bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of body mass index on 30-day complication rate and implant survival rate after simultaneous bilateral unicompartmental knee arthroplasty: a multicentre retrospective study
Authors: Xu Kuishuai , Wang Tianrui , Yu Tengbo , Zhao Xia , Zhang Yingze , Zhang Liang
Published: July 2024

Objective

The practice of simultaneous bilateral unicompartmental knee arthroplasty (SBUKA) remains a topic of debate, particularly in patients with obesity. Thus, the purpose of this study was to assess the impact of body mass index (BMI) on the 30-day complication rate and the survival rate of the implant following SBUKA.

Methods

We retrospectively examined the clinical records of 245 patients (490 knees) who underwent SBUKA at the Affiliated Hospital of Qingdao University and the Third Hospital of Hebei Medical University between January 2010 and December 2020. Patients were categorised based on their BMI at the time of surgery into four groups: normal weight (BMI 18.5 to 22.9 kg/m2), overweight (BMI 23.0 to 24.9 kg/m2), obese (BMI 25.0 to 29.9 kg/m2), and severely obese (BMI ≥30 kg/m2). Variables such as length of hospital stay, duration of surgery, and costs of hospitalisation were compared across all groups. Additionally, we recorded the 30-day postoperative complication rate and the time from surgery to any required revision. The Kaplan-Meier survival analysis was employed to evaluate and compare the implant survival rates.

Results

The follow-up period for the 245 patients ranged from 39 to 114 months, with an average of 77.05±18.71 months. The incidence of complications within 30 days post-surgery did not significantly differ across the groups (χ2 = 1.102, p = 0.777). The implant survival rates from the lowest to the highest BMI groups were 97.14%, 93.9%, 94.44%, and 96.43%, respectively. Both the rate of implant revision (χ2 =1.612, p = 0.657) and the survival curves of the implants (p = 0.639) showed no statistically significant differences among the groups.

Conclusions

BMI did not influence the 30-day complication rate nor the survival rate of implants following SBUKA, suggesting that SBUKA should not be contraindicated based on BMI alone.
Design of a novel multi-epitope vaccine against Marburg virus using immunoinformatics studies
Authors: Al-Zayadi Fouad Qasim Jubair , Shakir Ali S. , Kareem Ahmed Shayaa , Ghasemian Abdolmajid , Behmard Esmaeil
Published: July 2024

Marburg virus (MARV) is a highly contagious and virulent agent belonging to Filoviridae family. MARV causes severe hemorrhagic fever in humans and non-human primates. Owing to its highly virulent nature, preventive approaches are promising for its control. There is currently no approved drug or vaccine against MARV, and management mainly involves supportive care to treat symptoms and prevent complications. Our aim was to design a novel multi-epitope vaccine (MEV) against MARV using immunoinformatics studies. In this study, various proteins (VP35, VP40 and glycoprotein precursor) were used and potential epitopes were selected. CTL and HTL epitopes covered 79.44% and 70.55% of the global population, respectively. The designed MEV construct was stable and expressed in Escherichia coli (E. coli) host. The physicochemical properties were also acceptable. MARV MEV candidate could predict comprehensive immune responses such as those of humoral and cellular in silico. Additionally, efficient interaction to toll-like receptor 3 (TLR3) and its agonist (β-defensin) was predicted. There is a need for validation of these results using further in vitro and in vivo studies.
Hyaluronic acid impacts hematological endpoints and spleen histological features in African catfish (Clarias gariepinus)
Authors: Hamed Mohamed , Kotob Mohamed H. , Abou khalil Nasser S. , Anwari Esraa A. , El Gazzar Walaa Bayoumie , Idriss Shaimaa K. A. , Fakhry Michel E. , Farag Amina A. , Sabra Mahmoud S. , Salaah Sally M. , Abdel-Zaher Souzan , Yehia Saad Fatma Alzahraa , Naguib Mervat , Lee Jae-Seong , Sayed Alaa El-Din H.
Published: July 2024

Since its identification in the vitreous humour of the eye and laboratory biosynthesis, hyaluronic acid (HA) has been a vital component in several pharmaceutical, nutritional, medicinal, and cosmetic uses. However, little is known about its potential toxicological impacts on aquatic inhabitants. Herein, we investigated the hematological response of Clarias gariepinus to nominal doses of HA. To achieve this objective, 72 adult fish were randomly and evenly distributed into four groups: control, low-dose (0.5 mg/l HA), medium-dose (10 mg/l HA), and high-dose (100 mg/l HA) groups for two weeks each during both the exposure and recovery periods. The findings confirmed presence of anemia, neutrophilia, leucopoenia, lymphopenia, and eosinophilia at the end of exposure to HA. In addition, poikilocytosis and a variety of cytomorphological disturbances were observed. Dose-dependent histological alterations in spleen morphology were observed in the exposed groups. After HA removal from the aquarium for 2 weeks, the groups exposed to the two highest doses still exhibited a notable decline in red blood cell count, hemoglobin concentration, mean corpuscular hemoglobin concentration, and an increase in mean corpuscular volume. Additionally, there was a significant rise in neutrophils, eosinophils, cell alterations, and nuclear abnormalities percentages, along with a decrease in monocytes, coupled with a dose-dependent decrease in lymphocytes. Furthermore, only the highest dose of HA in the recovered groups continued to cause a significant increase in white blood cells. White blood cells remained lower, and the proportion of apoptotic RBCs remained higher in the high-dose group. The persistence of most of the haematological and histological disorders even after recovery period indicates a failure of physiological compensatory mechanisms to overcome the HA-associated problems or insufficient duration of recovery. Thus, these findings encourage the inclusion of this new hazardous agent in the biomonitoring program and provide a specific pattern of hematological profile in HA-challenged fish. Further experiments are highly warranted to explore other toxicological hazards of HA using dose/time window protocols.
Neuroimmune modulating and energy supporting nanozyme-mimic scaffold synergistically promotes axon regeneration after spinal cord injury
Authors: Zheng Genjiang , Yu Wei , Xu Zeng , Yang Chen , Wang Yunhao , Yue Zhihao , Xiao Qiangqiang , Zhang Wenyu , Wu Xiaodong , Zang Fazhi , Wang Jianxi , Wang Lei , Yuan Wei-En , Hu Bo , Chen Huajiang
Published: July 2024

