bluuebunny/crossref_metadata_2025 huggingface dataset:
Medical students’ perception of general practice: a cross-sectional survey
Authors: Pols D. H. J. , Kamps A. , Runhaar J. , Elshout G. , van Halewijn K. F. , Bindels Patrick J. E. , Stegers–Jager K. M.
Published: February 2023

Background

An increase in the demand for general practitioners is expected in many countries, but only a minority of medical students consider a career in general practice. More detailed and up-to-date knowledge about medical student’s perception of general practice would be helpful for efforts to encourage medical students to consider a career in general practice.

Methods

We performed a cross-sectional single center survey among Dutch medical students to evaluate their perception of general practice at three different stages in their study: Ba1: first-year bachelor students; Ba3: third-year bachelor students; Ma3: third-year master students. The impact of different factors on their attitudes and perceptions was quantified. A multivariate logistic regression was performed with ‘interest in general practice’ as the outcome variable.

Results

The median age for Ba1 was 18 (IQR: 18–19) and 71.5% were female, for Ba3 the median age was 20 (IQR: 20–21) and 70.6% were female and for Ma3 the median age was 25 years (IQR: 24–26) and 73.3% were female. On average, 31.2% of the respondents had a migration background. The mean response rate for this study was 77.1%. Of the participating Ba1 students (n = 340) only 22.4% considered working as a GP after medical school; for Ba3 students (n = 231) this percentage was 33.8%, and for Ma3 students (n = 210) it was significantly higher at 70.5%; in the final multivariate model this corresponded to an odds ratio (OR) of 4.3 (95%-CI:2.6–6.9) compared to Ba1 students. The strongest predictor in the final model was the opinion that general practice provides a pleasant working environment (OR 9.5; 95%-CI: 6.2–14.5).

Conclusion

This study showed that multiple factors are significantly related to medical students’ interest in general practice. Although students believed that general practice does not have a high status within the medical profession, they acknowledged the social importance and the pleasant working environment of general practice. Knowledge obtained in this study can be used when designing a medical curriculum or a general practice course.
From the Global North to the Global South: preparing students for away rotations
Authors: Serraino Riccardo , Owachi Darius , Byekwaso Susan Nassaka , Namara Catherine Misango , Naigambi Kennedy , Castelli Francesco , Torti Carlo
Published: February 2023

Makerere University College of Health Sciences, Kampala, Uganda, has established partnerships with several other institutions worldwide, including the University of Brescia and “Magna Græcia” University, which have agreed to collaborate for the primary purpose of student exchange. Our aim is to comment on students’ preparation for away rotations based on the authors’ own experiences and opinions alongside a review of selected papers on the preparation of students for global health and ethical collaboration. Medical electives represent a unique opportunity for all medical students, not merely for those who will work in resource-limited settings due to increasing globalization. The emergence of ethical international collaborations is of paramount importance to stimulate these projects and ensure that they are implemented safely and with adequate preparation even and especially during the COVID-19 pandemic.
Scale-up of a chronic care model-based programme for type 2 diabetes in Belgium: a mixed-methods study
Authors: Danhieux Katrien , Buffel Veerle , Remmen Roy , Wouters Edwin , van Olmen Josefien
Published: February 2023

Background

Type 2 diabetes (T2D) is an increasingly dominant disease. Interventions are more effective when carried out by a prepared and proactive team within an organised system — the integrated care (IC) model. The Chronic Care Model (CCM) provides guidance for its implementation, but scale-up of IC is challenging, and this hampers outcomes for T2D care. In this paper, we used the CCM to investigate the current implementation of IC in primary care in Flanders (Belgium) and its variability in different practice types.

Methods

Belgium contains three different primary-care practice types: monodisciplinary fee-for-service practices, multidisciplinary fee-for-service practices and multidisciplinary capitation-based practices. Disproportional sampling was used to select a maximum of 10 practices for each type in three Flemish regions, leading to a total of 66 practices. The study employed a mixed methods design whereby the Assessment of Chronic Illness Care (ACIC) was complemented with interviews with general practitioners, nurses and dieticians linked to the 66 practices.

Results

The ACIC scores of the fee-for-service practices — containing 97% of Belgian patients — only corresponded to basic support for chronic illness care for T2D. Multidisciplinary and capitation-based practices scored considerably higher than traditional monodisciplinary fee-for-service practices. The region had no significant impact on the ACIC scores. Having a nurse, being a capitation practice and having a secretary had a significant effect in the regression analysis, which explained 75% of the variance in ACIC scores. Better-performing practices were successful due to clear role-defining, task delegation to the nurse, coordination, structured use of the electronic medical record, planning of consultations and integration of self-management support, and behaviour-change intervention (internally or using community initiatives). The longer nurses work in primary care practices, the higher the chance that they perform more advanced tasks.

Conclusions

Besides the presence of a nurse or secretary, also working multidisciplinary under one roof and a capitation-based financing system are important features of a system wherein IC for T2D can be scaled-up successfully. Belgian policymakers should rethink the role of paramedics in primary care and make the financing system more integrated. As the scale-up of the IC varied highly in different contexts, uniform roll-out across a health system containing multiple types of practices may not be successful.
Patient-centered care in the Middle East and North African region: a systematic literature review
Authors: Alkhaibari Reeham Ahmed , Smith-Merry Jennifer , Forsyth Rowena , Raymundo Gianina Marie
Published: February 2023

Background

The need for patient centered care (PCC) and its subsequent implementation has gained policy maker attention worldwide. Despite the evidence showing the benefits and the challenges associated with practicing PCC in western countries there has been no comprehensive review of the literature on PCC practice in the Middle East and North African (MENA) region, yet there is good reason to think that the practices of PCC in these regions would be different.

