bluuebunny/crossref_metadata_2025 huggingface dataset:
High performance implementation of the hierarchical likelihood for generalized linear mixed models: an application to estimate the potassium reference range in massive electronic health records datasets
Authors: Bologa Cristian G. , Pankratz Vernon Shane , Unruh Mark L. , Roumelioti Maria Eleni , Shah Vallabh , Shaffi Saeed Kamran , Arzhan Soraya , Cook John , Argyropoulos Christos
Published: July 2021

Background

Converting electronic health record (EHR) entries to useful clinical inferences requires one to address the poor scalability of existing implementations of Generalized Linear Mixed Models (GLMM) for repeated measures. The major computational bottleneck concerns the numerical evaluation of multivariable integrals, which even for the simplest EHR analyses may involve millions of dimensions (one for each patient). The hierarchical likelihood (h-lik) approach to GLMMs is a methodologically rigorous framework for the estimation of GLMMs that is based on the Laplace Approximation (LA), which replaces integration with numerical optimization, and thus scales very well with dimensionality.

Methods

We present a high-performance, direct implementation of the h-lik for GLMMs in the R package TMB. Using this approach, we examined the relation of repeated serum potassium measurements and survival in the Cerner Real World Data (CRWD) EHR database. Analyzing this data requires the evaluation of an integral in over 3 million dimensions, putting this problem beyond the reach of conventional approaches. We also assessed the scalability and accuracy of LA in smaller samples of 1 and 10% size of the full dataset that were analyzed via the a) original, interconnected Generalized Linear Models (iGLM), approach to h-lik, b) Adaptive Gaussian Hermite (AGH) and c) the gold standard for multivariate integration Markov Chain Monte Carlo (MCMC).

Results

Random effects estimates generated by the LA were within 10% of the values obtained by the iGLMs, AGH and MCMC techniques. The H-lik approach was 4–30 times faster than AGH and nearly 800 times faster than MCMC. The major clinical inferences in this problem are the establishment of the non-linear relationship between the potassium level and the risk of mortality, as well as estimates of the individual and health care facility sources of variations for mortality risk in CRWD.

Conclusions

We found that the direct implementation of the h-lik offers a computationally efficient, numerically accurate approach for the analysis of extremely large, real world repeated measures data via theh-likapproach to GLMMs. The clinical inference from our analysis may guide choices of treatment thresholds for treating potassium disorders in the clinic.
Positive Health and the happy professional: a qualitative case study
Authors: Lemmen Caro H. C. , Yaron Gili , Gifford Rachel , Spreeuwenberg Marieke D.
Published: July 2021

Background

Primary care professionals (PCPs) face mounting pressures associated with their work, which has resulted in high burn-out numbers. Increasing PCPs’ job satisfaction is proposed as a solution in this regard. Positive Health (PH) is an upcoming, comprehensive health concept. Among others, this concept promises to promote PCPs’ job satisfaction. However, there is limited research into PH’s effects on this topic. This study, therefore, aims to provide insight into how adopting PH in a general practice affects PCPs’ job satisfaction.

Methods

An ethnographic case study was conducted in a Dutch general practice that is currently implementing PH. Data collected included 11 semi-structured interviews and archival sources. All data were analyzed thematically.

Results

Thematic analysis identified three themes regarding PCPs’ adoption of PH and job satisfaction, namely [1] adopting and adapting Positive Health, [2] giving substance to Positive Health in practice, and [3] changing financial and organizational structures. Firstly, the adoption of PH was the result of a match between the practice and the malleable and multi-interpretable concept. Secondly, PH supported PCPs to express, legitimize, and promote their distinctive approach to care work and its value. This strengthened them to further their holistic approach to health and stimulate autonomy in practice, with respect to both patients and professionals. Thirdly, the concept enabled PCPs to change their financial and organizational structures, notably freeing time to spend on patients and on their own well-being. This allowed them to enact their values. The changes made by the practice increased the job satisfaction of the PCPs.

Conclusions

PH contributed to the job satisfaction of the PCPs of the general practice by functioning as an adaptable frame for change. This frame helped them to legitimize and give substance to their vision, thereby increasing job satisfaction. PH’s malleability allows for the frame’s customization and the creation of the match. Simultaneously, malleability introduces ambiguity on what the concept entails. In that regard, PH is not a readily implementable intervention. We recommend that other organizations seeking to adopt PH consider whether they are willing and able to make the match and explore how PH can help substantiate their vision.
Serological and molecular epidemiology of the Dengue, Zika and Chikungunya viruses in a risk area in Brazil
Authors: Mota Magaly Lima , dos Santos Souza Marinho Robson , Duro Rodrigo Lopes Sanz , Hunter James , de Menezes Irwin Rose Alencar , de Lima Silva João Marcos Ferreira , Pereira Glaubervânio Leite Tavares , Sabino Ester Cerdeira , Grumach Anete , Diaz Ricardo Sobhie , do Socorro Lucena Maria , Komninakis Shirley Vasconcelos
Published: July 2021

Background

The co-circulation of types of arbovirus in areas where they are endemic increased the risk of outbreaks and limited the diagnostic methods available. Here, we analyze the epidemiological profile of DENV, CHIKV and ZIKV at the serological and molecular level in patients with suspected infection with these arboviruses in the city of Juazeiro do Norte, Ceará, Brazil.

