bluuebunny/crossref_metadata_2025 huggingface dataset:
Multimorbidity prevalence and health outcome prediction: assessing the impact of lookback periods, disease count, and definition criteria in health administrative data at the population-based level
Authors: Simard Marc , Rahme Elham , Dubé Marjolaine , Boiteau Véronique , Talbot Denis , Sirois Caroline
Published: May 2024

Background

Health administrative databases play a crucial role in population-level multimorbidity surveillance. Determining the appropriate retrospective or lookback period (LP) for observing prevalent and newly diagnosed diseases in administrative data presents challenge in estimating multimorbidity prevalence and predicting health outcome. The aim of this population-based study was to assess the impact of LP on multimorbidity prevalence and health outcomes prediction across three multimorbidity definitions, three lists of diseases used for multimorbidity assessment, and six health outcomes.

Methods

We conducted a population-based study including all individuals ages > 65 years on April 1st, 2019, in Québec, Canada. We considered three lists of diseases labeled according to the number of chronic conditions it considered: (1) L60 included 60 chronic conditions from the International Classification of Diseases (ICD); (2) L20 included a core of 20 chronic conditions; and (3) L31 included 31 chronic conditions from the Charlson and Elixhauser indices. For each list, we: (1) measured multimorbidity prevalence for three multimorbidity definitions (at least two [MM2+], three [MM3+] or four (MM4+) chronic conditions); and (2) evaluated capacity (c-statistic) to predict 1-year outcomes (mortality, hospitalisation, polypharmacy, and general practitioner, specialist, or emergency department visits) using LPs ranging from 1 to 20 years.

Results

Increase in multimorbidity prevalence decelerated after 5–10 years (e.g., MM2+, L31: LP = 1y: 14%, LP = 10y: 58%, LP = 20y: 69%). Within the 5–10 years LP range, predictive performance was better for L20 than L60 (e.g., LP = 7y, mortality, MM3+: L20 [0.798;95%CI:0.797-0.800] vs. L60 [0.779; 95%CI:0.777–0.781]) and typically better for MM3 + and MM4 + definitions (e.g., LP = 7y, mortality, L60: MM4+ [0.788;95%CI:0.786–0.790] vs. MM2+ [0.768;95%CI:0.766–0.770]).

Conclusions

In our databases, ten years of data was required for stable estimation of multimorbidity prevalence. Within that range, the L20 and multimorbidity definitions MM3 + or MM4 + reached maximal predictive performance.
Exploring how Australian general practice registrars define cultural safety with Aboriginal and Torres Strait Islander patients: a mixed method study
Authors: Brumpton Kay , Woodall Hannah , Evans Rebecca , Neill Henry , Gupta Tarun Sen , McArthur Lawrie , Ward Raelene
Published: May 2024

Background

Understanding how the general practice medical workforce defines cultural safety may help tailor education and training to better enable community-determined culturally safe practice. This project seeks to explore how Australian general practice registrars define cultural safety with Aboriginal and Torres Strait Islander patients and alignment with an Australian community derived definition of cultural safety.

Methods

This mixed method study involved a survey considering demographic details of general practice registrars, questionnaire, and semi-structured interviews to explore how general practice registrars defined cultural safety and a culturally safe consultation.

Results

Twenty-six registrars completed the survey. Sixteen registrars completed both the survey and the interview.

Conclusion

This study shows amongst this small sample that there is limited alignment of general practice registrars’ definitions of cultural safety with a community derived definition of cultural safety. The most frequently cited aspects of cultural safety included accessible healthcare, appropriate attitude, and awareness of differences.
Parkinson’s disease with anxiety: clinical characteristics and their correlation with oxidative stress, inflammation, and pathological proteins
Authors: Lian Tenghong , Zhang Weijiao , Li Danning , Guo Peng , He Mingyue , Zhang Yanan , Li Jinghui , Guan Huiying , Zhang Wenjing , Luo Dongmei , Zhang Weijia , Wang Xiaomin , Zhang Wei
Published: May 2024

Objective

This study was performed to explore the differences in the clinical characteristics and oxidative stress indicators, inflammatory factors, and pathological proteins in serum between Parkinson’s disease (PD) with anxiety (PD-A) and with no anxiety (PD-NA) patients, and further correlations among clinical characteristics and above variables were analyzed in PD-A and PD-NA groups.

Methods

A total of 121 patients with PD were enrolled in this study and assessed by the Hamilton Anxiety Scale (14 items) (HAMA-14). These patients were divided into PD-A and PD-NA groups according to a cut-off point of 7 of HAMA-14. Demographic variables were collected, and clinical symptoms were assessed by multiple rating scales. The levels of free radicals, inflammatory factors, and pathological proteins in serum were measured by chemical colorimetric method and enzyme-linked immunosorbent assay (ELISA). The differences of above variables were compared between PD-A and PD-NA groups, and the correlations of clinical symptoms with the abovevariables were analyzed in PD-A and PD-NA groups.