Objectives

This paper summarizes the existing research on the practice of PCC in the MENA region and uses this analysis to consider the key elements of a PCC definition based on MENA cultural contexts.

Methods

Five electronic databases were searched (EMBASE, Cochrane, Medline, CINAHL and Scopus) using the search terms: patient OR person OR client OR consumer AND centered OR centred AND care. The MENA countries included were Bahrain, Iran, Iraq, Jordan, Kuwait, Lebanon, Oman, Palestine, Israel, Qatar, Saudi Arabia, Syria, United Arab Emirates, Yemen, Algeria, Egypt, Libya, Morocco, Tunisia, Djibouti, Pakistan, Sudan, and Turkey. Identified papers were imported to Covidence where they were independently reviewed against the inclusion criteria by two authors. The following data were extracted for each paper: author, year, location (i.e., country), objectives, methodology, study population, and results as they related to patient centred care.

Result

The electronic search identified 3582 potentially relevant studies. Fifty articles met the inclusion criteria. Across all papers five themes were identified: 1) patient centered care principles; 2) patient and physician perceptions of PCC; 3) facilitators of PCC; 4) implementation and impact of PCC; and 5) barriers to PCC.

Conclusion

The preliminary findings suggest that the concept of PCC is practiced and supported to a limited extent in the MENA region, and that the implementation of PCC might be impacted by the cultural contexts of the region. Our review therefore highlights the importance of establishing patient-centered care definitions that clearly incorporate cultural practices in the MENA region. The elements and impact of culture in the MENA region should be investigated in future research.
Developing a single-stage continuous process strategy for vitamin B12 production with Propionibacterium freudenreichii
Authors: Calvillo Álvaro , Pellicer Teresa , Carnicer Marc , Planas Antoni
Published: February 2023

Background

Vitamin B12 is a widely used compound in the feed and food, healthcare and medical industries that can only be produced by fermentation because of the complexity of its chemical synthesis. Besides, the use of Generally Recognized as Safe (GRAS) and Qualified Presumption of Safety (QPS) microorganisms, like Propionibacterium freudenreichii, especially non-GMO wild-type producers, are becoming an interesting alternative in markets where many final consumers have high health and ecological awareness. In this study, the production of vitamin B12 using the Propionibacterium freudenreichii NBRC 12391 wild-type strain was characterized and optimized in shake flasks before assessing several scale-up strategies.

Results

Initial results established that: (i) agitation during the early stages of the culture had an inhibitory effect on the volumetric production, (ii) 5,6-dimethylbenzimidazole (DMBI) addition was necessary for vitamin B12 production, and (iii) kinetics of vitamin B12 accumulation were dependent on the induction time when DMBI was added. When scaling up in a bioreactor, both batch and fed-batch bioprocesses proved unsuitable for obtaining high volumetric productivities mainly due to carbon source limitation and propionic acid inhibition, respectively. To overcome these drawbacks, an anaerobic single-phase continuous bioprocess strategy was developed. This culture strategy was maintained stable during more than 5 residence times in two independent cultures, resulting in 5.7-fold increase in terms of volumetric productivity compared to other scale-up strategies.

Conclusion

Overall, compared to previously reported strategies aimed to reduce propionic acid inhibition, a less complex anaerobic single-phase continuous and more scalable bioprocess was achieved.
Study on the correlation between B vitamins and breast cancer
Authors: Xie Siqi , Tan Mingjian , Li Hongwan , Li Lv , Zhang Hengyu , Wang Qing , Li Sijia , Yang Jiali , Xie Haoling , Chen Pengyan , Liu Dequan , Guo Rong , Tang Shicong
Published: February 2023

Background

Relevant studies suggest that serum vitamin level is related to the risk of breast cancer, and dietary pattern and drug supplementation can significantly affect the level of vitamin in the body. Therefore, intervention of vitamin level in the body is expected to be a potential strategy to reduce the risk of breast cancer. However, the current epidemiological findings of serum vitamin levels and breast cancer risk are inconsistent, and the relationship between serum vitamin and breast cancer is still controversial. In this study, we compared the serum vitamin expression levels of healthy people, benign breast patients, and breast cancer patients, and evaluated the relationship between B vitamin levels and breast cancer risk.

Methods

The study used liquid chromatography-tandem mass spectrometry to determine the serum vitamin levels of 520 people who attended Yunnan Cancer Hospital from September 2020 to December 2020. After screening by exclusion criteria, 38 patients with benign breast diseases, 87 patients with breast cancer and 91 healthy controls were finally included. The kruskal–wallis H test was used to compare the differences in serum vitamin levels of subjects. Χ2 test was used to evaluate the relationship between B vitamin level and age,BMI,TNM staging,Ki-67,Her-2,surgery and chemotherapy, and other baseline characteristics and through binary logistic regression analysis, calculating odds ratio and 95% confidence interval (CI) to evaluate the relationship between B vitamins and breast cancer risk.

