bluuebunny/crossref_metadata_2025_split huggingface dataset:
The MITRE trial protocol: a study to evaluate the microbiome as a biomarker of efficacy and toxicity in cancer patients receiving immune checkpoint inhibitor therapy
Authors: Thompson Nicola A. , Stewart Grant D. , Welsh Sarah J. , Doherty Gary J. , Robinson Matthew J. , Neville B. Anne , Vervier Kevin , Harris Simon R. , Adams David J. , Dalchau Katy , Bruce David , Demiris Nikolaos , Lawley Trevor D. , Corrie Pippa G. 
Published: January 2022

Abstract
Background
The gut microbiome is implicated as a marker of response to  immune checkpoint inhibitors (ICI) based on preclinical mouse models and preliminary observations in limited patient series. Furthermore, early studies suggest faecal microbial transfer may have therapeutic potential, converting ICI non-responders into responders. So far, identification of specific responsible bacterial taxa has been inconsistent, which limits future application. The MITRE study will explore and validate a microbiome signature in a larger scale prospective study across several different cancer types.

Methods
Melanoma, renal cancer and non-small cell lung cancer patients who are planned to receive standard immune checkpoint inhibitors are being recruited to the MITRE study. Longitudinal stool samples are collected prior to treatment, then at 6 weeks, 3, 6 and 12 months during treatment, or at disease progression/recurrence (whichever is sooner), as well as after a severe (≥grade 3 CTCAE v5.0) immune-related adverse event. Additionally, whole blood, plasma, buffy coat, RNA and peripheral blood mononuclear cells (PBMCs) is collected at similar time points and will be used for exploratory analyses. Archival tumour tissue, tumour biopsies at progression/relapse, as well as any biopsies from body organs collected after a severe toxicity are collected. The primary outcome measure is the ability of the microbiome signature to predict 1 year progression-free survival (PFS) in patients with advanced disease. Secondary outcomes include microbiome correlations with toxicity and other efficacy end-points. Biosamples will be used to explore immunological and genomic correlates. A sub-study will evaluate both COVID-19 antigen and antibody associations with the microbiome.

Discussion
There is an urgent need to identify biomarkers that are predictive of treatment response, resistance and toxicity to immunotherapy. The data generated from this study will both help inform patient selection for these drugs and provide information that may allow therapeutic manipulation of the microbiome to improve future patient outcomes.

Trial registration
NCT04107168, ClinicalTrials.gov, registered 09/27/2019.
Protocol V3.2 (16/04/2021).
Sequential azacitidine and carboplatin induces immune activation in platinum-resistant high-grade serous ovarian cancer cell lines and primes for checkpoint inhibitor immunotherapy
Authors: Wong-Brown Michelle W. , van der Westhuizen Andre , Bowden Nikola A. 
Published: January 2022

AbstractBackgroundPlatinum chemoresistance results in high-grade serous ovarian cancer (HGSOC) disease recurrence. Recent treatment advances using checkpoint inhibitor immunotherapy has not benefited platinum-resistant HGSOC. In ovarian cancer, DNA methyltransferase inhibitors (DNMTi) block methylation and allow expression of silenced genes, primarily affecting immune reactivation pathways. We aimed to determine the epigenome and transcriptome response to sequential treatment with DNMTi and carboplatin in HGSOC.MethodsIn vitro studies with azacitidine or carboplatin alone and in sequential combination. Response was determined by cell growth, death and apoptosis. Genome-wide DNA methylation levels and transcript expression were compared between untreated and azacitidine and carboplatin sequential treatment.ResultsSequential azacitidine and carboplatin significantly slowed cell growth in 50% of cell lines compared to carboplatin alone. The combination resulted in significantly higher cell death in 25% of cell lines, and significantly higher cell apoptosis in 37.5% of cell lines, than carboplatin alone. Pathway analysis of upregulated transcripts showed that the majority of changes were in immune-related pathways, including those regulating response to checkpoint inhibitors.ConclusionsSequential azacitidine and carboplatin treatment slows cell growth, and demethylate and upregulate pathways involved in immune response, suggesting that this combination may be used to increase HGSOC response to immune checkpoint inhibitors in platinum-resistant patients who have exhausted all currently-approved avenues of treatment.
Treating refractory corneal hydrops in a male patient with vernal keratoconjunctivitis and mental retardation: a case report
Authors: Shih En-Jie , Lin Jung-Chia , Peng Kai-Ling , Chen Jiunn-Liang 
Published: January 2022

Abstract
Background
Keratoconus is the most common noninflammatory bilateral corneal ectasia. Vernal keratoconjunctivitis (VKC) and eye rubbing may be associated with keratoconus in children and young adults. Timely management of advanced keratoconus is important to improve visual quality. In addition, it is challenging to carry out VKC treatment with an intent to avoid the occurrence of punctate epithelial keratitis, ulceration, or corneal neovascularization on corneal grafts.

