bluuebunny/crossref_metadata_2025 huggingface dataset:
Time trends in incidence and prevalence of chronic pancreatitis: A 25‐year population‐based nationwide study
Authors: Olesen Søren S. , Mortensen Laust H. , Zinck Elisabeth , Becker Ulrik , Drewes Asbjørn M. , Nøjgaard Camilla , Novovic Srdan , Yadav Dhiraj , Tolstrup Janne S.
Published: November 2020

Background

Updated population‐based estimates on incidence and prevalence of chronic pancreatitis are scarce.

Methods

We used nationwide healthcare registries to identify all Danish patients diagnosed with chronic pancreatitis and computed crude and standardised incidence rates and prevalence estimates in 1994–2018. Incidence and prevalence were evaluated in relation to patients age and gender, aetiology (alcoholic vs. non‐alcoholic) and smoking and alcohol consumption in the general Danish population.

Results

The mean incidence rate of chronic pancreatitis during the study period was 12.6 per 100,000 person years for the total population, for women it was 8.6 per 100,000 person years and for men it was 16.7 per 100,000 person years. The standardised incidence rate was stable from 1994 to 2018, remaining at 12.5 per 100,000 person years in the last observation period (2014–2018). The point prevalence of chronic pancreatitis in 2016 was 153.9 per 100,000 persons. A gradual increase in standardised prevalence estimates was observed during the study period from 126.6 in 1996 to 153.9 in 2016. The mean age at chronic pancreatitis diagnosis increased from 52.1 to 60.0 years during the study period.

Conclusion

The prevalence of chronic pancreatitis is increasing in the Danish population despite a stable incidence level. Improved management strategies and changes in the underlying patient population may explain these observations.
CILP1 as a biomarker for right ventricular maladaptation in pulmonary hypertension
Authors: Keranov Stanislav , Dörr Oliver , Jafari Leili , Troidl Christian , Liebetrau Christoph , Kriechbaum Steffen , Keller Till , Voss Sandra , Bauer Timm , Lorenz Jakob , Richter Manuel J. , Tello Khodr , Gall Henning , Ghofrani Hossein A. , Mayer Eckhard , Wiedenroth Christoph B. , Guth Stefan , Lörchner Holger , Pöling Jochen , Chelladurai Prakash , Pullamsetti Soni Savai , Braun Thomas , Seeger Werner , Hamm Christian W. , Nef Holger
Published: November 2020

The aim of our study was to analyse the protein expression of cartilage intermediate layer protein (CILP)1 in a mouse model of right ventricular (RV) pressure overload and to evaluate CILP1 as a biomarker of cardiac remodelling and maladaptive RV function in patients with pulmonary hypertension (PH).

Pulmonary artery banding was performed in 14 mice; another nine mice underwent sham surgery. CILP1 protein expression was analysed in all hearts using Western blotting and immunostaining. CILP1 serum concentrations were measured in 161 patients (97 with adaptive and maladaptive RV pressure overload caused by PH; 25 with left ventricular (LV) hypertrophy; 20 with dilative cardiomyopathy (DCM); 19 controls without LV or RV abnormalities)

In mice, the amount of RV CILP1 was markedly higher after banding than after sham. Control patients had lower CILP1 serum levels than all other groups (p<0.001). CILP1 concentrations were higher in PH patients with maladaptive RV function than those with adaptive RV function (p<0.001), LV pressure overload (p<0.001) and DCM (p=0.003). CILP1 showed good predictive power for maladaptive RV in receiver operating characteristic analysis (area under the curve (AUC) 0.79). There was no significant difference between the AUCs of CILP1 and N-terminal pro-brain natriuretic peptide (NT-proBNP) (AUC 0.82). High CILP1 (cut-off value for maladaptive RV of ≥4373 pg·mL−1) was associated with lower tricuspid annular plane excursion/pulmonary artery systolic pressure ratios (p<0.001) and higher NT-proBNP levels (p<0.001).

CILP1 is a novel biomarker of RV and LV pathological remodelling that is associated with RV maladaptation and ventriculoarterial uncoupling in patients with PH.
Genome-wide identification of R2R3-MYB family in wheat and functional characteristics of the abiotic stress responsive gene TaMYB344
Authors: Wei Qiuhui , Chen Rong , Wei Xin , Liu Yuheng , Zhao Shujuan , Yin Xiaopu , Xie Tian
Published: November 2020

Background

MYB superfamily is one of the most abundant families in plants, which plays important roles in plant growth, development, and productivity. However, to date, researches on MYBs in wheat (Triticum aestivum L.) are scattered mostly, not comprehensive.

Results

In this study, a total of 393 R2R3-MYBs and 12 R1R2R3-MYBs were identified and analyzed including gene structure, chromosomal distribution, synteny relationship, and evolutionary relationship. Then, 29 clusters tandem duplication and 8 clusters segmental duplication genes were discovered. The expression profile of the identified genes under abiotic and biotic stress was analyzed using RNA-seq data. Based on expression patterns analysis, we screened many candidate genes involved in plant response to abiotic and biotic stress. Among them, the functional characteristics of TaMYB344 were further studied. TaMYB344 was localized in the nucleus and functioned as a weak transcriptional activator. We demonstrated that TaMYB344-overexpressing transgenic tobacco plants had enhanced tolerance to drought, heat, and high salt stress.

