bluuebunny/crossref_metadata_2025 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

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

Background

Platinum 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.

Methods

In 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.

Results

Sequential 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.

Conclusions

Sequential 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

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

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

Background

For 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.

Methods

We 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.

Results

The 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.

Conclusions

GLA 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

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

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

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

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

Pro-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

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.
Unleashing implementation research to accelerate national noncommunicable disease responses
Authors: Collins Tea , Akselrod Svetlana , Berlina Daria , Allen Luke N
Published: January 2022

Noncommunicable diseases (NCDs) are the leading cause of death and disability worldwide. They exact a disproportionate toll in low and middle-income countries, and the world is not on-track to meet international targets for reductions in premature NCD mortality. Largely, we know which policies work for tackling NCDs, and the World Health Organization (WHO) has developed a package of ‘best buy’ policies that are highly cost effective. However, we don’t necessarily know how to adapt and implement these policies in new populations and cultures. Implementation Research (IR) is emerging as a potent tool for gearing the international response, providing a scientific approach to study the processes used to implement policies and interventions and the contextual factors that affect these processes. Amidst growing interest from policymakers, we identify four main areas for action: high-level engagement with IR among international NCD leaders; domestic investment in technical capacity-building; the creation of new financing streams for IR research; and the development of multi-stakeholder engagement mechanisms that can convene and leverage the perspectives and resources of multiple actors with overlapping aims.
Different internal fixation methods for unstable distal clavicle fractures in adults: a systematic review and network meta-analysis
Authors: Xu Yinglong , Guo Xiaobo , Peng Hui , Dai Hai , Huang Zonggui , Zhao Jinmin
Published: January 2022

Background

Surgical treatment is advised for unstable distal clavicle fractures (UDCFs). Various kinds of internal fixation methods have been used, but the best fixation is still controversial.

Methods

We systematically searched all studies comparing postoperative outcomes of coracoclavicular (CC) reconstruction (TightRope, EndoButton, Mersilene tape, suture anchor or suture), fracture osteosynthesis (clavicular hook plate (HP), locking compression plate (LCP), Kirschner wire and tension band (KWTB), Kirschner wire (KW)), and a combination of the two methods (LCP + CC or KWTB + CC) for UDCF in PubMed, Web of Science Core Collection via Ovid, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and China Biology Medicine (CBM) databases up to September 16, 2021, with no language restrictions. A network meta-analysis (NMA) was conducted to integrate direct and indirect evidence and assess the relative effects of the internal fixation methods. The probability of being the best treatment was assessed by the surface under the cumulative ranking curve (SUCRA).

Results

A total of 41 studies were included, involving 1969 patients and seven internal fixation methods. The NMA showed that LCP + CC fixation was associated with better efficacy (odds ratio (OR) 0.60, 95% CI 0.19–1.02, probability rank = 0.93) and fewer complications (odds ratio (OR) 0.22, 95% CI 0.09–0.51, probability rank = 0.69) than any other internal fixation method for UDCFs. The SUCRA probabilities of LCP + CC fixation were 98.6% for the Constant–Murley score and 93.9% for total complications.

Conclusions

The results of this study indicate that LCP + CC appears to be the best internal fixation method for UDCF. Limited to the quality and quantity of the included studies, much larger and higher-quality RCTs are required to confirm these conclusions.
Chinese herbal medicine treatment based on subgroup differentiation as adjunct therapy for Parkinson’s disease: study protocol of a pilot add-on, randomised, controlled, pragmatic clinical trial
Authors: Yuen Sam Chun Sum , Chua Ka Kit , Zhong Linda L. D. , Chan Kam Wa , Chan Conrad Kwan Ho , Chan Kam Leung , Lin Zhixiu , Mok Vincent , Lau Alexander Y. , Li Min
Published: January 2022

Background

Parkinson’s disease (PD) is a prevalent and debilitating condition. Conventional medications cannot control all symptoms and may inflict adverse effects. A survey reported that Chinese herbal medicine (CHM) is frequently sought. Existing CHM trials were contradictory and often of poor quality due to lack of methodological rigor. A national clinical guideline was drafted in China with diagnostic criteria and treatment strategy of Chinese medicine (CM) patterns subgroups of PD. The suggested CHM were found to exhibit neuroprotective effect in in vitro and in vivo studies. This trial aims to preliminarily assess the effect of CHM prescribed based on pattern differentiation on PD symptoms and patients’ quality of life, and evaluate the feasibility of the trial design for a future large-scale trial.