Spinal cord injury (SCI) represents a profound central nervous system affliction, resulting in irreversibly compromised daily activities and disabilities. SCI involves excessive inflammatory responses, which are characterized by the existence of high levels of proinflammatory M1 macrophages, and neuronal mitochondrial energy deficit, exacerbating secondary damage and impeding axon regeneration. This study delves into the mechanistic intricacies of SCI, offering insights from the perspectives of neuroimmune regulation and mitochondrial function, leading to a pro-fibrotic macrophage phenotype and energy-supplying deficit. To address these challenges, we developed a smart scaffold incorporating enzyme mimicry nanoparticle-ceriumoxide (COPs) into nanofibers (NS@COP), which aims to pioneer a targeted neuroimmune repair strategy, rescuing CGRP receptor on macrophage and concurrently remodeling mitochondrial function. Our findings indicate that the integrated COPs restore the responsiveness of pro-inflammatory macrophages to calcitonin gene-related peptide (CGRP) signal by up-regulating receptor activity modifying protein 1 (RAMP1), a vital component of the CGRP receptor. This promotes macrophage fate commitment to an anti-inflammatory pro-resolution M2 phenotype, then alleviating glial scar formation. In addition, NS@COP implantation also protected neuronal mitochondrial function. Collectively, our results suggest that the strategy of integrating nanozyme COP nanoparticles into a nanofiber scaffold provides a promising therapeutic candidate for spinal cord trauma via rational regulation of neuroimmune communication and mitochondrial function.
Applying the WHO-INTEGRATE evidence-to-decision framework in the development of WHO guidelines on parenting interventions: step-by-step process and lessons learnt
Authors: Movsisyan Ani , Backhaus Sophia , Butchart Alexander , Gardner Frances , Strahwald Brigitte , Rehfuess Eva
Published: July 2024

Background

Development of guidelines for public health, health system, and health policy interventions demands complex systems thinking to understand direct and indirect effects of interventions within dynamic systems. The WHO-INTEGRATE framework, an evidence-to-decision framework rooted in the norms and values of the World Health Organization (WHO), provides a structured method to assess complexities in guidelines systematically, such as the balance of an intervention’s health benefits and harms and their human rights and socio-cultural acceptability. This paper provides a worked example of the application of the WHO-INTEGRATE framework in developing the WHO guidelines on parenting interventions to prevent child maltreatment, and shares reflective insights regarding the value added, challenges encountered, and lessons learnt.

Methods

The methodological approach comprised describing the intended step-by-step application of the WHO-INTEGRATE framework and gaining reflective insights from introspective sessions within the core team guiding the development of the WHO guidelines on parenting interventions and a methodological workshop.

Results

The WHO-INTEGRATE framework was used throughout the guideline development process. It facilitated reflective deliberation across a broad range of decision criteria and system-level aspects in the following steps: (1) scoping the guideline and defining stakeholder engagement, (2) prioritising WHO-INTEGRATE sub-criteria and guideline outcomes, (3) using research evidence to inform WHO-INTEGRATE criteria, and (4) developing and presenting recommendations informed by WHO-INTEGRATE criteria. Despite the value added, challenges, such as substantial time investment required, broad scope of prioritised sub-criteria, integration across diverse criteria, and sources of evidence and translation of insights into concise formats, were encountered.

Conclusions

Application of the WHO-INTEGRATE framework was crucial in the integration of effectiveness evidence with insights into implementation and broader implications of parenting interventions, extending beyond health benefits and harms considerations and fostering a whole-of-society-perspective. The evidence reviews for prioritised WHO-INTEGRATE sub-criteria were instrumental in guiding guideline development group discussions, informing recommendations and clarifying uncertainties. This experience offers important lessons for future guideline panels and guideline methodologists using the WHO-INTEGRATE framework.
Tonabersat suppresses priming/activation of the NOD-like receptor protein-3 (NLRP3) inflammasome and decreases renal tubular epithelial-to-macrophage crosstalk in a model of diabetic kidney disease
Authors: Cliff C. L. , Squires P. E. , Hills C. E.
Published: July 2024

Background

Accompanied by activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, aberrant connexin 43 (Cx43) hemichannel-mediated ATP release is situated upstream of inflammasome assembly and inflammation and contributes to multiple secondary complications of diabetes and associated cardiometabolic comorbidities. Evidence suggests there may be a link between Cx43 hemichannel activity and inflammation in the diabetic kidney. The consequences of blocking tubular Cx43 hemichannel-mediated ATP release in priming/activation of the NLRP3 inflammasome in a model of diabetic kidney disease (DKD) was investigated. We examined downstream markers of inflammation and the proinflammatory and chemoattractant role of the tubular secretome on macrophage recruitment and activation.

