bluuebunny/crossref_metadata_2025 huggingface dataset:
Associations of childhood trauma with long-term diseases and alcohol and nicotine use disorders in Czech and Slovak representative samples
Authors: Kascakova Natalia , Petrikova Martina , Furstova Jana , Hasto Jozef , Geckova Andrea Madarasova , Tavel Peter
Published: September 2022

Objective

The abuse and neglect of a child is a major public health problem with serious psychosocial, health and economic consequences. The aim of this study was to assess the relationship between various types of childhood trauma, selected long-term diseases and alcohol and nicotine use disorder in Czech and Slovak representative samples.

Methods

Data on retrospective reporting about selected long-term diseases, alcohol and nicotine use disorder (CAGE Questionnaire) and childhood maltreatment (Childhood Trauma Questionnaire; CTQ) in two representative samples (Czech sample: n = 1800, 48.7% men, mean age 46.61 ± 17.4; Slovak sample: n = 1018, 48.7% men, mean age: 46.2 ± 16.6) was collected. Multinomial logistic regression models were used to assess the relationships between childhood maltreatment and long-term diseases.

Results

There is a higher occurrence of some long-term diseases (such as diabetes, obesity, allergy, asthma) and alcohol and nicotine use disorder in the Czech sample; however, in the Slovak sample the associations between child maltreatment and long-term diseases are stronger overall. Emotional abuse predicts the occurrence of all the studied long-term diseases, and the concurrent occurrence of emotional abuse and neglect significantly predicts the reporting of most diseases. All types of childhood trauma were strong predictors of reporting the occurrence of three or more long-term diseases.

Conclusion

The extent of reporting childhood trauma and associations with long-term diseases in the Czech and Slovak population is a challenge for the strengthening of preventive and therapeutic programmes in psychosocial and psychiatric care for children and adolescents to prevent later negative consequences on health.
Personal and sexual boundaries: the experiences of people with intellectual disabilities
Authors: Svae Gøril Brevik , Blixt Line , Søndenaa Erik
Published: September 2022

Background

Previous research shows that people with intellectual disabilities have less knowledge about sexual health and are more vulnerable to victimisation. In cases of sexual abuse, they are likely to encounter the criminal justice system as vulnerable witnesses. Several challenges arise when people with intellectual disabilities are in communication with the criminal justice system. We aimed to explore the perceptions, experiences and knowledge of people with intellectual disabilities regarding personal and sexual boundaries in order to identify factors relevant for preventing sexual abuse, to develop future studies.

Method

The study had a qualitative design. Data were collected from seven people with mild intellectual disabilities (25–40 years; 2 men, five women) through one-to-one interviews in specialised health care services for people with intellectual disabilities (SHCS). The participants lived alone, in group homes and with their families. Many received professional support services. Data were analysed using thematic analysis.

Results

The interviews identified that the participants want to be in romantic relationships and that some, consider sex to be unimportant. Many of them have had trouble finding someone to have a romantic relationship with. The participants were unsure about sexual consent related to sexual activity, though many could explain the concept of consent in other contexts. Many participants reported that they had experienced sexual abuse, including online sexual abuse. Those participants who had reported the sexual abuse had positive experiences obtaining assistance from the criminal justice system. The participants who had experienced sexual abuse reported trauma and fear related to their experiences.

Conclusion

This study highlights the need for information about sexually abusive relationships, risks online and ways to get help. More attention should be given to the impact of trauma, police and mental health treatment following sexual abuse against people with intellectual disabilities.
Venous gas caused by emphysematous pyelonephritis: a case report and review of literature
Authors: Dong Xue , You Shuzong , Zhang Huangqi , Wang Dongnv , Pan Wenting , Zhang Binhao , Huang Shanqiang , Li Xin , Pang Jianxin , Ji Wenbin
Published: September 2022

Background

Emphysematous pyelonephritis (EPN) is a potentially life-threatening disease caused by a gas-producing necrotizing bacterial infection that involves the renal parenchyma, collecting system, and/or perinephric tissue. EPN is often complicated by a previous diagnosis of diabetes mellitus, and venous air bubbles are an uncommon complication of it. We describe a 52-year-old woman who was admitted in coma, with a history of vomiting, and was found to have EPN with air bubbles in the uterine veins. We discuss the presentation, diagnosis, and pathogenesis of this uncommon but clinically significant event, and briefly review other case reports of venous gas or thrombosis caused by EPN.

Case presentation

We report the case of a 52-year-old woman with past history of type 2 diabetes mellitus, presenting with loss of consciousness after vomiting for half a day. Abdominal computed tomography scan revealed unilateral EPN with air bubbles in the uterine veins. The blood, pus, and urine cultures were positive for extended-spectrum beta-lactamase-producing Escherichia coli. The patient’s condition improved well after conservative management comprising supportive measures, broad-spectrum antibiotics, percutaneous drainage therapy, and an open operation.

Conclusions

Venous air bubbles are rare but fatal complication of EPN. Early diagnosis and treatment are critical to ensure good results.
Association and interaction of the MC4R rs17782313 polymorphism with plasma ghrelin, GLP-1, cortisol, food intake and eating behaviors in overweight/obese Iranian adults
Authors: Rahati Sara , Qorbani Mostafa , Naghavi Anoosh , Pishva Hamideh
Published: September 2022

Background

Recent studies have shown that obesity is largely influenced by heredity and created by the interactions between several genes and environmental and behavioral factors. This study aimed to examine association between variant rs17782313 near melanocortin-4 receptor (MC4R) gene and behavioral and hormonal factors then evaluated interactions between variant MC4R rs17782313 with behavioral and hormonal factors on obesity.