Conclusions

In this study, 393 R2R3-MYBs and 12 R1R2R3-MYBs in wheat were systemically identified and analyzed. Differential expression analysis indicated that many R2R3-MYBs were involved in abiotic and biotic stress response. We identified a potential candidate gene TaMYB344, overexpression of which in tobacco plants enhanced drought, heat, and salt stress tolerance. These results will provide abundant molecular data for breeding new varieties of wheat in the future.
Resistance analysis of cherry rootstock ‘CDR-1’ (Prunus mahaleb) to crown gall disease
Authors: Liang Chenglin , Wan Tian , Wu Rendun , Zhao Mei , Zhao Yue , Cai Yuliang
Published: November 2020

Background

Crown gall disease, caused by the pathogenic bacteriumAgrobacterium tumefaciens, is responsible for extensive economic losses in orchards. Cherry rootstock ‘CDR-1’ (Prunus mahaleb) shows high resistance but the mechanism remains unclear. Here, we examined the morphology of pathogen-infected root neck surface, determined the activity of 10 defense-related enzymes and the content of salicylic acid (SA) and jasmonic acid (JA), and also applied transcriptome analysis, transient expression and transgenic verification to explore the crown gall resistance genes in ‘CDR-1’ plants.

Results

In our study, peroxidase increased in the first 10 days, while phenylalanine ammonialyase and lipoxygenase increased in the first 15 days post-infection. Four key enzymes in the AsA-GSH cycle also responded, to a certain extent; although JA content increased significantly after the treatment, the SA content did not. In a follow-up transcriptome analysis, the differentially expressed genesPm4CL2,PmCYP450,PmHCT1,PmHCT2, andPmCADwere up-regulated. Based on the above results, we focused on the lignin biosynthetic pathway, and further measured lignin content, and found it increased significantly. ThePm4CL2gene was used to conduct transient expression and transgenic experiments to verify its function in crown gall disease resistance. It showed the relative expression of the treatment group was almost 14-fold that of the control group at 12 h post-treatment. After the infection treatment, clear signs of resistance were found in the transgenic lines; this indicated that under the higher expression level and earlier activation ofPm4CL2, plant resistance was enhanced.

Conclusions

The crown gall resistance of ‘CDR-1’ is likely related to the lignin biosynthetic pathway, in whichPm4CL2functions crucially during the plant defense response to the pathogenA. tumefaciens. The results thus offer novel insights into the defense responses and resistance mechanism of cherry rootstock ‘CDR-1’ against crown gall disease.
The effect of concentration, reconstitution solution and pH on the stability of a remifentanil hydrochloride and propofol admixture for simultaneous co-infusion
Authors: Henkel Emily , Vella Rebecca , Behan Kieran , Austin David , Kruger Peter , Fenning Andrew
Published: November 2020

Background

There are scenarios where pre-mixing and infusing analgesic and anaesthetic agents as a single intravenous (IV) solution is highly desirable; however, it is important to ensure the agents are compatible when mixed. As such, the long-term stability of a remifentanil-propofol mixture, and means of improving this, were assessed across a range of remifentanil concentrations, diluents, and time points.

Methods

Remifentanil was reconstituted with ultrapure water, 0.9% saline, 20% saline, or 8.4% sodium bicarbonate solution (the latter two chosen for their pH characteristics, rather than their use in pharmaceutical reconstitution) and then mixed with propofol (1%) or further diluted with water to derive concentrations of 10–50 μg mL− 1. Remifentanil and propofol concentrations were determined initially and then periodically for up to 24 h using high performance liquid chromatography (HPLC). Mass spectrometry (MS) was used to detect degradation products in solutions containing 30 μg mL− 1 of remifentanil. Statistical analysis was performed using ANOVA and Student’s t-test, with a significance value of 0.05.

Results

Isolated remifentanil (pH < 4) and propofol (pH 7.35) did not degrade significantly when reconstituted with water or saline solution over 24 h, while remifentanil reconstituted with sodium bicarbonate degraded significantly (P < 0.001, pH 8.65). Mixing with propofol substantially increased the pH of the mixture and resulted in significant remifentanil degradation for all reconstitution solutions used, while propofol remained stable (pH 6.50). The amount of degradation product detected in samples containing isolated remifentanil and a mixture of the drugs was proportional to the remifentanil degradation observed.

Conclusions

Remifentanil stability is affected by both the reconstitution solution used and when mixed with propofol, with pH appearing to be a contributing factor to degradation. If the pH of the solution and concentration of remifentanil are correctly controlled, e.g. through the use of a more acidic diluent, an admixture of remifentanil and propofol may be useful clinically.
Increasing newly diagnosed inflammatory bowel disease and improving prognosis in China: a 30-year retrospective study from a single centre
Authors: Lv Hong , Jin Meng , Zhang Huimin , Chen Xuanfu , Wu Meixu , Guo Mingyue , Zhou Runing , Wang Zheng , Yang Hong , Qian Jiaming
Published: November 2020

Background

We aimed to characterize the trends of prognosis in ulcerative colitis (UC) and Crohn’s disease (CD) in a Chinese tertiary hospital.

Methods

A 30-year retrospective cohort analysis was conducted at Peking Union Medical College Hospital. Consecutive patients newly diagnosed with UC or CD from 1985 to 2014 were included. The primary outcome was in-hospital mortality. The secondary outcomes included surgery and length of stay in hospital. The Pearson correlation coefficient was applied to determine the relationship between time and prognosis. Multivariable logistic regression analysis was performed to determine the risk factors for in-hospital mortality and surgery.

