bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of second primary malignancy post–autologous transplantation on outcomes of multiple myeloma: a CIBMTR analysis
Authors: Ragon Brittany Knick , Shah Mithun Vinod , D’Souza Anita , Estrada-Merly Noel , Gowda Lohith , George Gemlyn , de Lima Marcos , Hashmi Shahrukh , Kharfan-Dabaja Mohamed A. , Majhail Navneet S. , Banerjee Rahul , Saad Ayman , Hildebrandt Gerhard C. , Mian Hira , Abid Muhammad Bilal , Battiwalla Minoo , Lekakis Lazaros J. , Patel Sagar S. , Murthy Hemant S. , Nieto Yago , Strouse Christopher , Badawy Sherif M. , Al Hadidi Samer , Dholaria Bhagirathbhai , Aljurf Mahmoud , Vesole David H. , Lee Cindy H. , Pawarode Attaphol , Gergis Usama , Miller Kevin C. , Holmberg Leona A. , Afrough Aimaz , Solh Melhem , Munshi Pashna N. , Nishihori Taiga , Anderson Larry D. , Wirk Baldeep , Kaur Gurbakhash , Qazilbash Muzaffar H. , Shah Nina , Kumar Shaji K. , Usmani Saad Z.
Published: February 2023

The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post–auto-HSCT.
BRASD trial: biomechanical reposition techniques in anterior shoulder dislocation—a randomized multicenter clinical trial
Authors: Baden David N. , Roetman Martijn H. , Boeije Tom , Mullaart Nieke , Boden Ralph , Houwert Roderick M. , Heng Marilyn , Groenwold Rolf H. H. , van der Meijden Olivier A. J.
Published: February 2023

Background

Biomechanical reduction techniques for shoulder dislocations have demonstrated high reduction success rates with a limited pain experience for the patient. We postulated that the combination of biomechanical reduction techniques with the shortest length of stay would also have the lowest pain experience and the highest first reduction success rate.

Methods

A randomized multicenter clinical trial was performed to compare different biomechanical reduction techniques in treating anterior shoulder dislocations without the use of invasive pain relief. Patients who were able to perform adduction of the arm were randomly assigned to Cunningham, the modified Milch, and the scapular manipulation technique. Those who were not able to do so were randomly assigned to modified Milch and the scapular manipulation technique. Primary outcomes were emergency department length of stay and pain experienced during the reduction process, measured by the numeric pain rating scale. Secondary outcomes were reduction time, reduction success, use of analgesics or sedatives, and complications.

Results

Three hundred eight patients were included, of whom 134 were in the adduction group. In both groups, no differences in emergency department length of stay and experienced pain were observed between the treatment arms. In the adduction group, the modified Milch technique had the highest first reduction success rates 52% (p = 0.016), within protocol 61% (p = 0.94), and with sedation in the ED 100% ( −). In the no-adduction group, the modified Milch was also the most successful primary reduction technique with 51% success (p = 0.040), within protocol 66% (p = 0.90), and with sedation in the ED 98% (p = 0.93). No complications were recorded in any of the techniques.

Conclusion

A combination of biomechanical techniques resulted in a similar length of stay in the emergency department and showed similar pain scores with an overall high success rate of reduction. In both groups, the modified Milch had the highest first-reduction success rate.

Trial registration

Netherlands Trial Register NTR5839—1 April 2016. Ethical committee Noord-Holland with the CCMO-number NL54173.094.15
The role of high serum triglyceride levels on pancreatic necrosis development and related complications
Authors: Hidalgo Nils Jimmy , Pando Elizabeth , Alberti Piero , Mata Rodrigo , Fernandes Nair , Adell Montse , Villasante Sara , Blanco Laia , Balsells Joaquim , Charco Ramon
Published: February 2023

Background

The relevance of elevated serum triglyceride (TG) levels in the early stages of acute pancreatitis (AP) not induced by hypertriglyceridemia (HTG) remains unclear. Our study aims to determine the role of elevated serum TG levels at admission in developing pancreatic necrosis.

Methods

We analyzed the clinical data collected prospectively from patients with AP. According to TG levels measured in the first 24 h after admission, we stratified patients into four groups: Normal TG (< 150 mg/dL), Borderline-high TG (150–199 mg/dL), High TG (200–499 mg/dL) and Very high TG (≥ 500 mg/dL). We analyzed the association of TG levels and other risk factors with the development of pancreatic necrosis.

Results

A total of 211 patients were included. In the Normal TG group: 122, in Borderline-high TG group: 38, in High TG group: 44, and in Very high TG group: 7. Pancreatic necrosis developed in 29.5% of the patients in the Normal TG group, 26.3% in the Borderline-high TG group, 52.3% in the High TG group, and 85.7% in the Very high TG group. The trend analysis observed a significant association between higher TG levels and pancreatic necrosis (p = 0.001). A multivariable analysis using logistic regression showed that elevated TG levels ≥ 200 mg/dL (High TG and Very high TG groups) were independently associated with pancreatic necrosis (OR: 3.27, 95% CI − 6.27, p < 0.001).