Methods

In 2016, the Central Public Health Laboratory (LACEN) of Juazeiro do Norte received 182 plasma samples from patients who visited health facilities with symptoms compatible with arbovirus infection. The LACEN performed serological tests for detection of IgM/IgG to DENV and CHIKV. They then sent these samples to the Retrovirology Laboratory of the Federal University of São Paulo and Faculty of Medical of the ABC where molecular analyses to confirm the infection by DENV, ZIKV and CHIKV were performed. The prevalence of IgM/IgG antibodies and of infections confirmed by RT-qPCR were presented with 95% confidence interval.

Results

In serologic analysis, 125 samples were positive for antibodies against CHIKV and all were positive for antibodies against DENV. A higher prevalence of IgG against CHIKV (63.20% with 95% CI: 45.76–70.56) than against DENV (95.05% with 95% CI: 78.09–98.12) was observed. When the samples were submitted to analysis by RT-qPCR, we observed the following prevalence: mono-infection by ZIKV of 19.23% (95% CI: 14.29–34.82) patients, mono-infection by CHIKV of 3.84% (95% CI: 2.01–5.44) and co-infection with ZIKV and CHIKV of 1.09% (95% CI: 0.89–4.56).

Conclusion

The serologic and molecular tests performed in this study were effective in analyzing the epidemiological profile of DENV, CHIKV and ZIKV in patients with suspected infection by these arboviruses in the city of Juazeiro do Norte, Ceará/Brazil.
Institutional guidelines on maternal care and investigations following antepartum stillbirth - a national survey
Authors: Muin Dana A. , Neururer Sabrina , Rotter Veronika , Leitner Hermann , Leutgeb Stephanie , Husslein Peter W. , Kiss Herbert , Kohlberger Petra
Published: July 2021

Background

Antepartum stillbirth, i.e., intrauterine fetal death (IUFD) above 24 weeks of gestation, occurs with a prevalence of 2.4–3.1 per 1000 live births in Central Europe. In order to ensure highest standards of treatment and identify causative and associated (risk) factors for fetal death, evidence-based guidelines on clinical practice in such events are recommended. Owing to a lack of a national guideline on maternal care and investigations following stillbirth, we, hereby, sought to assess the use of institutional guidelines and clinical practice after IUFD in Austrian maternity units.

Methods

A national survey with a paper-based 12-item questionnaire covering demographic variables, local facilities and practice, obstetrical care and routine post-mortem work-up following IUFD was performed among all Austrian secondary and tertiary referral hospitals with maternity units (n = 75) between January and July 2019. Statistical tests were conducted using Chi2 and Fisher’s Exact test, respectively. Univariate logistic regression analyses were performed to calculate odds ratio (OR) with a 95% confidence interval (CI).

Results

46 (61.3%) obstetrical departments [37 (80.4%) secondary; 9 (19.6%) tertiary referral hospitals] participated in this survey, of which 17 (37.0%) have implemented an institutional guideline. The three most common investigations always conducted following stillbirth are placental histology (20.9%), fetal autopsy (13.1%) and maternal antibody screen (11.5%). Availability of an institutional guideline was not significantly associated with type of hospital, on-site pathology department, or institutional annual live and stillbirth rates. Post-mortem consultations only in cases of abnormal investigations following stillbirth were associated with lower odds for presence of such guideline [OR 0.133 (95% CI 0.018–0.978); p = 0.047]. 26 (56.5%) departments consider a national guideline necessary.

Conclusions

Less than half of the surveyed maternity units have implemented an institutional guideline on maternal care and investigations following antepartum stillbirth, independent of annual live and stillbirth rate or type of referral centre.
Real-world study of the impact of recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) on quality of life and productivity in Europe
Authors: Singh Prianka , Bennett Bryan , Bailey Tom , Taylor-Stokes Gavin , Rajkovic Ivana , Contente Marta , Curtis Sharon , Curtis Chris
Published: July 2021

Background

Although current therapy for patients with early-stage squamous cell carcinoma of the head and neck (SCCHN) is potentially curative, the recurrence rate is high. Patients with recurrent or metastatic (R/M) SCCHN have a poor prognosis and substantial disease burden, including impaired health-related quality of life (HRQoL), productivity loss and indirect costs, such as need for caregiver support. The aim of this study was to characterize the impact of R/M SCCHN and its first-line treatment on patient and caregiver quality of life, daily activities and work productivity using real-world evidence from Europe.

Methods

This was a multicentre retrospective study of patients with R/M SCCHN in France, Germany, Italy, Spain and the United Kingdom incorporating patient and caregiver surveys, and a physician-reported medical chart review, conducted between January and May 2019. Patients aged 18 or over with a physician confirmed diagnosis R/M SCCHN completed four validated measures of disease activity and its impact on quality of life and work productivity, while caregivers also completed questionnaire to assess the burden of providing care. Physicians provided data for clinical characteristics, patient management, testing history and treatment patterns.

Results

A total of 195 medical/clinical oncologists provided data for 937, predominantly male (72%) patients, with almost half of patients aged over 65 years. The most frequently reported symptoms were fatigue (43%), weight loss (40%), pain (35%) and difficulty swallowing (32%). The EXTREME regimen was the most common first line therapy in over half of patients, who reported moderate or extreme pain/discomfort, and anxiety/depression, and problems with self-care resulting in a diminished health status compared with the general population. Only 14% were employed with high absenteeism or presenteeism, and over half of patients had a caregiver for whom the burden of care was substantial.

