bluuebunny/crossref_metadata_2025 huggingface dataset:
The Cost Variability of Orthobiologics
Authors: Momaya Amit Mukesh , McGee Andrew Sullivan , Dombrowsky Alexander R. , Wild Alan Joshua , Faroqui Naqeeb M. , Waldrop Raymond P. , He Jun Kit , Brabston Eugene W. , Ponce Brent Andrew
Published: October 2019

Background:

Mixed results exist regarding the benefit of orthobiologic injections. The purpose of this study was to assess the variability in costs for platelet-rich plasma (PRP) and stem cell (SC) injections and evaluate for variables that influence pricing.

Hypothesis:

There will be significant variability in the cost of PRP and SC injections throughout the United States.

Study Design:

Descriptive epidemiology study.

Level of Evidence:

Level 3.

Methods:

Calls were made to 1345 orthopaedic sports medicine practices across the United States inquiring into the availability of PRP or SC knee injections and associated costs. In addition to pricing, the practice type, number of providers, and population and income demographics were recorded. Univariate statistical analyses were used to identify differences in availability and cost between variables.

Results:

Of the contacted offices that provided information on both PRP and SC availability (n = 1325), 268 (20.2%) offered both treatments, 550 (41.5%) offered only PRP injections, 20 (1.5%) offered only SC injections, and 487 (36.8%) did not offer either treatment. The mean ± SD cost of a PRP injection was $707 ± $388 (range, $175-$4973), and the mean cost of an SC injection was $2728 ± $1584 (range, $300-$12,000). Practices offering PRP and SC injections tended to be larger (PRP, 12.0 physicians per practice vs. 8.1 [ P < 0.001]; SC, 13.6 vs 9.7 [ P < 0.001]). Practices that offered PRP injections were located in areas with higher median household income ( P = 0.047). Variables associated with higher cost of PRP injections included city population ( P < 0.001) and median income of residents ( P < 0.001).

Conclusion:

While the majority of sports medicine practices across the United States offer some type of orthobiologic injection, there exists significant variability in the cost of these injections.

Clinical Relevance:

This study demonstrates the significant variability in costs of orthobiologic injections throughout the country, which will allow sports medicine physicians to appreciate the value of these injections when counseling patients on available treatment options.
Prognostic value of six‐minute walk distance at a South American pulmonary hypertension referral center
Authors: Costa Gabriela O.S. , Ramos Roberta P. , Oliveira Rudolf K.F. , Cepêda Angelo , Vieira Elaine B. , Ivanaga Ivan T. , Ferreira Eloara V.M. , Ota‐Arakaki Jaquelina S.
Published: October 2019

Six‐minute walk distance (6MWD) assessment is recommended for pulmonary arterial hypertension multidimensional risk stratification. However, current 6MWD cut‐off values were mainly derived from North American and European pulmonary arterial hypertension registries. Therefore, it is unknown if such cut‐off values broadly apply to other geographical populations. In this study, we aimed to identify 6MWD cut‐off values for Brazilian pulmonary arterial hypertension patients and to contrast our findings to current international Pulmonary Hypertension guidelines recommendations. One‐hundred four consecutive pulmonary arterial hypertension patients were allocated in groups according to their 6MWD, considering 50 m as a clinically relevant 6MWD difference. Next, patients were categorized into different 6MWD ranges based on similar survival rates in each group: < 250 m, 250–400 m, and >400 m. The study outcome was all‐cause mortality and transplantation according to the 6MWD range. Survival was truncated at five years. Median follow‐up period was 4.35 years (0.48–5.00). Survival rates at 1, 2, 3, and 5 years were 96%, 89%, 81%, and 73%, respectively. Cox analyses adjusted for age, sex, and pulmonary arterial hypertension etiology showed that 6MWD < 250 m and >400 m were associated with higher and lower risk of all‐cause mortality and transplantation. According to Harrell's c‐statistic, the prognostic discrimination of the 6MWD cut‐off value identified by the current study was 0.70 while international Pulmonary Hypertension guidelines 6MWD cut‐offs value was 0.61. In conclusion, our findings suggest that 6MWD geographical variations should be considered when assessing risk stratification in pulmonary arterial hypertension.
Phenytoin and gingival mucosa: A molecular investigation
Authors: Candotto Valentina , Pezzetti Furio , Baj Alessandro , Beltramini Giada , Lauritano Dorina , Di Girolamo Michele , Cura Francesca
Published: October 2019

Several distinct classes of drugs, such as anticonvulsants, immunosuppressants, and calcium channel blockers, caused gingival overgrowth. One of the main drugs associated with the gingival overgrowth is the anti-epileptic such as phenytoin, which affects gingival tissues by altering extracellular matrix metabolism. In our study, we evaluate the effect of phenytoin, a drug whose active substance is phenytoin, on gingival fibroblasts of healthy volunteers. Gene expression of 29 genes was investigated in gingival fibroblasts’ cell culture treated with phenytoin compared with untreated cells. Among the studied genes, only 13 genes (CXCL5, CXCL10, CCR1, CCR3, CCR5, CCR6, IL-1A, IL-1B, IL-5, IL-7, IL-6R, BMP-2, and TNFSF-10) were statistically significant. All but one gene resulted downregulated after 24 h of treatment with phenytoin. BPM2 was the only, although weakly, up-expressed gene. Probably, we have not highlighted overexpression of the other inflammatory molecules because the study was performed on healthy people. Many studies show that phenytoin induces the overexpression of these cytokines but, probably, in our study, the drug does not have the same effect because we used gingival fibroblasts of healthy people.
The use of a new chemical device based on silver and cationic surfactants as a new approach for daily oral hygiene: A preliminary study on a group of periodontal patients
Authors: Lauritano Dorina , Palmieri Annalisa , D’Orto Ornella , Bolzoni Alessandro , Ottria Liliana , Gargari Marco , Di Girolamo Michele , Candotto Valentina
Published: October 2019