Methods

This cross-sectional study included 403 subjects, overweight and/or obesity, aged 20–50 years from Iran. The MC4R rs17782313 data were measured by the PCR–RFLP method. Dietary intake, physical activity, stress, anxiety, depression, appetite and emotional eating were assessed by using validated questionnaires. Ghrelin, glucagon-like peptide-1 and cortisol were measured by radioimmunoassay in plasma samples. Participants were also divided into three groups based on rs17782313 genotype and BMI.

Results

After adjustment for age, gender, energy intake and PA, significant associations were observed between food intake, appetite, emotional eating, stress and physical activity with MC4R rs17782313 (p ˂0.05). Also, significant interactions were observed between fat intake (p-interaction = 0.002), protein intake (p-interaction = 0.01), energy intake (p-interaction = 0.01), emotional eating (p-interaction = 0.02), appetite (p-interaction = 0.04), stress (p-interaction = 0.04), ghrelin (p-interaction = 0.03), cortisol (p-interaction = 0.04) and physical activity (p-interaction = 0.04) and MC4R rs17782313 in terms of BMI.

Conclusion

Interactions between the CC genotype and high intakes of fat and energy, emotional eating, high appetite, and too much stress with high levels of cortisol and ghrelin probably can have an effect on BMI in overweight/obese subjects.
The effects of Twinlight laser treatment on the titanium surface proliferation and osteogenic differentiation of mesenchymal stem cells
Authors: Zhao Mengzhen , Qiu Feng , Song Jianing , Zhang Congcong , Liu Taohong , Wu Mingxuan
Published: September 2022

Background

The study aimed to observe the effects of a Twinlight laser on the titanium surface proliferation of inflammatory Mesenchymal stem cells (MSCs), inflammatory cytokine expression, and osteogenic differentiation.

Methods

The MSCs were collected from bone tissue of healthy individuals.The cellular inflammatory model was established with 1 μg/mL lipopolysaccharide (LPS).Under the cellular inflammatory model,divided into five groups: the normal control group (C); the inflammatory control group (L); Er:YAG laser group (L + E); Nd:YAG laser group (L + N); Er:YAG laser and Nd:YAG laser group (L + E + N). The treated cells were inoculated onto titanium disks.The normal and inflammatory MSCs on the surface of titanium surface were examined by CCK-8, scanning election microscopy (SEM), quantitative real-time polymerase chain reaction (qRT‑PCR) and other methods for their proliferation, growth pattern, expression of inflammatory factors Interleukin-6 (IL-6), Interleukin-8 (IL-8) and osteogenic genes Runx2 (Runt-related transcription factor 2) and alkaline phosphatase (ALP), providing the theoretical basis and experimental data for the Twinlight laser-assisted treatment of peri-implantitis. Statistical analyses were performed using a Student's t test with SPSS 17.0 software.

Results

Through observation using SEM, the cell densities of the L + E + N, L + E, and L + N groups were similar, but cell bodies in the L + E + N group were fuller and each had more than two pseudopodia. The expression level of IL-6 mRNA in the L, L + N, L + E, and L + E + N groups was higher than in group C (P < 0.05), and the expression level of IL-8 mRNA in the L + E + N group was significantly lower than in group L (P < 0.0001). On day 7, the expression level of ALP mRNA in the L, L + N, L + E, and L + E + N groups was lower than in group C (P < 0.05). On day 14, there was no significant difference in the expression level of ALP mRNA among the L + N, L + E + N, and C groups (P > 0.05). On day 7, the expression level of RUNX2 mRNA in the L + E + N group was higher than in group L (P < 0.001). On day 14, the expression level of RUNX2 mRNA in the L + E + N group was higher than in group L (P < 0.01).

Conclusion

Twinlight laser treatment promoted cell proliferation, inhibited the expression of inflammatory cytokines, and effectively enhanced the osteogenic differentiation of cells on a titanium surface.
Vulval Aggressive Angiomyxoma in a 19 year teenager: a case report
Authors: Muskan Vitasta , Adhikari Purbesh , Thapa Baburam Dixit , Shrestha Ramesh
Published: September 2022

Background

Aggressive Angiomyxoma is a benign, slowly growing, locally aggressive and recurrent tumour that occurs in the pelvic-perineal region of females in their reproductive years. It presents as a painless, soft, gelatinous mass and metastasizes rarely. Suspicion can be made based on clinical examination and radiological imaging but final diagnosis is confirmed only after histopathology and immunohistochemistry. The choice of treatment is surgical wide local excision.

Case presentation

We hereby present a case of a 19-year, unmarried lady, with a body mass index of 21 kg/m2, who presented with a chief complaint of painless mass in left vulva which progressively increased in size in the past one year. Clinical examination revealed a large, cauliflower like, exophytic mass of 10 cm × 10 cm size. Radiological imaging confirmed involvement of lymph nodes. Wide local excision with adequate tumour free margin and depth was used as a treatment modality. The diagnosis was confirmed via histopathological examination of the excised specimen. There is no recurrence in the patient up to date.