Results

In total, 1467 patients were included in this study (898 cases with UC and 569 cases with CD). Annual admissions for UC and CD have increased significantly over the last 30 years (UC, r = 0.918, P < 0.05; CD, r = 0.898, P < 0.05). Decreased in-hospital mortality was observed both in patients with UC and CD (UC, from 2.44 to 0.27%, r = − 0.827, P < 0.05; CD, from 12.50 to 0.00%, r = − 0.978, P < 0.05). A decreasing surgery rate was observed in patients with CD (r = − 0.847, P < 0.05), while an increasing surgery rate was observed in patients with UC (r = 0.956, P < 0.05). Shortened average lengths of hospital stay were observed in both UC and CD patients (UC, from 47.83 ± 34.35 to 23.58 ± 20.05 days, r = − 0.970, P < 0.05; CD, from 65.50 ± 50.57 to 26.41 ± 18.43 days, r = − 0.913, P < 0.05). Toxic megacolon and septic shock were independent risk factors for in-hospital mortality in patients with UC. Intestinal fistula and intestinal perforation were independent risk factors for in-hospital mortality in patients with CD.

Conclusions

In this cohort, the admissions of patients with UC and CD were increased, with significantly improved prognoses during the past 30 years.
Application of spectral CT in the diagnosis of contrast encephalopathy following carotid artery stenting: a case report
Authors: Jiang Qiuhong , Shu Liming , Hong Hua
Published: November 2020

Background

Contrast encephalopathy is a rare complication of carotid artery stenting (CAS). Contrast encephalopathy is a diagnosis of exclusion that often needs to be distinguished from high perfusion syndrome, cerebral haemorrhage, subarachnoid haemorrhage (SAH), cerebral infarction and so on.

Case presentation

In this study, we report on a 70-year-old man who was admitted to the hospital with transient ischaemic attacks presenting paroxysmal weakness of limbs in the previous 2 years. He had severe stenosis of the left internal carotid artery diagnosed by digital subtraction angiography (DSA) and underwent CAS. Two hours after the operation, the patient developed paralysis of the right upper limb, unclear speech, fever and restlessness. Emergency skull computed tomography (CT) showed swelling and a linear high-density area in the left cerebral hemisphere. To clarify the components of this high-density area in the traditional CT, the patient had spectral CT, which made the diagnosis of the leakage of contrast clear. After 1 week of supportive treatment, the patient improved.

Conclusions

Spectral CT can easily distinguish the components of high-density areas on traditional CT, which is haemorrhage, calcification or iodine contrast leakage. Therefore, spectral CT is worth consideration for the differential diagnosis of complications of vascular intervention.
Propionic acidemia identified in twin siblings conceived by in vitro fertilization (IVF) with parents who were unknown carriers of a PCCA mutation
Authors: Tian Ye , Wang Guojie , Shi Wujuan , Bai Xiaohong
Published: November 2020

Background

Propionic acidemia (PA) is a severe monogenic disorder characterized by a deficiency of the mitochondrial protein propionyl-CoA carboxylase (PCC) enzyme, which is caused by mutations in the PCCA or PCCB gene. Preconception carrier screening could provide couples with meaningful information for their reproductive options; however, it is not widely performed in China.

Case presentation

This report describes a case of dizygotic twin siblings conceived by in vitro fertilization (IVF) and diagnosed with propionic acidemia (PA). Their parents had no history of PA. Tandem mass spectrometry and urine gas chromatography/mass spectrometry (GC/MS) of the twin siblings revealed markedly elevated propionyl carnitine (C3), C3/C2, and 3-hydroxypropionate in the plasma and urine. Whole-exome sequencing was performed for the twin siblings. A homozygous missense mutation, c.2002G > A (p.Gly668Arg) in PCCA, was identified in the twin siblings. Sanger sequencing confirmed the homozygous mutation in the twin siblings and identified their parents as heterozygous carriers of the c.2002G > A mutation in PCCA. Both neonates in this case died. This is an emotionally and financially devastating outcome that could have been avoided with genetic carrier screening before conception. If couples are screened before IVF and found to be silent carriers, then reproductive options (such as preimplantation genetic diagnosis or prenatal diagnosis) can be offered to achieve a healthy newborn.

Conclusion

This case is a reminder to infertile couples seeking IVF that it is beneficial to clarify whether they are silent carriers before undergoing IVF.
Psychological symptoms are associated with screen and exercise time: a cross-sectional study of Chinese adolescents
Authors: Zhang Feng , Yin Xiaojian , Bi Cunjian , Ji Liu , Wu Huipan , Li Yuqiang , Sun Yi , Ren Sien , Wang Guodong , Yang Xiaofang , Li Ming , Liu Yuan , Song Ge
Published: November 2020

Background

Mental disorders among adolescents have become a worldwide public health problem. This study aimed to estimate the best combination of exercise time and screen time to promote the mental health of Chinese adolescents.

Methods

Participants included 7200 Chinese adolescents aged 13–18 years from six regions of China. Screen and exercise time data were collected via a self-rated questionnaire. Psychological symptoms (e.g., often feeling depressed, school-weary) were evaluated with the “Multidimensional Sub-health Questionnaire of Adolescents”. Chi-squared tests and logistic regression analysis were conducted to investigate the differences in and correlations among screen time, exercise time, and psychological symptoms.

Results

The overall detection rate of psychological symptoms among Chinese adolescents was 21.4% (22.1% for boys and 20.6% for girls). Psychological symptom detection rates were lowest among adolescents with 1–2 h/d of screen time (19.5%) and those with 30–60 min/d of exercise time (17.3%). Screen time > 2 h/d (OR = 1.38, P < 0.001) and exercise time < 30 min/d (OR = 1.62, P < 0.001) were positively correlated with psychological symptoms.