The aim of this study was to evaluate the abatement power of oral microbial loading of a new gel formulation based on the complex silver-2-mercaptobenzoate, chlorhexidine digluconate and didecyldimethylammonium chloride (named ADC) through polymerase chain reaction (PCR). The study sample consists of a group of 20 patients with chronic periodontal disease. Patients were over 25 years of age and did not undergo surgical or non-surgical periodontal treatment in the previous 6 months. The study sample was allotted into two groups of 10 patients each, homogeneous by age and sex. The test group received a bottle containing ADC gel, while the control group received an identical one containing placebo, similar to ADC in consistence, colour, taste and odour. Sub-gingival samples of four sites, one in each quadrant, of greatest probing depth in each patient were used. Microbiological analyses were performed at baseline and at day 15. Paired t test was performed to detect statistical significant reduction in total bacterial loading and oral pathogens in the study groups. The analysis showed a statistically significant reduction in the total bacterial loading evaluated pre- and post-treatment ( P = 0.029) in the study groups. In the control group, the decrease in total bacterial loading was not significant ( P = 0.279). Clinically, ADC gel does not have any side effects and discomfort such as pain, burning, tingling sensation or numbness and produces no adverse reactions in time. Our study aimed to evaluate the efficacy of a new chemical formulation with antibacterial properties to use for daily oral hygiene with a preliminary study. Our results showed a statistically significant reduction in total bacterial loading after treatment, but the limitations of our study do not allow us to demonstrate the clinical efficacy of the ADC gel.
Education and Training in Pediatric Cardiac Critical Care: International Perspectives
Authors: Zyblewski Sinai C. , Callow Louise , Beke Dorothy M. , Jain Parag , Madathil Sai Bala , Schwartz Steven , Tabbutt Sarah , Bronicki Ronald A.
Published: October 2019

Pediatric cardiac intensive care is an evolving and maturing field. There have been advances in education and training in recent years, specifically progress toward standardization of curricula, competencies, and certifications. International partnerships have fostered similar advancements in less resourced countries. For all disciplines and levels of expertise, simulation remains a versatile and effective modality in education. Although there is improved standardization for the training of physicians and nurses, the certification process remains undetermined.
Applying Educational Theory to Interdisciplinary Education in Pediatric Cardiac Critical Care
Authors: McBride Mary E. , Almodovar Melvin C. , Florez Amy R. , Imprescia Annette , Su Lillian , Allan Catherine K.
Published: October 2019

At the 14th Annual International Meeting for the Pediatric Cardiac Intensive Care Society, the authors presented a simulation workshop for junior multidisciplinary providers focused on cardiopulmonary interactions. We provide an overview of educational theories of particular relevance to curricular design for simulation-based or enhanced activities. We then demonstrate how these theories are applied to curriculum development for individuals to teams and for novice to experts. We review the role of simulation in cardiac intensive care education and the education theories that support its use. Finally, we demonstrate how a conceptual framework, SIMZones, can be applied to design effective simulation-based teaching.
Quality Improvement Basics: A Crash Course for Pediatric Cardiac Care
Authors: Bates Katherine E. , Connor Jean , Chanani Nikhil K. , McLellan Mary C. , McCormick Andrea , Smith-Parrish Melissa , Moga Michael-Alice
Published: October 2019

Background:

Lack of knowledge of quality improvement (QI) methodology and change management principles can explain many of the difficulties encountered when trying to develop effective QI initiatives in health care.

Methods:

An interactive QI workshop at the 14th Annual Meeting of the Pediatric Cardiac Intensive Care Society provided an overview of the role of QI in health care, basic QI frameworks and tools, and leadership and organizational culture pitfalls. The top five QI projects submitted to the meeting were later presented to an expert QI panel in a separate session to illustrate examples of QI principles.

Results:

Workshop presenters introduced two major QI methodologies used to design QI projects. Important first steps include identifying a problem, forming a multidisciplinary team, and developing an aim statement. Key driver diagrams were highlighted as an important tool to develop a project’s framework. Several diagnostic tools used to understand the problem were discussed, including the “5 Why’s,” cause-and-effect charts, and process flowcharts. The importance of outcome, process, and balancing measures was emphasized. Identification of interventions, the value of plan-do-study-act cycles to fuel continuous QI, and use of statistical process control, including run charts or control charts, were reviewed. The importance of stakeholder engagement, transparency, and sustainability was discussed. Later, the top five QI projects presented highlighted multiple “QI done well” practices discussed during the preconference QI workshop.