Methods

Analysis of human transcriptomic data from the Nephroseq repository correlated gene expression to renal function in DKD. Primary human renal proximal tubule epithelial cells (RPTECs) and monocyte-derived macrophages (MDMs) were cultured in high glucose and inflammatory cytokines as a model of DKD to assess Cx43 hemichannel activity, NLRP3 inflammasome activation and epithelial-to-macrophage paracrine-mediated crosstalk. Tonabersat assessed a role for Cx43 hemichannels.

Results

Transcriptomic analysis from renal biopsies of patients with DKD showed that increased Cx43 and NLRP3 expression correlated with declining glomerular filtration rate (GFR) and increased proteinuria. In vitro, Tonabersat blocked glucose/cytokine-dependant increases in Cx43 hemichannel-mediated ATP release and reduced expression of inflammatory markers and NLRP3 inflammasome activation in RPTECs. We observed a reciprocal relationship in which NLRP3 activity exacerbated increased Cx43 expression and hemichannel-mediated ATP release, events driven by nuclear factor kappa-B (NFκB)-mediated priming and Cx43 hemichannel opening, changes blocked by Tonabersat. Conditioned media (CM) from RPTECs treated with high glucose/cytokines increased expression of inflammatory markers in MDMs, an effect reduced when macrophages were pre-treated with Tonabersat. Co-culture using conditioned media from Tonabersat-treated RPTECs dampened macrophage inflammatory marker expression and reduced macrophage migration.

Conclusion

Using a model of DKD, we report for the first time that high glucose and inflammatory cytokines trigger aberrant Cx43 hemichannel activity, events that instigate NLRP3-induced inflammation in RPTECs and epithelial-to-macrophage crosstalk. Recapitulating observations previously reported in diabetic retinopathy, these data suggest that Cx43 hemichannel blockers (i.e., Tonabersat) may dampen multi-system damage observed in secondary complications of diabetes.
The intratumoral microbiota biomarkers for predicting survival and efficacy of immunotherapy in patients with ovarian serous cystadenocarcinoma
Authors: Qin Hao , Liu Jie , Qu Yi , Li Yang-Yang , Xu Ya-Lan , Yan Yi-Fang
Published: July 2024

Background

Ovarian serous cystadenocarcinoma, accounting for about 90% of ovarian cancers, is frequently diagnosed at advanced stages, leading to suboptimal treatment outcomes. Given the malignant nature of the disease, effective biomarkers for accurate prediction and personalized treatment remain an urgent clinical need.

Methods

In this study, we analyzed the microbial contents of 453 ovarian serous cystadenocarcinoma and 68 adjacent non-cancerous samples. A univariate Cox regression model was used to identify microorganisms significantly associated with survival and a prognostic risk score model constructed using LASSO Cox regression analysis. Patients were subsequently categorized into high-risk and low-risk groups based on their risk scores.

Results

Survival analysis revealed that patients in the low-risk group had a higher overall survival rate. A nomogram was constructed for easy visualization of the prognostic model. Analysis of immune cell infiltration and immune checkpoint gene expression in both groups showed that both parameters were positively correlated with the risk level, indicating an increased immune response in higher risk groups.

Conclusion

Our findings suggest that microbial profiles in ovarian serous cystadenocarcinoma may serve as viable clinical prognostic indicators. This study provides novel insights into the potential impact of intratumoral microbial communities on disease prognosis and opens avenues for future therapeutic interventions targeting these microorganisms.
Methionine sulfoxide reductase B2 protects against cardiac complications in diabetes mellitus
Authors: Lee Seung Hee , Cho Suyeon , Lee Jong Youl , Kim Ji Yeon , Kim Suji , Jeong Myoungho , Hong Jung Yeon , Kim Geun-Young , Lee Seung Woo , Kim Eunmi , Kim Jihwa , Kim Jee Woong , Hwa John , Kim Won-Ho
Published: July 2024

Diabetes mellitus (DM) is a progressive, chronic metabolic disorder characterized by high oxidative stress, which can lead to cardiac damage. Methionine sulfoxylation (MetO) of proteins by excessive reactive oxygen species (ROS) can impair the basic functionality of essential cellular proteins, contributing to heart failure. Methionine sulfoxide reductase B2 (MsrB2) can reverse oxidation induced MetO in mitochondrial proteins, so we investigated its role in diabetic cardiomyopathy. We observed that DM-induced heart damage in diabetic mice model is characterized by increased ROS, increased protein MetO with mitochondria structural pathology, and cardiac fibrosis. In addition, MsrB2 was significantly increased in mouse DM cardiomyocytes, supporting the induction of a protective process. Further, MsrB2 directly induces Parkin and LC3 activation (mitophagy markers) in cardiomyocytes. In MsrB2, knockout mice displayed abnormal electrophysiological function, as determined by ECG analysis. Histological analysis confirmed increased cardiac fibrosis and disrupted cardiac tissue in MsrB2 knockout DM mice. We then corroborated our findings in human DM heart samples. Our study demonstrates that increased MsrB2 expression in the heart protects against diabetic cardiomyopathy.

