bluuebunny/crossref_metadata_2025 huggingface dataset:
A glimpse into the future: modelling global prevalence of hypertension
Authors: Boateng Emmanuel B. , Ampofo Ama G.
Published: October 2023

Background

Hypertension is a major risk factor for cardiovascular diseases. Insights and foresights on trends of hypertension prevalence are crucial to informing health policymaking. We examined and projected the patterns of hypertension prevalence among sexes.

Methods

Using annual hypertension prevalence (18 + years) data sourced from WHO Global Health Observatory data repository from 1975 to 2015, Prophet models were developed to forecast the 2040 prevalence of hypertension in males, females, and both sexes. We used k-means clustering and self-organising maps to determine the clusters of hypertension prevalence concerning both sexes among 176 countries.

Results

Worldwide, Croatia is estimated to have the highest prevalence of hypertension in males by 2040, while that of females is in Niger. Among the world’s most populated countries, Pakistan and India are likely to increase by 7.7% and 4.0% respectively in both sexes. South-East Asia is projected to experience the largest hypertension prevalence in males, whereas Africa is estimated to have the highest prevalence of hypertension in females. Low-income countries are projected to have the highest prevalence of hypertension in both sexes. By 2040, the prevalence of hypertension worldwide is expected to be higher in the male population than in female. Globally, the prevalence of hypertension is projected to decrease from 22.1% in 2015 to 20.3% (20.2 – 20.4%) in 2040. We also identified three patterns of hypertension prevalence in 2040, cluster one countries are estimated to have the highest prevalence of hypertension in males (29.6%, 22.2 – 41.1%) and females (29.6%, 19.4 – 38.7%).

Conclusion

These findings emphasise the need for new and effective approaches toward the prevention and control of hypertension in Africa, South-East Asia, and Low-income countries.
Associations of effort-reward imbalance at work and quality of life among workers after stroke: a one-year longitudinal study in Thailand
Authors: Naknoi Siripan , Li Jian , ramasoota Pongrama , Liu Xinyue , Chen Liwei , Phuanukoonnon Suparat , Soonthornworasiri Ngamphol , Kaewboonchoo Orawan
Published: October 2023

Stroke incidence is increasing among working-age population, but the role of psychosocial stress in the workplace in predicting quality of life (QoL) after stroke onset is understudied. This longitudinal study aimed to investigate the relationship between work stress, measured by the effort-reward imbalance (ERI) model, and QoL over one-year period among 103 Thai workers who had experienced a stroke. The study evaluated the effort (E)-reward (R) ratio and over-commitment, the extrinsic and intrinsic components of the ERI model, before discharge; QoL was repeatedly measured at baseline, six months, and 12 months after discharge, respectively, using the Short Form Version 2 (SF-12v2) indicators of physical and mental health composite scores. Generalized estimating equations were used to examine longitudinal relationships between work stress at baseline and QoL over one year by testing the hypotheses that E-R ratio and over-commitment would have direct effects on QoL, and potential moderating effects of over-commitment on E-R ratio and QoL. The results supported the ERI model partially, as over-commitment was significantly associated with poor mental health (coefficient − 8.50; 95% CI: -13.79, -3.20) after adjusting baseline sociodemographic, behavioral, and clinical characteristics, while the E-R ratio was not significantly associated with physical or mental health; the interaction between the E-R ratio and over-commitment was also not significant. These findings suggest that more attention should be paid to workers’ personal coping skills and ability to handle work-related problems and prioritize interventions that address over-commitment to promote long-term mental health among workers with stroke.
Acceptability and feasibility of tuberculosis-diabetes mellitus screening implementation in private primary care clinics in Yogyakarta, Indonesia: a qualitative study
Authors: Prakoso Denny Anggoro , Istiono Wahyudi , Mahendradhata Yodi , Arini Merita
Published: October 2023

Background

The relationship between Tuberculosis (TB) and Diabetes Mellitus (DM) is intricate and intertwined, posing significant global health challenges. In addition, the increasing prevalence of DM worldwide raises concerns regarding the potential resurgence of tuberculosis. The implementation of tuberculosis prevention strategies is of the utmost importance, especially in countries like Indonesia that encounter a dual burden of TB and DM. The significance of TB screening in private primary care settings for patients with diabetes cannot be overstated. Implementing TB screening protocols in private primary care settings can assist in identifying diabetic patients with tuberculosis. Therefore, this study aims to explore the acceptability and feasibility of tuberculosis-diabetes mellitus screening implementation in private primary care clinics.

Methods

We conducted implementation research with an exploratory qualitative design. Fifteen healthcare professionals from five private primary health care clinics in Yogyakarta, Indonesia, participated in five focus groups. The discussions were audio recorded, transcribed verbatim, and thematically analyzed. As part of the feasibility assessment, surveys were conducted in each clinic. We conducted a thematic analysis in accordance with the theoretical framework of acceptability and the feasibility assessment.

Results

We identified that most private primary care clinics deemed the implementation of TB screening in DM patients acceptable and practicable. We revealed that the majority of diabetes patients enthusiastically accepted TB-DM screening services. In addition, we found that the healthcare professionals at the clinic are aware of the nature of the intervention and demonstrates a positive attitude despite a subtle burden. The stigma associated with COVID-19 has emerged as a new implementation barrier, joining TB stigma, lack of resources, and regulatory issues. We identify concealed and tiered screening as a potential method for enhancing the implementation of TB-DM screening.

