinical improvement in social withdrawal, hyperactivity, and sensory symptoms.

Limitations
Results should be interpreted with caution given the small sample size and lack of a placebo control.

Conclusions
Overall, findings are promising and indicate the need for larger studies with rhGH in PMS.
Trial registration NCT04003207. Registered July 1, 2019, https://clinicaltrials.gov/ct2/show/NCT04003207.
G protein-coupled receptor kinase 3 modulates mesenchymal stem cell proliferation and differentiation through sphingosine-1-phosphate receptor regulation
Authors: Brozowski Jaime M. , Timoshchenko Roman G. , Serafin D. Stephen , Allyn Brittney , Koontz Jessica , Rabjohns Emily M. , Rampersad Rishi R. , Ren Yinshi , Eudy Amanda M. , Harris Taylor F. , Abraham David , Mattox Daniel , Rubin Clinton T. , Hilton Matthew J. , Rubin Janet , Allbritton Nancy L. , Billard Matthew J. , Tarrant Teresa K. 
Published: January 2022

Abstract
Background
The bone marrow niche supports hematopoietic cell development through intimate contact with multipotent stromal mesenchymal stem cells; however, the intracellular signaling, function, and regulation of such supportive niche cells are still being defined. Our study was designed to understand how G protein receptor kinase 3 (GRK3) affects bone marrow mesenchymal stem cell function by examining primary cells from GRK3-deficient mice, which we have previously published to have a hypercellular bone marrow and leukocytosis through negative regulation of CXCL12/CXCR4 signaling.

Methods
Murine GRK3-deficient bone marrow mesenchymal stromal cells were harvested and cultured to differentiate into three lineages (adipocyte, chondrocyte, and osteoblast) to confirm multipotency and compared to wild type cells. Immunoblotting, modified-TANGO experiments, and flow cytometry were used to further examine the effects of GRK3 deficiency on bone marrow mesenchymal stromal cell receptor signaling. Microcomputed tomography was used to determine trabecular and cortical bone composition of GRK3-deficient mice and standard ELISA to quantitate CXCL12 production from cellular cultures.

Results
GRK3-deficient, bone marrow-derived mesenchymal stem cells exhibit enhanced and earlier osteogenic differentiation in vitro. The addition of a sphingosine kinase inhibitor abrogated the osteogenic proliferation and differentiation, suggesting that sphingosine-1-phosphate receptor signaling was a putative G protein-coupled receptor regulated by GRK3. Immunoblotting showed prolonged ERK1/2 signaling after stimulation with sphingosine-1-phosphate in GRK3-deficient cells, and modified-TANGO assays suggested the involvement of β-arrestin-2 in sphingosine-1-phosphate receptor internalization.

Conclusions
Our work suggests that GRK3 regulates sphingosine-1-phosphate receptor signaling on bone marrow mesenchymal stem cells by recruiting β-arrestin to the occupied GPCR to promote internalization, and lack of such regulation affects mesenchymal stem cell functionality.
The common incidence-age multistep model of neurodegenerative diseases revisited: wider general age range of incidence corresponds to fewer disease steps
Authors: Gerovska Daniela , Araúzo-Bravo Marcos J. 
Published: January 2022

Abstract
Background
Previously, we collected age-stratified incidence data of 404 epidemiological datasets of 10 neurodegenerative diseases (NDs), namely Amyotrophic Lateral Sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Fronto Temporal Dementia (FTD), Dementia with Lewy Bodies (DLB), Parkinsonism (PDM), Parkinson’s disease with Dementia (PDD), Creutzfeldt–Jakob disease (CJD), and Multiple Sclerosis (MS). We tested whether each ND follows a multistep model, found the number of steps necessary for the onset of each ND, found the number of common steps with other NDs and the number of specific steps of each ND, and built a parsimony tree of the genealogy of the NDs. The tree disclosed three groups of NDs: the stem NDs with less than 3 steps; the trunk NDs with 5–7 steps; and the crown NDs with more than 7 steps.

Methods
We made a multidimensional reduction of the previously collected age-stratified incidence epidemiological data of the 10 NDs. We studied the general range of incidence of the 10 NDs using the age- and sex-stratified incidence data. First, we calculated the log of the incidence versus the log of the age for each ND. Next, we calculated the age intervals of the spread of the incidence of each ND. We calculated the regression of the steps obtained with the multistep model versus the age of incidence of the NDs.

Results
We found that the number of steps of the NDs is inversely correlated with the age of incidence of the NDs, and calculated the number of years required for a single step for each ND. Based on these results, we extended the genealogy tree model of the NDs to account for the time needed for a ND step to occur.