Graphic Abstract
A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with early Alzheimer’s Disease
Authors: Galasko Douglas , Farlow Martin R. , Lucey Brendan P. , Honig Lawrence S. , Elbert Donald , Bateman Randall , Momper Jeremiah , Thomas Ronald G. , Rissman Robert A. , Pa Judy , Aslanyan Vahan , Balasubramanian Archana , West Tim , Maccecchini Maria , Feldman Howard H.
Published: July 2024

Background

Amyloid beta protein (Aβ) is a treatment target in Alzheimer’s Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen, an orally administered small molecule, binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aβ. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aβ metabolism using Stable Isotope Labeling Kinetic (SILK) analysis.

Methods

Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) confirmed by low CSF Aβ42/40 were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21–23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 h. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aβ40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aβ and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21.

Results

From June 2017 to December 2021, 19 participants were enrolled, randomized within dose cohorts (5 active: 3 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aβ40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs. placebo groups.

Conclusions

Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects.

Trial registration

NCT02925650 on clinicaltrials.gov (registered on 10-24-2016).
Cost-effectiveness of immune checkpoint inhibitors as a first-line therapy for advanced hepatocellular carcinoma: a systematic review
Authors: Gong Hongyu , Ong Siew Chin , Li Fan , Shen Yan , Weng Zhiying , Zhao Keying , Jiang Zhengyou , Wang Meng
Published: July 2024

Since 2017, immune checkpoint inhibitors (ICIs) have been available for the treatment of advanced hepatocellular carcinoma (HCC) or unresectable HCC, but their adoption into national medical insurance programs is still limited. Cost-effectiveness evidence can help to inform treatment decisions. This systematic review aimed to provide a critical summary of economic evaluations of ICIs as a treatment for advanced HCC and identify key drivers (PROSPERO 2023: CRD42023417391). The databases used included Scopus, Web of Science, PubMed, Embase, and Cochrane Central. Economic evaluations of ICIs for the treatment of advanced HCC were included. Studies were screened by two people. Of the 898 records identified, 17 articles were included. The current evidence showed that ICIs, including atezolizumab plus bevacizumab, sintilimab plus bevacizumab/bevacizumab biosimilar, nivolumab, camrelizumab plus rivoceranib, pembrolizumab plus lenvatinib, tislelizumab, durvalumab, and cabozantinib plus atezolizumab, are probably not cost-effective in comparison with tyrosine kinase inhibitors or other ICIs. The most influential parameters were price of anticancer drugs, hazard ratios for progression-free survival and overall survival, and utility for health statest. Our review demonstrated that ICIs were not a cost-effective intervention in advanced HCC. Although ICIs can significantly enhance the survival of patients with advanced HCC, decision-makers should consider the findings of economic evaluations and affordability before adoption of new therapies.
Discrepancies between self-reported medication in adherence and indirect measurement adherence among patients undergoing antiretroviral therapy: a systematic review
Authors: Liao Rujun , Tang Zihuan , Zhang Na , Hu Lin , Chang Zongqi , Ren Jiayi , Bai Xuefei , Shi Jinhong , Fan Sisi , Pei Rong , Du Liang , Zhang Tao
Published: July 2024

Background

Given the critical importance of medication adherence in HIV/AIDS treatment, this study aims to compare medication adherence measured by self-report (SR) and indirect measurement among antiretroviral therapy (ART) patients, exploring the differences of adherence results measured by different tools.

Methods

We systematically searched PubMed, Embase, and the Cochrane Library to identify all relevant literature published up to November 22, 2023, without language restrictions, reporting adherence to ART measured by both SR and indirect measurement methods, while also analyzing individual and group adherence separately. Discrepancies between SR and indirect measurement results were assessed using the Mann–Whitney U test or Wilcoxon signed-rank test, with correlations evaluated using the Pearson correlation coefficient. Following one-to-one comparisons, meta-epidemiological one-step analysis was conducted, and network meta-analysis techniques were applied to compare results obtained through specific adherence assessment tools reported in the identified articles.

Results

The analysis encompassed 65 original studies involving 13,667 HIV/AIDS patients, leading to 112 one-to-one comparisons between SR and indirect measurement tools. Statistically significant differences were observed between SR and indirect measurement tools regarding both individual and group adherence (P < 0.05), with Pearson correlation coefficients of 0.843 for individual adherence and 0.684 for group adherence. During meta-epidemiological one-step analysis, SR-measured adherence was determined to be 3.94% (95% CI: -4.48–13.44%) higher for individual adherence and 16.14% (95% CI: 0.81–18.84%) higher for group adherence compared to indirectly measured results. Subgroup analysis indicated that factors such as the year of reporting and geographic region appeared to influence the discrepancies between SR and indirect measurements. Furthermore, network meta-analysis revealed that for both individual and group adherence, the results obtained from most SR and indirect measurement tools were higher than those from electronic monitoring devices, with some demonstrating statistical significance (P < 0.05).

Conclusions

The findings underscored the complexity of accurately measuring medication adherence among ART patients. Significant variability was observed across studies, with self-report methods showing a significant tendency towards overestimation. Year of reporting, geographic region, and adherence measurement tools appeared to influence the differences between SR and indirect measurements. Future research should focus on developing and validating integrated adherence measurements that can combine SR data with indirect measures to achieve a more comprehensive understanding of adherence behaviors.