Conclusions:

Understanding QI methodology and appropriately applying basic QI tools are pivotal steps to realizing meaningful and sustained improvement.
Trends in Medical Costs for Adolescent Idiopathic Scoliosis Surgery in Japan
Authors: Kobayashi Kazuyoshi , Ando Kei , Machino Masaaki , Tanaka Satoshi , Morozumi Masayoshi , Kanbara Shunsuke , Ito Sadayuki , Inoue Taro , Ishiguro Naoki , Imagama Shiro
Published: October 2019

Study Design:

A retrospective review of clinical data and costs was performed for surgeries for adolescent idiopathic scoliosis (AIS) conducted from 2008 to 2017.

Objective:

Cost containment and healthcare value have become focal points in Japanese health care policy. The purpose of the study was to investigate trends over time in medical costs for surgery for AIS.

Methods:

A total of 83 patients underwent surgery for AIS from 2008 to 2017 at our hospital. Clinical data and length of stay were collected, and medical costs for surgery, local bone grafting, fees per day, and surgical instruments were evaluated.

Results:

There were slight year-by-year decreases in fees per day and decreases in costs of surgical instruments. The average length of stay was 16.4 days and gradually decreased over time. In contrast, scoliosis surgery costs increased about 1.6 times in 10 years from $9515 to $15 130.

Conclusion:

The trends for decreases in fees per day and prices for surgical instruments reflect recent government medical cost control policies. The cost for scoliosis surgery is also defined by the government, and the increase over 10 years may reflect the perspective of valuing effective and advanced surgeries. This study of cost trends of operative spinal intervention provides an assessment of surgical benefit and is likely to influence health care costs.
Validation of the Shin Pain Scoring System: A Novel Approach for Determining Tibial Bone Stress Injuries
Authors: Nussbaum Eric D. , Gatt Charles J. , Epstein Robert , Bechler Jeffrey R. , Swan Kenneth G. , Tyler David , Bjornaraa Jaynie
Published: October 2019

Background:

The incidence of adolescent overuse injuries, including bone stress injuries (BSIs), is on the rise. The identification of a BSI in the early stages is key to successful treatment. The Shin Pain Scoring System (SPSS) was developed to aid clinicians in identifying patients with a BSI.

Hypothesis:

The SPSS will correlate with magnetic resonance imaging (MRI) grading of a BSI in an adolescent population.

Study Design:

Cohort study (diagnosis); Level of evidence, 2.

Methods:

Enrolled in this study were 80 adolescent high school athletes between the ages of 13 and 18 years participating in a variety of sports with more than 1 week of atraumatic shin pain. The SPSS questionnaire was completed for each participant, and physical examination findings were recorded. Each question and physical examination item was allotted a point value, which totaled 29 points. Radiographs and MRI scans of both lower legs were obtained for each participant. The SPSS score was statistically analyzed using logistic regression, a classification matrix, and a 2 × 2 contingency table to evaluate validity and predictability.

Results:

Logistic regression analysis of our data determined that 3 categories of SPSS scores provided the highest diagnostic value when compared with MRI grading based on the Fredericson classification (0-4). The SPSS correctly identified 43.5% of injuries for category 1 (MRI grades 0-1), 62.5% for category 2 (MRI grade 2), and 50.0% for category 3 (MRI grades 3-4). Overall, the SPSS correctly identified the degree of BSI in 54.4% of all tibias studied. Binary analysis for validity demonstrated a sensitivity of 96%, specificity of 26%, positive predictive value of 76%, and negative predictive value of 71% for the SPSS relative to the “gold standard” MRI results.

Conclusion:

The SPSS is a potentially valid method to identify tibial BSIs, given the sensitivity and negative and positive predictive values. It also provides helpful categorization to alert clinicians to the presence of a BSI and direct further diagnostics and/or interventions. The SPSS should be considered as an additional tool to use when evaluating adolescents with atraumatic tibial BSIs.
Midterm Outcomes of Bone Marrow Stimulation for Primary Osteochondral Lesions of the Talus: A Systematic Review
Authors: Toale James , Shimozono Yoshiharu , Mulvin Conor , Dahmen Jari , Kerkhoffs Gino M.M.J. , Kennedy John G.
Published: October 2019

Background:

Bone marrow stimulation (BMS) is a common surgical intervention in the treatment of small osteochondral lesions of the talus (OLTs). Evidence has shown good clinical outcomes after BMS in the short term, but several studies have shown less favorable results at midterm and long-term follow-up because of fibrocartilaginous repair tissue degeneration.

Purpose:

To evaluate the clinical and radiological outcomes of BMS in the treatment of primary OLTs at midterm and long-term follow-up and to investigate reported data in these studies.

Study Design:

Systematic review; Level of evidence, 4.

Methods:

A systematic search of the MEDLINE, Embase, and Cochrane Library databases was performed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clinical and radiological outcomes as well as reported data were evaluated.

Results:

A total of 15 studies comprising 853 patients (858 ankles) were included at a weighted mean follow-up time of 71.9 months. There were 9 studies that used the American Orthopaedic Foot & Ankle Society (AOFAS) score, with a weighted mean postoperative score of 89.9. There were 3 studies that measured postoperative magnetic resonance imaging results in the midterm using the MOCART (magnetic resonance observation of cartilage repair tissue) scoring system and showed 48% of patients with complete filling, 74% with complete integration, and 76% with surface damage. There was a complication rate of 3.4% and a reoperation rate of 6.0% after BMS in the midterm.

