bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of biopsy-proven renal disease in people living with HIV: 10 years experience in Sydney, Australia
Authors: Turner Dane , Drak Doug , Gracey David , Anderson Lyndal
Published: April 2022

Background

Acute and chronic kidney diseases are important comorbidities in People Living With HIV (PLWH). Biopsy is often pursued in this cohort with ongoing renal impairment without a clear aetiology, in order to establish the diagnosis and to guide management. Despite the importance of renal disease in PLWH, there is a paucity of biopsy data—especially in the Australian setting. Consequently, who and when to biopsy is mainly based on clinical experience. The aims of this study were to describe biopsy-proven renal disease in PLWH at our institution and to assess for correlation between any demographic or laboratory characteristics with histological diagnosis.

Methods

A retrospective review of all PLWH who underwent renal biopsy between January 2010 and December 2020 at Royal Prince Alfred Hospital, Sydney, Australia was performed. All PLWH over 18 years, who were not transplant recipients were included. Demographic, laboratory and biopsy data was extracted from the electronic medical records. Basic descriptive statistics were performed, and correlation was assessed using chi square and Kendall’s coefficient of rank test.

Results

19 renal biopsies were included in the study. The majority of PLWH were Australian born (53%), male (84%) and had a mean age of 48 years (SD 13). Comorbid hypertension and diabetes were present in 74% and 21% of people respectively. The mean serum creatinine was 132 µmol/L (SD 55) and the mean estimated glomerular filtration rate (eGFR) was 61 ml/min/1.73m2 (SD 24). The most common histological diagnosis was tubulointerstial nephritis in 5 people (24%). Hypertensive glomerulosclerosis and IgA nephropathy were present in 4 (19%) and 3 (14%) people respectively. There were no cases of HIV-associated nephropathy. There was no significant correlation between any cohort characteristics and diagnoses.

Conclusions

This study represents the first description of biopsy-proven kidney disease in the HIV-infected population of Australia. Our results support the use of renal biopsy in PLWH with ongoing renal impairment for accurate diagnosis and to guide further management. Although a small sample size, our study is larger than other published international biopsy studies.
Demographic and clinical features of pediatric uveitis and scleritis at a tertiary referral center in China
Authors: Sun Nan , Wang Chunxi , Linghu Wenrui , Li Xiaorong , Zhang Xiaomin
Published: April 2022

Background

To analyse demographic, clinical features, treatment and therapeutic outcomes of pediatric uveitis and scleritis patients.

Subjects

The clinical records of pediatric uveitis and scleritis cases between January 2012 and December 2020 at a tertiary uveitis service center in Tianjin Medical University Eye Hospital (TMUEH) were reviewed.

Results

In total, 209 patients (337 eyes) were included, 49.3% were male. The median onset age was 9.0 (IQR, 7.0–12.0) years. Chronic uveitis and scleritis accounted for 86.1%. Panuveitis (29.2%), anterior uveitis(29.2%), and intermediate uveitis (22.0%) were the most common presentations. The most common diagnoses were idiopathic (71.3%), JIA (8.1%), and infectious uveitis (4.8%). At baseline, 40.7% patients received oral corticosteroid therapy; during follow-up, corticosteroids (66.0%), disease-modifying antirheumatic drugs (61.2%), and biologic agents (35.4%) were the mainstay. Posterior synechia (26.1%) and cataracts (25.5%) were the most common complications. In acute cases, the median best corrected visual acuity (BCVA) was 0.99 (IQR, 0.5–1.0) at baseline and 0 (IQR, 0–0) at last follow-up; in chronic cases, the median BCVA improved from 1.09 (IQR, 0.5–2.0) to 0.27 (IQR, 0–0.5), with anterior chamber cell grade significantly declining. Ten eyes underwent cataract surgery during regular follow-up and achieved satisfactory long-term visual outcomes and decreased burden of immunosuppressants. The incidence of steroid-induced ocular hypertension was 41.0%, and children with frequent instillation of eyedrops were at high risk.

Conclusions

Most cases were of chronic uveitis and scleritis requiring long-term systemic immunosuppressive therapies in pediatric uveitis and scleritis in China. Good management of complications is important for long-term prognosis.
Study design of PerfectFit@Night, a workplace health promotion program to improve sleep, fatigue, and recovery of night shift workers in the healthcare sector
Authors: van Elk Fleur , Robroek Suzan J. W. , Smits-de Boer Sonja , Kouwenhoven-Pasmooij Tessa A. , Burdorf Alex , Oude Hengel Karen M.
Published: April 2022

Background

Healthcare workers need to be at work 24 h a day to ensure continuity of care in hospitals. However, shift work - particularly night shifts - can have negative acute and long-term effects on health and productivity due to disturbances in the circadian rhythm. Shift work is also associated with unhealthy lifestyle behaviors such as poor sleep hygiene and diet. The PerfectFit@Night intervention aims to improve sleep and recovery, and reduce fatigue, and therewith contribute to sustainable employability of healthcare workers. The current study describes the intervention and the evaluation and implementation.