Graphical Abstract
Prognostic significance of troponin in patients with malignancy (NIHR Health Informatics Collaborative TROP-MALIGNANCY study)
Authors: Samuel Nathan A. , Roddick Alistair , Glampson Ben , Mulla Abdulrahim , Davies Jim , Papadimitriou Dimitri , Panoulas Vasileios , Mayer Erik , Woods Kerrie , Shah Anoop D. , Gautama Sanjay , Elliott Paul , Hemmingway Harry , Williams Bryan , Asselbergs Folkert W. , Melikian Narbeh , Kharbanda Rajesh , Shah Ajay M. , Perera Divaka , Patel Riyaz S. , Channon Keith M. , Mayet Jamil , Shah Anoop S. V. , Kaura Amit
Published: July 2024

Background

Cardiac troponin is commonly raised in patients presenting with malignancy. The prognostic significance of raised troponin in these patients is unclear.

Objectives

We sought to investigate the relation between troponin and mortality in a large, well characterised cohort of patients with a routinely measured troponin and a primary diagnosis of malignancy.

Methods

We used the National Institute for Health Research (NIHR) Health Informatics Collaborative data of 5571 patients, who had troponin levels measured at 5 UK cardiac centres between 2010 and 2017 and had a primary diagnosis of malignancy. Patients were classified into solid tumour or haematological malignancy subgroups. Peak troponin levels were standardised as a multiple of each laboratory’s 99th -percentile upper limit of normal (xULN).

Results

4649 patients were diagnosed with solid tumours and 922 patients with haematological malignancies. Raised troponin was an independent predictor of mortality in all patients (Troponin > 10 vs. <1 adjusted HR 2.01, 95% CI 1.73 to 2.34), in solid tumours (HR 1.84, 95% CI 1.55 to 2.19), and in haematological malignancy (HR 2.72, 95% CI 1.99 to 3.72). There was a significant trend in increasing mortality risk across troponin categories in all three subgroups (p < 0.001).

Conclusion

Raised troponin level is associated with increased mortality in patients with a primary diagnosis of malignancy regardless of cancer subtype. Mortality risk is stable for patients with a troponin level below the ULN but increases as troponin level increases above the ULN in the absence of acute coronary syndrome.
Comparison of outcomes in kidney transplantations involving blood-related and non-blood-related living donors: a multicenter retrospective study by the Michinoku renal transplant network
Authors: Matsuura Tomohiko , Toyoshima Moe , Saitoh Mitsuru , Nishida Hayato , Hatakeyama Shingo , Maita Shinya , Murakami Reiichi , Sugimura Jun , Abe Takaya , Tomita Hirofumi , Saitoh Hisao , Tsuchiya Norihiko , Ohyama Chikara , Habuchi Tomonori , Obara Wataru
Published: July 2024

Background

This study aimed to compare the outcomes of living donor kidney transplantation with blood- and non-blood-related donors across multiple facilities. Previous reports comparing these outcomes have been single-center studies. As the donors were the recipients’ spouses in all cases with non-blood-related donors, we independently compared the outcomes of wife-to-husband (WTH) and husband-to-wife (HTW) transplantations. No previous multicenter studies have compared transplant outcomes between spouses in this manner.

Methods

This retrospective study used a shared database including 643 cases from 6 facilities that primarily used tacrolimus as a calcineurin inhibitor. We used propensity score matching to compare the outcomes of transplantations with blood- and non-blood-related donors and those of WTH and HTW transplantations.

Results

Of the 643 cases examined, 381 and 262 had blood- and non-blood-related donors, respectively. All non-blood-related donor cases had spouses as donors. After propensity score matching, 84 cases each were selected from the blood- and non-blood-related donor groups for comparison, with no significant intergroup difference in the time to graft loss. Among the 262 interspousal transplantations, 91 were HTW transplantations and 171 were WTH transplantations. Following propensity score matching, 58 cases each were selected from the WTH and HTW groups for comparison, with no significant intergroup difference in the time to graft loss.

Conclusions

In this large multicenter retrospective study, no significant differences were observed in the outcomes of transplantations with blood- and non-blood-related donors. Furthermore, no significant differences were observed in the outcomes of WTH and HTW cases. Many centers that use tacrolimus-based four-drug immunosuppressive therapy may have similar trends as those observed in this study, making our findings significant for planning transplantation involving kidneys donated from patients’ spouses.
Efficacy and safety of ruxolitinib in patients with lower risk myelofibrosis: A single-arm, exploratory and prospective study.
Authors: Hu Shiwei , Yang Xiudi , Tong Hongyan , Jin Jie , Huang Jian
Published: July 2024