Conclusions

An elevated TG level at admission ≥ 200 mg/dl is independently associated with the development of pancreatic necrosis. The incidence of pancreatic necrosis increases proportionally with the severity of HTG.
A multicenter evaluation of antibacterial use in hospitalized patients through the SARS-Cov-2 pandemic waves
Authors: Puzniak Laura A. , Bauer Karri A. , Yu Kalvin C. , Watts Janet A. , Ai ChinEn , Gupta Vikas
Published: February 2023

Background

Excessive use of antibiotics has been reported during the SARS-CoV-2 pandemic. We evaluated trends in antibiotic use and culture positive Gram-negative (GN)/Gram-positive (GP) pathogens in US hospitalized patients before and during the SARS-CoV-2 pandemic.

Methods

This multicenter, retrospective study included patients from 271 US facilities with > 1-day inpatient admission with discharge or death between July 1, 2019, and October 30, 2021, in the BD Insights Research Database. We evaluated microbiological testing data, antibacterial use, defined as antibacterial use ≥ 24 h in admitted patients, and duration of antibacterial therapy.

Results

Of 5,518,744 patients included in the analysis, 3,729,295 (67.6%) patients were hospitalized during the pandemic with 2,087,774 (56.0%) tested for SARS-CoV-2 and 189,115 (9.1%) testing positive for SARS-CoV-2. During the pre-pandemic period, 36.2% were prescribed antibacterial therapy and 9.3% tested positive for select GN/GP pathogens. During the SARS-CoV-2 pandemic, antibacterial therapy (57.8%) and positive GN/GP culture (11.9%) were highest in SARS-CoV-2-positive patients followed by SARS-CoV-2-negative patients (antibacterial therapy, 40.1%; GN/GP, pathogens 11.0%), and SARS-CoV-2 not tested (antibacterial therapy 30.4%; GN/GP pathogens 7.2%). Multivariate results showed significant decreases in antibacterial therapy and positive GN/GP cultures for both SARS-CoV-2-positive and negative patients during the pandemic, but no significant overall changes from the pre-pandemic period to the pandemic period.

Conclusions

There was a decline in both antibacterial use and positive GN/GP pathogens in patients testing positive for SARS-CoV-2. However, overall antibiotic use was similar prior to and during the pandemic. These data may inform future efforts to optimize antimicrobial stewardship and prescribing.
Phase II randomized, double blind, placebo controlled, clinical trial of safety and immunogenicity of an inactivated SARS-CoV-2 vaccine FAKHRAVAC in adults aged 18–70 years
Authors: Gholami Fatemeh , Hamidi Farahani Ramin , Karimi Rahjerdi Ahmad , Ahi Mohammadreza , Sheidaei Ali , Gohari Kimiya , Rahimi Zahra , Ansarifar Akram , Basiri Pouria , Moradi Milad , Jahangiri Arash , Naderi Kosar , Ghasemi Soheil , Khatami Pezhman , Honari Mohsen , Khodaverdloo Samane , Shooshtari Mohammad , Mehr Azin Hajar , Moradi Sohrab , Shafaghi Batool , Allahyari Hossein , Monazah Arina , Khodaei Poor Ali , Taghva Zahra , Bakhshande Hooman , Karimi Nia Mohammad , Solaymani Dodaran Masoud , Forooghizade Mohsen
Published: February 2023

Background

The FAKHRAVAC®, an inactivated SARS-CoV-2 vaccine, was assessed for safety and immunogenicity in a phase II trial.

Methods

We did a phase II, single-centered, randomized, double-blind, placebo-controlled clinical trial of the FAKHRAVAC inactivated SARS-CoV-2 vaccine on adults aged 18 to 70. The two parallel groups received two intramuscular injections of either a 10-µg vaccine or a placebo at 2-week intervals. The participants' immunogenicity responses and the occurrence of solicited and unsolicited adverse events were compared over the study period of up to 6 months. Immunogenicity outcomes include serum neutralizing antibody activity and specific IgG antibody levels.

Results

Five hundred eligible participants were randomly (1:1) assigned to vaccine or placebo groups. The median age of the participants was 36 years, and 75% were male. The most frequent local adverse reaction was tenderness (21.29% after the first dose and 8.52% after the second dose), and the most frequent systemic adverse reaction was headache (11.24% after the first dose and 8.94% after the second dose). Neutralizing antibody titers two and four weeks after the second injection in the vaccine group showed about 3 and 6 times increase compared to the placebo group (GMR = 2.69, 95% CI 2.32–3.12, N:309) and (GMR = 5.51, 95% CI 3.94–8.35, N:285). A four-fold increase in the neutralizing antibody titer was seen in 69.6% and 73.4% of the participants in the vaccine group two and four weeks after the second dose, respectively. Specific ELIZA antibody response against a combination of S1 and RBD antigens 4 weeks after the second injection increased more than three times in the vaccine compared to the placebo group (GMR = 3.34, 95% CI 2.5–4.47, N:142).

Conclusions

FAKHRAVAC® is safe and induces a significant humoral immune response to the SARS-CoV-2 virus at 10-µg antigen dose in adults aged 18–70. A phase III trial is needed to assess the clinical efficacy.

