bluuebunny/crossref_metadata_2025 huggingface dataset:
Deregulated immune cell recruitment orchestrated by c-MET impairs pulmonary inflammation and fibrosis
Authors: Barbosa-Matos Catarina , Borges-Pereira Caroline , Libório-Ramos Sofia , Fernandes Raquel , Oliveira Marcela , Mendes-Frias Ana , Silvestre Ricardo , Osório Nuno S. , Bastos Hélder N. , Santos Rita F. , Guimarães Susana , Morais António , Mazzone Massimiliano , Carvalho Agostinho , Cunha Cristina , Costa Sandra
Published: June 2024

Background

Pulmonary fibrosis (PF) represents the pathologic end stage of several interstitial lung diseases (ILDs) associated with high morbidity and mortality rates. However, current treatments can only delay disease progression rather than provide a cure. The role of inflammation in PF progression is well-established, but new insights into immune regulation are fundamental for developing more efficient therapies. c-MET signaling has been implicated in the migratory capacity and effector functions of immune cells. Nevertheless, the role of this signaling pathway in the context of PF-associated lung diseases remains unexplored.

Methods

To determine the influence of c-MET in immune cells in the progression of pulmonary fibrosis, we used a conditional deletion of c-Met in immune cells. To induce pulmonary fibrosis mice were administered with bleomycin (BLM) intratracheally. Over the course of 21 days, mice were assessed for weight change, and after euthanasia at different timepoints, bronchoalveolar lavage fluid cells and lung tissue were assessed for inflammation and fibrosis. Furthermore, c-MET expression was assessed in cryobiopsy sections, bronchoalveolar lavage fluid cells samples and single cell RNA-sequencing dataset from human patients with distinct interstitial lung diseases.

Results

c-MET expression was induced in lung immune cells, specifically in T cells, interstitial macrophages, and neutrophils, during the inflammatory phase of BLM-induced PF mouse model. Deletion of c-Met in immune cells correlated with earlier weight recovery and improved survival of BLM-treated mice. Moreover, the deletion of c-Met in immune cells was associated with early recruitment of the immune cell populations, normally found to express c-MET, leading to a subsequent attenuation of the cytotoxic and proinflammatory environment. Consequently, the less extensive inflammatory response, possibly coupled with tissue repair, culminated in less exacerbated fibrotic lesions. Furthermore, c-MET expression was up-regulated in lung T cells from patients with fibrosing ILD, suggesting a potential involvement of c-MET in the development of fibrosing disease.

Conclusions

These results highlight the critical contribution of c-MET signaling in immune cells to their enhanced uncontrolled recruitment and activation toward a proinflammatory and profibrotic phenotype, leading to the exacerbation of lung injury and consequent development of fibrosis.
The causal relationship and potential mediators between plasma lipids and atopic dermatitis: a bidirectional two-sample, two-step mendelian randomization
Authors: Zhang Yuke , Zhang Bohan , Wang Ru , Chen Xinghan , Xiao Haitao , Xu Xuewen
Published: June 2024

Background

Observational studies have indicated that the plasma lipid profiles of patients with atopic dermatitis show significant differences compared to healthy individuals. However, the causal relationship between these differences remains unclear due to the inherent limitations of observational studies. Our objective was to explore the causal effects between 179 plasma lipid species and atopic dermatitis, and to investigate whether circulating inflammatory proteins serve as mediators in this causal pathway.

Methods

We utilized public genome-wide association studies data to perform a bidirectional two-sample, two-step mendelian randomization study. The inverse variance-weighted method was adopted as the primary analysis technique. MR-Egger and the weighted median were used as supplementary analysis methods. MR-PRESSO, Cochran’s Q test, and MR-Egger intercept test were applied for sensitivity analyses to ensure the robustness of our findings.

Results

The Mendelian randomization analysis revealed that levels of Phosphatidylcholine (PC) (18:1_20:4) (OR: 0.950, 95% CI: 0.929–0.972, p = 6.65 × 10− 6), Phosphatidylethanolamine (O-18:1_20:4) (OR: 0.938, 95% CI: 0.906–0.971, p = 2.79 × 10− 4), Triacylglycerol (TAG) (56:6) (OR: 0.937, 95% CI: 0.906–0.969, p = 1.48 × 10− 4) and TAG (56:8) (OR: 0.918, 95% CI: 0.876–0.961, p = 2.72 × 10− 4) were inversely correlated with the risk of atopic dermatitis. Conversely, PC (18:1_20:2) (OR: 1.053, 95% CI: 1.028–1.079, p = 2.11 × 10− 5) and PC (O-18:1_20:3) (OR: 1.086, 95% CI: 1.039–1.135, p = 2.47 × 10− 4) were positively correlated with the risk of atopic dermatitis. The results of the reverse directional Mendelian randomization analysis indicated that atopic dermatitis exerted no significant causal influence on 179 plasma lipid species. The level of circulating IL-18R1 was identified as a mediator for the increased risk of atopic dermatitis associated with higher levels of PC (18:1_20:2), accounting for a mediation proportion of 9.07%.

Conclusion

Our research suggests that plasma lipids can affect circulating inflammatory proteins and may serve as one of the pathogenic factors for atopic dermatitis. Targeting plasma lipid levels as a treatment for atopic dermatitis presents a potentially novel approach.
Identification of lipid-modifying drug targets for autoimmune diseases: insights from drug target mendelian randomization
Authors: Hu Xiao , Zhang Peng , Gao Yuan , Ding Wen-Wen , Cheng Xue-Er , Shi Qian-Qian , Li Sheng , Zhu Yan-Yu , Pan Hai-Feng , Wang Peng
Published: June 2024

Backgrounds

A growing body of evidence has highlighted the interactions of lipids metabolism and immune regulation. Nevertheless, there is still a lack of evidence regarding the causality between lipids and autoimmune diseases (ADs), as well as their possibility as drug targets for ADs.

