bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between migraine and mitochondria: A Mendelian randomization study
Authors: Hong Ming-Yang , Chen Yu-Xin , Xiong Yi-Cheng , Sun Yi-Han , Al Mamun Abdullah , Xiao Jian
Published: December 2024

Background and objective:

Mitochondria are important organelles functioning in metabolic processes, inflammatory response and neurological disorders. Migraines are chronic and paroxysmal neurological disorders characterized by recurrent episodes of severe headache and other neurological symptoms. We explored whether mitochondria may be genetically and/or causally associated with migraine.

Methods:

Summary-level statistics of mitochondrial DNA copy number (mtDNA-CN), 69 mitochondria related exposures and migraine with aura, migraine without aura, migraine with aura and triptan purchases, migraine with aura, drug-induced, migraine without aura and triptan purchases and migraine without aura, drug-induced, were collected from genome-wide association studies (GWAS). The analysis employed two-sample Mendelian randomization, utilizing various methods including MR-Egger, inverse-variance weighted (IVW), MR-PRESSO (MR-pleiotropy residual sum and outlier), maximum likelihood, and weighted median.

Results:

We observed a potential association with decreased levels of mtDNA-CN with the risk of migraine without aura (Odds ratio (OR) 1.517, 95% Confidence interval (CI) 1.072–2.147, p = 0.019). Besides, for every 1 unit in NAD-dependent protein deacylase sirtuin-5 (SIRT5), relative risk of migraine without aura increased by 16.4%. For every 1 unit increase in Phenylalanine–transfer RNA (tRNA) ligase, relative risk of migraine without aura increased by 13.5%. For every 1 unit increase in Apoptosis-inducing factor 1, relative risk of migraine without aura increased by 27.4%.

Conclusion:

This study indicates fresh evidence of association between mtDNA-CN, mitochondrial related exposures and migraine especially migraine without aura. The findings may shed light on developing interventions targeting on the causal pathway from mitochondria to migraine.
Effect of randomized treatment withdrawal of budesonide oral suspension on clinically relevant efficacy outcomes in patients with eosinophilic esophagitis: a post hoc analysis
Authors: Dellon Evan S. , Collins Margaret H. , Katzka David A. , Mukkada Vincent A. , Falk Gary W. , Zhang Wenwen , Goodwin Bridgett , Terreri Brian , Boules Mena , Desai Nirav K. , Hirano Ikuo
Published: December 2024

Background:

Relapse after corticosteroid withdrawal in eosinophilic esophagitis is not well understood.

Objectives:

Budesonide oral suspension (BOS) 2.0 mg twice daily (b.i.d.) was evaluated in two consecutive phase III studies (12 and 36 weeks, respectively). For clinicopathologic responders after 12 weeks of BOS treatment, we assessed randomized treatment withdrawal for up to 36 weeks of therapy.

Design:

Post hoc analysis of a phase III, double-blind, randomized withdrawal study.

Methods:

Clinicopathologic responders (⩽6 eosinophils per high-power field (eos/hpf) and ⩾30% reduction in Dysphagia Symptom Questionnaire (DSQ) score from baseline) after 12 weeks of BOS were randomized to continue BOS 2.0 mg b.i.d. (BOS–BOS) or withdraw to placebo (PBO; BOS–PBO) for up to 36 weeks. Relapsers (⩾15 eos/hpf (⩾2 esophageal regions) and ⩾4 days of dysphagia (DSQ)) could reinitiate BOS 2.0 mg b.i.d. This post hoc analysis assessed a more clinically relevant relapse definition (⩾15 eos/hpf (⩾1 esophageal region) and ⩾4 days of dysphagia (DSQ)) for BOS–BOS versus BOS–PBO patients over 36 weeks. To account for BOS–PBO patients who reinitiated BOS before week 36, patients’ last observations before reinitiating BOS were carried forward (last observation carried forward (LOCF)) for histologic, symptom, and endoscopic efficacy endpoints (at weeks 12 and 36).

Results:

Of 48 patients included (BOS–BOS, n = 25; BOS–PBO, n = 23), significantly more BOS–PBO than BOS–BOS patients relapsed over 36 weeks using this post hoc relapse definition (60.9% vs 28.0%; p = 0.022). More BOS–BOS than BOS–PBO patients maintained histologic responses (all thresholds) and showed improvements in symptom and endoscopic efficacy endpoints.

Conclusion:

More BOS–PBO than BOS–BOS patients relapsed, determined by a more clinically relevant post hoc relapse definition. Using LOCF, more BOS–BOS than BOS–PBO patients also maintained or had improvements in efficacy endpoints.

Trial registration:

ClinicalTrials.gov identifiers ( https://clinicaltrials.gov/ ): NCT02605837, NCT02736409.
CD8+ cell dominance in immune checkpoint inhibitor-induced colitis and its heterogeneity across endoscopic features
Authors: Kim Min Kyu , Son Hye-Nam , Hong Seung Wook , Park Sang Hyoung , Yang Dong-Hoon , Ye Byong Duk , Byeon Jeong-Sik , Myung Seung-Jae , Yang Suk-Kyun , Yoon Shinkyo , Hwang Sung Wook
Published: December 2024

Background:

Immune checkpoint inhibitor (ICI)-induced colitis is a significant adverse event associated with ICI therapy, known to be linked to increased cytotoxic T-cell activity.

Objectives:

To compare T-cell subsets based on the endoscopic features of ICI-induced colitis and to compare these findings with those of inflammatory bowel disease (IBD).