Case presentation
We report the case of an 18-year-old male patient with a long-term history of mental retardation due to megalencephaly presenting with acute onset of corneal hydrops with prominent bulging and refractory steroid-induced glaucoma of the right eye. The topography of the right eye was unavailable due to advanced ectasia, and that of the left eye revealed central steepening with inferior-superior dioptric asymmetry. According to the clinical findings, the patient was diagnosed with keratoconus. Because of progressive corneal opacity and neovascularization, the patient underwent penetrating keratoplasty (PK) with combination of interrupted and intrastromal running suturing after receiving a preoperative subconjunctival injection of bevacizumab in his right eye, followed by lower eyelid correction. After surgery, the patient was treated with 0.1% tacrolimus dermatological ointment, 0.1% cyclosporine eye drops, artificial tears, and 0.5% loteprednol for keratoplasty and VKC. Repeated education on avoiding eye rubbing was offered to the patient. Two years after PK treatment, his best-corrected visual acuity of the right eye successfully improved from hand motion at 10 cm preoperatively to 6/20 postoperatively.

Conclusions
Large-diameter PK with intrastromal suturing technique for advanced keratoconus could achieve better visual outcomes and avoid suture-related complications. In addition, tacrolimus dermatological ointment rather than tacrolimus topical eye drops or ointment showed satisfactory efficacy when combined with topical cyclosporine and steroid that no significant VKC reactivation were noted after PK.
Gambling-related suicide in East African Community countries: evidence from press media reports
Authors: Kaggwa Mark Mohan , Mamun Mohammed A. , Najjuka Sarah Maria , Muwanguzi Moses , Kule Moses , Nkola Rahel , Favina Alain , Kihumuro Raymond Bernard , Munaru Gideon , Arinaitwe Innocent , Rukundo Godfrey Zari , Griffiths Mark D. 
Published: January 2022

Abstract
Background
Gambling activities and associated mental health problems have become a topic of increased concern globally. Many individuals with a severe gambling disorder have gambling-related suicidality. However, no study has explored gambling-related suicide in East African Community (EAC) countries. The present study investigated the press media reporting of gambling-related suicide cases from EAC countries.

Methods
As there is no established suicide database in that region, media reports were utilized to collect gambling-related suicide data. Gambling-related suicide case reports were searched for in EAC countries’ press media websites using Google. After removing duplicates, a total of 18 suicides were found.

Results
The victims were all males aged 16 to 40 years. The most prevalent reason for the death was university students who had used their university tuition fees for gambling and losing the money (n = 4/17). All the suicide deaths were in Kenya (10/18), Uganda (7/18), and Tanzania (1/18). Betting on soccer was the most common type of gambling reported (n = 11/15), and hanging was the most used mode of suicide (n = 10/16).

Conclusions
Based on the press media reports, 18 males were identified as having carried out gambling-related suicides. The countries with the most widespread opportunities to gamble had more gambling-related suicides, although the number of suicides was very small.
Facilitating health promoting ideas and actions: participatory research in an underserved Swedish residential area
Authors: Magnusson Maria , Vaughn Lisa M. , Wretlind Katharina , Forslund Heléne Bertéus , Berg Christina 
Published: January 2022