Objectives

This study was conducted to comprehensively understand the casual associations between lipid traits and ADs, and evaluate the therapeutic possibility of lipid-lowering drug targets on ADs.

Methods

Genetic variants for lipid traits and variants encoding targets of various lipid-lowering drugs were derived from Global Lipid Genetics Consortium (GLGC) and verified in Drug Bank. Summary data of ADs were obtained from MRC Integrative Epidemiology Unit (MER-IEU) database and FinnGen consortium, respectively. The causal inferences between lipid traits/genetic agents of lipid-lowering targets and ADs were evaluated by Mendelian randomization (MR), summary data-based MR (SMR), and multivariable MR (MVMR) analyses. Enrichment analysis and protein interaction network were employed to reveal the functional characteristics and biological relevance of potential therapeutic lipid-lowering targets.

Results

There was no evidence of causal effects regarding 5 lipid traits and 9 lipid-lowering drug targets on ADs. Genetically proxied 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibition was associated with a reduced risk of rheumatoid arthritis (RA) in both discovery (OR [odds ratio] = 0.45, 95%CI: 0.32, 0.63, P = 6.79 × 10− 06) and replicate datasets (OR = 0.37, 95%CI: 0.23, 0.61, P = 7.81 × 10− 05). SMR analyses supported that genetically proxied HMGCR inhibition had causal effects on RA in whole blood (OR = 0.48, 95%CI: 0.29, 0.82, P = 6.86 × 10− 03) and skeletal muscle sites (OR = 0.75, 95%CI: 0.56, 0.99, P = 4.48 × 10− 02). After controlling for blood pressure, body mass index (BMI), smoking and drinking alchohol, HMGCR suppression showed a direct causal effect on a lower risk of RA (OR = 0.33, 95%CI: 0.40, 0.96, P = 0.042).

Conclusions

Our study reveals causal links of genetically proxied HMGCR inhibition (lipid-lowering drug targets) and HMGCR expression inhibition with a decreased risk of RA, suggesting that HMGCR may serve as candidate drug targets for the treatment and prevention of RA.
The roles of lipids and inflammation in the association between the triglyceride-glucose index and arterial stiffness: evidence from two large population-based surveys
Authors: Li Jinlian , Ye Pei , Peng Xiangyan , Xiang Guangda
Published: June 2024

Background

The triglyceride-glucose (TyG) index is a risk marker for arterial stiffness; however, the extent to which the TyG index is associated with arterial stiffness via lipids and inflammation remains unknown. The first aim was to probe the relationship between the TyG index and arterial stiffness in two surveys. The second aim was to clarify whether lipids and inflammation mediate this relationship.

Methods

The sample size of 13,726 U.S. individuals from the National Examination Survey (NHANES) and 3,964 Chinese individuals from the China Health and Retirement Longitudinal Study (CHARLS 2015) were enrolled. Weighted multivariate logistic and linear regression models, as well as restricted cubic spline (RCS) and mediation analyses, were utilized to estimate complex relationships between the TyG index, arterial stiffness, lipids (non-high-density lipoprotein cholesterol [non-HDL-C]) and inflammation (C-reactive protein [CRP]) biomarkers.

Results

A total of 3,420 U.S. patients and 992 Chinese patients were diagnosed with increased arterial stiffness. Regression analyses demonstrated that higher quartiles of the TyG index were associated with a greater incidence of increased arterial stiffness (NHANES: OR = 2.610, 95% CI = 2.043–3.334, P < 0.001; CHARLS: OR = 1.579, 95% CI = 1.057–2.360, P < 0.001). Participants with a higher TyG index/higher CRP level or with a higher TyG index/higher non-HDL-C level had the highest incidence of increased arterial stiffness in the two surveys. The results were still consistent when the sensitivity analysis was implemented with stricter clinical cut-off values of non-HDL-C. Mediation analysis verified that lipids (mediated effect: β = 0.012, P < 0.001 in NHANES; β = 0.020, P < 0.001 in CHARLS) and inflammation (mediated effect: β = 0.003, P < 0.001 in NHANES; β = 0.006, P < 0.001 in CHARLS) partially mediated this relationship.

Conclusions

These results indicated a positive linear correlation between the TyG index, non-HDL-C level, CRP level and increased arterial stiffness in two surveys. Furthermore, lipids and inflammation could partly mediate the correlation of the TyG index with arterial stiffness in both surveys.
Endoscopy-assisted medial canthus incision for olfactory neuroblastoma: a case report
Authors: Li Yanwen , Zhao Xin , Tao Yanli
Published: June 2024

Sinonasal malignant tumors are a group of uncommon malignancies that account for less than 1% of all tumors. These tumors often involve the maxillary sinus and nasal cavity, with less cumulative incidence in the ethmoidal sinus, sphenoidal sinus, and frontal sinus. The lack of consensus on the management of sinonasal malignancies is due to their rarity, diagnostic challenges, and the heterogeneity of treatments. In this paper, we present a case of endoscopic-assisted medial canthus incision combined with radiotherapy in the treatment of sinonasal malignant tumors, with the aim of providing valuable insights to clinicians on the management of these tumors.
Impact of working time and industry type on disability incidence among older Japanese adults
Authors: Shimoda Takahiro , Tomida Kouki , Nakajima Chika , Kawakami Ayuka , Doi Takehiko , Shimada Hiroyuki
Published: June 2024

Purpose

Working influences health; however, there is still insufficient exploration on how the two are associated. Therefore, we aimed to investigate whether working time/week and industry type affect disability incidence in older adults.