Conclusion

Aggressive Angiomyxoma is a rare tumour and it is most often misdiagnosed. This report highlights the importance of considering Aggressive Angiomyxoma as a differential diagnosis of vulval masses and the two-step surgical approach for its treatment in low resource setting.
Lived experience of medical management in recurrent vulvovaginal candidiasis: a qualitative study of an uncertain journey
Authors: Bradfield Strydom Moira , Walpola Ramesh L. , McMillan Sara , Khan Sohil , Ware Robert S. , Tiralongo Evelin
Published: September 2022

Background

Recurrent vulvovaginal candidiasis (RVVC) is experienced by up to 10% of pre-menopausal women globally, yet there is limited research exploring the perspective of women living with this challenging condition.

Methods

Semi-structured interviews with Australian women experiencing RVVC were conducted between April–July 2021. Interviews were transcribed verbatim, and qualitative interpretative phenomenological analysis (IPA) was conducted.

Results

Ten RVVC patients were interviewed. IPA revealed an uncertain journey living with RVVC for all participants ranging from initial symptoms and difficulties in obtaining a diagnosis, the trial and error of symptom management, to the overall debilitating impact of living with a personal and intimate health condition. Four key themes were identified: Theme 1 outlined challenges and delays in diagnosis and clinically appropriate management. Theme 2 found that health care professional (HCP) knowledge limitations impacted RVVC management. Theme 3 illustrated the consequences of a lack of HCP support leading to self-referral and self-education. Theme 4 details the significant emotional and psycho-social repercussions of RVVC.

Conclusions

This debilitating, life-long disease has a prolonged effect on women both physically and psychologically. Living with RVVC seems an uncertain journey that, to a large degree, women feel they must navigate alone. While resilience and self-empowerment were noted, better support through evidence-based treatment options, educated and evidence-informed HCPs and a sympathetic social support network is needed to decrease the disease burden. Future clinical management guidelines and patient support need to consider the findings of this study.
Ethnobotanical study of Hakka traditional medicine in Ganzhou, China and their antibacterial, antifungal, and cytotoxic assessments
Authors: Hu Haibo , Yang Yanfang , Aissa Abdallah , Tekin Volkan , Li Jialin , Panda Sujogya Kumar , Huang Hao , Luyten Walter
Published: September 2022

Background

Traditional herbs played a crucial role in the health care of the Hakka people. However, studies to identify these traditional herbs are few. Here we document and assess the potential of these plants for treating microbial infections. Many herbs used by the Hakka people could potentially be a novel medicinal resource.

Methods

Local herb markets were surveyed via semi-structured interviews, complemented by direct observations to obtain information on herbal usage. For each herb selected for this study, extracts in four different solvents were prepared, and tested for activity against 20 microorganisms, as well as cancerous and noncancerous cells. All data were subjected to cluster analysis to discover relationships among herbs, plant types, administration forms, solvents, microorganisms, cells, etc., with the aim to discern promising herbs for medicine.

Results

Ninety-seven Hakka herbs in Ganzhou were documented from 93 plants in 62 families; most are used for bathing (97%), or as food, such as tea (32%), soup (12%), etc. Compared with the Chinese Pharmacopoeia and Chinese Materia Medica, 24 Hakka medicines use different plant parts, and 5 plants are recorded here for the first time as traditional medicines. The plant parts used were closely related with the life cycle: annual and perennial herbs were normally used as a whole plant, and woody plants as (tender) stem and leaf, indicating a trend to use the parts that are easily collected. Encouragingly, 311 extracts (94%) were active against one or more microorganisms. Most herbs were active against Gram-positive bacteria, such asStaphylococcus aureus(67%),Listeria innocua(64%), etc. Cytotoxicity was often observed against a tumor cell, but rarely against normal cells. Considering both antimicrobial activity and cytotoxicity, many herbs reported in this study show promise as medicine.

Conclusion

Hakka people commonly use easily-collected plant parts (aerial parts or entire herb) as medicine. External use of decoctions dominated, and may help combating microbial infections. The results offer promising perspectives for further research since little phytopharmacology and phytochemistry has been published to date.

Graphical Abstract
An ensemble learning with active sampling to predict the prognosis of postoperative non-small cell lung cancer patients
Authors: Hu Danqing , Zhang Huanyao , Li Shaolei , Duan Huilong , Wu Nan , Lu Xudong
Published: September 2022

Background

Lung cancer is the leading cause of cancer death worldwide. Prognostic prediction plays a vital role in the decision-making process for postoperative non-small cell lung cancer (NSCLC) patients. However, the high imbalance ratio of prognostic data limits the development of effective prognostic prediction models.

Methods

In this study, we present a novel approach, namely ensemble learning with active sampling (ELAS), to tackle the imbalanced data problem in NSCLC prognostic prediction. ELAS first applies an active sampling mechanism to query the most informative samples to update the base classifier to give it a new perspective. This training process is repeated until no enough samples are queried. Next, an internal validation set is employed to evaluate the base classifiers, and the ones with the best performances are integrated as the ensemble model. Besides, we set up multiple initial training data seeds and internal validation sets to ensure the stability and generalization of the model.

Results

We verified the effectiveness of the ELAS on a real clinical dataset containing 1848 postoperative NSCLC patients. Experimental results showed that the ELAS achieved the best averaged 0.736 AUROC value and 0.453 AUPRC value for 6 prognostic tasks and obtained significant improvements in comparison with the SVM, AdaBoost, Bagging, SMOTE and TomekLinks.