Conclusion

Screen and exercise time are associated with psychological symptoms in Chinese adolescents. A combination of 1–2 h/d of screen time and 30–60 min/d of exercise time is provided as a reference for better mental health.
Serious non-fatal unintentional injuries among in-school adolescents in Sri Lanka: results from the 2016 Sri Lankan global school-based health survey
Authors: Wickramasinghe Sashimali , Gunawardena Nalika Sepali , Punyadasa Dhanusha , Gunawardena Shanthi , Wickramasinghe Champika , Lokubalasooriya Ayesha , Peiris Renuka , Senanayake Sameera
Published: November 2020

Background

Unintentional injuries among adolescents is a major public health problem the world over. A great majority of the annual deaths among adolescents is due to unintentional injuries; it is also the leading cause of death among adolescents in the world. The aim of this study was to estimate the incidence of injuries and their associated factors among school going adolescents aged 13–17 years using data from the most recent Global School-Based Health Survey (GSHS) conducted in Sri Lanka.

Methods

A cross-sectional survey was conducted using a self-administered questionnaire, among 3262 adolescents attending government schools. The sample was selected through a two-staged cluster sampling technique. In the first stage, 40 schools were selected using probabilities proportional to school enrollment size, from all schools in the country that have classes in grades 8–12. Then, from the selected schools, classes were selected using systematic equal probability sampling with a random start. The weighted prevalence was calculated, and logistic regression analysis was conducted in order to determine the correlates.

Results

During the 12 months before the survey, 35.8% (95% CI-30.7 - 41.1) of the students reported being seriously injured one or more times. The injuries were more common among males, but were equally common among the two different age groups (13–15 age group vs 16–17 age group). The most common type of injury was cut or stab wounds (5.5%), followed by broken bones/dislocated joints (5.3%). Multivariable analysis revealed that only a few factors were associated with injury, such as being of the male sex, being bullied, being physically attacked, and/or being in a physical fight.

Conclusion

This study demonstrated that the prevalence of serious unintentional injuries among school going adolescents is a major public health problem in Sri Lanka. This timely and comprehensive survey would help policy makers and researchers identify the unmet needs related to adolescent injuries. Furthermore, evidence generated form the study should be given due consideration when designing school-based interventions to prevent adolescent injuries.
Relationship between medial meniscus extrusion and cartilage measurements in the knee by fully automatic three-dimensional MRI analysis
Authors: Aoki Hayato , Ozeki Nobutake , Katano Hisako , Hyodo Akinobu , Miura Yugo , Matsuda Junpei , Takanashi Kimiko , Suzuki Kenji , Masumoto Jun , Okanouchi Noriya , Fujiwara Takeo , Sekiya Ichiro
Published: November 2020

Background

We developed a fully automatic three-dimensional knee MRI analysis software that can quantify meniscus extrusion and cartilage measurements, including the projected cartilage area ratio (PCAR), which represents the ratio of the subject’s actual cartilage area to their ideal cartilage area. We also collected 3D MRI knee data from 561 volunteers (aged 30–79 years) from the “Kanagawa Knee Study.” Our purposes were to verify the accuracy of the software for automatic cartilage and meniscus segmentation using knee MRI and to examine the relationship between medial meniscus extrusion measurements and cartilage measurements from Kanagawa Knee Study data.

Methods

We constructed a neural network for the software by randomly choosing 10 healthy volunteers and 103 patients with knee pain. We validated the algorithm by randomly selecting 108 of these 113 subjects for training, and determined Dice similarity coefficients from five other subjects. We constructed a neural network using all data (113 subjects) for training. Cartilage thickness, cartilage volume, and PCAR in the medial femoral, lateral femoral, medial tibial, and lateral tibial regions were quantified by using the trained software on Kanagawa Knee Study data and their relationship with subject height was investigated. We also quantified the medial meniscus coverage ratio (MMCR), defined as the ratio of the overlapping area between the medial meniscus area and the medial tibial cartilage area to the medial tibial cartilage area. Finally, we examined the relationship between MMCR and PCAR at middle central medial tibial (mcMT) subregion located in the center of nine subregions in the medial tibial cartilage.

Results

Dice similarity coefficients for cartilage and meniscus were both approximately 0.9. The femoral and tibial cartilage thickness and volume at each region correlated with height, but PCAR did not correlate with height in most settings. PCAR at the mcMT was significantly correlated with MMCR.

Conclusions

Our software showed high segmentation accuracy for the knee cartilage and meniscus. PCAR was more useful than cartilage thickness or volume since it was less affected by height. Relations ips were observed between the medial tibial cartilage measurements and the medial meniscus extrusion measurements in our cross-sectional study.

Trial registration

UMIN, UMIN000032826; 1 September 2018,
The MD-PhD program in Geneva: a 10-year analysis of graduate demographics and outcomes
Authors: Dos Santos Rocha Andre , Combescure Cristophe , Negro Francesco
Published: November 2020

Background

MD-PhD programs confer degrees that empower medical doctors with in-depth scientific skills to contribute to biomedical research and academic medicine, alongside clinical practice. Whilst the career options and research opportunities related to graduates following these programs in the US are well documented, little is known about their European counterparts. In this article, we studied graduates who had completed the MD-PhD program at the University of Geneva between 2010 and 2019.

