bluuebunny/crossref_metadata_2025 huggingface dataset:
Prescription of therapeutic exercise in migraine, an evidence-based clinical practice guideline
Authors: La Touche Roy , Fierro-Marrero José , Sánchez-Ruíz Irene , Rodríguez de Rivera-Romero Borja , Cabrera-López Carlos Donato , Lerma-Lara Sergio , Requejo-Salinas Néstor , de Asís-Fernández Francisco , Elizagaray-García Ignacio , Fernández-Carnero Josué , Matesanz-García Luís , Pardo-Montero Joaquín , Paris-Alemany Alba , Reina-Varona Álvaro
Published: June 2023

The main objective of this clinical practice guideline is to provide a series of recommendations for healthcare and exercise professionals, such as neurologists, physical therapists, and exercise physiologists, regarding exercise prescription for patients with migraine.

This guideline was developed following the methodology and procedures recommended in the Appraisal of Guidelines for Research and Evaluation (AGREE). The quality of evidence and strength of recommendations were evaluated with the Scottish Intercollegiate Guidelines Network (SIGN). A systematic literature review was performed and an established appraisal process was employed to rate the quality of relevant scientific research (Grading of Recommendations Assessment, Development, and Evaluation methodology).

The evaluation of the current evidence, the elaboration of the grades of recommendation, and their validation show a B grade of recommendation for aerobic exercise, moderate-continuous aerobic exercise, yoga, and exercise and lifestyle recommendations for the improvement of symptoms, disability, and quality of life in patients with migraine. Relaxation techniques, high-intensity interval training, low-intensity continuous aerobic exercise, exercise and relaxation techniques, Tai Chi, and resistance exercise obtained a C grade of recommendation for the improvement of migraine symptoms and disability.
Transition metal-based nanoparticles as potential antimicrobial agents: recent advancements, mechanistic, challenges, and future prospects
Authors: Gautam Sonali , Das Dipak Kumar , Kaur Jasvinder , Kumar Anuj , Ubaidullah Mohd , Hasan Mudassir , Yadav Krishna Kumar , Gupta Ram K.
Published: June 2023

Bacterial transmission is considered one of the potential risks for communicable diseases, requiring promising antibiotics. Traditional drugs possess a limited spectrum of effectiveness, and their frequent administration reduces effectiveness and develops resistivity. In such a situation, we are left with the option of developing novel antibiotics with higher efficiency. In this regard, nanoparticles (NPs) may play a pivotal role in managing such medical situations due to their distinct physiochemical characteristics and impressive biocompatibility. Metallic NPs are found to possess extraordinary antibacterial effects that are useful in vitro as well as in vivo as self-modified therapeutic agents. Due to their wide range of antibacterial efficacy, they have potential therapeutic applications via diverse antibacterial routes. NPs not only restrict the development of bacterial resistance, but they also broaden the scope of antibacterial action without binding the bacterial cell directly to a particular receptor with promising effectiveness against both Gram-positive and Gram-negative microbes. This review aimed at exploring the most relevant types of metal NPs employed as antimicrobial agents, particularly those based on Mn, Fe, Co, Cu, and Zn metals, and their antimicrobial mechanisms. Further, the challenges and future prospects of NPs in biological applications are also discussed.
Association between physical activity and resistant hypertension in treated hypertension patients: analysis of the national health and nutrition examination survey
Authors: Zhang Weidai , Xu Ronghe , Cai Zhixiong , Zheng Xiaodong , Zheng Meiyi , Ni Chumin
Published: June 2023

Introduction

Current guidelines suggest that regular aerobic training might lower blood pressure in hypertensive individuals. However, evidence linking resistant hypertension (RH) with total daily physical activity (PA), including work-, transport-, and recreation-related PA, is limited. Therefore, this study assessed the association between daily PA and RH.

Method

A cross-sectional study was conducted using data acquired from a nationwide survey in the US (the National Health and Nutrition Examination Survey, NHANES). The weighted prevalence of RH was calculated, and moderate and vigorous daily PA was assessed using the Global Physical Activity Questionnaire (GPAQ). A multivariate logistic regression model determined the association between daily PA and RH.

Results

A total of 8,496 treated hypertension patients were identified, including 959 RH cases. The unweighted prevalence of RH among treated hypertension cases was 11.28%, while the weighted prevalence was 9.81%. Participants with RH had a low rate of recommended PA levels (39.83%), and daily PA and RH were significantly associated. PA exhibited significant dose-dependent trends with a low probability of RH (p-trends < 0.05). Additionally, participants with sufficient daily PA had a 14% lower probability of RH than those with insufficient PA [fully adjusted odds ratio (OR) = 0.86; 95% confidence interval (CI) = 0.74–0.99).

Conclusion

The present study revealed that RH has an incidence of up to 9.81% in treated hypertension patients. Hypertensive patients tended to be physically inactive, and insufficient PA and RH were significantly associated. Sufficient daily PA should be recommended to reduce the RH probability among treated hypertension patients.
Prediction of post-operative atrial fibrillation in patients after cardiac surgery using heart rate variability
Authors: Veselá Jana , Osmančík Pavel , Heřman Dalibor , Hassouna Sabri , Raková Radka , Veselý Tomáš , Budera Petr
Published: June 2023

Purpose

Post-operative atrial fibrillation (PoAF) occurs in ~ 30% of patients after cardiac surgery. The etiology of PoAF is complex, but a disbalance in autonomic systems plays an important role. The goal of this study was to assess whether pre-operative heart rate variability analysis can predict the risk of PoAF.