Conclusions

We conclude that the ELAS can effectively alleviate the imbalanced data problem in NSCLC prognostic prediction and demonstrates good potential for future postoperative NSCLC prognostic prediction.
Health systems resilience in practice: a scoping review to identify strategies for building resilience
Authors: Forsgren Lena , Tediosi Fabrizio , Blanchet Karl , Saulnier Dell D
Published: September 2022

Background

Research on health systems resilience has focused primarily on the theoretical development of the concept and its dimensions. There is an identified knowledge gap in the research on how to build resilience in health systems in practice and ‘what works’ in different contexts. The aim of this study is to identify practical strategies for building resilient health systems from the empirical research on health systems resilience.

Methods

A scoping review included empirical research on health systems resilience from peer-reviewed literature. The search in the electronic databases PubMed, Web of Science, Global Health was conducted during January to March 2021 for articles published in English between 2013 to February 2021. A total of 1771 articles were screened, and data was extracted from 22 articles. The articles included empirical, applied research on strategies for resilience, that observed or measured resilience during shocks or chronic stress through collection of primary data or analysis of secondary data, or if they were a review study of empirical research. A narrative summary was done by identifying action-oriented strategies, comparing them, and presenting them by main thematic areas.

Results

The results demonstrate examples of strategies used or recommended within nine identified thematic areas; use of community resources, governance and financing, leadership, surveillance, human resources, communication and collaboration, preparedness, organizational capacity and learning and finally health system strengthening.

Conclusions

The findings emphasize the importance of improved governance and financing, empowered middle-level leadership, improved surveillance systems and strengthened human resources. A re-emphasized focus on health systems strengthening with better mainstreaming of health security and international health regulations are demonstrated in the results as a crucial strategy for building resilience. A lack of strategies for recovery and lessons learnt from crises are identified as gaps for resilience in future.
A social network analysis to explore collaborative practice in home care: research protocol
Authors: Schorderet Chloé , Bastiaenen Caroline H. G. , Verloo Henk , de Bie Robert A. , Allet Lara
Published: September 2022

Background

The conceptualization of the home as a care environment and maintaining a high standard of care requires different professionals to collaborate. This study will explore collaborative practice in home care, needs and expectations of the stakeholders involved, and identify their roles and tasks. Secondly, it will investigate possible strategies to improve home care management and, more particularly, optimize collaborative practice in home care.

Methods

The study will be conducted during three distinct consecutive phases, within a multiphase mixed-methods design.Phase 1will use a quantitative approach in which a social network analysis will be conducted to have an overview of collaborative practice in home care in French-speaking Switzerland.Phases 2and3will be qualitative and focus on three different situations involving different locations (rural and urban) and different home care functioning (home care provided by agencies and home care providing by independent caregivers). In each situation, semi-structured interviews will be conducted with home care recipients and their home caregivers. Inphase 2, results ofphase 1’s network analysis will be discussed, such as roles, needs, and expectations of all stakeholders involved in home care. Inphase 3,phase 2’s findings will be discussed and strategies to improve home care and to optimize collaborative practice will be explored.

Discussion

Over the past years, home care has grown considerably. Therefore, more and more different caregivers are involved in the recipients' homes. Since optimal coordination between these different caregivers is a prerequisite for quality and safe care, it is essential to investigate the existing collaborative practice and how it is functioning. This study will provide knowledge on roles, needs and expectations of different caregivers involved in home care. It will also allow for strategies to optimize collaborative practice and thus ensure comprehensive care for recipients. Finally, it will serve as a basis for future studies that can be conducted to address identified needs.
Exploring the biological function of immune cell-related genes in human immunodeficiency virus (HIV)-1 infection based on weighted gene co-expression network analysis (WGCNA)
Authors: Bai Ruojing , Li Zhen , Lv Shiyun , Hua Wei , Dai Lili , Wu Hao
Published: September 2022

Background

Acquired immunodeficiency syndrome (AIDS) is a chronic infectious disease characterized by consistent immune dysfunction. The objective of this study is to determine whether immune cell-related genes can be used as biomarkers for the occurrence of AIDS and potential molecular mechanisms.

Methods

A weighted gene co-expression network analysis was performed using the GSE6740 dataset from the Gene Expression Synthesis Database to identify the Hub gene, which contained microarray data from HIV-1 positive (HIV-1+) and HIV-1 negative (HIV-1−) individuals. The HIV-1+-related differentially expressed genes were then identified using the limma package. Subsequently, the characteristic immune cell-related genes were identified as diagnostic biomarkers for HIV-1+ using the random forest model (RF), support vector machine model, and generalized linear model.

Results

MEdarkgreen exhibited the strongest correlation with HIV clinical features of any of these modules. As the best model for diagnosing HIV-1±, RF was used to select four critical immune cell-related genes, namely, ARRB1, DPEP2, LTBP3, and RGCC, and a nomogram model was created to predict the occurrence of HIV-1 infection based on four key immune cell-related genes. Diagnostic genes were shown to be engaged in immune-related pathways, suggesting that immunological molecules, immune cells, and immune pathways all have a role in HIV-1 infection. The CTD database was explored for prospective medications or molecular compounds that might be utilized to treat HIV-1+ patients. = Moreover, in HIV-1+ individuals, the ceRNA network revealed that ARRB1, DPEP2, LTBP3, and RGCC could be regulated by lncRNAs through the corresponding miRNAs. Ultimately, RT-PCR results from clinical blood samples demonstrated that the four diagnostic genes were significantly downregulated in HIV-1+ patients.

