bluuebunny/crossref_metadata_2025 huggingface dataset:
The association between prescription drugs and colorectal cancer prognosis: a nationwide cohort study using a medication-wide association study
Authors: Woo Hyeong-Taek , Jeong Seung-Yong , Shin Aesun
Published: July 2023

Background

With the availability of health insurance claim data, pharmacovigilance for various drugs has been suggested; however, it is necessary to establish an appropriate analysis method. To detect unintended drug effects and to generate new hypotheses, we conducted a hypothesis-free study to systematically examine the relationship between all prescription nonanticancer drugs and the mortality of colorectal cancer patients.

Methods

We used the Korean National Health Insurance Service-National Sample Cohort database. A total of 2,618 colorectal cancer patients diagnosed between 2004 and 2015 were divided into drug discovery and drug validation sets (1:1) through random sampling. Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification system: 76 drugs classified as ATC level 2 and 332 drugs classified as ATC level 4 were included in the analysis. We used a Cox proportional hazard model adjusted for sex, age, colorectal cancer treatment, and comorbidities. The relationship between all prescription nonanticancer drugs and the mortality of colorectal cancer patients was analyzed, controlling for multiple comparisons with the false discovery rate.

Results

We found that one ATC level-2 drug (drugs that act on the nervous system, including parasympathomimetics, addictive disorder drugs, and antivertigo drugs) showed a protective effect related to colorectal cancer prognosis. At the ATC level 4 classification, 4 drugs were significant: two had a protective effect (anticholinesterases and opioid anesthetics), and the other two had a detrimental effect (magnesium compounds and Pregnen [4] derivatives).

Conclusions

In this hypothesis-free study, we identified four drugs linked to colorectal cancer prognosis. The MWAS method can be useful in real-world data analysis.
Effect of reduced versus usual lipid emulsion dosing on bilirubin neurotoxicity and neurodevelopmental impairment in extremely preterm infants: study protocol for a randomized controlled trial
Authors: Holzapfel Lindsay F. , Arnold Cody , Tyson Jon E. , Shapiro Steven M. , Reynolds Eric W. , Pedroza Claudia , Stephens Emily K. , Kleinfeld Alan , Huber Andrew H. , Rysavy Matthew A. , del Mar Romero Lopez Maria , Khan Amir M.
Published: July 2023

Background

Bilirubin neurotoxicity (BN) occurs in premature infants at lower total serum bilirubin levels than term infants and causes neurodevelopmental impairment. Usual dose lipid infusions in preterm infants may increase free fatty acids sufficiently to cause bilirubin displacement from albumin, increasing passage of unbound bilirubin (UB) into the brain leading to BN and neurodevelopmental impairment not reliably identifiable in infancy. These risks may be influenced by whether cycled or continuous phototherapy is used to control bilirubin levels.

Objective

To assess differences in wave V latency measured by brainstem auditory evoked responses (BAER) at 34–36 weeks gestational age in infants born ≤ 750 g or < 27 weeks’ gestational age randomized to receive usual or reduced dose lipid emulsion (half of the usual dose) irrespective of whether cycled or continuous phototherapy is administered.

Methods

Pilot factorial randomized controlled trial (RCT) of lipid dosing (usual and reduced) with treatment groups balanced between cycled or continuous phototherapy assignment. Eligible infants are born at ≤ 750 g or < 27 weeks’ gestational age enrolled in the NICHD Neonatal Research Network RCT of cycled or continuous phototherapy. Infants will randomize 1:1 to reduced or usual dose lipid assignment during the first 2 weeks after birth and stratified by phototherapy assignment. Free fatty acids and UB will be measured daily using a novel probe. BAER testing will be performed at 34–36 weeks postmenstrual age or prior to discharge. Blinded neurodevelopmental assessments will be performed at 22–26 months. Intention-to-treat analyses will be performed with generalized linear mixed models with lipid dose and phototherapy assignments as random effects covariates, and assessment for interactions. Bayesian analyses will be performed as a secondary analysis.