Trial registration: Trial Registry Number: Ref., IRCT20210206050259N2 (http://irct.ir; registered on 08/06/2021)
Sepsis following acute pyelonephritis caused by Trueperella bernardiae: a case report and literature review
Authors: Matsuhisa Yuki , Kenzaka Tsuneaki , Kobayashi Shinichiro , Taguchi Jun , Hirose Hideo , Gotoh Tadao
Published: February 2023

Background

Trueperella bernardiae is a coryneform, gram-positive bacterium that is a commensal of the skin and upper respiratory tract. It is treated as a contaminant and rarely causes infections. Blood, urine, and abscesses have been previously reported as the most common sites of infection. Infections caused by T. bernardiae are rarely reported in bedridden very old patients with reduced activities of daily living (ADL). In this report, we describe a case of sepsis due to acute pyelonephritis caused by T. bernardiae in a very old patient with impaired ADL.

Case presentation

A 94-year-old woman had a home visit from her local physician. She was bedridden and used diapers. On the day of admission, she presented with fever and dyspnea and was admitted with a diagnosis of sepsis associated with acute pyelonephritis. T. bernardiae was detected in blood and urine cultures; furthermore, multiple bacteria were detected in a urine culture. She was treated with ampicillin/sulbactam 3 g every 12 h on the day of admission. The fever was controlled, and inhaled oxygen 1 L/min via a nasal cannula was administered for dyspnea until hospitalization day 2. On hospitalization day 2, her fever resolved to 36 °C. Antimicrobials were de-escalated and changed to cephazolin and then to cephalexin on hospitalization days 9 and 16, respectively, and were continued until day 22. On hospitalization day 28, the urinary tract infection flared up; however, her fever resolved by hospitalization day 38 after the re-administration of antimicrobial agents. She was discharged on hospitalization day 60.

Conclusions

We encountered a rare case of sepsis following acute pyelonephritis caused by T. bernardiae infection. When bedridden, diaper-using, very old patients present with urinary tract infections caused by multiple bacteria, the presence of rare opportunistic organisms, such as T. bernardiae, should be considered.
Perceptual and quantitative analysis of discoloration of orthodontic elastomeric chains by food
Authors: Chung Hyun-Joo , Lim Sun-Ah , Lim Ho-Kyung , Jung Seok-Ki
Published: February 2023

Background

The objectives of this study were to use a digital camera to measure the discoloration of orthodontic elastomeric chains in various immersion solutions over different time periods and to determine the valid acceptability tolerances for color changes in orthodontic elastomeric chains by surveying digital photographs.

Methods

Orthodontic elastomeric chains were applied to the maxillary anterior teeth of nine typodont models. The models were divided into three groups and immersed in the curry, coffee, and wine solutions. The digital images of the elastomeric modules were captured and processed using commercial software after 30 min of immersion, thrice a day, for 28 days. The differences in color changes ($$\Delta {\text{E}}$$ΔE), depending on the type of immersion solution and period, were analyzed using a repeated-measures analysis of variance (ANOVA) test. A web-based survey questionnaire was randomly distributed to 50 respondents for a visual analysis of the elastomeric chain discoloration. The relationship between the surveying score and$$\Delta {\text{E}}$$ΔEvalue was analyzed using Spearman’s correlation coefficient. The perceptibility and acceptability of elastomeric chain discoloration ($$\Delta {\text{E}}$$ΔE) based on the type of immersion solutions and periods were analyzed using a regression model.

Results

Significant differences were observed in the discoloration of the elastomeric power chain depending on the immersion solution and period. The amount of discoloration was highest in curry, followed by coffee and wine(P < 0.05). The mean discoloration ($$\Delta {\text{E}}$$ΔE) continued to increase over the entire immersion period. There was a significant correlation between visual scoring and discoloration ($$\Delta {\text{E}}$$ΔE) over the entire period, especially in the early stages compared to the later stages (r = 0.918, P < 0.05). In 50% of the respondents, the predicted clinically unacceptable discoloration was between 4.46 and 9.98 and in 90% of the respondents, it was between 16.52 and 19.85.

Conclusions

The amount of discoloration was the highest for curry, followed by coffee and wine, and continued to gradually increase during the observation period. Significant differences were found between the color measurements obtained and the visual assessment by observers. The observers varied in their tolerance for perceptibility and acceptability for elastomeric chain discoloration based on the type of dietary media.
Change in glycaemic control with structured diabetes self-management education in urban low-resource settings: multicentre randomised trial of effectiveness
Authors: Lamptey Roberta , Amoakoh-Coleman Mary , Barker Mary Moffett , Iddi Samuel , Hadjiconstantinou Michelle , Davies Melanie , Darko Daniel , Agyepong Irene , Acheampong Franklyn , Commey Mary , Yawson Alfred , Grobbee Diederick E. , Adjei George Obeng , Klipstein-Grobusch Kerstin
Published: February 2023

Background

In high-resource settings, structured diabetes self-management education is associated with improved outcomes but the evidence from low-resource settings is limited and inconclusive.

Aim

To compare, structured diabetes self-management education to usual care, in adults with type 2 diabetes, in low-resource settings.

Research design and methods.

Design

Single-blind randomised parallel comparator controlled multi-centre trial.

Adults (> 18 years) with type 2 diabetes from two hospitals in urban Ghana were randomised 1:1 to usual care only, or usual care plus a structured diabetes self-management education program. Randomisation codes were computer-generated, and allotment concealed in opaque numbered envelopes. The intervention effect was assessed with linear mixed models.