Methods

A cross-sectional survey was performed in April 2019, targeting all medical doctors who had obtained the MD-PhD degree from the University of Geneva since 2010. Demographics, opinions, and career outcomes of the MD-PhD graduates were assessed through an online anonymous questionnaire.

Results

Twenty-one questionnaires were collected from 31 MD-PhD graduates (response rate 65.5%). Most respondents (57.1%) had performed an MD-PhD training in basic sciences; however, only 14.3% had pursued this type of research thereafter. Most of the respondents held a position at a University hospital (90.5%), although a significant number of them were no longer involved in research in their current position (28.6%). 85.7% mentioned obstacles and challenges in combining clinical duties with research. Despite this, the majority (85.7%) declared that the MD-PhD degree had given them advantages in their career path, granting access to clinical and academic positions, as well as funding.

Conclusions

Graduates from the MD-PhD program in Geneva were for the most part, satisfied with their training. However, because of the challenges and obstacles in combining clinical duties with research, the implementation of research activities in their current position proved difficult.
Integrated 3D printing solution to mitigate shortages of airway consumables and personal protective equipment during the COVID-19 pandemic
Authors: Fillat-Gomà Ferran , Coderch-Navarro Sergi , Martínez-Carreres Laia , Monill-Raya Núria , Nadal-Mir Toni , Lalmolda Cristina , Luján Manel , de Haro Candelaria , Blanch Lluís
Published: November 2020

Background

To cope with shortages of equipment during the COVID-19 pandemic, we established a nonprofit end-to-end system to identify, validate, regulate, manufacture, and distribute 3D-printed medical equipment. Here we describe the local and global impact of this system.

Methods

Together with critical care experts, we identified potentially lacking medical equipment and proposed solutions based on 3D printing. Validation was based on the ISO 13485 quality standard for the manufacturing of customized medical devices. We posted the design files for each device on our website together with their technical and printing specifications and created a supply chain so that hospitals from our region could request them. We analyzed the number/type of items, petitioners, manufacturers, and catalogue views.

Results

Among 33 devices analyzed, 26 (78·8%) were validated. Of these, 23 (88·5%) were airway consumables and 3 (11·5%) were personal protective equipment. Orders came from 19 (76%) hospitals and 6 (24%) other healthcare institutions. Peak production was reached 10 days after the catalogue was published. A total of 22,135 items were manufactured by 59 companies in 18 sectors; 19,212 items were distributed to requesting sites during the busiest days of the pandemic. Our online catalogue was also viewed by 27,861 individuals from 113 countries.

Conclusions

3D printing helped mitigate shortages of medical devices due to problems in the global supply chain.
Cost of investigations during the acute hospital stay following total hip or knee arthroplasty, by complication status
Authors: Cheng Emma , Lewin Adriane , Churches Tim , Harris Ian A , Naylor Justine
Published: November 2020

Background

Total hip and total knee arthroplasties are among the most common types of surgery performed in Australia today and are effective treatments for severe osteoarthritis. However, the increasing financial burden on the health system owing to the increasing rates of surgery has led to a growing interest in improving the cost-effectiveness and safety of arthroplasty care. This study was designed to quantify the association between post-operative complications, a major cost driver, and the cost of investigations following total hip or knee arthroplasty.

Methods

This is a prospective cohort study of consecutive patients undergoing primary total hip or knee arthroplasty at an Australian public hospital. We measured the number and cost of imaging and pathology tests performed during the acute hospital stay and used linear regression to quantify the association between complication status and investigation costs.

Results

Five hundred patients were included in the analysis. On average, those with complications received more tests, and more expensive tests. The mean combined cost of imaging and pathology tests in patients with no complications was AU$ 187 (SD: 12.0). In comparison, patients with minor complications had a mean additional cost of AU$ 270 (SD: 31.0), and those with major complications had a mean additional cost of AU$ 493 (SD: 54.2) (p < 0.001).

Conclusions

In patients undergoing hip or knee arthroplasty, investigation costs are substantially greater in the presence of either minor or major complications. With growing volumes of total hip and total knee arthroplasties, a potential focus of future research could include optimising investigation practices for patients with and without complications.
Design of a care pathway for pharmacy-based PrEP delivery in Kenya: results from a collaborative stakeholder consultation
Authors:   on Behalf of Stakeholders for Pharmacy-based PrEP Delivery in Kenya Consultation, Ortblad Katrina F. , Mogere Peter , Roche Stephanie , Kamolloh Kevin , Odoyo Josephine , Irungu Elizabeth , Mugo Nelly R. , Pintye Jillian , Baeten Jared M. , Bukusi Elizabeth , Ngure Kenneth
Published: November 2020

Introduction

In Kenya, pre-exposure prophylaxis (PrEP) for HIV prevention is almost exclusively delivered at HIV clinics. Developing novel PrEP delivery models is important for increasing the reach of PrEP. Delivery of PrEP through pharmacies is one approach utilized in the US to improve accessibility. Retail pharmacies are commonly used as a first-line access point for medical care in Kenya, but have not been utilized for PrEP delivery. We conducted a collaborative consultative meeting of stakeholders to develop a care pathway for pharmacy-based PrEP delivery in Kenya.

Methods

In January 2020, we held a one-day meeting in Nairobi with 36 stakeholders from PrEP regulatory, professional, healthcare service delivery, civil society, and research organizations. Attendees reviewed a theory of change model, results from formative qualitative research with pharmacy providers and clients, and anticipated core components of pharmacy-based PrEP delivery: counseling, HIV testing, prescribing, and dispensing. Stakeholders participated in small and large group discussions to identify potential challenges and solutions. We synthesized the key findings from these discussions.