Discussion

Pragmatic trials are needed to evaluate whether lipid emulsion dosing modifies the effect of phototherapy on BN. This factorial design presents a unique opportunity to evaluate both therapies and their interaction. This study aims to address basic controversial questions about the relationships between lipid administration, free fatty acids, UB, and BN. Findings suggesting a reduced lipid dose can diminish the risk of BN would support the need for a large multicenter RCT of reduced versus usual lipid dosing.

Trial registration

Clinical Trials.gov, NCT04584983, Registered 14 October 2020, https://clinicaltrials.gov/ct2/show/NCT04584983

Protocol version: Version 3.2 (10/5/2022).
Network structure of mobile phone addiction and anxiety symptoms among rural Chinese adolescents
Authors: Wang Jingjing , Luo Yunjiao , Yan Na , Wang Yuhao , Shiferaw Blen Dereje , Tang Jie , Pei Yifei , Chen Qian , Zhu Yiyang , Wang Wei
Published: July 2023

Background

The incidence of mobile phone addiction among adolescents in rural areas of China is increasing year by year, and has already exceeded that of some cities. And phone addiction increases the risk of anxiety and poor sleep. Therefore, this study used network analysis to investigate the relationship between mobile phone addiction and anxiety symptoms, and the predictability to sleep quality.

Methods

From September 2021 to March 2022, a total of 1920 rural adolescents in Xuzhou, China were included. The survey included information on phone addiction, anxiety symptoms, and sleep quality. Network analysis was used to estimate the network structure of adolescents’ mobile phone addiction and anxiety symptoms. LOWESS curve and linear regression were used to test the predictive ability of node-centrality on sleep quality.

Results

In the network of mobile phone addiction-anxiety symptoms, the most influential symptoms were Failure to cut down the time, Anxiety if not used for some time, and Alleviate loneliness. Irritability was the most prominent bridging symptom. Gender difference had no effect on network structure. Nodes in the network are not predictive of sleep quality.

Conclusion

Failure to cut down the time is the most important symptom, suggesting that measures should be taken to reduce the amount of time spent on mobile phones. For example, increase outdoor exercise, increase the real company of friends and family, in order to reduce the occurrence of mobile phone addiction and anxiety.
Prevalence of depression and association with all-cause and cardiovascular mortality among individuals with type 2 diabetes: a cohort study based on NHANES 2005–2018 data
Authors: Feng Zhen , Tong Wai Kei , Zhang Xinyue , Tang Zhijia
Published: July 2023

Background

Individuals with diabetes have increased risk of depression, but there are limited nationally representative studies on this topic. We aimed to investigate the prevalence and predictors of depression, as well as its impact on all-cause and cardiovascular mortality in adults with type 2 diabetes (T2DM) using a prospective cohort study and a representative sample of the U.S. population.

Methods

We analyzed National Health and Nutrition Examination Survey (NHANES) data from 2005 to 2018 and linked it with the most recent publicly available National Death Index (NDI) data. Individuals aged 20 years or old who had depression measurements were included. Depression was defined as a Patient Health Questionnaire (PHQ-9) score ≥ 10, and categorized into moderate (10–14 points) and moderately severe to severe (≥ 15 points). Cox proportional hazard models were used to estimate the association between depression and mortality.

Results

Among 5695 participants with T2DM, 11.6% had depression. Depression was associated with female gender, younger age, overweight, lower education, being unmarried, smoking, and a history of coronary heart disease and stroke. During a mean follow-up period of 78.2 months, 1161 all-cause deaths occurred. Total depression and moderately severe to severe depression significantly increased all-cause mortality (adjusted hazard ratio [aHR] 1.36, 95% CI [1.09–1.70]; 1.67 [1.19–2.34]) and non-cardiovascular mortality (aHR 1.36, 95% CI [1.04–1.78]; 1.78, 95% CI [1.20–2.64]), but not cardiovascular mortality. Subgroup analysis showed a significant association between total depression and all-cause mortality in males (aHR 1.46, 95% CI [1.08–1.98]) and those aged 60 years or older (aHR 1.35, 95% CI [1.02–1.78]). Any severity of depression was not significantly associated with cardiovascular mortality in age- or gender- stratified subgroups.