AbstractBackgroundFor an intervention to contribute to decreased health gaps, people living in underserved areas must participate in the research-to-action process during the development of the intervention. The purpose of this study was to collaborate with residents living in a Swedish underserved area to generate health and wellness priorities and actions.MethodsWe applied Group Level Assessment (GLA) together with people living in a Swedish neighborhood where obesity, dental caries and other illnesses are prevalent. GLA is a qualitative, participatory methodology that is designed for a large group to generate and evaluate relevant needs and priorities within a lens of action for positive social change. Residents were recruited by posters, postcards and snowball sampling. In total, 47 residents participated. Eight GLA sessions were held over a five-month time period.ResultsThe GLA sessions resulted in reflections, proposals and actions for change by the residents. Adolescent and parent need for support, improved communication and more meeting places were highlighted as priorities for promoting health and well-being. The results were presented for stakeholders in a report and an exhibition and some of the participants started a language café.ConclusionsGLA emphasised the participants’ perspective. The participatory process helped them identify what they thought valuable and relevant concerning health issues and supported them in taking actions to achieve change.
Exploring the ability of self-report measures to identify risk of high treatment burden in chronic disease patients: a cross-sectional study
Authors: Hardman Ruth , Begg Stephen , Spelten Evelien 
Published: January 2022

Abstract
Background
Effective self-management of chronic health conditions is key to avoiding disease escalation and poor health outcomes, but self-management abilities vary. Adequate patient capacity, in terms of abilities and resources, is needed to effectively manage the treatment burden associated with chronic health conditions. The ability to measure different elements of capacity, as well as treatment burden, may assist to identify those at risk of poor self-management. Our aims were to: 1. Investigate correlations between established self-report tools measuring aspects of patient capacity, and treatment burden; and 2. Explore whether individual questions from the self-report tools will correlate to perceived treatment burden without loss of explanation. This may assist in the development of a clinical screening tool to identify people at risk of high treatment burden.

Methods
A cross-sectional survey in both a postal and online format. Patients reporting one or more chronic diseases completed validated self-report scales assessing social, financial, physical and emotional capacity; quality of life; and perceived treatment burden. Logistic regression analysis was used to explore relationships between different capacity variables, and perceived high treatment burden.

Results
Respondents (n = 183) were mostly female (78%) with a mean age of 60 years. Most participants were multimorbid (94%), with 45% reporting more than five conditions. 51% reported a high treatment burden. Following logistic regression analyses, high perceived treatment burden was correlated with younger age, material deprivation, low self-efficacy and usual activity limitation. These factors accounted for 50.7% of the variance in high perceived treatment burden. Neither disease burden nor specific diagnosis was correlated with treatment burden.

Conclusions
This study supports previous observations that psychosocial factors may be more influential than specific diagnoses for multimorbid patients in managing their treatment workload. A simple capacity measure may be useful to identify those who are likely to struggle with healthcare demands.
Modest alcohol intake and mortality in individuals with elevated alanine aminotransferase levels: a nationwide cohort study
Authors: Sinn Dong Hyun , Kang Danbee , Guallar Eliseo , Hong Yun Soo , Cho Juhee , Gwak Geum-Youn 
Published: January 2022

Abstract
Background
Alanine aminotransferase (ALT) levels are widely used to screen liver disease, and many asymptomatic individuals show elevated ALT levels. As elevated ALT level indicates liver injury, even a small amount of alcohol intake may be harmful in subjects with elevated ALT levels, but there is limited evidence of the effect of light to moderate amount of alcohol intake in this subgroup.

Methods
A cohort of 367,612 men and women without established liver diseases (including chronic viral hepatitis, alcohol-associated liver disease, cirrhosis, liver transplantation, or rare forms of liver disease) who underwent at least 1 health screening exam between 2009 and 2015 were assessed for liver-related and all-cause mortality. Elevated ALT levels were defined as ≥ 34 U/L for men and 25 U/L for women.

Results
In participants with normal ALT levels, the fully-adjusted hazard ratios (95% CI) for liver-related mortality comparing light and moderate drinkers to non-drinkers were 0.73 (0.51–1.05), and 1.06 (0.73–1.52), respectively. In participants with elevated ALT levels, the corresponding hazard ratios were 1.57 (1.08–2.28), and 2.09 (CI 1.46–2.99), respectively (p value for alcohol intake by ALT interaction < 0.01). For all-cause mortality, the fully-adjusted hazard ratios comparing light and moderate drinkers to non-drinkers in participants with normal ALT levels were 0.72 (0.66–0.77), and 0.89 (0.82–0.97), respectively. In participants with elevated ALT levels, the corresponding hazard ratios were 0.93 (0.81–1.08), and 1.31 (1.14–1.50), respectively (p value for alcohol intake by ALT interaction < 0.01).

