bluuebunny/crossref_metadata_2025 huggingface dataset:
Digital health competencies in medical school education: a scoping review and Delphi method study
Authors: Khurana Mark P. , Raaschou-Pedersen Daniel E. , Kurtzhals Jørgen , Bardram Jakob E. , Ostrowski Sisse R. , Bundgaard Johan S.
Published: February 2022

Introduction

In order to fulfill the enormous potential of digital health in the healthcare sector, digital health must become an integrated part of medical education. We aimed to investigate which knowledge, skills and attitudes should be included in a digital health curriculum for medical students through a scoping review and Delphi method study.

Methods

We conducted a scoping review of the literature on digital health relevant for medical education. Key topics were split into three sub-categories: knowledge (facts, concepts, and information), skills (ability to carry out tasks) and attitudes (ways of thinking or feeling). Thereafter, we used a modified Delphi method where experts rated digital health topics over two rounds based on whether topics should be included in the curriculum for medical students on a scale from 1 (strongly disagree) to 5 (strongly agree). A predefined cut-off of ≥4 was used to identify topics that were critical to include in a digital health curriculum for medical students.

Results

The scoping review resulted in a total of 113 included articles, with 65 relevant topics extracted and included in the questionnaire. The topics were rated by 18 experts, all of which completed both questionnaire rounds. A total of 40 (62%) topics across all three sub-categories met the predefined rating cut-off value of ≥4.

Conclusion

An expert panel identified 40 important digital health topics within knowledge, skills, and attitudes for medical students to be taught. These can help guide medical educators in the development of future digital health curricula.
Willingness to pay for an mHealth anti-retroviral therapy adherence and information tool: Transitioning to sustainability, Call for life randomised study experience in Uganda
Authors: Naggirinya Agnes Bwanika , Kyomugisha Eunice L. , Nabaggala Maria S. , Nasasira Benson , Akirana Josephine , Oseku Elizabeth , Kiragga Agnes , Castelnuovo Barbara , King Rachel L. , Katabira Elly , Byonanebye Dathan M. , Lamorde Mohammed , Parkes-Ratanshi Rosalind
Published: February 2022

Introduction

Evidence shows benefit of digital technology for people living with human immunodeficiency virus on antiretroviral therapy adherence and retention in care, however, scalability and sustainability have scarcely been evaluated. We assessed participants’ willingness to pay a fee for mHealth “Call for life Uganda” support, a mobile-phone based tool with the objective to assess sustainability and scalability.

Methods

“Call for Life study”, approved by Makerere University, School of Public Health research & ethics committee, at 2 sites in Uganda, evaluated a MoTech based software “CONNECT FOR LIFE™” mHealth tool termed “Call for life Uganda”. It provides short messages service or Interactive Voice Response functionalities, with a web-based interface, allows a computer to interact with humans through use of voice and tones input via keypad. Participants were randomized at 1:1 ratio to Standard of Care or standard of care plus Call for life Uganda. This sends pill reminders, visit reminders, voice messages and self-reported symptom support. At study visits 18 and 24 months, through mixed method approach we assessed mHealth sustainability and scalability. Participants were interviewed on desire to have or continue adherence support and willingness to pay a nominal fee for tool. We computed proportions willing to pay (± 95% confidence interval), stratified by study arm and predictors of willingness to continue and to pay using multivariate logistic regression model backed up by themes from qualitative interviews.

Results

95% of participants were willing to continue using C4LU with 77.8% willing to pay for the service. Persons receiving care at the peri-urban clinic (OR 3.12, 95% CI 1.43–9.11.86) and those with exposure to the C4LU intervention (OR 4.2, 95% CI 1.55–11.84) were more likely to continue and pay for the service. Qualitative interviews revealed mixed feelings regarding amounts to pay, those willing to pay, argued that since they have been paying for personal phone calls/messages, they should not fail to pay for Call for life.

Conclusions

Payment for the service offers opportunities to scale up and sustain mHealth interventions which may not be priorities for government funding. A co-pay model could be acceptable to PLHIV to access mHealth services in low resource settings.

Clinical Trial Number NCT 02953080.
Interpretable instance disease prediction based on causal feature selection and effect analysis
Authors: Chen YuWen , Zhang Ju , Qin XiaoLin
Published: February 2022

Background

In the big wave of artificial intelligence sweeping the world, machine learning has made great achievements in healthcare in the past few years, however, these methods are only based on correlation, not causation. The particularities of the healthcare determines that the research method must comply with the causality norm, otherwise the wrong intervention measures may bring the patients a lifetime of misfortune.

Methods

We propose a two-stage prediction method (instance feature selection prediction and causal effect analysis) for instance disease prediction. Feature selection is based on the counterfactual and uses the reinforcement learning framework to design an interpretable qualitative instance feature selection prediction. The model is composed of three neural networks (counterfactual prediction network, fact prediction network and counterfactual feature selection network), and the actor-critical method is used to train the network. Then we take the counterfactual prediction network as a structured causal model and improve the neural network attribution algorithm based on gradient integration to quantitatively calculate the causal effect of selection features on the output results.

Results

The results of our experiments on synthetic data, open source data and real medical data show that our proposed method can provide qualitative and quantitative causal explanations for the model while giving prediction results.