Conclusion

The levels of VitB1 and VitB5 in the serum of breast cancer patients and patients with benign breast diseases were higher than those in the healthy control group, while the expression levels of VitB3 in breast cancer patients were lower than those in the healthy control group and the breast benign disease groups. The level of VitB1 was positively correlated with breast cancer risk. The VitB3 level was negatively correlated with breast cancer risk. The VitB5 level is not significantly related to the risk of breast cancer.
“Two birds with one stone” strategy for the lung cancer therapy with bioinspired AIE aggregates
Authors: Lin Yinshan , Yi Mengmeng , Guan Xiaoling , Chen Enen , Yang Langyu , Li Songpei , Li Ying , Zhang Lingmin
Published: February 2023

Aggregation-induced emission luminogens (AIEgens) have emerged as novel phototherapeutic agents with high photostability and excellent performance to induce photodynamic and/or photothermal effects. In this study, a zwitterion-type NIR AIEgens C41H37N2O3S2 (named BITT) with biomimetic modification was utilized for lung cancer therapy. The tumor-associated macrophage (TAM)-specific peptide (CRV) was engineered into the lung cancer cell-derived exosomes. The CRV-engineered exosome membranes (CRV-EM) were obtained to camouflage the BITT nanoparticles (CEB), which targeted both lung cancer cells and TAMs through homotypic targeting and TAM-specific peptide, respectively. The camouflage with CRV-EM ameliorated the surface function of BITT nanoparticles, which facilitated the cellular uptake in both cell lines and induced significant cell death in the presence of laser irradiations in vitro and in vivo. CEB showed improved circulation lifetime and accumulations in the tumor tissues in vivo, which induced efficient photodynamic and photothermal therapy. In addition, CEB induced the tumor microenvironment remodeling as indicated by the increase of CD8 + and CD4 + T cells, as well as a decrease of M2 TAM and Myeloid-derived suppressor cells (MDSCs). Our work developed a novel style of bioinspired AIE aggregates, which could eliminate both lung cancer cells and TAMs, and remodel the tumor environments to achieve an efficient lung cancer therapy. To the best of our knowledge, we are the first to use this style of bioinspired AIE aggregates for photo-mediated immunotherapy in lung cancer therapy.
High-intensity interval training in children and adolescents with special educational needs: a systematic review and narrative synthesis
Authors: Poon Eric Tsz-Chun , Wongpipit Waris , Sun Fenghua , Tse Andy Choi-Yeung , Sit Cindy Hui-Ping
Published: February 2023

Background

High-intensity interval training (HIIT) has been promoted as a time-efficient exercise strategy to improve health and fitness in children and adolescents. However, there remains little consensus in the literature regarding its efficacy in children and adolescents with special educational needs (SEN). This study aimed to examine HIIT as a means of improving key health and fitness parameters in children and adolescents with SEN.

Methods

A systematic search was conducted on eight databases (MEDLINE, Embase, SPORTDiscus, Web of Science, Scopus, PsycINFO, CINAHL, and Cochrane Library). Studies were eligible if they 1) included an HIIT protocol, 2) examined parameters related to both physical and mental aspects of health and fitness, and 3) examined children and adolescents with SEN aged 5–17 years.

Results

Of the 1727 studies yielded by the database search, 13 (453 participants) were included and reviewed. We found that HIIT generally improved body composition, physical fitness, and cardiometabolic risk biomarkers across a spectrum of SEN (e.g., attention deficit hyperactivity disorder, cerebral palsy, developmental coordination disorder, and mental illness). Improvements in mental health and cognitive performance following HIIT have also been observed.

Conclusion

This review provides up-to-date evidence for HIIT as a viable exercise strategy for children and adolescents with SEN. Further research investigating the benefits of HIIT in a wider range of SEN populations is warranted.

Trial registration

This study was registered in the International Prospective Register of Systematic Review (PROSPERO; registration number CRD42022352696).
ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway
Authors: Chen Feng , Chen Yanting , Ke Qiongwei , Wang Yongxiang , Gong Zheng , Chen Xiongjin , Cai Yujie , Li Shengnan , Sun Yuanhong , Peng Xiaoping , Ji Yao , Zhang Tianzhen , Wu Wenxian , Cui Lili , Wang Yan
Published: February 2023

Background

Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes.

Methods

A meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and the SARS-CoV-2 primary receptor ACE2, ApoE and spike protein. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression.

Results

ApoE gene polymorphism (ε4 carrier genotypes VS non-ε4 carrier genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI 1.18–1.76) and progression (P < 0.00001, OR = 1.85, 95% CI 1.50–2.28) of COVID-19. ApoE interacts with both ACE2 and the spike protein but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1–7.

Conclusions

ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin–angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.
Inhibition of MMPs supports amoeboid angiogenesis hampering VEGF-targeted therapies via MLC and ERK 1/2 signaling
Authors: Chillà Anastasia , Anceschi Cecilia , Frediani Elena , Scavone Francesca , Del Rosso Tommaso , Pelagio Giuseppe , Tufaro Antonio , De Palma Giuseppe , Del Rosso Mario , Fibbi Gabriella , Chiarugi Paola , Laurenzana Anna , Margheri Francesca
Published: February 2023

Background

In the past decades studies on anti-tumoral drugs inhibiting matrix metalloproteinase (MMPs) were disappointing. Recently, we demonstrated that mature endothelial cells (ECs) and endothelial colony forming cells (ECFCs) can switch between invasion modes to cope with challenging environments, performing the “amoeboid angiogenesis” in the absence of proteases activity.