Design:

Prospective cohort study.

Methods:

We analyzed patients with ICI-induced colitis, confirmed through both endoscopic and histological evaluation. Biopsy specimens were examined using multiplex immunohistochemistry to assess their immune cell profile. Clinical outcomes were analyzed. Immune cell profiles were compared based on their endoscopic features and contrasted with those of patients with IBD.

Results:

Seventeen patients with ICI-induced colitis were included in the study. All patients showed clinical improvement after treatment, and steroids were administered to 11 patients (64.7%). Based on endoscopic features, the patients were classified as Crohn’s disease (CD)-like ( n = 3, 17.6%), ulcerative colitis (UC)-like ( n = 9, 52.9%), or microscopic colitis (MC)-like ( n = 5, 29.4%). In ICI-induced colitis, cytotoxic T cells (Tc cells) were more predominant than helper T cells (Th cells) ( p = 0.053), and this trend was most pronounced in the MC-like subtype ( p = 0.020). When comparing the number of CD8+ cells infiltrating the crypts, both the UC-like and MC-like subtypes had significantly more infiltrating cells than the CD-like subtype ( p = 0.008 and p = 0.016, respectively). In comparison to IBD, IBD exhibited a Th-dominant profile, whereas CD-like ICI-induced colitis had a lower Th cell density than CD ( p = 0.032) and UC-like ICI-induced colitis had a higher Tc density than UC ( p = 0.045).

Conclusion:

Analysis of T-cell subsets of ICI-induced colitis revealed a Tc-dominant profile, contrasting with the Th dominance observed in patients with IBD. The Tc-dominant profile was evident in UC-like and MC-like subtypes, with significant crypt infiltration by CD8+ cells. Tc may play an important role in the pathophysiology of ICI-induced colitis.
Analysis of outcomes in resected early-stage NSCLC with rare targetable driver mutations
Authors: Ghazali Nadia , Feng Jamie , Hueniken Katrina , Khan Khaleeq , Balaratnam Karmugi , Waddell Thomas K. , Yasufuku Kazuhiro , Pierre Andrew , Donahoe Laura , Wakeam Elliot , Cypel Marcelo , Yeung Jonathan , Keshavjee Shaf , de Perrot Marc , Leighl Natasha B. , Liu Geoffrey , Bradbury Penelope A. , Sacher Adrian , Eng Lawson , Stockley Tracy , Tsao Ming Sound , Shepherd Frances A.
Published: December 2024

Background:

Given advancements in adjuvant treatments for non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK)-targeted therapies, it is important to consider postoperative targeted therapies for other early-stage oncogene-addicted NSCLC. Exploring baseline outcomes for early-stage NSCLC with these rare mutations is crucial.

Objectives:

This study aims to assess relapse-free survival (RFS) and overall survival (OS) in patients with resected early-stage NSCLC with rare targetable driver mutations.

Methods:

This retrospective single-center study identified stage I–III NSCLC patients with rare targetable mutations who underwent curative surgery. Tissue-based molecular profiling identified mutations in KRASG12C, EGFR Exon20, Erb-B2 receptor tyrosine kinase 2 ( ERBB2), ALK, ROS1, B-Raf proto-oncogene ( BRAF) V600E, mesenchymal–epithelial transition factor ( MET) exon14 skipping, and rearranged during transfection ( RET). Baseline patient and tumor characteristics, mutation subtype, and TP53 co-mutation were correlated with RFS and OS using Cox regression. The KRASG12C cohort was used as the reference for survival comparisons.

Results:

Among 225 patients, mutations included the following: KRASG12C ( n = 101, 45%), MET exon 14 skipping ( n = 26, 12%), EGFR Exon 20 ( n = 25, 11%), ERBB2 ( n = 25, 11%), ALK fusion ( n = 16, 7%), ROS1 fusion ( n = 14, 6%), BRAF V600E mutation ( n = 13, 6%), and RET fusion ( n = 5, 2%). Five-year survival probabilities were 76% for stage I, 60% for stage II, and 58% for stage III. RFS was shorter across most mutation subgroups compared to KRASG12C, with ROS1 mutations showing significantly poorer RFS (HR 2.70, p = 0.019). By contrast, all mutation subgroups were associated with better OS than KRASG12C. The incidence of brain metastasis was highest in ERBB2 (22% at 5 years). TP53 co-mutation was associated with significantly worse OS (HR 2.35, p = 0.008).

Conclusion:

While RFS was poorer for most mutations compared to KRASG12C, OS generally was better, suggesting a potential role for postoperative targeted therapies. These findings warrant further investigation through prospective studies and clinical trials to optimize adjuvant treatment strategies for patients with early-stage NSCLC harboring rare driver mutations.
Severe refractory colitis after intraperitoneal infusion of CEA-directed CAR T cells in patients with colorectal cancer
Authors: Ye Kexin , Yu Chaohui , Shen Zhe
Published: December 2024

Chimeric antigen receptor T (CAR T) cells have shown their potential in hematological malignancies and the treatment of solid tumors, especially in metastases. However, CAR T-cell therapy may carry risks of inducing severe adverse effects, which are recognized as immune-related adverse events. Here, we report two cases of severe colitis presented with refractory bloody diarrhea, which were induced by carcinoembryonic antigen (CEA)-directed CAR T therapy in the treatment of metastatic colorectal adenocarcinoma. These patients were treated as part of a clinical trial. The clinical trial was registered at ClinicalTrials.gov (NCT05396300), submitted, and started on May 25, 2022. Glucocorticoids combined with vedolizumab were used to control their gastrointestinal symptoms but the outcomes were unsatisfactory. This report highlights the potentially serious risks of anti-CEA CAR T therapy and provides management options.
Impact of obesity on clinical outcomes and treatment continuation in rheumatoid arthritis patients receiving non-TNF-targeted therapies
Authors: Park Dong-Jin , Jeong Hyemin , Choi Sung-Eun , Kang Ji-Hyoun , Lee Shin-Seok
Published: December 2024

Background:

Recent studies have shown the impact of obesity on achieving low disease activity or remission in rheumatoid arthritis (RA) patients treated with tumor necrosis factor inhibitors. However, there is limited research on the effects of obesity on clinical responses to non-TNF-targeted treatments.