Results

The frequency of PD-A was 62.81%. PD-A group exhibited significantly impaired motor dysfunction and multiple non-motor symptoms, including fatigue, sleep behavior disorder, restless leg syndrome and autonomic dysfunction, and dramatically compromised activities of daily living compard with PD-NA group. PD-A group displayed prominently increasedlevels of hydroxyl radical (·OH) and tumor necrosis factor (TNF)-α, and a decreased nitric oxide (NO) level in serum compared with PD-NA group (P<0.001, P = 0.001, P= 0.027, respectively). ·OH, NO, and TNF-α were identified as the risk factors of PD-A (OR = 1.005, P = 0.036; OR = 0.956, P = 0.017; OR = 1.039, P = 0.033, respectively). In PD patients, HAMA-14 score was significantly and positively correlated with the levels of ·OH and TNF-α in serum (P<0.001, P = 0.002, respectively). In PD-A group, ·OH level was significantly and negatively correlated with Aβ1−42 level, while TNF-α level was significantly and positively correlated with P-tau (S396) level in serum.

Conclusions

The frequency of PD-A is high. PD-A patients present more severe motor dysfunction and multiple non-motor symptoms, and poorer activities of daily living. The increased levels of ·OH and TNF-α levels and the decreased NO level in serum are all associated with more severe anxiety in PD patients.Findings from this study may provide in-depth insights into the clinical characteristics, underlying mechanisms of PD-A, and potential correlations among anxiety, oxidative stress, inflammation, and cognitive decline in PD patients.
Associations of CBC-Derived inflammatory indicators with sarcopenia and mortality in adults: evidence from Nhanes 1999 ∼ 2006
Authors: Guo Botang , Liu Xinqing , Si Qi , Zhang Dongdong , Li Minyao , Li Xi , Zhao Yang , Hu Fulan , Zhang Ming , Liu Yu , Hu Dongsheng
Published: May 2024

Background

It has been proposed that inflammation plays a role in the development of sarcopenia. This study aimed to investigate the links of complete blood cell count (CBC) parameters and CBC-derived inflammatory indicators with sarcopenia and mortality.

Methods

Data pertaining to sarcopenia were extracted from the 1999–2006 National Health and Nutrition Examination Survey (NHANES), and mortality events were ascertained through the National Death Index up to December 31, 2019. The CBC-derived inflammatory indicators assessed in this study included the neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (dNLR), monocyte-to-lymphocyte ratio (MLR), neutrophil-monocyte to lymphocyte ratio (NMLR), systemic inflammatory response index (SIRI), and systemic immune-inflammation index (SII). The prognostic significance of these CBC-derived inflammatory indicators was evaluated using the random survival forests (RSF) analysis.

Results

The study encompassed a cohort of 12,689 individuals, among whom 1,725 were diagnosed with sarcopenia. Among individuals with sarcopenia, 782 experienced all-cause mortality, and 195 succumbed to cardiovascular causes. Following adjustment for confounding variables, it was observed that elevated levels of NLR, dNLR, NMLR, SIRI, and SII were associated with an increased prevalence of sarcopenia. Among participants with sarcopenia, those in the highest quartile of NLR (HR = 1.336 [1.095–1.631]), dNLR (HR = 1.274 [1.046–1.550]), MLR (HR = 1.619 [1.290–2.032]), NMLR (HR = 1.390 [1.132–1.707]), and SIRI (HR = 1.501 [1.210–1.862]) exhibited an elevated risk of all-cause mortality compared to those in the lowest quartile of these inflammation-derived indicators. These associations were similarly observed in cardiovascular mortality (HR = 1.874 [1.169–3.003] for MLR, HR = 1.838 [1.175–2.878] for SIRI). The RSF analysis indicated that MLR exhibited the highest predictive power for both all-cause and cardiovascular mortality among individuals with sarcopenia.

Conclusions

Our findings underscore the association between CBC-derived inflammatory indicators and mortality in adults with sarcopenia. Of note, MLR emerged as the most robust predictor of all-cause and cardiovascular mortality in this population.
A rare case of IgA lambda multiple myeloma in a 32-year-old woman with t(14;16) translocation associated with kidney injury and non-albumin proteinuria
Authors: Razzouk Ranim , Khattab Nour , Hoteit Maysaa , Kfoury Hala , Saleh Mustafa , Tanios Bassem , El-Cheikh Jean , Mallat Samir
Published: May 2024

Background

Multiple myeloma (MM) is a malignant disorder characterized by monoclonal differentiated plasma cells. While it is more commonly diagnosed in elderly individuals, it can also affect younger populations, though with a lower incidence.

Case presentation

Here, we present the case of a 32-year-old woman diagnosed with IgA lambda MM. She presented with fatigue, nausea, acute kidney injury (AKI) with a rapid increase in creatinine, and anemia. A kidney biopsy was done to rule out a rapidly progressive glomerular disease and a diagnosis was thus reached. A genetic workup revealed t(14;16) translocation and an extra copy of TP53. The patient received aggressive intravenous steroids and intravenous fluid resuscitation, resulting in an improvement in renal function. Treatment with daratumumab in combination with bortezomib, thalidomide, and dexamethasone was initiated and well tolerated. Despite the generally poor prognosis of IgA MM, our case emphasizes the importance of considering MM in young patients with unexplained kidney injury.