Methods

The study population will consist of healthcare workers, nurses and physicians, with night shifts in a large Dutch academic hospital. The intervention consists of individual and environmental intervention elements: i) an e-learning for healthcare workers to increase knowledge and awareness on a healthy lifestyle during night shifts, ii) a powernap bed to take powernaps during night shifts, iii) the availability of healthy food at the department during night shifts, iv) a workshop on healthy rostering at the level of the department, and v) individual sleep coaching among the high risk group. In a longitudinal prospective study, data will be collected 1 month before the start of the intervention, in the week before the start of the intervention, and three and 6 months after the start of the intervention. The primary outcomes are sleep, fatigue, and need for recovery. The implementation process will be evaluated using the framework of Steckler and Linnan. Cost-benefit analyses from the employers perspective will be conducted to understand the possible financial consequences or benefits of the implementation of PerfectFit@Night.

Discussion

The feasibility and effectiveness of this workplace health promotion program will be investigated by means of an effect, process and economic evaluation. If proven effective, PerfectFit@Night can be implemented on a larger scale within the healthcare sector.

Trial registration

Netherlands Trial Register trial number NL9224. Registered 17 January 2021.
The burden of aortic aneurysm in China from 1990 to 2019: findings from the Global Burden of Disease Study 2019
Authors: Hou Xinran , Zhang Fan , Ye Zhi , Xu Qian , Huang Lingjin , Guo Qulian , Liu Wei , Wang Lijun , Zhou Maigeng , Yin Peng , Zhu Maoen
Published: April 2022

Background

Aortic aneurysm (AA) is a global public health concern. However, little is known about the disease burden of AA in China.

Methods

Following the general analytic strategy used in the Global Burden of Disease Study (GBD) 2019, we analyzed the mortality and years of life lost (YLLs) due to AA, stratified by sex, age, and province-level region in China from 1990 to 2019. The temporal trend of AA burden in China was analyzed and the main attributable risk factors for AA in China were also explored.

Results

In China, the total AA deaths were 17,038 (95% UI: 14,392-19,980) in 2019, an increase of 136.1% compared with that in 1990, with an age-standardized death rate (ASDR) of 0.93 (95% UI: 0.79-1.08) per 100,000 person-years in 2019, a decrease of 6.8%. Meanwhile AA caused 378,578 (95% UI: 315,980-450,479) YLLs in 2019, an increase of 102.6% compared with that in 1990, with a crude YLL rate of 26.6 (95% UI: 22.2-31.7) per 100,000 person-years, an increase of 68.6%. The AA mortality and YLLs were higher in males than in females. AA caused most YLLs in the 65- to 75-year-old age group. The AA mortality and YLLs varied significantly among provinces in China, and the change in ASDR showed a negative correlation with the sociodemographic index of different provinces, namely, more decline of ASDR in developed provinces. High systolic blood pressure was shown to be the most significant attributable risk factor for AA burden in both males and females, and smoking was another major attributable risk factor, especially in males.

Conclusions

The disease burden of AA increased significantly from 1990 to 2019 in China, with higher mortality and YLLs in males, senior populations, and among residents of most western provinces in China. High systolic blood pressure and smoking were two major attributable risk factors for AA mortality in China.
Oil-based versus water-based contrast media for hysterosalpingography in infertile women of advanced age, with ovulation disorders or a high risk for tubal pathology: study protocol of a randomized controlled trial (H2Oil2 study)
Authors: Rosielle K. , Kamphuis D. , van Welie N. , Roest I. , Mozes A. , van Santbrink E. J. P. , van de Laar T. , Hooker A. B. , Huppelschoten A. G. , Li W. , Bongers M. Y. , Stoker J. , van Wely M. , Koks C. , Lambalk C. B. , Hemingway A. , Mol B. W. J. , Dreyer K. , Mijatovic V.
Published: April 2022

Background

In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography (HSG) increases ongoing pregnancy and subsequent live birth rates when compared to tubal flushing with water-based contrast. It is currently unclear whether an HSG with oil-based contrast also results in more ongoing pregnancies and live births in women of advanced age, women with ovulation disorders, and women with potential tubal pathology when compared to an HSG with water-based contrast.

Methods

We plan an international, multicentre, open-label, randomized controlled trial (RCT) studying three groups of infertile women who have an indication for tubal patency testing according to their treating physician and additionally; (1) are 39 years of age or older, (2) have an ovulation disorder or (3) have a high risk for tubal pathology based on their medical history. Women with an allergy for iodinated contrast medium are excluded, as are women with diabetes, hyperprolactinemia or untreated hyper- or hypothyroidism, and women with a partner with severe male infertility. After informed consent, women will be randomly allocated to the intervention, tubal flushing with the use of oil-based contrast during HSG or the control group, tubal flushing with the use of water-based contrast during HSG in a 1:1 ratio by the web-based system Castor. The primary endpoint will be ongoing pregnancy leading to live birth with conception within six months after randomization. Secondary outcomes are other pregnancy outcomes, used fertility treatments, adverse events and cost-effectiveness. Based on the expected ongoing pregnancy rate of 17% in the control group and 27% in the intervention group, the sample size will be 930 women (465 per group). Study inclusion is expected to be complete in four years.

Discussion

This multicentre RCT will establish whether, for women of advanced age, women with ovulatory disease, and women who have a high risk for tubal pathology, there is a fertility enhancing effect of tubal flushing with oil-based contrast during HSG and whether the use of this contrast medium is cost-effective.

