bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-stage acellular dermal matrix reconstruction of defects in the nose and ears with exposed cartilage: a prospective case series
Authors: Lei Yung-Hsu , Huang Shu-Hung
Published: December 2022

Background

The treatment of soft tissue defects with exposed cartilage after tumor excision is challenging. Local flap reconstruction causes occasional scarring, especially in non-Caucasian populations. Scar treatment requires secondary procedures for aesthetic modifications. Two-step reconstruction with an acellular dermal matrix addresses this issue and yields highly acceptable aesthetic resultsWe aimed to investigate the efficacy of an artificial dermal matrix cover using one-step reconstruction for defects with cartilage exposure.

Methods

From July 2018 to September 2020, seven patients were enrolled and underwent a single-stage operation using acellular dermal matrices. Patients were followed up for at least 6 months and the size of the wound, days to heal, patient satisfaction, and scar scale scores were recorded.

Results

Patients were followed up for an average of 25.7 months. The average time to heal was 23.4 days postoperatively. No hyperpigmentation, tumor recurrence, or retraction was noted. High acceptance and satisfaction with the outcome were observed in all patients.

Conclusions

Single-stage reconstruction yielded high acceptance of aesthetic results similar to that in two-stage reconstruction. Less time and cost make this an effective and efficient treatment for soft tissue defects compared with traditional techniques.
The effect of mechanical and chemo-mechanical temporary cement cleaning methods on shear bond strength with self-adhesive resin cement (an in-vitro study)
Authors: Arafa Ahmed Mohamed , Aboalazm Emad , Kamel Mostafa Hussein
Published: December 2022

Background

Adhesive tooth-colored restorations are strongly dependent on the substrate surface cleanliness to allow intimate contact between resin cement and dentin surface, so several methods were adopted for the total cleaning of temporary cement residues. This study aimed to assess the effect of mechanical and chemo-mechanical cleaning methods of temporary cement on the immediate shear bond strength of self-adhesive resin cement to dentin surface.

Methods

Forty freshly extracted lower first premolars were cut to expose a flat dentin surface. Discs of temporary crown composite resin material were constructed and cemented to the flat dentin surface using resin-based and non-eugenol temporary cement then stored at room temperature in distilled water. Dividing of samples into two groups according to the method of temporary cement cleaning. Group I (n = 20) mechanical cleaning using the rotary instrument, and group II (n = 20) chemo-mechanical cleaning using chlorhexidine-containing scrub. CAD/CAM reinforced Composite discs were bonded to the dentin surface using self-adhesive composite resin cement, then measurement of shear bond strength was done using a universal testing machine. Further analysis of failure mode after debonding was performed by Scanning electron microscope.

Results

No statistically significant difference was found between the mean shear bond strength of the two cleaning methods (P-value = 0.636). Regardless of the cleaning method, the group cemented with resin-based temporary cement showed statistically significantly higher mean shear bond strength than non-eugenol temporary cement (P-value = 0.048).

Conclusion

Both cleaning methods (mechanical and chemo-mechanical) applied in this study were effective in cleaning temporary cement remnants from the dentin substrate surface with statistically significant differences between results of shear bond strength with significantly higher values recorded with resin-based temporary cement.
Effects of mindfulness-based stress reduction training on rumination in patients with breast cancer
Authors: Bagherzadeh Razieh , Sohrabineghad Rezvan , Gharibi Taiebeh , Mehboodi Farkhondeh , Vahedparast Hakimeh
Published: December 2022

Background

Breast cancer has been a serious public health dilemma for women worldwide, with not only physical and social impairments but also psychological stress responses such as rumination. Rumination is a constant preoccupation with thoughts. The present study aimed to investigate the effectiveness of mindfulness-based stress reduction training in lowering rumination among women diagnosed with breast cancer.

Method

This randomized controlled trial with a pretest, posttest, control group, and one-month follow-up design included 46 female breast cancer survivors, recruited from the clinics and hematology wards of Bushehr, Iran. The inclusion criterion was that at least three months should have passed since the last chemotherapy/radiotherapy. The participants were randomly assigned to two experimental and control groups. The experimental group received eight sessions of mindfulness-based stress reduction training. A demographic information form and a rumination questionnaire were used for data collection, and the participants completed the questionnaire in the pretest, posttest, and follow-up stages. Chi-square, Mann–Whitney U, and repeated-measures ANOVA were used to analyze the data. P < 0.05 was considered statistically significant.

Results

There was no significant difference in the rumination scores of the experimental group at three measurement stages. For the control group, the mean rumination scores on the posttest and follow-up were both significantly higher than on the pre-test (P < 0.001). The control group's mean follow-up rumination score was significantly higher than that of the post-test (P = 0.02). A comparison of the two groups adjusted for the baseline showed a significant difference between them in terms of the mean rumination score on the post-test (P = 0.01) and follow-up (P < 0.001).

Conclusion

The experimental group was more successful in avoiding increased rumination than the control group, an ability that can be attributed to the effect of mindfulness training. The use of this method is recommended because it is non-invasive, non-pharmacological, free from complications, and can be easily performed by women. However, future studies should consider larger samples and long-term follow-ups.
Video-based communication assessment for weight management counseling training in medical residents: a mixed methods study
Authors: Faro Jamie M. , D’Addario Angelo , King Ann M. , Mazor Kathleen M. , Pbert Lori , Sadasivam Rajani S. , Geller Alan C. , Murphy Elizabeth A. , Ockene Judith K.
Published: December 2022

Background

Physician delivered weight management counseling (WMC) occurs infrequently and physicians report lack of training and poor self-efficacy. The purpose of this study was to develop and test the Video-based Communication Assessment (VCA) for weight management counseling (WMC) training in medical residents.