Conclusions

The experimental results demonstrate that causality can further explore more essential relationships between variables and the prediction method based on causal feature selection and effect analysis can build a more reliable disease prediction model.
A mixed-method study on the provision of remote consultations for non-communicable disease patients during the first wave of the COVID-19 pandemic in Latvia: lessons for the future
Authors: Kursīte Mirdza , Stars Inese , Strēle Ieva , Gobiņa Inese , Ķīvīte-Urtāne Anda , Behmane Daiga , Dūdele Alina , Villeruša Anita
Published: February 2022

Background

The COVID-19 pandemic has challenged the ability of healthcare systems to ensure the continuity of health services for patients with non-communicable diseases (NCDs). The issue of remote consultations has emerged. Before the COVID-19 pandemic, remote consultations were not routinely provided or covered by public health funding in Latvia. This study aimed to describe the dynamics of consultations and the volume of remote consultations provided for patients with particular NCD and explore clinicians’ experiences of providing remote consultations during the first wave of the COVID-19 pandemic in Latvia.

Methods

A mixed-method study focusing on the first wave of the COVID-19 pandemic in Latvia in Spring 2020 was conducted. Quantitative data from the National Health Services were analysed to assess the dynamics of consultations for patients with selected NCDs. Qualitative data were collected through 34 semi-structured interviews with general practitioners (GPs) and specialists and were analysed using an inductive thematic analysis. Purposive maximum variation sampling was used for participant selection.

Results

During the period with the strongest restrictions of scheduled on-site consultations, a decrease in the total number of consultations was observed for a variety of NCDs. A significant proportion of consultations in this period were provided remotely. GPs provided approximately one-third of cancer-related consultations and almost half of consultations for the other selected conditions remotely. Among specialists, endocrinologists had the highest proportion of remote consultations (up to 72.0%), while urologists had the lowest (16.4%). Thematic analysis of the semi-structured interviews revealed five themes: 1) Adjusting in a time of confusion and fear, 2) Remote consultations: safety versus availability, 3) Sacrifice and loss of privacy, 4) Advantages and disadvantages of communication technologies, and 5) Different form of communication and a health literacy challenge.

Conclusions

During the first wave of the COVID-19 pandemic in Latvia, disruptions to health care services decreased the total number of consultations for patients with NCDs provided by both GPs and specialists. In this period, remote consultations proved to be an important instrument for ensuring the continuity of health care for patients with NCDs, and the necessity to develop a well-designed system for telemedicine in Latvia was highlighted.
CoQ10 enhances the efficacy of airway basal stem cell transplantation on bleomycin-induced idiopathic pulmonary fibrosis in mice
Authors: Liu Huanbin , Liu Shuna , Jiang Jinjun , Zhang Yidi , Luo Yulong , Zhao Jingxin , Xu Jian , Xie Yuan , Liao Weiping , Wang Wei , Nie Yichu , Li Shiyue , Deng Wenbin
Published: February 2022

Background

Recent studies have demonstrated that airway basal stem cells (BCs) transplantation can ameliorate bleomycin-induced idiopathic pulmonary fibrosis (IPF) through lung regeneration promotion. However, BCs under oxidative stress in the alveolar microenvironment are poor in survival, causing unsatisfied efficacy of BCs transplantation. In this study, we investigated whether Coenzyme Q10(CoQ10) counteracts oxidative stress in the alveolar microenvironment, thus improved the efficacy of BCs transplantation for IPF treatment.

Methods

The protective effects of CoQ10 on H2O2-induced BCs apoptosis and cytoplasmic reactive oxygen species (ROS) level were tested by flow cytometry in vitro. The therapeutic effects of BCs combined with CoQ10 were compared to a single BCs transplantation protocol in IPF treatment after 2 weeks and were evaluated by parameters including changes of body weight and survival rate, as well as various levels of pulmonary inflammation, α-SMA expression and hydroxyproline (HYP) in IPF mouse lung tissues.

Results

CoQ10 preincubation with BCs (10 mM, 24 h) significantly reduced the late apoptosis of BCs and the number of oxidative stressful BCs as a result of H2O2 stimulation (1 mM, 6 h) in vitro. IPF mouse model was constructed through bleomycin (5 mg/kg) intratracheal instillation. Bleomycin-induced IPF mice showed weight loss continuously and mortality increased progressively during modeling. Serious pulmonary inflammatory cell infiltration, collagen fiber proliferation, and collagen protein deposition were observed in lung tissues of IPF mice. Though BCs transplantation alone improved indicators above in bleomycin-induced IPF mice to some extent, the combination with CoQ10 improved the transplantation efficacy and obtained better therapeutic effects.

Conclusion

CoQ10 blocked H2O2-induced apoptosis of BCs and ROS production in vitro, and enhanced the efficacy of BCs transplantation against bleomycin-induced IPF in mice.
Application of two statistical approaches (Bayesian Kernel Machine Regression and Principal Component Regression) to assess breast cancer risk in association to exposure to mixtures of brominated flame retardants and per- and polyfluorinated alkylated substances in the E3N cohort
Authors: Frenoy Pauline , Perduca Vittorio , Cano-Sancho German , Antignac Jean-Philippe , Severi Gianluca , Mancini Francesca Romana
Published: February 2022

Background

Brominated flame retardants (BFR) and per- and polyfluorinated alkylated substances (PFAS) are two groups of substances suspected to act as endocrine disruptors. Such substances could therefore be implicated in the occurrence of breast cancer, nevertheless, previous studies have led to inconstant results. Due to the large correlation between these substances, and the possibly non-linear effects they exert, evaluating their joint impact as mixtures on health remains challenging.