Conclusion

Our results provide real-world insight into the multi-faceted burden associated with R/M SCCHN. The combination of poor HRQoL and the impairment in daily activities, social life and employment illustrates the wider impact of R/M SCCHN on patients and their caregivers, and highlights a need for novel 1 L treatment regimens to improve the humanistic and productivity burdens of this cancer.
The Urinary Uric Acid / Cr ratio as a marker of morbidity and mortality of preterm infants: a case—control study
Authors: Sadeghzadeh Mansour , Khoshnevisasl Parisa , Fallah Ramezan , Marzban Asghar , Mirrajei Seyyedeh Maryam
Published: July 2021

Background

Perinatal asphyxia is one of the main causes of preterm infant mortality. Some studies have shown that The Urinary Uric Acid / Cr (UUA/Cr) ratio may be used as an additional marker for perinatal asphyxia.This study intend to investigate the relationship of this ratio with outcomes of preterm infants admitted to NICU.

Methods

This case–control study was carried on 102 preterm newborn infants with gestational age of 30 weeks to 33 weeks and 6 days admitted in the neonatal intensive care unit.The case group, consisted of 51 premature neonates with a history of intubation, cardiopulmonary resuscitation, mechanical ventilation and Nasal continuous positive airway pressure (NCPAP) at birth, were compared with 51 matched neonates. The UUA/Cr ratio was measured in the first 24 h after birth. Complications during hospitalization, duration of hospitalization, and final outcome were evaluated.

Results

The mean level of UUA/Cr ratio in case and control group were 5.4 ± 4.1 and 3.6 9 ± 2.9 respectively and this difference was statistically significant (p = 0.014). The UUA/Cr ratio were significantly higher in females, cesarean section delivery, Apgar score ≥ 8, neonates without any complication and neonates with less than 10 days of hospitalization. However, this ratio has no predictive value for the incidence of complications during hospitalization and long-term hospital stay for infants of the case group.

Conclusions

The Urinary Uric Acid / Cr ratio in the first 24 h after birth in preterm neonates who underwent intubation, NCPAP or cardiopulmonary resuscitation was higher than healthy neonates.
A risk index for COVID-19 severity is associated with COVID-19 mortality in New York City
Authors: Lieberman-Cribbin Wil , Alpert Naomi , Flores Raja , Taioli Emanuela
Published: July 2021

Background

New York City (NYC) was the epicenter of the COVID-19 pandemic, and is home to underserved populations with higher prevalence of chronic conditions that put them in danger of more serious infection. Little is known about how the presence of chronic risk factors correlates with mortality at the population level. Here we determine the relationship between these factors and COVD-19 mortality in NYC.

Methods

A cross-sectional study of mortality data obtained from the NYC Coronavirus data repository (03/02/2020–07/06/2020) and the prevalence of neighborhood-level risk factors for COVID-19 severity was performed. A risk index was created based on the CDC criteria for risk of severe illness and complications from COVID-19, and stepwise linear regression was implemented to predict the COVID-19 mortality rate across NYC zip code tabulation areas (ZCTAs) utilizing the risk index, median age, socioeconomic status index, and the racial and Hispanic composition at the ZCTA-level as predictors.

Results

The COVID-19 death rate per 100,000 persons significantly decreased with the increasing proportion of white residents (βadj = − 0.91, SE = 0.31, p = 0.0037), while the increasing proportion of Hispanic residents (βadj = 0.90, SE = 0.38, p = 0.0200), median age (βadj = 3.45, SE = 1.74, p = 0.0489), and COVID-19 severity risk index (βadj = 5.84, SE = 0.82, p <  0.001) were statistically significantly positively associated with death rates.

Conclusions

Disparities in COVID-19 mortality exist across NYC and these vulnerable areas require increased attention, including repeated and widespread testing, to minimize the threat of serious illness and mortality.
Various structural factors influenced early antiretroviral therapy initiation amongst HIV infected prisoners: a qualitative exploration in South Ethiopia
Authors: Fuge Terefe Gone , Tsourtos George , Miller Emma R.
Published: July 2021

Background

Early initiation of antiretroviral therapy (ART) reduces the development of acquired immunodeficiency syndrome (AIDS), non-AIDS related comorbidities and mortality, and prevents transmission. However, the prevalence of delayed ART initiation amongst prisoners in sub-Saharan African countries is high and the contributing factors to this are relatively unknown.

Methods

Qualitative interviewing was employed to understand the prisoners’ lived world with regard to initiating ART and associated barriers and facilitators in the South Ethiopian prison system. We interviewed seven (five male and two female) inmates living with HIV (ILWH) and eleven stakeholders who had a role in human immunodeficiency virus (HIV) care provision for incarcerated people. A phenomenological approach was used to analyse the interview data in which meaning attributed to the lived experiences of the participants was abstracted.

Results

In this study, participants discussed both barriers to, and facilitators of, early ART initiation during incarceration. The barriers included a lack of access to voluntary counselling and testing (VCT) services, poor linkage to care due to insufficient health staff training, uncooperative prison security systems and loss of privacy regarding disclosure of HIV status. Insufficient health staff training and uncooperative prison security systems both contributed to a loss of patient privacy, ultimately resulting in treatment refusal. Although most participants described the importance of peer education and support for enhancing HIV testing and treatment programs amongst prisoners, there had been a decline in such interventions in the correctional facilities. Service providers suggested opportunities that a prison environment offers for identification and treatment of HIV infected individuals and implementation of peer education programs.