Conclusions

The implementation of TB screening in DM patients in private primary care clinics had the potential to be acceptable and feasible. To achieve a successful implementation, consideration should be given to supporting factors, hindering factors, and strategies to improve TB screening in DM patients.
Circulating inflammatory cytokines and risk of idiopathic pulmonary fibrosis: a Mendelian randomization study
Authors: Jia Qinyao , Lei Yanmei , Chen Shaoping , Liu Shengming , Wang Tao , Cheng Yao
Published: October 2023

Background

The previous epidemiological and experimental evidence has implied the linkage between chronic inflammation to idiopathic pulmonary fibrosis (IPF). However, it was still unclear whether there were casual associations between circulating inflammatory cytokines and IPF development. The objective of present study was to examine whether altered genetically predicted concentration of circulating cytokines were associated with IPF development using a two-sample Mendelian randomization (MR) analysis.

Materials and methods

The causal effects of 23 circulating inflammatory cytokines were evaluated on IPF using MR analysis. The primary approach of MR analysis was the inverse variance-weighted (IVW) method. The sensitivity analyses were conducted by simple median, weighted median, penalized weighted median and MR-Egger regression methods.

Results

The present MR study found suggestive evidence that a higher circulating IL-14 level was associated with an increased risk of IPF (random effects IVW method: odds ratio: 1.001, 95% confidence interval: 1.000-1.001, P = 0.026). The sensitivity analysis yielded directionally similar results for IL-14. There was no significant association found between other circulating inflammatory cytokines and IPF.

Conclusion

The high level of IL14 predicted by genes had a casual relationship with the increased risk of IPF. This finding provided epidemiological evidence for drug therapy targeting inflammatory factors in the prevention and treatment of IPF. It’s warranted further exploration to validate the clinical significance of IL14 associated with developmental risk of IPF.
Serum antioxidant enzymes in spinal stenosis patients with lumbar disc herniation: correlation with degeneration severity and spinal fusion rate
Authors: Guo Youfeng , Zhou Yu , Zhao Haihong , Hu Tao , Wu Desheng
Published: October 2023

Objective

To determine whether superoxide dismutase (SOD) and glutathione reductase (GR) correlated with the intervertebral disc degeneration (IDD) severity and the postoperative spinal fusion rate in lumbar spinal stenosis patients accompanied with lumbar disc herniation.

Methods

This retrospective study investigated 310 cases of posterior lumbar decompression and fusion. The cumulative grade was calculated by adding the pfirrmann grades of all the lumbar discs. Subjects were grouped based on the median cumulative grade. Logistic regression was used to determine the associations among the demographical, clinical, and laboratory indexes and severe degeneration and fusion. The receiver operating characteristic (ROC) curve was performed to measure model discrimination, and Hosmer-Lemeshow (H-L) test was used to measure calibration.

Results

SOD and GR levels were significantly lower in the severe degeneration group (cumulative grade > 18) than in the mild to moderate degeneration group (cumulative grade ≤ 18). Furthermore, the SOD and GR concentrations of the fusion group were significantly higher than that of the non-fusion group (p < 0.001 and p = 0.006). The multivariate binary logistic models revealed that SOD and GR were independently influencing factors of the severe degeneration (OR: 0.966, 95%CI: 0.950–0.982, and OR: 0.946, 95%CI: 0.915–0.978, respectively) and non-fusion (OR: 0.962; 95% CI: 0.947–0.978; OR: 0.963; 95% CI: 0.933–0.994). The models showed excellent discrimination and calibration. Trend analysis indicated that the levels of SOD and GR tended to decrease with increasing severity (p for trend < 0.001 and 0.003). In addition, it also revealed that SOD provided protection from non-fusion in a concentration-dependent manner (p for trend < 0.001). However, GR concentration-dependent effects were not apparent (p for trend = 0.301).

Conclusion

High serum SOD and GR levels are associated with a better fusion prognosis and a relief in degeneration severity.
Plus Sutures for preventing surgical site infection: a systematic review of clinical outcomes with economic and environmental models
Authors: Edwards M. , Graziadio S. , Shore J. , Schmitz N. D. , Galvain T. , Danker W. A. , Kocaman M. , Pournaras D. J. , Bowley D. M. , Hardy K. J.
Published: October 2023

Background

Surgical site infections (SSIs) represent ~ 20% of all hospital-acquired infections in surgical patients and are associated with prolonged hospital stay, admission to intensive care, and mortality. We conducted a systematic review with economic and environmental models to assess whether triclosan-coated sutures (Plus Sutures) provide benefits over non-coated sutures in the reduction of SSI risk.

Methods

Searches were conducted in fifteen databases. A total of 1,991 records were retrieved. Following deduplication and screening by two independent reviewers, 31 randomized controlled trials in adults and children were included in the review.

Similarity of the studies was assessed by narrative review and confirmed by quantitative assessment. A fixed effects meta-analysis of SSI incidence model including all groups of patients estimated a risk ratio of 0.71 (95% confidence interval: 0.64 to 0.79) indicating those in the Plus Sutures group had a 29% reduction in the risk of developing an SSI compared with those in the control group (p < 0.001). Safety outcomes were analysed qualitatively.

Results

The economic model estimated the use of Plus Sutures to result in average cost savings of £13.63 per patient. Plus Sutures remained cost-saving in all subgroup analyses with cost-savings ranging between £11 (clean wounds) and £140 (non-clean wounds).