Conclusion

We screened four immune cell-related genes, ARRB1, DPEP2, LTBP3, and RGCC, which may be considered as the diagnostic markers for HIV-1/AIDS. Our findings reveal that immune related genes and pathways involved in HIV-1 pathogenesis were regulated on both genetic and epigenetic levels by constructing a ceRNA network associated with lncRNA.
Immune-inflammatory biomarkers and the risk of cardiac injury in COVID-19 patients with diabetes: a retrospective cohort study
Authors: Bo Yi , Yuli Cai , Ye Wang , Junfeng Li , Xiaolin Chen , Yan Bao , Zhongyuan Wen
Published: September 2022

Background

To determine the risk-assessment role of the immune-inflammatory biomarkers on myocardial damage in COVID-19 patients with diabetes mellitus (DM).

Methods

This retrospective study was conducted on 822 COVID-19 inpatients from 1 January to 10 March 2020 at Renmin Hospital of Wuhan University. The demographic data, clinical data, and immune-inflammatory parameters of participants were collected. The predictors of cardiac injury were assessed by Logistics regression analysis.

Results

A total of 246 COVID-19 inpatients were diagnosed with DM (29.9%). The incidence of cardiac injury was higher in patients with DM than in non-DM cases (28.9% vs 9.0%, p < 0.001), even grouped by age, gender, and the level of fasting plasma glucose (FPG). The mortality in diabetic COVID-19 patients with cardiac injury and without cardiac injury was 42.9% and 3.4%, respectively (p < 0.001). COVID-19 patients with DM and cardiac injury presented a decreased number of immunocyte subsets, lower C3 concentration, and a higher level of interleukin-6 (IL-6) and immunoglobulin A (IgA). The independent risk factors for cardiac injury in COVID-19 patients with DM were CD3+CD4+ T cells counts ≤ 288 cells/μl (adjusted Odds ratio (OR), 2.501; 95% confidence interval (CI) 1.282–4.877; p = 0.007) and IL-6 > 25.68mpg/ml (adjusted OR, 4.345; 95% CI 2.192–10.374; p < 0.001) (all Pinteraction < 0.05).

Conclusions

For diabetic patients with COVID-19, cardiac injury not only induce severer immune-inflammatory responses, but also increase in-hospital mortality. The decreased number of CD3+CD4+ T cells and increased IL-6 are recommended to distinguish the people who refer to high risk of cardiac injury and mortality from those persons. However, it remains a testable theory whether decision-making strategies based on the risk status of cardiac injury in COVID-19 patients, especially with DM, would be expected to get better outcomes.
An accurate strategy for pointing the key biocatalytic sites of bre2691A protein for modification of the brevilaterin from Brevibacillus laterosporus
Authors: Han Panpan , Chen Zhou , Liu Yangliu , Ma Aijin , Li Siting , Jia Yingmin
Published: September 2022

Background

Brevilaterin A-E, a novel class of multi-component cationic antimicrobial lipopeptides, were biosynthesized by a non-ribosomal peptides synthetase (NRPS) in Brevibacillus laterosporus. However, the antimicrobial abilities of different brevilaterin components varied greatly, and this multi-component form was impeding the scale production of the excellent component, and a little information about the brevilaterin biosynthesis mechanism was available to apply in brevilaterin design modification. In this study, we used an accurate strategy that revealed the reason for producing multi-component was the substrate selectivity of bre2691A protein being not enough specific and pinpointed the key design sites to make the specificity of bre2691A enhanced.

Results

Bioinformatic analysis revealed that the biocatalytic site of bre2691A, which was an adenylation domain catalyzed and recognized methionine, leucine, valine and isoleucine and thus introduced them into brevilaterins and caused different components (brevilaterin A-E), was consisted of A1 ~ A10 residues named specificity-conferring code. Coupling molecular docking simulations with mutation studies identified A2 and A7 as critical residues, where determined substrate-specificity and impacted activity. The in virto activity assay showed that the A2 mutant (G193A) would lose activity against methionine and have no effect on the other three amino acids, the A7 mutant (G285C) would enhance the catalytic activity against four substrates, especially against leucine at almost a double activity. When the A2 and A7 residues were synchronously mutated, this mutant would be more focused on recognizing leucine.

Conclusions

An accurate strategy that combined with bioinformatics and site-directed mutation techniques revealed the pivotal site A2 and A7 positions of bre2691A protein that could be used to design and modify brevilaterins, thus further providing a reasonable direction of genetic engineering for Brevibacillus laterosporus. A deeper understanding of the function of crucial residues in the adenylation domain would make it get more accurate and highly efficient design and more fully utilized. Furthermore, it would contribute to biotechnological applications, namely for the large centralized synthesis of antimicrobial peptides, or for the optimization of their production.

Graphic Abstract
Implementation of a high cell density fed-batch for heterologous production of active [NiFe]-hydrogenase in Escherichia coli bioreactor cultivations
Authors: Fan Qin , Waldburger Saskia , Neubauer Peter , Riedel Sebastian L. , Gimpel Matthias
Published: September 2022

Background

O2-tolerant [NiFe]-hydrogenases offer tremendous potential for applications in H2-based technology. As these metalloenzymes undergo a complicated maturation process that requires a dedicated set of multiple accessory proteins, their heterologous production is challenging, thus hindering their fundamental understanding and the development of related applications. Taking these challenges into account, we selected the comparably simple regulatory [NiFe]-hydrogenase (RH) from Cupriavidus necator as a model for the development of bioprocesses for heterologous [NiFe]-hydrogenase production. We already reported recently on the high-yield production of catalytically active RH in Escherichia coli by optimizing the culture conditions in shake flasks.