Methods

This study was a mixed methods pilot conducted in 3 phases. First, we created five vignettes based on our prior data and expert feedback, then administered the vignettes via the VCA to Internal Medicine categorical residents (n = 16) from a University Medical School. Analog patients rated responses and also provided comments. We created individualized feedback reports which residents were able to view on the VCA. Lastly, we conducted debriefing interviews with the residents (n = 11) to obtain their feedback on the vignettes and personalized feedback. Interviews were transcribed, and we used thematic analysis to generate and apply codes, followed by identifying themes.

Results

Descriptive statistics were calculated and learning points were created for the individualized feedback reports. In VCA debriefing interviews with residents, five themes emerged: 1) Overall the VCA was easy to use, helpful and more engaging than traditional learning and assessment modes, 2) Patient scenarios were similar to those encountered in the clinic, including diversity, health literacy and different stages of change, 3) The knowledge, skills, and reminders from the VCA can be transferred to practice, 4) Feedback reports were helpful, to the point and informative, including the exemplar response of how to best respond to the scenario, and 5) The VCA provide alternatives and practice scenarios to real-life patient situations when they aren’t always accessible.

Conclusions

We demonstrated the feasibility and acceptability of the VCA, a technology delivered platform, for delivering WMC to residents. The VCA exposed residents to diverse patient experiences and provided potential opportunities to tailor providers responses to sociological and cultural factors in WMC scenarios. Future work will examine the effect of the VCA on WMC in actual clinical practice.
Acceptable objectives of empirical research in bioethics: a qualitative exploration of researchers’ views
Authors: Mihailov Emilian , Provoost Veerle , Wangmo Tenzin
Published: December 2022

Background

This is the first qualitative study to investigate how researchers, who do empirical work in bioethics, relate to objectives of empirical research in bioethics (ERiB). We explore reasons that make some objectives more acceptable, while others are deemed less acceptable.

Methods

Using qualitative exploratory study design, we interviewed bioethics researchers, who were selected to represent different types of scholars working in the field. The interview data of 25 participants were analyzed in this paper using thematic analysis.

Results

From the eight objectives presented to the study participants, understanding the context of a bioethical issue and identifying ethical issues in practice received unanimous agreement. Participants also supported other objectives of ERiB but with varying degrees of agreement. The most contested objectives were striving to draw normative recommendations and developing and justifying moral principles. The is-ought gap was not considered an obstacle to ERiB, but rather a warning sign to critically reflect on the normative implications of empirical results.

Conclusions

Our results show that the most contested objectives are also the more ambitious ones, whereas the least contested ones focus on producing empirical results. The potential of empirical research to be useful for bioethics was mostly based on the reasoning pattern that empirical data can provide a testing ground for elements of normative theory. Even though empirical research can inform many parts of bioethical inquiry, normative expertise is recommended to guide ERiB. The acceptability of ambitious objectives for ERiB boils down to finding firm ground for the integration of empirical facts in normative inquiry.
A machine learning approach for predicting high risk hospitalized patients with COVID-19 SARS-Cov-2
Authors: Bottrighi Alessio , Pennisi Marzio , Roveta Annalisa , Massarino Costanza , Cassinari Antonella , Betti Marta , Bolgeo Tatiana , Bertolotti Marinella , Rava Emanuele , Maconi Antonio
Published: December 2022

Background

This study aimed to explore whether explainable Artificial Intelligence methods can be fruitfully used to improve the medical management of patients suffering from complex diseases, and in particular to predict the death risk in hospitalized patients with SARS-Cov-2 based on admission data.

Methods

This work is based on an observational ambispective study that comprised patients older than 18 years with a positive SARS-Cov-2 diagnosis that were admitted to the hospital Azienda Ospedaliera “SS Antonio e Biagio e Cesare Arrigo”, Alessandria, Italy from February, 24 2020 to May, 31 2021, and that completed the disease treatment inside this structure. The patients’medical history, demographic, epidemiologic and clinical data were collected from the electronic medical records system and paper based medical records, entered and managed by the Clinical Study Coordinators using the REDCap electronic data capture tool patient chart. The dataset was used to train and to evaluate predictive ML models.

Results

We overall trained, analysed and evaluated 19 predictive models (both supervised and unsupervised) on data from 824 patients described by 43 features. We focused our attention on models that provide an explanation that is understandable and directly usable by domain experts, and compared the results against other classical machine learning approaches. Among the former, JRIP showed the best performance in 10-fold cross validation, and the best average performance in a further validation test using a different patient dataset from the beginning of the third COVID-19 wave. Moreover, JRIP showed comparable performances with other approaches that do not provide a clear and/or understandable explanation.