Main outcome: Change in HbA1c after 3-month follow-up.

Primary analysis involved all participants.

Clinicaltrial.gov identifier:NCT04780425, retrospectively registered on 03/03/2021.

Results

Recruitment: 22nd until 29th January 2021.

We randomised 206 participants (69% female, median age 58 years [IQR: 49–64], baseline HbA1c median 64 mmol/mol [IQR: 45–88 mmol/mol],7.9%[IQR: 6.4–10.2]). Primary outcome data was available for 79 and 80 participants in the intervention and control groups, respectively. Reasons for loss to follow-up were death (n = 1), stroke(n = 1) and unreachable or unavailable (n = 47). A reduction in HbA1c was found in both groups; -9 mmol/mol [95% CI: -13 to -5 mmol/mol], -0·9% [95% CI: -1·2% to -0·51%] in the intervention group and -3 mmol/mol [95% CI -6 to 1 mmol/mol], -0·3% [95% CI: -0·6% to 0.0%] in the control group. The intervention effect was 1 mmol/mol [95%CI:-5 TO 8 p = 0.726]; 0.1% [95% CI: -0.5, 0.7], p = 0·724], adjusted for site, age, and duration of diabetes.

No significant harms were observed.

Conclusion

In low-resource settings, diabetes self-management education might not be associated with glycaemic control. Clinician’s expectations from diabetes self-management education must therefore be guarded.
A narrative inquiry into healthcare staff resilience and the sustainability of Quality Improvement implementation efforts during Covid-19
Authors: Hughes Spence Shannon , Khurshid Zuneera , Flynn Maureen , Fitzsimons John , De Brún Aoife
Published: February 2023

Background

Recent research, which explored the use of Quality Improvement (QI) methods in the Covid-19 pandemic response, found that Quality Improvement principles were utilised during the crisis management period, albeit without direct intention. Following on from this work, the aim of this paper extends that study by investigating the sustainability and resilience of not only the changes implemented by healthcare staff during Covid-19 in Ireland, but the resilience of the wellbeing of healthcare staff themselves through the various waves of Covid-19.

Methods

To explore healthcare staffs experience of Quality Improvement and the sustainability and resilience of both Quality Improvement initiatives and healthcare staff, a qualitative design was implemented. Semi-structured interviews took place online over Zoom with 11 healthcare staff members from the Irish healthcare service in the Spring of 2022. An analysis of the narratives was conducted using thematic analysis supported by NVivo12.

Results

Four key themes were evident from the data: (i) From fear to exhaustion; (ii) maintaining person-centred approaches to care; (iii) Covid-19 as a medium for change, and; (iv) staff resilience and appetite for Quality Improvement.

Discussion

The results of this work identified three key learnings; (i) integrating learning into policies and practice: (ii) the role of collective leadership and devolving/sharing power; and (iii) key drivers/factors that promote sustainability of QI interventions. Despite the challenges in recruitment of research participants experienced during the pandemic, a narrative approach supported the collation of rich and nuanced insights into the experiences of healthcare staff during this time.

Conclusion

A growing body of literature currently exists on how healthcare staff felt during the Covid-19 pandemic. However, as the waves of Covid-19 have declined, it is vital to examine how the feelings of burnout and disillusionment will affect engagement with Quality Improvement in the future. It is also worth noting and examining the feeling of purpose and pride participants expressed from working through the Covid-19 pandemic. This study has helped to address this gap.
Inheritance of perturbed methylation and metabolism caused by uterine malnutrition via oocytes
Authors: Tang Shou-Bin , Zhang Ting-Ting , Yin Shen , Shen Wei , Luo Shi-Ming , Zhao Yong , Zhang Cui-Lian , Klinger Francesca Gioia , Sun Qing-Yuan , Ge Zhao-Jia
Published: February 2023

Background

Undernourishment in utero has deleterious effects on the metabolism of offspring, but the mechanism of the transgenerational transmission of metabolic disorders is not well known. In the present study, we found that undernourishment in utero resulted in metabolic disorders of female F1 and F2 in mouse model.

Results

Undernutrition in utero induced metabolic disorders of F1 females, which was transmitted to F2 females. The global methylation in oocytes of F1 exposed to undernutrition in utero was decreased compared with the control. KEGG analysis showed that genes with differential methylation regions (DMRs) in promoters were significantly enriched in metabolic pathways. The altered methylation of some DMRs in F1 oocytes located at the promoters of metabolic-related genes were partially observed in F2 tissues, and the expressions of these genes were also changed. Meanwhile, the abnormal DNA methylation of the validated DMRs in F1 oocytes was also observed in F2 oocytes.

Conclusions

These results indicate that DNA methylation may mediate the transgenerational inheritance of metabolic disorders induced by undernourishment in utero via female germline.
There is no such thing as a validated prediction model
Authors: Van Calster Ben , Steyerberg Ewout W. , Wynants Laure , van Smeden Maarten
Published: February 2023

Background

Clinical prediction models should be validated before implementation in clinical practice. But is favorable performance at internal validation or one external validation sufficient to claim that a prediction model works well in the intended clinical context?

Main body

We argue to the contrary because (1) patient populations vary, (2) measurement procedures vary, and (3) populations and measurements change over time. Hence, we have to expect heterogeneity in model performance between locations and settings, and across time. It follows that prediction models are never truly validated. This does not imply that validation is not important. Rather, the current focus on developing new models should shift to a focus on more extensive, well-conducted, and well-reported validation studies of promising models.