Objectives:

This study investigated the influence of body mass index (BMI) on clinical response to non-TNF-targeted treatments in RA patients.

Design:

We used data from the KOrean nationwide BIOlogics & targeted therapy (KOBIO) registry, a multicenter, prospective, observational cohort that included RA patients in South Korea.

Methods:

Patients who received at least one prescription for non-TNF-targeted treatments, including abatacept, tocilizumab, and Janus kinase inhibitors, were included. They were categorized into three BMI groups: under 25 kg/m2 (434 patients), between 25 and 30 kg/m2 (146 patients), and over 30 kg/m2 (22 patients). After 1 year of treatment, treatment continuation rates and clinical responses among these BMI groups were compared. Time on treatment for each category was analyzed using Kaplan–Meier curves and Cox regression, adjusting for confounders.

Results:

The 1-year continuation rate of the targeted treatment was significantly lower in the obese group (81.8%) compared to the normal BMI (93.8%) and overweight (89.0%) groups ( p = 0.033). Disease Activity Score of 28 joints-erythrocyte sedimentation rate score improvement was less in the obese group (2.06 ± 2.14) than in the normal BMI group (2.76 ± 1.55) ( p = 0.045). Multivariable Cox proportional hazard analysis showed a higher discontinuation rate in the obese group (hazard ratio: 3.407, 95% confidence interval: 1.157–10.211; p = 0.029).

Conclusion:

Higher BMI in RA patients was associated with poorer clinical response and higher discontinuation rates for non-TNF-targeted treatments.
Rivalry on Human Rights: Narratives in Human Rights Reports of the United States and China
Authors: Glanz Keyu Alexander Chen
Published: December 2024

Human rights have developed into one of the most polarizing issues within the US-China relations, reflecting deeply-rooted ideological divisions between two powers. While current studies often focus on the human rights politics of each country in isolation, there is a lack of comparative analysis of their respective human rights narratives. This study employs an innovative narrative approach to contextualise the study of human rights in the US–China competition. By examining how the US and China have competed in human rights reports during the past two decades through cluster and linguistic analysis, this study reveals divergent strategies of both powers to conceptualise human rights, assign responsibility, delegitimise the rival political systems, and undermine the rival's global reputation on human rights. The findings have implications for the fields of foreign policy narrative and the US–China relations.
Current landscape of paroxysmal nocturnal hemoglobinuria in the era of complement inhibitors and regulators
Authors: Shi Julia J. , Ozcan Yusuf M. , Santos Carlos I. Ayala , Patel Hetalkumari , Shammo Jamile , Bat Taha
Published: December 2024

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder which is caused by mutations in phosphatidylinositol glycan class A leading to hemolysis of red blood cells via complement inhibition. The first treatment for PNH, eculizumab, was FDA approved in 2007. Since then, many new treatment options for PNH have arisen. This critical review will examine all medications available for PNH on the US market, highlight several major medications in development, and discuss the risks and treatment considerations associated with each option. It is not intended to address PNH clonal dynamics, disease presentation, or discussions on when to initiate treatment.
Body ownership and tactile processing: Effects of bilateral rubber hand illusion on tactile temporal order judgment
Authors: Shibuya Satoshi , Ohki Yukari
Published: December 2024

In the rubber hand illusion (RHI), individuals perceive a fake hand as their own if an unseen hand and a visible fake hand are stroked simultaneously. We examined how the RHI on either hand influenced the temporal order judgment (TOJ) of bimanual stimulation. In Experiment 1, participants performed TOJ during RHI or non-RHI conditions. When the fake hand was oriented in an anatomically incongruent position (non-RHI condition), the point of subjective simultaneity (PSS) from TOJ showed no difference between the stroke sides. However, during the RHI condition, the PSS tended to shift in the opposite direction to the stroke, resulting in a significant difference between the sides. This implies slower tactile processing in the illusion-affected hand. When participants performed an identical TOJ while watching the fake hand without stroking (Experiment 2), no PSS modulation was found. Our findings suggest the possibility that the RHI attenuates tactile processing, but its magnitude is small.
Enhancing analysis of EEG image data sets using machine learning techniques: Dealing with class imbalances and data uncertainty
Authors: Mishra Sneha , Jaiswal Umesh Chandra
Published: December 2024