Conclusions

The ML supervised models showed to correctly discern between low-risk and high-risk patients, even when the medical disease context is complex and the list of features is limited to information available at admission time. Furthermore, the models demonstrated to reasonably perform on a dataset from the third COVID-19 wave that was not used in the training phase. Overall, these results are remarkable: (i) from a medical point of view, these models evaluate good predictions despite the possible differences entitled with different care protocols and the possible influence of other viral variants (i.e. delta variant); (ii) from the organizational point of view, they could be used to optimize the management of health-care path at the admission time.
But what do we mean by “health”? A critical perspective on the concept of health in the adolescent transition program of a Norwegian university hospital
Authors: Fløtten Kjersti J. Ø. , Aujoulat Isabelle , Wyller Vegard B. B. , Solevåg Anne Lee
Published: December 2022

Background

To understand better what influences the practice of our transition program, we wanted to explore the underlying theory of health.

Methods

We performed a qualitative content analysis of the written material that guides the program, comprising a quality system guideline, two checklists, a guide to health professionals and managers, and three patient brochures.

Results

The analysis resulted in the formulation of three themes; “Being on top of medical management”, “Ability to promote own health” and “Awareness of own goals and expectations”.

Conclusion

Our analysis indicates that the program content revolves mainly around medical management and that other dimensions of health are not emphasised. We question what the goals of the program are and if these goals are explicit and shared among the program stakeholders. An explicit program theory is vital and needs to be evident in material supporting transition programs.
Malaria in Angola: recent progress, challenges and future opportunities using parasite demography studies
Authors: Tavares Wilson , Morais Joana , Martins José F. , Scalsky Ryan J. , Stabler Thomas C. , Medeiros Márcia M. , Fortes Filomeno J. , Arez Ana Paula , Silva Joana C.
Published: December 2022

Over the past two decades, a considerable expansion of malaria interventions has occurred at the national level in Angola, together with cross-border initiatives and regional efforts in southern Africa. Currently, Angola aims to consolidate malaria control and to accelerate the transition from control to pre-elimination, along with other country members of the Elimination 8 initiative. However, the tremendous heterogeneity in malaria prevalence among Angolan provinces, as well as internal population movements and migration across borders, represent major challenges for the Angolan National Malaria Control Programme. This review aims to contribute to the understanding of factors underlying the complex malaria situation in Angola and to encourage future research studies on transmission dynamics and population structure of Plasmodium falciparum, important areas to complement host epidemiological information and to help reenergize the goal of malaria elimination in the country.
Retraction Note: Decreased expression of miR-939 contributes to chemoresistance and metastasis of gastric cancer via dysregulation of SLC34A2 and Raf/MEK/ERK pathway
Authors: Zhang Jia-Xing , Xu Yi , Gao Ying , Chen Cui , Zheng Zhou-San , Yun Miao , Weng Hui-Wen , Xie Dan , Ye Sheng
Published: December 2022

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-017-0586-y.
Acidic and hypoxic tumor microenvironment regulation by CaO2-loaded polydopamine nanoparticles
Authors: Ruan Shuangrong , Yin Weimin , Chang Jiao , Yang Yan , Sun Jiuyuan , Ma Xiaoyi , Liu Ying , Zang Jie , Liu Yiqiong , Li Yongyong , Ren Tianbin , Dong Haiqing
Published: December 2022

Hypoxia and high accumulation of lactic acid in the tumor microenvironment provide fertile soil for tumor development, maintenance and metastasis. Herein, we developed a calcium peroxide (CaO2)-loaded nanostructure that can play a role of “one stone kill two birds”, i.e., acidic and hypoxic tumor microenvironment can be simultaneously regulated by CaO2 loaded nanostructure. Specifically, CaO2-loaded mesoporous polydopamine nanoparticles modified with sodium hyaluronate (denoted as CaO2@mPDA-SH) can gradually accumulate in a tumor site. CaO2 exposed in acidic microenvironment can succeed in consuming the lactic acid with oxygen generation simultaneously, which could remodel the acid and hypoxia tumor microenvironment. More importantly, the relief of hypoxia could further reduce lactate production from the source by down-regulating the hypoxia inducible factor-1α (HIF-1α), which further down-regulated the glycolysis associated enzymes including glycolysis-related glucose transporter 1 (GLUT1) and lactate dehydrogenase A (LDHA). As a result, CaO2@mPDA-SH alone without the employment of other therapeutics can dually regulate the tumor hypoxia and lactic acid metabolism, which efficiently represses tumor progression in promoting immune activation, antitumor metastasis, and anti-angiogenesis.
Scaling up the “24/7 BHU” strategy to provide round-the-clock maternity care in Punjab, Pakistan: a theory-driven, coproduced implementation study
Authors: Salway Sarah , Mumtaz Zubia , Bhatti Afshan , Barnes Amy , Dawson Jeremy , Jhangri Gian Singh
Published: December 2022

Background

Pakistan’s maternal mortality rate remains persistently high at 186/100,000 live births. The country’s government-run first-level healthcare facilities, the basic health units (BHUs), are an important source of maternity care for rural women. However,BHUsonly operate on working days from 8:00 am to 2:00 pm. Recognizing that this severely constrains access to maternity services, the government is implementing the “24/7 BHU” initiative to upgrade BHUs to provide round-the-clock care. Although based on a successful pilot project, initial reports reveal challenges in scaling up the initiative. This implementation research project aims to address a key concern of the Government of Punjab: How can the 24/7 BHU initiative be successfully implemented at scale to provide high-quality, round-the-clock skilled maternity care in rural Punjab?