This exploratory study aimed to generate hypotheses on the relationship between circulating levels of 7 BFR (6 polybrominated diphenyl ethers and 1 polybrominated biphenyls) and 11 PFAS and the risk of breast cancer in a case–control study nested in the E3N French prospective cohort by performing two methods: Principal Component Regression (PCR) models, and Bayesian Kernel Machine Regression (BKMR) models.

Methods

194 post-menopausal breast cancer cases and 194 controls were included in the present study. Circulating levels of BFR and PFAS were measured by gas chromatography coupled to high-resolution mass spectrometry and liquid chromatography coupled to tandem mass spectrometry, respectively. The first statistical approach was based on Principal Component Analysis (PCA) followed by logistic regression models that included the identified principal components as main exposure variables. The second approach used BKMR models with hierarchical variable selection, this latter being suitable for highly correlated exposures. Both approaches were also run separately for Estrogen Receptor positive (ER +) and Estrogen Receptor negative (ER-) breast cancer cases.

Results

PCA identified four principal components accounting for 67% of the total variance. Component 3 showed a marginal association with ER + breast cancer risk. No clear association between BFR and PFAS mixtures and breast cancer was identified using BKMR models, and the credible intervals obtained were very wide. Finally, the BKMR models suggested a negative cumulative effect of BFR and PFAS on ER- breast cancer risk, and a positive cumulative effect on ER + breast cancer risk.

Conclusion

Although globally no clear association was identified, both approaches suggested a differential effect of BFR and PFAS mixtures on ER + and ER- breast cancer risk. However, the results for ER- breast cancer should be interpreted carefully due to the small number of ER- cases included in the study. Further studies evaluating mixtures of substances on larger study populations are needed.
FTO protects human granulosa cells from chemotherapy-induced cytotoxicity
Authors: Wang Rongli , Wang Wei , Wang Lijun , Yuan Linnan , Cheng Feiyan , Guan Xin , Zheng Nini , Yang Xinyuan
Published: February 2022

Background

Premature ovarian failure (POF) is a serious problem for young women who receive chemotherapy, and its pathophysiological basis is the dysfunction of granulosa cells. According to previous reports, menstrual-derived stem cells (MenSCs) can restore ovarian function and folliculogenesis in mice with chemotherapy-induced POF. Fat mass- and obesity-associated (FTO) was reported to be associated with oocyte development and maturation. FTO was decreased in POF and may be a biomarker for the occurrence of POF. Knockdown of FTO in granulosa cells promoted cell apoptosis and inhibited proliferation. But the relationship between FTO and ovarian repair was still unclear. This study was aimed at investigating the FTO expression level and the role of FTO in the MenSCs recovering the function of injured granulosa cells.

Method

First, cisplatin was used to establish a granulosa cell injury model. Then, the MenSCs and injured granulosa cell coculture model and POF mouse model were established in this study to explore the role of FTO. Furthermore, gain- and loss-of-function studies, small interfering RNA transfection, and meclofenamic acid (MA), a highly selective inhibitor of FTO, studies were also conducted to clarify the regulatory mechanism of FTO in granulosa cells.

Results

MenSCs coculture could improve the function of injured granulosa cells by increasing the expression of FTO. MenSCs transplantation restored the expression of FTO in the ovaries of POF mice. Overexpression of FTO restored the injured cell proliferation and decreased apoptosis by regulating the expression of BNIP3. Down-regulation of FTO got the opposite results.

Conclusions

In the treatment of MenSCs, FTO has a protective effect, which could improve the viability of granulosa cells after cisplatin treatment by decreasing the expression of BNIP3. Meanwhile, FTO may provide new insight into therapeutic targets for the chemotherapy-induced POF.
LXR agonist improves peripheral neuropathy and modifies PNS immune cells in aged mice
Authors: Gavini Chaitanya K. , Elshareif Nadia , Aubert Gregory , Germanwala Anand V. , Calcutt Nigel A. , Mansuy-Aubert Virginie
Published: February 2022

Background

Peripheral neuropathy is a common and progressive disorder in the elderly that interferes with daily activities. It is of importance to find efficient treatments to treat or delay this age-related neurodegeneration. Silencing macrophages by reducing foamy macrophages showed significant improvement of age-related degenerative changes in peripheral nerves of aged mice. We previously demonstrated that activation of the cholesterol sensor Liver X receptor (LXR) with the potent agonist, GW3965, alleviates pain in a diet-induced obesity model. We sought to test whether LXR activation may improve neuropathy in aged mice.

Methods

21-month-old mice were treated with GW3965 (25 mg/Kg body weight) for 3 months while testing for mechanical allodynia and thermal hyperalgesia. At termination, flow cytometry was used to profile dorsal root ganglia and sciatic nerve cells. Immune cells were sorted and analyzed for cholesterol and gene expression. Nerve fibers of the skin from the paws were analyzed. Some human sural nerves were also evaluated. Comparisons were made using either t test or one-way ANOVA.

Results

Treatment with GW3965 prevented the development of mechanical hypersensitivity and thermal hyperalgesia over time in aged mice. We also observed change in polarization and cholesterol content of sciatic nerve macrophages accompanied by a significant increase in nerve fibers of the skin.