Conclusion:

This systematic review found good clinical outcomes after BMS at midterm follow-up for primary OLTs. Radiological outcomes showed repair tissue surface damage in the majority of patients, which may be a harbinger for long-term problems. Data were variable, and numerous data were underreported. Further high-quality studies, a validated outcome scoring system, and further radiological reports at midterm follow-up are required to accurately assess the success of BMS in the midterm.
Systematic Prediction of FFAT Motifs Across Eukaryote Proteomes Identifies Nucleolar and Eisosome Proteins With the Predicted Capacity to Form Bridges to the Endoplasmic Reticulum
Authors: Slee John A. , Levine Timothy P.
Published: October 2019

The endoplasmic reticulum (ER), the most pervasive organelle, exchanges information and material with many other organelles, but the extent of its interorganelle connections and the proteins that form bridges are not well known. The integral ER membrane protein vesicle-associated membrane protein-associated protein (VAP) is found in multiple bridges, interacting with many proteins that contain a short linear motif consisting of “two phenylalanines in an acidic tract” (FFAT). The VAP-FFAT interaction is the most common mechanism by which cytoplasmic proteins, particularly interorganelle bridges, target the ER. Therefore, predicting new FFAT motifs may both find new individual peripheral ER proteins and identify new routes of communication involving the ER. Here, we searched for FFAT motifs across whole proteomes. The excess of eukaryotic proteins with FFAT motifs over background was ≥0.8%, suggesting that this is the minimum number of peripheral ER proteins. In yeast, where VAP was previously known to bind 4 proteins with FFAT motifs, a detailed analysis of a subset of proteins predicted 20 FFAT motifs. Extrapolating these findings to the whole proteome estimated the number of FFAT motifs in yeast at approximately 50 to 55 (0.9% of proteome). Among these previously unstudied FFAT motifs, most have known functions outside the ER, so could be involved in interorganelle communication. Many of these can target well-characterized membrane contact sites; however, some are in nucleoli and eisosomes, organelles previously unknown to have molecular bridges to the ER. We speculate that the nucleolar and eisosomal proteins with predicted motifs may function while bridging to the ER, indicating novel ER–nucleolus and ER–eisosome routes of interorganelle communication.
Associations between early home environment and trajectories of disruptive behavior among preschoolers reared in CPS-referred families
Authors: Bick Johanna , Lipschutz Rebecca , Lind Teresa , Zajac Lindsay , Dozier Mary
Published: October 2019

Young children who experience maltreatment are at increased risk for disruptive behavior problems. In high-risk environments, children’s difficulties regulating negative emotions and behavior may be an important precursor to later disruptive behavior problems. This longitudinal study examined associations between early home risk factors and trajectories of disruptive behavior in young children in Child Protective Services–involved families. Standardized observations of disruptive behavior, home environment quality, and parenting risk were measured when children ( N = 142) were 36 and 48 months old. Results of multiple indicator latent change models showed that early childhood anger dysregulation decreased over the early preschool period. Early home and parenting risk factors (increased harsh parenting, reduced organization of the home, and decreased parental involvement and responsiveness) were associated with higher baseline values of anger dysregulation at 36 months, but not with change in anger dysregulation over the preschool period. These findings hold important implications for early prevention and intervention for externalizing problems among children in the child welfare system.
Processes of Stroke Unit Care and Outcomes at Discharge in Vietnam: Findings from the Registry of Stroke Care Quality (RES-Q) in a Major Public Hospital
Authors: Nguyen Thang Huy , Gall Seana , Cadilhac Dominique A. , Nguyen Hoang , Terry Daniel , Pham Binh N. , Nguyen Trung Q. , Nguyen An T. , Dao Nha T. , Duong Chinh D. , Phan Bau V. , Phan Hoang T.
Published: October 2019

Background: An essential strategy to reduce mortality and disability after stroke is to ensure access to evidence-based care. In developed countries, it has been shown that if hospitals improve the quality of care, the impact of stroke is attenuated. However, in developing countries, data on the processes of care and associated patient outcomes are scarce. We examined the care processes and outcomes among patients with acute stroke from a stroke unit in a major public hospital in Vietnam whereby there are approximately 15,000 hospital admissions for stroke per year.

Methods: We included first-ever strokes admitted to the 115 People’s Hospital (June 2017-March 2018). Data were collected in the Registry of Stroke Care Quality which is used in >50 countries. Baseline characteristics, stroke-related factors (e.g., type and severity), processes of care (e.g., thrombolysis), and outcomes at discharge were examined including mortality and functional outcome, assessed as the walking ability without assistance.

Results: Data were available for 6601 patients with first-ever stroke (44% women, 80% ischemic stroke [IS], median age: 62 years, interquartile range [IQR]: 53-72) who received stroke unit care. The median time from stroke onset to hospital arrival was 15.7 hours (IQR: 5.6-37.5). At admission, the median National Institute of Health Stroke Scale score indicating stroke severity was 7 (IQR: 4-12). Among those with IS, 9% received intravenous thrombolysis. Over 90% of the participants received recommended process of care including dysphasia screening (99%), antihypertensive agents (92%), cholesterol-lowering medication (IS = 99%), and antithrombotic medication (IS = 98%). At discharge (median length of stay: 4 days, IQR: 3-6), 3% of all cases died and 46% were able to walk independently. Advanced age, stroke severity, and not receiving antihypertensive agent(s) were contributing factors to mortality and poorer functional outcome.