Results

Stakeholders were enthusiastic about a model for pharmacy-based PrEP delivery. Potential challenges identified included insufficient pharmacy provider knowledge and skills, regulatory hurdles to providing affordable HIV testing at pharmacies, and undefined pathways for PrEP procurement. Potential solutions identified included having pharmacy providers complete the Kenya Ministry of Health-approved PrEP training, use of a PrEP prescribing checklist with remote clinician oversight and provider-assisted HIV self-testing, and having the government provide PrEP and HIV self-testing kits to pharmacies during a pilot test. A care pathway was developed over the course of the meeting.

Conclusions

PrEP delivery stakeholders in Kenya were strongly supportive of developing and testing a model for pharmacy-based PrEP delivery to increase PrEP access. We collaboratively developed a care pathway for pilot testing that has the potential to expand PrEP delivery options in Kenya and other similar settings.
Modelling the household-level impact of a maternal respiratory syncytial virus (RSV) vaccine in a high-income setting
Authors: Campbell Patricia T. , Geard Nicholas , Hogan Alexandra B.
Published: November 2020

Background

Respiratory syncytial virus (RSV) infects almost all children by the age of 2 years, with the risk of hospitalisation highest in the first 6 months of life. Development and licensure of a vaccine to prevent severe RSV illness in infants is a public health priority. A recent phase 3 clinical trial estimated the efficacy of maternal vaccination at 39% over the first 90 days of life. Households play a key role in RSV transmission; however, few estimates of population-level RSV vaccine impact account for household structure.

Methods

We simulated RSV transmission within a stochastic, individual-based model framework, using an existing demographic model, structured by age and household and parameterised with Australian data, as an exemplar of a high-income country. We modelled vaccination by immunising pregnant women and explicitly linked the immune status of each mother-infant pair. We quantified the impact on children for a range of vaccine properties and uptake levels.

Results

We found that a maternal immunisation strategy would have the most substantial impact in infants younger than 3 months, reducing RSV infection incidence in this age group by 16.6% at 70% vaccination coverage. In children aged 3–6 months, RSV infection was reduced by 5.3%. Over the first 6 months of life, the incidence rate for infants born to unvaccinated mothers was 1.26 times that of infants born to vaccinated mothers. The impact in older age groups was more modest, with evidence of infections being delayed to the second year of life.

Conclusions

Our findings show that while individual benefit from maternal RSV vaccination could be substantial, population-level reductions may be more modest. Vaccination impact was sensitive to the extent that vaccination prevented infection, highlighting the need for more vaccine trial data.
Pharmacokinetics and pharmacodynamics of HTD1801 (berberine ursodeoxycholate, BUDCA) in patients with hyperlipidemia
Authors: Di Bisceglie Adrian M. , Watts Gerald F. , Lavin Philip , Yu Meng , Bai Ru , Liu Liping
Published: November 2020

Background

Reduction in elevated serum cholesterol concentrations is important in the management of individuals at risk of atherosclerotic cardiovascular disease (ASCVD), such as myocardial infarction and thrombotic stroke. Although HMGCoA reductase inhibitors (“statins”) are frequently used for this purpose, a significant proportion of patients remain at increased residual risk of ASCVD as they do not adequately address some of the associated co-morbidities such as diabetes and fatty liver disease.

Methods

A double-blind, randomized, placebo-controlled, dose ranging study was carried out that compared three doses of berberine ursodeoxycholate (BUDCA) to placebo in a cohort of subjects with a history of hypercholesterolemia and serum LDL cholesterol levels above 2.59 mmol/L (> 99.9 mg/dL). BUDCA was administered in two divided doses each day for 28 days. The primary endpoints of the study were safety and tolerability of this new compound, as well as its effect in lowering serum lipid and lipoprotein concentrations.

Results

A total of 50 subjects were enrolled into three dose cohorts in this study. BUDCA was generally well tolerated, even at doses of 2000 mg per day (the highest dose group); there were no significant adverse effects reported and this highest dose was associated with significant reductions in LDL cholesterol. By day 28 and with the highest dose of BUDCA, there were significant reductions in the serum concentrations of total cholesterol by 8.2% (P = 0.0004) and LDL cholesterol by 10.4% (P = 0.0006), but no significant changes in triglyceride and HDL cholesterol concentrations.

Conclusions

BUDCA is a new single molecular entity that has a significant but modest effect in safely lowering serum LDL-cholesterol concentrations in individuals with a history of hypercholesterolemia. It has a potential use for treating hypercholesterolemia in individuals who cannot take statins, and possibly as adjunctive to other agents, such as ezetimibe or bempedoic acid.

Trial registration

The study was registered onClinicaltrials.gov(NCT03381287).
How donors support civil society as government accountability advocates: a review of strategies and implications for transition of donor funding in global health
Authors: McDonough Amy , Rodríguez Daniela C.
Published: November 2020

Background

Global health donors are increasingly transitioning funding responsibility to host governments as aid budgets plateau or decline and countries meet development and disease burden goals. Civil society organizations (CSOs) can play a critical role as accountability mechanisms over their governments, but transitions raise questions about how donor-supported CSOs will fare following transition, especially in environments of limited political commitment. Decreases in funding may force CSOs to scale back activities, seek other funding, or rely on their governments for funding. Vulnerable populations most in need of support may lose critical advocates, compromising their access to lifesaving care and threatening the reversal of global health achievements. This review investigates donor strategies used in the past to support CSOs as accountability advocates across the international development sector by exploring what activities are supported, how support is provided and who receives support. It provides considerations for global health donors to better equip civil society as advocates during and following transition.