The environmental impact of SSI is substantial, and the model suggests that the introduction of Plus Sutures could result in potential environmental benefits.

Conclusions

The evidence suggests that Plus Sutures are associated with a reduced incidence of SSI across all surgery types alongside cost savings when compared with standard sutures.
Comparison of add-on medications for persistent storage symptoms after α-blocker treatment in BPH patients – a network meta-analysis
Authors: Su Yi-Ting , Chen Hsiao-Ling , Teoh Jeremy Yuen-Chun , Chan Vinson Wai-Shun , Wu Wen-Jeng , Lee Hsiang-Ying
Published: October 2023

Background

Patients with benign prostatic hyperplasia (BPH) receive α-blockers as first-line therapy to treat lower urinary tract symptoms; however, some individuals still experience residual storage symptoms. Antimuscarinics, β3-agonists, and desmopressin are effective add-on medications. Nevertheless, there is currently no evidence for the appropriate choice of the first add-on medication. This systematic review aimed to investigate the clinical benefits of antimuscarinics, β3-agonists, and desmopressin, in addition to α-blockers, for persistent storage symptoms in BPH patients.

Methods

A comprehensive literature search of randomized controlled trials (RCTs) comparing the efficacy of different add-on medications in BPH patients with persistent storage symptoms despite α-blocker treatment was conducted. Clinical outcomes included the International Prostate Symptom Score (IPSS), IPSS storage subscore, nocturia, micturition, and urgency. A network meta-analysis was performed to estimate the effect size. Surface under cumulative ranking curves (SUCRAs) were used to rank the included treatments for each outcome.

Results

A total of 15 RCTs were identified. Add-on imidafenacin and mirabegron resulted in significant improvement in all outcomes assessed. Other add-on medications such as desmopressin, tolterodine, solifenacin, fesoterodine, and propiverine showed positive benefits for most, but not all, outcomes. Based on the SUCRA rankings, add-on desmopressin was the best-ranked treatment for IPSS and nocturia, and add-on imidafenacin was the best for the IPSS storage subscore and micturition.

Conclusions

BPH patients presenting with persistent storage symptoms despite α-blocker administration are recommended to include additional treatment. Desmopressin and imidafenacin may be considered high-priority add-on treatments because of their superior efficacy compared with other medications.
Assessing clinical reasoning in the OSCE: pilot-testing a novel oral debrief exercise
Authors: Régent Alexis , Thampy Harish , Singh Mini
Published: October 2023

Introduction

Clinical reasoning (CR) is a complex skill enabling transition from clinical novice to expert decision maker. The Objective Structured Clinical Examination (OSCE) is widely used to evaluate clinical competency, though there is limited literature exploring how this assessment is best used to assess CR skills. This proof-of-concept study explored the creation and pilot testing of a post-station CR assessment, named Oral Debrief (OD), in the context of undergraduate medical education.

Methods

A modified-Delphi technique was used to create a standardised domain-based OD marking rubric encapsulating the key skills of CR that drew upon existing literature and our existing placement-based CR tool. 16 OSCE examiners were recruited to score three simulated OD recordings that were scripted to portray differing levels of competency. Adopting a think-aloud approach, examiners vocalised their thought processes while utilising the rubric to assess each video. Thereafter, semi-structured interviews explored examiners’ views on the OD approach. Recordings were transcribed, anonymised and analysed deductively and inductively for recurring themes. Additionally, inter-rater agreement of examiners’ scoring was determined using the Fleiss Kappa statistic both within group and in comparison to a reference examiner group.

Results

The rubric achieved fair to good levels of inter-rater reliability metrics across its constituent domains and overall global judgement scales. Think-aloud scoring revealed that participating examiners considered several factors when scoring students’ CR abilities. This included the adoption of a confident structured approach, discriminating between relevant and less-relevant information, and the ability to prioritise and justify decision making. Furthermore, students’ CR skills were judged in light of potential risks to patient safety and examiners’ own illness scripts. Feedback from examiners indicated that whilst additional training in rubric usage would be beneficial, OD offered a positive approach for examining CR ability.

Conclusion

This pilot study has demonstrated promising results for the use of a novel post-station OD task to evaluate medical students’ CR ability in the OSCE setting. Further work is now planned to evaluate how the OD approach can most effectively be implemented into routine assessment practice.
“We felt so proud by the president calling us my heroes.” An exploration of the nurse’s experiences in the management of COVID-19 patients in Uganda
Authors: Nawagi Faith , Lubega Martin , Ajambo Aidah , Mukisa John , Nabirye Rose
Published: October 2023

Introduction

Adequate and intensive nursing care was a key characteristic of recovery of the COVID-19 patients globally and in Uganda. However, there is limited literature on the experiences of nurses who participated in the care of COVID-19 patients in Uganda, East Africa, and Africa at large, yet imperative in designing approaches to increase the efficiency of the health systems’ response to future pandemics. To address this gap, this study aimed to explore the experiences of the nurses who managed COVID-19 patients at Mulago National Referral Hospital in Uganda.

Methods

This was an exploratory qualitative study that used purposive sampling to identify 21 nurses who treated COVID-19 patients at Mulago National Referral Hospital in Uganda. Focus Group Discussions were used to collect data. Thematic Analysis was used to analyze the data. Common codes were identified and grouped to create subthemes and major themes.