6573

Background: The COMFORT studies assessed the efficacy and safety of ruxolitinib in patients with intermediate-2 and high risk myelofibrosis (MF), and JUMP study has broadened the investigation including patients with intermediate-1 MF in the classification of DIPSS. However, there have been limited prospective studies evaluating the efficacy and safety of patients with low risk MF in the classification of more comprehensive scoring system. Here we present a single-arm, exploratory and prospective study to assess the efficacy and safety of ruxolitinib in patients with lower risk MF in China. Methods: Lower risk was defined as MIPSS-70 ≤ 3, MIPSS+V2.0 ≤ 3, DIPSS-Plus ≤ 1, DIPSS ≤ 2 or MYSEC-PM < 14 according to the expert guidelines. Patients aged ≥ 18 with overt primary myelofibrosis (overt-PMF), prefibrotic primary myelofibrosis (pre-PMF), post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocythemia myelofibrosis (post-ET MF), classified as lower risk were enrolled. The primary endpoint was the proportion of patients with a spleen length reduction of ≥ 50% from baseline at week 48. Secondary endpoints included the best spleen response, the proportion of patients with a ≥ 50% reduction in Total Symptom Score (TSS50) and safety. Results: A total of 40 patients were enrolled in the lower risk group, including 7 pre-PMF, 17 overt-PMF, 8 PPV-MF, and 8 PET-MF patients. The median age was 62.0 years. 32 (80%) were JAK2V617F positive. 16 patients had next generation sequencing (NGS), the most frequent non-driver mutation was in TET2 (43.8%), followed by BCOR (12.5%). By week 48, 26 (65.0%) patients achieved a ≥ 50% decrease in palpable spleen length. 32 (80.0%) patients achieved a ≥ 50% reduction from baseline at any time. The median time to a spleen response was 4.3 weeks. The TSS50 rates at week 48 was 25%. No patients required red blood cell transfusion at baseline. And only 1 patient had a baseline hemoglobin (HB) <100 g/L, which remained stable during the follow-up process. The most common grade ≥ 3 hematological treatment emergent adverse events (TEAEs) were anemia (10.0%) and thrombocytopenia (2.5%). 6 (15.0%) and 15 (37.5%) patients experienced grade 1 or 2 anemia and thrombocytopenia, respectively. The mostly common non-hematological TEAEs was infection (12.5), including upper respiratory tract infection (7.5%), urinary infection (2.5%), fever (2.5%), predominantly of grade 1 or 2. Of note, 1 patient developed staphylococcal sepsis and 1 patient experienced acute renal failure. No one discontinued ruxolitinib treatment due to TEAEs. Conclusions: Ruxolitinib is an effective treatment for patients with intermediate-1 and low risk MF, resulting in improved spleen and symptom responses, along with fewer hematological and non-hematological TEAEs. This trial was registered as ChiCTR2200064250 at ClinicalTrials.gov . Clinical trial information: ChiCTR2200064250.
Impact of EGFR mutation and types of treatment on the longitudinal recurrence risk in patients with completely resected non-small cell lung cancer: A combined analysis of two phase III studies (JIPANG and IMPACT).
Authors: Akamatsu Hiroaki , Nishikawa Tomomi , Misumi Toshihiro , Aoki Tadashi , Shoda Hiroyasu , Yamashita Motohiro , Sakakura Noriaki , Daga Haruko , Sugawara Shunichi , Okishio Kyoichi , Kenmotsu Hirotsugu , Yamamoto Nobuyuki , Tada Hirohito , Tsuboi Masahiro , Mitsudomi Tetsuya
Published: July 2024

8023

Background: In completely resected non-small cell lung cancer patients who received adjuvant treatment, the impact of EGFR mutation and types of treatment on the longitudinal recurrence risk has not been elucidated. Methods: The individual data was obtained from two adjuvant phase III trials conducted almost the same period in Japan (JIPANG [CDDP + PEM versus CDDP + VNR] and IMPACT [gefitinib versus CDDP+VNR]). According to EGFR mutation status and types of adjuvant treatment, 626 patients were categorized into three groups (arm A [ EGFR wild-type, chemo: n = 299], arm B [ EGFR mutant, chemo: n = 211], and arm C [ EGFR mutant, gefitinib: n = 116]). Disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method, and sites of recurrence were compared. Additionally, the longitudinal recurrence risk was analyzed by estimating hazard function among the arms. The impact of EGFR mutation and the types of adjuvant treatment on the recurrence site (central nervous system vs others) and death was also analyzed using the multi-state model. Results: Median follow-up time was 69.3 months (range, 0.0 to 113.4 months). DFS was not different between the arms (median DFS: 42.2 months in arm A, 30.3 months in arm B, and 35.9 months in arm C, respectively), however, the DFS rate at 8 years was numerically different (arm A: 40.4%, arm B: 33.9%, and arm C: 22.3%, respectively: Table). Median OS was not reached in each arm, and OS rates at 8 years were 61.3%, 67.7%, and 59.8%, respectively. In the longitudinal recurrence risk analysis, arms A and B had a higher hazard function level than arm C for the first two years and the curves crossed thereafter. Risks in arms A and B gradually decreased and reached a plateau at a lower level, whereas arm C sustained a recurrence risk and finally it was higher than arms A and B. Regarding sites of recurrence, arm C showed a slightly higher distant relapse (51.7%) than arm A (47.2%) or arm B (45.5%), of those, CNS was the most frequent site (33.8%). Among EGFR mutant cases, gefitinib likely to have higher risk of CNS relapse (HR 1.46, 95% confidence interval: 0.62-3.45) than chemotherapy. When treated with chemotherapy, EGFR mutation status did not affect any types of recurrence. Conclusions: In patients with completely resected NSCLC, chemotherapy led to cure regardless of EGFRmutation status, whereas gefitinib showed a sustained recurrence risk even after completion. Clinical trial information: UMIN000006252 and UMIN000006737. [Table: see text]
High-dose furmonertinib in patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastases: A real-world study.
Authors: Chen Haiyang , Wang Lili , Wu Yingxi , Wu Yufeng , Ma Shuxiang , Yang Sen , He Zhen , Mo Yuqing , Zhang Cuicui , Wang Qiming
Published: July 2024