Trial Registration The study was prospectively registered in the Netherlands Trial Register on August 1st 2019 as ‘H2Oil2’ (reference number NL7925, https://www.trialregister.nl/trial/7925).
Face-to-face versus distance learning of basic suturing skills in novice learners: a quantitative prospective randomized trial
Authors: Zaghal Ahmad , Marley Charles , Rahhal Salim , Hassanieh Joelle , Saadeh Rami , El-Rifai Arwa , Qaraqe Taha , ElBejjani Martine , Jaafar Rola , Hoballah Jamal J.
Published: April 2022

Background and aim

Traditionally, practical skills are taught on face-to-face (F-F) basis. COVID-19 pandemic brought distance learning (DL) to the spotlight because of the social distancing mandates. We sought to determine the acceptability and effectiveness of DL of basic suturing in novice learners.

Methods

A prospective randomized controlled trial involving 118 students was conducted. Participants were randomized into two groups for learning simple interrupted suturing: F-F and DL-groups. Evaluation was conducted by two assessors using a performance checklist and a global rating tool. Agreement between the assessors was calculated, and performance scores of the participants were compared. Participants’ satisfaction was assessed via a questionnaire.

Results

Fifty-nine students were randomized to the F-F group and 59 to the DL-group. Satisfactory agreement between the assessors was demonstrated. All participants were successful in placing three interrupted sutures, with no significant difference in the performance between the groups. 25(44.6%) of the respondents in the DL-group provided negative comments related to the difficulties of remotely learning visuospatial concepts, 16(28.5%) preferred the F-F approach.

Conclusion

DL of basic suturing is as effective as the F-F approach in novice learners. It is acceptable by the students despite the challenges related to the remote learning of practical skills.
Is glycaemic control associated with dietary patterns independent of weight change in people newly diagnosed with type 2 diabetes? Prospective analysis of the Early-ACTivity-In-Diabetes trial
Authors: Garbutt James , England C. , Jones A. G. , Andrews R. C. , Salway R. , Johnson L.
Published: April 2022

Background

It is unclear whether diet affects glycaemic control in type 2 diabetes (T2D), over and above its effects on bodyweight. We aimed to assess whether changes in dietary patterns altered glycaemic control independently of effects on bodyweight in newly diagnosed T2D.

Methods

We used data from 4-day food diaries, HbA1c and potential confounders in participants of the Early-ACTivity-In-Diabetes trial measured at 0, 6 and 12 months. At baseline, a ‘carb/fat balance’ dietary pattern and an ‘obesogenic’ dietary pattern were derived using reduced-rank regression, based on hypothesised nutrient-mediated mechanisms linking dietary intake to glycaemia directly or via obesity. Relationships between 0 and 6 month change in dietary pattern scores and baseline-adjusted HbA1c at 6 months (n = 242; primary outcome) were assessed using multivariable linear regression. Models were repeated for periods 6–12 months and 0–12 months (n = 194 and n = 214 respectively; secondary outcomes).

Results

Reductions over 0–6 months were observed in mean bodyweight (− 2.3 (95% CI: − 2.7, − 1.8) kg), body mass index (− 0.8 (− 0.9, − 0.6) kg/m2), energy intake (− 788 (− 953, − 624) kJ/day), and HbA1c (− 1.6 (− 2.6, -0.6) mmol/mol). Weight loss strongly associated with lower HbA1c at 0–6 months (β = − 0.70 [95% CI − 0.95, − 0.45] mmol/mol/kg lost). Average fat and carbohydrate intakes changed to be more in-line with UK healthy eating guidelines between 0 and 6 months. Dietary patterns shifting carbohydrate intakes higher and fat intakes lower were characterised by greater consumption of fresh fruit, low-fat milk and boiled/baked potatoes and eating less of higher-fat processed meats, butter/animal fats and red meat. Increases in standardised ‘carb/fat balance’ dietary pattern score associated with improvements in HbA1c at 6 months independent of weight loss (β = − 1.54 [− 2.96, − 0.13] mmol/mol/SD). No evidence of association with HbA1c was found for this dietary pattern at other time-periods. Decreases in ‘obesogenic’ dietary pattern score were associated with weight loss (β = − 0.77 [− 1.31, − 0.23] kg/SD) but not independently with HbA1c during any period.

Conclusions

Promoting weight loss should remain the primary nutritional strategy for improving glycaemic control in early T2D. However, improving dietary patterns to bring carbohydrate and fat intakes closer to UK guidelines may provide small, additional improvements in glycaemic control.

Trial registration

ISRCTN92162869. Retrospectively registered on 25 July 2005
Visual detection of porcine epidemic diarrhea virus by recombinase polymerase amplification combined with lateral flow dipstrip
Authors: Ma Lei , Lian Kaiqi , Zhu Mengjie , Tang Yajie , Zhang Mingliang
Published: April 2022

Background

Porcine epidemic diarrhea virus (PEDV) is one of the most important enteric viruses causing diarrhea in pigs. The establishment of a rapid detection method applicable in field conditions will be conducive to early detection of pathogen and implementation of relevant treatment. A novel nucleic acid amplification method, recombinase polymerase amplification (RPA), has been widely used for infectious disease diagnosis.