Conclusions

In a nationally representative sample of U.S. adults with T2DM, approximately 10% experienced depression. Depression did not significantly associate with cardiovascular mortality. However, comorbid depression in T2DM patients increased the risk of all-cause and non-cardiovascular mortality. The impact of depression on mortality varied across subgroups. Therefore, healthcare providers should consider incorporating depression screening and management into routine care, especially for subgroups with specific risk factors, due to the increased risk of all-cause mortality in T2DM patients with depression.
College students’ influence on COVID-19 vaccination uptake among seniors in China: a protocol of combined cross-sectional and experimental study
Authors: Bian Junye , Guo Zhihui , Zhang Weijie , Li Xinyi , Sun Caijun , Xu Xuelian , Zou Huachun
Published: July 2023

Background

College students generally have good knowledge about COVID-19 and may facilitate COVID-19 vaccination in family. The purpose of this study is to understand college students’ willingness to persuade their grandparents to initiate COVID-19 vaccination and the effect of their persuasion.

Methods

A combined cross-sectional and experimental study will be conducted online. In the cross-sectional study (Phase I), eligible participants are college students who are aged ≥ 16 years and have at least one living grandparent aged ≥ 60 years who has/have not completed the COVID-19 vaccination. Participants self-complete Questionnaire A to collect information on the socio-demographics of themselves and their grandparents, their knowledge about older adults’ COVID-19 vaccination, as well as Health Belief Model (HBM) and Theory of Planned Behavior (TPB) predictor variables. The primary outcome at Phase I is college students’ willingness to persuade grandparents to receive COVID-19 vaccines. Those who are willing to persuade grandparents and participate in a follow-up survey will be invited to participate in a randomized controlled trial (Phase II). At Phase II, eligible participants are those who have at least one living grandparent aged ≥ 60 years who completed the COVID-19 initial vaccination series but has/have not received a booster dose. At the baseline, participants self-complete Questionnaire B to collect information on individual grandparents’ COVID-19 vaccination status, attitude towards and intention to COVID-19 booster dose. Participants will then be randomly allocated 1:1 to either intervention arm (one-week smartphone-based health education on older adults’ COVID-19 vaccination plus two weeks’ waiting period) or control arm (three weeks’ waiting period). At the end of week three, participants in both arms self-complete Questionnaire C to collect information on their grandparents’ COVID-19 vaccination status. The primary outcome at Phase II is the uptake rate of COVID-19 booster dose among grandparents. Secondary outcomes include grandparents’ attitude and intention to get a COVID-19 booster dose.

Discussion

No previous study had measured the effect of college students’ persuasion on COVID-19 vaccination uptake in older adults. Findings from this study will provide evidence for innovative and potentially feasible interventions that further promote COVID-19 vaccination in older adults.

Trial registration

Chinese Clinical Trial Registry: ChiCTR2200063240. Registered 2 September 2022.
Barriers to tuberculosis treatment adherence in high-burden tuberculosis settings in Ashanti region, Ghana: a qualitative study from patient’s perspective
Authors: Appiah Maxwell Afranie , Arthur Joshua Appiah , Gborgblorvor Delphine , Asampong Emmanuel , Kye-Duodu Gideon , Kamau Edward Mberu , Dako-Gyeke Phyllis
Published: July 2023

Background

Despite having an effective community-based Directly Observed Therapy Short-course (DOTS) strategy for tuberculosis (TB) care, treatment adherence has been a major challenge in many developing countries including Ghana. Poor adherence results in discontinuity of treatment and leads to adverse treatment outcomes which pose an increased risk of drug resistance. This study explored barriers to TB treatment adherence and recommended potential patient-centered strategies to improve treatment adherence in two high-burden TB settings in the Ashanti region of Ghana.

Methods

The study was conducted among TB patients who defaulted on treatment in the Obuasi Municipal and Obuasi East districts in the Ashanti region. A qualitative phenomenology approach was used to explore the barriers to TB treatment adherence. Purposive sampling was adopted to select study participants with different sociodemographic backgrounds and experiences with TB care. Eligible participants were selected by reviewing the medical records of patients from health facility TB registers (2019–2021). Sixty-one (61) TB patients met the eligibility criteria and were contacted via phone call. Out of the 61 patients, 20 were successfully reached and consented to participate. In-depth interviews were conducted with participants using a semi-structured interview guide. All interviews were audio recorded and transcribed verbatim. The transcripts were imported into Atlas.ti version 8.4 software and analyzed using thematic content analysis.