Conclusions

These results suggest that activation of the LXR may delay the PNS aging by modifying nerve-immune cell lipid content. Our study provides new potential targets to treat or delay neuropathy during aging.
Frequency of osteoradionecrosis of the lower jaw after radiotherapy of oral cancer patients correlated with dosimetric parameters and other risk factors
Authors: Lang Kristin , Held Thomas , Meixner Eva , Tonndorf-Martini Eric , Ristow Oliver , Moratin Julius , Bougatf Nina , Freudlsperger Christian , Debus Jürgen , Adeberg Sebastian
Published: February 2022

Objectives

Osteoradionecrosis (ORN) of the lower jaw is a serious late complication after radiotherapy in patients with oral cavity cancer. The aim of this study is to generate more insight into which patient- and treatment-related factors are associated with the development of ORN in oral cavity cancer patients undergoing postoperative radiotherapy.

Material and methods

Retrospective evaluation and comparison of 44 patients with ORN (event group 1) matched according to 45 patients without ORN (control group 2) who received postoperative radiotherapy of oral cavity squamous cell carcinoma at our institution between 2012 and 2020. Dosimetric factors that favor the occurrence of ORN should be detected. The cumulative occurrence rate of ORN was calculated according to the Kaplan–Meier method and analyzed by Cox regression and log-rank test.

Results

The median time to develop ORN was 18 months (3–93 months) after radiotherapy. Dental status before radiotherapy (RT) treatment (HR 4.5; 1.8–11.5) and dosimetric parameters including Dmean > 45 Gy (HR 2.4; 1.0–5.7), Dmax > 60 Gy (HR 1.3; 1.1–2.8) and planning target volume (PTV) proportion > 40% intersection with the lower jaw (HR 1.1; 1.0–1.1) were significantly associated with ORN.

Conclusion

The results of this retrospective study reveal that oral cavity cancer patients who underwent pre-RT dental surgery as well as dosimetric parameters using Dmax > 60 Gy, higher mean doses > 45 Gy and more than 40% PTV intersection with the lower jaw bone are independent risk factors for ORN. These findings can assist in the management of patients undergoing RT for head and neck cancer regarding ORN prevention.

Clinical relevance

Poor oral hygiene and desolate dental status as well as high radiation doses to the mandibular bone significantly increase the risk of developing osteoradionecrosis. Before irradiating a patient with oral cavity cancer, an appointment with the dentist should be made and teeth sanitized if necessary. Likewise, maximum radiation doses to the lower jaw should be minimized.
Application of a novel microscopic technique for quantifying CA125 binding to circulating mononuclear cells in longitudinal specimens during treatment for ovarian cancer
Authors: Lakatos Kornél , González Germán , Hoballah Jawad , Brooker Jeff , Jeong Sinyoung , Evans Conor , Krauledat Petra , Hansen W. Peter , Elias Kevin M. , Patankar Manish , Fülöp Vilmos , Konstantinopoulos Panagiotis A. , Cramer Daniel W.
Published: February 2022

Background

Measurement of serum CA125, an antigenic fragment of human mucin 16 (MUC16), is used to monitor the clinical progression of epithelial ovarian cancer (EOC). However, rather than simply a passive marker reflecting tumor burden, MUC16 may have a more active role by binding to immune cells and altering their tumor response. We developed a research tool to measure MUC16-binding to the surfaces of peripheral blood mononuclear cell (PBMC) subtypes and tested its research value using specimens collected serially from a woman being treated for high grade serous EOC.

Methods

Cryopreserved PBMCs were mixed with anti-CA125 antibody-labeled plasmonic gold nanoparticles (PNPs) to detect cell surface MUC16-binding along with fluorescent stains to identify B cells, NK cells, NK-T cells, T cells, and monocytes. From 3D darkfield images, a computer algorithm was applied to enumerate PNP-binding and fluorescence microscopy to identify cell lineage. Average MUC16-binding was determined by fitting a Poisson distribution to PNP-counts across similar cell types. MUC16-binding to cell types was correlated with treatment details, CA125 levels, and complete blood count (CBC) data.

Results

Over a 21-month period, monocytes had the highest level of MUC16-binding which was positively correlated with serum CA125 and inversely correlated with circulating monocyte and lymphocyte counts. Fluctuations of PNP-binding to NK cells were associated temporally with types of chemotherapy and surgical events. Levels of MUC16 bound to NK cells were positively correlated with levels of MUC16 bound to T and NK-T cells and inversely correlated with circulating platelets.

Conclusions

Assessment of MUC16-binding among cryopreserved PBMC cell types can be accomplished using darkfield and fluorescence microscopy. Correlations observed between level of binding by cell type with serum CA125, CBC data, and treatment details suggest that the new techniques may offer novel insights into EOC’s clinical course.
Clinical features of gout in adult patients with type Ia glycogen storage disease: a single-centre retrospective study and a review of literature
Authors: Xu Na , Han Xinxin , Zhang Yun , Huang Xiaoming , Zhu Weiguo , Shen Min , Zhang Wen , Jialin Chen , Wei Min , Qiu Zhengqing , Zeng Xuejun
Published: February 2022

Background

This study aimed to explore the clinical features of gout in adult patients with glycogen storage disease type Ia (GSD Ia).