Methods

In this study, we included data from 4679 participants aged ≥ 65 years. Working time/week and industry types were divided into < 20, 20–40, and > 40 h/week, and primary, secondary, and tertiary categories. Cox regression analysis was used to determine the association between working hours and industry type with disability incidence.

Results

After a median of 83 months, 836 (17.9%) experienced a disability. The effects of working hours and industry type on disability incidence were found to be associated with age and sex. Individuals who were 74 years and younger and who worked for 20–40 h/week had a lower risk of disability incidence compared with non-workers (HR, 0.52; 95% CI, 0.27–0.99); however, there was no statistically significant difference in those 75 years and older. Females and individuals aged 74 years and younger who worked in teriary industries has a lower risk of disability incidence compared with non-workers (HR, 0.54; 95% CI, 0.35–0.82: HR, 0.53; 95% CI, 0.35–0.81); however, no statistically significant difference was found in males or those 75 years and older.

Conclusions

Short working hours and tertiary industry employment were associated with a lower risk of developing disability, especially in females and those under 74 years. Paid work promotes physical health, but it is important to consider work hours and type of industry when choosing employment.
Chiropractors’ perceptions on the use of spinal radiographs in clinical practice: a qualitative study
Authors: Searant Isaac , Brown Benjamin T. , Jenkins Hazel J
Published: June 2024

Background

Radiography is commonly used in the assessment of spinal disorders, despite a lack of high-quality evidence demonstrating improved clinical outcomes or additional benefit to the patient. There is disagreement amongst chiropractors regarding the appropriate use of radiography for clinical management. This study aims to qualitatively explore chiropractors’ perceptions on the use of spinal radiographs in clinical practice with respect to how they determine when to order radiographs; and how they use radiographs to inform clinical management.

Methods

Online qualitative semi-structured interviews were conducted with 17 Australian chiropractors who currently manage patients with spinal disorders. Convienence, snowball, and purposive sampling strategies were used to ensure an appropriate breadth and depth of participant characterisitcs and beliefs. Interview data were recorded, transcribed and analysed using framework analysis.

Results

Three themes were developed to describe how chiropractors determined when to order radiographs. These themes included specific findings from the clinical encounter that may inform clinical management, their perceptions of radiation risk, and the influence of clinical experience/intuition. Three themes and four subthemes were developed for how chiropractors use radiographs to inform their management. These themes explored the use of radiography for the application of chiropractic technique, as well as the role of radiographs in predicting patient prognosis, and as an educational tool to provide reassurance.

Conclusion

Australian chiropractors’ decision-making around spinal radiography is diverse and can be influenced by a number of clinical and external factors. Previously unexplored uses of spinal radiography in clinical practice were highlighted. Some chiropractors reported potential benefits of radiography that are currently not supported by research evidence. Future research should address how radiographic findings are reported to patients with spinal disorders and how this could be optimised to improve patient outcomes.
Transformation of t(14;18)-negative follicular lymphoma to plasmablastic lymphoma: a case report with analysis of genetic evolution
Authors: Lim Sojung , Koh Jiwon , Bae Jeong Mo , Yun Hongseok , Lee Cheol , Paik Jin Ho , Kim Tae Min , Jeon Yoon Kyung
Published: June 2024

Background

Follicular lymphoma (FL) is characterized by t(14;18)(q32;q21) involving the IGH and BCL2 genes. However, 10–15% of FLs lack the BCL2 rearrangement. These BCL2-rearrangement−negative FLs are clinically, pathologically, and genetically heterogeneous. The biological behavior and histological transformation of such FLs are not adequately characterized. Here, we report the first case of t(14;18)-negative FL that rapidly progressed to plasmablastic lymphoma (PBL).

Case presentation

A previously healthy 51-year-old man presented with leg swelling. Computed tomography (CT) showed enlarged lymph nodes (LNs) throughout the body, including both inguinal areas. Needle biopsy of an inguinal LN suggested low-grade B-cell non-Hodgkin lymphoma. Excisional biopsy of a neck LN showed proliferation of centrocytic and centroblastic cells with follicular and diffuse growth patterns. Immunohistochemical analysis showed that the cells were positive for CD20, BCL6, CD10, and CD23. BCL2 staining was negative in the follicles and weak to moderately positive in the interfollicular areas. BCL2 fluorescence in situ hybridization result was negative. Targeted next-generation sequencing (NGS) revealed mutations in the TNFRSF14, CREBBP, STAT6, BCL6, CD79B, CD79A, and KLHL6 genes, without evidence of BCL2 or BCL6 rearrangement. The pathologic and genetic features were consistent with t(14;18)-negative FL. Two months after one cycle of bendamustine and rituximab chemotherapy, the patient developed left flank pain. Positron emission tomography/CT showed new development of a large hypermetabolic mass in the retroperitoneum. Needle biopsy of the retroperitoneal mass demonstrated diffuse proliferation of large plasmablastic cells, which were negative for the B-cell markers, BCL2, BCL6, and CD10; they were positive for MUM-1, CD138, CD38, and C-MYC. The pathologic findings were consistent with PBL. The clonal relationship between the initial FL and subsequent PBL was analyzed via targeted NGS. The tumors shared the same CREBBP, STAT6, BCL6, and CD79B mutations, strongly suggesting that the PBL had transformed from a FL clone. The PBL also harbored BRAF V600E mutation and IGH::MYC fusion in addition to IGH::IRF4 fusion.