Methods

Patients without a history of AF with an indication for cardiac surgery were included. Two-hour ECG recordings one day before surgery was used for the HRV analysis. Univariate and multivariate logistic regression, including all HRV parameters, their combination, and clinical variables, were calculated to find the best predictive model for post-operative AF.

Results

One hundred and thirty-seven patients (33 women) were enrolled in the study. PoAF occurred in 48 patients (35%, AF group); the remaining 89 patients were in the NoAF group. AF patients were significantly older (69.1 ± 8.6 vs. 63.4 ± 10.5 yrs., p = 0.002), and had higher CHA2DS2-VASc score (3 ± 1.4 vs. 2.5 ± 1.3, p = 0.01). In the multivariate regression model, parameters independently associated with higher risk of AF were pNN50, TINN, absolute power VLF, LF and HF, total power, SD2, and the Porta index. A combination of clinical variables with HRV parameters in the ROC analysis achieved an AUC of 0.86, a sensitivity of 0.95, and a specificity of 0.57 and was more effective in PoAF prediction than a combination of clinical variables alone.

Conclusion

A combination of several HRV parameters is helpful in predicting the risk of PoAF. Attenuation of heart rate variability increases the risk for PoAF.
Update of dialysis initiation timing in end stage kidney disease patients: is it a resolved question? A systematic literature review
Authors: Jia Xiaoyan , Tang Xueqing , Li Yunfeng , Xu Dongmei , Moreira Paulo
Published: June 2023

Background

The exact optimal timing of dialysis for ESKD patients remains unknown. This study systematically reviewed the available evidence with regard to the optimal initiation of maintenance dialysis in ESKD patients.

Methods

An electronic search was performed in Embase, PubMed and the Cochrane Library in order to find studies investigating associations between variables reference to “start of dialysis” and outcomes. Quality assessment and bias assessment were performed by the Newcastle–Ottawa scale and the ROBINSI tool. Due to the heterogeneity of studies, a meta-analysis could not be performed.

Results

Thirteen studies were included; four studies included only haemodialysis patients, three peritoneal dialysis, six both; study outcomes included mortality, cardiovascular events, technique failure, quality of life and others. Nine studies mainly focused on the optimal GFR of maintenance dialysis initiation; five studies showed none association between GFR and mortality or other adverse outcomes, two studies showed dialysis initiation at higher GFR levels were with poor prognosis, and 2 studies showed higher GFR levels with better prognosis. Three studies paid attention to comprehensive assessment of uremic signs and/or symptoms for optimal dialysis initiation; uremic burden based on 7 uremic indicators (hemoglobin, serum albumin, blood urea nitrogen, serum creatinine, potassium, phosphorus, and bicarbonate) were not associated with mortality; another equation (combination of sex, age, serum creatinine, blood urea nitrogen, serum albumin, haemoglobin, serum phosphorus, diabetes mellitus, and heart failure) based on fuzzy mathematics to assess the timing of haemodialysis initiation was accuracy to prognose 3-year survival; the third study found that volume overload or hypertension was associated with the highest risk for subsequent mortality. Two studies compared urgent or optimal start in dialysis, a study reported increased survival in optimal start patients, another reported no differences between Urgent-Start-PD and Early-Start-PD regarding 6-month outcomes. Limitations: Heterogeneity among the studies was quite high, with differences in sample size, variable and group characteristics; no RCT studies were included, which weakened the strength of evidences.

Conclusions

The criteria for dialysis initiation were varied. Most studies proved that GFR at dialysis initiation was not associated with mortality, timing of dialysis initiation should not be based on GFR, assessments of volume load and patient’s tolerance to volume overload are prospective approaches.
Serum levels of galactose-deficient IgA are elevated in patients with IgA nephropathy but do not correlate to disease activity or progression
Authors: Elíasdóttir Sigridur , Khramova Alina , Saeed Aso , Guron Gregor , Boi Roberto , Mölne Johan , Ebefors Kerstin , Nyström Jenny
Published: June 2023

Introduction

IgA nephropathy (IgAN) is the most common glomerulonephritis globally. Because of the heterogeneity of the disease prognostic biomarkers are highly needed.

Aim

To investigate associations between galactose-deficient IgA1 (Gd-IgA1) concentrations in plasma and urine and disease activity and progression in patients with IgAN.

Methods

Serum and urine samples were collected at the time of kidney biopsy (baseline) in patients with IgAN (n = 40) and analysed for Gd-IgA1. Patients with chronic kidney disease (CKD) without IgAN (n = 21) and healthy controls (n = 19) were examined as controls. In 19 patients with IgAN, analyses of Gd-IgA1 were repeated after a median follow up time of approximately 10 years.

Results

Serum Gd-IgA1 and Gd-IgA1:IgA were significantly elevated at the time of kidney biopsy in patients with IgAN compared to patients with non-IgAN CKD and healthy controls (p < 0.001). Urinary Gd-IgA1:creatinine was significantly elevated in patients with IgAN compared to patients with non-IgAN CKD. Neither serum Gd-IgA1, nor serum Gd-IgA1:IgA, correlated significantly to estimated GFR, urine albumin:creatinine (UACR), or blood pressure, at baseline. Serum Gd-IgA1 and Gd-IgA1:IgA at time of biopsy did not correlate significantly to annual changes in eGFR or UACR during follow up. In patients with IgAN, serum Gd-IgA1 decreased significantly over time during approximately 10 years of follow up (Δ-20 ± 85%, p = 0.027). Urinary Gd-IgA1:creatinine showed a strong positive correlation to UACR in patients with IgAN and likely reflected unspecific glomerular barrier injury.