Methods

Ninety-five adult patients with GSD Ia admitted to Peking Union Medical College Hospital were retrospectively analysed. A clinical diagnosis of GSD Ia was confirmed in all patients through gene sequencing. All patients had hyperuricaemia; 31 patients complicated with gout were enrolled, and 64 adult GSD Ia patients with asymptomatic hyperuricaemia were selected as a control group during the same period. Clinical characteristics were analysed and compared between the two groups.

Results

Thirty-one of the 95 patients had complications of gout (median age, 25 years; 11 (35.5%) females). All 31 patients had hepatomegaly, abnormal liver function, fasting hypoglycaemia, hyperuricaemia, hyperlipaemia, and hyperlacticaemia. A protuberant abdomen, growth retardation, recurrent epistaxis, and diarrhoea were the most common clinical manifestations. Among these 31 patients, 10 patients (32.3%) had gout as the presenting manifestation and were diagnosed with GSD Ia at a median time of 5 years (range, 1–14) after the first gout flare. The median age of gout onset was 18 years (range, 10–29). Fifteen of the 31 GSD Ia-related gout patients were complicated with gouty tophi, which has an average incidence time of 2 years after the first gouty flare. The mean value of the maximum serum uric acid (SUA) was 800.5 μmol/L (range, 468–1068). The incidence of gout in adult GSD Ia patients was significantly associated with the initial age of regular treatment with raw corn starch, the proportion of urate-lowering therapy initiated during the asymptomatic hyperuricaemic stage, maximum SUA level, and mean cholesterol level.

Conclusions

Determination of GSD Ia should be performed for young-onset gout patients with an early occurrence of gouty tophi, especially in patients with hepatomegaly, recurrent hypoglycaemia, or growth retardation. Early detection and long-term regulatory management of hyperuricaemia, in addition to early raw corn starch and lifestyle intervention, should be emphasized for GSD Ia patients in order to maintain good metabolic control.

Trial registration

Retrospectively registered.
Sensitive and reproducible MEG resting-state metrics of functional connectivity in Alzheimer’s disease
Authors: Schoonhoven Deborah N. , Briels Casper T. , Hillebrand Arjan , Scheltens Philip , Stam Cornelis J. , Gouw Alida A.
Published: February 2022

Background

Analysis of functional brain networks in Alzheimer’s disease (AD) has been hampered by a lack of reproducible, yet valid metrics of functional connectivity (FC). This study aimed to assess both the sensitivity and reproducibility of the corrected amplitude envelope correlation (AEC-c) and phase lag index (PLI), two metrics of FC that are insensitive to the effects of volume conduction and field spread, in two separate cohorts of patients with dementia due to AD versus healthy elderly controls.

Methods

Subjects with a clinical diagnosis of AD dementia with biomarker proof, and a control group of subjective cognitive decline (SCD), underwent two 5-min resting-state MEG recordings. Data consisted of a test (AD = 28; SCD = 29) and validation (AD = 29; SCD = 27) cohort. Time-series were estimated for 90 regions of interest (ROIs) in the automated anatomical labelling (AAL) atlas. For each of five canonical frequency bands, the AEC-c and PLI were calculated between all 90 ROIs, and connections were averaged per ROI. General linear models were constructed to compare the global FC differences between the groups, assess the reproducibility, and evaluate the effects of age and relative power. Reproducibility of the regional FC differences was assessed using the Mann-WhitneyUtests, with correction for multiple testing using the false discovery rate (FDR).

Results

The AEC-c showed significantly and reproducibly lower global FC for the AD group compared to SCD, in the alpha (8–13 Hz) and beta (13–30 Hz) bands, while the PLI revealed reproducibly lower FC for the AD group in the delta (0.5–4 Hz) band and higher FC for the theta (4–8 Hz) band. Regionally, the beta band AEC-c showed reproducibility for almost all ROIs (except for 13 ROIs in the frontal and temporal lobes). For the other bands, the AEC-c and PLI did not show regional reproducibility after FDR correction. The theta band PLI was susceptible to the effect of relative power.

Conclusion

For MEG, the AEC-c is a sensitive and reproducible metric, able to distinguish FC differences between patients with AD dementia and cognitively healthy controls. These two measures likely reflect different aspects of neural activity and show differential sensitivity to changes in neural dynamics.
Rituximab and dupilumab improve eosinophilic granulomatosis with polyangiitis with multiple pulmonary thrombi
Authors: Adachi Sei , Oshikata Chiyako , Kaneko Takeshi , Tsurikisawa Naomi
Published: February 2022

Background

Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by a necrotizing vasculitis with tissue and peripheral blood eosinophilia affecting small and medium-sized arteries, capillaries, and veins. Venous thromboembolic events are uncommon in EGPA. Moreover, there are only a few reported cases of EGPA complicated by pulmonary embolism or infarction.

Case presentation

We report the case of a 43-year-old woman with eosinophilic granulomatosis with polyangiitis and acute respiratory and heart failure due to bilateral pulmonary artery thrombosis and left femoral vein thrombosis 12 years after disease onset. She also had cardiac involvement (myocarditis, pericardial effusion, and diastolic dysfunction), gastrointestinal symptoms, and peripheral neuropathy. The condition was refractory to treatment with systemic corticosteroids, intravenous cyclophosphamide, and mepolizumab, but the thrombosis and associated acute cardiac failure, as well as the cardiac and gastrointestinal symptoms and multiple polyneuropathy, improved after a switch to rituximab. However, the heart failure did not improve sufficiently and the patient continued to need inhaled oxygen at 1 L/min and asthma exacerbations occurred. We then swapped the patient’s mepolizumab treatment for dupilumab. Not only did she have no further asthma attacks after switching to dupilumab, but also her vasculitis symptoms improved. Oxygen therapy was discontinued as the heart failure improved 5 months after starting the dupilumab.

