bluuebunny/crossref_metadata_2025 huggingface dataset:
The factors influencing clinician use of hypertension guidelines in different resource settings: a qualitative study investigating clinicians’ perspectives and experiences
Authors: Kataria Golestaneh Amelia , Clarke Jonathan M , Appelbaum Nicholas , Gonzalvez Carmen Rodriguez , Jose Arun P , Philip Richu , Poulter Neil R , Beaney Thomas
Published: August 2021

Background

Hypertension accounts for the greatest burden of disease worldwide, yet hypertension awareness and control rates are suboptimal, especially within low- and middle-income countries. Guidelines can enable consistency of care and improve health outcomes. A small body of studies investigating clinicians’ perceptions and implementation of hypertension guidelines exists, mostly focussed on higher income settings. This study aims to explore how hypertension guidelines are used by clinicians across different resource settings, and the factors influencing their use.

Methods

A qualitative approach was employed using convenience sampling and in-depth semi-structured interviews. Seventeen medical doctors were interviewed over video or telephone call from March to August 2020. Two clinicians worked in low-income countries, ten in middle-income countries, and five in high-income countries. Interviews were recorded, transcribed, and coded inductively. Reflexive thematic analysis was used.

Results

Themes were generated at three levels at which clinicians perceived influencing factors to be operating: healthcare worker, healthcare worker interactions with patients, and the wider health system. Within each level, influencing factors were described as barriers to and facilitators of guideline use. Variation in factors occurred across income settings. At the healthcare worker level, usability of guidelines, trust in guidelines, attitudes and views about guidelines’ purpose, and relevance to patient populations were identified as themes. Influencing factors at the health system level were accessibility of equipment and medications, workforce, and access to healthcare settings. Influences at the patient level were clinician perceived patient motivation and health literacy, and access to, and cost of treatment, although these represented doctors’ perceptions rather than patient perceived factors.

Conclusions

This study adds a high level global view to previous studies investigating clinician perspectives on hypertension guideline use. Guidelines should be evidence-based, regularly updated and attention should be given to increasing applicability to LMICs and a range of healthcare professionals.
Health services utilization of Chinese patients with Huntington’s disease: a cross-sectional study
Authors: Ke Huiyi , Cao Xi , Song Yanyan , Cao Li
Published: August 2021

Background

Huntington’s disease (HD) is a hereditary disease which could have a large impact on patients’ quality of life. As the neurodegenerative disorders progress, HD patients are expected to regularly take follow-up medical visits for proper treatment. This study aimed to analyze the general situation of health services utilization of Chinese HD patients and factors associated with their adherence to follow-up medical visits.

Methods

We collected data from a questionnaire-based investigation conducted by the Chinese Huntington’s Disease Association. Data from 232 respondents were included to investigate whether they adhered to regular follow-up medical visits and the influencing factors. Based on Andersen’s behavioral model, the independent variables were categorized into predisposing, enabling and need factors. The variables were analyzed by chi-square test and stepwise logistic regression analysis.

Results

Thirty-one point nine percent of the respondents had regular follow-up medical visits over the past year. Univariate analysis showed that there were significant differences with 6 factors (P < 0.05), among which, according to logistic regression, 2 enabling factors (reimbursement of health insurance, need for accompanying family members to follow-up visits) and 3 need factors (perceived stage of disease, perceived effectiveness of drugs, self-care ability) were independent influencing factors of follow-up medical behaviors of Chinese HD patients. The predisposing factors investigated here did not play a part in determining patients’ adherence to follow-up visits.

Conclusions

Poor adherence to medical visits among Chinese HD patients is derived from multiple factors, including reimbursement of health insurance, perceived stage of disease and effectiveness of drugs, need for accompanying family members and self-care ability. To promote HD patients’ health services utilization, the improvement of the health insurance system, the enhancement of social support and the development of therapeutic approaches still have a long way to go.
Interprofessional advanced access – a quality improvement protocol for expanding access to primary care services
Authors: Gaboury Isabelle , Breton Mylaine , Perreault Kathy , Bordeleau François , Descôteaux Sarah , Maillet Lara , Hudon Catherine , Couturier Yves , Duhoux Arnaud , Vachon Brigitte , Cossette Benoit , Rodrigues Isabel , Poitras Marie-Eve , Loignon Christine , Vasiliadis Helen-Maria
Published: August 2021

Background

The Advanced Access (AA) Model has shown considerable success in improving timely access for patients in primary care settings. As a result, a majority of family physicians have implemented AA in their organizations over the last decade. However, despite its widespread use, few professionals other than physicians and nurse practitioners have implemented the model. Among those who have integrated it to their practice, a wide variation in the level of implementation is observed, suggesting a need to support primary care teams in continuous improvement with AA implementation. This quality improvement research project aims to document and measure the processes and effects of practice facilitation, to implement and improve AA within interprofessional teams.

Methods

Five primary care teams at various levels of organizational AA implementation will take part in a quality improvement process. These teams will be followed independently over PDSA (Plan-Do-Study-Act) cycles for 18 months. Each team is responsible for setting their own objectives for improvement with respect to AA.

The evaluation process consists of a mixed-methods plan, including semi-structured interviews with key members of the clinical and management teams, patient experience survey and AA-related metrics monitored from Electronic Medical Records over time.