Conclusions

Our study identified crucial barriers to and facilitators of early ART initiation amongst prisoners, a key HIV priority population group. Interventions that address the barriers while strengthening the facilitators may enhance a greater utilisation of ART.
Higher body mass index is associated with larger postoperative improvement in patient-reported outcomes following total knee arthroplasty
Authors: Giesinger K , Giesinger JM , Hamilton DF , Rechsteiner J , Ladurner A
Published: July 2021

Background

Total knee arthroplasty is known to successfully alleviate pain and improve function in endstage knee osteoarthritis. However, there is some controversy with regard to the influence of obesity on clinical benefits after TKA. The aim of this study was to investigate the impact of body mass index (BMI) on improvement in pain, function and general health status following total knee arthroplasty (TKA).

Methods

A single-centre retrospective analysis of primary TKAs performed between 2006 and 2016 was performed. Data were collected preoperatively and 12-month postoperatively using WOMAC score and EQ-5D. Longitudinal score change was compared across the BMI categories identified by the World Health Organization.

Results

Data from 1565 patients [mean age 69.1, 62.2% women] were accessed. Weight distribution was: 21.2% BMI < 25.0 kg/m2, 36.9% BMI 25.0–29.9 kg/m2, 27.0% BMI 30.0–34.9 kg/m2, 10.2% BMI 35.0–39.9 kg/m2, and 4.6% BMI ≥ 40.0 kg/m2. All outcome measures improved between preoperative and 12-month follow-up (p < 0.001). In pairwise comparisons against normal weight patients, patients with class I-II obesity showed larger improvement on the WOMAC function and total score. For WOMAC pain improvements were larger for all three obesity classes.

Conclusions

Post-operative improvement in joint-specific outcomes was larger in obese patients compared to normal weight patients. These findings suggest that obese patients may have the greatest benefits from TKA with regard to function and pain relief one year post-op. Well balanced treatment decisions should fully account for both: Higher benefits in terms of pain relief and function as well as increased potential risks and complications.

Trial registration

This trial has been registered with the ethics committee of Eastern Switzerland (EKOS; Project-ID: EKOS 2020–00,879)
A logistic analysis prediction model of TMJ condylar erosion in patients with TMJ arthralgia
Authors: Emshoff Rüdiger , Bertram Annika , Hupp Linus , Rudisch Ansgar
Published: July 2021

Background

In terms of diagnostic and therapeutic management, clinicians should adequately address the frequent aspects of temporomandibular joint (TMJ) osteoarthritis (OA) associated with disk displacement. Condylar erosion (CE) is considered an inflammatory subset of OA and is regarded as a sign of progressive OA changes potentially contributing to changes in dentofacial morphology or limited mandibular growth. The purpose of this study was to establish a risk prediction model of CE by a multivariate logistic regression analysis to predict the individual risk of CE in TMJ arthralgia. It was hypothesized that there was a closer association between CE and magnetic resonance imaging (MRI) indicators.

Methods

This retrospective paired-design study enrolled 124 consecutive TMJ pain patients and analyzed the clinical and TMJ-related MRI data in predicting CE. TMJ pain patients were categorized according to the research diagnostic criteria for temporomandibular disorders (RDC/TMD) Axis I protocol. Each patient underwent MRI examination of both TMJs, 1–7 days following clinical examination.

Results

In the univariate analysis analyses, 9 influencing factors were related to CE, of which the following 4 as predictors determined the binary multivariate logistic regression model: missing posterior teeth (odds ratio [OR] = 1.42; P = 0.018), RDC/TMD of arthralgia coexistant with disk displacement without reduction with limited opening (DDwoR/wLO) (OR = 3.30, P = 0.007), MRI finding of disk displacement without reduction (OR = 10.96, P < 0.001), and MRI finding of bone marrow edema (OR = 11.97, P < 0.001). The model had statistical significance (chi-square = 148.239, Nagelkerke R square = 0.612, P < 0.001). Out of the TMJs, 83.9% were correctly predicted to be CE cases or Non-CE cases with a sensitivity of 81.4% and a specificity of 85.2%. The area under the receiver operating characteristic curve was 0.916.

Conclusion

The established prediction model using the risk factors of TMJ arthralgia may be useful for predicting the risk of CE. The data suggest MRI indicators as dominant factors in the definition of CE. Further research is needed to improve the model, and confirm the validity and reliability of the model.
A mixed-method service evaluation of health information exchange in England: technology acceptance and barriers and facilitators to adoption
Authors: Watkinson Fiona , Dharmayat Kanika I. , Mastellos Nikolaos
Published: July 2021

Background

The need for information exchange and integrated care has stimulated the development of interoperability solutions that bring together patient data across the health and care system to enable effective information sharing. Health Information Exchange (HIE) solutions have been shown to be effective in supporting patient care, however, user adoption often varies among users and care settings. This service evaluation aimed to measure user acceptance of HIE and explore barriers and facilitators to its wider uptake.

Methods

A mixed-method study design was used. A questionnaire was developed using the Unified Theory of Acceptance and Use of Technology and administered to HIE users to assess technology acceptance. Pearson Chi2 tests were used to examine differences in acceptance between user groups and care settings. Web-based, semi-structured interviews were conducted drawing on the Normalisation Process Theory to explore barriers and facilitators to adoption. Interview data were analysed thematically using the Framework Approach.