Results

In this study, we further increase the RH yield and ensure consistent product quality by a rationally designed high cell density fed-batch cultivation process. Overall, the bioreactor cultivations resulted in ˃130 mg L−1 of catalytically active RH which is a more than 100-fold increase compared to other RH laboratory bioreactor scale processes with C. necator. Furthermore, the process shows high reproducibility of the previously selected optimized conditions and high productivity.

Conclusions

This work provides a good opportunity to readily supply such difficult-to-express complex metalloproteins economically and at high concentrations to meet the demand in basic and applied studies.
Intratumoral delivery of TransCon™ TLR7/8 Agonist promotes sustained anti-tumor activity and local immune cell activation while minimizing systemic cytokine induction
Authors: Zúñiga Luis Alejandro , Leßmann Torben , Uppal Karan , Bisek Nicola , Hong Enping , Rasmussen Caroline E. , Karlsson Jens-Jakob , Zettler Joachim , Holten-Andersen Lars , Bang Kathy , Thakar Dhruv , Lee Yu-Chi , Martinez Salomon , Sabharwal Simran Singh , Stark Sebastian , Faltinger Frank , Kracker Oliver , Weisbrod Samuel , Müller Robin , Voigt Tobias , Bigott Kornelia , Tabrizifard Mohammad , Breinholt Vibeke Miller , Mirza Amer M. , Rosen David B. , Sprogøe Kennett , Punnonen Juha
Published: September 2022

Background

Intratumoral (IT) delivery of toll-like receptor (TLR) agonists has shown encouraging anti-tumor benefit in preclinical and early clinical studies. However, IT delivery of TLR agonists may lead to rapid effusion from the tumor microenvironment (TME), potentially limiting the duration of local inflammation and increasing the risk of systemic adverse events.

Methods

To address these limitations, TransCon™ TLR7/8 Agonist—an investigational sustained-release prodrug of resiquimod that uses a TransCon linker and hydrogel technology to achieve sustained and predictable IT release of resiquimod—was developed. TransCon TLR7/8 Agonist was characterized for resiquimod release in vitro and in vivo, in mice and rats, and was assessed for anti-tumor efficacy and pharmacodynamic activity in mice.

Results

Following a single IT dose, TransCon TLR7/8 Agonist mediated potent tumor growth inhibition which was associated with sustained resiquimod release over several weeks with minimal induction of systemic cytokines. TransCon TLR7/8 Agonist monotherapy promoted activation of antigen-presenting cells in the TME and tumor-draining lymph nodes, with evidence of activation and expansion of CD8+ T cells in the tumor-draining lymph node and TME. Combination of TransCon TLR7/8 Agonist with systemic immunotherapy further promoted anti-tumor activity in TransCon TLR7/8 Agonist-treated tumors. In a bilateral tumor setting, combination of TransCon TLR7/8 Agonist with systemic IL-2 potentiated tumor growth inhibition in both injected and non-injected tumors and conferred protection against tumor rechallenge following complete regressions.

Conclusions

Our findings show that a single dose of TransCon TLR7/8 Agonist can mediate sustained local release of resiquimod in the TME and promote potent anti-tumor effects as monotherapy and in combination with systemic immunotherapy, supporting TransCon TLR7/8 Agonist as a novel intratumoral TLR agonist for cancer therapy. A clinical trial to evaluate the safety and efficacy of TransCon TLR7/8 Agonist, as monotherapy and in combination with pembrolizumab, in cancer patients is currently ongoing (transcendIT-101; NCT04799054).
In utero particulate matter exposure in association with newborn mitochondrial ND4L10550A>G heteroplasmy and its role in overweight during early childhood
Authors: Cosemans Charlotte , Wang Congrong , Alfano Rossella , Martens Dries S. , Sleurs Hanne , Dockx Yinthe , Vanbrabant Kenneth , Janssen Bram G. , Vanpoucke Charlotte , Lefebvre Wouter , Smeets Karen , Nawrot Tim S. , Plusquin Michelle
Published: September 2022

Background

Mitochondria play an important role in the energy metabolism and are susceptible to environmental pollution. Prenatal air pollution exposure has been linked with childhood obesity. Placental mtDNA mutations have been associated with prenatal particulate matter exposure and MT-ND4L10550A>Gheteroplasmy has been associated with BMI in adults. Therefore, we hypothesized that in utero PM2.5exposure is associated with cord blood MT-ND4L10550A>Gheteroplasmy and early life growth. In addition, the role of cord blood MT-ND4L10550A>Gheteroplasmy in overweight during early childhood is investigated.

Methods

This study included 386 mother-newborn pairs. Outdoor PM2.5concentrations were determined at the maternal residential address. Cord blood MT-ND4L10550A>Gheteroplasmy was determined using Droplet Digital PCR. Associations were explored using logistic regression models and distributed lag linear models. Mediation analysis was performed to quantify the effects of prenatal PM2.5exposure on childhood overweight mediated by cord blood MT-ND4L10550A>Gheteroplasmy.