Results

Food insecurity, cost of transportation to the treatment center, lack of family support, income insecurity, long distance to the treatment center, insufficient knowledge about TB, side effect of drugs, improvement in health after the intensive phase of the treatment regimen, and difficulty in accessing public transportation were the main co-occurring barriers to treatment adherence among the TB patients.

Conclusion

The main barriers to TB treatment adherence identified in this study reveal major implementation gaps in the TB programme including gaps related to social support, food security, income security, knowledge, and proximity to treatment centers. Hence, to improve treatment adherence there is a need for the government and the National Tuberculosis Programme (NTP) to collaborate with different sectors to provide comprehensive health education, social and financial support as well as food aid to TB patients.
Student knowledge gains among first-time and repeat attendees of school-based asthma education program
Authors: Volerman Anna , Kappel Nicole , Tayal Ashu , Rosenwinkel Mary , Salem Erica , Vipond Lesli
Published: July 2023

Background

Because children spend much of their time in schools, schools can play an important role in asthma education for the one in 12 affected children in the United States. School-based asthma education programs are commonly repeated annually, however few studies have evaluated the impact of repeated participation in asthma education in school-based programs.

Methods

This observational study evaluated the impact of Fight Asthma Now© (FAN), a school-based asthma education program for children in Illinois schools. Participants completed a survey at the start and end of the program, including demographics, prior asthma education, and 11 asthma knowledge questions (maximum knowledge score = 11).

Results

Among 4,951 youth participating in the school-based asthma education program, mean age was 10.75 years. Approximately half were male and Black. Over half reported no prior asthma education (54.6%). At baseline, repeat attendees had significantly higher knowledge versus first-time attendees (mean: 7.45 versus 5.92; p < 0.001). After the program, both first-time and repeat attendees had significant knowledge improvements (first-time: mean = 5.92◊9.32; p < 0.001; repeat: mean = 7.45◊9.62; p < 0.001).

Conclusions

School-based asthma education is effective for increasing asthma knowledge. Notably, repeated asthma education in school leads to incremental benefits for knowledge. Future studies are needed to understand the effects of repeated asthma education on morbidity.
Diagnostic and prognostic value of echocardiography in pulmonary hypertension: an umbrella review of systematic reviews and meta-analyses
Authors: Dong Tian-Xin , Zhu Qing , Wang Shi-Tong , Wang Yong-Huai , Li Guang-Yuan , Kong Fan-Xin , Ma Chun-Yan
Published: July 2023

Background

The role of echocardiography in the diagnostic and prognostic assessment of pulmonary hypertension (PH) has been widely studied recently. However, these findings have not undergone normative evaluation and may provide confusing evidence for clinicians. To evaluate and summarize existing evidence, we performed an umbrella review.

Methods

Systematic reviews and meta-analyses were searched in PubMed, Embase, Web of Science, and Cochrane Library from inception to September 4, 2022. The methodological quality of the included studies was assessed using Assessment of Multiple Systematic Reviews (AMSTAR), and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the quality of evidence.

Results

Thirteen meta-analyses (nine diagnostic and four prognostic studies) were included after searching four databases. The methodological quality of the included studies was rated as high (62%) or moderate (38%) by AMSTAR. The thirteen included meta-analyses involved a total of 28 outcome measures. The quality of evidence for these outcomes were high (7%), moderate (29%), low (39%), and very low (25%) using GRADE methodology. In the detection of PH, the sensitivity of systolic pulmonary arterial pressure is 0.85–0.88, and the sensitivity and specificity of right ventricular outflow tract acceleration time are 0.84. Pericardial effusion, right atrial area, and tricuspid annulus systolic displacement provide prognostic value in patients with pulmonary arterial hypertension with hazard ratios between 1.45 and 1.70. Meanwhile, right ventricular longitudinal strain has independent prognostic value in patients with PH, with a hazard ratio of 2.96–3.67.