Results

A total of 105 HIE users completed the survey and another 12 participated in the interviews. Significant differences were found in HIE acceptance between users groups and care settings, with high adopters demonstrating higher acceptance and social care users showing lower acceptance. Participants identified several drivers to adoption, including increased information accessibility, better care coordination, informed decision-making, improved patient care, reduced duplication of procedures, and time and cost savings. However, they also highlighted a number of barriers, such as lack of awareness about the solution and its value, suboptimal communication strategies, inadequate training and lack of resources for knowledge dissemination, absence of champions to support the implementation, lack of end-user involvement in the implementation and evaluation of HIE, unclear accountability and responsibility for the overall success of the programme, and patient confidentiality concerns.

Conclusions

Working to better engage stakeholders, considering the needs of users from different care settings, providing users with training resources and support to increase their knowledge and confidence in using the system, developing implementation strategies to seek user feedback and monitor performance, and using communication strategies to increase awareness of the product and its value, can help improve uptake and adoption of HIE.
Efficacy of extracorporeal membrane oxygenation for acute respiratory failure with interstitial lung disease: a case control nationwide dataset study in Japan
Authors: Usagawa Yuko , Komiya Kosaku , Yamasue Mari , Fushimi Kiyohide , Hiramatsu Kazufumi , Kadota Jun-ichi
Published: July 2021

Background

Whether acute respiratory failure in patients with interstitial lung disease is reversible remains uncertain. Consequently, indications for extracorporeal membrane oxygenation in these patients are still controversial, except as a bridge to lung transplantation. The objective of this study was to clarify in-hospital mortality and prognostic factors in interstitial lung disease patients undergoing extracorporeal membrane oxygenation.

Methods

In this case–control study using the Japanese Diagnosis Procedure Combination database, hospitalized interstitial lung disease patients receiving invasive mechanical ventilation and extracorporeal membrane oxygenation from 2010 to 2017 were reviewed. Patients’ characteristics and treatment regimens were compared between survivors and non-survivors to identify prognostic factors. To avoid selection biases, patients treated with extracorporeal membrane oxygenation as a bridge to lung transplantation were excluded.

Results

A total of 164 interstitial lung disease patients receiving extracorporeal membrane oxygenation were included. Their in-hospital mortality was 74.4% (122/164). Compared with survivors, non-survivors were older and received high-dose cyclophosphamide, protease inhibitors, and antifungal drugs more frequently, but macrolides and anti-influenza drugs less frequently. On multivariate analysis, the following factors were associated with in-hospital mortality: advanced age (odds ratio [OR] 1.043; 95% confidence interval [CI] 1.009–1.078), non-use of macrolides (OR 0.305; 95% CI 0.134–0.698), and use of antifungal drugs (OR 2.416; 95% CI 1.025–5.696).

Conclusions

Approximately three-quarters of interstitial lung disease patients undergoing extracorporeal membrane oxygenation died in hospital. Moreover, advanced age, non-use of macrolides, and use of antifungal drugs were found to correlate with a poor prognosis.
A cell engineering approach to enzyme-based fed-batch fermentation
Authors: Sibley Michael , Ward John M.
Published: July 2021

Background

A fundamental problem associated with E. coli fermentations is the difficulty in achieving high cell densities in batch cultures, attributed in large part to the production and accumulation of acetate through a phenomenon known as overflow metabolism when supplying enough glucose for the cell density desired. Although a fed-batch configuration is the standard method for reducing such issues, traditional fed-batch systems require components which become problematic when applying them at smaller scale. One alternative has been the development of a system whereby the enzymatic degradation of starch is used to release glucose at a controlled rate. However, to date, amylolytic enzymes have only been applied to the culture exogenously, whereas our goal is to design and construct a self-secreting amylolytic chassis capable of self-regulated enzyme-based fed-batch fermentation.

Results

A putative glucoamylase from C. violaceum has been cloned and expressed in E. coli BL21(DE3) and W3110, which exhibits significant glucose releasing amylolytic activity. Extracellular amylolytic activity was enhanced following a replacement of the enzymes native signal peptide with the DsbA signal sequence, contributing to a glucoamylase secreting strain capable of utilising starch as a sole carbon source in defined media. Introduction of PcstA, a glucose sensitive K12 compatible promoter, and the incorporation of this alongside C. violaceum glucoamylase in E. coli W3110, gave rise to increased cell densities in cultures grown on starch (OD600 ∼ 30) compared to those grown on an equivalent amount of glucose (OD600 ∼ 15). Lastly, a novel self-secreting enzyme-based fed-batch fermentation system was demonstrated via the simultaneous expression of the C. violaceum glucoamylase and a recombinant protein of interest (eGFP), resulting in a fourfold increase in yield when grown in media containing starch compared with the glucose equivalent.

Conclusions

This study has developed, through the secretion of a previously uncharacterised bacterial glucoamylase, a novel amylolytic E. coli strain capable of direct starch to glucose conversion. The ability of this strain to achieve increased cell densities as well as an associated increase in recombinant protein yield when grown on starch compared with an equivalent amount of glucose, demonstrates for the first time a cell engineering approach to enzyme-based fed-batch fermentation.
What causes failure of fixed orthodontic retention? – systematic review and meta-analysis of clinical studies
Authors: Jedliński Maciej , Grocholewicz Katarzyna , Mazur Marta , Janiszewska-Olszowska Joanna
Published: July 2021

Background

Orthodontic retention aims to maintain optimal teeth positions after active treatment. The stability is affected by numerous factors, including patients’ individual features, thus retention should be adjusted in the most optimal way. Bonding a retainer makes retention less dependent on patient’s compliance.