Conclusion

Early recognition and prompt intervention are essential in managing MM patients, especially in those with high-risk cytogenetic abnormalities. This case serves as a reminder for clinicians to maintain a high index of suspicion for MM, even in younger populations, when presented with unexplained kidney injury.
New and old lessons from a devastating case of neonatal E coli meningitis
Authors: Saleh Tawny , Kamau Edwin , Rathe Jennifer A.
Published: May 2024

Background

Neonatal Escherichia coli (E coli) meningitis results in significant morbidity and mortality. We present a case of a premature infant with extensive central nervous system (CNS) injury from recurrent E coli infection and the non-traditional methods necessary to identify and clear the infection.

Case Presentation

The infant was transferred to our institution’s pediatric intensive care unit (PICU) after recurrence of E coli CNS infection requiring neurosurgical intervention. He had been treated for early onset sepsis (EOS) with ampicillin and gentamicin for 10 days followed by rapid development of ampicillin-resistant E coli septic shock and meningitis after discontinuation of antibiotics. Sterility of the CNS was not confirmed at the end of 21 days of cefepime therapy and was subsequently followed by recurrent ampicillin-resistant E coli septic shock and CNS infection. Despite 6 weeks of appropriate therapy with sterility of CSF by traditional methods, he suffered from intractable seizures with worsening hydrocephalus. Transferred to our institution, he underwent endoscopic 3rd ventriculostomy with cyst fenestration revealing purulent fluid and significant pleocytosis. An additional 3 weeks of systemic and intraventricular antibiotics with cefepime and tobramycin were given but a significant CNS neutrophil-predominant pleocytosis persisted (average of $$\sim$$ 21,000 cells/mm3). Repeated gram stains, cultures, polymerase chain reaction (PCR) testing, and metagenomic next generation sequencing (NGS) testing of CSF were negative for pathogens but acridine orange stain (AO) revealed numerous intact rod-shaped bacteria. After the addition of ciprofloxacin, sterility and resolution of CSF pleocytosis was finally achieved.

Conclusion

Neonatal E coli meningitis is a well-known entity but unlike other bacterial infections, it has not proven amenable to shorter, more narrow-spectrum antibiotic courses or limiting invasive procedures such as lumbar punctures. Further, microbiologic techniques to determine CSF sterility suffer from poorly understood limitations leading to premature discontinuation of antibiotics risking further neurologic damage in vulnerable hosts.
Associations between immune cell phenotypes and lung cancer subtypes: insights from mendelian randomization analysis
Authors: Zheng Jin-Min , Lou Chen-Xi , Huang Yu-Liang , Song Wen-Tao , Luo Yi-Chen , Mo Guan-Yong , Tan Lin-Yuan , Chen Shang-Wei , Li Bai-Jun
Published: May 2024

Introduction

Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear.

Methods

This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings.

Results

Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627–1.1344, p < 0.0001) and CD45RA + CD28- CD8 + T cell %T cell (OR 1.0011, 95% CI: 1.0007; 1.0015, p < 0.0001) were associated with increased susceptibility to LUSC. Conversely, CCR2 expression on monocytes (OR 0.9399, 95% CI: 0.9177–0.9625, p < 0.0001) was correlated with a decreased risk of LUSC. However, no significant causal relationships were established between any immune cell phenotypes and LUAD.

Conclusion

This study demonstrates that specific immune cell types are associated with the risk of LUSC but not with LUAD. While these findings are derived solely from European populations, they still provide clues for a deeper understanding of the immunological mechanisms underlying lung cancer and may offer new directions for future therapeutic strategies and preventive measures.
Variables that predict hospital stay and the outcome of Fournier gangrene at King Abdulaziz University Hospital: a retrospective study
Authors: Alhubaishy Bandar , Bahassan Omar M. , Alsabban Abdulrahman E. , Alkhzaim Ali H. , Alnefaie Ziyad A. , Algarni Kamal S. , Almehmadi Sultan G. , Alqahtani Saud N.
Published: May 2024

Background

The aggressive nature of Fournier gangrene and the associated health issues can result in a more complex clinical course and potentially a longer hospital stay. This study aimed to assess factors that affect the length of hospital stay (LHS) and its relation to the outcome of Fournier gangrene patients.

Methods

A retrospective study was performed at King Abdulaziz University Hospital (KAUH), Saudi Arabia, on patients diagnosed with Fournier gangrene between 2017 and 2023. Data about length of hospital stay (LHS), age, BMI, clinical and surgical data and outcome was obtained.

Results

The mean age of the studied patients was 59.23 ± 11.19 years, the mean body mass index (BMI) was 26.69 ± 7.99 kg/m2, and the mean duration of symptoms was 10.27 ± 9.16 days. The most common presenting symptoms were swelling or induration (64%), 88% had comorbidities with diabetes mellitus (DM) (84%), and 76% had uncontrolled DM. of patients, 24% had a poly-microbial infection, with E. coli being the most common (52%). The mean length of hospital stay (LHS) was 54.56 ± 54.57 days, and 24% of patients had an LHS of more than 50 days. Longer LHS (> 50 days) was associated with patients who did not receive a compatible initial antibiotic, whereas shorter LHS was associated with patients who received Impenem or a combination of vancomycin and meropenem as alternative antibiotics following incompatibility. Reconstruction patients had significantly longer LHS and a higher mean temperature. However, none of the studied variables were found to be predictors of long LHS in the multivariate regression analysis.