Results

In the present study, a reverse transcription (RT)-RPA assay combined with lateral flow dipstrip (LFD) was established for the visual detection of PEDV by targeting the N gene. The RT-RPA-LFD assay detected as low as 102 copies/µL of PEDV genomic RNA standard. Moreover, the novel RT-RPA-LFD assay did not show cross-reactivity with common swine pathogens, demonstrating high specificity. The performance of the assay for detection of clinical samples was also evaluated. A total number of 86 clinical samples were tested by RT-RPA-LFD and RT-PCR. The detection results of RT-RPA-LFD were compared with those of RT-PCR, with a coincidence rate of 96.5%.

Conclusion

The newly established RT-RPA-LFD assay in our study had high sensitivity and specificity, with a potential to use in resource-limited areas and countries.
Identification of two novel pathogenic variants of the NR1H4 gene in intrahepatic cholestasis of pregnancy patients
Authors: Lai Hua , Liu Xianxian , Xin Siming , Zheng Jiusheng , Liu Huai , Ouyang Yu , Yang Huoxiu , Zeng Yang , Zou Yang , Zeng Xiaoming
Published: April 2022

Background

Intrahepatic cholestasis of pregnancy (ICP) can cause adverse pregnancy outcomes, such as spontaneous preterm delivery and stillbirth. It is a complex disease influenced by multiple factors, including genetics and the environment. Previous studies have reported that functioning nuclear receptor subfamily 1 group H member 4 (NR1H4) plays an essential role in bile acid (BA) homeostasis. However, some novel variants and their pathogenesis have not been fully elucidated. Therefore, this research aimed to investigate the genetic characteristics of theNR1H4gene in ICP.

Methods

In this study, we sequenced the entire coding region ofNR1H4in 197 pregnant women with ICP disease. SIFT and PolyPhen2 were used to predict protein changes. Protein structure modelling and comparisons between NR1H4 reference and modified protein structures were performed by SWISS-MODEL and Chimera 1.14rc, respectively. T-tests were used to analyse the potential significant differences betweenNR1H4mutations and wild types for 29 clinical features. Fisher’s test was conducted to test the significance of differences in mutation frequencies between ICP and the three databases.

Results

We identified four mutations: two novel missense mutations, p.S145F and p.M185L; rs180957965 (A230S); and rs147030757 (N275N). The two novel missense mutations were absent in 1029 controls and three databases, including the 1000 Genomes Project (1000G_ALL), Exome Aggregation Consortium (ExAC) and ChinaMAP. Two web-available tools, SIFT and PolyPhen2, predicted that these mutations are harmful to the function of the protein. Moreover, compared to the wild-type protein structure, theNR1H4p.S145F and p.M185L protein structure showed a slight change in the chemical bond in two zinc finger structures. Combined clinical data indicate that the mutation group had higher levels of total bile acid (TBA) than the wild-type group. Therefore, we hypothesized that these two mutations altered the protein structure ofNR1H4, which impaired the function ofNR1H4itself and its target gene and caused an increase in TBA.

Conclusions

To our knowledge, this is the first study to identify the novel p.S145F and p.M185L mutations in 197 ICP patients. Our present study provides new insights into the genetic architecture of ICP involving the two novelNR1H4mutations.
Bilirubin as an indicator of cardiometabolic health: a cross-sectional analysis in the UK Biobank
Authors: Seyed Khoei Nazlisadat , Wagner Karl-Heinz , Sedlmeier Anja M. , Gunter Marc J. , Murphy Neil , Freisling Heinz
Published: April 2022

Background

Mildly elevated bilirubin, a by-product of hemoglobin breakdown, might mitigate cardiometabolic risk factors including adiposity, dyslipidemia, and high blood pressure (BP). We investigated the cross-sectional relationship between (total) bilirubin and baseline cardiometabolic risk factors in 467,519 UK Biobank study participants.

Methods

We used multivariable-adjusted linear regression to estimate associations between bilirubin levels and risk factors of cardiometabolic diseases including body mass index (BMI), waist and hip circumferences (WC, HC), waist-to-hip ratio (WHR), fat mass (FM), and trunk FM, and the blood lipids: apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), apoB/apoA-I, lipoprotein (a), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL/HDL, TC/HDL, triglycerides (TG). Log-transformed bilirubin was modelled with restricted cubic splines and predicted mean values with 99% confidence intervals (CI) for each risk marker were estimated, separately. Second, we applied principal component analysis (PCA) for dimension reduction to in turn six anthropometric traits (height, weight, BMI, WC, HC, and WHR) and all above lipids. Last, we estimated associations (99%CI) between bilirubin and three components of the metabolic syndrome, i.e. WC, TG, and BP using logistic regression.