Methods

A literature review of four databases of peer-reviewed literature, websites focused on civil society support and snowball searching identified 180 documents for review, after application of exclusion criteria, covering up to December 2019. Results were categorized and analyzed by who, what and how donors have supported civil society’s accountability role.

Results

Donors support a variety of civil society actors, including individual organizations and networks, through capacity building, access to information, backing participation in policy dialogues, securing citizen engagement and targeting the broader policy context. Funding may be provided directly or through pooled, intermediary or bridge mechanisms. Key concerns identified include insufficient engagement of CSOs in defining support, limited donor flexibility, tensions in balancing organizational professionalization with community connections, and jeopardized CSO legitimacy and independence from relying on foreign funds.

Conclusions

Given the urgency of global health donor transitions, the literature demonstrates that any donor support to CSO advocates should emphasize transition preparations from the start. Capacity building, institutionalizing mechanisms for civil society participation, planning for information needs, and flexible funding are priority mechanisms to ensure that vulnerable populations continue accessing lifesaving care and global health progress is not reversed.
Correction to: Treatment of the mandibular shift in an adult woman and the diagnostic value of joint space index: a case report
Authors: Xia Kai , Sun Wentian , Yu Liyuan , Huang Xinqi , Zhao Zhihe , Liu Jun
Published: November 2020

An amendment to this paper has been published and can be accessed via the original article.
Cyclotron-based production of 68Ga, [68Ga]GaCl3, and [68Ga]Ga-PSMA-11 from a liquid target
Authors: Rodnick Melissa E. , Sollert Carina , Stark Daniela , Clark Mara , Katsifis Andrew , Hockley Brian G. , Parr D. Christian , Frigell Jens , Henderson Bradford D. , Abghari-Gerst Monica , Piert Morand R. , Fulham Michael J. , Eberl Stefan , Gagnon Katherine , Scott Peter J. H.
Published: November 2020

Purpose

To optimize the direct production of68Ga on a cyclotron, via the68Zn(p,n)68Ga reaction using a liquid cyclotron target. We Investigated the yield of cyclotron-produced68Ga, extraction of [68Ga]GaCl3and subsequent [68Ga]Ga-PSMA-11 labeling using an automated synthesis module.

Methods

Irradiations of a 1.0 M solution of [68Zn]Zn(NO3)2in dilute (0.2–0.3 M) HNO3were conducted using GE PETtrace cyclotrons and GE68Ga liquid targets. The proton beam energy was degraded to a nominal 14.3 MeV to minimize the co-production of67Ga through the68Zn(p,2n)67Ga reaction without unduly compromising68Ga yields. We also evaluated the effects of varying beam times (50–75 min) and beam currents (27–40 μA). Crude68Ga production was measured. The extraction of [68Ga]GaCl3was performed using a 2 column solid phase method on the GE FASTlab Developer platform. Extracted [68Ga]GaCl3was used to label [68Ga]Ga-PSMA-11 that was intended for clinical use.

Results

The decay corrected yield of68Ga at EOB was typically > 3.7 GBq (100 mCi) for a 60 min beam, with irradiations of [68Zn]Zn(NO3)2at 0.3 M HNO3.Target/chemistry performance was more consistent when compared with 0.2 M HNO3. Radionuclidic purity of68Ga was typically > 99.8% at EOB and met the requirements specified in the European Pharmacopoeia (< 2% combined66/67Ga) for a practical clinical product shelf-life. The activity yield of [68Ga]GaCl3was typically > 50% (~ 1.85 GBq, 50 mCi); yields improved as processes were optimized. Labeling yields for [68Ga]Ga-PSMA-11 were near quantitative (~ 1.67 GBq, 45 mCi) at EOS. Cyclotron produced [68Ga]Ga-PSMA-11 underwent full quality control, stability and sterility testing, and was implemented for human use at the University of Michigan as an Investigational New Drug through the US FDA and also at the Royal Prince Alfred Hospital (RPA).

Conclusion

Direct cyclotron irradiation of a liquid target provides clinically relevant quantities of [68Ga]Ga-PSMA-11 and is a viable alternative to traditional68Ge/68Ga generators.
Towards safer risperidone prescribing in Alzheimer's disease
Authors: Reeves Suzanne , Bertrand Julie , Uchida Hiroyuki , Yoshida Kazunari , Otani Yohei , Ozer Mikail , Liu Kathy Y. , Bramon Elvira , Bies Robert , Pollock Bruce G. , Howard Robert
Published: November 2020

Background

In the treatment of psychosis, agitation and aggression in Alzheimer's disease, guidelines emphasise the need to ‘use the lowest possible dose’ of antipsychotic drugs, but provide no information on optimal dosing.

Aims

This analysis investigated the pharmacokinetic profiles of risperidone and 9-hydroxy (OH)-risperidone, and how these related to treatment-emergent extrapyramidal side-effects (EPS), using data from The Clinical Antipsychotic Trials of Intervention Effectiveness in Alzheimer's Disease study (Clinicaltrials.gov identifier: NCT00015548).