Results

Six themes were identified: 1) Motivation to work on COVID-19 patients, 2 ) Roles performed by nurses, 3) High workload and professional role strain, 4) Challenges with maintaining personal health and relationships, 5) Institutional and government support, 6) Acquired professional knowledge and skills to manage critical patients and epidemics. Most of the nurses faced work burnout, social isolation, stress, and psychological trauma. However, interprofessional collaboration, financial incentives, government recognition, and provision of personal protective equipment, were key motivators for the nurses. The majority reported to have gained new knowledge and skills in the management of pandemics and highly infectious diseases.

Conclusion

The nurses experienced negative scenarios like work burnout due to high workload, social isolation, and psychological stress. Therefore, there is a need for health systems to develop approaches and policies that support nurses’ well-being. Nevertheless, key attributes like resilience, adaptability, and diligence to serve enabled them to persevere despite the hardships faced.
The effects of simulated video education about falling on falling rate and fear of falling among hospitalized elderly people: a randomized clinical trial
Authors: Valieiny Nasrin , Pashaeypoor Shahzad , Poortaghi Sarieh , Sharifi Farshad
Published: October 2023

Background and aim

Management of falling and its consequences is a major challenge of elderly nursing care. An effective educational strategy is essential to prevent falling among elderly people. The aim of this study was to evaluate the effects of simulated video education (SVE) about falling on falling rate and fear of falling (FOF) among hospitalized elderly people.

Methods

This randomized controlled clinical trial was conducted from May 2021 to February 2022. Participants were 132 elderly people conveniently selected from a leading hospital in Qom, Iran, and randomly allocated to an intervention and a control group through block randomization. Data collection instruments were a demographic and clinical questionnaire, a researcher-made falling rate questionnaire, and the Falls Efficacy Scale-International. Participants in the intervention group individually watched three simulated videos (fifteen minutes in total) and had access to the videos for frequent watching. Their FOF was assessed on the first day of hospitalization, hospital discharge, and one and three months after hospital discharge. The data were analyzed at a significance level of less than 0.05 using the SPSS software (v. 16.0).

Results

Groups did not significantly differ from each other respecting baseline demographic and clinical characteristics (P > 0.05). After the intervention, falling rate in the intervention group was 46% less than the control group (incidence rate ratio = 0.5454, 95% CI = 0.307–0.968; P = 0.039). Moreover, the posttest mean score of FOF in the intervention group was significantly less than the control group (P < 0.001).

Conclusion

SVE is effective in significantly reducing falling rate and FOF. Context-based SVE is recommended to reduce falling rate and FOF among hospitalized elderly people.

Clinical trial registration

The effects of simulated video education about falling on falling rate and fear of falling among hospitalized elderly people. Clinical trial registration: this research was registered (17/09/2021) in the https://www.irct.ir with registration number: IRCT20210910052427N1).
Breast feeding, obesity, and asthma association: clinical and molecular views
Authors: Kian Naghmeh , Bagheri Alireza , Salmanpour Fardis , Soltani Afsaneh , Mohajer Zahra , Samieefar Noosha , Barekatain Behzad , Kelishadi Roya
Published: October 2023

Asthma is a chronic condition that affects children worldwide. Accumulating number of studies reported that the prevalence of pediatric obesity and asthma might be altered through breastfeeding. It has been proposed that Leptin, which exists in human milk, is oppositely associated with weight increase in newborns. It may also influence peripheral immune system by promoting TH1 responses and suppressing TH2 cytokines. Leptin influences body weight and immune responses through complex signaling pathways at molecular level. Although previous studies provide explanations for the protective role of breastfeeding against both obesity and asthma, other factors such as duration of breastfeeding, parental, and prenatal factors may confound this relationship which requires further research.
Comparison of distal radius fracture plating surgery under wide-awake local anesthesia no tourniquet technique and balanced anesthesia: a retrospective cohort study
Authors: Chen Chih-Ting , Chou Shih-Hsiang , Huang Hsuan-Ti , Fu Yin-Chih , Jupiter Jesse B. , Liu Wen-Chih
Published: October 2023

Background

Distal radius fractures (DRF) are frequently treated with internal fixation under general anesthesia or a brachial plexus block. Recently, the wide-awake local anesthesia with no tourniquet (WALANT) technique has been suggested as a method that results in higher patient satisfaction. This study aimed to evaluate the functional outcomes, complications, and patient-reported outcomes of DRF plating surgery under both the WALANT and balanced anesthesia (BA).

Methods

Ninety-three patients with DRFs who underwent open reduction and plating were included. Regarding the anesthetic technique, 38 patients received WALANT, while 55 received BA, comprised of multimodal pain control brachial plexus anesthesia with light general support. The patient's overall satisfaction in both groups and the intraoperative numerical rating scale of pain and anxiety (0–10) in the WALANT group were recorded. The peri-operative radiographic parameters were measured; the clinical outcomes, including Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) score, wrist mobility, and grip strength, were recorded in up to 1-year follow-up. Results presented with a mean difference and 95% confidence intervals and mean ± standard deviation.