Results

After multivariable adjustments, higher levels of bilirubin were inversely associated with indicators of general adiposity (BMI and FM) and of body fat distribution (WC, HC, WHR, and trunk FM) in both men and women. For example, women with mildly elevated bilirubin (95th percentile equal to 15.0 µmol/L), compared to women with low bilirubin (5th percentile equal to 4.5 µmol/L), had on average a 2.0 kg/m2 (99% CI 1.9–2.1) lower BMI. Inverse associations were also observed with dyslipidemia among men and women. For example, mildly elevated bilirubin among men (95th percentile equal to 19.4 µmol/L) compared to low levels of bilirubin (5th percentile equal to 5.5 µmol/L) were associated with approx. 0.55 mmol/L (99% CI 0.53–0.56) lower TG levels, with similar inverse associations among women. Multiple-trait analyses using PCA confirmed single-trait analyses. Men and women with mildly elevated bilirubin levels ≥ 17.1 µmol/L, compared to low-normal bilirubin < 10 µmol/L had 13% (99% CI 8%–18%) and 11% (99% CI 4%–17%) lower odds of exceeding systolic BP levels of ≥ 130 mm Hg, respectively.

Conclusions

Higher levels of bilirubin were inversely associated with cardiometabolic risk factors including adiposity, dyslipidemia, and hypertension.
Whole-genome analysis of coxsackievirus B3 reflects its genetic diversity in China and worldwide
Authors: Yang Qian , Yan Dongmei , Song Yang , Zhu Shuangli , He Yun , Han Zhenzhi , Wang Dongyan , Ji Tianjiao , Zhang Yong , Xu Wenbo
Published: April 2022

Background

Coxsackievirus B3 (CVB3) has emerged as an active pathogen in myocarditis, aseptic meningitis, hand, foot, and mouth disease (HFMD), and pancreatitis, and is a heavy burden on public health. However, CVB3 has not been systematically analyzed with regard to whole-genome diversity and recombination. Therefore, this study was undertaken to systematically examine the genetic characteristics of CVB3 based on its whole genome.

Methods

We combined CVB3 isolates from our national HFMD surveillance and global sequences retrieved from GenBank. Phylogenetic analysis was performed to examine the whole genome variety and recombination forms of CVB3 in China and worldwide.

Results

Phylogenetic analysis showed that CVB3 strains isolated worldwide could be classified into clusters A–E based on the sequence of the entire VP1 region. The predominant CVB3 strains in China belonged to cluster D, whereas cluster E CVB3 might be circulated globally compared to other clusters. The average nucleotide substitution rate in the P1 region of CVB3 was 4.82 × 10–3 substitutions/site/year. Myocarditis was more common with cluster A. Clusters C and D presented more cases of acute flaccid paralysis, and cluster D may be more likely to cause HFMD. Multiple recombination events were detected among CVB3 variants, and there were twenty-three recombinant lineages of CVB3 circulating worldwide.

Conclusions

Overall, this study provides full-length genomic sequences of CVB3 isolates with a wide geographic distribution over a long-term time scale in China, which will be helpful for understanding the evolution of this pathogen. Simultaneously, continuous surveillance of CVB3 is indispensable to determine its genetic diversity in China as well as worldwide.
Cross-border mobility responses to COVID-19 in Europe: new evidence from facebook data
Authors: Docquier Fredérić , Golenvaux Nicolas , Nijssen Siegfried , Schaus Pierre , Stips Felix
Published: April 2022

Background

Assessing the impact of government responses to Covid-19 is crucial to contain the pandemic and improve preparedness for future crises. We investigate here the impact of non-pharmaceutical interventions (NPIs) and infection threats on the daily evolution of cross-border movements of people during the Covid-19 pandemic. We use a unique database on Facebook users’ mobility, and rely on regression and machine learning models to identify the role of infection threats and containment policies. Permutation techniques allow us to compare the impact and predictive power of these two categories of variables.

Results

In contrast with studies on within-border mobility, our models point to a stronger importance of containment policies in explaining changes in cross-border traffic as compared with international travel bans and fears of being infected. The latter are proxied by the numbers of Covid-19 cases and deaths at destination. Although the ranking among coercive policies varies across modelling techniques, containment measures in the destination country (such as cancelling of events, restrictions on internal movements and public gatherings), and school closures in the origin country (influencing parental leaves) have the strongest impacts on cross-border movements.

Conclusion

While descriptive in nature, our findings have policy-relevant implications. Cross-border movements of people predominantly consist of labor commuting flows and business travels. These economic and essential flows are marginally influenced by the fear of infection and international travel bans. They are mostly governed by the stringency of internal containment policies and the ability to travel.
Current challenges and opportunities in the care of patients with fibrodysplasia ossificans progressiva (FOP): an international, multi-stakeholder perspective
Authors: Pignolo Robert J. , Bedford-Gay Christopher , Cali Amanda , Davis Michelle , Delai Patricia L. R. , Gonzales Kristi , Hixson Candace , Kent Alastair , Newport Hope , Robert Manuel , Scott Christiaan , Kaplan Frederick S.
Published: April 2022

Background

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare, disabling genetic disorder characterized by congenital malformations of the great toes and progressive heterotopic ossification of soft and connective tissues. Assiduous attention to the unmet needs of this patient community is crucial to prevent potential iatrogenic harm and optimize care for individuals with FOP.

Objective

To gather international expert opinion and real-world experience on the key challenges for individuals with FOP and their families, highlight critical gaps in care, communication, and research, and provide recommendations for improvement.

Methods

An international group of expert clinicians, patients and patient advocates, caregivers and representatives from the international FOP community participated in a virtual, half-day meeting on 22 March 2021 to discuss the key unmet needs of individuals with FOP.