Questions arise

What wire or fiber splint type provides the best treatment stability? What materials should be used to bond the wire or fiber splint? Should be the bonding procedure be direct or indirect? The aim of the study is to assess and synthesize available controlled trials investigating failures of fixed retainers.

Methods

Literature searches of free text and MeSH terms were performed in Scopus, Web of Science, Embase and PubMed Central in order to find studies, referring to failures of fixed retention (12th February 2021). The keywords were: (“orthodontic retainers AND failure AND wire”). The framework of this systematic review according to PICO was: Population: orthodontic patients; Intervention: fixed orthodontic retainer bonding; Comparison: Different protocols of fixed orthodontic retention applied; Outcomes: failure rate, survival rate. Three different specific scales from the Cochrane Collaboration Handbook were used, according to each study type. Additionally, a meta-analysis was conducted to compare the effectiveness of retention using fiber reinforced composite and multistranded steel wire.

Results

The search identified 177 potential articles: 114 from PubMed, 41 from Scopus, 20 from Web of Science and 2 from Embase. After excluding studies inconsistent with selection criteria, 21 studies were included and subjected to qualitative analysis. The main outcome investigated was failure rate. This systematic review has some potential limitations due to the heterogeneity of design between included studies.

Conclusions

No retainer is proved to guarantee a perfect stability of dental alignment. The retainer should be bonded to all adherent teeth, preferably with additional use of bonding resin. No wire or fiber splint present superior characteristics concerning failure rate. Fiber reinforced composite retention is more sensitive to operator skills, and with imperfect bonding technique, failure rate is much higher. During the first 6 months after bonding retainer the patient should be under frequent control. The study protocol was registered in PROSPERO database with the number CRD42021233406.
Implementation and experimental evaluation of Mega-voltage fan-beam CT using a linear accelerator
Authors: Gong Hao , Tao Shengzhen , Gagneur Justin D. , Liu Wei , Shen Jiajian , McCollough Cynthia H. , Hu Yanle , Leng Shuai
Published: July 2021

Background

Mega-voltage fan-beam Computed Tomography (MV-FBCT) holds potential in accurate determination of relative electron density (RED) and proton stopping power ratio (SPR) but is not widely available.

Objective

To demonstrate the feasibility of MV-FBCT using a medical linear accelerator (LINAC) with a 2.5 MV imaging beam, an electronic portal imaging device (EPID) and multileaf collimators (MLCs).

Methods

MLCs were used to collimate MV beam along z direction to enable a 1 cm width fan-beam. Projection data were acquired within one gantry rotation and preprocessed with in-house developed artifact correction algorithms before the reconstruction. MV-FBCT data were acquired at two dose levels: 30 and 60 monitor units (MUs). A Catphan 604 phantom was used to evaluate basic image quality. A head-sized CIRS phantom with three configurations of tissue-mimicking inserts was scanned and MV-FBCT Hounsfield unit (HU) to RED calibration was established for each insert configuration using linear regression. The determination coefficient ($${R}^{2}$$

R

2

) was used to gauge the accuracy of HU-RED calibration. Results were compared with baseline single-energy kilo-voltage treatment planning CT (TP-CT) HU-RED calibration which represented the current standard clinical practice.

Results

The in-house artifact correction algorithms effectively suppressed ring artifact, cupping artifact, and CT number bias in MV-FBCT. Compared to TP-CT, MV-FBCT was able to improve the prediction accuracy of the HU-RED calibration curve for all three configurations of insert materials, with $${R}^{2}$$

R

2

> 0.9994 and $${R}^{2}$$

R

2

< 0.9990 for MV-FBCT and TP-CT HU-RED calibration curves of soft-tissue inserts, respectively. The measured mean CT numbers of blood-iodine mixture inserts in TP-CT drastically deviated from the fitted values but not in MV-FBCT. Reducing the radiation level from 60 to 30 MU did not decrease the prediction accuracy of the MV-FBCT HU-RED calibration curve.

Conclusion

We demonstrated the feasibility of MV-FBCT and its potential in providing more accurate RED estimation.
Biomarker potential of lncRNA GNAS-AS1 in osteosarcoma prognosis and effect on cellular function
Authors: Mi Zhanhu , Dong Yanyun , Wang Zhibiao , Ye Peng
Published: July 2021

Background

Osteosarcoma (OS) is a type of bone cancer that occurs in children and adolescents at a rate of 5%. The purpose of this study is to explore the lncRNA GNAS-AS1 expression profile, prognosis significance in OS, and biological effect on OS cell function.

Methods

One hundred eight pairs of tissues were collected, and OS cell lines were purchased. lncRNA GNAS-AS1 expression in these tissues and cells were analyzed by qRT-PCR. Clinical data were analyzed using chi-square tests, Kaplan-Meier curves (log-rank test), and Cox regression. CCK-8 and transwell assay were conducted to analyze the effect of lncRNA GNAS-AS1 on cell proliferation, invasion, and migration. The downstream miRNA was presumed.