Conclusions

We propose that transformation or divergent clonal evolution of FL into PBL can occur when relevant genetic mutations are present. This study broadens the spectrum of histological transformation of t(14;18)-negative FL and emphasizes its biological and clinical heterogeneity.
Torsional stability of fixation methods in basicervical femoral neck fractures: a biomechanical study
Authors: Mahaisavariya Chantas , Jitprapaikulsarn Surasak , Mahaisavariya Banchong , Chantarapanich Nattapon
Published: June 2024

Background

Basicervical femoral neck fracture is a rare proximal femur fracture with a high implant failure rate. Biomechanical comparisons between cephalomedullary nails (CMNs) and dynamic hip screws (DHSs) under torsion loading are lacking. This study compared the biomechanical performance of three fixations for basicervical femoral neck fractures under torsion load during early ambulation.

Methods

The biomechanical study models used three fixations: a DHS, a DHS with an anti-rotation screw, and a short CMN. Finite element analysis was used to simulate hip rotation with muscle forces related to leg swing applied to the femur. The equivalent von Mises stress (EQV) on fixation, fragment displacement, and strain energy density at the proximal cancellous bone were monitored for fixation stability.

Results

The EQV of the short CMN construct (304.63 MPa) was comparable to that of the titanium DHS construct (293.39 MPa) and greater than that of the titanium DHS with an anti-rotation screw construct (200.94 MPa). The proximal fragment displacement in the short CMN construct was approximately 0.13 mm, the greatest among the constructs. The risk of screw cutout for the lag screw in short CMNs was 3.1–5.8 times greater than that for DHSs and DHSs with anti-rotation screw constructs.

Conclusions

Titanium DHS combined with an anti-rotation screw provided lower fragment displacement, stress, and strain energy density in the femoral head than the other fixations under torsion load. Basicervical femoral neck fracture treated with CMNs may increase the risk of lag screw cutout.

Graphical abstract
Survival outcomes of segmentectomy and lobectomy for early stage non-small cell lung cancer: a systematic review and meta-analysis
Authors: Li Tongxin , He Wang , Zhang Xiaolong , Zhou Yu , Wang Dong , Huang Shengyuan , Li Xiangyang , Fu Yong
Published: June 2024

Background

The question of whether segmentectomy and lobectomy have similar survival outcomes for patients with early-stage non-small cell lung cancer (NSCLC) is a matter of debate.

Methods

A cohort study and randomized controlled trial were included, comparing segmentectomy and lobectomy, by utilizing computerized access to the Pubmed, Web of Science, and Cochrane Library databases up until July 2022. The Cochrane Collaboration tool was used to evaluate the randomized controlled trials, while the Newcastle-Ottawa Scale (NOS) was used to evaluate the cohort studies. Sensitivity analyses were also carried out.

Results

The analysis incorporated 17 literature studies, including one randomized controlled trial and 16 cohort studies, and was divided into a segmentectomy group (n = 2081) and a lobectomy group (n = 2395) based on the type of surgery the patient underwent. Each study was followed up from 27 months to 130.8 months after surgery. Over survival (OS): HR = 1.14, 95%CI(0.97,1.32), P = 0.10; disease-free survival (DFS): HR = 1.13, 95%CI(0.91,1.41), P = 0.27; recurrence-free survival (RFS): HR = 0.95, 95%CI(0.81,1.12), P = 0.54.

Conclusion

The results of the study suggest that the survival outcomes of the segmentectomy group were not inferior to that of the lobectomy group. Segmentectomy should therefore be considered as a treatment option for early stage NSCLC.
Del Nido cardioplegia versus cold blood cardioplegia in adult cardiac surgery: a meta-analysis of randomized clinical trials
Authors: Li Congcong , Xiang Haiyan , Yang Heng , Liu Wu , Lan Wanqi , Luo Chao , Han Shuangjian , Li Yongqin , Tang Yanhua
Published: June 2024

Objective

Systematic evaluation of the safety of del Nido cardioplegia compared to cold blood cardioplegia in adult cardiac surgery.

Methods

We systematically searched PubMed, EMbase, The Cochrane Library and ClinicalTrials.gov for randomized clinical trials (published by 14 January 2024) comparing del Nido cardioplegia to cold blood cardioplegia in adult. Our main endpoints were myocardial injury markers and clinical outcomes. We assessed pooled data by use of a random-effects model or a fixed-effects model.

Results

A total of 10 studies were identified, incorporating 889 patients who received del Nido cardioplegia and 907 patients who received cold blood cardioplegia. The meta-analysis results showed that compared with the cold blood cardioplegia, the del Nido cardioplegia had less volume of cardioplegia, higher rate of spontaneous rhythm recovery after cross clamp release, lower levels of postoperative cardiac troponin T and creatinine kinase-myocardial band, all of which were statistically significant. However, there was no statistically significant difference in postoperative troponin I and postoperative left ventricular ejection fraction. The clinical outcomes including mechanical ventilation time, intensive care unit stay time, hospital stay time, postoperative stroke, postoperative new-onset atrial fibrillation, postoperative heart failure requiring intra-aortic balloon pump mechanical circulation support, and in-hospital mortality of both are comparable.

Conclusion

Existing evidence suggests that del Nido cardioplegia reduced volume of cardioplegia administration and attempts of defibrillation. The superior postoperative results in CTnT and CK-MB may provide a direction for further research on improvement of the composition of cardioplegia.