Quality Assurance and output focused algorithm design is the trend, which is a current day research challenge. Inter- and intra- behavioral changes in the system influence on quality of outputs, this due to class imbalance problem prevailing in the data sets, that read uncertain values causes class imbalance problem (CIP). Predictive models that depend on such states of data sets become highly imbalanced. As the CIP on uncertain data starts from selection of samples and candidates for the algorithms; the selected random samples project high variation of classes, a very smaller class or even larger than expected. EEG image data sets are generated from the electro-encephalogram are always random and often never repeating because they vary coarsely based on subjects, ailments and various levels of voltages generated at various types of montage points. Irrespective of montage points and the voltage generated from the electro-encephalogram, the outcome of the algorithms is to develop a predictive model of the subject’s epileptical state. In this regard, the problem of class imbalance (CIP) shall be addressed and handled with various types of heuristic and sampling methods. We shall work on various types of sampling methods and heuristics that develop a predictive model on the uncertain data and draw comparisons to select based on the uncertain state of the data.
Health During Relationship Transitions: Policy Implications for Dating, New Parenthood, and Bereavement
Authors: Jolink Tatum A. , Salomon Rebecca E.
Published: December 2024

Romantic relationships impact individuals’ mental and physical health across the lifespan. The link between relationships and health may be especially intertwined during major relationship transitions. Three transitional seasons of romantic relationships—dating, the transition to parenthood, and bereavement—are uniquely linked with health. To best support the health of relationships and the individuals in them, season-specific policy recommendations address experiences of dating, pregnancy/parenting, and grieving. Broad-scale recommendations cover education, placemaking, research and funding, and community efforts to support individual health within romantic relationships across time.
Fear among Hispanic and Non-Hispanic White Youth in Texas during a Period of Punitive Immigration Policies (2009–2017)
Authors: Mark Nicholas D. E. , Weitzman Abigail , Behrman Julia
Published: December 2024

Heightened partisan rhetoric surrounding immigration, combined with increasingly punitive immigration policies, has the potential to affect how children interact with their social environment, with implications for racially and spatially variegated developmental processes. In this data visualization, the authors use data from the 2009 to 2017 waves of the National Crime Victimization Survey’s School Crime Supplement to show that Hispanic students in Texas reported a significant increase in fear of harm in 2017, a change that was not observed among among non-Hispanic white students in Texas, or among either group in California. Despite increased fear, Hispanic students in Texas did not report corresponding increases in bullying, indicating that their rising fear was attributable to something beyond peer interaction. Together, these findings highlight emergent changes in Hispanic youth’s perceived hostility alongside changes in the surrounding political and legal landscape.
The role of checkpoint inhibitor rechallenge in patients with metastatic renal cell carcinoma: A systematic review
Authors: Patel Kanishka , Gulati Shuchi , Mitsiades Nicholas , Lara Primo N , Parikh Mamta
Published: December 2024

Background

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC) and combination regimens with targeted therapy are the current standard of care. Given their success in the first-line setting, re-use or continuation of ICIs in subsequent line settings has been a growing area of research interest.

Objective

This systematic review assesses the safety and efficacy of ICI re-challenge in patients with refractory mRCC.

Methods

Scopus, Embase, Cochrane, Ovid MEDLINE, and TRIP databases as well as clinicaltrials.gov were searched systematically for published prospective and upcoming clinical trials from inception to August 15, 2023. Inclusion criteria included patients with clear cell histology who had received at least one prior line of systemic therapy including an ICI. Trials with ICI as an intervention either in second-line or beyond were included and did not require a control arm. Safety and efficacy outcomes including overall response rates, overall survival, progression free survival, median duration of response, and grade 3 or higher adverse events (AEs) were extracted.

Results

Seven prospective studies and 49 upcoming clinical trials were identified. mPFS ranged from 3.7 to 12.2 months, with longer PFS rates being associated with ICI/VEGF combination re-challenge. However, data from the only phase III randomized controlled trial (CONTACT-03) did not support rechallenge of ICI with tyrosine kinase inhibitor (TKI) versus TKI alone. Rates of grade 3 or higher AEs ranged from 28–65%.

Conclusions

Given the paucity of current data regarding efficacy as well as high toxicity rates, patients with mRCC should not receive ICI-rechallenge unless as part of a prospective clinical trial.
Exploring Infection in Primary Total Ankle Arthroplasty
Authors: Anastasio Albert T. , Wu Kevin , O'Neill Conor N. , Luo Emily Joan , Kim Billy I. , Nunley James A. , DeOrio James K. , Easley Mark E. , Adams Samuel B.
Published: December 2024

Category:

Ankle; Ankle Arthritis

Introduction/Purpose:

Infection is a serious complication of primary total ankle arthroplasty (TAA) and can lead to implant failure and revision surgery. While various patient demographics, comorbidities, and surgical factors have been associated with an increased risk of infection, evidence is limited, and further research is required to better understand infection in TAA. This study aims to analyze risk factors of infection and explore outcomes following infected TAA.

Methods:

A retrospective cohort study was conducted using data from a single institution from 2002 to 2022. Patients who underwent primary TAA and had subsequent infection were identified and matched using propensity-score matching (PSM) based on various demographic, comorbidity, and surgical factors. Demographics were compared between the matched groups using Mann-Whitney U test and Fisher's exact test. The outcomes following infection were identified and summarized using descriptive statistics.

Results:

A total of 1,863 patients who underwent primary TAA were identified, and 19 (1%) were diagnosed with an infection. After PSM, there were no significant differences in age, gender, BMI, and smoking status between the cohorts. There was a statistically significant increase in the rate of diabetes in the infected cohort (26.3 vs. 15.3; p =0.01). Subsequent surgical intervention resulted in limb salvage in 18 (94.7%) cases. Two-stage revision to total ankle replacement was performed in 7 cases (36.8%), while revision to arthrodesis and isolated polyethylene exchange were each carried out in 4 cases (21.1%). One patient had to undergo amputation, however, at the time of the most recent follow-up (5.3%). All patients were found to be free of infection.