Conclusion: There was a considerable delay in the time from stroke onset to hospital arrival. Evidence-based care at the stroke unit was consistently provided. It remains unclear whether other hospitals in Vietnam and other developing countries perform as well. Greater public awareness of stroke to reduce onset to arrival times and more stroke units are warranted to achieve the excellent outcomes in the major public hospital.
Unreported Summary Statistics in Trial Publications and Risk of Bias in Stroke Rehabilitation Systematic Reviews: An International Survey of Review Authors and Examination of Practical Solutions
Authors: Weir Christopher J. , Assi Valentina , Na Lumine , Lewis Stephanie C. , Murray Gordon D. , Langhorne Peter , Brady Marian C.
Published: October 2019

Objective: Continuous outcome measures are essential in rehabilitation research. Incomplete reporting of their mean and standard deviation, required for meta-analysis, potentially introduces bias and imprecision if it prevents studies being included. We aimed to determine how often systematic reviewers encounter missing mean or standard deviation values and to recommend practical statistical solutions.

Design: 1. Cross-sectional survey of systematic review authors. 2. Reanalysis of Cochrane review data to evaluate how accurately statistical methods for recovering missing mean or standard deviation values estimate the true meta-analysis treatment effect.

Setting: Rehabilitation intervention systematic reviews.

Participants: Cochrane stroke rehabilitation review authors; stroke patients.

Interventions: Reanalysis of a Cochrane review of early supported discharge services.

Main measures: Hospital length of stay.

Results: Survey responses covered 53 of 70 Cochrane reviews. Almost all studied continuous outcome measures, 68% encountering missing summary statistics. Various solutions were attempted but 76% of meta-analyses omitted at least one study due to missing information. In the review reanalysis ( N = 1055), a method based on the minimum and maximum performed best in recovering missing standard deviations; a method based on the median, lower and upper quartiles successfully estimated a missing mean.

Conclusion: Practical statistical methods help reduce risk of bias, maximise the evidence included in rehabilitation meta-analyses and offer a clear hierarchy of solutions to handling unreported mean and standard deviation values.
Services Export and Economic Growth in ASEAN Countries
Authors: Sermcheep Sineenat
Published: October 2019

Based on the panel data from 1980 to 2014, this article examines the effect of services export on economic growth in the ASEAN countries. The results show that there has been evidence of services export-led growth in ASEAN during the past decades. The services export data are disaggregated into modern and traditional services exports, and the estimations show that both exports contribute to the GDP growth with the less strong positive effect from the modern services exports. The goods export, conventional engine of growth, also maintains its significant and robust role as the growth-enhancing factor for ASEAN. In the period of a slow growth of goods exports and the direction of the growth policy towards services-oriented sector, the services exports have become increasingly significant as a new engine of growth, which also complement to the existing growth engine.

JEL Codes: F43, O4
Etranacogene dezaparvovec (AMT-061 phase 2b): normal/near normal FIX activity and bleed cessation in hemophilia B
Authors: Von Drygalski Annette , Giermasz Adam , Castaman Giancarlo , Key Nigel S. , Lattimore Susan , Leebeek Frank W. G. , Miesbach Wolfgang , Recht Michael , Long Alison , Gut Robert , Sawyer Eileen K. , Pipe Steven W.
Published: October 2019

Etranacogene dezaparvovec (AMT-061) is a recombinant AAV5 vector including a gene cassette containing the factor IX (FIX) Padua variant under the control of a liver-specific promoter. A phase 2b study was conducted to confirm that a single dose of 2 × 1013 genome copies per kilogram of etranacogene dezaparvovec will result in FIX activity ≥5% 6 weeks after dosing. Secondary end points included FIX activity at other time points, bleed frequency, FIX replacement, and safety. Etranacogene dezaparvovec was administered as a single IV infusion to 3 adults with severe to moderately severe hemophilia B. Before treatment, participants had low levels of preexisting neutralizing antibodies to AAV5. This article reports a planned 26-week interim assessment. At week 6, mean FIX activity was 31% (23.9%-37.8%), increasing to 47% (33.2%-57.0%) at 26 weeks, with 2 subjects exhibiting sustained activity >40%. Consistent with the FIX activity, etranacogene dezaparvovec was associated with a complete bleed cessation with no need for FIX replacement therapy up to 26 weeks. Etranacogene dezaparvovec was generally well tolerated. No clinically significant elevations in levels of liver enzymes or inflammatory markers were observed, and no use of corticosteroids related to treatment was required. In individuals with severe to moderately severe hemophilia B, etranacogene dezaparvovec resulted in clinically relevant increases in FIX activity, cessation of bleeds, and abrogation of the need for FIX replacement, despite the presence of preexisting anti-AAV5 neutralizing antibodies detected by using a highly sensitive luciferase assay. Consistency of results in the 3 participants supported an expanded evaluation of the safety/efficacy of etranacogene dezaparvovec in the HOPE-B (Health Outcomes With Padua Gene; Evaluation in Hemophilia-B) phase 3 trial. The current trial was registered at www.clinicaltrials.gov as #NCT03489291.
Variable agreement between wearable heart rate monitors during exercise in cystic fibrosis
Authors: Gaynor Madeline , Sawyer Abbey , Jenkins Sue , Wood Jamie
Published: October 2019