Results

The expression of lncRNA GNAS-AS1 was significantly increased in OS cells and tissues, and related to Enneking staging and distant metastasis. Patients with high lncRNA GNAS-AS1 expression represented shorter overall survival and was an independent prognostic predictor of OS. LncRNA GNAS-AS1 knockdown inhibited cell proliferation, migration, and invasion by regulated miR-490-3p partly at least.

Conclusions

LncRNA GNAS-AS1 can be used as a prognostic indicator and its inhibition suppress the development of OS, suggesting its value as novel therapeutic strategies in OS.
Partial deletion of chromosome 6p causing developmental delay and mild dysmorphisms in a child: molecular and developmental investigation and literature search
Authors: Vrachnis Nikolaos , Papoulidis Ioannis , Vrachnis Dionysios , Siomou Elisavet , Antonakopoulos Nikolaos , Oikonomou Stavroula , Zygouris Dimitrios , Loukas Nikolaos , Iliodromiti Zoi , Pavlidou Efterpi , Thomaidis Loretta , Manolakos Emmanouil
Published: July 2021

Background

The interstitial 6p22.3 deletions concern rare chromosomal events affecting numerous aspects of both physical and mental development. The syndrome is characterized by partial deletion of chromosome 6, which may arise in a number of ways.

Case presentation

We report a 2.8-year old boy presenting with developmental delay and mild dysmorphisms. High-resolution oligonucleotide microarray analysis revealed with high precision a 2.5 Mb interstitial 6p deletion in the 6p22.3 region which encompasses 13 genes.

Conclusions

Identification and in-depth analysis of cases presenting with mild features of the syndrome will sharpen our understanding of the genetic spectrum of the 6p22.3 deletion.
Statins: a repurposed drug to fight cancer
Authors: Jiang Wen , Hu Jin-Wei , He Xu-Ran , Jin Wei-Lin , He Xin-Yang
Published: July 2021

As competitive HMG-CoA reductase (HMGCR) inhibitors, statins not only reduce cholesterol and improve cardiovascular risk, but also exhibit pleiotropic effects that are independent of their lipid-lowering effects. Among them, the anti-cancer properties of statins have attracted much attention and indicated the potential of statins as repurposed drugs for the treatment of cancer. A large number of clinical and epidemiological studies have described the anticancer properties of statins, but the evidence for anticancer effectiveness of statins is inconsistent. It may be that certain molecular subtypes of cancer are more vulnerable to statin therapy than others. Whether statins have clinical anticancer effects is still an active area of research. Statins appear to enhance the efficacy and address the shortcomings associated with conventional cancer treatments, suggesting that statins should be considered in the context of combined therapies for cancer. Here, we present a comprehensive review of the potential of statins in anti-cancer treatments. We discuss the current understanding of the mechanisms underlying the anti-cancer properties of statins and their effects on different malignancies. We also provide recommendations for the design of future well-designed clinical trials of the anti-cancer efficacy of statins.
Rationale and study design of an early care, therapeutic education, and psychological intervention program for the management of post-intensive care syndrome and chronic pain after COVID-19 infection (PAIN-COVID): study protocol for a randomized controlled trial
Authors: Ojeda Antonio , Calvo Andrea , Cuñat Tomas , Artigas Ricard Mellado , Comino-Trinidad Oscar , Aliaga Jorge , Arias Marilyn , Ahuir Maribel , Ferrando Carlos , Dürsteler Christian
Published: July 2021

Background

Critically ill patients with COVID-19 are an especially susceptible population to develop post-intensive care syndrome (PICS) due to acute respiratory distress syndrome (ARDS). Patients can suffer acute severe pain and may have long-term mental, cognitive, and functional health deterioration after discharge. However, few controlled trials are evaluating interventions for the prevention and treatment of PICS. The study hypothesis is that a specific care program based on early therapeutic education and psychological intervention improves the quality of life of patients at risk of developing PICS and chronic pain after COVID-19. The primary objective is to determine whether the program is superior to standard-of-care on health-related quality of life at 6 months after hospital discharge. The secondary objectives are to determine whether the intervention is superior to standard-of-care on health-related quality of life, incidence of chronic pain and degree of functional limitation, incidence of anxiety, depression, and post-traumatic stress syndrome at 3 and 6 months after hospital discharge.

Methods

The PAINCOVID trial is a unicentric randomized, controlled, patient-blinded superiority trial with two parallel groups. The primary endpoint is the health-related quality of life at 6 months after hospital discharge, and randomization will be performed with a 1:1 allocation ratio. This paper details the methodology and statistical analysis plan of the trial and was submitted before outcome data were available.

The estimated sample size is 84 patients, 42 for each arm. Assuming a lost to follow-up rate of 20%, a sample size of 102 patients is necessary (51 for each arm).

Discussion

This is the first randomized clinical trial assessing the effectiveness of an early care therapeutic education, and psychological intervention program for the management of PICS and chronic pain after COVID-19. The intervention will serve as proof of the need to implement early care programs at an early stage, having an incalculable impact given the current scenario of the pandemic.

Trial registration

This study is being conducted in accordance with the tenets of the Helsinki Declaration and has been approved by the authors’ institutional review board Comité Ético de Investigación Clínica del Hospital Clínic de Barcelona (approval number: HCB/2020/0549) and was registered on May 9, 2020, at clinicaltrials.gov (NCT04394169).
Cerebral localization of chronic myelomonocytic leukemia: a case report
Authors: Haméon Clémence , Rousselot Cécilia , Arbion Flavie , Cibron Justine , Cottier Jean-Philippe , Destrieux Christophe , Hérault Olivier , Gyan Emmanuel
Published: July 2021

Background

Chronic myelomonocytic leukemia is a myelodysplastic/myeloproliferative neoplasm characterized by the infiltration of blood and bone marrow by immature monocytes. Cerebral localization of chronic myelomonocytic leukemia has never been described.