Conclusion

Knowledge of the values that predict LHS allows for patient-centered treatment and may be useful in predicting more radical treatments or the need for additional treatment in high-risk patients. Future multicenter prospective studies with larger sample sizes are needed to assess the needed variables and predictors of long LHS.
Knowledge and attitude of spouses of puerperas towards breastfeeding
Authors: Yuan Zhan-Wang , Ma Li , Chen Yu-Ling , Ge Wen-Li , Zhao Hong , Du Yun , Li Xiu-Xiu
Published: May 2024

Objective

To investigate the extent of knowledge about breastfeeding and attitudes towards infant feeding among spouses of puerperas at the time of discharge from hospital, and explore the factors influencing spousal attitudes toward breastfeeding.

Methods

We conducted a questionnaire survey among 204 spouses of puerperas who were admitted in the maternity wards at a tertiary hospital in Shaanxi Province between October 2021 and December 2021. Respondents who fulfilled the inclusion criteria were identified using convenient sampling.

Results

(1) The score of breastfeeding knowledge among spouses prior to discharge from the hospital was (10.56 ± 3.78), with an accuracy rate of 59.6%, and the lowest accuracy rate was for Item 1 “Newborns should be fed on time, not on demand” (42.6%) and Item 5 “Breastfeeding can prevent infant rickets” (49.5%). (2) The average score of spouses’ infant feeding attitudes was (58.15 ± 5.55), and the lowest scoring was for Item 17 “Daily urine volume of infants is a reliable indicator to judge whether they get enough breast milk” (1.99 ± 1.14). (3) Generalized linear model analysis showed a more positive attitude (higher score) among spousal attitudes towards infant feeding in those who had received breastfeeding education [OR = 4.588, 95% CI (0.160 ∼ 3.598)] and those with a master’s degree or above [OR = 18.278, 95% CI (3.471 ∼ 9.346)].

Conclusion

(1) Spouses that received breastfeeding education and those that had a Masters Degree and above had more positive attitude towards infant feeding. (2) Medical staff should focus on puerperas’spouses with degrees below master’s level who had not received breastfeeding education. We recommend using a variety of education methods to enable them to acquire more knowledge on breastfeeding and develop a more positive attitude towards breastfeeding, which will further enhance spousal support for breastfeeding, thus positivizing postpartum co-parenting attitudes and improving the rate of exclusive breastfeeding.
The effects of grape seed extract supplementation on cardiovascular risk factors, liver enzymes and hepatic steatosis in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study
Authors: Ghanbari Parisa , Raiesi Davoud , Alboebadi Roghayeh , Zarejavid Ahmad , Dianati Mostafa , Razmi Hamidreza , Bazyar Hadi
Published: May 2024

Background

Despite the high antioxidant potential of grape seed extract (GSE), very limited studies have investigated its effect on non-alcoholic fatty liver disease (NAFLD). Therefore, this study was conducted with the aim of investigating the effect of GSE on metabolic factors, blood pressure and steatosis severity in patients with NAFLD.

Methods

In this double-blind randomized clinical trial study, 50 NAFLD patients were divided into two groups of 25 participants who were treated with 520 mg/day of GSE or the placebo group for 2 months. The parameters of glycemic, lipid profile, blood pressure and steatohepatitis were measured before and after the intervention.

Results

The GSE group had an average age of 43.52 ± 8.12 years with 15 women and 10 men, while the placebo group had an average age of 44.88 ± 10.14 years with 11 women and 14 men. After 2 months of intervention with GSE, it was observed that insulin, HOMA-IR, TC, TG, LDL-c, ALT, AST, AST/ALT, SBP, DBP and MAP decreased and QUICKi and HDL-c increased significantly (p-value for all < 0.05). Also, before and after adjustment based on baseline, the average changes indicated that the levels of insulin, HOMA-IR, TC, TG, LDL-c, SBP, DBP, MAP in the GSE group decreased more than in the control group (p for all < 0.05). Furthermore, the changes in HDL-c were significantly higher in the GSE group (p < 0.05). The between-groups analysis showed a significant decrease in the HOMA-β and AST before and after adjustment based on baseline levels (p < 0.05). Moreover, the changes in QUICKi after adjustment based on baseline levels were higher in the GSE group than in the control group. Also, between-groups analysis showed that the severity of hepatic steatosis was reduced in the intervention group compared to the placebo group (P = 0.002).

Conclusions

It seems that GSE can be considered one of the appropriate strategies for controlling insulin resistance, hyperlipidemia, hypertension and hepatic steatosis in NAFLD patients.

Trial Registration

The clinical trial was registered in the Iranian Clinical Trial Registration Center (IRCT20190731044392N1). https://irct.behdasht.gov.ir/trial/61413. (The registration date: 30/03/2022)
Nurturing transformative local structures of multisectoral collaboration for primary health care: qualitative insights from select states in India
Authors: Singh Shalini , Miller Emily , Closser Svea
Published: May 2024

Background

Multisectoral collaboration is essential for advancing primary health care (PHC). In low- and middle-income countries (LMICs), limited institutional capacities, governance issues, and inadequate stakeholder engagement impede multisectoral collaboration. India faces similar challenges, especially at the meso-level (districts and subdistricts). Owing to its dependence on context, and insufficient evidence, understanding “How” to improve multisectoral collaboration remains challenging. This study aims to elicit specific recommendations to strengthen meso-level stewardship in India for multisectoral collaboration. The findings from this study may offer lessons for other LMICs.