Visual Abstract
Partial cardiopulmonary bypass through left thoracotomy for coarctation repair in children
Authors: Joo Kunihiko , Ochiai Yoshie , Motomatsu Yuma , Hashizumi Yuki , Maniwa Yutaka , Sugitani Yuichiro , Watanabe Mamie , Muneuchi Jun , Tokunaga Shigehiko
Published: June 2024

Background

A left thoracotomy approach is anatomically appropriate for childhood aortic coarctation; however, the pediatric femoral arteriovenous diameters are too small for cardiopulmonary bypass cannulation. We aimed to determine the safety of a partial cardiopulmonary bypass through the main pulmonary artery and the descending aorta in pediatric aortic coarctation repair.

Methods

We retrospectively reviewed 10 patients who underwent coarctation repair under partial main pulmonary artery-to-descending aorta cardiopulmonary bypass with a left thoracotomy as the CPB group. During the same period, 16 cases of simple coarctation of the aorta repair, with end-to-end anastomosis through a left thoracotomy without partial CPB assistance, were included as the non-CPB group to evaluate the impact of partial CPB.

Results

The median age and weight at surgery of the CPB group were 3.1 years (range, 9 days to 17.9 years) and 14.0 (range, 2.8–40.7) kg, respectively. Indications for the partial cardiopulmonary bypass with overlap were as follows: age > 1 year (n = 7), mild aortic coarctation (n = 3), and predicted ischemic time > 30 min (n = 5). Coarctation repair using autologous tissue was performed in seven cases and graft replacement in three. The mean partial cardiopulmonary bypass time, descending aortic clamp time, and cardiopulmonary bypass flow rate were 73 ± 37 min, 57 ± 27 min, and 1.6 ± 0.2 L/min/m2, respectively. Urine output during descending aortic clamping was observed in most cases in the CPB group (mean: 9.1 ± 7.9 mL/kg/h), and the total intraoperative urine output was 3.2 ± 2.7 mL/kg/h and 1.2 ± 1.5 mL/kg/h in the CPB and non-CPB group, respectively (p = 0.020). The median ventilation time was 1 day (range, 0–15), and the intensive care unit stay duration was 4 days (range, 1–16) with no surgical deaths. No major complications, including paraplegia or recurrent coarctation, occurred postoperatively during a median observation period of 8.1 (range, 3.4–17.5) years in the CPB group. In contrast, reoperation with recurrent coarctation was observed in 2 cases in the non-CPB group (p = 0.37).

Conclusions

Partial cardiopulmonary bypass through the main pulmonary artery and descending aorta via a left thoracotomy is a safe and useful option for aortic coarctation repair in children.
Phytotherapeutic potential against MRSA: mechanisms, synergy, and therapeutic prospects
Authors: He Qiqi , Meneely Julie , Grant Irene R. , Chin Jason , Fanning Séamus , Situ Chen
Published: June 2024

Background

Rising resistance to antimicrobials, particularly in the case of methicillin-resistant Staphylococcus aureus (MRSA), represents a formidable global health challenge. Consequently, it is imperative to develop new antimicrobial solutions. This study evaluated 68 Chinese medicinal plants renowned for their historical applications in treating infectious diseases.

Methods

The antimicrobial efficacy of medicinal plants were evaluated by determining their minimum inhibitory concentration (MIC) against MRSA. Safety profiles were assessed on human colorectal adenocarcinoma (Caco-2) and hepatocellular carcinoma (HepG2) cells. Mechanistic insights were obtained through fluorescence and transmission electron microscopy (FM and TEM). Synergistic effects with vancomycin were investigated using the Fractional Inhibitory Concentration Index (FICI).

Results

Rheum palmatum L., Arctium lappa L. and Paeonia suffructicosaas Andr. have emerged as potential candidates with potent anti-MRSA properties, with an impressive low MIC of 7.8 µg/mL, comparable to the 2 µg/mL MIC of vancomycin served as the antibiotic control. Crucially, these candidates demonstrated significant safety profiles when evaluated on Caco-2 and HepG2 cells. Even at 16 times the MIC, the cell viability ranged from 83.3% to 95.7%, highlighting their potential safety. FM and TEM revealed a diverse array of actions against MRSA, such as disrupting the cell wall and membrane, interference with nucleoids, and inducing morphological alterations resembling pseudo-multicellular structures in MRSA. Additionally, the synergy between vancomycin and these three plant extracts was evident against MRSA (FICI < 0.5). Notably, aqueous extract of R. palmatum at 1/4 MIC significantly reduced the vancomycin MIC from 2 µg/mL to 0.03 µg/mL, making a remarkable 67-fold decrease.

Conclusions

This study unveil new insights into the mechanistic actions and pleiotropic antibacterial effectiveness of these medicinal plants against resistant bacteria, providing robust evidence for their potential use as standalone or in conjunction with antibiotics, to effectively combat antimicrobial resistance, particularly against MRSA.
A phase 3 randomised double-blind placebo-controlled trial of mirtazapine as a pharmacotherapy for methamphetamine use disorder: a study protocol for the Tina Trial
Authors: McKetin Rebecca , Degan Tayla J. , Saunders Lucy , Nguyen Long , Dore Gregory , Shoptaw Steven , Farrell Michael , Degenhardt Louisa , Kelly Peter J. , Turner Alyna , Clare Philip J. , Dean Olivia M. , Arunogiri Shalini , Colledge-Frisby Samantha , Koeijers Juanita , Goodman-Meza David , Sinclair Barbara , Reid David , Hill Harry , Hayllar Jeremy , Christmass Michael , Cordaro Frank , Lundin Robert , Liaw Willy , Liu Danica , Holyoak Ellie , Wu Brian Tid-Fung , Keygan Joel , Kontogiannis Ava , Palmer Lily , Morrison Caity , Wrobel Anna , Hyland Bec , Byrne Marianne , Russell Samantha , Zahra Emma , Berk Michael
Published: June 2024

Background

There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo-controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder.