Methods

We first set out to investigate by ELISA if the inhibitors of the main protease family involved in angiogenesis were differently expressed during breast cancer progression. We used Marimastat, a broad-spectrum MMP inhibitor, as a means of inducing amoeboid characteristics and studied VEGF role in amoeboid angiogenesis. Thus, we performed invasion and capillary morphogenesis assay, morphological, cell signaling and in vivo mouse studies.

Results

Our data showed that TIMP1, TIMP2, alpha2-antiplasmin, PAI-1 and cystatin increase in breast cancer serum of patients with primary cancer and lymph node positive compared to healthy women. In vitro results revealed that the most high-powered protease inhibitors able to induce amoeboid invasion of ECFCs were TIMP1, 2 and 3. Surprisingly, Marimastat promotes ECFC invasion and tubular formation in vitro and in vivo, inducing amoeboid characteristics. We observed that the combination of Marimastat plus VEGF doesn’t boost neither cell invasion nor vessel formation capacity. Moreover, inhibition of VEGF activity with Bevacizumab in the presence of Marimastat confirmed that amoeboid angiogenesis is independent from the stimulus of the main vascular growth factor, VEGF.

Conclusions

We underline the importance to consider the amoeboid mechanism of endothelial and cancer cell invasion, probably responsible for the failure of synthetic metalloproteinase inhibitors as cancer therapy and tumor resistance to VEGF-targeted therapies, to set-up new drugs to be used in cancer therapy.
Enteric neuroanatomy and smooth muscle activity in the western diamondback rattlesnake (Crotalus atrox)
Authors: Kohl Tobias , Ridzal Lejla , Kuch Birgit , Hartel Marlene , Kreft Corinna , Musoski Ahmed , Michel Klaus , Luksch Harald , Schemann Michael , Annaházi Anita
Published: February 2023

Background

Gastrointestinal (GI) functions are controlled by the enteric nervous system (ENS) in vertebrates, but data on snakes are scarce, as most studies were done in mammals. However, the feeding of many snakes, including Crotalus atrox, is in strong contrast with mammals, as it consumes an immense, intact prey that is forwarded, stored, and processed by the GI tract. We performed immunohistochemistry in different regions of the GI tract to assess the neuronal density and to quantify cholinergic, nitrergic, and VIPergic enteric neurons. We recorded motility patterns and determined the role of different neurotransmitters in the control of motility. Neuroimaging experiments complemented motility findings.

Results

A well-developed ganglionated myenteric plexus (MP) was found in the oesophagus, stomach, and small and large intestines. In the submucous plexus (SMP) most neurons were scattered individually without forming ganglia. The lowest number of neurons was present in the SMP of the proximal colon, while the highest was in the MP of the oesophagus. The total number of neurons in the ENS was estimated to be approx. 1.5 million. In all regions of the SMP except for the oesophagus more nitric oxide synthase+ than choline-acetyltransferase (ChAT)+ neurons were counted, while in the MP ChAT+ neurons dominated. In the SMP most nerve cells were VIP+, contrary to the MP, where numerous VIP+ nerve fibers but hardly any VIP+ neuronal cell bodies were seen. Regular contractions were observed in muscle strips from the distal stomach, but not from the proximal stomach or the colon. We identified acetylcholine as the main excitatory and nitric oxide as the main inhibitory neurotransmitter. Furthermore, 5-HT and dopamine stimulated, while VIP and the ß-receptor-agonist isoproterenol inhibited motility. ATP had only a minor inhibitory effect. Nerve-evoked contractile responses were sodium-dependent, insensitive to tetrodotoxin (TTX), but sensitive to lidocaine, supported by neuroimaging experiments.

Conclusions

The structure of the ENS, and patterns of gastric and colonic contractile activity of Crotalus atrox are strikingly different from mammalian models. However, the main excitatory and inhibitory pathways appear to be conserved. Future studies have to explore how the observed differences are an adaptation to the particular feeding strategy of the snake.
Gastrodin ameliorates atherosclerosis by inhibiting foam cells formation and inflammation through down-regulating NF-κB pathway
Authors: Xue Xiaofei , Li Fulei , Xu Mengke , Chen Bowen , Zhao Yanyan , Wang Mengyu , Li Ling
Published: February 2023

Background

Gastrodin is an effective polyphenol extracted from Chinese natural herbal Gastrodiae elata Blume, which exhibits antioxidant and anti-inflammatory effects. It has been reported to benefit neurodegenerative diseases, but the effect of Gastrodin on atherosclerosis and the underlying mechanisms remain elusive. The aim of this study is to investigate the function and mechanism of Gastrodin in atherosclerosis.