Conclusion

Although serum Gd-IgA1 and the Gd-IgA1:IgA ratio were significantly elevated in patients with IgAN at the time of kidney biopsy they were not related to disease activity or progression in this patient cohort.
Age affects the diagnostic accuracy of the cancer ratio for malignant pleural effusion
Authors: Huang Jin-Hong , Chen Hong , Zhang Zhi-Cheng , Gu Jie , Yan Li , Jiang Meng-Ping , Zheng Wen-Qi , Hu Zhi-De , Jiang Ting-Wang
Published: June 2023

Background and objective

Cancer ratio (CR), which is defined as serum lactate dehydrogenase (LDH) to pleural fluid adenosine deaminase (ADA) ratio, has been reported to be a useful diagnostic marker for malignant pleural effusion (MPE). Whether its diagnostic accuracy is affected by age remains unknown. This study aimed to investigate the effects of age on the diagnostic accuracy of CR.

Methods

The participants in this study were from a prospective cohort (SIMPLE cohort, n = 199) and a retrospective cohort (BUFF cohort, n = 158). All participants were patients with undiagnosed pleural effusion (PE). We used receiver operating characteristic (ROC) curves to evaluate the diagnostic accuracy of CR. The effect of age on the diagnostic accuracy of CR was investigated by adjusting the upper limit of age for participant enrolment.

Results

Eighty-eight MPE patients were verified in the SIMPLE cohort, and thirty-five MPE patients were verified in the BUFF cohort. The AUCs of CR in the SIMPLE and BUFF cohorts were 0.60 (95% CI: 0.52–0.68) and 0.63 (95% CI: 0.54–0.71), respectively. In both cohorts, the AUCs of CR decreased with the advancement of age.

Conclusion

Age can affect the diagnostic accuracy of CR for MPE. CR has limited diagnostic value in older patients.

Key message

Cancer ratio is a promising diagnostic marker for malignant pleural effusion.

This study revealed that its diagnostic accuracy decreased in older patients.

Its diagnostic accuracy is overestimated by previous studies using tuberculosis and pneumonia patients as controls.
Trajectory of bolt and length of plate in femoral neck system determine the stability of femur neck fracture and risk of subsequent subtrochanteric fracture : a finite element analysis
Authors: Jung Chang-Ho , Cha Yonghan , Chung Jun Young , Park Chan Ho , Kim Tae Young , Yoo Jun-Il , Kim Jung-Taek , Jeon Yongho
Published: June 2023

Background

This study aimed to analyze the differences in the stability of fractures, stress distribution around the distal-most screw according to the length of the plate and the trajectory of the bolt in Pauwels type III femoral neck fracture using the femoral neck system (FNS).

Methods

Finite element models of Pauwels type III femoral neck fractures were established with surgical variations in the trajectory of the bolt (central, inferior, valgus, and varus) and length of the lateral plate (1- and 2-hole plate). The models were subsequently subjected to normal walking and stair-climbing loads.

Results

The screw-holding cortical bone in subtrochanter in the model with a 2-hole plate and the bolt in the inferior trajectory and the models with 1-hole or 2-hole plate and the bolt in valgus trajectory had shown greater maximum principal strain than the models with central or varus trajectories. The gap and sliding distance on the fracture surface were larger with inferior or varus trajectories of the bolt and smaller with the valgus trajectory of the bolt under both loads, compared to those of the central trajectory.

Conclusion

For the fixation of Pauwels type III femoral neck fracture, the trajectory of the FNS bolt and the length of the plate affect the mechanical stability of the fracture and the strain of cortical bone around the distal-most screw. The surgical target should stay on the central trajectory of the bolt and the 2-hole plate’s mechanical benefits did not exceed the risk.
Short-term outcomes of robotic versus open hepatectomy among overweight patients with hepatocellular carcinoma: a propensity score-matched study
Authors: Lin Zhao-Yi , Zhang Xiu-Ping , Zhao Guo-Dong , Li Cheng-Gang , Wang Zhao-Hai , Liu Rong , Hu Ming-Gen
Published: June 2023

Background

Robotic hepatectomy (RH) has gradually been accepted as it has overcome some of the limitations of open hepatectomy (OH). This study was to compare short-term outcomes in RH and OH for overweight (preoperative body mass index ≥ 25 kg/m²) patients with hepatocellular carcinoma (HCC).

Methods

Perioperative and postoperative data from these patients who underwent RH or OH between January 2010 and December 2020 were retrospectively analyzed. Propensity score matching (PSM) analysis was performed to determine the impact of RH versus OH on the prognosis of overweight HCC patients.

Results

All 304 overweight HCC patients were included, 172 who were underwent RH, and 132 who were underwent OH. After the 1:1 PSM, there were 104 patients in both RH and OH groups. After PSM, the RH group of patients had a shorter operative time, less estimated blood loss (EBL), a longer total clamping time, a shorter postoperative length of stay (LOS), less chance of surgical site infection and less rates of blood transfusion (all P < 0.05) compared to the OH patients. The differences between operative time, EBL and LOS were more significant in obese patients. RH was found to be an independent protective factor of EBL ≥ 400ml relative to OH in overweight patients for the first time.