Methods

This is a multi-site phase 3 randomised, double-blind, placebo-controlled parallel trial. Participants are randomly allocated (1:1) to receive either mirtazapine (30 mg/day for 12 weeks) or matched placebo, delivered as a take-home medication. The target population is 340 people aged 18–65 years who have moderate to severe methamphetamine use disorder. The trial is being conducted through outpatient alcohol and other drug treatment clinics in Australia. The primary outcome is measured as self-reported days of methamphetamine use in the past 4 weeks at week 12. Secondary outcomes are methamphetamine-negative oral fluid samples, depressive symptoms, sleep quality, HIV risk behaviour and quality of life. Other outcomes include safety (adverse events), tolerability, and health service use. Medication adherence is being monitored using MEMS® Smart Caps fitted to medication bottles.

Discussion

This trial will provide information on the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder when delivered as an outpatient medication in routine clinical practice. If found to be safe and effective, this trial will support an application for methamphetamine use disorder to be included as a therapeutic indication for the prescription of mirtazapine.

Trial registration

Australian and New Zealand Clinical Trials Registry ACTRN12622000235707. Registered on February 9, 2022.
Modeling of the brain-lung axis using organoids in traumatic brain injury: an updated review
Authors: Kim Jong-Tae , Song Kang , Han Sung Woo , Youn Dong Hyuk , Jung Harry , Kim Keun-Suh , Lee Hyo-Jung , Hong Ji Young , Cho Yong-Jun , Kang Sung-Min , Jeon Jin Pyeong
Published: June 2024

Clinical outcome after traumatic brain injury (TBI) is closely associated conditions of other organs, especially lungs as well as degree of brain injury. Even if there is no direct lung damage, severe brain injury can enhance sympathetic tones on blood vessels and vascular resistance, resulting in neurogenic pulmonary edema. Conversely, lung damage can worsen brain damage by dysregulating immunity. These findings suggest the importance of brain-lung axis interactions in TBI. However, little research has been conducted on the topic. An advanced disease model using stem cell technology may be an alternative for investigating the brain and lungs simultaneously but separately, as they can be potential candidates for improving the clinical outcomes of TBI.

In this review, we describe the importance of brain-lung axis interactions in TBI by focusing on the concepts and reproducibility of brain and lung organoids in vitro. We also summarize recent research using pluripotent stem cell-derived brain organoids and their preclinical applications in various brain disease conditions and explore how they mimic the brain-lung axis. Reviewing the current status and discussing the limitations and potential perspectives in organoid research may offer a better understanding of pathophysiological interactions between the brain and lung after TBI.
Prognosticating the outcome of intensive care in older patients—a narrative review
Authors: Beil Michael , Moreno Rui , Fronczek Jakub , Kogan Yuri , Moreno Rui Paulo Jorge , Flaatten Hans , Guidet Bertrand , de Lange Dylan , Leaver Susannah , Nachshon Akiva , van Heerden Peter Vernon , Joskowicz Leo , Sviri Sigal , Jung Christian , Szczeklik Wojciech
Published: June 2024

Prognosis determines major decisions regarding treatment for critically ill patients. Statistical models have been developed to predict the probability of survival and other outcomes of intensive care. Although they were trained on the characteristics of large patient cohorts, they often do not represent very old patients (age ≥ 80 years) appropriately. Moreover, the heterogeneity within this particular group impairs the utility of statistical predictions for informing decision-making in very old individuals. In addition to these methodological problems, the diversity of cultural attitudes, available resources as well as variations of legal and professional norms limit the generalisability of prediction models, especially in patients with complex multi-morbidity and pre-existing functional impairments. Thus, current approaches to prognosticating outcomes in very old patients are imperfect and can generate substantial uncertainty about optimal trajectories of critical care in the individual. This article presents the state of the art and new approaches to predicting outcomes of intensive care for these patients. Special emphasis has been given to the integration of predictions into the decision-making for individual patients. This requires quantification of prognostic uncertainty and a careful alignment of decisions with the preferences of patients, who might prioritise functional outcomes over survival. Since the performance of outcome predictions for the individual patient may improve over time, time-limited trials in intensive care may be an appropriate way to increase the confidence in decisions about life-sustaining treatment.
Myoglobin adsorption and saturation kinetics of the cytokine adsorber Cytosorb® in patients with severe rhabdomyolysis: a prospective trial
Authors: Graf Helen , Gräfe Caroline , Bruegel Mathias , Zoller Michael , Maciuga Nils , Frank Sandra , Weidhase Lorenz , Paal Michael , Scharf Christina
Published: June 2024

Background

Rhabdomyolysis is a serious condition that can lead to acute kidney injury with the need of renal replacement therapy (RRT). The cytokine adsorber Cytosorb® (CS) can be used for extracorporeal myoglobin elimination in patients with rhabdomyolysis. However, data on adsorption capacity and saturation kinetics are still missing.