In people with cystic fibrosis (CF), greater cardiorespiratory fitness is associated with improved survival and quality of life. Wearable activity monitors are a popular method of monitoring exercise, with measures of heart rate used to indicate exercise intensity. We assessed the agreement of heart rate recordings obtained using the Fitbit Charge HR™, Polar® H7 heart rate sensor and Masimo SET® Rad-5v pulse oximeter with the three-lead ECG during continuous and interval exercise.

Adults with CF completed two exercise sessions, of 15-min duration per session, on a cycle ergometer while wearing the previously mentioned monitors. Firstly, participants cycled at 30% of estimated peak workload (Wpeak). Secondly, participants cycled at 1-min intervals at 60% ofWpeakinterspersed with 2 min of unloaded cycling. Heart rate readings on all devices were recorded at minute intervals and their agreement was analysed using the Bland–Altman method.

The Polar® H7 heart rate sensor had the best agreement with three-lead ECG, with a bias of 0±1 bpm during both continuous and interval exercise. The Masimo SET® Rad-5v pulse oximeter had good agreement, with a bias of 1±7 bpm and 1±5 bpm during continuous and interval exercise, respectively. The Fitbit Charge HR™demonstrated less agreement, with a bias of 9±17 bpm and 5±13 bpm during continuous and interval exercise, respectively.

The Fitbit Charge HR™is not recommended for assessing heart rate during exercise in adults with CF. Findings support the use of the Polar® H7 for accurate heart rate monitoring.
Pregnancy after lung and heart–lung transplantation: a French multicentre retrospective study of 39 pregnancies
Authors: Bry Charlotte , Hubert Dominique , Reynaud-Gaubert Martine , Dromer Claire , Mal Hervé , Roux Antoine , Boussaud Véronique , Claustre Johanna , Le Pavec Jérôme , Murris-Espin Muriel , Danner-Boucher Isabelle
Published: October 2019

Pregnancy after lung and heart–lung transplantation remains rare. This French study deals with change in lung function after a pregnancy and the maternal and newborn outcomes.

We retrospectively included 39 pregnancies in 35 women aged >20 years. Data on patients, course of pregnancies and newborns were collected from nine transplantation centres.

Mean age at time of pregnancy was 28 years. Cystic fibrosis affected 71% of patients. Mean±sdtime between transplantation and pregnancy was 63±44 months. 26 births occurred (67%) with a mean term of 36 weeks of amenorrhoea and a mean birthweight of 2409 g. Prematurity was observed in 11 cases (43%). Forced expiratory volume in 1 s was 83.9% of predicted before pregnancy and 77.3% of predicted 1 year after the end of pregnancy (p=0.04). 10 patients developed chronic lung allograft dysfunction after delivery. Nine patients died at a mean±sdtime after transplantation of 8.2±7 years and a mean±sdtime after pregnancy of 4.6±6.5 years.

These data show that pregnancy remains feasible in lung and heart–lung transplant recipients, with more frequent maternal and newborn complications than in the general population. Survival in this cohort appears to be similar to the global survival observed in lung transplant recipients. Planned pregnancy and multidisciplinary follow-up are crucial.
The appropriate dosing of erenumab for migraine prevention after multiple preventive treatment failures: a critical appraisal
Authors: Ornello Raffaele , Tiseo Cindy , Frattale Ilaria , Perrotta Giulia , Marini Carmine , Pistoia Francesca , Sacco Simona
Published: October 2019

Background

Erenumab, a fully human monoclonal antibody directed against the calcitonin gene-related peptide receptor, was approved for the prevention of episodic (EM) or chronic migraine (CM) at the monthly dose of 70 mg or 140 mg. We reviewed the available literature to understand if patients with prior preventive treatment failures benefit more from the 140 mg dose than the 70 mg.

Main body

We searched papers indexed in PubMed and conference abstracts published in the last 2 years which assessed the safety and efficacy of erenumab in patients with prior preventive treatment failures. We reviewed the results of 3 randomized controlled trials and their subgroup analyses and open-label extensions. The 140 mg monthly dose of erenumab had a numerical advantage over the 70 mg monthly dose in patients with prior preventive treatment failures, both in EM and CM (with or without medication overuse) during the double blind phases of the trials and their open-label extensions. The numerical difference between the two doses increased with the increase in the number of prior preventive treatment failures.