Conclusions

RH was safe and feasible in overweight HCC patients. Compared with OH, RH has advantages in terms of operative time, EBL, postoperative LOS, and surgical site infection. Carefully selected overweight patients should be considered for RH.
A better interpretation of data regarding the opioid switching to methadone
Authors: Mercadante Sebastiano
Published: June 2023

In a recent study methadone has been reported more effective witha 3-day switch (3DS) was more effective than the stop and go strategy (SAG). Many shorcomings, however, are of concerns. The poor selection fo patients with low level of pain intensity, the incomprehensibile choice of of SAG or 3DS, and considerations reported in a previous controlled study with evident methodological limits, make their conclusion inaccurate. Controlled studies are fundamental in research. However, a pragmatic approach reflecting daily practice should be carefully taken into consideration. A more flexible use of SAG strategy and strict clinical observation to change doses according to the clinical response may provide the optimal treatment in patients receiving high doses of opioids.
Assessing the implementation of nurse practitioner-led huddles in long-term care using the Consolidated Framework for Implementation Research (CFIR)
Authors: Wills Aria , Krassikova Alexandra , Keatings Margaret , Escrig-Pinol Astrid , Bethell Jennifer , McGilton Katherine S.
Published: June 2023

Background

The COVID-19 pandemic created major challenges in long-term care (LTC) homes across Canada and globally. A nurse practitioner-led interdisciplinary huddle intervention was developed to support staff wellbeing in two LTC homes in Ontario, Canada. The objective of this study was to identify the constructs strongly influencing the process of implementation of huddles across both sites, capturing the overall barriers and facilitators and the intervention’s intrinsic properties.

Methods

Nineteen participants were interviewed about their experiences, pre-, post-, and during huddle implementation. The Consolidated Framework for Implementation Research (CFIR) was used to guide data collection and analysis. CFIR rating rules and a cross-comparison analysis was used to identify differentiating factors between sites. A novel extension to the CFIR analysis process was designed to assess commonly influential factors across both sites.

Results

Nineteen of twenty selected CFIR constructs were coded in interviews from both sites. Five constructs were determined to be strongly influential across both implementation sites and a detailed description is provided: evidence strength and quality; needs and resources of those served by the organization; leadership engagement; relative priority; and champions. A summary of ratings and an illustrative quote are provided for each construct.

Conclusion

Successful huddles require long-term care leaders to consider their involvement, the inclusion all team members to help build relationships and foster cohesion, and the integration of nurse practitioners as full-time staff members within LTC homes to support staff and facilitate initiatives for wellbeing. This research provides an example of a novel approach using the CFIR methodology, extending its use to identify significant factors for implementation when it is not possible to compare differences in success.
Aptamer functionalized nucleic acid nano drug for targeted synergistic therapy for colon cancer
Authors: Zhu Liye , Yuhan Jieyu , Yu Hao , Zhang Boyang , Zhu Longjiao , He Xiaoyun , Huang Kunlun , Xu Wentao
Published: June 2023

Due to its complicated pathophysiology, propensity for metastasis, and poor prognosis, colon cancer is challenging to treat and must be managed with a combination of therapy. Using rolling circle transcription (RCT), this work created a nanosponge therapeutic medication system (AS1411@antimiR-21@Dox). Using the AS1411 aptamer, this approach accomplished targeted delivery to cancer cells. Furthermore, analysis of cell viability, cell apoptosis, cell cycle arrest, reactive oxygen species (ROS) content, and mitochondrial membrane potential (MMP) levels revealed that functional nucleic acid nanosponge drug (FND) can kill cancer cells. Moreover, transcriptomics uncovered a putative mechanism for the FND anti-tumor effect. These pathways, which included mitotic metaphase and anaphase as well as the SMAC-mediated dissociation of the IAP: caspase complexes, were principally linked to the cell cycle and cell death. In conclusion, by triggering cell cycle arrest and apoptosis, the nano-synergistic therapeutic system allowed for the intelligent and effective targeted administration of RNA and chemotherapeutic medicines for colon cancer treatment. The system allowed for payload efficiency while being customizable, targeted, reliable, stable, and affordable.
Characterization of chimeric antigen receptor modified T cells expressing scFv-IL-13Rα2 after radiolabeling with 89Zirconium oxine for PET imaging
Authors: Leland Pamela , Kumar Dhiraj , Nimmagadda Sridhar , Bauer Steven R. , Puri Raj K. , Joshi Bharat H.
Published: June 2023

Background

Chimeric antigen receptor (CAR) T cell therapy is an exciting cell-based cancer immunotherapy. Unfortunately, CAR-T cell therapy is associated with serious toxicities such as cytokine release syndrome (CRS) and neurotoxicity. The mechanism of these serious adverse events (SAEs) and how homing, distribution and retention of CAR-T cells contribute to toxicities is not fully understood. Enabling in vitro methods to allow meaningful, sensitive in vivo biodistribution studies is needed to better understand CAR-T cell disposition and its relationship to both effectiveness and safety of these products.

Methods

To determine if radiolabelling of CAR-T cells could support positron emission tomography (PET)-based biodistribution studies, we labeled IL-13Rα2 targeting scFv-IL-13Rα2-CAR-T cells (CAR-T cells) with 89Zirconium-oxine (89Zr-oxine) and characterized and compared their product attributes with non-labeled CAR-T cells. The 89Zr-oxine labeling conditions were optimized for incubation time, temperature, and use of serum for labeling. In addition, T cell subtype characterization and product attributes of radiolabeled CAR-T cells were studied to assess their overall quality including cell viability, proliferation, phenotype markers of T-cell activation and exhaustion, cytolytic activity and release of interferon-γ upon co-culture with IL-13Rα2 expressing glioma cells.