Conclusion:

This study demonstrated significantly increased rates of smoking and diabetes in the infected TAA cohort. Two-stage revision to TAR and revision to arthrodesis with isolated polyethylene exchange were successful in eradicating infection. Overall, a high rate of limb salvage was reported.
Large language models for autistic and neurodivergent individuals: Concerns, benefits and the path forward
Authors: Papadopoulos Chris
Published: December 2024

The emergence of large language models (LLMs) like ChatGPT has transformed access to information, offering immediate responses to diverse queries. While these technologies present significant opportunities, they also pose unique challenges for the autistic and wider neurodivergent community. This commentary critically examines the implications of LLMs within this community, focusing on potential misinformation, reinforcement of stigmatising medical models, misrepresentation of non-speaking neurodivergent individuals, and issues of equity and privacy. Through personal experimentation with LLMs and discussions with community members, concerns are raised about the perpetuation of stereotypes, the risk of over-reliance on potentially flawed AI outputs, and the inadequate support for diverse communication needs. Conversely, LLMs offer transformative benefits such as accessible information, personalised learning, and supportive tools for communication and professional development. To maximise these benefits while mitigating risks, a multifaceted approach is proposed, emphasising awareness, collaborative development with neurodivergent individuals, ongoing feedback mechanisms, policy advocacy, and positive representation.
One Third of Alcohol Use Disorder Diagnoses are Missed by ICD Coding
Authors: Mercurio Laura , Garcia Augusto , Ruest Stephanie , Duffy Susan J. , Eickhoff Carsten
Published: December 2024

Background/Significance:

Alcohol use carries significant morbidity and mortality, yet accurate identification of alcohol use disorder (AUD) remains a multi-layered problem for both researchers and clinicians.

Objective:

To fine-tune a language model to AUD in the clinical narrative and to detect AUDs not accounted for by ICD-9 coding in the MIMIC-III database.

Materials and Methods:

We applied clinicalBERT to unique patient discharge summaries. For classification, patients were divided into nonoverlapping groups stratified by the presence/absence of AUD ICD diagnosis for model training (80%), validation (10%), and testing (10%). For detection, the model was trained (80%) and validated (20%) on 1:1 positive/negative patients, then applied to remaining negative patient population. Physicians adjudicated 600 samples from the full model confidence spectrum to confirm AUD by Diagnostic and Statistical Manual of Mental Disorders-V criteria.

Results:

The model exhibited the following characteristics (mean, standard deviation): precision (0.9, 0.02), recall (0.65, 0.03), F-1 (0.75, 0.02), area under the receiver operating curve (0.97, 0.01), and area under the precision-recall curve (0.86, 0.01). Adjudication produced an estimated 4% under-documentation rate for the total study population. As model confidence increased, AUD under-documentation rate rose to 30% of the number of patients identified as positive by ICD-9 coding.

Conclusion:

Our model improves the identification of patients meeting AUD criteria, outperforming ICD codes in detecting cases of AUD. Detection discrepancy between ICD and free-text highlights clinician under documentation, not under recognition. Adjudication revealed model over-sensitivity to language around substance use, withdrawal, and chronic liver disease; future study requires application to a broader set of patient age and acuity. This model has the potential to improve rapid identification of patients with AUD and enhance treatment allocation.
Enhancing the seismic stability of buckling-restrained steel braced frames in subduction interface seismic regions using viscoelastic dampers
Authors: Hariri Bashar , Montgomery Michael , Zhong Chiyun , Christopoulos Constantin
Published: December 2024

This article proposes a stability-enhanced alternative to traditional buckling-restrained steel braced frames (BRBFs) for application in tall-rise steel buildings located in high seismic regions. The viscoelastic (VE)-BRBF is a BRBF featuring V or inverted-V bracing configurations and integrates vertically aligned VE dampers at beam–brace intersections on each story. The incorporation of VE dampers addresses two significant drawbacks of traditional BRBFs. First, it enhances the post-elastic lateral story shear stiffness, crucial for mitigating P-delta-induced inelastic drift concentrations and global instability, particularly under subduction interface events. Second, it augments inherent damping, a parameter typically low in conventional steel buildings. These improvements alleviate the need for the stability-related stringent height limitations imposed by design codes, such as the 40 m limit for SC4 buildings in Canada. Utilizing nonlinear response history analysis, the seismic stability performance of the proposed system is assessed against traditional BRBFs designed with classical strength amplification through an inelastic stability coefficient. The assessment is conducted on 10- and 20-story steel buildings in Vancouver, BC, considering seismic excitations involving the subduction interface. The results demonstrate that traditional BRBF designed overlooking height limitations failed to meet design code acceptance criteria, with several stability cases exhibiting global instability and excessive drifting. In contrast, the incorporation of VE dampers in the VE-BRBF demonstrated responses that met the design code acceptance criteria, with uniform drift distributions and mitigated P-delta effects and with residual post-earthquake drifts within repair limits, regardless of building height or seismic excitation type.
How I Treat AML relapse after allogeneic HCT
Authors: Gooptu Mahasweta , Murdock H. Moses , Soiffer Robert J.
Published: December 2024