Discussion

Most theories on organizational change indicate that practice facilitation should enable involvement of stakeholders in the process of change and enable improved interprofessional collaboration through a team-based approach. Improving access to primary care services is one of the top priorities of the Quebec’s ministry of health and social services. This study will identify key barriers to quality improvement initiatives within primary care and help to develop successful strategies to help teams improve and broaden implementation of AA to other primary care professionals.
Identification and integrative analysis of ACLY and related gene panels associated with immune microenvironment reveal prognostic significance in hepatocellular carcinoma
Authors: Xu Yunfeng , Zhang Ze , Xu Da , Yang Xin , Zhou Lina , Zhu Ying
Published: August 2021

Background

Cumulating evidence reveals the key role of aberrant lipogenesis and immunogenomic features in hepatocellular carcinoma (HCC). However, there are still obstacles in our understanding of the complicated interaction between metabolic reprogramming and tumor immune microenvironment.

Methods

We compared metabolomic, transcriptomic and immunogenomic characteristics of portal vein tumor thrombosis (PVTT) and primary tumor to seek valuable markers. Human HCC samples with PVTT (n  =  28) was analyzed through ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS). Transcript levels of mRNA in two cohorts from published database GEO (n  =  60) and TCGA (n  =  411) were downloaded to explore differentially expressed genes and functional enriched gene set. Evaluation of immune infiltration was estimated and validated from transcriptomic data in both cohorts through six immune deconvolution algorithms and in a high-resolution mode (CIBERSORTx). Survival analysis (Kaplan–Meier and multivariable Cox regression model) was performed to examine prognostic value of ACLY, related immune checkpoints and immune infiltration levels from TCGA cohort. LASSO regression was further conducted to determine a gene panel to further predict survival outcomes associated with ACLY.

Results

We identified a novel signature, ATP citrate lyase, through transcriptomic and metabolomic approaches. We demonstrated that the metabolism adaptations in both fatty acid and cholesterol biosynthesis triggered by ACLY oncogenic activation. We illustrated the crucial function of ACLY in lipogenesis and its potential interaction with immune microenvironment. CD276, a promising target in immune checkpoint blockade, showed correlation to ACLY and differential expression in ACLY risk classification. Combination of ACLY, CD276 and immune infiltration level and a novel ACLY-associated panel from a predictive model retrieved from published database validated the prognostic value to risk stratification in patients with HCC.ACLY blockade to counteract metabolic activation and immunosuppressive status of the tumor microenvironment highlighted attractive prospect for translational application.

Conclusions

We investigated ACLY and its indispensable role in metabolism, immune function and a prognostic gene panel in HCC. We anticipate that the multifaced role of ACLY may reveal the potential value for mechanistic research and combinational therapy, suggesting that the combination blockade of ACLY and immune checkpoints may work as a promising strategy.
The triple burden of communicable and non-communicable diseases and injuries on sex differences in life expectancy in Ethiopia
Authors: Jung Myunggu , Jembere Gizachew Balew , Park Young Su , Muhwava William , Choi Yeohee , Cho Youngtae , Ko Woorim
Published: August 2021

Background

Ethiopia has experienced great improvements in life expectancy (LE) at birth over the last three decades. Despite consistent increases in LE for both males and females in Ethiopia, the country has simultaneously witnessed an increasing discrepancy in LE between males and females.

Methods

This study used Pollard’s actuarial method of decomposing LE to compare age- and cause- specific contributions to changes in sex differences in LE between 1995 and 2015 in Ethiopia.

Results

Life expectancy at birth in Ethiopia increased for both males and females from 48.28 years and 50.12 years in 1995 to 65.59 years and 69.11 years in 2015, respectively. However, the sex differences in LE at birth also increased from 1.85 years in 1995 to 3.51 years in 2015. Decomposition analysis shows that the higher male mortality was consistently due to injuries and respiratory infections, which contributed to 1.57 out of 1.85 years in 1995 and 1.62 out of 3.51 years in 2015 of the sex differences in LE. Increased male mortality from non-communicable diseases (NCDs) also contributed to the increased difference in LE between males and females over the period, accounting for 0.21 out of 1.85 years and 1.05 out of 3.51 years in 1995 and 2015, respectively.

Conclusions

While injuries and respiratory infections causing male mortality were the most consistent causes of the sex differences in LE in Ethiopia, morality from NCDs is the main cause of the recent increasing differences in LE between males and females. However, unlike the higher exposure of males to death from injuries due to road traffic injuries or interpersonal violence, to what extent sex differences are caused by the higher male mortality compared to female mortality from respiratory infection diseases is unclear. Similarly, despite Ethiopia’s weak social security system, an explanation for the increased sex differences after the age of 40 years due to either longer female LE or reduced male LE should be further investigated.
Identification of proteins associated with development of psoriatic arthritis in peripheral blood mononuclear cells: a quantitative iTRAQ-based proteomics study
Authors: Zhu Jie , Han Ling , Liu Ruilai , Zhang Zhenghua , Huang Qiong , Fang Xu , Yang Ke , Huang Guiqin , Zheng Zhizhong , Yawalkar Nikhil , Deng Hui , Yan Kexiang
Published: August 2021

Background

Biomarkers for distinguishing psoriatic arthritis (PsA) from psoriasis without arthritis (PsO) are still lacking.