Results

The mean age of patients in the WALANT group was higher than in the BA group (63 ± 17 vs. 54 ± 17, P = 0.005), and there were fewer intra-articular DRF fractures in the WALANT group than in the BA group (AO type A/B/C: 30/3/5 vs. 26/10/19, P = 0.009). The reduction and plating quality were similar in both groups. The clinical outcomes at follow-up were comparable between the two groups, except the WALANT group had worse postoperative 3-month pronation (88% vs. 96%; − 8.0% [ − 15.7 to − 0.2%]) and 6-month pronation (92% vs. 100%; − 9.1% [ − 17.0 to − 1.2%]), and better postoperative 1-year flexion (94% vs. 82%; 12.0% [2.0–22.1%]). The overall satisfaction was comparable in the WALANT and BA groups (8.7 vs. 8.5; 0.2 [ − 0.8 to 1.2]). Patients in the WALANT group reported an injection pain scale of 1.7 ± 2.0, an intraoperative pain scale of 1.2 ± 1.9, and an intraoperative anxiety scale of 2.3 ± 2.8.

Conclusion

The reduction quality, functional outcomes, and overall satisfaction were comparable between the WALANT and BA groups. With meticulous preoperative planning, the WALANT technique could be an alternative for DRF plating surgery in selected patients.

Trial registration This retrospective study was approved by the Institutional Review Board of Kaohsiung Medical University Hospital (KMUHIRB-E(I)-20210201).
Gastric cancer-derived LBP promotes liver metastasis by driving intrahepatic fibrotic pre-metastatic niche formation
Authors: Xie Li , Qiu Shengkui , Lu Chen , Gu Chao , Wang Jihuan , Lv Jialun , Fang Lang , Chen Zetian , Li Ying , Jiang Tianlu , Xia Yiwen , Wang Weizhi , Li Bowen , Xu Zekuan
Published: October 2023

Background

Liver metastasis (LM) is one of the most common distant metastases of gastric cancer (GC). However, the mechanisms underlying the LM of GC (GC-LM) remain poorly understood. This study aimed to identify the tumour-secreted protein associated with GC-LM and to investigate the mechanisms by which this secreted protein remodels the liver microenvironment to promote GC-LM.

Methods

Data-independent acquisition mass spectrometry (DIA-MS), mRNA expression microarray, quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) were performed to identify and validate the GC-secreted proteins associated with GC-LM. A modified intrasplenic injection mouse model of LM was used to evaluate the progression and tumour burden of LM in vivo. Flow cytometry, immunofluorescence (IF), western blots (WB) and IHC were performed to validate the pre-metastatic niche (PMN) formation in the pre-modelling mouse models. mRNA sequencing of PMA-treated THP-1 cells with or without lipopolysaccharide binding protein (LBP) treatment was used to identify the functional target genes of LBP in macrophages. Co-immunoprecipitation (Co-IP), WB, ELISA, IF and Transwell assays were performed to explore the underlying mechanism of LBP in inducing intrahepatic PMN formation.

Results

LBP was identified as a critical secreted protein associated with GC-LM and correlated with a worse prognosis in patients with GC. LBP activated the TLR4/NF-κB pathway to promote TGF-β1 secretion in intrahepatic macrophages, which, in turn, activated hepatic satellite cells (HSCs) to direct intrahepatic fibrotic PMN formation. Additionally, TGF-β1 enhanced the migration and invasion of incoming metastatic GC cells in the liver. Consequently, selective targeting of the TGF-β/Smad signaling pathway with galunisertib demonstrated its efficacy in effectively preventing GC-LM in vivo.

Conclusions

The results of this study provide compelling evidence that serological LBP can serve as a valuable diagnostic biomarker for the early detection of GC-LM. Mechanistically, GC-derived LBP mediates the crosstalk between primary GC cells and the intrahepatic microenvironment by promoting TGF-β1 secretion in intrahepatic macrophages, which induces intrahepatic fibrotic PMN formation to promote GC-LM. Importantly, selectively targeting the TGF-β/Smad signaling pathway with galunisertib represents a promising preventive and therapeutic strategy for GC-LM.
Enteral citrulline supplementation versus placebo on SOFA score on day 7 in mechanically ventilated critically ill patients: the IMMUNOCITRE randomized clinical trial
Authors: Tadié Jean-Marc , Locher Clara , Maamar Adel , Reignier Jean , Asfar Pierre , Commereuc Morgane , Lesouhaitier Mathieu , Gregoire Murielle , Le Pabic Estelle , Bendavid Claude , Moreau Caroline , Diehl Jean-Luc , Gey Alain , Tartour Eric , Le Tulzo Yves , Thibault Ronan , Terzi Nicolas , Gacouin Arnaud , Roussel Mikael , Delclaux Christophe , Tarte Karin , Cynober Luc
Published: October 2023

Background

Restoring plasma arginine levels through enteral administration of L-citrulline in critically ill patients may improve outcomes. We aimed to evaluate whether enteral L-citrulline administration reduced organ dysfunction based on the Sequential Organ Failure Assessment (SOFA) score and affected selected immune parameters in mechanically ventilated medical intensive care unit (ICU) patients.

Methods

A randomized, double-blind, multicenter clinical trial of enteral administration of L-citrulline versus placebo for critically ill adult patients under invasive mechanical ventilation without sepsis or septic shock was conducted in four ICUs in France between September 2016 and February 2019. Patients were randomly assigned to receive enteral L-citrulline (5 g) every 12 h for 5 days or isonitrogenous, isocaloric placebo. The primary outcome was the SOFA score on day 7. Secondary outcomes included SOFA score improvement (defined as a decrease in total SOFA score by 2 points or more between day 1 and day 7), secondary infection acquisition, ICU length of stay, plasma amino acid levels, and immune biomarkers on day 3 and day 7 (HLA-DR expression on monocytes and interleukin-6).