Conclusion

Principled validation strategies are needed to understand and quantify heterogeneity, monitor performance over time, and update prediction models when appropriate. Such strategies will help to ensure that prediction models stay up-to-date and safe to support clinical decision-making.
A novel de novo nonsense mutation in SALL4 causing duane radial ray syndrome: a case report and expanding the phenotypic spectrum
Authors: Ajam-Hosseini Mobarakeh , Parvini Farshid , Angaji Abdolhamid
Published: February 2023

Background

SALL4, a member of the SALL genes family, encodes a zinc-finger transcriptional factor that either activates or represses gene transcription depending on cell type during embryonic development. SALL4 mutations cause extremely variable conditions including Duane-radial ray (DRR), Okihiro, Holt-oram, Acro-renal ocular and IVIC syndromes, all with autosomal dominant inheritance pattern. However, all these syndromes with different terminologies are actually the same entity termed SALL4 related disorders.

Case presentation

Herein, we examine an Iranian patient suspected to DRR syndrome which has not been previously described in the population. Whole-exome sequencing (WES) was performed to examine pathogenic genes in the proband. Subsequently, Sanger sequencing was used to confirm the mutation found. To elucidate the effects of the identified mutation, clinical data of patient was collected. Morever, the possible impact of the mutation found on the corresponding protein was evaluated using bioinformatics tools. WES identifed a novel de novo heterozygous nonsense mutation in exon 2 of SALL4 gene (c.712 C > T:p.Q238X). Subsequently, segregation and phenotype-genotype correlation analysis as well as in-silico approaches confirmed the autosomal dominance inheritance and disease-causing nature of the identified mutation. In addition, studied patient had features not described previously, including kyphoscoliosis, dimple presacral sinus, barrel chest and artric disc (C6–C7). These manifestations could be additional characteristics of the growing phenotypic spectrum of SALL4 related disorders.

Conclusion

Our findings could extend the pathogenic mutations and phenotypic spectrum of SALL4 related disorders. Such reports can also aid to conduct genetic counseling, prenatal diagnosis and clinical management for individuals at high risk of SALL4 related disorders.
The effects of folic acid supplementation on endothelial function in adults: a systematic review and dose-response meta-analysis of randomized controlled trials
Authors: Zamani Mohammad , Rezaiian Fatemeh , Saadati Saeede , Naseri Kaveh , Ashtary-Larky Damoon , Yousefi Mohsen , Golalipour Elnaz , Clark Cain C. T. , Rastgoo Samira , Asbaghi Omid
Published: February 2023

Background

Endothelial dysfunction serves as an early marker for the risk of cardiovascular disease (CVD); therefore, it is an attractive site of therapeutic interventions to reduce the risk of CVD. This study was conducted to investigate the effect of folic acid supplementation on endothelial function markers in randomized controlled trials (RCTs).

Methods

PubMed, ISI web of science, and Scopus databases were searched up to July 2022 for detecting eligible studies. A random-effects model was used for meta-analysis, and linear Meta-regression and non-linear dose-response analysis were performed to assess whether the effect of folic acid supplementation was affected by the dose and duration of intervention. Cochrane tools were also used to assess the risk of bias in the included studies.

Results

Twenty-one studies, including 2025 participants (1010 cases and 1015 controls), were included in the present meta-analysis. Folic acid supplementation significantly affected the percentage of flow-mediated dilation (FMD%) (WMD: 2.59%; 95% CI: 1.51, 3.67; P < 0.001) and flow-mediated dilation (FMD) (WMD: 24.38 μm; 95% CI: 3.08, 45.68; P = 0.025), but not end-diastolic diameter (EDD) (WMD: 0.21 mm; 95% CI: − 0.09, 0.52; P = 0.176), and intercellular adhesion molecule (ICAM) (WMD: 0.18 ng/ml; 95% CI: − 10.02, 13.81; P = 0.755).

Conclusions

These findings suggest that folic acid supplementation may improve endothelial function by increasing FMD and FMD% levels.

Trial registration

PROSPERO registration cod: CRD42021289744.
Left atrial reservoir strain measurements derived from intracardiac echocardiography in patients with atrial fibrillation: comparison with transthoracic echocardiography
Authors: Lin Jingru , Cai Yuqi , Meng Xu , Liu Shangyu , Wang Fengyang , Liu Limin , Zhu Zhenhui , Liu Mengyi , Ding Ligang , Wu Weichun , Wang Hao , Yao Yan
Published: February 2023

Background

Intracardiac echocardiography (ICE) provides accurate left atrial (LA) anatomical information in the procedure of atrial fibrillation (AF) ablation but lacks LA functional assessment. LA reservoir strain (LASr) is an excellent marker of LA reservoir function. This study aimed to assess the agreement between LASr derived from ICE and transthoracic echocardiography (TTE) in AF patients and analyze the reproducibility of LASr assessed by ICE combined with speckle tracking imaging.