Methods

We applied isobaric tags for relative and absolute quantification (iTRAQ) and LC–MS/MS to analyze the proteome profile of peripheral blood mononuclear cells (PBMCs) collected from patients with PsO, patients with PsA, and healthy controls. Bioinformatics analysis and western blotting were performed to identify and validate differentially expressed proteins.

Results

We identified 389, 199, 291, and 60 significantly differentially expressed proteins (adj.p < 0.05) in the comparison of all psoriatic patients versus healthy controls, PsO group versus healthy controls, PsA group versus healthy controls, and PsA group versus PsO group, respectively. Among these proteins, 14 proteins may represent promising biomarkers for PsA: SIRT2, NAA50, ARF6, ADPRHL2, SF3B6, SH3KBP1, UBA3, SCP2, RPS5, NUDT5, NCBP1, SYNE1, NDUFB7, HTATSF1. Furthermore, western blotting confirmed that SIRT2 expression was significantly higher in PBMCs from PsA patients than PsO and healthy controls, and was negatively correlated with the phosphorylation of p38 mitogen-activated protein kinase (p-p38MAPK; p = 0.006, r = − 0.582).

Conclusions

This pilot study provided a broad characterization of the proteome of PBMCs in PsA as compared to PsO and healthy controls, which may help to provide prospective strategies for PsA diagnosis.
Leukocytoclastic vasculitis in patients with IL12B or IL12RB1 deficiency: case report and review of the literature
Authors: Sharifinejad Niusha , Mahdaviani Seyed Alireza , Jamee Mahnaz , Daneshmandi Zahra , Moniri Afshin , Marjani Majid , Tabarsi Payam , Farnia Parisa , Rekabi Mahsa , Fallahi Mazdak , Hashemimoghaddam Seyedeh Atefeh , Mohkam Masoumeh , Bustamante Jacinta , Casanova Jean-Laurent , Mansouri Davood , Velayati Ali Akbar
Published: August 2021

Background

Mendelian susceptibility to mycobacterial disease (MSMD) is an inborn error of immunity, resulting in susceptibility to weakly virulent mycobacteria and other intramacrophagic pathogens. Rheumatologic manifestations and vasculitis are considered rare manifestations in MSMD patients.

Case presentation

In this study, we reported a 20-year-old female who was presented with recurrent lymphadenitis following bacillus Calmette-Guérin (BCG) vaccination and a history of recurrent disseminated rash diagnosed as leukocytoclastic vasculitis (LCV). A slight reduction in lymphocyte subsets including CD4+, CD19+, and CD 16 + 56 T-cell count, as well as an elevation in immunoglobulins level (IgG, IgA, IgM, IgE), were observed in the patient. Whole exome sequencing revealed a homozygous Indel-frameshift mutation, c.527_528delCT (p. S176Cfs*12), at the exon 5 of theIL12Bgene. She experienced symptom resolution after treatment with anti-mycobacterial agents and subcutaneous IFN-γ. We conducted a manual literature search for MSMD patients reported with vasculitis in PubMed, Web of Science, and Scopus databases. A total of 18 MSMD patients were found to be affected by a variety of vasculitis phenotypes mainly including LCV and Henoch-Schönlein purpura (HSP) with often skin involvement. Patients were all involved with vasculitis at the median age of 6.8 (2.6–7.7) years, nearly 6.1 years after the initial presentations. Sixteen patients (88.9%) hadIL12RB1defects and concurrentSalmonellainfection was reported in 15 (88.2%) patients.

Conclusion

The lack of IL-12 and IL-23 signaling/activity/function and salmonella infection may be triggering factors for the development of leukocytoclastic vasculitis. IL12B or IL12RB1 deficiency and salmonellosis should be considered in MSMD patients with vasculitis.
Household income and medical help-seeking for fertility problems among a representative population in Japan
Authors: Iba Arisa , Maeda Eri , Jwa Seung Chik , Yanagisawa-Sugita Ayako , Saito Kazuki , Kuwahara Akira , Saito Hidekazu , Terada Yukihiro , Ishihara Osamu , Kobayashi Yasuki
Published: August 2021

Background

Fertility treatments help many infertile couples to have children. However, disparities exist in access to fertility tests and treatments. We investigated the association between household income and medical help-seeking for fertility in Japan.

Methods

We conducted a cross-sectional study using nationally representative data from the National Fertility Survey 2015. Respondents were 6598 married women younger than 50 years old. The primary outcome was medical help-seeking for fertility among those who experienced fertility problems. Multiple logistic regression models were used to assess the association between household income and medical help-seeking, adjusting for age, length of marriage, educational level, employment status, number of children, childbearing desires, living with parents, and region of residence.

Results

Among 2253 (34%) women who experienced fertility problems, 1154 (51%) sought medical help. The proportion of help-seekers increased linearly from 43% in the low-income group (< 4 million Japanese yen [JPY]) to 59% in the high-income group (≥ 8 million JPY) (P for trend < 0.001). Respondents with upper-middle (6–8 million JPY) or high household income were more likely to seek medical help, compared to those with low household income: adjusted odds ratio [aOR] 1.37 (95% confidence interval [CI]: 1.00–1.86) and aOR 1.78 (95% CI: 1.29–2.47), respectively.