Allogeneic hematopoietic stem-cell transplantation (HCT) is one of the principal curative approaches in the treatment of acute myeloid leukemia (AML); however, relapse post-transplantation remains a catastrophic event with poor prognosis. The incidence of relapse has remained unchanged over the last three decades despite an evolving understanding of the immunobiology of the graft-versus leukemia effect and the immune escape mechanisms that lead to post-HCT relapse. The approach to post-transplant relapse is highly individualized and is dictated both by disease biology and genomics as well as the patient's clinical status at the time of relapse and the interval between relapse and transplantation. With the help of three illustrative cases, we discuss our approach to early, late, and incipient relapse. Current therapeutic strategies incorporate immunosuppression taper when feasible, a variety of targeted and non-targeted chemotherapeutic agents and consolidative cellular therapies including donor lymphocyte infusions or a second allogeneic transplant. We then summarize evolving frontiers in the treatment and prognostication of relapse including the critical role of measurable residual disease. Finally, we emphasize enrollment on clinical trials and thoughtful discussions regarding goals of care and supporting frail patients as universal principles that should be incorporated in approaches to treatment of AML relapse post-transplantation.
Aerobic exercise inhibits GSDME-dependent myocardial cell pyroptosis to protect ischemia-reperfusion injury
Authors: Li Yi , Wang Xiang , Meng Xuyang , Xia Chenxi , Yang Chenguang , Wang Jun , Yang Jiefu , Wang Fang
Published: December 2024

Background

Acute myocardial infarction (AMI) remains a significant cause of global mortality, exacerbated by ischemia-reperfusion (IR) injury. Myocardial cell pyroptosis has emerged as a critical pathway influencing IR injury severity.

Methods

We aimed to investigate the cardioprotective effects of aerobic exercise on IR injury by examining the modulation of IGFBP2 and its impact on GSDME-dependent myocardial cell pyroptosis. Mechanistic pathways were explored using western blot analysis, ELISA, immunofluorescence, and echocardiography.

Results

Our findings demonstrate that aerobic exercise leads to increased circulating levels of IGFBP2, which effectively suppresses GSDME-dependent myocardial cell pyroptosis. This regulation occurs via the AKT-GSK3β signaling pathway, involving VDAC1 phosphorylation, thereby enhancing mitochondrial function and reducing oxidative stress.

Conclusion

In conclusion, our study highlights the role of IGFBP2 in mitigating GSDME-dependent pyroptosis as a mechanism through which aerobic exercise exerts cardioprotective effects against IR injury. These insights suggest potential therapeutic targets for managing acute myocardial infarction.
Meta-assembly of genomic associations to identify cattle fat depot candidate genes and pleiotropic effects
Authors: Yao Junpeng , Bottema Cynthia D.K. , Khatkar Mehar Singh
Published: December 2024

Background

Fat traits in cattle are considered important due to their contribution to beef eating quality and carcass economic value. Discovering the genes controlling fat traits in cattle will enable better selection of these traits, but identifying these genes in individual experiments has proven difficult. Compared to individual experiments, meta-analyses allow greater statistical power for detecting quantitative trait loci and identifying genes that influence single and multiple economically important fat traits.

Results

This meta-analysis study focussed on fat traits related to the major adipose depots in cattle (namely, carcass fat, intramuscular fat, internal fat, intermuscular fat, and subcutaneous fat) and was conducted using data from the Animal Quantitative Trait Loci (QTL) database. There were more Meta-QTL regions for intramuscular fat and subcutaneous fat (n = 158 and n = 55 regions, respectively) and far fewer for carcass fat and internal fat (n = 2 regions each). There were no Meta-QTL regions found for intermuscular fat. Of these 216 Meta-QTL regions, only 16 regions overlapped and affected two or more fat depots. The number of genes found for the fat depots was reflected in the size and number of the Meta-QTL regions (n = 20, 84, 1336 and 3853 genes for the carcass, internal, subcutaneous and intramuscular fat, respectively). The identification of these QTL allowed a more refined search for candidate genes. For example, the 232 genes in the Meta-QTL regions for carcass fat on BTA2, for intramuscular fat on BTA12, and the overlapping Meta-QTL regions on BTA2, BTA5, and BTA6 were readily screened, and 26 candidate genes were nominated based on their physiological roles using the GeneCards and DAVID databases.

Conclusions

The number of Meta-QTL regions for the various fat depots was relative to the number of associations in the database. However, the scarcity of overlapping Meta-QTL regions suggests that pleiotropic gene variants, which control multiple fat depots in cattle, are rare. The identification of candidate genes in the Meta-QTL regions will improve our knowledge of the genes with regulatory functions in adipose metabolism affecting meat quality and carcass economic value.
Generalizing from qualitative data: a case example using critical realist thematic analysis and mechanism mapping to evaluate a community health worker-led screening program in India
Authors: Broderick Kathryn , Vaidyanathan Arthi , Ponticiello Matthew , Hooda Misha , Kulkarni Vaishali , Chalem Andrea , Chebrolu Puja , Onawale Ashlesha , Baumann Ana , Mathad Jyoti , Sundararajan Radhika
Published: December 2024

Background

A central goal of implementation science is to generate insights that allow evidence-based practices to be successfully applied across diverse settings. However, challenges often arise in preserving programs’ effectiveness outside the context of their intervention development. We propose that qualitative data can inform generalizability via elucidating mechanisms of an intervention. Critical realist thematic analysis provides a framework for applying qualitative data to identify causal relationships. This approach can be used to develop mechanism maps, a tool rooted in policy that has been used in health systems interventions, to explain how and why interventions work. We illustrate use of these approaches through a case example of a community health worker (CHW)-delivered gestational diabetes (GDM) screening intervention in Pune, India. CHWs successfully improved uptake of oral glucose tolerance tests (OGTT) among pregnant women, however clinical management of GDM was suboptimal.