Method

A statistical model, which described the concentration–time course of risperidone and 9-OH-risperidone, was used to predict peak, trough and average concentrations of risperidone, 9-OH-risperidone and ‘active moiety’ (combined concentrations) (n= 108 participants). Logistic regression was used to investigate the associations of pharmacokinetic biomarkers with EPS. Model-based predictions were used to simulate the dose adjustments needed to avoid EPS.

Results

The model showed an age-related reduction in risperidone clearance (P< 0.0001), reduced renal elimination of 9-OH-risperidone (elimination half-life 27 h), and slower active moiety clearance in 22% of patients, (concentration-to-dose ratio: 20.2 (s.d. = 7.2)v.7.6 (s.d. = 4.9) ng/mL per mg/day, Mann–WhitneyU-test,P< 0.0001). Higher trough 9-OH-risperidone and active moiety concentrations (P< 0.0001) and lower Mini-Mental State Examination (MMSE) scores (P< 0.0001), were associated with EPS. Model-based predictions suggest the optimum dose ranged from 0.25 mg/day (85 years, MMSE of 5), to 1 mg/day (75 years, MMSE of 15), with alternate day dosing required for those with slower drug clearance.

Conclusions

Our findings argue for age- and MMSE-related dose adjustments and suggest that a single measure of the concentration-to-dose ratio could be used to identify those with slower drug clearance.
Structural Gray and White Matter Differences in Patients With Type 1 Diabetes and Impaired Awareness of Hypoglycemia
Authors: Stantonyonge Nicole , Sampedro Frederic , Méndez Jorge , Martínez-Horta Saül , Chico Ana , Gómez-Anson Beatriz
Published: November 2020

Context

Type 1 diabetes (T1D) is associated with an increased risk of cognitive decline, where severe hypoglycemia (SH) and impaired awareness of hypoglycemia (IAH) may play a role. While there is evidence of a possible association between IAH and brain damage, the potential brain changes remain poorly characterized by magnetic resonance imaging (MRI).

Objective

To investigate whether there are structural brain differences in a group of T1D patients with IAH compared with normal awareness of hypoglycemia (NAH).

Design

General practice, population-based, cross-sectional study (July 2018 to July 2019).

Setting

Endocrinology Department, Hospital Santa Creu i Sant Pau.

Participants

A total of 40 T1D patients (20 each with IAH and NAH) matched for age, sex, T1D duration, and education level.

Main Outcome Measures

Using different neuroimaging techniques, we compared whole-brain gray matter (GM) and white matter (WM) differences. We used voxel-based morphometry and cortical surface area analysis methods to assess GM differences, and fractional anisotropy (FA) to assess WM differences.

Results

Compared with patients with T1D-NAH, patients with T1D-IAH had reduced GM volumes and cortical surface areas, especially in frontal and parietal regions (P < 0.05 corrected), and also showed reduced FA values in major WM tracts. The observed MRI differences correlated with both SH frequency and IAH severity.

Conclusions

MRI for patients with T1D show that IAH is associated with brain changes involving both GM and WM. Further research is needed to elucidate whether the observed differences are a consequence of increased SH episode frequency and increased IAH severity.
Severe Shivering on Venoarterial Extracorporeal Membrane Oxygenation—Raising the Circuit Temperature to Stop Rhabdomyolysis: A Case Report
Authors: Kadar Rachel B. , Atassi Giancarlo , Jarzebowski Mary , Ault Michael L.
Published: November 2020

We report a case of severe shivering resulting in rhabdomyolysis while on venoarterial extracorporeal membrane oxygenation (ECMO) that resolved after hyperthermia was induced using the ECMO circuit. The patient developed shivering approximately 24 hours after venoarterial ECMO cannulation for refractory ventricular tachycardia. The shivering caused rhabdomyolysis and necessitated cisatracurium infusion. The shivering failed to resolve after the patient was diagnosed and treated for ventilator-associated pneumonia. Suspecting sepsis as the etiology of shivering, the ECMO circuit temperature was increased to 38 °C, and the shivering was resolved. This case demonstrates therapeutic hyperthermia to treat infection-induced severe shivering and rhabdomyolysis while on ECMO.
Ambient dose during intraoral radiography with current techniques: part 3: effect of tube voltage
Authors: Hoogeveen Reinier Cornelis , van Beest Dirk , Berkhout Erwin
Published: November 2020

Objectives:

This study was conducted to assess the impact of tube voltage on ambient dose during intraoral radiography, specifically remnant-beam transmission and scattered radiation.

Methods and materials:

Remnant-beam and scattered radiation doses were recorded using a phantom at tube voltages of 60, 63, 66 and 70 kV. Mathematical equations depicting their relations were then formulated, and reference values were calculated at the various voltages tested. Total ambient doses per exposure at 60 kV and at 70 kV were compared.

Results:

Both remnant-beam transmission and scattered radiation increased ~40% by increasing tube voltage from 60 kV to 70 kV, and the relation was linear. A remnant beam transmission reference value of 7.5% was established at 70 kV, as well as a conversion factor of 0.035 µSv/mAs at 1 m for scattered radiation at 60 kV. Given longer exposure times at 60 kV, total ambient dose proved higher at 60 kV than at 70 kV.

Conclusion:

Higher tube voltage results in higher remnant-beam transmission and more scattered radiation per workload. The relation is linear in the range between 60kV and 70 kV. Remnant-beam transmission at 70 kV is safely assessed at 7.5%. A conversion factor at 60 kV of 0.035 µSv/mAs at 1 m for the scattered radiation dose can be proposed. Total ambient dose per exposure was higher at 60kV than at 70 kV.