Conclusions

We found that higher household income was associated with a higher probability of seeking medical help among Japanese women who experienced fertility problem. Along with policy discussion about additional financial support, further studies from societal, cultural, or psychological views are required.
Evolutionary trajectory of SARS-CoV-2 and emerging variants
Authors: Singh Jalen , Pandit Pranav , McArthur Andrew G. , Banerjee Arinjay , Mossman Karen
Published: August 2021

The emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and more recently, the independent evolution of multiple SARS-CoV-2 variants has generated renewed interest in virus evolution and cross-species transmission. While all known human coronaviruses (HCoVs) are speculated to have originated in animals, very little is known about their evolutionary history and factors that enable some CoVs to co-exist with humans as low pathogenic and endemic infections (HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1), while others, such as SARS-CoV, MERS-CoV and SARS-CoV-2 have evolved to cause severe disease. In this review, we highlight the origins of all known HCoVs and map positively selected for mutations within HCoV proteins to discuss the evolutionary trajectory of SARS-CoV-2. Furthermore, we discuss emerging mutations within SARS-CoV-2 and variants of concern (VOC), along with highlighting the demonstrated or speculated impact of these mutations on virus transmission, pathogenicity, and neutralization by natural or vaccine-mediated immunity.
Temporal response of an injectable calcium phosphate material in a critical size defect
Authors: Landeck Jacob T. , Walsh William R. , Oliver Rema A. , Wang Tian , Gordon Mallory R. , Ahn Edward , White Colin D.
Published: August 2021

Background

Calcium phosphate-based bone graft substitutes are used to facilitate healing in bony defects caused by trauma or created during surgery. Here, we present an injectable calcium phosphate-based bone void filler that has been purposefully formulated with hyaluronic acid to offer a longer working time for ease of injection into bony defects that are difficult to access during minimally invasive surgery.

Methods

The bone substitute material deliverability and physical properties were characterized, and in vivo response was evaluated in a critical size distal femur defect in skeletally mature rabbits to 26 weeks. The interface with the host bone, implant degradation, and resorption were assessed with time.

Results

The calcium phosphate bone substitute material could be injected as a paste within the working time window of 7–18 min, and then self-cured at body temperature within 10 min. The material reached a maximum ultimate compressive strength of 8.20 ± 0.95 MPa, similar to trabecular bone. The material was found to be biocompatible and osteoconductive in vivo out to 26 weeks, with new bone formation and normal bone architecture observed at 6 weeks, as demonstrated by histological evaluation, microcomputed tomography, and radiographic evaluation.

Conclusions

These findings show that the material properties and performance are well suited for minimally invasive percutaneous delivery applications.
Role of pre-operative red cell distribution width estimation in the prediction of in-hospital mortality after off-pump coronary artery bypass grafting
Authors: Joshi Dharmendra , Chowdhury Md. Abir Tazim , Alauddin Md. , Ranjan Redoy , Khan Omar Sadeque , Hoque Md. Rezwanul
Published: August 2021

Background

Red cell distribution width (RDW) level is routinely provided in a simple and inexpensive complete blood count report. However, RDW is sometimes overlooked. Recently a higher RDW level is found associated with postoperative mortality after off-pump coronary artery bypass. Many risk-prediction tools are available, like the European System for Cardiac Operative Risk Evaluation, Society of Thoracic Surgeons score, etc. but all need improvement for better prediction. So, a new risk-factor should be discovered which is simple enough for clinical use and cost-effective, and improves the risk assessment tools that help to predict and avoid preventable mortality following cardiac surgery.

Methods

The prospective study was conducted, taking a total of 150 patients of coronary artery disease who underwent elective isolated off-pump coronary artery bypass. The study population was grouped according to their preoperative RDW level as Group A (RDW ≤ 14%), Group B (RDW 14–16%), and Group C (RDW ≥ 16%). The receiver operating characteristic (ROC) curve was constructed and multivariate regression analysis was done to see the predictive value of RDW for in-hospital mortality.

Results

The mortality rate was 2.7%, N = 150. ROC curve revealed Area Under the Curve 0.841 and p = 0.020 that indicates the RDW as the reliable predictor for in-hospital mortality. Multivariate regression analysis showed the RDW to be the only variable independently predicting in-hospital mortality after off-pump coronary artery bypass among possible haematological predictors. (OR 1.838, 95% CI 1.061–3.186, p = 0.030).

Conclusion

Preoperative raised RDW level is a novel predictor of in-hospital mortality after off-pump coronary artery bypass. Further studies should be done to determine the associated mechanism.
Retrospective study on growth in infants with isolated Robin sequence treated with the Tuebingen Palate Plate
Authors: Wiechers Cornelia , Iffländer Regina , Gerdes Rieke , Ciuffolotti Melissa , Arand Jörg , Weise Christina , Peters Katharina , Grandke Bärbel , Reinert Siegmar , Koos Bernd , Poets Christian F.
Published: August 2021

Background

Children with Robin sequence (RS) are at risk of growth failure, mainly due to their increased work of breathing and feeding difficulties. Various conservative and surgical treatment approaches exist, but their impact on weight gain has not yet been adequately addressed. A functional treatment concept, used in our center for > 20 years, includes a pre-epiglottic baton plate (Tuebingen palatal plate) and intensive feeding training.

Objective

To investigate the effect of the Tuebingen treatment protocol on growth and weight trajectories during infancy.