Conclusions

The available data suggest that erenumab 140 mg monthly might be preferred over the 70 mg monthly dose in patients with EM or CM and prior preventive treatment failures. Further data are needed to assess the long-term efficacy in clinical practice of the two doses of erenumab, while their safety profile is comparable.
Random forest-based imputation outperforms other methods for imputing LC-MS metabolomics data: a comparative study
Authors: Kokla Marietta , Virtanen Jyrki , Kolehmainen Marjukka , Paananen Jussi , Hanhineva Kati
Published: October 2019

Background

LC-MS technology makes it possible to measure the relative abundance of numerous molecular features of a sample in single analysis. However, especially non-targeted metabolite profiling approaches generate vast arrays of data that are prone to aberrations such as missing values. No matter the reason for the missing values in the data, coherent and complete data matrix is always a pre-requisite for accurate and reliable statistical analysis. Therefore, there is a need for proper imputation strategies that account for the missingness and reduce the bias in the statistical analysis.

Results

Here we present our results after evaluating nine imputation methods in four different percentages of missing values of different origin. The performance of each imputation method was analyzed by Normalized Root Mean Squared Error (NRMSE). We demonstrated that random forest (RF) had the lowest NRMSE in the estimation of missing values for Missing at Random (MAR) and Missing Completely at Random (MCAR). In case of absent values due to Missing Not at Random (MNAR), the left truncated data was best imputed with minimum value imputation. We also tested the different imputation methods for datasets containing missing data of various origin, and RF was the most accurate method in all cases. The results were obtained by repeating the evaluation process 100 times with the use of metabolomics datasets where the missing values were introduced to represent absent data of different origin.

Conclusion

Type and rate of missingness affects the performance and suitability of imputation methods. RF-based imputation method performs best in most of the tested scenarios, including combinations of different types and rates of missingness. Therefore, we recommend using random forest-based imputation for imputing missing metabolomics data, and especially in situations where the types of missingness are not known in advance.
PPR-SSM: personalized PageRank and semantic similarity measures for entity linking
Authors: Lamurias Andre , Ruas Pedro , Couto Francisco M.
Published: October 2019

Background

Biomedical literature concerns a wide range of concepts, requiring controlled vocabularies to maintain a consistent terminology across different research groups. However, as new concepts are introduced, biomedical literature is prone to ambiguity, specifically in fields that are advancing more rapidly, for example, drug design and development. Entity linking is a text mining task that aims at linking entities mentioned in the literature to concepts in a knowledge base. For example, entity linking can help finding all documents that mention the same concept and improve relation extraction methods. Existing approaches focus on the local similarity of each entity and the global coherence of all entities in a document, but do not take into account the semantics of the domain.

Results

We propose a method, PPR-SSM, to link entities found in documents to concepts from domain-specific ontologies. Our method is based on Personalized PageRank (PPR), using the relations of the ontology to generate a graph of candidate concepts for the mentioned entities. We demonstrate how the knowledge encoded in a domain-specific ontology can be used to calculate the coherence of a set of candidate concepts, improving the accuracy of entity linking. Furthermore, we explore weighting the edges between candidate concepts using semantic similarity measures (SSM). We show how PPR-SSM can be used to effectively link named entities to biomedical ontologies, namely chemical compounds, phenotypes, and gene-product localization and processes.

Conclusions

We demonstrated that PPR-SSM outperforms state-of-the-art entity linking methods in four distinct gold standards, by taking advantage of the semantic information contained in ontologies. Moreover, PPR-SSM is a graph-based method that does not require training data. Our method improved the entity linking accuracy of chemical compounds by 0.1385 when compared to a method that does not use SSMs.
Cooperative evolution of two different TEs results in lineage-specific novel transcripts in the BLOC1S2 gene
Authors: Cho Hyeon-Mu , Park Sang-Je , Choe Se-Hee , Lee Ja-Rang , Kim Sun-Uk , Jin Yeung-Bae , Kim Ji-Su , Lee Sang-Rae , Kim Young-Hyun , Huh Jae-Won
Published: October 2019

Background

TheBLOC1S2gene encodes the multifunctional protein BLOS2, a shared subunit of two lysosomal trafficking complexes: i) biogenesis of lysosome-related organelles complex-1 and i) BLOC-1-related complex. In our previous study, we identified an intriguing unreported transcript of theBLOC1S2gene that has a novel exon derived from two transposable elements (TEs), MIR andAluSp. To investigate the evolutionary footprint and molecular mechanism of action of this transcript, we performed PCR and RT-PCR experiments and sequencing analyses using genomic DNA and RNA samples from humans and various non-human primates.

Results

The results showed that the MIR element had integrated into the genome of our common ancestor, specifically in theBLOC1S2gene region, before the radiation of all primate lineages and that theAluSp element had integrated into the genome of our common ancestor, fortunately in the middle of the MIR sequences, after the divergence of Old World monkeys and New World monkeys. The combined MIR andAluSp sequences provide a 3′ splice site (AG) and 5′ splice site (GT), respectively, and generate the Old World monkey-specific transcripts. Moreover, branch point sequences for the intron removal process are provided by the MIR andAluSp combination.

Conclusions

We show for the first time that sequential integration into the same location and sequence divergence events of two different TEs generated lineage-specific transcripts through sequence collaboration during primate evolution.
Complete nontuberculous mycobacteria whole genomes using an optimized DNA extraction protocol for long-read sequencing
Authors: Bouso Jennifer M. , Planet Paul J.
Published: October 2019

Background

Nontuberculous mycobacteria (NTM) are a major cause of pulmonary and systemic disease in at-risk populations. Gaps in knowledge about transmission patterns, evolution, and pathogenicity during infection have prompted a recent surge in genomic NTM research. Increased availability and affordability of whole genome sequencing (WGS) techniques provide new opportunities to sequence and construct complete bacterial genomes faster and at a lower cost. However, extracting large quantities of pure genomic DNA is particularly challenging with NTM due to its slow growth and recalcitrant cell wall. Here we report a DNA extraction protocol that is optimized for long-read WGS of NTM, yielding large quantities of highly pure DNA with no additional clean-up steps.