Results

Prenatal PM2.5exposure was positively associated with childhood overweight during the whole pregnancy (OR = 2.33; 95% CI: 1.20 to 4.51;p = 0.01), which was mainly driven by the second trimester. In addition, prenatal PM2.5exposure was associated with cord blood MT-ND4L10550A>Gheteroplasmy from gestational week 9 – 13. The largest effect was observed in week 10, where a 5 µg/m3increment in PM2.5was linked with cord blood MT-ND4L10550A>Gheteroplasmy (OR = 0.93; 95% CI: 0.87 to 0.99). Cord blood MT-ND4L10550A>Gheteroplasmy was also linked with childhood overweight (OR = 3.04; 95% CI: 1.15 to 7.50;p = 0.02). The effect of prenatal PM2.5exposure on childhood overweight was mainly direct (total effect OR = 1.18; 95% CI: 0.99 to 1.36; natural direct effect OR = 1.20; 95% CI: 1.01 to 1.36)) and was not mediated by cord blood MT-ND4L10550A>Gheteroplasmy.

Conclusions

Cord blood MT-ND4L10550A>Gheteroplasmy was linked with childhood overweight. In addition, in utero exposure to PM2.5during the first trimester of pregnancy was associated with cord blood MT-ND4L10550A>Gheteroplasmy in newborns. Our analysis did not reveal any mediation of cord blood MT-ND4L10550A>Gheteroplasmy in the association between PM2.5exposure and childhood overweight.
Fat-to-muscle ratio as a predictor for dyslipidaemia in transitional-age youth
Authors: Zhang Jia-Xing , Li Wen , Tao Xiu-Juan , Chen Chen , Wang Qing-An , Liu Wan-Lu , Yang Chan , Wang Kai-Rong , Qiu Jiang-Wei , Zhao Yi , Zhang Yu-Hong
Published: September 2022

Background

Although dyslipidaemia may have a crucial impact on cardiovascular health in adults, there is a lack of specific data in transitional-age youth. Therefore, this study attempted to evaluate the association of dyslipidaemia with fat-to-muscle ratio (FMR), and establish FMR thresholds for diagnosing dyslipidaemia in transitional-age youth.

Methods

One thousand six hundred sixty individuals aged 16 to 24 years from the baseline of a subcohort in the Northwest China Natural Population Cohort: Ningxia Project were analysed. Anthropometric characteristics were gauged by a bioelectrical impedance analyser, and dyslipidaemia components were measured using a Beckman AU480 chemistry analyser. Additionally, this study used logistic regression to estimate the risk of dyslipidaemia based on FMR quintiles, and calculate the gender-specific ideal cut-off values of dyslipidaemia and its components by the receiver operating characteristic (ROC) curve.

Results

Of the 1660 participants, aged 19.06 ± 1.14 years, 558 males and 1102 females. The prevalence of dyslipidaemia was 13.4% and was significantly associated with FMR quintiles among all participants (P < 0.05). The ideal values of FMR in diagnosing dyslipidaemia were 0.2224 for males and 0.4809 for females, while males had a higher AUC than females (0.7118 vs. 0.6656). Meanwhile, high FMR values were significantly associated with adverse outcomes of dyslipidaemia, hypercholesterolemia and hypertriglyceridaemia (P < 0.05).

Conclusions

The FMR was positively correlated with the prevalence of dyslipidaemia. The FMR can be used as an effective body composition index for diagnosing dyslipidaemia, especially in males, and preventive strategies should be initiated in transitional-age youth to decrease obesity-related dyslipidaemia.
Myocardial contrast echocardiography assessment of perfusion abnormalities in hypertrophic cardiomyopathy
Authors: Roldan Paola , Ravi Sriram , Hodovan James , Belcik J. Todd , Heitner Stephen B. , Masri Ahmad , Lindner Jonathan R.
Published: September 2022

Background

Perfusion defects during stress can occur in hypertrophic cardiomyopathy (HCM) from either structural or functional abnormalities of the coronary microcirculation. In this study, vasodilator stress myocardial contrast echocardiography (MCE) was used to quantify and spatially characterize hyperemic myocardial blood flow (MBF) deficits in HCM.

Methods

Regadenoson stress MCE was performed in patients with septal-variant HCM (n = 17) and healthy control subjects (n = 15). The presence and spatial distribution (transmural diffuse, patchy, subendocardial) of perfusion defects was determined by semiquantitative analysis. Kinetic analysis of time-intensity data was used to quantify MBF, microvascular flux rate (β), and microvascular blood volume. In patients undergoing septal myectomy (n = 3), MCE was repeated > 1 years after surgery. 

Results

In HCM subjects, perfusion defects during stress occurred in the septum in 80%, and in non-hypertrophied regions in 40%. The majority of septal defects (83%) were patchy or subendocardial, while 67% of non-hypertrophied defects were transmural and diffuse. On quantitative analysis, hyperemic MBF was approximately 50% lower (p < 0.001) in the hypertrophied and non-hypertrophied regions of those with HCM compared to controls, largely based on an inability to augment β, although hypertrophic regions also had blood volume deficits. There was no correlation between hyperemic MBF and either percent fibrosis on magnetic resonance imaging or outflow gradient, yet those with higher degrees of fibrosis (≥ 5%) or severe gradients all had low septal MBF during regadenoson. Substantial improvement in hyperemic MBF was observed in two of the three subjects undergoing myectomy, both of whom had severe pre-surgical outflow gradients at rest.