Methods

The project consists of two overlapping work packages (WP). WP1 includes three modules generating data at the directorate, district and BHU levels. Module 1 uses document analysis and policy-maker interviews to explicateprogrammetheory and begin to build a system model. Module 2 compares government-collected data with data generated from a survey of 1500 births to assess BHU performance. Module 3 uses institutional ethnographies in 4–5 BHUs in three districts to provide a detailed system for understanding and identifying processes that influence scale-up. WP2 includes two modules. First, two workshops and regular meetings with stakeholders integrate WP1 findings, identify feasible changes and establish priorities. Next, “change ideas” are selected for testing in one district and 2–3 BHUs through carefully documented pilots using the PDSA (plan–do–study–act) improvement approach. An integrated knowledge translation approach will engage key policy and practice stakeholders throughout the project.

Discussion

This theory-driven implementation research project willcoproducesignificant new understandings of the wider system in which the 24/7 BHU initiative is being implemented, and actionable knowledge that will highlight ways the implementation processes might be modified to enable BHUs to meet service provision goals. This study will also produce insights that will be relevant for other South Asian and low- and middle-income countries (LMICs) that experience similar challenges of programme scale-up and delivery of maternal health services to remote and marginalized communities.
Knowledge of HIV/AIDS among married women in Bangladesh: analysis of three consecutive multiple indicator cluster surveys (MICS)
Authors: Hasan Mohammad Nayeem , Tambuly Sumi , Trisha Kaniz Fatema , Haque Md. Ashiqul , Chowdhury Muhammad Abdul Baker , Uddin Md Jamal
Published: December 2022

Married women have a higher risk of contracting human immunodeficiency virus (HIV) or develop acquired immune deficiency syndrome (AIDS) than men. Knowledge of HIV/AIDS contributes significantly to describing the prevalence and consequences of such virus/disease. The study aimed to investigate the level of HIV/AIDS knowledge and the socio-demographic variables that influence HIV/AIDS knowledge among married women in Bangladesh. We used three waves of Multiple Indicator Cluster Survey (MICS), which included 33,843, 20,727, and 29,724 married women from 2006, 2012, and 2019 MICS. A score was prepared through their interrogation to determine the level of knowledge and logistic regression models were used for analyzing the data. This study found that the prevalence of knowledge level of HIV/AIDS in different questions increased from 55.20% in 2006 to 58.69% in 2019. In our study, respondents having highest education had 4.03 (95% CI 3.50–4.64) times more chance to obtain “High Score” in 2019 MICS which is 5.30 times in 2012 MICS (95% CI 4.41–6.37) and 2.58 times in 2006 MICS (95% CI 2.28–2.93) compared to illiterate married women. Moreover, respondents from urban area were 1.13 times more likely to obtain “High Score” in 2019 MICS which is 1.14 times in 2012 MICS and 1.16 times in 2006 MICS, respectively than the rural married women. This study also found respondent’s age, division, mass media access, and wealth status have played an important role in HIV/AIDS knowledge. Although a significant proportion of women had adequate knowledge of HIV/AIDS, more knowledge is still required to protect against such viruses/diseases. Thus, we advocate for the implementation of educational program in the curriculum, counselling, particularly in rural areas, and mass media access to ensure quality knowledge throughout the country.
Suppression of porcine hemagglutinating encephalomyelitis virus replication by resveratrol
Authors: Liu Yuzhu , Song Deguang , Liu Xueli , Wang Yuanqi , Wang Gaili , Lan Yungang
Published: December 2022

Background

Porcine hemagglutinating encephalomyelitis virus (PHEV), a member of the genus Betacoronavirus, is the causative agent of neurological disease in pigs. No effective therapeutics are currently available for PHEV infection. Resveratrol has been shown to exert neuroprotective and antiviral effects. Here resveratrol was investigated for its ability to inhibit PHEV replication in nerve cells and central nervous system tissues.

Methods

Anti-PHEV effect of resveratrol was evaluated using an in vitro cell-based PHEV infection model and employing a mouse PHEV infection model. The collected cells or tissues were used for quantitative PCR analysis, western blot analysis, or indirect immunofluorescence assay. The supernatants were collected to quantify viral loads by TCID50 assay in vitro. EC50 and CC50 were determined by dose–response experiments, and the ratio (EC50/CC50) was used as a selectivity index (SI) to measure the antiviral versus cytotoxic activity.

Results

Our results showed that resveratrol treatment reduced PHEV titer in a dose-dependent manner, with a 50% inhibition concentration of 6.24 μM. A reduction of > 70% of viral protein expression and mRNA copy number and a 19-fold reduction of virus titer were achieved when infected cells were treated with 10 µM resveratrol in a pre-treatment assay. Quantitative PCR analysis and TCID50 assay results revealed that the addition of 10 μM resveratrol to cells after adsorption of PHEV significantly reduced 56% PHEV mRNA copy number and eightfold virus titer. 10 µM resveratrol treatment reduced 46% PHEV mRNA copy number and fourfold virus titer in virus inactivation assay. Moreover, the in vivo data obtained in this work also demonstrated that resveratrol inhibited PHEV replication, and anti-PHEV activities of resveratrol treatment via intranasal installation displayed better than oral gavage.