Methods

Qualitative interviews were conducted with 53 purposively sampled participants (pregnant women, CHWs, maternal health clinicians). Interview transcripts were reviewed using a critical realist thematic analysis approach to develop a coding scheme pertinent to our research questions: “What caused high uptake of GDM screening?” and “Why did most women with GDM referred to clinics did not receive evidence-based management?”. Mechanism maps were retrospectively generated using short- and long-term outcomes as fenceposts to illustrate causal pathways of the CHW–delivered program and subsequent clinical GDM management.

Results

Critical realist thematic analysis generated mechanism maps showed that CHWs facilitated GDM screening uptake through affective, cognitive and logistic pathways of influence. Lack of evidence-based treatment of GDM at clinics was caused by 1) clinicians lacking time or initiative to provide GDM counseling and 2) low perceived pre-test probability of GDM in this population of women without traditional risk factors. Mechanism mapping identified areas for adaptation to improve the intervention for future iterations.

Conclusions

Mechanism maps created by repeated engagement following the critical realist thematic analysis method can provide a retrospective framework to understand causal relationships between factors driving intervention successes or failures. This process, in turn, can inform the generalizability of health programs by identifying constituent factors and their interrelationships that are central to implementation.
Electroacupuncture ameliorates inflammatory pain through CB2 receptor-dependent activation of the AMPK signaling pathway
Authors: Lan Yuye , Jing Xianghong , Zhou Ziyu , Rao Yiqing , Wang Kaichen , Qin Renjie , Wu Yisong , Sun Jingjing , Zhang Ke , Liu Xinyue , Wang Zixiao , Xu Jiahao , zhao Minzhen , Yuan Xiao Cui , Liu Yongmin , Zhang Hong , Hu Xuefei , Pan Huilin , Hou Tengfei , Li Man
Published: December 2024

Background

Chronic inflammatory pain is a pervasive condition, and electroacupuncture (EA) is an effective treatment, but its mechanisms are not fully understood. AMP-activated protein kinase (AMPK), a key energy sensor, is involved in pain relief and EA’s effects. EA may work by increasing endocannabinoids, upregulating CB2 receptors (CB2R), and stimulating β-endorphin (β-END). This study tests if EA activates AMPK via CB2R to modulate β-END and reduce pain.

Methods

The inflammatory pain model was established with Complete Freund’s adjuvant (CFA), and EA was administered daily for six consecutive days, targeting the acupoints “Zusanli” (ST36) and “Shangjuxu” (ST37). Pain sensitivity was evaluated using Von Frey filaments for mechanical thresholds and a hot plate for thermal thresholds. Ultra-high Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS) was used to quantitatively determine the levels of endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA). The expression levels of the CB2R and β-END were measured by Western blotting, along with the activation of AMPK. Immunofluorescence double-labeling was applied to visualize AMPK activation and β-END expression within CD68-positive macrophages. The study encompassed both wild-type and CB2R gene knockout mice, elucidating the role of CB2R in EA-induced AMPK activation.

Results

CFA-induced inflammatory pain model mice exhibited mechanical allodynia and thermal hyperalgesia. EA activated AMPK in the inflamed skin tissue when it exerted analgesic effect on the inflammatory pain. Pre-administration of the AMPK inhibitor Compound C significantly inhibited the effect of EA on pain relief. EA elevated β-END expression in inflamed skin tissue, which was reversed by Compound C, indicating that AMPK has a regulatory role in EA inducing β-END expression. In addition, EA significantly upregulated the levels of 2-AG, AEA and the expression of CB2Rs in the inflamed skin tissue compared with the CFA group. In wild-type mice, EA activates AMPK in macrophages, while CB2 knockout reduced EA's ability to activate AMPK in these cells.

Conclusion

EA activates AMPK through CB2R, enhancing β-END expression in inflamed skin to alleviate inflammatory pain. This study reveals a new link between endocannabinoids, endorphins, and AMPK in analgesic effects of EA, highlighting the CB2R-AMPK-β-END pathway.
Multiomic molecular patterns of lipid dysregulation in a subphenotype of sepsis with higher shock incidence and mortality
Authors: Augustin Beulah , Wu Dongyuan , Black Lauren Page , Bertrand Andrew , Sulaiman Dawoud , Hopson Charlotte , Jacob Vinitha , Shavit Jordan A. , Hofmaenner Daniel A. , Labilloy Guillaume , Smith Leslie , Cagmat Emilio , Graim Kiley , Datta Susmita , Reddy Srinivasa T. , Guirgis Faheem W.
Published: December 2024

Background

Lipids play a critical role in defense against sepsis. We sought to investigate gene expression and lipidomic patterns of lipid dysregulation in sepsis.

Methods

Data from four adult sepsis studies were analyzed and findings were investigated in two external datasets. Previously characterized lipid dysregulation subphenotypes of hypolipoprotein (HYPO; low lipoproteins, increased mortality) and normolipoprotein (NORMO; higher lipoproteins, lower mortality) were studied. Leukocytes collected within 24 h of sepsis underwent RNA sequencing (RNAseq) and shotgun plasma lipidomics was performed.