Methods

This retrospective study analyzed longitudinal data from infants with isolated RS admitted to Tuebingen University Children’s Hospital, Germany between 1998 and 2019. Through our electronic patient database, we evaluated anthropometric parameters until reaching 1-year follow-up. Results are shown as median (IQR).

Results

In 307 infants analyzed, median Z-score for weight decreased from − 0.28 at birth to − 1.12 upon admission to our center at a median age of 22 days. Z-score then remained largely unchanged until discharge (Z-score difference, − 0.08), while the proportion of infants receiving tube feedings decreased from 55.1 to 13.7%. Z-score subsequently increased from − 1.17 at discharge to − 0.44 at the 1-year follow-up (p < 0.001).

Conclusion

Based on a comparatively large cohort, this functional treatment was associated with better weight gain and improved feeding. As RS infants often show postnatal growth failure, weight monitoring may be a valuable parameter for monitoring treatment effectiveness.

Clinical Trial RegistrationNot necessary due to the retrospective design.
Endophenotypical drift in Huntington’s disease: a 5-year follow-up study
Authors: Hellem Marie N. N. , Hendel Rebecca K. , Vinther-Jensen Tua , Larsen Ida U. , Nielsen Troels T. , Hjermind Lena E. , Budtz-Jørgensen Esben , Vogel Asmus , Nielsen Jørgen E.
Published: August 2021

Background

Huntington’s disease (HD) is clinically characterized by progressing motor, cognitive and psychiatric symptoms presenting as varying phenotypes within these three major symptom domains. The disease is caused by an expanded CAG repeat tract in the huntingtin gene and the pathomechanism leading to these endophenotypes is assumed to be neurodegenerative. In 2012/2013 we recruited 107 HD gene expansion carriers (HDGECs) and examined the frequency of the three cardinal symptoms and in 2017/2018 we followed up 74 HDGECs from the same cohort to describe the symptom trajectories and individual drift between the endophenotypes as well as potential predictors of progression and remission.

Results

We found higher age to reduce the probability of improving on psychiatric symptoms; increasing disease burden score ((CAG-35.5) * age) to increase the risk of developing cognitive impairment; increasing disease burden score and shorter education to increase the risk of motor onset while lower disease burden score and higher Mini Mental State Examination increased the probability of remaining asymptomatic. We found 23.5% (N = 8) to improve from their psychiatric symptoms.

Conclusions

There is no clear pattern in the development of or drift between endophenotypes. In contrast to motor and cognitive symptoms we find that psychiatric symptoms may resolve and thereby not entirely be caused by neurodegeneration. The probability of improving from psychiatric symptoms is higher in younger age and advocates for a potential importance of early treatment.
Long-term efficacy and safety of sapropterin in patients who initiated sapropterin at < 4 years of age with phenylketonuria: results of the 3-year extension of the SPARK open-label, multicentre, randomised phase IIIb trial
Authors: Muntau Ania C. , Burlina Alberto , Eyskens François , Freisinger Peter , Leuzzi Vincenzo , Sivri Hatice Serap , Gramer Gwendolyn , Pazdírková Renata , Cleary Maureen , Lotz-Havla Amelia S. , Lane Paul , Alvarez Ignacio , Rutsch Frank
Published: August 2021

Background

During the initial 26-week SPARK (Safety Paediatric efficAcy phaRmacokinetic with Kuvan®) study, addition of sapropterin dihydrochloride (Kuvan®; a synthetic formulation of the natural cofactor for phenylalanine hydroxylase, tetrahydrobiopterin; BH4), to a phenylalanine (Phe)-restricted diet, led to a significant improvement in Phe tolerance versus a Phe-restricted diet alone in patients aged 0–4 years with BH4-responsive phenylketonuria (PKU) or mild hyperphenylalaninaemia (HPA). Based on these results, the approved indication for sapropterin in Europe was expanded to include patients < 4 years of age. Herein, we present results of the SPARK extension study (NCT01376908), evaluating the long-term safety, dietary Phe tolerance, blood Phe concentrations and neurodevelopmental outcomes in patients < 4 years of age at randomisation, over an additional 36 months of treatment with sapropterin.

Results

All 51 patients who completed the 26-week SPARK study period entered the extension period. Patients who were previously treated with a Phe-restricted diet only (‘sapropterin extension’ group; n = 26), were initiated on sapropterin at 10 mg/kg/day, which could be increased up to 20 mg/kg/day. Patients previously treated with sapropterin plus Phe-restricted diet, remained on this regimen in the extension period (‘sapropterin continuous’ group; n = 25). Dietary Phe tolerance increased significantly at the end of the study versus baseline (week 0), by 38.7 mg/kg/day in the ‘sapropterin continuous’ group (95% CI 28.9, 48.6;p < 0.0001). In the ‘sapropterin extension’ group, a less pronounced effect was observed, with significant differences versus baseline (week 27) only observed between months 9 and 21; dietary Phe tolerance at the end of study increased by 5.5 mg/kg/day versus baseline (95% CI − 2.8, 13.8;p = 0.1929). Patients in both groups had normal neuromotor development and growth parameters.

Conclusions

Long-term treatment with sapropterin plus a Phe-restricted diet in patients who initiated sapropterin at < 4 years of age with BH4-responsive PKU or mild HPA maintained improvements in dietary Phe tolerance over 3.5 years. These results continue to support the favourable risk/benefit profile for sapropterin in paediatric patients (< 4 years of age) with BH4-responsive PKU. Frequent monitoring of blood Phe levels and careful titration of dietary Phe intake to ensure adequate levels of protein intake is necessary to optimise the benefits of sapropterin treatment.