Results

Our DNA extraction method was compared to 6 other methods with variations in timing of mechanical disruption and enzymatic digestion of the cell wall, quantity of matrix material, and reagents used in extraction and precipitation. We tested our optimized method on 38 clinical isolates from the M. avium and M. abscessus complexes, which yielded optimal quality and quantity measurements for Oxford Nanopore Technologies sequencing. We also present the efficient completion of circularized M. avium subspecies hominissuis genomes using our extraction technique and the long-read sequencing MinION platform, including the identification of a novel plasmid.

Conclusions

Our optimized extraction protocol and assembly pipeline was both sufficient and efficient for genome closure. We expect that our finely-tuned extraction method will prove to be a valuable tool in long-read sequencing and completion of mycobacterial genomes going forward. Utilization of comprehensive, long-read based approaches will advance the understanding evolution and pathogenicity of NTM infections.
Analysis of the fecal microbiota of fast- and slow-growing rainbow trout (Oncorhynchus mykiss)
Authors: Chapagain Pratima , Arivett Brock , Cleveland Beth M. , Walker Donald M. , Salem Mohamed
Published: October 2019

Background

Diverse microbial communities colonizing the intestine of fish contribute to their growth, digestion, nutrition, and immune function. We hypothesized that fecal samples representing the gut microbiota of rainbow trout could be associated with differential growth rates observed in fish breeding programs. If true, harnessing the functionality of this microbiota can improve the profitability of aquaculture. The first objective of this study was to test this hypothesis if gut microbiota is associated with fish growth rate (body weight). Four full-sibling families were stocked in the same tank and fed an identical diet. Two fast-growing and two slow-growing fish were selected from each family for 16S rRNA microbiota profiling.

Microbiota diversity varies with different DNA extraction methods. The second objective of this study was to compare the effects of five commonly used DNA extraction methods on the microbiota profiling and to determine the most appropriate extraction method for this study. These methods were Promega-Maxwell, Phenol-chloroform, MO-BIO, Qiagen-Blood/Tissue, and Qiagen-Stool. Methods were compared according to DNA integrity, cost, feasibility and inter-sample variation based on non-metric multidimensional scaling ordination (nMDS) clusters.

Results

Differences in DNA extraction methods resulted in significant variation in the identification of bacteria that compose the gut microbiota. Promega-Maxwell had the lowest inter-sample variation and was therefore used for the subsequent analyses. Beta diversity of the bacterial communities showed significant variation between breeding families but not between the fast- and slow-growing fish. However, an indicator analysis determined that cellulose, amylose degrading and amino acid fermenting bacteria (Clostridium, Leptotrichia, and Peptostreptococcus) are indicator taxa of the fast-growing fish. In contrary, pathogenic bacteria (Corynebacterium and Paeniclostridium) were identified as indicator taxa for the slow-growing fish.

Conclusion

DNA extraction methodology should be carefully considered for accurate profiling of the gut microbiota. Although the microbiota was not significantly different between the fast- and slow-growing fish groups, some bacterial taxa with functional implications were indicative of fish growth rate. Further studies are warranted to explore how bacteria are transmitted and potential usage of the indicator bacteria of fast-growing fish for development of probiotics that may improve fish health and growth.
Microevolution within ST11 group Clostridioides difficile isolates through mobile genetic elements based on complete genome sequencing
Authors: Wu Yuan , Yang Lin , Li Wen-Ge , Zhang Wen Zhu , Liu Zheng Jie , Lu Jin-Xing
Published: October 2019

Background

Clade 5Clostridioides difficilediverges significantly from the other clades and is therefore, attracting increasing attention due its great heterogeneity. In this study, we used third-generation sequencing techniques to sequence the complete whole genomes of three ST11C. difficileisolates, RT078 and another two new ribotypes (RTs), obtained from three independent hospitalized elderly patients undergoing antibiotics treatment. Mobile genetic elements (MGEs), antibiotic-resistance, drug resistance genes, and virulent-related genes were analyzed and compared within these three isolates.

Results

Isolates 10,010 and 12,038 carried a distinct deletion intcdAcompared with isolate 21,062. Furthermore, all three isolates had identical deletions and point-mutations intcdC, which was once thought to be a unique characteristic of RT078. Isolate 21,062 (RT078) had a unique plasmid, different numbers of transposons and genetic organization, and harboring special CRISPR spacers. All three isolates retained high-level sensitivity to 11 drugs and isolate 21,062 (RT078) carried distinct drug-resistance genes and loss of numerous flagellum-related genes.

Conclusions

We concluded that capillary electrophoresis based PCR-ribotyping is important for confirming RT078. Furthermore, RT078 isolates displayed specific MGEs, indicating an independent evolutionary process. In the further study, we could testify these findings with more RT078 isolates of divergent origins.