Conclusions
Small amounts of alcohol intake were associated with increased liver-related and all-cause mortality among individuals with elevated ALT levels. Subjects with elevated ALT levels should be advised complete abstinence from alcohol.
HbA1c variability predicts cardiovascular complications in type 2 diabetes regardless of being at glycemic target
Authors: Ceriello Antonio , Lucisano Giuseppe , Prattichizzo Francesco , La Grotta Rosalba , Franzén Stefan , Svensson Ann-Marie , Eliasson Björn , Nicolucci Antonio 
Published: January 2022

Abstract
Background
HbA1c variability has emerged as risk factor for cardiovascular diseases in diabetes. However, the impact of HbA1c variability on cardiovascular diseases in subjects within the recommended HbA1c target has been relatively unexplored.

Methods
Using data from a large database, we studied 101,533 people with type 2 diabetes without cardiovascular diseases. HbA1c variability was expressed as quartiles of the standard deviation of HbA1c during three years (exposure phase). The primary composite outcome included non-fatal myocardial infarction, non-fatal stroke, all-cause mortality and was assessed during five years following the first three years of exposure to HbA1c variability (longitudinal phase). An expanded composite outcome including non-fatal myocardial infarction, non-fatal stroke, coronary revascularization/reperfusion procedures, peripheral revascularization procedures, and all-cause mortality was also considered, as well as a series of specific cardiovascular complications. Cox models were adjusted for a large range of risk factors and results were expressed as adjusted hazard ratios.

Results
An association between HbA1c variability and all the outcomes considered was found. The correlation between HbA1c variability and cardiovascular complications development was confirmed in both the subgroups of subjects with a mean HbA1c ≤ 53 mmol/mol (recommended HbA1c target) or > 53 mmol/mol during the exposure phase. The risk related to HbA1c variability was higher in people with mean HbA1c ≤ 53 mmol/mol for the primary outcome (p for interaction 0.004), for the expanded secondary outcome (p for interaction 0.001) and for the stroke (p for interaction 0.001), even though HbA1c remained at the target during the follow-up.

Conclusions
These findings suggest that HbA1c variability may provide additional information for an optimized management of diabetes, particularly in people within the target of HbA1c.
Interaction between smoking and diabetes in relation to subsequent risk of cardiovascular events
Authors: Yang Yang , Peng Nianchun , Chen Gang , Wan Qin , Yan Li , Wang Guixia , Qin Yingfen , Luo Zuojie , Tang Xulei , Huo Yanan , Hu Ruying , Ye Zhen , Qin Guijun , Gao Zhengnan , Su Qing , Mu Yiming , Zhao Jiajun , Chen Lulu , Zeng Tianshu , Yu Xuefeng , Li Qiang , Shen Feixia , Chen Li , Zhang Yinfei , Wang Youmin , Deng Huacong , Liu Chao , Wu Shengli , Yang Tao , Li Mian , Xu Yu , Xu Min , Zhao Zhiyun , Wang Tiange , Lu Jieli , Bi Yufang , Wang Weiqing , Ning Guang , Zhang Qiao , Shi Lixin 
Published: January 2022

Abstract
Background
Whether smoking modifies the associations of diabetes and risk factor management with subsequent risk of cardiovascular disease (CVD), and whether the smoking related CVD risk differs among people with and without diabetes are unclear. This study aimed to examine the associations and interactions of smoking, diabetes, and risk factor management in relation to incident CVD.

Methods
This nationwide, population-based, prospective cohort study of 20 communities from various geographic regions recruited adults aged 40 years or older during 2011–2012. The follow-up survey was conducted between 2014 and 2016. This study included 126,181 participants who were free from CVD at baseline.

Results
Study participants included 19,397 current smokers (15.4%), 6,049 former smokers (4.8%), and 100,735 never smokers (79.8%). Mean (SD) age ranged from 55.8 (8.6) years to 60.7 (9.1) years. Compared with never smokers, heavy smokers exhibited a greater risk of CVD events among participants with diabetes (multivariable-adjusted hazard ratio [HR], 1.45; 95% CI, 1.17–1.78) than among participants without diabetes (HR, 1.20; 95% CI, 1.01–1.42; P for interaction = 0.006). Compared with participants without diabetes, participants with diabetes who were never smokers and had 5 or more controlled risk factors showed no significantly excess CVD risk (HR, 0.93; 95% CI, 0.71–1.22), but the cardiovascular benefits from risk factor management were counteracted among participants with diabetes who were current smokers (HR, 1.28; 95% CI, 0.77–2.14) or former smokers (HR, 1.22; 95% CI, 0.66–2.28).