Conclusion

The umbrella review recommends echocardiography for PH detection and prognosis. Systolic pulmonary arterial pressure and right ventricular outflow tract acceleration time can be utilized for detection, while several factors including pericardial effusion, right atrial area, tricuspid annular systolic displacement, and right ventricular longitudinal strain have demonstrated prognostic significance.

Trial registration

PROSPERO (CRD42022356091), https://www.crd.york.ac.uk/prospero/.
Distal radius fractures in children aged 5–12 years: a Swedish nationwide register-based study of 25 777 patients
Authors: Bergkvist Anna , Lundqvist Eva , Pantzar-Castilla Evelina
Published: July 2023

Background

Distal radius fracture (DRF) is the most common type of fracture in children. There is no clear consensus on primary treatment for complete DRFs. Kirschner wire (K-wire) fixation has been recommended, to avoid the risk of redislocation. However, recent studies have indicated that casting can be sufficient, at least for children with two or more years left to grow. There is no recent study regarding pediatric DRFs and the extent of K-wire fixations in the Swedish population. The purpose of this study was to investigate epidemiology and treatment of pediatric DRFs registered in the Swedish Fracture Register (SFR).

Methods

In this retrospective study, based on data from SFR for children aged 5–12 years with DRF between January 2015 and October 2022, we investigated epidemiology and choice of treatment. Sex, age, type of DRF, treatment, cause and mechanism of injury, were analyzed.

Results

In total, 25,777 patients were included, 7,173 (27%) with complete fractures. Number and peak age of girls vs. boys with fractures were 11,742 (46%), 10 years, and 14,035 (54%), 12 years, respectively. Odds ratio (OR) for a K-wire fixation in girls vs. boys was 0.81 (95% confidence interval (CI) 0.74–0.89, p < .001). With age 5 -7 years as reference, OR for age group 8–10 years was 0.88 (95% CI 0.80–0.98 p = .019) and OR for age group 11–12 years was 0.81 (95% CI 0.73–0.91 p =  < .001.

Conclusion

Casting only was the preferred treatment for all fractures (76%). Boys acquired DRFs more often than girls, with a peak age of 12 years. Younger children and boys with a complete fracture were more likely than older children and girls to receive a K-wire. Further research regarding indications for K-wiring of DRFs in the pediatric population is needed.
Effect of post-surgical flap position on soft tissue regrowth and keratinized tissue increase following fibre retention osseous resective surgery: a 6-month randomized study with multilevel analysis
Authors: Piccoli Gian Marco , Romano Federica , Giraudi Marta , La Bruna Nicolò , Citterio Filippo , Mariani Giulia Maria , Baima Giacomo , Aimetti Mario
Published: July 2023

Background

The aim of this randomized split-mouth study was to assess the influence of primary flap position on the amount of coronal soft tissue regrowth and keratinized tissue (KT) 6 months after osseous resective surgery with fiber retention technique (FibReORS).

Materials and methods

Two contralateral posterior sextants in 16 patients were treated with FibReORS and randomly assigned to flap positioning either 2 mm below the bone crest (apical group) or at the level of bone crest (crestal group). Clinical parameters were recorded at 1, 3 and 6 months and patient-related outcomes during the first two post-operative weeks.

Results

Healing period was uneventful. Patient’s discomfort was similar in both groups. The overall soft tissue rebound was higher in the apical than in the crestal group (2.0 ± 1.3 mm versus 1.3 ± 0.7 mm), but the difference was statistically significant only interproximally (2.2 ± 1.3 mm versus 1.6 ± 0.8 mm). Multilevel analyses showed higher soft tissue rebound in sites with normal compared to thin phenotype (1.5 mm, p < 0.0001) and treated with flap positioned 2 mm apically to the bone crest (0.7 mm, p < 0.001). An additional 0.5 mm KT increase was observed at interdental sites in the apical group.

Conclusions

Apical flap positioning increases soft tissue rebound and KT width, mainly at the interdental sites, with reduced patient discomfort.