Results

We observed that radiolabeling of CAR-T cells with 89Zr-oxine is quick, efficient, and radioactivity is retained in the cells for at least 8 days with minimal loss. Also, viability of radiolabeled CAR-T cells and subtypes such as CD4 + , CD8 + and scFV-IL-13Rα2 transgene positive T cell population were characterized and found similar to that of unlabeled cells as determined by TUNEL assay, caspase 3/7 enzyme and granzyme B activity assay. Moreover, there were no significant changes in T cell activation (CD24, CD44, CD69 and IFN-γ) or T cell exhaustion (PD-1, LAG-3 and TIM3) markers expression between radiolabeled and unlabeled CAR-T cells. In chemotaxis assays, migratory capability of radiolabeled CAR-T cells to IL-13Rα2Fc was similar to that of non-labeled cells.

Conclusions

Importantly, radiolabeling has minimal impact on biological product attributes including potency of CAR-T cells towards IL-13Rα2 positive tumor cells but not IL-13Rα2 negative cells as measured by cytolytic activity and release of IFN-γ. Thus, IL-13Rα2 targeting CAR-T cells radiolabeled with 89Zr-oxine retain critical product attributes and suggest 89Zr-oxine radiolabeling of CAR-T cells may facilitate biodistribution and tissue trafficking studies in vivo using PET.
A quantitative method to measure geranylgeranyl diphosphate (GGPP) and geranylgeranyl monophosphate (GGP) in tomato (Solanum lycopersicum) fruit
Authors: Zita Wayne , Shanmugabalaji Venkatasalam , Ezquerro Miguel , Rodriguez-Concepcion Manuel , Kessler Felix , Glauser Gaetan
Published: June 2023

Background

Isoprenoids are a very large class of metabolites playing a key role in plant physiological processes such as growth, stress resistance, fruit flavor, and color. In chloroplasts and chromoplasts, the diterpene compound geranylgeranyl diphosphate (GGPP) is the metabolic precursor required for the biosynthesis of tocopherols, plastoquinones, phylloquinone, chlorophylls, and carotenoids. Despite its key role for the plant metabolism, reports on GGPP physiological concentrations in planta have been extremely scarce.

Results

In this study, we developed a method to quantify GGPP and its hydrolysis product geranylgeranyl monophosphate (GGP) from tomato fruit, using ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC–MS/MS). Quantification was done by external calibration and the method was validated in terms of specificity, precision, accuracy, and detection and quantitation limits. We further demonstrate the validity of our approach by analysing GGPP contents in the ripe fruits of wild-type tomatoes and mutants defective in GGPP production. Finally, we also show that the sample preparation is key to prevent GGPP hydrolysis and mitigate its conversion to GGP.

Conclusion

Our study provides an efficient tool to investigate the metabolic fluxes required for GGPP supply and consumption in tomato fruit.
Technical guidelines for risk assessment of heavy metals in traditional Chinese medicines
Authors: Zuo Tian-Tian , Zhang Lei , Wang Ying , Nie Li-Xing , Shen Ming-Rui , Liu Li-Na , Yu Jian-Dong , Jin Hong-Yu , Wei Feng , Ma Shuang-Cheng
Published: June 2023

Background

Heavy metals are considered a global concern because they can deteriorate human health. This guideline aims to scientifically evaluate health risk of heavy metals in TCM and to propose a reference for decision making in developing TCM-related health policies.

Methods

Using a multidisciplinary approach, a steering committee oversaw the development of the guideline. To obtain a reasonable and accurate risk assessment, key exposure assessment parameters for TCM, e.g., exposure frequency (EF), exposure duration (ED), and daily ingestion rate (IR) were obtained from surveys. In addition, transfer rates for heavy metals from Chinese medicinal materials (CMM) to decoctions or preparations were examined.

Results

Based on the scientific theory of risk control, the guideline was designed systematically, and principles and procedures for the risk assessment of heavy metals in TCM were identified. The guideline can be utilized to assess the risk of heavy metals in CMM and Chinese patent medicines (CPM).

Conclusion

This guideline may help standardize the risk assessment of heavy metals in TCM, advance regulatory standards for heavy metals in TCM, and ultimately improve human health through scientific TCM usage in clinic.
Prevalence and influencing factors of sleep disorders among preschool children in Urumqi city: a cross-sectional survey
Authors: Gao Yongwei , Xu Peiru , Aizetiguli Maiming , Surong Shan , Zhu Zhaoxuan , Zhang Jing
Published: June 2023

Background

Sleep disorders refer to physiological and psychological states that cause adverse consequences due to the inability to fall asleep or poor sleep quality. The prevalence of sleep disorders varies greatly in different countries and regions due to different causes. This study aimed to investigate the prevalence and influencing factors of sleep disorders among preschool children in Urumqi city, China.

Methods

A cross-sectional study was conducted with stratified random cluster sampling. Children aged 3–6 years old in one kindergarten randomly selected from each of the 8 districts of Urumqi from March to July 2022, and their parents were surveyed with a sleep quality questionnaire.