Conclusion

These results indicated that resveratrol exerted antiviral effects under various drug treatment and virus infection conditions in vitro and holds promise as a treatment for PHEV infection in vivo.
Neoadjuvant radiotherapy for resectable retroperitoneal sarcoma: a meta-analysis
Authors: Li Xiangji , Dong Ruihan , Xiao Mengmeng , Min Li , Luo Chenghua
Published: December 2022

Background

Neoadjuvant radiotherapy (NRT) for resectable retroperitoneal sarcoma (RPS) has been shown to be systematically feasible. Whether NRT has equivalent or better clinical effects compared to surgery alone for RPS patients remains controversial.

Methods

We performed a systematic literature search of PubMed, Web of Science, Embase, ASCO Abstracts, and Cochrane library databases for studies in humans with defined search terms. Articles were independently assessed by 2 reviewers, and only randomized controlled trials and cohort studies were included. The hazard ratios (HRs) of overall survival (OS), recurrence-free survival (RFS), and local recurrence (LR) were extracted from included studies. Heterogeneity among study-specific HRs was assessed by the Q statistic and I2statistic. Overall HR was assessed by random-effects or fixed-effects models. Publication bias was tested by Begg’s tests, and the quality of each study was assessed with the Newcastle Ottawa Scale.

Results

A total of 12 eligible studies with 7778 resectable RPS patients were finally included in this study. The pooled analysis revealed the distinct advantages of NRT as compared to surgery alone, including longer OS (HR = 0.81,P < 0.001), longer RFS (HR = 0.58,P = 0.04), and lower LR (HR = 0.70,P = 0.03). No evidence of publication bias was observed.

Conclusion

NRT is likely to be beneficial for resectable RPS patients in terms of OS and RFS.However, more multicenter clinical trials are needed to confirm these findings.
The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy for unresectable rectal cancer (SUNRISE): interim analysis of a randomized phase II trial
Authors: Liu Wen-Yang , Shi Jin-Ming , Li Ning , Wang Xin , Gao Yuan-Hong , Chi Yihebali , Sun Yong-Kun , Zhao Qing , Zhu Yong-Jian , Chen Hong-Da , Fang Hui , Lu Ning-Ning , Qi Shu-Nan , Chen Bo , Wang Shu-Lian , Song Yong-Wen , Liu Yue-Ping , Li Ye-Xiong , Liu Zheng , Zhou Hai-Tao , Liang Jian-Wei , Wang Xi-Shan , Zhang Hai-Zeng , Tang Yuan , Jin Jing
Published: December 2022

Purpose

The safety of an MRI simulation-guided boost after short-course preoperative radiotherapy (SCPRT) for unresectable rectal cancer is assessed with a planned interim analysis.

Methods and materials

Patients diagnosed with clinical stage T3-4 or regional lymph node-positive disease with positive mesorectal fascia or T4b disease evaluated by pelvic MRI were randomly assigned to the SCPRT-boost group (25 Gy in 5 fractions plus 4 Gy delivered to the gross tumor volume, followed by four cycles of chemotherapy) or preoperative chemoradiotherapy group (50 Gy in 25 fractions with concurrent chemotherapy). Then, patients received total mesorectal excision surgery after preoperative treatment. The primary endpoint was the R0 resection rate. The interim analysis was performed when 42 patients completed their assigned treatments.

Results

From October 2018 to November 2019, a total of 43 patients were enrolled, and 42 patients were included in the interim analysis. During preoperative therapy, grade 3 or above toxicities were observed in 10/21 (47.6%) patients in the experimental group, and 4/21 (19.0%) patients in the control group. A total of 17 (81.0%) and 13 (61.9%) patients in the experimental group and control group underwent surgery, respectively. Overall, 65.1% of the patients achieved R0 resection in the intention-to-treat analysis. Surgery-related adverse complications were observed in 2 patients (11.8%) in the experimental group and 1 patient (7.7%) in the control group.

Conclusion

Our results show that the toxicity of an MRI simulation-guided boost after SCPRT for unresectable rectal cancer is acceptable. Thus, this clinical trial will be continued as planned.
The role of genetic testing in diagnosis and care of inherited cardiac conditions in a specialised multidisciplinary clinic
Authors: Stafford Fergus , Krishnan Neesha , Richardson Ebony , Butters Alexandra , Hespe Sophie , Burns Charlotte , Gray Belinda , Medi Caroline , Nowak Natalie , Isbister Julia C. , Raju Hariharan , Richmond David , Ryan Mark P. , Singer Emma S. , Sy Raymond W. , Yeates Laura , Bagnall Richard D. , Semsarian Christopher , Ingles Jodie
Published: December 2022

Background

The diagnostic yield of genetic testing for inherited cardiac diseases is up to 40% and is primarily indicated for screening of at-risk relatives. Here, we evaluate the role of genomics in diagnosis and management among consecutive individuals attending a specialised clinic and identify those with the highest likelihood of having a monogenic disease.

Methods

A retrospective audit of 1697 consecutive, unrelated probands referred to a specialised, multidisciplinary clinic between 2002 and 2020 was performed. A concordant clinical and genetic diagnosis was considered solved. Cases were classified as likely monogenic based on a score comprising a positive family history, young age at onset, and severe phenotype, whereas low-scoring cases were considered to have a likely complex aetiology. The impact of a genetic diagnosis was evaluated.