Methods

The prospective Cyto-SOLVE study (NCT04913298) included 20 intensive care unit patients with severe rhabdomyolysis (plasma myoglobin > 5000 ng/ml), RRT due to acute kidney injury and the use of CS for myoglobin elimination. Myoglobin and creatine kinase (CK) were measured in the patient´s blood and pre- and post-CS at defined time points (ten minutes, one, three, six, and twelve hours after initiation). We calculated Relative Change (RC, %) with: $$1 - \left( {concentration(pre - post)\,/\,concentration\left( {pre} \right)} \right)*100$$. Myoglobin plasma clearances (ml/min) were calculated with: $$\left( {bloodflow*\left( {1 - hematocrit} \right)} \right)*\left( {concentration\left( {pre - post} \right)\,/\,concentration\left( {pre} \right)} \right)$$

Results

There was a significant decrease of the myoglobin plasma concentration six hours after installation of CS (median (IQR) 56,894 ng/ml (11,544; 102,737 ng/ml) vs. 40,125 ng/ml (7879; 75,638 ng/ml) (p < 0.001). No significant change was observed after twelve hours. Significant extracorporeal adsorption of myoglobin can be seen at all time points (p < 0.05) (ten minutes, one, three, six, and twelve hours after initiation). The median (IQR) RC of myoglobin at the above-mentioned time points was − 79.2% (-85.1; -47.1%), -34.7% (-42.7;-18.4%), -16.1% (-22.1; -9.4%), -8.3% (-7.5; -1.3%), and − 3.9% (-3.9; -1.3%), respectively. The median myoglobin plasma clearance ten minutes after starting CS treatment was 64.0 ml/min (58.6; 73.5 ml/min), decreasing rapidly to 29.1 ml/min (26.5; 36.1 ml/min), 16.1 ml/min (11.9; 22.5 ml/min), 7.9 ml/min (5.5; 12.5 ml/min), and 3.7 ml/min (2.4; 6.4 ml/min) after one, three, six, and twelve hours, respectively.

Conclusion

The Cytosorb® adsorber effectively eliminates myoglobin. However, the adsorption capacity decreased rapidly after about three hours, resulting in reduced effectiveness. Early change of the adsorber in patients with severe rhabdomyolysis might increase the efficacy. The clinical benefit should be investigated in further clinical trials.

Trial registration

ClinicalTrials.gov NCT04913298. Registered 07 May 2021, https//clinicaltrials.gov/study/NCT04913298.

Graphical Abstract
Factors affecting communication during telephone triage in medical call centres: a mixed methods systematic review
Authors: Fotland Siri-Linn Schmidt , Midtbø Vivian , Vik Jorunn , Zakariassen Erik , Johansen Ingrid Hjulstad
Published: June 2024

Background

Telephone triage is used to optimise patient flow in emergency primary healthcare. Poor communication can lead to misunderstandings and compromise patient safety. To improve quality, a comprehensive understanding of factors affecting communication in medical call centres in primary care is needed. The aim of this review was to identify such factors and to describe how they affect communication during telephone triage.

Method

A mixed-method systematic review was performed. In April 2021 and June 2023, MEDLINE, Embase, CINAHL, and Web of Science were searched for original studies describing communication during telephone triage in primary care medical call centres handling all types of medical problems from an unselected population. All studies were screened by two authors, blinded to each other’s decisions. Disagreements were resolved by a third author. A framework was created by the thematic synthesis of the qualitative data and later used to synthesise the quantitative data. By using convergent integrated synthesis, the qualitative and quantitative findings were integrated. The Mixed Methods Appraisal Tool was used to assess methodological limitations.

Results

Out of 5087 studies identified in the search, 62 studies were included, comprising 40 qualitative, 16 quantitative and six mixed-method studies. Thirteen factors were identified and organised into four main themes: organisational factors, factors related to the operator, factors related to the caller and factors in the interaction. Organisational factors included availability, working conditions and decision support systems. Factors related to the operator were knowledge and experience, personal qualities and communication strategies. Factors related to the caller were individual differences and the presented medical problem. Factors in the interaction were faceless communication, connection between operator and caller, third-person caller and communication barriers. The factors seem interrelated, with organisational factors affecting all parts of the conversation, and the operator’s communication in particular.

Conclusion

Many factors affect the structure, content, and flow of the conversation. The operators influence the communication directly but rely on the organisation to create a working environment that facilitates good communication. The results are mainly supported by qualitative studies and further studies are needed to explore and substantiate the relevance and effect of individual factors.

Systematic review registration

PROSPERO CRD42022298022.
Perioperative capacity and contextual challenges in teaching hospitals of southern Ethiopia: explanatory sequential mixed-methods research
Authors: Mulugeta Hailemariam , Zemedkun Abebayehu , Mergia Getachew , Abate Semagn M. , Gebremariam Mintesnot , Jemal Bedru , Nenko Getachew , Gebremichael Genet , Besha Aschalew , Aregu Mekonnen B.
Published: June 2024

Background

Previous Ethiopian literature on surgical capacity and challenges has focused on quantitative investigations, lacking contextual understanding. This explanatory sequential mixed-methods research (MMR) aimed to assess perioperative capacity and contextual challenges at three teaching hospitals in southern Ethiopia.

Methods

A quantitative survey assessed workforce, infrastructure, service delivery, financing, and information systems. The survey findings were explained by qualitative semi-structured interviews of twenty perioperative providers. Descriptive statistics were integrated with qualitative thematic analysis findings using the narrative waving approach. Key findings from both datasets were linked using a joint display table.