Methods

Atherosclerosis mouse model was established by fed low density lipoprotein receptor-deficient (Ldlr−/−) mice with a high fat diet (HFD, 20% fat and 0.5 cholesterol) for 8 weeks and Gastrodin was administered daily via oral gavage. Plasma lipid levels were measured using commercial kits. En face and aortic sinus lipid accumulation were analyzed with Oil Red O staining. In vitro cell models using foam cell formation model and classical atherosclerosis inflammation model, macrophages were incubated with oxygenized low-density lipoproteins (ox-LDL) or lipopolysaccharide (LPS) in the presence of different concentration of Gastrodin or vehicle solution. Foam cell formation and cellular lipid content were evaluated by Oil Red O staining and intracellular lipids extraction analysis. Gene expression and proteins related to cholesterol influx and efflux were examined by quantitative reverse transcription PCR (RT-qPCR) and western blotting analysis. Furthermore, the effect of Gastrodin on LPS induced macrophage inflammatory responses and NF-κB pathway were evaluated by RT-qPCR and western blotting analysis.

Results

Gastrodin administration reduced the body weight, plasma lipid levels in Ldlr−/− mice after fed a high fat diet. Oil Red O staining showed Gastrodin-treated mice displayed less atherosclerosis lesion area. Furthermore, Gastrodin treatment significantly ameliorated ox-LDL-induced macrophage-derived foam cells formation through suppressing genes expression related to cholesterol efflux including scavenger receptor class B and ATP-binding cassette transporter A1. Moreover, Gastrodin markedly suppressed pro-inflammatory cytokines secretion and LPS induced inflammatory response in macrophage through downregulating NF-κB pathway.

Conclusions

Our study demonstrated that Gastrodin attenuates atherosclerosis by suppressing foam cells formation and LPS-induced inflammatory response and represents a novel therapeutic target for the treatment of atherosclerosis.
Establishing relationships between particle-induced in vitro and in vivo inflammation endpoints to better extrapolate between in vitro markers and in vivo fibrosis
Authors: McLean Polly , Mueller William , Gosens Ilse , Cassee Flemming R. , Rothen-Rutishauser Barbara , Boyles Matthew , Tran Lang
Published: February 2023

Background

Toxicity assessment for regulatory purposes is starting to move away from traditional in vivo methods and towards new approach methodologies (NAM) such as high-throughput in vitro models and computational tools. For materials with limited hazard information, utilising quantitative Adverse Outcome Pathways (AOPs) in a testing strategy involving NAM can produce information relevant for risk assessment. The aim of this work was to determine the feasibility of linking in vitro endpoints to in vivo events, and moreover to key events associated with the onset of a chosen adverse outcome to aid in the development of NAM testing strategies. To do this, we focussed on the adverse outcome pathway (AOP) relating to the onset of pulmonary fibrosis.

Results

We extracted in vivo and in vitro dose–response information for particles known to induce this pulmonary fibrosis (crystalline silica, specifically α-quartz). To test the in vivo–in vitro extrapolation (IVIVE) determined for crystalline silica, cerium dioxide nanoparticles (nano-CeO2) were used as a case study allowing us to evaluate our findings with a less studied substance. The IVIVE methodology outlined in this paper is formed of five steps, which can be more generally summarised into two categories (i) aligning the in vivo and in vitro dosimetry, (ii) comparing the dose–response curves and derivation of conversion factors.

Conclusion

Our analysis shows promising results with regards to correlation of in vitro cytokine secretion to in vivo acute pulmonary inflammation assessed by polymorphonuclear leukocyte influx, most notable is the potential of using IL-6 and IL-1β cytokine secretion from simple in vitro submerged models as a screening tool to assess the likelihood of lung inflammation at an early stage in product development, hence allowing a more targeted investigation using either a smaller, more targeted in vivo study or in the future a more complex in vitro protocol. This paper also highlights the strengths and limitations as well as the current difficulties in performing IVIVE assessment and suggestions for overcoming these issues.
Preoperative pericardial hematoma in patients with acute type A aortic dissection (AAAD): Do we need an adjusted treatment?
Authors: Kaufeld Tim , Beckmann Erik , Rudolph Linda , Krüger Heike , Natanov Ruslan , Arar Morsi , Korte Wilhelm , Schilling Tobias , Haverich Axel , Martens Andreas , Shrestha Malakh
Published: February 2023

Objective

An acute type A aortic dissection (AAAD) is a critical emergency and remains one of the most challenging diseases in cardiothoracic surgery. The existence of a pericardial hematoma caused by an aortic rupture can dramatically reduce the chances of survival (Jerzewski and Kulik in J Card Surg 29(4):529–530, 2014; Mehta et al. in Circulation 105(2):200–206, 2002; Gilon et al. in Am J Cardiol 103(7):1029–1031, 2009; Isselbacher et al. in Circulation 90(5):2375–2378, 1994). We assessed the surgical outcome of a high-risk group of patients with AAAD and a pericardial hematoma.

Methods

In this study we included 430 Patients (67% male; median age: 64 years) who received surgical treatment between January 2000 and January 2018 at our facility for acute aortic dissection DeBakey type I. We divided the cohort in two groups: Group A consisted of high-risk patients with a pericardial hematoma (n = 162) and Group B of patients without pericardial hematoma (n = 268).

Results

Patients with a preoperative pericardial hematoma had a significantly higher requirement for preoperative mechanical resuscitation (A: 21%; B: 1.5%; P: < 0.001) and were relevantly more frequently admitted to the operation theater with an intubated status (A: 19.8%; B: 8.6%; P: < 0.001). The incidence of visceral malperfusion differed significantly between both groups (A. 11.7%, B. 6:0%; P: 0.034). Limited aortic arch repair (proximal aortic arch replacement) was preferred in the high-risk group (A: 51.9%; B: 40.3%; P: 0.020). However, survival time was generally reduced in these patients (A: 7.5 y; B: 9.9 y).