Methods

Using purposive, maximum variation sampling, the study team conducted semi-structured interviews with 20 diverse participants, including policymakers, implementers, development agency representatives, and academics experienced in multisectoral initiatives. The interviews delved into participants’ experiences, the current situation, enablers, and recommendations for enhancing stakeholder engagement and capacities at the meso-level for multisectoral collaboration.

Results

Context and power are critical elements to consider in fostering effective collaboration. Multisectoral collaboration was particularly successful in three distinct governance contexts: the social-democratic context as in Kerala, the social governance context in Chhattisgarh, and the public health governance context in Tamil Nadu. Adequate health system input and timely guidance instil confidence among local implementers to collaborate. While power plays a role through local leadership’s influence in setting agendas, convening stakeholders, and ensuring accountability. To nurture transformative local leaders for collaboration, holistic, equity-driven, community-informed approaches are essential. The study participants proposed several concrete steps: at the state level, establish “central management units” for supervising local implementers and ensuring bottom-up feedback; at the district level, rationalise committees and assign deliverables to stakeholders; and at the block level, expand convergence structures and involve local self-governments. Development partners can support data-driven priority setting, but local implementers with contextual familiarity should develop decentralised plans collaboratively, articulating rationales, activities, and resources. Finally, innovative training programs are required at all levels, fostering humility, motivation, equity awareness, leadership, problem- solving, and data use proficiency.

Conclusion

This study offers multiple solutions to enhance local implementers’ engagement in multisectoral efforts, advocating for the development, piloting, and evaluation of innovative approaches such as the block convergence model, locally-led collaboration efforts, and novel training methods for local implementers.
Generalizability of polygenic prediction models: how is the R2 defined on test data?
Authors: Staerk Christian , Klinkhammer Hannah , Wistuba Tobias , Maj Carlo , Mayr Andreas
Published: May 2024

Background

Polygenic risk scores (PRS) quantify an individual’s genetic predisposition for different traits and are expected to play an increasingly important role in personalized medicine. A crucial challenge in clinical practice is the generalizability and transferability of PRS models to populations with different ancestries. When assessing the generalizability of PRS models for continuous traits, the $$R^2$$

R
2

is a commonly used measure to evaluate prediction accuracy. While the $$R^2$$

R
2

is a well-defined goodness-of-fit measure for statistical linear models, there exist different definitions for its application on test data, which complicates interpretation and comparison of results.

Methods

Based on large-scale genotype data from the UK Biobank, we compare three definitions of the $$R^2$$

R
2

on test data for evaluating the generalizability of PRS models to different populations. Polygenic models for several phenotypes, including height, BMI and lipoprotein A, are derived based on training data with European ancestry using state-of-the-art regression methods and are evaluated on various test populations with different ancestries.

Results

Our analysis shows that the choice of the $$R^2$$

R
2

 definition can lead to considerably different results on test data, making the comparison of $$R^2$$

R
2

 values from the literature problematic. While the definition as the squared correlation between predicted and observed phenotypes solely addresses the discriminative performance and always yields values between 0 and 1, definitions of the $$R^2$$

R
2

based on the mean squared prediction error (MSPE) with reference to intercept-only models assess both discrimination and calibration. These MSPE-based definitions can yield negative values indicating miscalibrated predictions for out-of-target populations. We argue that the choice of the most appropriate definition depends on the aim of PRS analysis — whether it primarily serves for risk stratification or also for individual phenotype prediction. Moreover, both correlation-based and MSPE-based definitions of $$R^2$$

R
2

can provide valuable complementary information.

Conclusions

Awareness of the different definitions of the $$R^2$$

R
2

on test data is necessary to facilitate the reporting and interpretation of results on PRS generalizability. It is recommended to explicitly state which definition was used when reporting $$R^2$$

R
2

values on test data. Further research is warranted to develop and evaluate well-calibrated polygenic models for diverse populations.
Intelligent nanovesicle for remodeling tumor microenvironment and circulating tumor chemoimmunotherapy amplification
Authors: Huai Manxiu , Wang Yingjie , Li Junhao , Pan Jiaxing , Sun Fang , Zhang Feiyu , Zhang Yi , Xu Leiming
Published: May 2024