Results

Of 120 randomized patients (mean age, 60 ± 17 years; 44 [36.7%] women; ICU stay 10 days [IQR, 7–16]; incidence of secondary infections 25 patients (20.8%)), 60 were allocated to L-citrulline and 60 were allocated to placebo. Overall, there was no significant difference in organ dysfunction as assessed by the SOFA score on day 7 after enrollment (4 [IQR, 2–6] in the L-citrulline group vs. 4 [IQR, 2–7] in the placebo group; Mann‒Whitney U test, p = 0.9). Plasma arginine was significantly increased on day 3 in the treatment group, while immune parameters remained unaffected.

Conclusion

Among mechanically ventilated ICU patients without sepsis or septic shock, enteral L-citrulline administration did not result in a significant difference in SOFA score on day 7 compared to placebo.

Trial registration: ClinicalTrials.gov Identifier NCT02864017 (date of registration: 11 August 2016).
Evaluation of the association of area-level socioeconomic deprivation and breast cancer recurrence by oestrogen receptor subtypes in Scotland
Authors: Dunlop Hayley M. , Williams Linda J. , Hall Peter S. , Barber Matthew , Dodds Christine , Figueroa Jonine D.
Published: October 2023

Background

Women from socioeconomically deprived areas have lower breast cancer (BC) incidence rates for screen-detected oestrogen receptor (ER) + tumours and higher mortality for select tumour subtypes. We aimed to determine if ipsilateral breast cancer recurrence (IBR) differs by Scottish Index of Multiple Deprivation (SIMD) quintile and tumour subtype in Scotland.

Methods

Patient data for primary invasive BC diagnosed in 2007–2008 in Scotland was analysed. Manual case-note review for 3495 patients from 10 years post-diagnosis was used. To determine the probability of IBR while accounting for the competing risk of death from any cause, cumulative incidence functions stratified by ER subtype and surgery were plotted. Multivariable Cox Proportional Hazards models were used to estimate the association of SIMD accounting for other predictors of IBR.

Results

Among 2819 ER + tumours, 423 patients had a recurrence and 438 died. SIMD was related to death (p = 0.018) with the most deprived more likely to have died in the 10-year period (17.7% vs. 12.9%). We found no significant differences by SIMD in prognostic tumour characteristics (grade, TNM stage, treatment, screen-detection) or risk of IBR. Among 676 patients diagnosed with ER- tumours, 105 died and 185 had a recurrence. We found no significant differences in prognostic tumour characteristics by SIMD except screen detection with the most deprived more likely than the least to have their tumours detected from screening (46.9% vs. 28%, p = 0.03). Among patients with ER- tumours, 50% had mastectomy and the most deprived had increased 5-year IBR risk compared to the least deprived (HR 3.03 [1.41–6.53]).

Conclusions

IBR is not a major contributor to mortality differences by SIMD for the majority of BC patients in our study. The lack of inequities in IBR are likely due to standardised treatment protocols and access to healthcare. The association with socioeconomic deprivation and recurrence for ER- tumours requires further study.
Identification of methylation-regulated genes modulating microglial phagocytosis in hyperhomocysteinemia-exacerbated Alzheimer’s disease
Authors: Wang Xianwei , Liu Lu , Jiang Xiaohua , Saredy Jason , Xi Hang , Cueto Ramon , Sigler Danni , Khan Mohsin , Wu Sheng , Ji Yong , Snyder Nathaniel W. , Hu Wenhui , Yang Xiaofeng , Wang Hong
Published: October 2023

Background

Hyperhomocysteinemia (HHcy) has been linked to development of Alzheimer’s disease (AD) neuropathologically characterized by the accumulation of amyloid β (Aβ). Microglia (MG) play a crucial role in uptake of Aβ fibrils, and its dysfunction worsens AD. However, the effect of HHcy on MG Aβ phagocytosis remains unstudied.

Methods

We isolated MG from the cerebrum of HHcy mice with genetic cystathionine-β-synthase deficiency (Cbs−/−) and performed bulk RNA-seq. We performed meta-analysis over transcriptomes of Cbs−/− mouse MG, human and mouse AD MG, MG Aβ phagocytosis model, human AD methylome, and GWAS AD genes.

Results

HHcy and hypomethylation conditions were identified in Cbs−/− mice. Through Cbs−/− MG transcriptome analysis, 353 MG DEGs were identified. Phagosome formation and integrin signaling pathways were found suppressed in Cbs−/− MG. By analyzing MG transcriptomes from 4 AD patient and 7 mouse AD datasets, 409 human and 777 mouse AD MG DEGs were identified, of which 37 were found common in both species. Through further combinatory analysis with transcriptome from MG Aβ phagocytosis model, we identified 130 functional-validated Aβ phagocytic AD MG DEGs (20 in human AD, 110 in mouse AD), which reflected a compensatory activation of Aβ phagocytosis. Interestingly, we identified 14 human Aβ phagocytic AD MG DEGs which represented impaired MG Aβ phagocytosis in human AD. Finally, through a cascade of meta-analysis of transcriptome of AD MG, functional phagocytosis, HHcy MG, and human AD brain methylome dataset, we identified 5 HHcy-suppressed phagocytic AD MG DEGs (Flt1, Calponin 3, Igf1, Cacna2d4, and Celsr) which were reported to regulate MG/MΦ migration and Aβ phagocytosis.