Conclusions

This may be the first case report of the successful treatment by rituximab of pulmonary thromboembolism associated with EGPA. In addition, in this patient, treatment with dupilumab was effective not only for the asthma symptoms but also for the symptoms of vasculitis and heart failure.
Cost-effectiveness of a photopethysmographic procedure for screening for atrial fibrillation in 6 European countries
Authors: Wahler Steffen , Birkemeyer Ralf , Alexopoulos Dimitrios , Siudak Zbigniew , Müller Alfred , von der Schulenburg Johann-Matthias
Published: February 2022

Background

Strokes cause an estimated annual health care burden of 170 billion euros across Europe. Atrial fibrillation is one of the major risk factors for stroke and increases the individual risk 4.2-fold. But prevention with anticoagulants may reduce this risk by 70%. Screening methods are employed to detect previously undetected atrial fibrillation. Screening studies in various European countries show a high degree of undetected atrial fibrillation. This study aims to assess the cost-effectiveness of systematic screening with a smartphone application, named Preventicus Heartbeats. It is a hands-on screening tool for use on smartphone to diagnose AF with high sensitivity and specificity.

Methods

A previously published model for calculating screening cost-effectiveness was extended to 6 European countries covering a wide range in terms of treatment costs and epidemiologic parameters.

Results

The use of screening lowers the cost per case in countries with comparatively high levels of health care costs (Switzerland: -€75; UK: -€7). Moderate higher costs per case were observed in 4 countries (Greece: €6; Netherlands: €15). Low levels of health care costs result in less or no potential for further cost reduction (Poland: €20; Serbia: €33). In all countries considered, the model showed an increase in effectiveness measures both in the number of strokes avoided and the quality adjusted life years. The number of strokes avoided per 1000 participants ranged from 2.52 (Switzerland) to 4.44 (Poland). Quality-adjusted life-years per case gained from screening ranged from 0.0105 (Switzerland) to 0.0187 (Poland). The screening procedure dominated in two countries (Switzerland, UK). For the remaining countries, the incremental cost effectiveness ratio ranged from €489/QALY (Greece) to €2548/QALY (Serbia).

Conclusion

The model results showed a strong dependence of the results on the country-specific costs for stroke treatment. The use of the investigated screening method is close to cost-neutral or cost-reducing in the Western European countries and Greece. In countries with low price levels, higher cost increases due to AF screening are to be expected. Lower costs of anticoagulation, which are expected due to the upcoming patent expiry of direct anticoagulants, have a positive effect on the cost result.
Adolescent smoking, alcohol use, inebriation, and use of narcotics during the Covid-19 pandemic
Authors: Kapetanovic Sabina , Ander Birgitta , Gurdal Sevtap , Sorbring Emma
Published: February 2022

Background

The aim of the study was to investigate how general family relations, reported changes in family interaction and involvement with peers during the Covid-19 pandemic, and following rules and recommendations during the pandemic relate to adolescent smoking, alcohol use, inebriation, and use of narcotics during Covid-19.

Methods

An online national survey of Swedish adolescents (n = 1818) aged 15–19 years was conducted in June 2020. Hierarchical regression analysis was used to predict adolescents’ reported change in substance use during the pandemic. Person-oriented analyses, were used to identify clusters of participants characterized by similar patterns of substance use following ANOVA analysis with Scheffe post hoc tests testing differences between clusters in terms of family relations, reported changes in family interaction and involvement with peers during the Covid-19 pandemic, and following rules and recommendations during the pandemic.

Results

Higher general family conflict, increased involvement with peers, a strained relationship with parents, and less compliance with rules and restrictions during the pandemic predicted a reported increase in adolescent substance use during this period. The grouping of scores for adolescent smoking, alcohol use, inebriation, and use of narcotics resulted in a six-cluster solution. One cluster (n = 767) either did not use or had decreased use of substances during the Covid-19 pandemic. Five other clusters, thus risk clusters, had retained or increased use of substances during the pandemic. Poor general family relations, increased peer involvement, and difficulties to conform to the rules and restrictions during the covid-19 pandemic were characteristics of risk clusters.

Conclusions

Most of adolescents in our study did not increase their substance use during the pandemic. However, adolescents with poor family relations who turn to peers during stressful times and who have difficulty following the government’s rules and restrictions, are at risk of increased substance use during the pandemic. This is a potential threat both to adolescents themselves and others in their surroundings which is why at-risk adolescents and their families need more attention from public health and social services during this time of crisis.
Study progress, recreational activities, and loneliness in young adult carers: a national student survey
Authors: Haugland Bente Storm Mowatt , Hysing Mari , Sivertsen Børge
Published: February 2022

Background

Young adults (18–25 years) with informal care responsibilities have received limited attention in the research literature, and little is known on how caring responsibilities are related to functioning across different life domains. In the present study we examine associations between care responsibilities and study progress, recreational life, and loneliness in young adults in higher education.