Methods

This trial will be a pilot assessor- and data analyst blind, add-on, randomised, controlled, pragmatic clinical trial. 160 PD patients will be recruited and randomised into treatment or control groups in a 1:1 ratio. The trial will be conducted over 32 weeks. PD patients in the treatment group will be stratified into subgroups based on CM pattern and receive CHM accordingly in addition to conventional medication (ConM). The control group will receive ConM only. The primary outcome will be part II of the Movement Disorder Society Sponsored Revision of Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). Secondary outcomes will include part and total scores of MDS-UPDRS, domain and total scores of Non-motor symptom scale (NMSS). Adverse events will be monitored by monthly follow-ups and questionnaires. Mixed models will be used to analyse data by Jamovi and R.

Expected outcomes

The success of our trial will show that the pragmatic design with subgroup differentiation is feasible and can produce reliable results. It will also provide preliminary data of the effect of CHM on improving clinical outcomes and quality of PD patients. Data collected will be used to optimize study design of the future large-scale clinical study.

Ethical clearance

Ethical clearance of this study was given by the Research Ethics Committee of Hong Kong Baptist University (REC/20-21/0206).

Trial registration This trial is registered on ClinicalTrials.gov (NCT05001217, Date: 8/10/2021, https://clinicaltrials.gov/ct2/show/NCT05001217). Type of manuscript: clinical trial protocol (date: 3rd November, 2021, version 1)
Double aneuploidy mosaicism involving chromosomes 18 and 21 in a neonate
Authors: Mendiola Christina , Ortega Veronica , Britt Allison , Fonseca Rafael , Velagaleti Gopalrao
Published: January 2022

Background

Double aneuploidy is common, especially in products of conception, frequently involving a combination of a sex chromosome and an acrocentric chromosome. Double autosomal trisomies are rare with only five cases reported. Double aneuploidy mosaicism involving two different cell lines is rarer with only three cases reported.

Case presentation

We report a fourth case of double aneuploidy mosaicism on a baby. Results of a 24-h preliminary chromosome analysis at birth showed a mosaic karyotype, 47,XX,+18[15]/47,XX,+21[8]/48,XX,+21,+mar[7]. Reflex testing to SNP microarray with the same sample collected at birth showed gain of a 77.9 Mb region on chromosome 18 and gain of a 32.5 Mb region on chromosome 21. Microarray did not show any other copy number variants indicating that the marker chromosome may not contain any euchromatic material. A repeat chromosome analysis at 1-year of age showed a mosaic karyotype, 47,XX,+18[76]/47,XX,+21[4] with loss of the marker cell line.

Conclusion

Based on our results, we propose that the mosaic double autosomal trisomy in our case was due to two independent non-disjunction events in a normal zygote very early during embryogenesis.
SMARCA5 interacts with NUP98-NSD1 oncofusion protein and sustains hematopoietic cells transformation
Authors: Jevtic Zivojin , Matafora Vittoria , Casagrande Francesca , Santoro Fabio , Minucci Saverio , Garre’ Massimilliano , Rasouli Milad , Heidenreich Olaf , Musco Giovanna , Schwaller Jürg , Bachi Angela
Published: January 2022

Background

Acute myeloid leukemia (AML) is characterized by accumulation of aberrantly differentiated hematopoietic myeloid progenitor cells. The karyotyping-silent NUP98-NSD1 fusion is a molecular hallmark of pediatric AML and is associated with the activating FLT3-ITD mutation in > 70% of the cases. NUP98-NSD1 fusion protein promotes myeloid progenitor self-renewal in mice via unknown molecular mechanism requiring both the NUP98 and the NSD1 moieties.

Methods

We used affinity purification coupled to label-free mass spectrometry (AP-MS) to examine the effect of NUP98-NSD1 structural domain deletions on nuclear interactome binding. We determined their functional relevance in NUP98-NSD1 immortalized primary murine hematopoietic stem and progenitor cells (HSPC) by inducible knockdown, pharmacological targeting, methylcellulose assay, RT-qPCR analysis and/or proximity ligation assays (PLA). Fluorescence recovery after photobleaching and b-isoxazole assay were performed to examine the phase transition capacity of NUP98-NSD1 in vitro and in vivo.