Conclusions

We established molecular signatures for a compensatory response of Aβ phagocytosis activation in human and mouse AD MG and impaired Aβ phagocytosis in human AD MG. Our discoveries suggested that hypomethylation may modulate HHcy-suppressed MG Aβ phagocytosis in AD.
Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation
Authors: Li Dan , Zhou Jiefei , Wang Lingyu , Gong Zizhen , Le Huijuan , Huang Ye , Xu Congfeng , Tian Chunyan , Cai Wei , Wu Jin
Published: October 2023

Background

High-fat diet (HFD) is closely associated with the increased prevalence of inflammatory bowel disease (IBD). Excessive gut microbial metabolite deoxycholic acid (DCA) caused by HFD plays significant roles in eliciting intestinal inflammation, however, the mechanism underlining the induction of inflammatory response by DCA has not been fully elucidated. The purpose of this study was to investigate the role of DCA in the triggering of inflammation via affecting CD4+ T cell differentiation.

Results

Murine CD4+T cells were cultured under Th1, Th2 or Th17-polarizing conditions treated with or without different dosage of DCA, and flowcytometry was conducted to detect the effect of DCA on CD4+ T cell differentiation. Alteration of gene expression in CD4+ T cells upon DCA treatment was determined by RNA-sequencing and qRT-PCR. Bioinformatic analysis, cholesterol metabolic profiling, ChIP assay and immuno-fluorescent staining were further applied to explore the DCA-regulated pathway that involved in CD4+T cell differentiation. The results showed that DCA could dose-dependently promote the differentiation of CD4+ T cell into Th17 linage with pathogenic signature. Mechanistically, DCA stimulated the expression of cholesterol biosynthetic enzymes CYP51 and led to the increased generation of endogenous RORγt agonists, including zymosterol and desmosterol, therefore facilitating Th17 differentiation. Up-regulation of CYP51 by DCA was largely mediated via targeting transcription factor SREBP2 and at least partially through bile acid receptor TGR5. In addition, DCA-supplemented diet significantly increased intestinal Th17 cell infiltration and exacerbated TNBS-induced colitis. Administration of cholestyramine to eliminate fecal bile acid obviously alleviated colonic inflammation accompanied by decreased Th17 cells in HFD-fed mice.

Conclusions

Our data establish a link between DCA-induced cholesterol biosynthesis in immune cells and gut inflammation. Modulation of bile acid level or targeting cholesterol metabolic pathway may be potential therapeutic measurements for HFD-related colitis.
Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer’s disease brains
Authors: Gamache Julia , Gingerich Daniel , Shwab E. Keats , Barrera Julio , Garrett Melanie E. , Hume Cordelia , Crawford Gregory E. , Ashley-Koch Allison E. , Chiba-Falek Ornit
Published: October 2023

Background

The genetic underpinnings of late-onset Alzheimer’s disease (LOAD) are yet to be fully elucidated. Although numerous LOAD-associated loci have been discovered, the causal variants and their target genes remain largely unknown. Since the brain is composed of heterogenous cell subtypes, it is imperative to study the brain on a cell subtype specific level to explore the biological processes underlying LOAD.

Methods

Here, we present the largest parallel single-nucleus (sn) multi-omics study to simultaneously profile gene expression (snRNA-seq) and chromatin accessibility (snATAC-seq) to date, using nuclei from 12 normal and 12 LOAD brains. We identified cell subtype clusters based on gene expression and chromatin accessibility profiles and characterized cell subtype-specific LOAD-associated differentially expressed genes (DEGs), differentially accessible peaks (DAPs) and cis co-accessibility networks (CCANs).

Results

Integrative analysis defined disease-relevant CCANs in multiple cell subtypes and discovered LOAD-associated cell subtype-specific candidate cis regulatory elements (cCREs), their candidate target genes, and trans-interacting transcription factors (TFs), some of which, including ELK1, JUN, and SMAD4 in excitatory neurons, were also LOAD-DEGs. Finally, we focused on a subset of cell subtype-specific CCANs that overlap known LOAD-GWAS regions and catalogued putative functional SNPs changing the affinities of TF motifs within LOAD-cCREs linked to LOAD-DEGs, including APOE and MYO1E in a specific subtype of microglia and BIN1 in a subpopulation of oligodendrocytes.

Conclusions

To our knowledge, this study represents the most comprehensive systematic interrogation to date of regulatory networks and the impact of genetic variants on gene dysregulation in LOAD at a cell subtype resolution. Our findings reveal crosstalk between epigenetic, genomic, and transcriptomic determinants of LOAD pathogenesis and define catalogues of candidate genes, cCREs, and variants involved in LOAD genetic etiology and the cell subtypes in which they act to exert their pathogenic effects. Overall, these results suggest that cell subtype-specific cis–trans interactions between regulatory elements and TFs, and the genes dysregulated by these networks contribute to the development of LOAD.
Model-based clustering of multipath propagation in powerline communication channels
Authors: Mokise Kealeboga L. , Myburgh Herman C.
Published: October 2023