Trial registration

The trial was registered at ClinicalTrials.gov (ID: NCT05140681, Registration date: 1/12/2021, retrospectively registered).
The impact of the COVID-19 pandemic on contraceptive methods, abortion, and unintended pregnancy: a cross-sectional study
Authors: Rezaei Fatemeh , Amiri-Farahani Leila , Haghani Shima , Pezaro Sally , Behmanesh Fereshteh
Published: July 2023

Background and Aim

By creating an international emergency, the COVID-19 pandemic may have led to compromised reproductive health care, including family planning services, and thus increased unintended pregnancies and unsafe abortions. This study was conducted to compare methods of contraception, abortion, and unintended pregnancies in those served by the health centers of Babol city in Iran, both before and during the COVID-19 pandemic.

Methods

A cross-sectional study was conducted including 425 participants registered to the health centers of Babol city, Mazandaran province, Iran. Using a multi-stage method, 6 urban health centers and 10 rural centers were selected for inclusion. Proportional allocation method was used for sampling those who met the inclusion criteria. A questionnaire was used to collect data in relation to individual characteristics and reproductive behaviors via 6 questions focused upon methods and preparation of contraception, number and type of abortions, and number and causes of unintended pregnancy from July to November 2021. The data were analyzed using SPSS software version 26. Significance level was considered to be p < 0.05 in all tests.

Results

Most participants aged between 20 and 29 years old had a diploma level of education, were housewives and lived in the city. Prior to the pandemic, 32.0% used modern contraceptive methods and 31.6% used these during the pandemic. No change in the combination of contraceptive methods used was observed between these two periods. Approximately two-thirds used the withdrawal method in both periods. The majority of participants in both periods purchased their contraceptives from a pharmacy. Unintended pregnancy increased from 20.4% prior to the pandemic to 25.4% during the pandemic. Abortions increased from 19.1% prior to the pandemic to 20.9% during the pandemic, although these findings were not found to be statistically significant. Contraceptive methods had a statistically significant relationship with age, education, spouse’s education, spouse’s occupation, and place of residence. The number of unintended pregnancies had a significant relationship with age, the educational level of both participants and their spouses and socio-economic status, and the number of abortions had a statistically significant relationship with the age and education level of the spouse (p > 0.05).

Conclusion

Despite there being no change in contraceptive methods compared to the pre-pandemic period, an increase in the number of unintended pregnancies, abortions and illegal abortions was observed. This may be indicative of an unmet need for family planning services during the COVID-19 pandemic.
Integrated personal health record (PHR) security: requirements and mechanisms
Authors: Hosseini Azamossadat , Emami Hassan , Sadat Yousef , Paydar Somayeh
Published: July 2023

Background

Personal Health Records (PHRs) are designed to fulfill the goals of electronic health (eHealth) and empower the individual in the process of self-care. Integrated PHR can improve the quality of care, strengthen the patient-healthcare provider relationship, and reduce healthcare costs. Still, the process of PHR acceptance and use has been slow and mainly hindered by people’s concerns about the security of their personal health information. Thus, the present study aimed to identify the Integrated PHR security requirements and mechanisms.

Methods

In this applied study, PHR security requirements were identified with a literature review of (library sources, research articles, scientific documents, and reliable websites). The identified requirements were classified, and a questionnaire was developed accordingly. Thirty experts completed the questionnaire in a two-round Delphi technique, and the data were analyzed by descriptive statistics.

Results

The PHR security requirements were identified and classified into seven dimensions confidentiality, availability, integrity, authentication, authorization, non-repudiation, and right of access, each dimension having certain mechanisms. On average, the experts reached an agreement about the mechanisms of confidentiality (94.67%), availability (96.67%), integrity (93.33%), authentication (100%), authorization (97.78%), non-repudiation (100%), and right of access (90%).