Methods

A national survey was conducted among Norwegian students in higher education (the SHoT2018-study). The response rate was 30.8%. The current sample is a subsample of the respondents, including young adults 18 to 25 years old, comprising 40.205 participants (70.2% women, mean age 22.0 years, SD = 1.7). Participants reported whether they had regular care responsibility for someone with physical or mental illness, disabilities, or substance misuse. They also answered questions on study progress, number of hours studying, physical exercise, involvement in organized volunteer student activities, number of close friends, and feelings of loneliness. Data were analyzed by Chi-square tests and logistic regression analyses, adjusting for age, sex, and chronic illness.

Results

Compared to students without care responsibility, young adult carers (n = 2228, 5.5% of study sample) were more likely to report delayed study progress (OR 1.20, p < .001), higher average number of failed exams (e.g., having failed three times or more, OR 1.31, p = .002), more feelings of loneliness (OR 1.26, p < .001), and slightly fewer friends. Those with limited care responsibility (≤ 1 h daily) were more likely to participate in organized volunteer student activities, whereas students with 2 h or more of caring per day were less likely to participate in leisure student activities. Both study progress and feelings of loneliness were related to care responsibility in a response-dose pattern, with worse outcomes for those with 2 h or more of daily caring responsibility. All comparisons were adjusted for age, sex, and chronic illness.

Conclusions

Study progress, recreational activities, and loneliness among young adults are associated with informal caring responsibilities. Professionals in the educational system as well as health personnel should be sensitized to the needs of young adult carers and necessary support made available.
Zootherapy as a potential pathway for zoonotic spillover: a mixed-methods study of the use of animal products in medicinal and cultural practices in Nigeria
Authors: Friant Sagan , Bonwitt Jesse , Ayambem Wilfred A. , Ifebueme Nzube M. , Alobi Alobi O. , Otukpa Oshama M. , Bennett Andrew J. , Shea Corrigan , Rothman Jessica M. , Goldberg Tony L. , Jacka Jerry K.
Published: February 2022

Background

Understanding how and why people interact with animals is important for the prevention and control of zoonoses. To date, studies have primarily focused on the most visible forms of human-animal contact (e.g., hunting and consumption), thereby blinding One Health researchers and practitioners to the broader range of human-animal interactions that can serve as cryptic sources of zoonotic diseases. Zootherapy, the use of animal products for traditional medicine and cultural practices, is widespread and can generate opportunities for human exposure to zoonoses. Existing research examining zootherapies omits details necessary to adequately assess potential zoonotic risks.

Methods

We used a mixed-methods approach, combining quantitative and qualitative data from questionnaires, key informant interviews, and field notes to examine the use of zootherapy in nine villages engaged in wildlife hunting, consumption, and trade in Cross River State, Nigeria. We analyzed medicinal and cultural practices involving animals from a zoonotic disease perspective, by including details of animal use that may generate pathways for zoonotic transmission. We also examined the sociodemographic, cultural, and environmental contexts of zootherapeutic practices that can further shape the nature and frequency of human-animal interactions.

Results

Within our study population, people reported using 44 different animal species for zootherapeutic practices, including taxonomic groups considered to be “high risk” for zoonoses and threatened with extinction. Variation in use of animal parts, preparation norms, and administration practices generated a highly diverse set of zootherapeutic practices (n = 292) and potential zoonotic exposure risks. Use of zootherapy was patterned by demographic and environmental contexts, with zootherapy more commonly practiced by hunting households (OR = 2.47,p < 0.01), and prescriptions that were gender and age specific (e.g., maternal and pediatric care) or highly seasonal (e.g., associated with annual festivals and seasonal illnesses). Specific practices were informed by species availability and theories of healing (i.e., “like cures like” and sympathetic healing and magic) that further shaped the nature of human-animal interactions via zootherapy.

Conclusions

Epidemiological investigations of zoonoses and public health interventions that aim to reduce zoonotic exposures should explicitly consider zootherapy as a potential pathway for disease transmission and consider the sociocultural and environmental contexts of their use in health messaging and interventions.
Pathogenic Variants in ZSWIM7 Cause Primary Ovarian Insufficiency
Authors: Yatsenko Svetlana A , Gurbuz Fatih , Topaloglu Ali Kemal , Berman Andrea J , Martin Pierre-Marie , Rodríguez-Escribà Marta , Qin Yingying , Rajkovic Aleksandar
Published: February 2022

Context

Primary ovarian insufficiency (POI) is a genetically heterogeneous condition associated with infertility and an increased risk of comorbidities. An increased number of genes implicated in DNA damage response pathways has been associated with POI as well as predisposition to cancers.

Objective

We sought to identify and characterize patients affected by POI caused by pathogenic variants in genes involved in DNA damage response during meiosis.

Setting

Study subjects were recruited at academic centers.

Patients or Other Participants

Individuals with a diagnosis of POI and their family members were enrolled for genetic analysis. Clinical findings, family history, and peripheral blood samples were collected.

Research design

Exome sequencing was performed on the study participants and their family members (when available). Protein conservation analysis and in silico modeling were used to obtain the structural model of the detected variants in the ZSWIM7 gene.

Main Outcome Measure(s)

Rare deleterious variants in known and candidate genes associated with POI.