Results

Individuals with FOP often face the frustration of long diagnostic journeys, the burden of self-advocacy and the navigation of novel care pathways. Globally, patients with FOP are also confronted with inequities in access to diagnosis and specialist care, and consequently, unequal access to registries, clinical trials, and essential support from patient associations. Organizations such as the International FOP Association, the International Clinical Council on FOP, and national FOP organizations work to provide information, facilitate access to expert clinical guidance, nurture patient empowerment, fund FOP research and/or foster meaningful collaborations with the research community. The non-profit Tin Soldiers Global FOP Patient Search program aims to identify and provide a pathway to diagnosis and care for individuals with FOP, particularly in underserved communities. Such global initiatives and the increasingly widespread use of telemedicine and digital platforms offer opportunities to improve vital access to care and research.

Conclusions

This multi-stakeholder perspective highlights some of the unmet needs of individuals with FOP and their families. Regional and international organizations play an important role in improving the quality of life of those they reach in the global FOP community. However, globally, fundamental issues remain around raising awareness of FOP among healthcare professionals, identifying individuals with FOP, reducing time to diagnosis, and ensuring access to best practice in care, support, and clinical research. Medical writing support was industry-sponsored.
The involvement of rare disease patient organisations in therapeutic innovation across rare paediatric neurological conditions: a narrative review
Authors: Nguyen Christina Q. , Alba-Concepcion Kristine , Palmer Elizabeth E. , Scully Jackie L. , Millis Nicole , Farrar Michelle A.
Published: April 2022

Background

The patient voice is becoming increasingly prominent across all stages of therapeutic innovation. It pervades research domains from funding and recruitment, to translation, care, and support. Advances in genomic technologies have facilitated novel breakthrough therapies, whose global developments, regulatory approvals, and confined governmental subsidisations have stimulated renewed hope amongst rare disease patient organisations (RDPOs). With intensifying optimism characterising the therapeutic landscape, researcher-advocate partnerships have reached an inflexion point, at which stakeholders may evaluate their achievements and formulate frameworks for future refinement.

Main text

Through this narrative review, we surveyed relevant literature around the roles of RDPOs catering to the rare paediatric neurological disease community. Via available literature, we considered RDPO interactions within seven domains of therapeutic development: research grant funding, industry sponsorship, study recruitment, clinical care and support, patient-reported outcome measures, and research prioritisation. In doing so, we explored practical and ethical challenges, gaps in understanding, and future directions of inquiry. Current literature highlights the increasing significance of ethical and financial challenges to patient advocacy. Biomedical venture philanthropy is gaining momentum amongst RDPOs, whose small grants can incrementally assist laboratories in research, training, and pursuits of more substantial grants. However, RDPO seed funding may encounter long-term sustainability issues and difficulties in selecting appropriate research investments. Further challenges include advocate-industry collaborations, commercial biases, and unresolved controversies regarding orphan drug subsidisation. Beyond their financial interactions, RDPOs serve instrumental roles in project promotion, participant recruitment, biobank creation, and patient registry establishment. They are communication conduits between carers, patients, and other stakeholders, but their contributions may be susceptible to bias and unrealistic expectations.

Conclusion

Further insights into how RDPOs navigate practical and ethical challenges in therapeutic development may enhance cooperative efforts. They may also inform resources, whose distribution among advocates, parents, and clinicians, may assist decision-making processes around rare disease clinical trials and treatments.
Fluid resuscitation with balanced crystalloids versus normal saline in critically ill patients: a systematic review and meta-analysis
Authors: Dong Wei-Hua , Yan Wen-Qing , Song Xin , Zhou Wen-Qiang , Chen Zhi
Published: April 2022

Background

Intravenous fluids are used commonly for almost all intensive care unit (ICU) patients, especially for patients in need of resuscitation. The selection and use of resuscitation fluids may affect the outcomes of patients; however, the optimal resuscitative fluid remains controversial.

Methods

We systematically searched PubMed, Embase, and CENTRAL. Studies comparing balanced crystalloids and normal saline in ICU patients were selected. We used the Cochrane Collaboration tool to assess the risk of bias in studies. The primary outcome was mortality at the longest follow-up. Secondary outcomes included the incidence of acute kidney injury (AKI) and new renal replacement therapy (RRT).

Results

A total of 35,456 patients from eight studies were included. There was no significant difference between balanced crystalloid solutions and saline in mortality (risk ratio [RR]: 0.96; 95% confidence interval [CI]:0.92–1.01). The subgroup analysis with traumatic brain injury (TBI) showed lower mortality in patients receiving normal saline (RR:1.25; 95% CI 1.02–1.54). However, in patients with non-TBI, balanced crystalloid solutions achieved lower mortality than normal saline (RR: 0.94; 95% CI 0.90–0.99). There was no significant difference in moderate to severe AKI (RR: 0.96; 95% CI 0.90–1.01) or new RRT (RR: 0.94; 95% CI 0.84–1.04).