Results

We show that NUP98-NSD1 core interactome binding is largely dependent on the NUP98 phenylalanine-glycine (FG) repeat domains which mediate formation of liquid-like phase-separated NUP98-NSD1 nuclear condensates. We identified condensate constituents including imitation switch (ISWI) family member SMARCA5 and BPTF (bromodomain PHD finger transcription factor), both members of the nucleosome remodeling factor complex (NURF). We validated the interaction with SMARCA5 in NUP98-NSD1+ patient cells and demonstrated its functional role in NUP98-NSD1/FLT3-ITD immortalized primary murine hematopoietic cells by genetic and pharmacological targeting. Notably, SMARCA5 inhibition did not affect NUP98-NSD1 condensates suggesting that functional activity rather than condensate formation per se is crucial to maintain the transformed phenotype.

Conclusions

NUP98-NSD1 interacts and colocalizes on the genome with SMARCA5 which is an essential mediator of the NUP98-NSD1 transformation in hematopoietic cells. Formation of NUP98-NSD1 phase-separated nuclear condensates is not sufficient for the maintenance of transformed phenotype, which suggests that selective targeting of condensate constituents might represent a new therapeutic strategy for NUP98-NSD1 driven AML.
Impact of psychological distress and psychophysical wellbeing on posttraumatic symptoms in parents of preterm infants after NICU discharge
Authors: Salomè Serena , Mansi Giuseppina , Lambiase Carmine V. , Barone Marta , Piro Valeria , Pesce Marcella , Sarnelli Giovanni , Raimondi Francesco , Capasso Letizia
Published: January 2022

Backgorund

Parents after Neonatal Intensive Care Unit (NICU) hospitalization of preterm infant may develop psychopathological symptoms.

The aim of the study was to determine how parental stress and psychophysical wellbeing affect posttraumatic symptoms (PTTS) in parents during the first year after NICU discharge. Moreover, this study aimed to explore any gender-specific difference in psychological distress among mothers and fathers.

Methods

Prospective study design from September 2018 to September 2019. 20 pairs of parents of preterm infants admitted to a tertiary-level NICU were enrolled. Primary outcome was evaluation of PTTS in parents of preterm infants at one year after NICU discharge through Impact of Event Scale- Revised. Secondary outcomes were: impact of parental stress, psychophysical wellbeing, anxiety and depression respectively through Parental Stressor Scale: NICU, Short Form Health Survey-36(SF-36), Self-rating Anxiety Scale and Self-rating Depression Scale.

Results

Mothers experienced higher rates of PTTS than fathers across the first year after NICU discharge (55% vs 20%). Maternal avoidance symptoms were associated with perception of their own infant look. Emotional aspects linked to maternal role predicted 36,8% of their hyperarousal symptoms. Maternal PTTS severity was predicted by their social functioning. Paternal mental health was associated both with maternal and paternal intrusive symptoms.. Maternal stress was associated with paternal avoidance symptoms. Paternal mental health predicted their hyperarousal symptoms (40%) and PTSD severity (52%).

Conclusions

Parents who experienced NICU hospitalization of their own infant are at heightened risk to develop psychopathological symptoms. According to our initial hypothesis, investigating parental psychophysical wellbeing, through SF-36, originally provides a valuable support to detect parents at higher risk to develop posttraumatic outcomes across the first year after NICU discharge. In addition, paternal depression deserves to be taken into account since hospitalization as it could impact paternal PTSD development. Finally, these findings provide an initial evidence of gender-related patterns in PTSD development and psychological distress among mothers and fathers across the first year of their infant.
Over-dispersed Trypanosoma cruzi parasite load in sylvatic and domestic mammals and humans from northeastern Argentina
Authors: Enriquez Gustavo Fabián , Bua Jacqueline , Orozco María Marcela , Macchiaverna Natalia Paula , Otegui Julián Antonio Alvarado , Argibay Hernán Darío , Fernández María del Pilar , Gürtler Ricardo Esteban , Cardinal Marta Victoria
Published: January 2022

Background

The distribution of parasite load across hosts may modify the transmission dynamics of infectious diseases. Chagas disease is caused by a multi-host protozoan, Trypanosoma cruzi, but the association between host parasitemia and infectiousness to the vector has not been studied in sylvatic mammalian hosts. We quantified T. cruzi parasite load in sylvatic mammals, modeled the association of the parasite load with infectiousness to the vector and compared these results with previous ones for local domestic hosts.