Trial registrationClinicalTrials.gov, NCT01376908. Registered 17 June 2011,https://clinicaltrials.gov/ct2/show/NCT01376908.
Preventive use of nitisinone in alkaptonuria
Authors: Wolffenbuttel Bruce H. R. , Heiner-Fokkema M. Rebecca , van Spronsen Francjan J.
Published: August 2021

Alkaptonuria (AKU, OMIM 203500) is a rare congenital disorder caused by a deficiency of the enzyme homogentisate-1,2,-dioxygenase. The long-term consequences of AKU are joint problems, cardiac valve abnormalities and renal problems. Landmark intervention studies with nitisinone 10 mg daily, suppressing an upstream enzyme activity, demonstrated its beneficial effects in AKU patients with established complications, which usually start to develop in the fourth decade. Lower dose of nitisinone in the range of 0.2–2 mg daily will already reduce urinary homogentisic acid (uHGA) excretion by > 90%, which may prevent AKU-related complications earlier in the course of the disease while limiting the possibility of side-effects related to the increase of plasma tyrosine levels caused by nitisinone. Future preventive studies should establish the lowest possible dose for an individual patient, the best age to start treatment and also collect evidence to which level uHGA excretion should be reduced to prevent complications.
Probability calibration-based prediction of recurrence rate in patients with diffuse large B-cell lymphoma
Authors: Fan Shuanglong , Zhao Zhiqiang , Zhang Yanbo , Yu Hongmei , Zheng Chuchu , Huang Xueqian , Yang Zhenhuan , Xing Meng , Lu Qing , Luo Yanhong
Published: August 2021

Background

Although many patients receive good prognoses with standard therapy, 30–50% of diffuse large B-cell lymphoma (DLBCL) cases may relapse after treatment. Statistical or computational intelligent models are powerful tools for assessing prognoses; however, many cannot generate accurate risk (probability) estimates. Thus, probability calibration-based versions of traditional machine learning algorithms are developed in this paper to predict the risk of relapse in patients with DLBCL.

Methods

Five machine learning algorithms were assessed, namely, naïve Bayes (NB), logistic regression (LR), random forest (RF), support vector machine (SVM) and feedforward neural network (FFNN), and three methods were used to develop probability calibration-based versions of each of the above algorithms, namely, Platt scaling (Platt), isotonic regression (IsoReg) and shape-restricted polynomial regression (RPR). Performance comparisons were based on the average results of the stratified hold-out test, which was repeated 500 times. We used the AUC to evaluate the discrimination ability (i.e., classification ability) of the model and assessed the model calibration (i.e., risk prediction accuracy) using the H-L goodness-of-fit test, ECE, MCE and BS.

Results

Sex, stage, IPI, KPS, GCB, CD10 and rituximab were significant factors predicting the 3-year recurrence rate of patients with DLBCL. For the 5 uncalibrated algorithms, the LR (ECE = 8.517, MCE = 20.100, BS = 0.188) and FFNN (ECE = 8.238, MCE = 20.150, BS = 0.184) models were well-calibrated. The errors of the initial risk estimate of the NB (ECE = 15.711, MCE = 34.350, BS = 0.212), RF (ECE = 12.740, MCE = 27.200, BS = 0.201) and SVM (ECE = 9.872, MCE = 23.800, BS = 0.194) models were large. With probability calibration, the biased NB, RF and SVM models were well-corrected. The calibration errors of the LR and FFNN models were not further improved regardless of the probability calibration method. Among the 3 calibration methods, RPR achieved the best calibration for both the RF and SVM models. The power of IsoReg was not obvious for the NB, RF or SVM models.

Conclusions

Although these algorithms all have good classification ability, several cannot generate accurate risk estimates. Probability calibration is an effective method of improving the accuracy of these poorly calibrated algorithms. Our risk model of DLBCL demonstrates good discrimination and calibration ability and has the potential to help clinicians make optimal therapeutic decisions to achieve precision medicine.
SorGSD: updating and expanding the sorghum genome science database with new contents and tools
Authors: Liu Yuanming , Wang Zhonghuang , Wu Xiaoyuan , Zhu Junwei , Luo Hong , Tian Dongmei , Li Cuiping , Luo Jingchu , Zhao Wenming , Hao Huaiqing , Jing Hai-Chun
Published: August 2021

Background

As the fifth major cereal crop originated from Africa, sorghum (Sorghum bicolor) has become a key C4 model organism for energy plant research. With the development of high-throughput detection technologies for various omics data, much multi-dimensional and multi-omics information has been accumulated for sorghum. Integrating this information may accelerate genetic research and improve molecular breeding for sorghum agronomic traits.