Conclusions

Compared with normal saline, balanced crystalloids may not improve the outcomes of mortality, the incidence of AKI, and the use of RRT for critically ill patients. However, balanced crystalloids reduce the risk of death in patients with non-TBI but increase the risk of death in those with TBI. Large-scale rigorous randomized trials with better designs are needed, especially for specific patient populations.
Planning a method for covariate adjustment in individually randomised trials: a practical guide
Authors: Morris Tim P. , Walker A. Sarah , Williamson Elizabeth J. , White Ian R.
Published: April 2022

Background

It has long been advised to account for baseline covariates in the analysis of confirmatory randomised trials, with the main statistical justifications being that this increases power and, when a randomisation scheme balanced covariates, permits a valid estimate of experimental error. There are various methods available to account for covariates but it is not clear how to choose among them.

Methods

Taking the perspective of writing a statistical analysis plan, we consider how to choose between the three most promising broad approaches: direct adjustment, standardisation and inverse-probability-of-treatment weighting.

Results

The three approaches are similar in being asymptotically efficient, in losing efficiency with mis-specified covariate functions and in handling designed balance. If a marginal estimand is targeted (for example, a risk difference or survival difference), then direct adjustment should be avoided because it involves fitting non-standard models that are subject to convergence issues. Convergence is most likely with IPTW. Robust standard errors used by IPTW are anti-conservative at small sample sizes. All approaches can use similar methods to handle missing covariate data. With missing outcome data, each method has its own way to estimate a treatment effect in the all-randomised population. We illustrate some issues in a reanalysis ofGetTested, a randomised trial designed to assess the effectiveness of an electonic sexually transmitted infection testing and results service.

Conclusions

No single approach is always best: the choice will depend on the trial context. We encourage trialists to consider all three methods more routinely.
The distribution of Dermacentor reticulatus in the Czech Republic re-assessed: citizen science approach to understanding the current distribution of the Babesia canis vector
Authors: Daněk Ondřej , Hrazdilová Kristýna , Kozderková Dominika , Jirků Daria , Modrý David
Published: April 2022

Background

The range of the ornate dog tick Dermacentorreticulatus is rapidly expanding in Europe. This tick species is the vector of canine babesiosis, caused by Babesiacanis, and also plays a role in the transmission of Theileriaequi and Babesiacaballi in equids.

Methods

The geographic range of D.reticulatus in the Czech Republic was re-assessed, and an up-to-date distribution map is presented based on material and data obtained during a nationwide citizen science campaign. Received and flagged individuals of D.reticulatus were also analysed for the presence of B.canis DNA.

Results

In striking contrast to historical records, D.reticulatus was found in all regions of the Czech Republic, with most reports coming from the southeast and northwest of the country. Between February 2018 and June 2021, the project team received 558 photo reports of ticks and 250 packages containing ticks. Of the former, 71.1% were identified as Dermacentor sp. with the remainder identified as Ixodes sp., Haemaphysalis sp., Argas sp. or Hyalomma sp. The majority of specimens in the subset of ticks that were received (N = 610) were D.reticulatus (N = 568, 93.7%), followed by Ixodesricinus and Hyalomma spp. A total of 783 adult D.reticulatus, either received (568) or collected by flagging (215), were tested for the presence of B.canis DNA using species-specific nested PCR targeting part of the 18S rRNA gene; B.canis DNA was demonstrated in 22 samples (2.81%).

Conclusions

The continuous spread of D.reticulatus in the Czech Republic was documented in this study. In addition, DNA of B.canis was also detected in a number of ticks, suggesting the establishment of B.canis in the Czech Republic. These results suggest that veterinarians need to consider the possibility of canine babesiosis even in dogs without a history of travel.

Graphical Abstract
Associations of the baseline level and change in glycosylated hemoglobin A1c with incident hypertension in non-diabetic individuals: a 3-year cohort study
Authors: Liu Lijuan , Zhen Donghu , Fu Songbo , Sun Weiming , Li Hongli , Zhao Nan , Hou Lijie , Tang Xulei
Published: April 2022

Background

Diabetes mellitus increases the risk of developing hypertension. The relationship between glycosylated hemoglobin A1c (HbA1c) level and incident hypertension remains controversial. This study examined the associations of the baseline level and change in the HbA1c level over 3 years with incident hypertension in non-diabetic individuals.

Methods

This community-based cohort study was conducted with 2591 individuals aged 40–75 years without hypertension or diabetes at baseline, who participated in a longitudinal (REACTION) study program. Questionnaires were administered during interviews, and anthropometric and laboratory measurements were performed at baseline (2011) and follow-up (2014–2015). Multivariate logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of incident hypertension.

Results

Over a median follow-up period of 3.08 years (interquartile range 3.00, 3.25), 384 (14.82%) subjects developed hypertension. In the fully adjusted linear regression models, change in HbA1c remained significantly associated with changes in systolic blood pressure and diastolic blood pressure [β-coefficient (95% CI), 4.421 (2.811–6.032), 1.681 (0.695–2.667)]. Logistic regression analyses showed that baseline HbA1c level was positively associated with incident hypertension in the unadjusted model; however, the association was no longer significant after further adjustment. Change in HbA1c was positively associated with the development of hypertension, both as a categorical variable stratified by tertiles [adjusted OR (95% CI) in the highest tertile was 1.690 (1.240–2.303) versus the lowest tertile)] and as a continuous variable [adjusted OR (95% CI), 1.242 (1.106–1.394)], independent of age, sex, body mass index, systolic blood pressure, fasting plasma glucose level, lipid profile, the HbA1c level at baseline and 3-year change in body mass index.