Methods

The bloodstream parasite load in each of 28 naturally infected sylvatic mammals from six species captured in northern Argentina was assessed by quantitative PCR, and its association with infectiousness to the triatomine Triatoma infestans was evaluated, as determined by natural or artificial xenodiagnosis. These results were compared with our previous results for 88 humans, 70 dogs and 13 cats, and the degree of parasite over-dispersion was quantified and non-linear models fitted to data on host infectiousness and bloodstream parasite load.

Results

The parasite loads of Didelphis albiventris (white-eared opossum) and Dasypus novemcinctus (nine-banded armadillo) were directly and significantly associated with infectiousness of the host and were up to 190-fold higher than those in domestic hosts. Parasite load was aggregated across host species, as measured by the negative binomial parameter, k, and found to be substantially higher in white-eared opossums, cats, dogs and nine-banded armadillos (range: k = 0.3–0.5) than in humans (k = 5.1). The distribution of bloodstream parasite load closely followed the “80–20 rule” in every host species examined. However, the 20% of human hosts, domestic mammals or sylvatic mammals exhibiting the highest parasite load accounted for 49, 25 and 33% of the infected triatomines, respectively.

Conclusions

Our results support the use of bloodstream parasite load as a proxy of reservoir host competence and individual transmissibility. The over-dispersed distribution of T. cruzi bloodstream load implies the existence of a fraction of highly infectious hosts that could be targeted to improve vector-borne transmission control efforts toward interruption transmission. Combined strategies that decrease the parasitemia and/or host–vector contact with these hosts would disproportionally contribute to T. cruzi transmission control.

Graphical Abstract
An early prediction model for gestational diabetes mellitus based on genetic variants and clinical characteristics in China
Authors: Wu Qi , Chen Yanmin , Zhou Menglin , Liu Mengting , Zhang Lixia , Liang Zhaoxia , Chen Danqing
Published: January 2022

Objectives

To evaluate the influence of genetic variants and clinical characteristics on the risk of gestational diabetes mellitus (GDM) and to construct and verify a prediction model of GDM in early pregnancy.

Methods

Four hundred seventy five women with GDM and 487 women without, as a control, were included to construct the prediction model of GDM in early pregnancy. Both groups had complete genotyping results and clinical data. They were randomly divided into a trial cohort (70%) and a test cohort (30%). Then, the model validation cohort, including 985 pregnant women, was used for the external validation of the GDM early pregnancy prediction model.

Results

We found maternal age, gravidity, parity, BMI and family history of diabetes were significantly associated with GDM (OR > 1; P < 0.001), and assisted reproduction was a critical risk factor for GDM (OR = 1.553, P = 0.055). MTNR1B rs10830963, C2CD4A/B rs1436953 and rs7172432, CMIP rs16955379 were significantly correlated with the incidence of GDM (AOR > 1, P < 0.05). Therefore, these four genetic susceptible single nucleotide polymorphisms (SNPs) and six clinical characteristics were included in the construction of the GDM early pregnancy prediction model. In the trial cohort, a predictive model of GDM in early pregnancy was constructed, in which genetic risk score was independently associated with GDM (AOR = 2.061, P < 0.001) and was the most effective predictor with the exception of family history of diabetes. The ROC-AUC of the prediction model was 0.727 (95% CI 0.690–0.765), and the sensitivity and specificity were 69.9% and 64.0%, respectively. The predictive power was also verified in the test cohort and the validation cohort.

Conclusions

Based on the genetic variants and clinical characteristics, this study developed and verified the early pregnancy prediction model of GDM. This model can help screen out the population at high-risk for GDM in early pregnancy, and lifestyle interventions can be performed for them in a timely manner in early pregnancy.
Model-based stratification of progression along the Alzheimer disease continuum highlights the centrality of biomarker synergies
Authors: Sadiq Muhammad Usman , Kwak Kichang , Dayan Eran ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: January 2022

Background

The progression rates of Alzheimer’s disease (AD) are variable and dynamic, yet the mechanisms that contribute to heterogeneity in progression rates remain ill-understood. Particularly, the role of synergies in pathological processes reflected by biomarkers for amyloid-beta (‘A’), tau (‘T’), and neurodegeneration (‘N’) in progression along the AD continuum is not fully understood.