Results

The prevalence of sleep disorders among preschool children in Urumqi was 14.29% (191/1336), and the prevalence of different symptoms was 42.81% for limb movements, 19.61% for snoring, 18.11% for bruxism, 16.39% for sleep talking, 12.57% for sweating, 11.60% for nocturnal awakening, 8.46% for nightmares, 6.89% for bed wetting, 3.74% for apnea, and 3.29% for sleepwalking. The prevalence of body movements, snoring, sweating, night-wake, nightmares, bed-wetting, apnea, and sleepwalking among different ethnicities were significantly different (P < 0.05). Multivariate analysis revealed that the major risk factors of sleep disorders were difficulty adapting to new environments, unwillingness to express emotions, inconsistent attitudes of the family toward children’s education, running before bedtime, strict family education methods, etc.

Conclusion

The prevalence of sleep disorders in preschool children in Urumqi is lower than the average level reported in other studies. Many factors affect the prevalence of sleep disorders in preschool children, but it is necessary to focus on the ability to adapt to new environments, psychological problems, and the impact of family education on sleep disorders. Further studies on the prevention and treatment of sleep disorders are needed for different ethnicities.
Anticoagulation options for continuous renal replacement therapy in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials
Authors: Zhou Zhifeng , Liu Chen , Yang Yingying , Wang Fang , Zhang Ling , Fu Ping
Published: June 2023

Background

Continuous renal replacement therapy (CRRT) is a widely used standard therapy for critically ill patients with acute kidney injury (AKI). Despite its effectiveness, treatment is often interrupted due to clot formation in the extracorporeal circuits. Anticoagulation is a crucial strategy for preventing extracorporeal circuit clotting during CRRT. While various anticoagulation options are available, there were still no studies synthetically comparing the efficacy and safety of these anticoagulation options.

Methods

Electronic databases (PubMed, Embase, Web of Science, and the Cochrane database) were searched from inception to October 31, 2022. All randomized controlled trials (RCTs) that examined the following outcomes were included: filter lifespan, all-cause mortality, length of stay, duration of CRRT, recovery of kidney function, adverse events and costs.

Results

Thirty-seven RCTs from 38 articles, comprising 2648 participants with 14 comparisons, were included in this network meta-analysis (NMA). Unfractionated heparin (UFH) and regional citrate anticoagulation (RCA) are the most frequently used anticoagulants. Compared to UFH, RCA was found to be more effective in prolonging filter lifespan (MD 12.0, 95% CI 3.8 to 20.2) and reducing the risk of bleeding. Regional-UFH plus Prostaglandin I2 (Regional-UFH + PGI2) appeared to outperform RCA (MD 37.0, 95% CI 12.0 to 62.0), LMWH (MD 41.3, 95% CI 15.6 to 67.0), and other evaluated anticoagulation options in prolonging filter lifespan. However, only a single included RCT with 46 participants had evaluated Regional-UFH + PGI2. No statistically significant difference was observed in terms of length of ICU stay, all-cause mortality, duration of CRRT, recovery of kidney function, and adverse events among most evaluated anticoagulation options.

Conclusions

Compared to UFH, RCA is the preferred anticoagulant for critically ill patients requiring CRRT. The SUCRA analysis and forest plot of Regional-UFH + PGI2 are limited, as only a single study was included. Additional high-quality studies are necessary before any recommendation of Regional-UFH + PGI2. Further larger high-quality RCTs are desirable to strengthen the evidence on the best choice of anticoagulation options to reduce all-cause mortality and adverse events and promote the recovery of kidney function.

Trial registration The protocol of this network meta-analysis was registered on PROSPERO (CRD42022360263). Registered 26 September 2022.
Lymphocyte activation gene 3 is increased and affects cytokine production in rheumatoid arthritis
Authors: Pedersen Janni Maria , Hansen Aida Solhøj , Skejø Cæcilie , Juul-Madsen Kristian , Junker Peter , Hørslev-Petersen Kim , Hetland Merete Lund , Stengaard-Pedersen Kristian , Østergaard Mikkel , Møller Bjarne Kuno , Dreyer Lene , Hauge Ellen-Margrethe , Hvid Malene , Greisen Stinne , Deleuran Bent
Published: June 2023

Background

Lymphocyte activation gene-3 (LAG-3) inhibits T cell activation and interferes with the immune response by binding to MHC-II. As antigen presentation is central in rheumatoid arthritis (RA) pathogenesis, we studied aspects of LAG-3 as a serological marker and mediator in the pathogenesis of RA. Since Galectin-3 (Gal-3) is described as an additional binding partner for LAG-3, we also aimed to study the functional importance of this interaction.

Methods

Plasma levels of soluble (s) LAG-3 were measured in early RA patients (eRA, n = 99) at baseline and after 12 months on a treat-to-target protocol, in self-reportedly healthy controls (HC, n = 32), and in paired plasma and synovial fluid (SF) from chronic RA patients (cRA, n = 38). Peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) were examined for LAG-3 expression by flow cytometry. The binding and functional outcomes of LAG-3 and Gal-3 interaction were assessed with surface plasmon resonance (SPR) and in cell cultures using rh-LAG3, an antagonistic LAG-3 antibody and a Gal-3 inhibitor.