Conclusion

Perfusion defects on vasodilator MCE are common in HCM, particularly in those with extensive fibrosis, but have a different spatial pattern for the hypertrophied and non-hypertrophied segments, likely reflecting different contributions of functional and structural abnormalities. Improvement in hyperemic perfusion is possible in those undergoing septal myectomy to relieve obstruction. 

Trial registration

ClinicalTrials.gov NCT02560467.

Graphical Abstract
The glycocalyx affects the mechanotransductive perception of the topographical microenvironment
Authors: Chighizola Matteo , Dini Tania , Marcotti Stefania , D’Urso Mirko , Piazzoni Claudio , Borghi Francesca , Previdi Anita , Ceriani Laura , Folliero Claudia , Stramer Brian , Lenardi Cristina , Milani Paolo , Podestà Alessandro , Schulte Carsten
Published: September 2022

The cell/microenvironment interface is the starting point of integrin-mediated mechanotransduction, but many details of mechanotransductive signal integration remain elusive due to the complexity of the involved (extra)cellular structures, such as the glycocalyx. We used nano-bio-interfaces reproducing the complex nanotopographical features of the extracellular matrix to analyse the glycocalyx impact on PC12 cell mechanosensing at the nanoscale (e.g., by force spectroscopy with functionalised probes). Our data demonstrates that the glycocalyx configuration affects spatio-temporal nanotopography-sensitive mechanotransductive events at the cell/microenvironment interface. Opposing effects of major glycocalyx removal were observed, when comparing flat and specific nanotopographical conditions. The excessive retrograde actin flow speed and force loading are strongly reduced on certain nanotopographies upon strong reduction of the native glycocalyx, while on the flat substrate we observe the opposite trend. Our results highlight the importance of the glycocalyx configuration in a molecular clutch force loading-dependent cellular mechanism for mechanosensing of microenvironmental nanotopographical features.

Graphical Abstract
Cartilage targeting therapy with reactive oxygen species-responsive nanocarrier for osteoarthritis
Authors: Jiang Zengxin , Wang Hao , Zhang Zeng , Pan Jianfeng , Yuan Hengfeng
Published: September 2022

Targeting cartilage is a promising strategy for the treatment of osteoarthritis, and various delivery vehicles were developed to assist the therapeutic agents into cartilage. However, the underlying biomechanisms and potential bioactivities remain oversimplified. Inspired by oxidative stress in the pathogenesis of osteoarthritis, we firstly testified the antioxidant capacity of a synthetic small molecule compound, oltipraz (OL), to the chondrocytes treated by IL-1β. Then a functional reactive oxygen species (ROS) responsive nanocarrier, mesoporous silica nanoparticles (MSN) modified with methoxy polyethylene glycol-thioketal, was constructed. In vitro biomolecular results showed that compared with OL alone, MSN-OL could significantly activate Nrf2/HO-1 signaling pathway, which exhibited better ROS-scavenging proficiency and greater anti-apoptotic ability to protect mitochondrial membrane potential of chondrocytes. Further bioinformatics analysis revealed that MSN-OL suppressed clusters of genes associated with extracellular matrix organization, cell apoptosis and cellular response to oxidative stress. Animal experiments further confirmed the great cartilage-protecting ability of MSN-OL through upregulating the expression of Nrf2/HO-1 signaling pathway without obvious toxicity. In summary, this study provided a delivery system through ROS-responsive regulation of the therapeutic agents into chondrocytes of the cartilage, and confirmed the exact biological mechanisms of this innovative strategy.
The prognostic impact of lead times in colorectal cancer patients undergoing cytoreductive surgery and HIPEC
Authors: Jansson Ylva , Graf Wilhelm , Ghanipour Lana
Published: September 2022

Background

National lead time goals have been implemented across Sweden to standardize and improve cancer patient care. However, the prognostic impact of lead times has not yet been studied in patients with colorectal cancer and peritoneal metastases scheduled for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC).

Aim

To study the correlation between lead times and overall survival and operability.

Methods

One hundred forty-eight patients with peritoneal metastases originating from colorectal cancer and scheduled for CRS + HIPEC from June 2012 to December 2019 were identified using a HIPEC register at Uppsala University Hospital. Data were collected from medical records concerning operability, overall survival, recurrence and time from diagnosis, and decision to operate to the date of surgery. Patients who had neoadjuvant therapy or no malignant cells in the resected specimens were excluded. Statistical calculations were made with the chi-squared test, Cox regression analysis, and log-rank test.

Results

The median age was 66 years (27–82). Ninety-five were women and 53 were men. One hundred six underwent CRS + HIPEC, 13 CRS only, and 29 were inoperable (open-close). No difference in overall survival was seen when comparing patients with lead times ≤ 34 days and ≥ 35 days from the decision to operate at the multidisciplinary conference to the surgery but there was a higher frequency of open-close (p = 0.023) in the group with longer lead time. Factors that impacted overall survival were open-close (p < 0.001), liver metastases (p = 0.003), and peritoneal cancer index score ≥ 20 (p < 0.001).

Conclusion

A long lead time from multidisciplinary conference to surgery has no direct impact on overall survival but can result in more cases of inoperability. In a larger cohort, this might translate into decreased survival, and efforts should therefore be made to complete preoperative work up as soon as possible and reduce overall time span. Important factors for survival are related to patient selection and extent of disease.