Powerline communication (PLC) channels are known to exhibit multipath propagation behaviour. The authors present a model-based framework to address the challenge of clustering multipath propagation components (MPCs) in PLC channels for indoor low-voltage (LV) environments. The framework employs a range of finite-mixture models (FMMs), including the gamma mixture model, the inverse gamma mixture model, the Gaussian mixture model, the inverse Gaussian mixture model, the Nakagami mixture model, the inverse Nakagami mixture model (INMM) and the Rayleigh mixture model, to identify clusters of MPCs. A measurement campaign of an unknown indoor LV PLC channel is conducted to obtain a channel response. From the channel response, the delay and magnitude parameters of the MPCs are extracted using the space-alternating generalised expectation maximisation algorithm adopted only for these parameters. A maximum likelihood approach and the expectation–maximisation algorithm are employed to fit the FMMs to the MPC delay-magnitude dataset to cluster MPCs in the delay domain. The results of the model-fitting process are then evaluated using the corrected Akaike information criterion (AICc), which enables a fair comparison of the candidate models over the feasible and finite range of clusters. A novel algorithm is introduced for estimating the feasible and finite range of clusters using the extracted delay and magnitude MPC parameters. The AICc’s ranking results show that the INMM model provides the best fit. Davies–Bouldin (DB) and Calinski–Harabasz (CH) indexes are used to compare the model-based clustering approach to the conventional distance-based clustering methods. Validation results show that CH and DB indexes closely agree in the optimal number of MPC clusters for model-based clustering, which corresponds to the most within-cluster compactness of MPCs and to the most between-cluster separation in the delay domain.
Whole-exome sequencing reveals candidate high-risk susceptibility genes for endometriosis
Authors: Nousiainen Susanna , Kuismin Outi , Reinikka Siiri , Manninen Roosa , Khamaiseh Sara , Kuivalainen Mari , Terho Anna , Koivurova Sari , Niinimäki Maarit , Salokas Kari , Varjosalo Markku , Ahtikoski Anne , Bützow Ralf , Lindgren Outi , Uimari Outi , Vahteristo Pia
Published: October 2023

Background

Endometriosis is a common, chronic disease among fertile-aged women. Disease course may be highly invasive, requiring extensive surgery. The etiology of endometriosis remains elusive, though a high level of heritability is well established. Several low-penetrance predisposing loci have been identified, but high-risk susceptibility remains undetermined. Endometriosis is known to increase the risk of epithelial ovarian cancers, especially of endometrioid and clear cell types. Here, we have analyzed a Finnish family where four women have been diagnosed with surgically verified, severely symptomatic endometriosis and two of the patients also with high-grade serous carcinoma.

Results

Whole-exome sequencing revealed three rare candidate predisposing variants segregating with endometriosis. The variants were c.1238C>T, p.(Pro413Leu) in FGFR4, c.5065C>T, p.(Arg1689Trp) in NALCN, and c.2086G>A, p.(Val696Met) in NAV2. The only variant predicted deleterious by in silico tools was the one in FGFR4. Further screening of the variants in 92 Finnish endometriosis and in 19 endometriosis–ovarian cancer patients did not reveal additional carriers. Histopathology, positive p53 immunostaining, and genetic analysis supported the high-grade serous subtype of the two tumors in the family.

Conclusions

Here, we provide FGFR4, NALCN, and NAV2 as novel high-risk candidate genes for familial endometriosis. Our results also support the association of endometriosis with high-grade serous carcinoma. Further studies are required to validate the findings and to reveal the exact pathogenesis mechanisms of endometriosis. Elucidating the genetic background of endometriosis defines the etiology of the disease and provides opportunities for expedited diagnostics and personalized treatments.
Relationship between disgust and orthorexia nervosa and psychometric properties of the Italian Dusseldorf orthorexia scale in a general population sample
Authors: Aloi Matteo , Moniaci Martina , Rania Marianna , Carbone Elvira Anna , Martino Gabriella , Segura-Garcia Cristina , Liuzza Marco Tullio
Published: October 2023

Background

It remains unclear among clinicians and researchers whether orthorexia nervosa (ON) is a part of the obsessive–compulsive disorder spectrum or eating disorders. Disgust seems to be a shared psychopathological factor in these clinical presentations, indicating a potentially crucial role in ON. On the other hand, numerous psychometric tools have been developed to evaluate ON. The Dusseldorf Orthorexia Scale (DOS) was recently validated in an Italian sample. However, the study's primary limitation was that the scale was only administered to undergraduate university students. This study aimed to investigate the psychometric properties (including factorial structure, reliability, and measurement invariance conditional on sex) of the Italian version of the DOS (I-DOS) on a sample from the general population. Additionally, the study sought to determine the nomological validity of the I-DOS by examining its relationship with disgust sensitivity.

Methods

A sample of 521 participants took part in this study and completed a battery that assessed ON and disgust sensitivity. To assess the I-DOS structure, reliability, and measurement invariance we respectively conducted confirmatory factor analysis (CFA), computed McDonalds’s omega, and performed hierarchical series of multigroup CFAs. Then, we tested the relationship between ON and disgust sensitivity.

Results

CFA confirmed the unifactorial model of I-DOS and it respected the configural, metric, and strict invariance while a partial scalar invariance was achieved. It also showed good reliability with an omega of 0.87. In addition, we found a positive relationship between ON and disgust sensitivity, thus confirming the nomological validity of I-DOS.

Conclusions

Our findings suggest that the Italian version of the Dusseldorf orthorexia scale (I-DOS) exhibits strong psychometric properties and can be an effective instrument for assessing ON in a general population sample. Notably, the most significant and innovative outcome was the positive correlation between ON and disgust sensitivity. As disgust has been linked to other clinical presentations, this preliminary result could serve as a foundation for future research exploring this phenomenon in greater detail.