Methods

This study prospectively enrolled 110 patients with a clinical diagnosis of AF who were ready for AF ablation, including 71 patients with paroxysmal AF and 39 with persistent AF. TTE and ICE examinations were performed on each individual before AF ablation. LASr measurements derived from ICE and TTE images were using dedicated LA-tracking software. Pearson correlation coefficients (r) and Bland–Altman plots were used to evaluate the agreement of LASr between the two modalities. Intraclass correlation coefficients (ICCs) were used to assess intra- and inter-observer reproducibility.

Results

The agreement between LASr obtained from ICE and TTE, especially between LASrLPV (LASr derived from LA left pulmonary vein view of ICE) and LASrTTE (LASr derived from TTE) were good in both paroxysmal and persistent AF patients [r = 0.890 (P < 0.001) for overall population; r = 0.815 (P < 0.001) and Bias ± LOA: -0.3 ± 9.9% for paroxysmal AF; r = 0.775 (P < 0.001) and Bias ± LOA: -2.6 ± 3.9% for persistent AF, respectively]. But the values of LASr derived from ICE were slightly lower than those of TTE, especially in patients with persistent AF. The ICCs for LASr derived from ICE were excellent (all ICCs > 0.90).

Conclusions

In patients with AF, LASr derived from ICE demonstrated excellent reproducibility and showed good agreement with LASr obtained from TTE. Obtaining LASr from ICE images may be a supplementary method to evaluate LA reservoir function in AF patients and expands the potential of ICE in the field of cardiac function assessment.

Graphical Abstract
Transient receptor potential melastatin 2 regulates neutrophil extracellular traps formation and delays resolution of neutrophil-driven sterile inflammation
Authors: Cao Xue , Li Yanhong , Luo Yubin , Chu Tianshu , Yang Hang , Wen Ji , Liu Yi , Zhao Yi , Herrmann Martin
Published: February 2023

The formation of neutrophil extracellular traps (NETs) is a process releasing into the extracellular space networks of chromatin fibers decorated with granular proteins. It is implicated in infection-related as well as sterile inflammation. Monosodium urate (MSU) crystals serve as damage-associated molecular pattern (DAMP) in various conditions of disease. Formation of NETs or aggregated NETs (aggNETs) orchestrates initiation and resolution of MSU crystals-triggered inflammation, respectively. Elevated intracellular calcium levels and the generation of reactive oxygen species (ROS) are crucial for the formation of MSU crystal-induced NETs. However, the exact signaling pathways involved are still elusive. Herein, we demonstrate that the ROS-sensing, non-selective calcium-permeable channel transient receptor potential cation channel subfamily M member 2 (TRPM2) is required for a full-blown MSU crystal-induced NET formation. Primary neutrophils from TRPM2−/− mice showed reduced calcium influx and ROS production and, consequently a reduced formation of MSU crystal-induced NETs and aggNETs. Furthermore, in TRPM2−/− mice the infiltration of inflammatory cells into infected tissues and their production of inflammatory mediators was suppressed. Taken together these results describe an inflammatory role of TRPM2 for neutrophil-driven inflammation and identify TRPM2 as potential target for therapeutic intervention.
Motives for alcohol use, risky drinking patterns and harm reduction practices among people who experience homelessness and alcohol dependence in Montreal
Authors: Motta-Ochoa Rossio , Incio-Serra Natalia , Brulotte Alexandre , Flores-Aranda Jorge
Published: February 2023

Background

People experiencing homelessness are disproportionately affected by harms related to alcohol use. Indeed, their alcohol dependence is associated with numerous physical and mental health problems along with strikingly high rates of alcohol-related mortality. Recent research has extensively examined alcohol use patterns among people experiencing homelessness in an effort to develop interventions and treatments for this problem. However, only a few studies have incorporated the perspectives of the individuals under study about their drinking or examined the ways in which they manage the associated harms. To bridge this gap, we conducted a qualitative study exploring the relation between the drinking motives, risky drinking patterns and harm reduction practices of a group of people (n = 34) experiencing homelessness in Montreal, Canada.

Methods

The qualitative methods we used consisted of semi-structured interviews (n = 12) and focus groups (n = 2, with a total of 22 participants). The content of the collected data was then analyzed.

Results

Participants identified their various motives for alcohol use (coping with painful memories, dealing with harsh living conditions, socializing/seeking a sense of belonging, enjoying themselves/having fun); their risky drinking patterns (binge drinking, mixing alcohol with drugs, non-beverage alcohol drinking, failing to keep sufficient alcohol on hand to prevent acute withdrawal, drinking in public settings); their harm reduction practices (planning how much to drink, keeping a supply of alcohol to prevent acute withdrawal, hiding to drink, concealing alcohol, drinking alone, drinking/hanging out with others, drinking non-beverage alcohol, and taking benzodiazepines, cocaine or other stimulant drugs); and the rationales underpinning their alcohol use and harm reduction practices.

Conclusion

Associating the drinking motives of a group of study participants with their risky drinking patterns and harm reduction practices shed light on their rationales for alcohol use, yielding insights that could be used to better tailor policies and interventions to their needs.
Valtrate, an iridoid compound in Valeriana, elicits anti-glioblastoma activity through inhibition of the PDGFRA/MEK/ERK signaling pathway
Authors: Liu Xuemeng , Hu Yaotian , Xue Zhiyi , Zhang Xun , Liu Xiaofei , Liu Guowei , Wen Muzi , Chen Anjing , Huang Bin , Li Xingang , Yang Ning , Wang Jian
Published: February 2023

Background

Valtrate, a natural compound isolated from the root ofValeriana, exhibits antitumor activity in many cancers through different mechanisms. However, its efficacy for the treatment of glioblastoma (GBM), a tumor type with a poor prognosis, has not yet been rigorously investigated.