Results

A total of 888 probands fulfilled the inclusion criteria, and genetic testing identified likely pathogenic or pathogenic (LP/P) variants in 330 individuals (37%) and suspicious variants of uncertain significance (VUS) in 73 (8%). Research-focused efforts identified 46 (5%) variants, missed by conventional genetic testing. Where a variant was identified, this changed or clarified the final diagnosis in a clinically useful way for 51 (13%). The yield of suspicious VUS across ancestry groups ranged from 15 to 20%, compared to only 10% among Europeans. Even when the clinical diagnosis was uncertain, those with the most monogenic disease features had the greatest diagnostic yield from genetic testing.

Conclusions

Research-focused efforts can increase the diagnostic yield by up to 5%. Where a variant is identified, this will have clinical utility beyond family screening in 13%. We demonstrate the value of genomics in reaching an overall diagnosis and highlight inequities based on ancestry. Acknowledging our incomplete understanding of disease phenotypes, we propose a framework for prioritising likely monogenic cases to solve their underlying cause of disease.
Axl regulated survival/proliferation network and its therapeutic intervention in mouse models of glomerulonephritis
Authors: Zhen Yuxuan , Ren Yan , Medvedovic Mario , Adams David E. , Wang Diping , Shao Wen-Hai
Published: December 2022

Background

Lupus nephritis (LN) is the most common and serious complication of systemic lupus erythematosus (SLE). LN pathogenesis is not fully understood. Axl receptor tyrosine kinase is upregulated and contributes to the pathogenic progress in LN. We have reported that Axl disruption attenuates nephritis development in mice.

Methods

In this study, we analyzed the gene expression profiles with RNA-seq using renal cortical samples from nephritic mice. Axl-KO mice were bred onto a B6.lpr spontaneous lupus background, and renal disease development was followed and compared to the Axl-sufficient B6.lpr mice. Finally, anti-glomerular basement membrane (anti-GBM) Ab-induced nephritic mice were treated with Axl small molecule inhibitor, R428, at different stages of nephritis development. Blood urine nitrogen levels and renal pathologies were evaluated.

Results

Transcriptome analysis revealed that renal Axl activation contributed to cell proliferation, survival, and motility through regulation of the Akt, c-Jun, and actin pathways. Spontaneous lupus-prone B6.lpr mice with Axl deficiency showed significantly reduced kidney damages and decreased T cell infiltration compared to the renal damage and T cell infiltration in Axl-sufficient B6.lpr mice. The improved kidney function was independent of autoAb production. Moreover, R428 significantly reduced anti-GBM glomerulonephritis at different stages of GN development compared to the untreated nephritic control mice. R428 administration reduced inflammatory cytokine (IL-6) production, T cell infiltration, and nephritis disease activity.

Conclusions

Results from this study emphasize the important role of Axl signaling in LN and highlight Axl as an attractive target in LN.
Changing epidemiology of acute kidney injury in critically ill patients with COVID-19: a prospective cohort
Authors: Lumlertgul Nuttha , Baker Eleanor , Pearson Emma , Dalrymple Kathryn V. , Pan Jacqueline , Jheeta Anup , Weerapolchai Kittisak , Wang Yanzhong , Leach Richard , Barrett Nicholas A. , Ostermann Marlies
Published: December 2022

Background

Acute kidney injury (AKI) is common in critically ill patients with coronavirus disease-19 (COVID-19). We aimed to explore the changes in AKI epidemiology between the first and the second COVID wave in the United Kingdom (UK).

Methods

This was an observational study of critically ill adult patients with COVID-19 in an expanded tertiary care intensive care unit (ICU) in London, UK. Baseline characteristics, organ support, COVID-19 treatments, and patient and kidney outcomes up to 90 days after discharge from hospital were compared.

Results

A total of 772 patients were included in the final analysis (68% male, mean age 56 ± 13.6). Compared with wave 1, patients in wave 2 were older, had higher body mass index and clinical frailty score, but lower baseline serum creatinine and C-reactive protein (CRP). The proportion of patients receiving invasive mechanical ventilation (MV) on ICU admission was lower in wave 2 (61% vs 80%; p < 0.001). AKI incidence within 14 days of ICU admission was 76% in wave 1 and 51% in wave 2 (p < 0.001); in wave 1, 32% received KRT compared with 13% in wave 2 (p < 0.001). Patients in wave 2 had significantly lower daily cumulative fluid balance (FB) than in wave 1. Fewer patients were dialysis dependent at 90 days in wave 2 (1% vs. 4%; p < 0.001).

Conclusions

In critically ill adult patients admitted to ICU with COVID-19, the risk of AKI and receipt of KRT significantly declined in the second wave. The trend was associated with less MV, lower PEEP and lower cumulative FB.

Trial registration: NCT04445259.
Interventions to treat and prevent postpartum depression: a protocol for systematic review of the literature and parallel network meta-analyses
Authors: Monks David Thomas , Ankalagi Basavaraj , Singh Preet Mohinder , Carter Ebony , Doering Michelle , Guard Meg , Lenze Shannon
Published: December 2022

Introduction

Postpartum depression has costly consequences for the mother, baby, and society. Numerous pharmacological and non-pharmacological interventions are available for the prevention and treatment of postpartum depression. To date, no attempt has been made to synthesize the evidence from comparisons of interventions both within and across these categories.