Results

Homozygous deleterious variants in the ZSWIM7 gene were identified in 2 unrelated patients with amenorrhea, an absence of puberty, and prepubertal ovaries and uterus. Observed variants were shown to alter the ZSWIM7 DNA-binding region, possibly affecting its function.

Conclusions

Our study highlights the pivotal role of the ZSWIM7 gene involved in DNA damage response during meiosis on ovarian development and function. Characterization of patients with defects in DNA repair genes has important diagnostic and prognostic consequences for clinical management and reproductive decisions.
Intestinal Epithelial NAD+ Biosynthesis Regulates GLP-1 Production and Postprandial Glucose Metabolism in Mice
Authors: Nagahisa Taichi , Yamaguchi Shintaro , Kosugi Shotaro , Homma Koichiro , Miyashita Kazutoshi , Irie Junichiro , Yoshino Jun , Itoh Hiroshi
Published: February 2022

Obesity is associated with perturbations in incretin production and whole-body glucose metabolism, but the precise underlying mechanism remains unclear. Here, we tested the hypothesis that nicotinamide phosphoribosyltransferase (NAMPT), which mediates the biosynthesis of nicotinamide adenine dinucleotide (NAD+), a key regulator of cellular energy metabolism, plays a critical role in obesity-associated intestinal pathophysiology and systemic metabolic complications. To this end, we generated a novel mouse model, namely intestinal epithelial cell-specific Nampt knockout (INKO) mice. INKO mice displayed diminished glucagon-like peptide-1 (GLP-1) production, at least partly contributing to reduced early-phase insulin secretion and postprandial hyperglycemia. Mechanistically, loss of NAMPT attenuated the Wnt signaling pathway, resulting in insufficient GLP-1 production. We also found that diet-induced obese mice had compromised intestinal NAMPT-mediated NAD+ biosynthesis and Wnt signaling pathway, associated with impaired GLP-1 production and whole-body glucose metabolism, resembling the INKO mice. Finally, administration of a key NAD+ intermediate, nicotinamide mononucleotide (NMN), restored intestinal NAD+ levels and obesity-associated metabolic derangements, manifested by a decrease in ileal Proglucagon expression and GLP-1 production as well as postprandial hyperglycemia in INKO and diet-induced obese mice. Collectively, our study provides mechanistic and therapeutic insights into intestinal NAD+ biology related to obesity-associated dysregulation of GLP-1 production and postprandial hyperglycemia.
High temperature perception in leaves promotes vascular regeneration and graft formation in distant tissues
Authors: Serivichyaswat Phanu T. , Bartusch Kai , Leso Martina , Musseau Constance , Iwase Akira , Chen Yu , Sugimoto Keiko , Quint Marcel , Melnyk Charles W.
Published: February 2022

Cellular regeneration in response to wounding is fundamental to maintain tissue integrity. Various internal factors including hormones and transcription factors mediate healing, but little is known about the role of external factors. To understand how the environment affects regeneration, we investigated the effects of temperature upon the horticulturally relevant process of plant grafting. We found that elevated temperatures accelerated vascular regeneration in Arabidopsis thaliana and tomato grafts. Leaves were crucial for this effect, as blocking auxin transport or mutating PHYTOCHROME INTERACTING FACTOR 4 (PIF4) or YUCCA2/5/8/9 in the cotyledons abolished the temperature enhancement. However, these perturbations did not affect grafting at ambient temperatures, and temperature enhancement of callus formation and tissue adhesion did not require PIF4, suggesting leaf-derived auxin specifically enhanced vascular regeneration in response to elevated temperatures. We also found that elevated temperatures accelerated the formation of inter-plant vascular connections between the parasitic plant Phtheirospermum japonicum and host Arabidopsis, and this effect required shoot-derived auxin from the parasite. Taken together, our results identify a pathway whereby local temperature perception mediates long distance auxin signaling to modify regeneration, grafting and parasitism.

This article has an associated ‘The people behind the papers’ interview.
The β8 integrin cytoplasmic domain activates extracellular matrix adhesion to promote brain neurovascular development
Authors: De Arpan , Morales John E. , Chen Zhihua , Sebastian Sumod , McCarty Joseph H.
Published: February 2022

In the developing mammalian brain, neuroepithelial cells interact with blood vessels to regulate angiogenesis, blood-brain barrier maturation and other key neurovascular functions. Genetic studies in mice have shown that neurovascular development is controlled, in part, by Itgb8, which encodes the neuroepithelial cell-expressed integrin β8 subunit. However, these studies have involved complete loss-of-function Itgb8 mutations, and have not discerned the relative roles for the β8 integrin extracellular matrix (ECM) binding region versus the intracellular signaling tail. Here, Cre/lox strategies have been employed to selectively delete the cytoplasmic tail of murine Itgb8 without perturbing its transmembrane and extracellular domains. We report that the β8 integrin cytoplasmic domain is essential for inside-out modulation of adhesion, including activation of latent-TGFβs in the ECM. Quantitative sequencing of the brain endothelial cell transcriptome identifies TGFβ-regulated genes with putative links to blood vessel morphogenesis, including several genes linked to Wnt/β-catenin signaling. These results reveal that the β8 integrin cytoplasmic domain is essential for the regulation of TGFβ-dependent gene expression in endothelial cells and suggest that cross-talk between TGFβs and Wnt pathways is crucial for neurovascular development.