8587

Background: Leptomeningeal metastasis (LM) is one of the most severe complications of non-small cell lung cancer (NSCLC) and always accompanied with poor prognosis. Furmonertinib is a pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with high brain penetration and wide therapeutic window. This study aimed to evaluate the efficacy and safety of high-dose furmonertinib in patients with EGFR-mutated NSCLC and LM in the real world. Methods: Eligible patients were aged at least 18 years old and had histological or cytological confirmed advanced NSCLC harboring an EGFR mutation. Patients were diagnosed as probable or confirmed LM according to the EANO-ESMO criteria. Patients were treated with furmonertinib 240mg once daily. The primary endpoint was overall survival (OS), time to treatment discontinuation (TTD) and clinical response rate were secondary endpoints. Clinical response rate assessed with improvement of neurologic symptoms or signs and changes in the performance status. Additional efficacy evaluations included changes in brain magnetic resonance imaging (MRI) according to the RANO-LM radiologic criteria. Results: Between May 1, 2021, and December 28, 2023, 48 patients were enrolled at Henan Cancer Hospital. All of the enrolled patients had poor performance status, 13 (27.1%) patients had an ECOG score of 2, 35 (72.9%) patients had an ECOG score of 3. And 35 (72.9%) patients had received other 3rd generation EGFR-TKIs. The median follow-up time was 15 months. 31 OS events occurred at the data cut-off. The primary endpoint of median OS was 8.433 months (95%CI, 5.481 to 11.386 months). The secondary endpoint of median TTD was 8.267 months (95%CI, 5.395 to 11.138 months). The clinical response rate was 75%. The LM objective response rate (ORR) and disease control rate (DCR) assessed by investigator according to RANO-LM radiologic criteria were 47.4% and 92.1%, respectively. The adverse event profiles were consistent with previous reports of furmonertinib. 22 (45.8%) patients had adverse events (AEs) possibly related to furmonertinib. 3 (6.3%) patients had grade 3 elevated aminotransaminase or nausea or leucopenia, respectively, leading to dose reduction to 160mg daily. Conclusions: In the real world, high-dose furmonertinib demonstrated significant clinical efficacy and tolerable safety in patients of EGFR-mutated NSCLC with LM, even in patients who had been treated with other 3rd generation EGFR-TKIs previously. Clinical trial information: ChiCTR2300072092.
Comparison of Surgical Modalities for Giant Pituitary Adenoma: A Systematic Review and Meta-Analysis of 1413 Patients
Authors: Tang Oliver Y. , Chen Jia-Shu , Monje Silas , Kumarapuram Siddhant , Eloy Jean Anderson , Liu James K.
Published: July 2024

BACKGROUND AND OBJECTIVES:

Giant pituitary adenomas (GPAs) are a challenging clinical entity, composing 5% to 15% of all pituitary adenomas. While the endoscopic endonasal transsphenoidal (EET) approach has surpassed the microsurgical transsphenoidal (MT) and transcranial (TC) approaches as the first-line surgical modality in most institutions, a systematic review comparing the 3 approaches has not been undertaken since 2012. Given growing adoption of EET and development of novel operative techniques over the past decade, an updated comparison of GPA surgical modalities is warranted.

METHODS:

We identified all studies related to the surgical management of GPAs in PubMed, Embase, and Web of Science from inception to December 31, 2021. End points assessed included gross total resection (GTR) rates, postoperative visual improvement, mortality, and perioperative complications.

RESULTS:

After screening of 1701 studies, we identified 45 studies on the surgical management of GPAs for meta-analysis. Thirty-one used the EET approach (n = 1413), 11 studies used the MT approach (n = 601), and 10 used the TC approach (n = 416). The cumulative number of patients treated by EET did not exceed that of patients treated by the TC or MT approaches until 2014 and 2015, respectively. Despite patients undergoing EET having the highest average tumor diameter, pooled rates for GTR were significantly higher for EET (42%) than MT (33%, P < .001) and TC (8%, P < .001) and EET similarly exhibited superior rates of visual improvement (85%) than MT (73%, P < .001) and TC (56%, P < .001). Mortality rates were comparable between EET (0.6%) and MT (1.6%), but EET had significantly lower mortality than TC (2.7%, P < .001). Compared with MT, EET had lower rates of hypopituitarism (8.5% vs 14.9%, P = .012) but higher rates of diabetes insipidus (3.1% vs 0.5%, P = .001).

CONCLUSION:

In an updated meta-analysis of 1413 patients with GPA, EET resection conferred significantly higher rates of visual improvement and GTR, when compared with the MT and TC approaches.
Does Valve Design Affect the Tensile Strength of Ventriculoperitoneal Shunts?
Authors: Patel Parth , Arshad Haroon , Jefferys Kirsten , Gernsback Joanna
Published: July 2024

BACKGROUND AND OBJECTIVES:

The most common treatment for hydrocephalus is ventriculoperitoneal (VP) shunting, which is problematic as shunts are prone to failure. Shunt disconnections account for a minority (8%-15%) of VP shunt failures but could be reduced through better shunt design. A better understanding of the mechanical properties of VP shunts would help explain why shunt disconnections occur. The objective of this study was to determine if the tensile properties of VP shunts differ by design.