Methods

We will perform a systematic review of the literature and perform network meta-analysis of interventions to (a) prevent and (b) treat postpartum depression. This review will include studies of primiparous or multiparous women during pregnancy or within 12 months of delivery of their baby that assess either interventions initiated during pregnancy or within 1 year of childbirth. Comparators will be other eligible interventions or control conditions. The outcome of interests will be related to the antidepressant efficacy of the interventions as well as their acceptability. The published literature will be searched in Ovid MEDLINE 1946-, Embase.com 1947-, Scopus 1823-, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. The search will use a combination of standardized terms and keywords for postpartum depression, a sensitive search filter to limit for randomized controlled trials, and a librarian-created “humans” filter. The search results will be uploaded to the Covidence online systematic review platform (Veritas Health Information Ltd., Victoria, Australia) where two review team members will independently screen articles. We will extract data to include year of publication, language, country, participants (number, demographic data, eligibility criteria, psychiatric symptoms, and co-morbidities), characteristics of the intervention and control conditions, and reported outcomes. Risk of bias for each study will be assessed independently by two review authors using the RoB 2: A revised Cochrane risk of bias tool for randomized trials. Network meta-analysis will be performed using a Bayesian hierarchical model supplemented with a Markov chain Monte Carlo approach.

Discussion

Postpartum depression is a devastating disease with long-lasting consequences. Given the numerous available interventions to both prevent and treat postpartum depression and the great number of studies comparing them, it is imperative that clinicians and patients are provided with an assessment of their comparative efficacy and acceptability.

Systematic review registration

Prospero registration (CRD42022303247).
Targeting the overexpressed mitochondrial protein VDAC1 in a mouse model of Alzheimer’s disease protects against mitochondrial dysfunction and mitigates brain pathology
Authors: Verma Ankit , Shteinfer-Kuzmine Anna , Kamenetsky Nikita , Pittala Srinivas , Paul Avijit , Nahon Crystal Edna , Ouro Alberto , Chalifa-Caspi Vered , Pandey Swaroop Kumar , Monsonego Alon , Vardi Noga , Knafo Shira , Shoshan-Barmatz Varda
Published: December 2022

Background

Alzheimer's disease (AD) exhibits mitochondrial dysfunctions associated with dysregulated metabolism, brain inflammation, synaptic loss, and neuronal cell death. As a key protein serving as the mitochondrial gatekeeper, the voltage-dependent anion channel-1 (VDAC1) that controls metabolism and Ca2+homeostasis is positioned at a convergence point for various cell survival and death signals. Here, we targeted VDAC1 with VBIT-4, a newly developed inhibitor of VDAC1 that prevents its pro-apoptotic activity, and mitochondria dysfunction.

Methods

To address the multiple pathways involved in AD, neuronal cultures and a 5 × FAD mouse model of AD were treated with VBIT-4. We addressed multiple topics related to the disease and its molecular mechanisms using immunoblotting, immunofluorescence, q-RT-PCR, 3-D structural analysis and several behavioral tests.

Results

In neuronal cultures, amyloid-beta (Aβ)-induced VDAC1 and p53 overexpression and apoptotic cell death were prevented by VBIT-4. Using an AD-like 5 × FAD mouse model, we showed that VDAC1 was overexpressed in neurons surrounding Aβ plaques, but not in astrocytes and microglia, and this was associated with neuronal cell death. VBIT-4 prevented the associated pathophysiological changes including neuronal cell death, neuroinflammation, and neuro-metabolic dysfunctions. VBIT-4 also switched astrocytes and microglia from being pro-inflammatory/neurotoxic to neuroprotective phenotype. Moreover, VBIT-4 prevented cognitive decline in the 5 × FAD mice as evaluated using several behavioral assessments of cognitive function. Interestingly, VBIT-4 protected against AD pathology, with no significant change in phosphorylated Tau and only a slight decrease in Aβ-plaque load.

Conclusions

The study suggests that mitochondrial dysfunction with its gatekeeper VDAC1 is a promising target for AD therapeutic intervention, and VBIT-4 is a promising drug candidate for AD treatment.
Assessing the causes and consequences of gut mycobiome variation in a wild population of the Seychelles warbler
Authors: Worsley Sarah F. , Davies Charli S. , Mannarelli Maria-Elena , Komdeur Jan , Dugdale Hannah L. , Richardson David S.
Published: December 2022

Background

Considerable research has focussed on the importance of bacterial communities within the vertebrate gut microbiome (GM). However, studies investigating the significance of other microbial kingdoms, such as fungi, are notably lacking, despite their potential to influence host processes. Here, we characterise the fungal GM of individuals living in a natural population of Seychelles warblers (Acrocephalus sechellensis). We evaluate the extent to which fungal GM structure is shaped by environment and host factors, including genome-wide heterozygosity and variation at key immune genes (major histocompatibility complex (MHC) and Toll-like receptor (TLR)). Importantly, we also explore the relationship between fungal GM differences and subsequent host survival. To our knowledge, this is the first time that the genetic drivers and fitness consequences of fungal GM variation have been characterised for a wild vertebrate population.