Results

Of 288 included patients, 43% were HYPO and 57% were NORMO. HYPO patients exhibited higher median SOFA scores (9 vs 5, p = < 0.001), vasopressor use (67% vs 34%, p = < 0.001), and 28-day mortality (30% vs 16%, p = 0.004). Leukocyte RNAseq identified seven upregulated lipid metabolism genes in HYPO (PCSK9, DHCR7, LDLR, ALOX5, PLTP, FDFT1, and MSMO1) vs. NORMO patients. Lipidomics revealed lower cholesterol esters (CE, adjusted p = < 0.001), lysophosphatidylcholines (LPC, adjusted p = 0.001), and sphingomyelins (SM, adjusted p = < 0.001) in HYPO patients. In HYPO patients, DHCR7 expression strongly correlated with reductions in CE, LPC, and SM (p < 0.01), while PCSK9, MSMO1, DHCR7, PLTP, and LDLR upregulation were correlated with low LPC (p < 0.05). DHCR7, ALOX5, and LDLR correlated with reductions in SM (p < 0.05). Mortality and phenotype comparisons in two external datasets (N = 824 combined patients) corroborated six of the seven upregulated lipid genes (PCSK9, DHCR7, ALOX5, PLTP, LDLR, and MSMO1).

Conclusion

We identified a genetic lipid dysregulation signature characterized by seven lipid metabolism genes. Five genes in HYPO sepsis patients most strongly correlated with low CE, LPC, and SMs that mediate cholesterol storage and innate immunity.
Ecological multivariate assisted spectrophotometric methods for determination of antipyrine and benzocaine HCl in presence of antipyrine official impurity and benzocaine HCl degradant: toward greenness and whiteness
Authors: Kelani Khadiga M. , Hegazy Maha A. , Hassan Amal M. , Nadim Ahmed H.
Published: December 2024

A simple and green chemometrics-assisted spectrophotometric technique has beendeveloped and validated for the determination of antipyrine (ANT) and benzocaine HCl (BEN) along with the official impurity of ANT, antipyrine impurity A (ANT imp-A), and the degradation product of BEN, p-amino benzoic acid (PABA), in their quaternary mixture. Three models were developed and compared: partial least squares (PLS), artificial neural networks (ANN), and multivariate curve resolution-alternating least squares (MCR-ALS) where the four studied drugs were successfully quantified. The quantitative determination of the studied drugs was assessed using percentage recoveries, standard errors of prediction, and root mean square errors of prediction. The ANN model demonstrated the lowest error and the best correlation making it the most accurate method for analysis. The models were constructed in the ranges of 5.0–9.0 µg mL−1 for ANT, 1.0–5.0 µg mL−1 for BEN, 0.5–2.5 µg mL−1 for ANT imp-A, and 0.25–1.25 µg mL−1 for PABA. The established models successfully determined ANT, BEN, ANT imp-A, and PABA with detection limits of 0.312, 0.178, 0.093, and 0.042 µg mL−1 for PLS, 0.185, 0.085, 0.001, and 0.034 µg mL−1 for ANN; and 0.473, 0.240, 0.073, and 0.069 µg mL−1 for MCR-ALS, respectively. The greenness and the whiteness of the proposed method were assessed using two green evaluating approaches: analytical Eco-scale, and AGREE, along with one white analytical chemistry evaluating tool, RGB. The three proposed models were successfully applied for determination of ANT and BEN in their pharmaceutically co-formulated dosage forms. They are also recommended for stability assays and purity testing of these drugs in quality control laboratories.
Update on tick-borne rickettsioses in mainland Portugal: emerging threats and potential vectors
Authors: Moerbeck Leonardo , Parreira Ricardo , Seixas Gonçalo , Velez Rita , Domingos Ana , Antunes Sandra
Published: December 2024

Background

Tick-borne rickettsioses (TBR) are emerging, neglected, zoonoses, caused by intracellular α-proteobacteria of the genus Rickettsia, that pose a growing public health concern. The aim of the present study was to evaluate rickettsial infections in questing ticks collected from four different ecological areas in mainland Portugal.

Methods

Over a two-year period, a total of 707 questing ticks were collected. Individual adult ticks and pooled nymphs were submitted to DNA extraction, followed by qPCR assays targeting the gltA rickettsial gene. Positive samples were then submitted to conventional PCR targeting the gltA and the ompA genes for phylogenetic analysis.

Results

In total, eight tick species were identified: Dermacentor marginatus, Haemaphysalis inermis, Haemaphysalis punctata, Hyalomma lusitanicum, Ixodes frontalis, Ixodes ricinus, Rhipicephalus pusillus, and Rhipicephalus sanguineus sensu lato. Additionally, rickettsial infection was associated with seven of these species, with I. frontalis being the exception. Notably, the prevalence of Rickettsia spp. was 26.35%, with phylogenetic validation confirming infections with R. helvetica, R. massiliae, R. monacensis, Candidatus R. rioja, and R. slovaca.

Conclusions

The present study highlights the necessity for ongoing surveillance to map and monitor both questing and feeding ticks, along with their vertebrate hosts. Effective control strategies are of utmost importance to mitigate the escalating threat of TBR. Additionally, the present study provides valuable epidemiological insights into TBR in Portugal, including the identification of R. slovaca infecting I. ricinus - an unconventional tick-pathogen relationship - and the first report of Candidatus R. rioja infecting D. marginatus in Portugal. In conclusion, this study contributes with valuable data regarding epidemiological results on ticks and TBR circulating in Portugal, emphasizing the importance of proactive measures to address this emerging public health challenge.

Graphical abstract