Case presentation

We report the case of a Caucasian 59 year-old man with multiorgan chronic myelomonocytic leukemia infiltration, associated with uncommon brain involvement. There was no evidence of evolution to acute myeloid leukemia. The evidence of cerebral infiltration by chronic myelomonocytic leukemia was made after autopsy.

Conclusions

The fatal outcome of the patient raises the question of the potential benefit of early specific treatment, such as demethylating agents or intensive chemotherapy. Sharing such images of atypical and rapidly evolving chronic myelomonocytic leukemia and the disease history may help clinical decision-making in the future.
The impact of the opioid crisis on U.S. state prison systems
Authors: Scott Christy K. , Dennis Michael L. , Grella Christine E. , Mischel Allison F. , Carnevale John
Published: July 2021

Background

Prior studies have documented limited use of medications to treat opioid use disorders (OUD) for people incarcerated within state prisons in the United States. Using the framework of the criminal justice OUD service cascade, this study interviewed representatives of prison systems in states most heavily impacted by opioid overdose regarding the provision of medications for OUD (MOUD).

Methods

A stratified sampling strategy included states with high indicators of opioid-overdose deaths. Two sampling strata targeted states with: 1) OUD overdose rates significantly higher than the per capita national average; or 2) high absolute number of OUD overdose fatalities. Interviews were completed with representatives from 21 of the 23 (91%) targeted states in 2019, representing 583 prisons across these states. Interviews assessed service provision across the criminal justice OUD service cascade, including OUD screening, withdrawal management, MOUD availability and provision, overdose prevention, re-entry services, barriers, and needs for training and technical assistance.

Results

MOUD (buprenorphine, methadone, or naltrexone) was available in at least one prison in approximately 90% of the state prison systems and all three medications were available in at least one prison in 62% of systems. However, MOUD provision was limited to subsets of prisons within these systems: 15% provided buprenorphine, 9% provided methadone, 36% provided naltrexone, and only 7% provided all three. Buprenorphine and methadone were most frequently provided to pregnant women or individuals already receiving these at admission, whereas naltrexone was primarily used at release. Funding was the most frequently cited barrier for all medications.

Conclusion

Study findings yield a complex picture of how, when, and to whom MOUD is provided across prisons within prison systems in states most heavily impacted by opioid overdose in the United States and have implications for expanding availability.
Mortality of septic shock patients is associated with impaired mitochondrial oxidative coupling efficiency in lymphocytes: a prospective cohort study
Authors: Nedel Wagner Luis , Kopczynski Afonso , Rodolphi Marcelo Salimen , Strogulski Nathan Ryzewski , De Bastiani Marco , Montes Tiago Hermes Maeso , Abruzzi Jr Jose , Galina Antonio , Horvath Tamas L. , Portela Luis Valmor
Published: July 2021

Background

Septic shock is a life-threatening condition that challenges immune cells to reprogram their mitochondrial metabolism towards to increase ATP synthesis for building an appropriate immunity. This could print metabolic signatures in mitochondria whose association with disease progression and clinical outcomes remain elusive.

Method

This is a single-center prospective cohort study performed in the ICU of one tertiary referral hospital in Brazil. Between November 2017 and July 2018, 90 consecutive patients, aged 18 years or older, admitted to the ICU with septic shock were enrolled. Seventy-five patients had Simplified Acute Physiology Score (SAPS 3) assessed at admission, and Sequential Organ Failure Assessment (SOFA) assessed on the first (D1) and third (D3) days after admission. Mitochondrial respiration linked to complexes I, II, V, and biochemical coupling efficiency (BCE) were assessed at D1 and D3 and Δ (D3–D1) in isolated lymphocytes. Clinical and mitochondrial endpoints were used to dichotomize the survival and death outcomes. Our primary outcome was 6-month mortality, and secondary outcomes were ICU and hospital ward mortality.

Results

The mean SAPS 3 and SOFA scores at septic shock diagnosis were 75.8 (± 12.9) and 8 (± 3) points, respectively. The cumulative ICU, hospital ward, and 6-month mortality were 32 (45%), 43 (57%), and 50 (66%), respectively. At the ICU, non-surviving patients presented elevated arterial lactate (2.8 mmol/L, IQR, 2–4), C-reactive protein (220 mg/L, IQR, 119–284), and capillary refill time (5.5 s, IQR, 3–8). Respiratory rates linked to CII at D1 and D3, and ΔCII were decreased in non-surviving patients. Also, the BCE at D1 and D3 and the ΔBCE discriminated patients who would evolve to death in the ICU, hospital ward, and 6 months after admission. After adjusting for possible confounders, the ΔBCE value but not SOFA scores was independently associated with 6-month mortality (RR 0.38, CI 95% 0.18–0.78; P = 0.009). At a cut-off of − 0.002, ΔBCE displayed 100% sensitivity and 73% specificity for predicting 6-month mortality

Conclusions

The ΔBCE signature in lymphocytes provided an earlier recognition of septic shock patients in the ICU at risk of long-term deterioration of health status.