Results

Baseline sLAG-3 in the plasma was increased in eRA compared to HC and remained significantly elevated throughout 12 months of treatment. A high level of sLAG-3 at baseline was associated with the presence of IgM-RF and anti-CCP as well as radiographic progression. In cRA, sLAG-3 was significantly increased in SF compared with plasma, and LAG-3 was primarily expressed by activated T cells in SFMCs compared to PBMCs. Adding recombinant human LAG-3 to RA cell cultures resulted in decreased cytokine secretion, whereas blocking LAG-3 with an antagonistic antibody resulted in increased cytokine secretion. By SPR, we found a dose-dependent binding between LAG-3 and Gal-3. However, inhibiting Gal-3 in cultures did not further change cytokine production.

Conclusions

sLAG-3 in the plasma and synovial fluid is increased in both early and chronic RA patients, particularly in the inflamed joint. High levels of sLAG-3 are associated with autoantibody seropositivity and radiographic progression in eRA, and LAG-3 plays a biologically active role in cRA by decreasing inflammatory cytokine production. This functional outcome is not affected by Gal-3 interference. Our results suggest that LAG-3 is a faceted regulator of inflammation in early and chronic RA.
Endometrium-derived mesenchymal stem cells suppress progression of endometrial cancer via the DKK1-Wnt/β-catenin signaling pathway
Authors: Xu Yuhui , Hu Jiali , Lv Qiaoying , Shi Chenyi , Qiu Mengdi , Xie Liying , Liu Wei , Yang Bingyi , Shan Weiwei , Cheng Yali , Zhao Bing , Chen Xiaojun
Published: June 2023

Background

Mesenchymal stem cell (MSC) therapy is an attractive treatment option for various cancers. Whether MSCs can be used to treat well-differentiated endometrial cancer (EC) remains unclear. The aim of this study is to explore the potential therapeutic effects of MSCs on EC and the underlying mechanisms.

Methods

The effects of adipose-derived MSCs (AD-MSCs), umbilical-cord-derived MSCs (UC-MSCs), and endometrium-derived MSCs (eMSCs) on the malignant behaviors of EC cells were explored via in vitro and in vivo experiments. Three EC models, including patient-derived EC organoid lines, EC cell lines, and EC xenograft model in female BALB/C nude mice, were used for this study. The effects of MSCs on EC cell proliferation, apoptosis, migration, and the growth of xenograft tumors were evaluated. The potential mechanisms by which eMSCs inhibit EC cell proliferation and stemness were explored by regulating DKK1 expression in eMSCs or Wnt signaling in EC cells.

Results

Our results showed that eMSCs had the highest inhibitory effect on EC cell viability, and EC xenograft tumor growth in mice compared to AD-MSCs and UC-MSCs. Conditioned medium (CM) obtained from eMSCs significantly suppressed the sphere-forming ability and stemness-related gene expression of EC cells. In comparison to AD-MSCs and UC-MSCs, eMSCs had the highest level of Dickkopf-related protein 1 (DKK1) secretion. Mechanistically, eMSCs inhibited Wnt/β-catenin signaling in EC cells via secretion of DKK1, and eMSCs suppressed EC cell viability and stemness through DKK1-Wnt/β-catenin signaling. Additionally, the combination of eMSCs and medroxyprogesterone acetate (MPA) significantly inhibited the viability of EC organoids and EC cells compared with eMSCs or MPA alone.

Conclusions

The eMSCs, but not AD-MSCs or UC-MSCs, could suppress the malignant behaviors of EC both in vivo and in vitro via inhibiting the Wnt/β-catenin signaling pathway by secreting DKK1. The combination of eMSCs and MPA effectively inhibited EC growth, indicating that eMSCs may potentially be a new therapeutic strategy for young EC patients desiring for fertility preservation.
The global antimicrobial resistance response effort must not exclude marginalised populations
Authors: Adebisi Yusuff Adebayo , Ogunkola Isaac Olushola
Published: June 2023

Antimicrobial resistance (AMR), a rising global health crisis causing about 700,000 deaths annually and potentially 10 million deaths by 2050, disproportionately impacts marginalised populations. Due to socioeconomic, ethnic, geographic, and other barriers, these communities often have restricted healthcare access, compounding the AMR threat. Unequal access to effective antibiotics, inadequate living conditions, and a lack of awareness exacerbate the crisis in marginalised communities, making them more susceptible to AMR. A broader, inclusive response is needed to ensure equitable access to antibiotics, improved living conditions, education, and policy changes to challenge the root socio-economic disparities. Ignoring marginalised populations in the fight against AMR is both a moral and strategic failure. Therefore, inclusivity must be a central tenet in combating AMR. This article not only critically dissects this prevailing oversight but also urgently calls for comprehensive action to address this significant shortcoming in our response efforts.
Blame or discovery? Walter Benjamin's Jetztzeit, Purdue Pharma LP and ‘our values and our historical understanding of psychiatrists’
Authors: Ikkos George
Published: June 2023

This commentary explores issues of professional identity, fairness and discovery in the history of psychiatry in the light of Walter Benjamin's (1892–1940) philosophy of history, especially his concept of Jetztzeit (now-time) and the profession's relationship with the founder and owners of Purdue Pharma LP.
A randomised phase II multicentre study of ipilimumab with temozolomide vs temozolomide alone after surgery and chemoradiotherapy in patients with recently diagnosed glioblastoma: Ipi-Glio.
Authors: Mulholland Paul James , Brown Nicholas Fraser , McBain Catherine , Brazil Lucy , Peoples Sharon , Jefferies Sarah , Harris Fiona , Plaha Puneet , Vinayan Anup , Brooks Claire , Hussain Samia , Dutton Susan J. , Ng Stasya , Levy Stephanie , Coutts Timothy
Published: June 2023