METHODS:

Linear tensile testing was conducted on 5 different valve designs (Codman Certas Plus Programmable Valve, Medtronic Delta, Integra Orbis Sigma Valve II, Medtronic PS Medical, Medtronic Strata Adjustable Valve) at both the proximal and distal ends to determine the maximum load which could be applied to different shunt designs. Each valve was progressively subjected to increasing force until the catheter disconnected from the valve, the catheter fractured, or our maximum testing limits were reached.

RESULTS:

Catheters disconnected or fractured during testing with all valves. The maximum load resisted during tensile testing for similar locations in all valve designs were found to be statistically similar to one another. Only the PS Medical and Orbis Sigma II valves showed an increased maximum load at the distal end compared with the proximal end within the same device.

CONCLUSION:

No single valve design was superior at preventing disconnections in VP shunts. Shunt disconnections remain a concerning problem as VP shunts are the gold standard for combating hydrocephalus.
Craniofacial studies in chicken embryos confirm the pathogenicity of human FZD2 variants associated with Robinow syndrome
Authors: Tophkhane Shruti S. , Fu Katherine , Verheyen Esther M. , Richman Joy M.
Published: July 2024

Robinow syndrome is a rare disease caused by variants of seven WNT pathway genes. Craniofacial features include widening of the nasal bridge and jaw hypoplasia. We used the chicken embryo to test whether two missense human FZD2 variants (1301G>T, p.Gly434Val; 425C>T, p.Pro142Lys) were sufficient to change frontonasal mass development. In vivo, the overexpression of retroviruses with wild-type or variant human FZD2 inhibited upper beak ossification. In primary cultures, wild-type and variant human FZD2 significantly inhibited chondrogenesis, with the 425C>T variant significantly decreasing activity of a SOX9 luciferase reporter compared to that for the wild type or 1301G>T. Both variants also increased nuclear shuttling of β-catenin (CTNNB1) and increased the expression of TWIST1, which are inhibitory to chondrogenesis. In canonical WNT luciferase assays using frontonasal mass cells, the variants had dominant-negative effects on wild-type FZD2. In non-canonical assays, the 425C>T variant failed to activate the reporter above control levels and was unresponsive to exogenous WNT5A. This is the first single amino acid change to selectively alter ligand binding in a FZD receptor. Therefore, FZD2 missense variants are pathogenic and could lead to the altered craniofacial morphogenesis seen in Robinow syndrome.
Surveillance for Distant Metastasis in Breast Cancer Patients Who Underwent Contemporary Management: A Report from the Korean Breast Cancer Society Survivor Research Group
Authors: Cheun Jong-Ho , Chung Sooyeon , Han Jai Hong , Lee Young-Won , Jung Ji-Jung , Chun Jung Whan , Lee Eun-Gyeong , Min Jun Won , Kim Zisun , Lee Jihyoun , Jung So-Youn , Kim Yoo Seok , Yu Jong Han , Kim Eun-Kyu , Lee Jong-Won , Hwang Ki-Tae , Kim Ku Sang , Youn Hyun Jo , Moon Hyeong-Gon
Published: July 2024

Background

Current guidelines recommend against the use of routine imaging tests to detect distant metastasis in asymptomatic breast cancer patients. However, recent advancements in effective therapeutics and diagnostic accuracy have raised the need to reassess the clinical efficacy of intensive metastasis surveillance. We report the results of a multicenter retrospective study to investigate the association between intensive imaging studies and survival outcomes.

Patients and Methods

We retrospectively reviewed the data of 4130 patients who underwent surgery from 11 hospitals in Korea between January 2010 and December 2011. Patients were divided into two groups on the basis of the intensity of metastasis imaging studies during their disease-free period. The types and intervals of the imaging studies were based on each physician’s decisions.

Results

High-intensive screening showed a shorter distant metastasis-free survival [p < 0.001, hazard ratio (HR) 1.62; 95% confidence interval (CI) 1.29–2.04], especially for patients in whom bone or lung was the first site of metastasis. With a median follow-up period of 110.0 months, the 5-year breast cancer-specific survival (BCSS) rate was 96.5%. The high-intensity screening group showed significantly poorer BCSS compared with the low-intensity screening group (p < 0.001, HR 3.13; 95% CI 2.32–4.21). However, both multivariable analysis and propensity score matching analysis showed no significant association between the screening intensity and BCSS.

Conclusions

Frequent imaging studies to detect distant metastasis were associated with earlier detection of distant metastasis, especially for lung and bone metastasis. However, intensive surveillance showed no apparent association with BCSS despite the use of currently available treatments.
PCC ou políticas públicas? Uma análise da redução dos homicídios em São Paulo
Authors: Alvarenga Bruno
Published: July 2024

Desde o início dos anos 2000, tem-se observado, no estado de São Paulo (SP), a redução das taxas de homicídios, contrastando com o cenário nacional. Com o escopo de entender o fenômeno, hipóteses passaram a ser apresentadas, e, entre estas, a de que a redução dos homicídios em SP teria ocorrido por conta da atuação da facção criminosa Primeiro Comando da Capital (PCC). Apresenta-se revisão de estudos que abordam tal hipótese e busca-se avaliá-la por meio de análises comparativas da tendência dos homicídios com outros indicadores criminais e entre territórios em que a facção criminosa teria maior ou menor poder de influência. Propõem-se novos olhares para o fenômeno, apresentando um modelo multivariado, integrando indicadores socioeconômicos, demográficos e de distribuição do policiamento. Apresentam-se indícios que permitem contestar a hipótese PCC como fator determinante para a redução dos homicídios em SP.