Methods

GBM cell lines were treated with valtrate and CCK-8, colony formation and EdU assays, flow cytometry, and transwell, 3D tumor spheroid invasion and GBM-brain organoid co-culture invasion assays were performed to assess properties of proliferation, viability, apoptosis and invasion/migration. RNA sequencing analysis on valtrate-treated cells was performed to identify putative target genes underlying the antitumor activity of the drug in GBM cells. Western blot analysis, immunofluorescence and immunohistochemistry were performed to evaluate protein levels in valtrate-treated cell lines and in samples obtained from orthotopic xenografts. A specific activator of extracellular signal-regulated kinase (ERK) was used to identify the pathways mediating the effect.

Results

Valtrate significantly inhibited the proliferation of GBM cells in vitro by inducing mitochondrial apoptosis and suppressed invasion and migration of GBM cells by inhibiting levels of proteins associated with epithelial mesenchymal transition (EMT). RNA sequencing analysis of valtrate-treated GBM cells revealed platelet-derived growth factor receptor A (PDGFRA) as a potential target downregulated by the drug. Analysis of PDGFRA protein and downstream mediators demonstrated that valtrate inhibited PDGFRA/MEK/ERK signaling. Finally, treatment of tumor-bearing nude mice with valtrate led to decreased tumor volume (fivefold difference at day 28) and enhanced survival (day 27 vs day 36, control vs valtrate-treated) relative to controls.

Conclusions

Taken together, our study demonstrated that the natural product valtrate elicits antitumor activity in GBM cells through targeting PDGFRA and thus provides a candidate therapeutic compound for the treatment of GBM.
Large-scale in vitro microdosimetry via live cell microscopy imaging: implications for radiosensitivity and RBE evaluations in alpha-emitter radiopharmaceutical therapy
Authors: Bastiaannet Remco , Liatsou Ioanna , F Hobbs Robert , Sgouros George
Published: February 2023

Background

Alpha-emitter radiopharmaceutical therapy (αRPT) has shown promising outcomes in metastatic disease. However, the short range of the alpha particles necessitates dosimetry on a near-cellular spatial scale. Current knowledge on cellular dosimetry is primarily based on in vitro experiments using cell monolayers. The goal of such experiments is to establish cell sensitivity to absorbed dose (AD). However, AD cannot be measured directly and needs to be modeled. Current models, often idealize cells as spheroids in a regular grid (geometric model), simplify binding kinetics and ignore the stochastic nature of radioactive decay. It is unclear what the impact of such simplifications is, but oversimplification results in inaccurate and non-generalizable results, which hampers the rigorous study of the underlying radiobiology.

Methods

We systematically mapped out 3D cell geometries, clustering behavior, agent binding, internalization, and subcellular trafficking kinetics for a large cohort of live cells under representative experimental conditions using confocal microscopy. This allowed for realistic Monte Carlo-based (micro)dosimetry. Experimentally established surviving fractions of the HER2 + breast cancer cell line treated with a 212Pb-labelled anti-HER2 conjugate or external beam radiotherapy, anchored a rigorous statistical approach to cell sensitivity and relative biological effectiveness (RBE) estimation. All outcomes were compared to a reference geometric model, which allowed us to determine which aspects are crucial model components for the proper study of the underlying radiobiology.

Results

In total, 567 cells were measured up to 26 h post-incubation. Realistic cell clustering had a large (2x), and cell geometry a small (16.4% difference) impact on AD, compared to the geometric model. Microdosimetry revealed that more than half of the cells do not receive any dose for most of the tested conditions, greatly impacting cell sensitivity estimates. Including these stochastic effects in the model, resulted in significantly more accurate predictions of surviving fraction and RBE (permutation test; p < .01).

Conclusions

This comprehensive integration of the biological and physical aspects resulted in a more accurate method of cell survival modelling in αRPT experiments. Specifically, including realistic stochastic radiation effects and cell clustering behavior is crucial to obtaining generalizable radiobiological parameters.
Human umbilical cord-derived mesenchymal stem cell transplantation supplemented with curcumin improves the outcomes of ischemic stroke via AKT/GSK-3β/β-TrCP/Nrf2 axis
Authors: Li Yuan , Huang Jialu , Wang Jie , Xia Simin , Ran Hong , Gao Lenyu , Feng Chengjian , Gui Li , Zhou Zhenhua , Yuan Jichao
Published: February 2023

Background

Human umbilical cord-derived mesenchymal stem cell (hUC-MSC) engraftment is a promising therapy for acute ischemic stroke (AIS). However, the harsh ischemic microenvironment limits the therapeutic efficacy of hUC-MSC therapy. Curcumin is an anti-inflammatory agent that could improve inflammatory microenvironment. However, whether it enhances the neuroprotective efficacy of hUC-MSC transplantation is still unknown. In the present study, we investigated the therapeutic efficacy and the possible mechanism of combined curcumin and hUC-MSC treatment in AIS.