LBA2023

Background: Median survival for patients with glioblastoma is less than a year. Standard treatment comprises surgical debulking if feasible followed by temozolomide (TMZ) chemoradiotherapy. The objective of this clinical trial is to evaluate whether the addition of the CTLA-4 immune checkpoint inhibitor ipilimumab (IPI) improves survival. Methods: Ipi-Glio is an academic phase II, open label, stratified randomised multicentre study of IPI + TMZ (Arm A) vs TMZ alone (Arm B), after surgery and radical radiotherapy with concomitant temozolomide in patients with recently diagnosed de-novo glioblastoma. Following completion of chemoRT, patients were randomised 2:1 Arm A:B, with stratification to extent of surgery and MGMT promotor methylation. IPI 3mg/kg was administered q3/52 for 4 cycles, and TMZ 150-200mg/m2 days 1-5 q4/52 for 6 cycles. Primary outcome was overall survival (OS), treatment difference reported as hazard ratio (HR) with 60% confidence intervals (CI) and OS at 18 months. Secondary outcomes were progression-free Survival (PFS) and safety. Results: 119 patients were randomly assigned, 79 to Arm A and 40 to Arm B, at seven centres in the UK between Jan 2019 and April 2021. Patient characteristics (Arm A vs B): median Age 53 vs 48 years; male sex 70% vs 65%; ECOG PS0 70 vs 70%, PS1 30 vs 30%; MGMT promotor methylation 39% vs 40%; IDH mutation 11% vs 10%; surgical gross total resection 61% vs 60%. PFS (Arm A vs B): median PFS 10.9 months (m) vs 12.5mo, HR 1.252 (60%CI 1.01-1.54, p=0.369); 18m PFS 22% (60%CI 17-27%) vs 43% (34-51%). Overall Survival (Arm A vs B): median OS 22.7 vs 26.4 months, HR 1.223 (60% CI 0.986-1.516, p=0.431); 18 month OS 53% (60%CI 48-58%) vs 64% (56-70%). Adverse events (AE) reported by CTCAE grade (Arm A vs B): total reported AEs 1058 vs 329; no. of reported AEs per patient: mean 13.5 (SD 10.1) vs mean 8.2 (SD 7.3). Conclusions: No improvement in PFS or OS was observed with the addition of ipilimumab to temozolomide. This study does not support further investigation of this regimen in this setting. Clinical trial information: ISRCTN84434175 .
Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: 7-year results of PRODIGE 23 phase III trial, a UNICANCER GI trial.
Authors: Conroy Thierry , Etienne Pierre-Luc , Rio Emmanuel , Evesque Ludovic , Mesgouez-Nebout Nathalie , Vendrely Veronique , Artignan Xavier , Bouche Olivier , Boileve Alice , Delaye Matthieu , Gargot Dany , Boige Valerie , Bonichon-Lamichhane Nathalie , Louvet Christophe , De La Fouchardiere Christelle , Morand Clotilde , Pezzella Veronica , Rullier Eric , Castan Florence , Borg Christophe
Published: June 2023

LBA3504

Background: We have reported that neoadjuvant chemotherapy (NACT) with FOLFIRINOX followed by chemoradiotherapy (CRT), surgery, and adjuvant chemotherapy (ACT) significantly improved outcomes in patients (pts) with locally advanced rectal cancer (LARC) compared with pts who received standard CRT, surgery, and ACT. We now report the primary and secondary endpoints with mature follow-up (F/U). Methods: PRODIGE 23 is a phase III randomized clinical trial. Eligible pts had cT3 or cT4, M0 rectal adenocarcinomas <15 cm from the anal verge, age 18-75 years, and WHO PS ≤1. Randomization was stratified by center, T stage, N status, T location, and T extramural spread. Arm A pts received preoperative CRT (50 Gy, 2 Gy/fr; 25 fr + capecitabine), surgery, then ACT for 6 months (mos). Arm B pts received 6 cycles of mFOLFIRINOX, then the same preoperative CRT, surgery and 3 mos of ACT, mFOLFOX6 or capecitabine. From 6/2012 to 6/2017, pts were randomly assigned in Arm A (n=230) and B (n=231) by 35 participating centers. Analysis was performed on intent-to-treat population. For survival outcomes, HR and 95% CI were estimated by a stratified Cox proportional hazard (PH) model. However, we observed non-PH. So we used the restricted mean survival time (RMST) to evaluate the treatment effect (Liang F & al Ann Oncol 2018, Pak K & al JAMA Oncol 2017). Results: With a median F/U of 82.2 mos, death was reported for 55 pts in arm A and 42 in Arm B. All survival endpoints were better for Arm B vs Arm A. The absolute increase in 5-year survival were 7.6% for Disease-Free Survival (DFS), 6.9% for Overall Survival (OS), 9.9% for Metastasis-Free Survival (MFS), and 5.7% for Cancer Specific Survival (CSS) in Arm B compared to Arm A. Survival results at 7 years are presented in the Table. 7-year cumulative incidence of locoregional relapses are 5.3% in arm B vs 8.1% in arm A (p= 0.38). Conclusions: NACT with mFOLFIRINOX followed by CRT, surgery, and ACT significantly improved all outcomes, including OS in pts with LARC vs those who received standard CRT, surgery, and ACT. Clinical trial information: NCT01804790 . [Table: see text]