Results

We updated the Sorghum Genome SNP Database (SorGSD) by adding new data, new features and renamed it to Sorghum Genome Science Database (SorGSD). In comparison with the original version SorGSD, which contains SNPs from 48 sorghum accessions mapped to the reference genome BTx623 (v2.1), the new version was expanded to 289 sorghum lines with both single nucleotide polymorphisms (SNPs) and small insertions/deletions (INDELs), which were aligned to the newly assembled and annotated sorghum genome BTx623 (v3.1). Moreover, phenotypic data and panicle pictures of critical accessions were provided in the new version. We implemented new tools including ID Conversion, Homologue Search and Genome Browser for analysis and updated the general information related to sorghum research, such as online sorghum resources and literature references. In addition, we deployed a new database infrastructure and redesigned a new user interface as one of the Genome Variation Map databases. The new version SorGSD is freely accessible online at http://ngdc.cncb.ac.cn/sorgsd/.

Conclusions

SorGSD is a comprehensive integration with large-scale genomic variation, phenotypic information and incorporates online data analysis tools for data mining, genome navigation and analysis. We hope that SorGSD could provide a valuable resource for sorghum researchers to find variations they are interested in and generate customized high-throughput datasets for further analysis.
Effectiveness of sarolaner in the clinical management of furuncular myiasis in dogs naturally infested with Dermatobia hominis (Diptera: Cuterebridae)
Authors: Andriotti Paula A. , Souza Clarissa P. , Oliveira Priscila C. , Melo Rodrigo C. , Verocai Guilherme G. , Fernandes Julio I.
Published: August 2021

Background

The human botfly, Dermatobia hominis, is a common cause of furuncular myiasis in dogs in Latin America. Lesions can be single or multiple, each harboring an individual larva, presented as an erythematous nodule that causes pruritus and pain. Typical treatment consists of sedation for removal of larvae by surgical incision or manual pressure. Medications to kill the larva before its extraction can reduce inflammation and discomfort and provide a less traumatic larval removal. Isoxazolines are broad-spectrum ectoparasiticides with larvicidal activity previously reported in the treatment of screwworm myiasis in companion animals. The aim of this study was to evaluate the effectiveness of sarolaner as part of the clinical management of furuncular myiasis in dogs caused by D. hominis larvae.

Methods

Ten short-haired mixed breed dogs naturally infested with D. hominis were enrolled. Clinical diagnosis was achieved by observation of skin nodules and visualization of larval motility through the lesion orifice. Sarolaner was administered at manufacturer recommended dose for fleas and ticks. Lesions were reexamined 24 h post-treatment and assessed for viability of larvae. Larvae were removed by digital compression and identified as D. hominis.

Results

Seventy-five D. hominis larvae were retrieved from ten dogs. No live larvae were observed, demonstrating 100% larvicidal efficacy of sarolaner. Skin lesions were healed 30 days post-treatment and new lesions were not observed.

Conclusions

Sarolaner seems to be effective as larvicidal treatment for dogs with furuncular myiasis, reducing discomfort caused by the presence of the larva in the skin and facilitating its safe removal.

Graphical abstract
The hepatoprotective effects of Pyrus biossieriana buhse leaf extract on tert-butyl hydroperoxide toxicity in HepG2 cell line
Authors: Mir Hamed , Elieh Ali Komi Daniel , Pouramir Mahdi , Parsian Hadi , Moghadamnia Ali Akbar , Seyfizadeh Nayer , Lakzaei Mostafa
Published: August 2021

Objective

In present study, the effects of the leaf extract ofPyrus biossierianaBuhse ontert-Butyl hydroperoxide (t-BHP) induced toxicity in the HepG2 cell line were investigated.

Results

HepG2 cells were exposed to different concentrations of both extract (1.5, 2.0, and 2.5 mg/mL) and t-BHP (100, 150, and 200 μM). The total flavonoid and phenolic contents, the cell viability, lipid peroxidation, NO generation, and the total antioxidant capacity in cell media were assessed. The amount of arbutin was estimated 12.6% of the dry weight of leaves (equivalent to 126 mg/g). Additionally, the amounts of flavonoids and phenols in extract were estimated 119 mg/g and 418 mg/g, respectively. The cells incubated with t-BHP showed a significant decrease in survival (p < 0.001). Preincubation with extract (1.5 mg/mL and 2.0 mg/mL) attenuated the t-BHP toxicity and increased the cell viability in cells exposed even to the highest concentration of t-BHP (200 μM) (p value < 0.001, and p value = 0.035) respectively. Additionally, treatment with extract reduced the cell growth suppression caused by t-BHP. TheP. biossierianaBuhse leaf extract at concentrations of 1.5 and 2.0 mg/mL is capable of attenuating t-BHP-induced cytotoxicity in HepG2 cells.
A targeted multi-omics approach reveals paraoxonase-1 as a determinant of obesity-associated fatty liver disease
Authors: Diels Sara , Cuypers Bart , Tvarijonaviciute Asta , Derudas Bruno , Van Dijck Evelien , Verrijken An , Van Gaal Luc F. , Laukens Kris , Lefebvre Philippe , Ceron Jose J. , Francque Sven , Vanden Berghe Wim , Van Hul Wim
Published: August 2021

Background

The multifactorial nature of non-alcoholic fatty liver disease cannot be explained solely by genetic factors. Recent evidence revealed that DNA methylation changes take place at proximal promoters within susceptibility genes. This emphasizes the need for integrating multiple data types to provide a better understanding of the disease’s pathogenesis. One such candidate gene is paraoxonase-1 (PON1). Substantial interindividual differences in PON1 are apparent and could influence disease risk later in life. The aim of this study was therefore to determine the different regulatory aspects of PON1 variability and to examine them in relation to the predisposition to obesity-associated fatty liver disease.