Conclusion

AAAD patients with preoperative pericardial hematoma present themselves in potentially lethal conditions, with a significantly higher rate of visceral malperfusion. Despite the existence of this risk factor, a limited arch repair was favored. We have proven that cardiac compression is associated with preoperative intubation and mechanical resuscitation. Patients with pericardial hematoma must be further evaluated for preoperative pericardial drainage. In the event of long transfer times to an aortic center a slow drainage should be discussed to prevent early mortality.
Procoxacin bidirectionally inhibits osteoblastic and osteoclastic activity in bone and suppresses bone metastasis of prostate cancer
Authors: Kong Depei , Ye Chen , Zhang Chenxi , Sun Xiaochen , Wang Fubo , Chen Rui , Xiao Guangan , He Shipeng , Xu Jianrong , Rao Xiwu , Ai Jianzhong , Gao Xu , Li Hong , Su Li
Published: February 2023

Background

Bone is the most common site of metastasis of prostate cancer (PCa). PCa invasion leads to a disruption of osteogenic-osteolytic balance and causes abnormal bone formation. The interaction between PCa and bone stromal cells, especially osteoblasts (OB), is considered essential for the disease progression. However, drugs that effectively block the cancer-bone interaction and regulate the osteogenic-osteolytic balance remain undiscovered.

Methods

A reporter gene system was constructed to screen compounds that could inhibit PCa-induced OB activation from 631 compounds. Then, the pharmacological effects of a candidate drug, Procoxacin (Pro), on OBs, osteoclasts (OCs) and cancer-bone interaction were studied in cellular models. Intratibial inoculation, micro-CT and histological analysis were used to explore the effect of Pro on osteogenic and osteolytic metastatic lesions. Bioinformatic analysis and experiments including qPCR, western blotting and ELISA assay were used to identify the effector molecules of Pro in the cancer-bone microenvironment. Virtual screening, molecular docking, surface plasmon resonance assay and RNA knockdown were utilized to identify the drug target of Pro. Experiments including co-IP, western blotting and immunofluorescence were performed to reveal the role of Pro binding to its target. Intracardiac inoculation metastasis model and survival analysis were used to investigate the therapeutic effect of Pro on metastatic cancer.

Results

Luciferase reporter gene consisted of Runx2 binding sequence, OSE2, and Alp promotor could sensitively reflect the intensity of PCa-OB interaction. Pro best matched the screening criteria among 631 compounds in drug screening. Further study demonstrated that Pro effectively inhibited the PCa-induced osteoblastic changes without killing OBs or PCa cells and directly killed OCs or suppressed osteoclastic functions at very low concentrations. Mechanism study revealed that Pro broke the feedback loop of TGF-β/C-Raf/MAPK pathway by sandwiching into 14–3-3ζ/C-Raf complex and prevented its disassociation. Pro treatment alleviated both osteogenic and osteolytic lesions in PCa-involved bones and reduced the number of metastases of PCa in vivo.

Conclusions

In summary, our study provides a drug screening strategy based on the cancer-host microenvironment and demonstrates that Pro effectively inhibits both osteoblastic and osteoclastic lesions in PCa-involved bones, which makes it a promising therapeutic agent for PCa bone metastasis.

Graphical Abstract
The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma
Authors: Feng Mei , Xu Hao , Zhou Wenyuan , Pan Yisheng
Published: February 2023

Background

Advanced gastric cancer (GC) is a lethal malignancy, harboring recurrent alterations in cell cycle pathway, especially the CDKN2A-CDK4/CDK6/CCND1 axis. However, monotherapy of CDK4/6 inhibitors has shown limited antitumor effects for GC, and combination treatments were urgently needed for CDK4/6 inhibitors.

Methods

Here, we performed a comprehensive analysis, including drug screening, pan-cancer genomic dependency analysis, and epigenetic sequencing to identify the candidate combination with CDK4/6 inhibitors. Mechanisms were investigated by bulk RNA-sequencing and experimental validation was conducted on diverse in vitro or in vivo preclinical GC models.

Results

We found that the BRD4 inhibitor JQ1 augments the antitumor efficacy of the CDK4/6 inhibitor abemaciclib (ABE). Diverse in vitro and in vivo preclinical GC models are examined and synergistic benefits from the combination therapy are obtained consistently. Mechanistically, the combination of ABE and JQ1 enhances the cell cycle arrest of GC cells and induces unique characteristics of cellular senescence through the induction of DNA damage, which is revealed by transcriptomic profiling and further validated by substantial in vitro and in vivo GC models.

Conclusion

This study thus proposes a candidate combination therapy of ABE and JQ1 to improve the therapeutic efficacy and worth further investigation in clinical trials for GC.
Effect of hysterectomy on ovarian function: a systematic review and meta-analysis
Authors: Huang Yibao , Wu Meng , Wu Chuqing , Zhu Qingqing , Wu Tong , Zhu Xiaoran , Wu Mingfu , Wang Shixuan
Published: February 2023

Background

Hysterectomy is one of the most frequently gynecologic surgeries performed in premenopausal women. Many premenopausal patients are unwilling to undergo hysterectomy due to the probable decreased ovarian function. The aim of this study is to determine the effect of hysterectomy on ovarian function.