Imperceptible examination and unideal treatment effect are still intractable difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). At present, despite 5-fluorouracil (5-FU), as a clinical first-line FOLFIRINOX chemo-drug, has achieved significant therapeutic effects. Nevertheless, these unavoidable factors such as low solubility, lack of biological specificity and easy to induce immunosuppressive surroundings formation, severely limit their treatment in PDAC. As an important source of energy for many tumor cells, tryptophan (Trp), is easily degraded to kynurenine (Kyn) by indolamine 2,3- dioxygenase 1 (IDO1), which activates the axis of Kyn-AHR to form special suppressive immune microenvironment that promotes tumor growth and metastasis. However, our research findings that 5-FU can induce effectively immunogenic cell death (ICD) to further treat tumor by activating immune systems, while the secretion of interferon-γ (IFN-γ) re-induce the Kyn-AHR axis activation, leading to poor treatment efficiency. Therefore, a metal matrix protease-2 (MMP-2) and endogenous GSH dual-responsive liposomal-based nanovesicle, co-loading with 5-FU (anti-cancer drug) and NLG919 (IDO1 inhibitor), was constructed (named as ENP919@5-FU). The multifunctional ENP919@5-FU can effectively reshape the tumor immunosuppression microenvironment to enhance the effect of chemoimmunotherapy, thereby effectively inhibiting cancer growth. Mechanistically, PDAC with high expression of MMP-2 will propel the as-prepared nanovesicle to dwell in tumor region via shedding PEG on the nanovesicle surface, effectively enhancing tumor uptake. Subsequently, the S-S bond containing nanovesicle was cut via high endogenous GSH, leading to the continued release of 5-FU and NLG919, thereby enabling circulating chemoimmunotherapy to effectively cause tumor ablation. Moreover, the combination of ENP919@5-FU and PD-L1 antibody (αPD-L1) showed a synergistic anti-tumor effect on the PDAC model with abdominal cavity metastasis. Collectively, ENP919@5-FU nanovesicle, as a PDAC treatment strategy, showed excellent antitumor efficacy by remodeling tumor microenvironment to circulate tumor chemoimmunotherapy amplification, which has promising potential in a precision medicine approach.
The impact of the COVID-19 pandemic on people who use drugs in three Canadian cities: a cross-sectional analysis
Authors: Mitra Sanjana , Bouck Zachary , Larney Sarah , Zolopa Camille , Høj Stine , Minoyan Nanor , Upham Katie , Rammohan Indhu , Mok Wing Yin , Hayashi Kanna , Milloy M-J , DeBeck Kora , Scheim Ayden , Werb Dan
Published: May 2024

Background

The COVID-19 pandemic had a disproportionate impact on the health and wellbeing of people who use drugs (PWUD) in Canada. However less is known about jurisdictional commonalities and differences in COVID-19 exposure and impacts of pandemic-related restrictions on competing health and social risks among PWUD living in large urban centres.

Methods

Between May 2020 and March 2021, leveraging infrastructure from ongoing cohorts of PWUD, we surveyed 1,025 participants from Vancouver (n = 640), Toronto (n = 158), and Montreal (n = 227), Canada to describe the impacts of pandemic-related restrictions on basic, health, and harm reduction needs.

Results

Among participants, awareness of COVID-19 protective measures was high; however, between 10 and 24% of participants in each city-specific sample reported being unable to self-isolate. Overall, 3–19% of participants reported experiencing homelessness after the onset of the pandemic, while 20–41% reported that they went hungry more often than usual. Furthermore, 8–33% of participants reported experiencing an overdose during the pandemic, though most indicated no change in overdose frequency compared the pre-pandemic period. Most participants receiving opioid agonist therapy in the past six months reported treatment continuity during the pandemic (87–93%), however, 32% and 22% of participants in Toronto and Montreal reported missing doses due to service disruptions. There were some reports of difficulty accessing supervised consumption sites in all three sites, and drug checking services in Vancouver.

Conclusion

Findings suggest PWUD in Canada experienced difficulties meeting essential needs and accessing some harm reduction services during the COVID-19 pandemic. These findings can inform preparedness planning for future public health emergencies.
Characteristics of built food environments associated with alternative protein food choices: a systematic review
Authors: Zaleskiewicz Hanna , Kulis Ewa , Siwa Maria , Szczuka Zofia , Banik Anna , Grossi Francesca , Chrysochou Polymeros , Nystrand Bjørn Tore , Perrea Toula , Samoggia Antonella , Xhelili Arlind , Krystallis Athanasios , Luszczynska Aleksandra
Published: May 2024

Background

This systematic review contributes to the understanding of the characteristics of built food environments that may be associated with choices of alternative protein foods (APF). Using the built food environment typology proposed by Downs et al., we investigated various environmental structures (e.g., supermarkets, other retailers, farmers’ markets, restaurants, schools, and online vendors) and the characteristics that may facilitate or hinder consumers’ choices. For example, facilitators and barriers may refer to the physical characteristics of environmental structures, food presentation practices, the organizational strategies or policies operating in the setting, or the actions that retailers or consumers engage in while selling, serving, choosing, trying, or purchasing APF in these environmental structures.

Methods

A systematic review (PROSPERO database preregistration; no. CRD42023388700) was conducted by searching 13 databases for peer-reviewed journals focusing on the fields of economics and business, agriculture, medical sciences, and social sciences. Data searches, coding, and quality evaluations were conducted by at least 2 researchers. A total of 31 papers (36 original studies) were included. The risk of bias was evaluated with the Joanna Briggs Institute quality evaluation tool, with 24 publications presenting low risk of bias.

Results

The findings indicate that perceived and actual availability facilitate consumers’ APF choices across a built food environment. Several barriers/facilitators were associated with APF choices in specific types of built food environments: the way food is presented in produce sections (supermarkets), consumer habits in terms of green and specialty shopping (grocery stores), and mismatches among retailer actions in regard to making APF available in one type of food environment structure (e-commerce) and consumers’ preferences for APF being available in other food environment structures (supermarkets, grocery stores). The effect of a barrier/facilitator may depend on the APF type; for example, social norms regarding masculinity were a barrier affecting plant-based APF choices in restaurants, but these norms were not a barrier affecting the choice of insect-based APF in restaurants.