Conclusions

A higher baseline HbA1c level was not an independent risk factor for incident hypertension, whereas the change in HbA1c was independently associated with a greater longitudinal increase in blood pressure and an increased risk of incident hypertension in non-diabetic individuals.
Oropharyngeal symptoms without systemic reactions as a risk factor for food allergen intolerance: a longitudinal pediatric study
Authors: Hamada Masaaki , Saeki Keigo , Sakurai Yoshihiko
Published: April 2022

Background

The determinants of tolerance to food allergens are not fully understood. We aimed to elucidate the longitudinal association between oropharyngeal symptoms without systemic reactions (OSw/oS) and tolerance to food allergens.

Methods

We included all patients diagnosed with single food allergy to egg (n = 121), milk (n = 55), and wheat (n = 41) using the oral food challenge test (OFC) from 2014 to 2017. These patients received oral immunotherapy at home and/or in the hospital after diagnosis by OFC. We compared the incidence proportion of tolerance within 2 years by OSw/oS and other variables for 217 patients with food allergy. We defined OSw/oS as isolated symptoms of oropharyngeal discomfort that occurred after ingestion of a safe dose of the allergenic food determined by the OFC in the first 6 months.

Results

Of the 217 patients (median age 37.5 months, male 64.5%), 53 developed OSw/oS (24.4%), and 151 (egg, 85 milk, 36 and wheat, 30) attained tolerance in 2 years. Patients without OSw/oS showed a significantly higher incidence of tolerance than those with the symptoms (crude hazard ratio [HR] 5.62, 95% confidence interval [CI] 3.58–8.82, p < 0.001). The association was consistently significant in the multivariable model (adjusted HR 9.50, 95% CI 5.25–17.20, p < 0.001) independent of other risk factors for intolerance, such as concomitant bronchial asthma (adjusted HR 3.33), history of anaphylaxis (adjusted HR 2.16), milk allergy (adjusted HR 2.02), and allergic symptoms with low dose OFC (adjusted HR 1.52).

Conclusion

Our results suggest that OSw/oS may be a risk factor for intolerance to food allergens. To reveal a high risk of food allergen intolerance may help patients and their families as well as healthcare professionals prepare for the challenge of continuing oral immunotherapy.
Is the relative thickness of ammonoid septa influenced by ocean acidification, phylogenetic relationships and palaeogeographic position?
Authors: Weber Céline , Hautmann Michael , Tajika Amane , Klug Christian
Published: April 2022

The impact of increasing atmospheric CO2and the resulting decreasing pH of seawater are in the focus of current environmental research. These factors cause problems for marine calcifiers such as reduced calcification rates and the dissolution of calcareous skeletons. While the impact on recent organisms is well established, little is known about long-term evolutionary consequences. Here, we assessed whether ammonoids reacted to environmental change by changing septal thickness. We measured the septal thickness of ammonoid phragmocones through ontogeny in order to test the hypothesis that atmosphericpCO2, seawater pH and other factors affected aragonite biomineralisation in ammonoids. Particularly, we studied septal thickness of ammonoids before and after the ocean acidification event in the latest Triassic until the Early Cretaceous. Early Jurassic ammonoid lineages had thinner septa relative to diameter than their Late Triassic relatives, which we tentatively interpret as consequence of a positive selection for reduced shell material as an evolutionary response to this ocean acidification event. This response was preserved within several lineages among the Early Jurassic descendants of these ammonoids. By contrast, we did not find a significant correlation between septal thickness and long-term atmosphericpCO2or seawater pH, but we discovered a correlation with palaeolatitude.
Larger 18F-fluoroboronotyrosine (FBY) active volume beyond MRI contrast enhancement in diffuse gliomas than in circumscribed brain tumors
Authors: Kong Ziren , Li Zhu , Chen Junyi , Ma Wenbin , Wang Yu , Yang Zhi , Liu Zhibo
Published: April 2022

Background

To investigate the relationship between 18F-fluoroboronotyrosine (FBY) positron emission tomography (PET)- and magnetic resonance imaging (MRI)-defined tumor volumes in contrast-enhanced diffuse gliomas and circumscribed brain tumors.

Methods

A total of 16 diffuse gliomas and 7 circumscribed brain tumors were included, and two types of three-dimensional regions of interest (ROIs), namely, MRI-based ROI (ROIMRI) and FBY-based ROI (ROIFBY), were semiautomatically defined. The overlap volume and DICE score were calculated to reveal the spatial relationship between the ROIMRI and ROIFBY.

Results

The ROIMRI was smaller than the ROIFBY and was mostly contained by the ROIFBY with an overlap volume of 0.995 ± 0.006 in the whole population. A significant difference in the DICE score was observed between circumscribed tumors and diffuse tumors (0.886 ± 0.026 vs. 0.684 ± 0.165, p = 0.004), and for the regions that have increased FBY metabolism but not MRI contrast enhancement, diffuse tumors and circumscribed tumors showed similar SUVmean values (0.630 ± 0.19 vs. 0.671 ± 0.18, p = 0.625).

Conclusion

FBY uptake beyond contrast enhancement is more significant in diffuse tumors than in circumscribed tumors, which may aid the delineation of active tumor areas and facilitate boron neutron capture therapy.