Results

The survey revealed shortages in the specialist workforce (with a ratio of 0.58 per 100,000 population), surgical volume (at 115 surgeries per 100,000 population), equipment, supplies, financing, and perioperative data tracking. Hospitals’ radiology services and blood products were only available 25–50% of the time, while anesthetic agents and essential laboratory services were often available 51–75% of the time. Perioperative management protocols were used rarely (1–25% of the time). Over 90% of patients lack health insurance coverage. Qualitative data also revealed scarcity of perioperative resources and equipment; unaffordable perioperative costs, lack of health insurance coverage, and unforeseen expenses; poor patient safety culture and communication barriers across the perioperative continuum of care; workforce shortages, job dissatisfaction, and concerns of competence; and weak national governance, and sociopolitical turmoil, and global market volatility exacerbating local challenges. These challenges are linked to risks in quality of care and patient safety, according to clinicians.

Conclusion

The study identifies deficiencies in the health system and sociopolitical landscape affecting safe surgery conduct. It highlights the need for comprehensive health system strengthening to expand workforce, upgrade facilities, improve safety culture, resilience, and leadership to ensure timely access to essential surgery. Exploring external factors, such as the impact of national governance and sociopolitical stability on reform efforts is also essential.
The (In)Vulnerable: the futures of the Halligen in the North Sea in the face of climate change
Authors: Jank-Humann Anna
Published: June 2024

Islands and small island groups are among the areas most affected by global climate change and face major adaptation challenges. Their role as hotspots of climate change impacts is widely recognized in the scientific literature, and it is not uncommon for small islands to act as poster children for particular climate-related vulnerability. Nonetheless, many island communities have a long tradition of living with oceanic influences, and the question is whether such habitats, where terrestrial and marine ecosystems overlap, have characteristics that contribute to greater self-regulation and resilience. The question is further whether and how the future or possible futures of such an exposed region and society could unfold, considering the negative impact of climate change and the resulting burden of natural disasters. The Halligen in the southern North Sea are an exceptional example of such a situation, and they are to be examined in this study particularly due to their extremely uncertain future. Questions regarding the future arise even more urgently due to the rapidly advancing sea-level rise in the course of climate change. They were already evident in a local field research in 2014 and for current reasons the collected interview material shall be analyzed under this prospective point of view. So what, under these harsh circumstances, might the futures of the Halligen look like? What does it mean for the future of a habitat and a society when the constant risk of storm surges is multiplied by the global risk of climate change and rising sea level? By examining this question from an interdisciplinary perspective in the present study, multiple answers can be provided. The futures differ significantly depending on the perspective from which one looks into the future. However, it is precisely this multidimensionality and heterogeneity that can pose an advantage when considering the unpredictability of future developments. Choosing this very specific region for the study also adds to the benefit – because: If the conditions change, if the strength of the environmental influences change in regions where two ecosystems overlap and which are particularly vulnerable due to their islandness, dealing with and adapting to the consequences of global warming becomes a glimpse into the future of all of us.
Characterization of systolic and diastolic function, alongside proteomic profiling, in doxorubicin-induced cardiovascular toxicity in mice
Authors: Krüger Dustin N. , Bosman Matthias , Van Assche Charles X.L. , Wesley Callan D. , Cillero-Pastor Berta , Delrue Leen , Heggermont Ward , Bartunek Jozef , De Meyer Guido R. Y. , Van Craenenbroeck Emeline M. , Guns Pieter-Jan , Franssen Constantijn
Published: June 2024

Background

The anthracycline doxorubicin (DOX) is a highly effective anticancer agent, especially in breast cancer and lymphoma. However, DOX can cause cancer therapy-related cardiovascular toxicity (CTR-CVT) in patients during treatment and in survivors. Current diagnostic criteria for CTR-CVT focus mainly on left ventricular systolic dysfunction, but a certain level of damage is required before it can be detected. As diastolic dysfunction often precedes systolic dysfunction, the current study aimed to identify functional and molecular markers of DOX-induced CTR-CVT with a focus on diastolic dysfunction.

Methods

Male C57BL/6J mice were treated with saline or DOX (4 mg/kg, weekly i.p. injection) for 2 and 6 weeks (respectively cumulative dose of 8 and 24 mg/kg) (n = 8 per group at each time point). Cardiovascular function was longitudinally investigated using echocardiography and invasive left ventricular pressure measurements. Subsequently, at both timepoints, myocardial tissue was obtained for proteomics (liquid-chromatography with mass-spectrometry). A cohort of patients with CTR-CVT was used to complement the pre-clinical findings.

Results

DOX-induced a reduction in left ventricular ejection fraction from 72 ± 2% to 55 ± 1% after 2 weeks (cumulative 8 mg/kg DOX). Diastolic dysfunction was demonstrated as prolonged relaxation (increased tau) and heart failure was evident from pulmonary edema after 6 weeks (cumulative 24 mg/kg DOX). Myocardial proteomic analysis revealed an increased expression of 12 proteins at week 6, with notable upregulation of SERPINA3N in the DOX-treated animals. The human ortholog SERPINA3 has previously been suggested as a marker in CTR-CVT. Upregulation of SERPINA3N was confirmed by western blot, immunohistochemistry, and qPCR in murine hearts. Thereby, SERPINA3N was most abundant in the endothelial cells. In patients, circulating SERPINA3 was increased in plasma of CTR-CVT patients but not in cardiac biopsies.

Conclusion

We showed that mice develop heart failure with impaired systolic and diastolic function as result of DOX treatment. Additionally, we could identify increased SERPINA3 levels in the mice as well as patients with DOX-induced CVT and demonstrated expression of SERPINA3 in the heart itself, suggesting that SERPINA3 could serve as a novel biomarker.