Results

Environmental factors, including season and territory quality, explain the largest proportion of variance in the fungal GM. In contrast, neither host age, sex, genome-wide heterozygosity, norTLR3genotype was associated with fungal GM differences in Seychelles warblers. However, the presence of four MHC-I alleles and one MHC-II allele was associated with changes in fungal GM alpha diversity. Changes in fungal richness ranged from between 1 and 10 sequencing variants lost or gained; in some cases, this accounted for 20% of the fungal variants carried by an individual. In addition to this, overall MHC-I allelic diversity was associated with small, but potentially important, changes in fungal GM composition. This is evidenced by the fact that fungal GM composition differed between individuals that survived or died within 7 months of being sampled.

Conclusions

Our results suggest that environmental factors play a primary role in shaping the fungal GM, but that components of the host immune system—specifically the MHC—may also contribute to the variation in fungal communities across individuals within wild populations. Furthermore, variation in the fungal GM can be associated with differential survival in the wild. Further work is needed to establish the causality of such relationships and, thus, the extent to which components of the GM may impact host evolution.
Alterations of oral microbiota and impact on the gut microbiome in type 1 diabetes mellitus revealed by integrated multi-omic analyses
Authors: Kunath B. J. , Hickl O. , Queirós P. , Martin-Gallausiaux C. , Lebrun L. A. , Halder R. , Laczny C. C. , Schmidt T. S. B. , Hayward M. R. , Becher D. , Heintz-Buschart A. , de Beaufort C. , Bork P. , May P. , Wilmes P.
Published: December 2022

Background

Alterations to the gut microbiome have been linked to multiple chronic diseases. However, the drivers of such changes remain largely unknown. The oral cavity acts as a major route of exposure to exogenous factors including pathogens, and processes therein may affect the communities in the subsequent compartments of the gastrointestinal tract. Here, we perform strain-resolved, integrated meta-genomic, transcriptomic, and proteomic analyses of paired saliva and stool samples collected from 35 individuals from eight families with multiple cases of type 1 diabetes mellitus (T1DM).

Results

We identified distinct oral microbiota mostly reflecting competition between streptococcal species. More specifically, we found a decreased abundance of the commensal Streptococcus salivarius in the oral cavity of T1DM individuals, which is linked to its apparent competition with the pathobiont Streptococcus mutans. The decrease in S. salivarius in the oral cavity was also associated with its decrease in the gut as well as higher abundances in facultative anaerobes including Enterobacteria. In addition, we found evidence of gut inflammation in T1DM as reflected in the expression profiles of the Enterobacteria as well as in the human gut proteome. Finally, we were able to follow transmitted strain-variants from the oral cavity to the gut at the individual omic levels, highlighting not only the transfer, but also the activity of the transmitted taxa along the gastrointestinal tract.

Conclusions

Alterations of the oral microbiome in the context of T1DM impact the microbial communities in the lower gut, in particular through the reduction of “mouth-to-gut” transfer of Streptococcus salivarius. Our results indicate that the observed oral-cavity-driven gut microbiome changes may contribute towards the inflammatory processes involved in T1DM. Through the integration of multi-omic analyses, we resolve strain-variant “mouth-to-gut” transfer in a disease context.
Assessment of different regions of interest-based methods for [99mTc]Tc DAT-SPECT quantification using an anthropomorphic striatal phantom
Authors: Alexandre-Santos Leonardo , Trevisan Ana Carolina , Pitella Felipe Arriva , Tumas Vitor , Silvah Jose Henrique , Kato Mery , de Moraes Eder Rezende , Wichert-Ana Lauro
Published: December 2022

Background and aims

Molecular imaging of the dopamine transporters (DAT) provides valuable information about neurodegenerative diseases, such as Parkinson’s. This study assessed the accuracy and precision of DAT-SPECT quantification methods.

Methods

Twenty-three DAT-SPECT images of a striatal phantom were acquired. The specific (caudate and putamen) and the non-specific (background activity) chambers were filled with [99mTc]Tc. Different specific-to-non-specific activity ratios (10, 9, 8, 7, 6, 5, 4, 3 and 2 to 1) and the specific binding ratio (SBR) were calculated. Five methods using ROIs were assessed: (a) Manual ROIs on SPECT images; (b) TwoBox and (c) ThreeBox methods and Volume of Interest (VOI) using structural images; (d) MRI and (e) CT. Accuracy was evaluated by the concordance correlation coefficient (CCC) and precision by Pearson’s coefficient and linear regression.

Results

The SBR quantified in the specific and striatal chambers resulted in a CCC increase with a decrease in the nominal values. For lower SBR, MRI and CT showed higher CCCs when caudate ($$\hbox {CCC}_{\mathrm{MRI-CA}}$$

CCC

MRI
-
CA

= 0.89 e $$\hbox {CCC}_{\mathrm{CT-CA}}$$

CCC

CT
-
CA

= 0.84) and putamen ($$\hbox {CCC}_{\mathrm{MRI-PU}}$$

CCC

MRI
-
PU

= 0.86 e $$\hbox {CCC}_{\mathrm{CT-PU}}$$

CCC

CT
-
PU

= 0.82) were evaluated. For striatal assessments, the TwoBox method was the most accurate ($$\hbox {CCC}_{\mathrm{TWOBOX-ST}}$$

CCC

TWOBOX
-
ST

= 0.95). High Pearson’s coefficients were found in the correlations between all methods.

conclusions

All five methods showed high precision even when applied to images with different activities. MRI and CT were the most accurate for assessing the caudate or putamen. To assess the striatal chamber and in the absence of structural information, the TwoBox method is advisable.