Methods

A meta-analysis has been reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and the A Measurement Tool to Assess Systematic Reviews (AMSTAR) guidelines. We mainly searched the Embase, PubMed and Web of Science databases for eligible studies. The outcomes were the levels of common indicators of ovarian function, such as anti-müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B, estradiol (E2) and luteinizing hormone (LH). The evidence was synthesized using meta-analysis via fixed or random effect model according to heterogeneity. Subgroup analyses were performed to examine the potential sources of heterogeneity.

Results

The 14 included studies were conducted between 1989 and 2021, involving a total of 1,457 premenopausal women with 760 and 697 in the hysterectomy and control group, respectively. We found that hysterectomy damage ovarian function compared to the control group, with lower AMH level [Weighted mean difference (WMD) = -0.56, 95% confidence interval (95% CI): -0.72 to -0.39, P = 0.000], higher FSH levels (WMD = 2.96, 95% CI: 1.47 to 4.44, P = 0.000), lower inhibin B levels (WMD = -14.34, 95% CI: -24.69 to -3.99, P = 0.000) and higher LH levels (WMD = 4.07, 95% CI: 1.78 to 6.37, P = 0.000). In addition, E2 levels have a decreasing trend (WMD = -17.13, 95% CI: -35.10 to 0.85, P = 0.631) in the hysterectomy group but were not statistically significant.

Conclusion

Hysterectomy has a negative impact on ovarian function, especially in female patients over 40 years old. So, the older patients should closely monitor their ovarian function for early diagnosis and treatment of menopausal symptoms.
The end-tidal alveolar dead space fraction for risk stratification during the first week of invasive mechanical ventilation: an observational cohort study
Authors: Bhalla Anoopindar K. , Chau Ariya , Khemani Robinder G. , Newth Christopher J. L.
Published: February 2023

Background

The end-tidal alveolar dead space fraction (AVDSf = [PaCO2−PETCO2]/PaCO2) is a metric used to estimate alveolar dead space. Higher AVDSf on the first day of mechanical ventilation is associated with mortality and fewer ventilator-free days. It is not clear if AVDSf is associated with length of ventilation in survivors, how AVDSf performs for risk stratification beyond the first day of ventilation, or whether AVDSf adds predictive value to oxygenation (oxygenation index [OI]) or severity of illness (Pediatric Risk of Mortality [PRISM III]) markers.

Methods

Retrospective single-center observational cohort study of children and young adults receiving invasive mechanical ventilation. In those with arterial or capillary blood gases, AVDSf was calculated at the time of every blood gas for the first week of mechanical ventilation.

Results

There were 2335 children and young adults (median age 5.8 years [IQR 1.2, 13.2]) enrolled with 8004 analyzed AVDSf values. Higher AVDSf was associated with mortality and longer length of ventilation in survivors throughout the first week of ventilation after controlling for OI and PRISM III. Higher OI was not associated with increased mortality until ≥ 48 h of ventilation after controlling for AVDSf and PRISM III. When using standardized variables, AVDSf effect estimates were generally higher than OI for mortality, whereas OI effect estimates were generally higher than AVDSf for the length of ventilation in survivors. An AVDSf > 0.3 was associated with a higher mortality than an AVDSf < 0.2 within each pediatric acute respiratory distress syndrome severity category.

The maximum AVDSf within 12 h of intensive care unit admission demonstrated good risk stratification for mortality (AUC 0.768 [95% CI 0.732, 0.803]). AVDSf did not improve mortality risk stratification when added to PRISM III but did improve mortality risk stratification when added to the gas exchange components of PRISM III (minimum 12-h PaO2 and maximum 12-h PCO2) (p < 0.00001).

Conclusions

AVDSf is associated with mortality and length of ventilation in survivors throughout the first week of invasive mechanical ventilation. Some analyses suggest AVDSf may better stratify mortality risk than OI, whereas OI may better stratify risk for prolonged ventilation in survivors than AVDSf.
Inter-vendor and inter-observer reliability of diffusion tensor imaging in the musculoskeletal system: a multiscanner MR study
Authors: Chianca Vito , Albano Domenico , Rizzo Stefania , Maas Mario , Sconfienza Luca Maria , Del Grande Filippo
Published: February 2023

Background

To evaluate the inter-observer and inter-vendor reliability of diffusion tensor imaging parameters in the musculoskeletal system.

Methods

This prospective study included six healthy volunteers three men (mean age: 42; range: 31–52 years) and three women (mean age: 36; range: 30–44 years).

Each subject was scanned using different 3 Tesla magnetic resonance scanners from three different vendors at three different sites bilaterally. First, the intra-class correlation coefficient was used to determine between-observers agreement for overall measurements and clinical sites. Next, between-group comparisons were made through the nonparametric Friedman’s test. Finally, the Bland–Altman method was used to determine agreement among the three scanner measurements, comparing them two by two.

Results

A total of 792 measurement were calculated. ICC reported high levels of agreement between the two observers. ICC related to MD, FA, and RD measurements ranged from 0.88 (95% CI 0.85–0.90) to 0.95 (95% CI 0.94–0.96), from 0.85 (95% CI 0.81–0.88) to 0.95 (95% CI 0.93–0.96), and from 0.89 (0.85–0.90) to 0.92 (0.90–0.94).