Conclusions

Addressing barriers/facilitators identified in this review will help in developing environment-matching interventions that aim to make alternative proteins mainstream.

Trial registration

PROSPERO database registration: #CRD42023388700.
Endothelial EGLN3-PKM2 signaling induces the formation of acute astrocytic barrier to alleviate immune cell infiltration after subarachnoid hemorrhage
Authors: Duan Mingxu , Ru Xufang , Zhou Jiru , Li Yuanshu , Guo Peiwen , Kang Wenbo , Li Wenyan , Chen Zhi , Feng Hua , Chen Yujie
Published: May 2024

Background

Most subarachnoid hemorrhage (SAH) patients have no obvious hematoma lesions but exhibit blood–brain barrier dysfunction and vasogenic brain edema. However, there is a few days between blood‒brain barrier dysfunction and vasogenic brain edema. The present study sought to investigate whether this phenomenon is caused by endothelial injury induced by the acute astrocytic barrier, also known as the glial limitans.

Methods

Bioinformatics analyses of human endothelial cells and astrocytes under hypoxia were performed based on the GEO database. Wild-type, EGLN3 and PKM2 conditional knock-in mice were used to confirm glial limitan formation after SAH. Then, the effect of endothelial EGLN3-PKM2 signaling on temporal and spatial changes in glial limitans was evaluated in both in vivo and in vitro models of SAH.

Results

The data indicate that in the acute phase after SAH, astrocytes can form a temporary protective barrier, the glia limitans, around blood vessels that helps maintain barrier function and improve neurological prognosis. Molecular docking studies have shown that endothelial cells and astrocytes can promote glial limitans-based protection against early brain injury through EGLN3/PKM2 signaling and further activation of the PKC/ERK/MAPK signaling pathway in astrocytes after SAH.

Conclusion

Improving the ability to maintain glial limitans may be a new therapeutic strategy for improving the prognosis of SAH patients.
Targeted treatment in complex lymphatic anomaly: a case of synergistic efficacy of trametinib and sirolimus
Authors: Seront Emmanuel , Froidure Antoine , Revencu Nicole , Dekeuleneer Valerie , Clapuyt Philippe , Dumitriu Dana , Vikkula Miikka , Boon Laurence M.
Published: May 2024

Repurposing anticancer drugs to vascular malformations has significantly improved patient outcomes. Complex Lymphatic Anomalies (CLA) are part of the spectrum of lymphatic malformations (LMs) that share similar oncogenic mutations to cancer. We report the case of a young patient with highly symptomatic CLA who was initially treated with sirolimus, due to the frequent involvement of the PI3K-AKT-mTOR pathway in CLA pathogenesis. Despite an initial reduction in symptoms, sirolimus progressively lost its effectiveness. After an unsuccessful attempt with trametinib alone, sirolimus was added to trametinib and resulted in a significant, rapid and sustained improvement in symptoms. This suggests that, contrary to current dogmas, combination therapy using sub-therapeutic doses targeting both the PI3K and RAS pathways retains efficacy without generating the toxicity known for combination therapies, and is beneficial in the management of CLAs and potentially other vascular anomalies.
Worldwide absence of canonical benzimidazole resistance-associated mutations within β-tubulin genes from Ascaris
Authors: Jones Ben P. , Kozel Kezia , Alonte Allen Jethro I. , Llanes Kennesa Klariz R. , Juhász Alexandra , Chaudhry Umer , Roose Sara , Geldhof Peter , Belizario Vicente Y. , Nejsum Peter , Stothard J. Russell , LaCourse E. James , van Vliet Arnoud H. M. , Paller Vachel Gay V. , Betson Martha
Published: May 2024

Background

The giant roundworm Ascaris is an intestinal nematode, causing ascariasis by infecting humans and pigs worldwide. Recent estimates suggest that Ascaris infects over half a billion people, with chronic infections leading to reduced growth and cognitive ability. Ascariasis affects innumerable pigs worldwide and is known to reduce production yields via decreased growth and condemnation of livers. The predominant anthelminthic drugs used to treat ascariasis are the benzimidazoles. Benzimidazoles interact with β-tubulins and block their function, and several benzimidazole resistance-associated mutations have been described in the β-tubulins of ruminant nematodes. Recent research on ascarids has shown that these canonical benzimidazole resistance-associated mutations are likely not present in the β-tubulins of Ascaris, Ascaridia or Parascaris, even in phenotypically resistant populations.

Methods

To further determine the putative absence of key β-tubulin polymorphisms, we screened two β-tubulin isotypes of Ascaris, highly expressed in adult worms. Using adult and egg samples of Ascaris obtained from pigs and humans worldwide, we performed deep amplicon sequencing to look for canonical resistance-associated mutations in Ascaris β-tubulins. Subsequently, we examined these data in closer detail to study the population dynamics of Ascaris and genetic diversity within the two isotypes and tested whether genotypes appeared to partition across human and pig hosts.