Conclusions
Smoking and diabetes interacted with each other in relation to increased risk of CVD events, and the beneficial effect of risk factor management on CVD risk among participants with diabetes was attenuated by current or former smoking.
Biomimetic manganese-eumelanin nanocomposites for combined hyperthermia-immunotherapy against prostate cancer
Authors: Liu Yu , Shang Wenting , Liu Heng , Hui Hui , Wu Jun , Zhang Wei , Gao Pengli , Guo Kunxiong , Guo Yanli , Tian Jie 
Published: January 2022

AbstractPro-tumoral and immunosuppressive M2-like tumor-associated macrophages (TAMs) contribute to tumor progression, recurrence and distal metastasis. However, current TAMs-modulating therapeutic strategies often encounter challenges including insufficient immune activation, weak antigen presentation ability and unsatisfactory antitumor immune performance. Herein, cyclic RGD peptide functionalized and manganese doped eumelanin-like nanocomposites (RMnMels) are reported for combined hyperthermia-immunotherapy against PC3 prostate cancer. The RMnMels could promote M2-to-M1 macrophage repolarization via scavenging multiple reactive oxygen species and remodeling the immunosuppressive tumor microenvironment. Following near-infrared light irradiation, RMnMels-mediated thermal ablation not only could destroy tumor cells directly, but also elicit the release of damage associated molecular patterns and tumor-associated antigens, provoking robust tumor immunogenicity and strong antitumor immune responses. The results showed that RMnMels could effectively scavenge reactive oxygen species and promote M2-to-M1 macrophage repolarization both in vitro and in vivo. Synergistically enhanced anti-tumor therapeutic efficacy was achieved following single administration of RMnMels plus single round of laser irradiation, evidenced by decreased primary tumor sizes and decreased number of distant liver metastatic nodules. The as-developed RMnMels may represent a simple and high-performance therapeutic nanoplatform for immunomodulation and enhanced antitumor immune responses.
Graphical Abstract
Long-term growth and final adult height outcome in childhood-onset systemic lupus erythematosus
Authors: Ponin Lalita , Poomthavorn Preamrudee , Pirojsakul Kwanchai , Lerkvaleekul Butsabong , Soponkanaporn Sirisucha , Chitrapazt Niyata , Vilaiyuk Soamarat 
Published: January 2022

Abstract
Background
Growth impairment is the most common complication in patients with childhood-onset systemic lupus erythematosus (cSLE). There are limited data on risk factors affecting growth development in Asian patients with cSLE. This study aimed to determine the predictors of growth impairment in such patients.

Methods
All SLE patients aged < 15 years diagnosed in Ramathibodi Hospital between 2006 and 2016 were enrolled in a retrospective cohort study. Baseline characteristics, including height, weight, clinical manifestations, disease activity score, and medications, were reviewed from medical records from the time at diagnosis to achievement of final adult height (FAH). Age at menarche in girls, adult voice appearance in boys, and parental height were collected by interview. Parent-adjusted FAH (PaFAH) Z-score was calculated as the difference between FAH Z-score for chronological age of the patients and their mid parental height-Z score. The patients were classified into two groups: (1) normal growth (PaFAH Z-score ≥ − 1.5, 2) growth impairment (PaFAH Z-score < − 1.5). Descriptive statistics and logistic regression analysis were used to analyze the data.

Results
Of 106 cSLE patients, 19 (18%) were male and 87 (82%) were female. The mean age at study enrollment was 20.6 ± 3.0 years, mean age at diagnosis 12.1 ± 2.3 years, and mean age at achievement of FAH 17.5 ± 1.9 years. Growth impairment was found in 23.6% of patients (52.6% in boys and 17.2% in girls). Predictors of growth impairment were male sex, duration of disease before menarche in girls and adult voice appearance in boys, and cumulative corticosteroid dose (prednisolone equivalent) ≥230 mg/kg received before the late phase of puberty, with odds ratios of 7.07 (95%CI 2.11–23.74), 1.26 (95% CI 1.02–1.56), and 6.99 (95%CI 1.63–30.02), respectively.

Conclusions
One-fourth of cSLE patients developed growth impairment, which mostly affected male patients. Longer duration of disease before the late phase of puberty and corticosteroid dose ≥230 mg/kg received before the late phase of puberty were factors predictive of growth impairment.