Methods

Here, we used a combination of model and data-driven approaches to address this question. Working with a large dataset (N= 321 across the training and testing cohorts), we first applied unsupervised clustering on longitudinal cognitive assessments to divide individuals on the AD continuum into those showing fast vs. moderate decline. Next, we developed a deep learning model that differentiated fast vs. moderate decline using baseline AT(N) biomarkers.

Results

Training the model with AT(N) biomarker combination revealed more prognostic utility than any individual biomarkers alone. We additionally found little overlap between the model-driven progression phenotypes and established atrophy-based AD subtypes. Our model showed that the combination of all AT(N) biomarkers had the most prognostic utility in predicting progression along the AD continuum. A comprehensive AT(N) model showed better predictive performance than biomarker pairs (A(N) and T(N)) and individual biomarkers (A, T, or N).

Conclusions

This study combined data and model-driven methods to uncover the role of AT(N) biomarker synergies in the progression of cognitive decline along the AD continuum. The results suggest a synergistic relationship between AT(N) biomarkers in determining this progression, extending previous evidence of A-T synergistic mechanisms.
Utilisation of virtual non-contrast images and virtual mono-energetic images acquired from dual-layer spectral CT for renal cell carcinoma: image quality and radiation dose
Authors: Zhang Xiaoxiao , Zhang Gumuyang , Xu Lili , Bai Xin , Lu Xiaomei , Yu Shenghui , Sun Hao , Jin Zhengyu
Published: January 2022

Background

Renal cell carcinoma (RCC) is the most common renal malignant tumour. We evaluated the potential value and dose reduction of virtual non-contrast (VNC) images and virtual monoenergetic images (VMIs) from dual-layer spectral CT (DL-CT) in the diagnosis of RCC.

Results

Sixty-two patients with pathologically confirmed RCC who underwent contrast-enhanced DL-CT were retrospectively analysed. For the comparison between true non-contrast (TNC) and VNC images of the excretory phase, the attenuation, image noise, signal-to-noise ratio (SNR) and subjective image quality of tumours and different abdominal organs and tissues were evaluated. To compare corticomedullary phase images and low keV VMIs (40 to 100 keV) from the nephrographic phase, the attenuation, image noise, SNR and subjective lesion visibility of the tumours and renal arteries were evaluated. For the tumours, significant differences were not observed in attenuation, noise or SNR between TNC and VNC images (p > 0.05). For the abdominal organs and tissues, except for fat, the difference in attenuation was 100% within 15 HU and 96.78% within 10 HU. The subjective image quality of TNC and VNC images was equivalent (p > 0.05). The attenuation of lesions in 40 keV VMIs and renal arteries in 60 keV VMIs were similar to those in the corticomedullary images (p > 0.05). The subjective lesion visibility in low keV VMIs is slightly lower than that in the corticomedullary images (p < 0.05). Using VNC and VMIs instead of TNC and corticomedullary phase images could decrease the radiation dose by 50.5%.

Conclusion

VNC images and VMIs acquired from DL-CT can maintain good image quality and decrease the radiation dose for diagnosis of RCC.
Antineutrophil cytoplasmic antibody-associated vasculitis in presence of positive antiphospholipid antibody: a case report
Authors: Akhlaghi Kalahroodi Maassoumeh , Loghman Maryam , Ramezanpoor Mahsa , Shahriarirad Reza , Rahmanian Ehsan
Published: January 2022

Background

Antineutrophil cytoplasmic antibody-associated vasculitis is dominated by inflammatory occlusion of small vessels, causing tissue ischemia in various organs. This disorder has rarely been associated with vasculopathy, such as antiphospholipid syndrome.

Case presentation

We report a case of a 48-year-old Persian male presenting with distal digital gangrene along with inflammatory arthralgia. High titers of anti-proteinase 3 and antiphospholipid antibodies (anticardiolipin antibody) were detected in laboratory evaluation. Therefore, a diagnosis of antineutrophil cytoplasmic antibody-associated vasculitis and antiphospholipid syndrome was made and treated with anticoagulant along with monthly pulses of cyclophosphamide and a daily dose of 1 mg/kg prednisolone.

Conclusion

Our case, along with other reports, illustrates that these two entities can coexist. Therefore, monitoring antiphospholipid antibodies in patients with antineutrophil cytoplasmic antibody-associated vasculitis with or without clinical evidence of any thrombosis and ruling out thrombosis in cases that do not respond to proper treatment of vasculitis may be relevant to prevent irreversible or fatal organ damage.