Results

In the 187 isolates, 69 genotypes were found, made up of eight haplotypes of β-tubulin isotype A and 20 haplotypes of isotype B. Single nucleotide polymorphisms were seen at 14 and 37 positions for β-tubulin isotype A and isotype B, respectively. No evidence of any canonical benzimidazole resistance-associated mutations was found in either human- or pig-derived Ascaris isolates. There was, however, a difference in the genetic diversity of each isotype and distribution of β-tubulin genotypes between human- and pig-derived Ascaris. Statistical tests of population differentiation show significant differences (p < 0.001) between pig- and human-derived worms; however, more diversity was seen between worms from different populations than worms from different hosts.

Conclusions

Our work suggests an absence of canonical β-tubulin mutations within Ascaris, but alternative modes of anthelminthic resistance may emerge necessitating continued genetic scrutiny alongside monitoring of drug efficacy.

Graphical Abstract
DNA methylation and type 2 diabetes: a systematic review
Authors: Nadiger Nikhil , Veed Jyothisha Kana , Chinya Nataraj Priyanka , Mukhopadhyay Arpita
Published: May 2024

Objective

DNA methylation influences gene expression and function in the pathophysiology of type 2 diabetes mellitus (T2DM). Mapping of T2DM-associated DNA methylation could aid early detection and/or therapeutic treatment options for diabetics.

Design

A systematic literature search for associations between T2DM and DNA methylation was performed. Prospero registration ID: CRD42020140436.

Methods

PubMed and ScienceDirect databases were searched (till October 19, 2023). Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and New Castle Ottawa scale were used for reporting the selection and quality of the studies, respectively.

Result

Thirty-two articles were selected. Four of 130 differentially methylated genes in blood, adipose, liver or pancreatic islets (TXNIP, ABCG1, PPARGC1A, PTPRN2) were reported in > 1 study. TXNIP was hypomethylated in diabetic blood across ethnicities. Gene enrichment analysis of the differentially methylated genes highlighted relevant disease pathways (T2DM, type 1 diabetes and adipocytokine signaling). Three prospective studies reported association of methylation in IGFBP2, MSI2, FTO, TXNIP, SREBF1, PHOSPHO1, SOCS3 and ABCG1 in blood at baseline with incident T2DM/hyperglycemia. Sex-specific differential methylation was reported only for HOOK2 in visceral adipose tissue (female diabetics: hypermethylated, male diabetics: hypomethylated). Gene expression was inversely associated with methylation status in 8 studies, in genes including ABCG1 (blood), S100A4 (adipose tissue), PER2 (pancreatic islets), PDGFA (liver) and PPARGC1A (skeletal muscle).

Conclusion

This review summarizes available evidence for using DNA methylation patterns to unravel T2DM pathophysiology. Further validation studies in diverse populations will set the stage for utilizing this knowledge for identifying early diagnostic markers and novel druggable pathways.
Subtype prediction of intrahepatic cholangiocarcinoma using dynamic contrast-enhanced ultrasound
Authors: Zhu Ming-Rui , Zhao Chong-Ke , Sun Yi-Kang , Li Xiao-Long , Yin Hao-Hao , Lu Dan , Ye Xin , Hu Xin-Yuan , Wang Xi , Xia Han-Sheng , Han Hong , Zhou Bo-Yang , Xu Hui-Xiong , Wang Li-Fan
Published: May 2024

Objective

The study aimed to investigate the predictive value of dynamic contrast-enhanced ultrasound (DCE-US) in differentiating small-duct (SD) and large-duct (LD) types of intrahepatic cholangiocarcinoma (ICC).

Methods

This study retrospectively enrolled 110 patients with pathologically confirmed ICC lesions who were subject to preoperative contrast-enhanced ultrasound (CEUS) examinations between January 2022 and February 2023. Patients were further classified according to the subtype: SD-type and LD-type, and an optimal predictive model was established and validated using the above pilot cohort. The test cohort, consisting of 48 patients prospectively enrolled from March 2023 to September 2023, was evaluated.

Results

In the pilot cohort, compared with SD-type ICCs, more LD-type ICCs showed elevated carcinoembryonic antigen (p < 0.001), carbohydrate antigen 19-9 (p = 0.004), ill-defined margin (p = 0.018), intrahepatic bile duct dilation (p < 0.001). Among DCE-US quantitative parameters, the wash-out area under the curve (WoAUC), wash-in and wash-out area under the curve (WiWoAUC), and fall time (FT) at the margin of lesions were higher in the SD-type group (all p < 0.05). Meanwhile, the mean transit time (mTT) and wash-out rate (WoR) at the margin of the lesion were higher in the LD-type group (p = 0.041 and 0.007, respectively). Logistic regression analysis showed that intrahepatic bile duct dilation, mTT, and WoR were significant predictive factors for predicting ICC subtypes, and the AUC of the predictive model achieved 0.833 in the test cohort.

Conclusions

Preoperative DCE-US has the potential to become a novel complementary method for predicting the pathological subtype of ICC.

Critical relevance statement

DCE-US has the potential to assess the subtypes of ICC lesions quantitatively and preoperatively, which allows for more accurate and objective differential diagnoses, and more appropriate treatments and follow-up or additional examination strategies for the two subtypes.

Key Points

Preoperative determination of intrahepatic cholangiocarcinoma (ICC) subtype aids in surgical decision-making.

Quantitative parameters from dynamic contrast-enhanced US (DCE-US) allow for the prediction of the ICC subtype.

DCE-US-based imaging has the potential to become a novel complementary method for predicting ICC subtypes.

Graphical Abstract