Methods

Middle cerebral artery occlusion (MCAO) mice and oxygen glucose deprivation (OGD) microglia were administrated hUC-MSCs with or without curcumin. Neurological deficits assessment, brain water content and TTC were used to assess the therapeutic effects of combined treatment. To elucidate the mechanism, MCAO mice and OGD microglia were treated with AKT inhibitor MK2206, GSK3β activator sodium nitroprusside (SNP), GSK3β inhibitor TDZD-8 and Nrf2 gene knockout were used. Immunofluorescence, flow cytometric analysis, WB and RT-PCR were used to evaluate the microglia polarization and the expression of typical oxidative mediators, inflammatory cytokines and the AKT/GSK-3β/β-TrCP/Nrf2 pathway protein.

Results

Compared with the solo hUC-MSC-grafted or curcumin groups, combined curcumin-hUC-MSC therapy significantly improved the functional performance outcomes, diminished the infarct volumes and the cerebral edema. The combined treatment promoted anti-inflammatory microglia polarization via Nrf2 pathway and decreased the expression of ROS, oxidative mediators and pro-inflammatory cytokines, while elevating the expression of the anti-inflammatory cytokines. Nrf2 knockout abolished the antioxidant stress and anti-inflammation effects mediated with combined treatment. Moreover, the combined treatment enhanced the phosphorylation of AKT and GSK3β, inhibited the β-TrCP nucleus translocation, accompanied with Nrf2 activation in the nucleus. AKT inhibitor MK2206 activated GSK3β and β-TrCP and suppressed Nrf2 phosphorylation in nucleus, whereas MK2206 with the GSK3β inhibitor TDZD-8 reversed these phenomena. Furthermore, combined treatment followed by GSK3β inhibition with TDZD-8 restricted β-TrCP nucleus accumulation, which facilitated Nrf2 expression.

Conclusions

We have demonstrated that combined curcumin-hUC-MSC therapy exerts anti-inflammation and antioxidant stress efficacy mediated by anti-inflammatory microglia polarization via AKT/GSK-3β/β-TrCP/Nrf2 axis and an improved neurological function after AIS.
The presence of human respiratory syncytial virus in the cerebrospinal fluid of a child with Anti-N-methyl-D-aspartate receptor encephalitis of unknown trigger
Authors: Yu Siyan , Hua Ying , Qian Jun , Sun Mingxia , Kang Yan-Jun
Published: February 2023

Background

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an important type of brain inflammation caused by autoantibody. As one of the primary agents responsible for respiratory tract infection, the human respiratory syncytial virus (hRSV) has also been reported to be capable of causing extrapulmonary diseases. Here, we first describe a case of anti-NMDAR encephalitis when hRSV was shown to be present in the cerebrospinal fluid.

Case presentation

The child was noted to have ataxia and positive anti-NMDA receptors in the cerebrospinal fluid, diagnosed as anti-NMDA receptor encephalitis in combination with cranial MRI images. After high-dose hormone pulse therapy and medication, the disease improved, and he was discharged. However, a relapse occurred almost a year later, and the cranial MRI imaging showed progressive cerebellar atrophy. An hRSV strain from group B was detected in his cerebrospinal fluid, and the whole genome sequence was recovered using transcriptome sequencing.

Conclusions

To our knowledge, this is the first report of hRSV being found in the cerebrospinal fluid of a patient with anti-NMDAR encephalitis. Even though more clinical records and experimental evidence are needed for validation, this work expands the types of diseases linked to hRSV and the likely cause of anti-NMDAR encephalitis.
Implementation costs of hospital-based computerised decision support systems: a systematic review
Authors: Donovan Thomasina , Abell Bridget , Fernando Manasha , McPhail Steven M. , Carter Hannah E.
Published: February 2023

Background

The importance of accurately costing implementation strategies is increasingly recognised within the field of implementation science. However, there is a lack of methodological guidance for costing implementation, particularly within digital health settings. This study reports on a systematic review of costing analyses conducted alongside implementation of hospital-based computerised decision support systems.

Methods

PubMed, Embase, Scopus and CINAHL databases were searched between January 2010 and August 2021. Two reviewers independently screened and selected original research studies that were conducted in a hospital setting, examined the implementation of a computerised decision support systems and reported implementation costs. The Expert Recommendations for Implementing Change Framework was used to identify and categorise implementation strategies into clusters. A previously published costing framework was applied to describe the methods used to measure and value implementation costs. The reporting quality of included studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards checklist.

Results

Titles and abstracts of 1836 articles were screened, with nine articles eligible for inclusion in the review. Implementation costs were most frequently reported under the ‘evaluative and iterative strategies’ cluster, followed by ‘provide interactive assistance’. Labour was the largest implementation-related cost in the included papers, irrespective of implementation strategy. Other reported costs included consumables, durable assets and physical space, which was mostly associated with stakeholder training. The methods used to cost implementation were often unclear. There was variation across studies in the overall quality of reporting.

Conclusions

A relatively small number of papers have described computerised decision support systems implementation costs, and the methods used to measure and value these costs were not well reported. Priorities for future research should include establishing consistent terminology and appropriate methods for estimating and reporting on implementation costs.

Trial registration

The review protocol is registered with PROSPERO (ID: CRD42021272948).