Results

A targeted multi-omics approach was applied to investigate the interplay between PON1 genetic variants, promoter methylation, expression profile and enzymatic activity in an adult patient cohort with extensive metabolic and hepatic characterisation including liver biopsy. Alterations in PON1 status were shown to correlate with waist-to-hip ratio and relevant features of liver pathology. Particularly, the regulatory polymorphism rs705379:C > T was strongly associated with more severe liver disease. Multivariable data analysis furthermore indicated a significant association of combined genetic and epigenetic PON1 regulation. This identified relationship postulates a role for DNA methylation as a mediator between PON1 genetics and expression, which is believed to further influence liver disease progression via modifications in PON1 catalytic efficiency.

Conclusions

Our findings demonstrate that vertical data-integration of genetic and epigenetic regulatory mechanisms generated a more in-depth understanding of the molecular basis underlying the development of obesity-associated fatty liver disease. We gained novel insights into how NAFLD classification and outcome are orchestrated, which could not have been obtained by exclusively considering genetic variation.
Abnormal sleep physiology in children with 15q11.2-13.1 duplication (Dup15q) syndrome
Authors: Saravanapandian Vidya , Nadkarni Divya , Hsu Sheng-Hsiou , Hussain Shaun A. , Maski Kiran , Golshani Peyman , Colwell Christopher S. , Balasubramanian Saravanavel , Dixon Amos , Geschwind Daniel H. , Jeste Shafali S.
Published: August 2021

Background

Sleep disturbances in autism spectrum disorder (ASD) represent a common and vexing comorbidity. Clinical heterogeneity amongst these warrants studies of the mechanisms associated with specific genetic etiologies. Duplications of 15q11.2-13.1 (Dup15q syndrome) are highly penetrant for neurodevelopmental disorders (NDDs) such as intellectual disability and ASD, as well as sleep disturbances. Genes in the 15q region, particularly UBE3A and a cluster of GABAA receptor genes, are critical for neural development, synaptic protein synthesis and degradation, and inhibitory neurotransmission. During awake electroencephalography (EEG), children with Dup15q syndrome demonstrate increased beta band oscillations (12–30 Hz) that likely reflect aberrant GABAergic neurotransmission. Healthy sleep rhythms, necessary for robust cognitive development, are also highly dependent on GABAergic neurotransmission. We therefore hypothesized that sleep physiology would be abnormal in children with Dup15q syndrome.

Methods

To test the hypothesis that elevated beta oscillations persist in sleep in Dup15q syndrome and that NREM sleep rhythms would be disrupted, we computed: (1) beta power, (2) spindle density, and (3) percentage of slow-wave sleep (SWS) in overnight sleep EEG recordings from a cohort of children with Dup15q syndrome (n = 15) and compared them to age-matched neurotypical children (n = 12).

Results

Children with Dup15q syndrome showed abnormal sleep physiology with elevated beta power, reduced spindle density, and reduced or absent SWS compared to age-matched neurotypical controls.

Limitations

This study relied on clinical EEG where sleep staging was not available. However, considering that clinical polysomnograms are challenging to collect in this population, the ability to quantify these biomarkers on clinical EEG—routinely ordered for epilepsy monitoring—opens the door for larger-scale studies. While comparable to other human studies in rare genetic disorders, a larger sample would allow for examination of the role of seizure severity, medications, and developmental age that may impact sleep physiology.

Conclusions

We have identified three quantitative EEG biomarkers of sleep disruption in Dup15q syndrome, a genetic condition highly penetrant for ASD. Insights from this study not only promote a greater mechanistic understanding of the pathophysiology defining Dup15q syndrome, but also lay the foundation for studies that investigate the association between sleep and cognition. Abnormal sleep physiology may undermine healthy cognitive development and may serve as a quantifiable and modifiable target for behavioral and pharmacological interventions.
Efficacy of damage control surgery and staged endoscopic pancreatic ductal double stenting therapy for severe pancreatic head injury: a case report
Authors: Nagashima Futoshi , Inoue Satoshi , Matsui Daisaku , Bansyoutani Yuki , Tokuda Rina , Fuzisaki Osamu , Kobayashi Makoto
Published: August 2021

Background

A high-grade pancreatic injury is a life-threatening injury that is associated with high mortality and morbidity. It is currently unclear which treatment strategy results in good clinical outcomes.

Case presentation

A 23-year-old Japanese woman sustained severe injury in a motor vehicle accident. Abdominal computed tomography revealed severe pancreatic head injury with extravasation of contrast media. Since it was not possible to insert an endoscopic pancreatic stenting tube into the main pancreatic duct, damage control surgery was performed. On day 3, we could insert the endoscopic pancreatic stenting tube from the ampulla of Vater and an endoscopic nasopancreatic drainage tube in the distal pancreatic duct from the accessory ampulla before the second operation. Drainage tubes were placed around the pancreatic head in the second operation. The endoscopic nasopancreatic drainage tube tube was converted to endoscopic pancreatic stenting tube on day 9. On day 51, the patient was discharged on foot from our hospital without serious complications.

Conclusion

Early and effective hemostasis, staged pancreatic duct drainage with stenting, and surgical external drainage around the pancreas in combination with an endoscopic procedure and damage control surgery were considered appropriate therapeutic strategy for high-grade pancreatic injury.