Conclusion
The extended genealogy tree disclosed three groups of NDs according to the estimated time needed for a step to occur: the stem ND, HD, with 32.5 years/step, the trunk NDs ALS, FTD, PD and CJD, with 6.7–13.7 years/step; and the crown NDs PDM, PDD, AD and DLB, with 2.3–3.8 years/step. Thus, the NDs cluster into three groups according to both the number of steps and the number of years for a step to occur.
Role of extracorporeal membrane oxygenation in pediatric cancer patients: a systematic review and meta-analysis of observational studies
Authors: Slooff Valerie , Hoogendoorn Rianne , Nielsen Jeppe Sylvest Angaard , Pappachan John , Amigoni Angela , Caramelli Fabio , Aziz Omer , Wildschut Enno , Verbruggen Sascha , Crazzolara Roman , Dohna-Schwake Christian , Potratz Jenny , Willems Jef , Llevadias Judit , Moscatelli Andrea , Montaguti Alessia , Bottari Gabriella , Di Nardo Matteo , Schlapbach Luregn , Wösten-van Asperen Roelie ,   the POKER (PICU Oncology Kids in Europe Research group) research consortium of ESPNIC (European Society of Paediatric Neonatal Intensive Care)
Published: January 2022

Abstract
Background
The use of extracorporeal membrane oxygenation (ECMO) in pediatric patients with underlying malignancies remains controversial. However, in an era in which the survival rates for children with malignancies have increased significantly and several recent reports have demonstrated effective ECMO use in children with cancer, we aimed to estimate the outcome and complications of ECMO treatment in these children.

Methods
We searched MEDLINE, Embase and CINAHL databases for studies on the use ECMO in pediatric patients with an underlying malignancy from inception to September 2020. This review was conducted in adherence to Preferred Reporting Items for Systematic Review and Meta-Analysis statement. Study eligibility was independently assessed by two authors and disagreements resolved by a third author. Included studies were evaluated for quality using the Newcastle–Ottawa Scale (NOS). Random effects meta-analyses (DerSimonian and Laird) were performed. The primary outcomes were mortality during ECMO or hospital mortality.

Results
Thirteen retrospective, observational cohort studies were included, most of moderate quality (625 patients). The commonest indication for ECMO was severe respiratory failure (92%). Pooled mortality during ECMO was 55% (95% confidence interval [CI], 47–63%) and pooled hospital mortality was 60% (95% CI 54–67%). Although heterogeneity among the included studies was low, confidence intervals were large. In addition, the majority of the data were derived from registries with overlapping patients which were excluded for the meta-analyses to prevent resampling of the same participants across the included studies. Finally, there was a lack of consistent complications reporting among the studies.

Conclusion
Significantly higher mortalities than in general PICU patients was reported with the use of ECMO in children with malignancies. Although these results need to be interpreted with caution due to the lack of granular data, they suggest that ECMO appears to represents a viable rescue option for selected patients with underlying malignancies. There is an urgent need for additional data to define patients for whom ECMO may provide benefit or harm.
Supporting retention in HIV care through a holistic, patient-centred approach: a qualitative evaluation
Authors: Chinyandura Cathrine , Jiyane Anele , Tsalong Xolani , Struthers Helen E. , McIntyre James A. , Rees Kate 
Published: January 2022

Abstract
Background
HIV is a complex disease which affects different facets (social, economic, physical, emotional and spiral) of an individual’s life, making the goals of retention in care and adherence to treatment difficult to achieve. Holistic patient-centred approaches to providing care for people living with HIV bind together economic, social, emotional and physiological aspects and have the potential to improve retention in care and ART adherence. Case management is a holistic, patient-centred approach which is increasingly being implemented in the management of chronic illnesses.

Methods
We conducted a qualitative study based on semi-structured interviews with key informants (retention officers and social auxiliary workers) and patients. A total of 60 patients and 17 KIs (11 retention officers and 6 social auxiliary workers) participated in the study. The study was conducted in Johannesburg District, Gauteng province, South Africa. Key informants (KIs) and patients were drawn from 8 health facilities located in four management clusters of the district.

Results
The findings identified facilitators and barriers to adherence and retention in care, and demonstrated that case management offered holistic, patient-centred services which patients considered to be beneficial to their well-being and helped them overcome some of these barriers. The success of case management was driven by its holistic and patient-centred approach, which extended the focus to patients’ non-clinical needs which impact on their quality of life. Complex interacting barriers and facilitators at different levels influenced implementation of the model and its outcomes.

Conclusion
Holistic approaches such as case management have a strong potential to improve retention in care and adherence to ART. HIV is a complex disease which impacts different facets of an individual’s life, hence requires holistic care to address all facets. Health systems need to transition towards holistic care to ensure that some patients do not slip through the cracks, improve patient outcomes and efficiency.