No statistically significant inter-vendor differences were observed. The Bland–Altmann method confirmed a high correlation between parameter values.

Conclusion

An excellent inter-observer and inter-vendor reliability was found in our study.
ABCB5+ mesenchymal stromal cells therapy protects from hypoxia by restoring Ca2+ homeostasis in vitro and in vivo
Authors: Yan Kaixuan , Zheng Jiaxing , Kluth Mark Andreas , Li Lin , Ganss Christoph , Yard Benito , Magdeburg Richard , Frank Markus H. , Pallavi Prama , Keese Michael
Published: February 2023

Background

Hypoxia in ischemic disease impairs Ca2+ homeostasis and may promote angiogenesis. The therapeutic efficacy of mesenchymal stromal cells (MSCs) in peripheral arterial occlusive disease is well established, yet its influence on cellular Ca2+ homeostasis remains to be elucidated. We addressed the influence of ATP-binding cassette subfamily B member 5 positive mesenchymal stromal cells (ABCB5+ MSCs) on Ca2+ homeostasis in hypoxic human umbilical vein endothelial cells (HUVECs) in vitro and in vivo.

Methods

Hypoxia was induced in HUVECs by Cobalt (II) chloride (CoCl2) or Deferoxamine (DFO). Dynamic changes in the cytosolic- and endoplasmic reticulum (ER) Ca2+ and changes in reactive oxygen species were assessed by appropriate fluorescence-based sensors. Metabolic activity, cell migration, and tube formation were assessed by standard assays. Acute-on-chronic ischemia in Apolipoprotein E knock-out (ApoE−/−) mice was performed by double ligation of the right femoral artery (DFLA). ABCB5+ MSC cells were injected into the ischemic limb. Functional recovery after DFLA and histology of gastrocnemius and aorta were assessed.

Results

Hypoxia-induced impairment of cytosolic and ER Ca2+ were restored by ABCB5+ MSCs or their conditioned medium. Similar was found for changes in intracellular ROS production, metabolic activity, migratory ability and tube formation. The restoration was paralleled by an increased expression of the Ca2+ transporter Sarco-/endoplasmic reticulum ATPase 2a (SERCA2a) and the phosphorylation of Phospholamban (PLN). In acute-on-chronic ischemia, ABCB5+ MSCs treated mice showed a higher microvascular density, increased SERCA2a expression and PLN phosphorylation relative to untreated controls.

Conclusions

ABCB5+ MSCs therapy can restore cellular Ca2+ homeostasis, which may beneficially affect the angiogenic function of endothelial cells under hypoxia in vitro and in vivo.
Safety and efficacy outcomes after intranasal administration of neural stem cells in cerebral palsy: a randomized phase 1/2 controlled trial
Authors: Lv Zhongyue , Li Ying , Wang Yachen , Cong Fengyu , Li Xiaoyan , Cui Wanming , Han Chao , Wei Yushan , Hong Xiaojun , Liu Yong , Ma Luyi , Jiao Yang , Zhang Chi , Li Huanjie , Jin Mingyan , Wang Liang , Ni Shiwei , Liu Jing
Published: February 2023

Background

Neural stem cells (NSCs) are believed to have the most therapeutic potential for neurological disorders because they can differentiate into various neurons and glial cells. This research evaluated the safety and efficacy of intranasal administration of NSCs in children with cerebral palsy (CP). The functional brain network (FBN) analysis based on electroencephalogram (EEG) and voxel-based morphometry (VBM) analysis based on T1-weighted images were performed to evaluate functional and structural changes in the brain.

Methods

A total of 25 CP patients aged 3–12 years were randomly assigned to the treatment group (n = 15), which received an intranasal infusion of NSCs loaded with nasal patches and rehabilitation therapy, or the control group (n = 10) received rehabilitation therapy only. The primary endpoints were the safety (assessed by the incidence of adverse events (AEs), laboratory and imaging examinations) and the changes in the Gross Motor Function Measure-88 (GMFM-88), the Activities of Daily Living (ADL) scale, the Sleep Disturbance Scale for Children (SDSC), and some adapted scales. The secondary endpoints were the FBN and VBM analysis.

Results

There were only four AEs happened during the 24-month follow-up period. There was no significant difference in the laboratory examinations before and after treatment, and the magnetic resonance imaging showed no abnormal nasal and intracranial masses. Compared to the control group, patients in the treatment group showed apparent improvements in GMFM-88 and ADL 24 months after treatment. Compared with the baseline, the scale scores of the Fine Motor Function, Sociability, Life Adaptability, Expressive Ability, GMFM-88, and ADL increased significantly in the treatment group 24 months after treatment, while the SDSC score decreased considerably. Compared with baseline, the FBN analysis showed a substantial decrease in brain network energy, and the VBM analysis showed a significant increase in gray matter volume in the treatment group after NSCs treatment.

Conclusions

Our results showed that intranasal administration of NSCs was well-tolerated and potentially beneficial in children with CP.

Trial registration: The study was registered in ClinicalTrials.gov (NCT03005249, registered 29 December 2016, https://www.clinicaltrials.gov/ct2/show/NCT03005249) and the Medical Research Registration Information System (CMR-20161129-1003).