Conclusion

Integrated PHR security is a requirement for its acceptance and use. To design a useful and reliable integrated PHR, system designers, health policymakers, and healthcare organizations must identify and apply security requirements to guarantee the privacy and confidentiality of data.
Costs of reproduction are present but latent in eusocial bumblebee queens
Authors: Collins David H. , Prince David C. , Donelan Jenny L. , Chapman Tracey , Bourke Andrew F. G.
Published: July 2023

Background

The standard evolutionary theory of ageing proposes that ageing occurs because of a trade-off between reproduction and longevity. Eusocial insect queens exhibit positive fecundity-longevity associations and so have been suggested to be counter-examples through not expressing costs of reproduction and through remodelling conserved genetic and endocrine networks regulating ageing and reproduction. If so, eusocial evolution from solitary ancestors with negative fecundity-longevity associations must have involved a stage at which costs of reproduction were suppressed and fecundity and longevity became positively associated. Using the bumblebee (Bombus terrestris), we experimentally tested whether queens in annual eusocial insects at an intermediate level of eusocial complexity experience costs of reproduction, and, using mRNA-seq, the extent to which they exhibit a remodelling of relevant genetic and endocrine networks. Specifically, we tested whether costs of reproduction are present but latent, or whether a remodelling of relevant genetic and endocrine networks has already occurred allowing queens to reproduce without costs.

Results

We experimentally increased queens’ costs of reproduction by removing their eggs, which caused queens to increase their egg-laying rate. Treatment queens had significantly reduced longevity relative to control queens whose egg-laying rate was not increased. Reduced longevity in treatment queens was not caused by increased worker-to-queen aggression or by increased overall activity in queens. In addition, treatment and control queens differed in age-related gene expression based on mRNA-seq in both their overall expression profiles and the expression of ageing-related genes. Remarkably, these differences appeared to occur principally with respect to relative age, not chronological age.

Conclusions

This study represents the first simultaneously phenotypic and transcriptomic experimental test for a longevity cost of reproduction in eusocial insect queens. The results support the occurrence of costs of reproduction in annual eusocial insects of intermediate social complexity and suggest that reproductive costs are present but latent in queens of such species, i.e. that these queens exhibit condition-dependent positive fecundity-longevity associations. They also raise the possibility that a partial remodelling of genetic and endocrine networks underpinning ageing may have occurred in intermediately eusocial species such that, in unmanipulated conditions, age-related gene expression depends more on chronological than relative age.
The novel compound heterozygous variants identified in a Chinese family with glucose phosphate isomerase deficiency and pathogenicity analysis
Authors: Wang Yang , Liu Tao , Liu Jiaqi , Xiang Yan , Huang Lan , Li Jiacheng , An Xizhou , Cui Shengyan , Feng Zishuai , Yu Jie
Published: July 2023

Background and Aims:

Glucose phosphate isomerase (GPI) deficiency is an extremely rare autosomal recessive disorder caused by mutations in the GPI gene. In this research, the proband displaying typical manifestations of haemolytic anaemia and his family members were recruited to analyse the pathogenicity of the detected variants.

Methods:

Peripheral blood samples were collected from the family members and genomic DNA was extracted and targeted for capture and sequencing. The effect of the candidate pathogenic variants on splicing was further investigated using the minigene splicing system. The computer simulation was also used for further analysis of the detected data.

Results:

The proband carried the compound heterozygous variants c.633 + 3 A > G and c.295G > T in the GPI gene, which have never been reported before. In the genealogy, co-segregation of the mutant genotype with the phenotype was established. The minigene study showed that intronic mutations resulted in abnormal pre-mRNA splicing. Specifically, the two aberrant transcripts: r.546_633del and r.633 + 1_633 + 2insGT were transcribed by the minigene plasmid expressing the c.633 + 3 A > G variant. The missense mutation c.295G > T in exon 3 resulted in altering glycine at codon 87 to cysteine which was predicted to be pathogenic in an in silico analysis. Deeper analyses revealed that the Gly87Cys missense mutation led to steric hindrance. Compared to the wild-type, the mutation G87C led to a significant increase in intermolecular forces.

Conclusion:

Overall, the novel compound heterozygous variants in the GPI gene contributed to the etiology of the disease. Genetic testing can assist in the diagnosis. The novel gene variants identified in the present study has further expanded the mutational spectrum of GPI deficiency, which can better guide family counselling.
Disability and disease-related damage in Thai children and adolescents with juvenile idiopathic arthritis
Authors: Tangcheewinsirikul Sirikarn , Sukharomana Maynart , Charuvanij Sirirat
Published: July 2023

Background

Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer from disability and disease-related damage. This study aimed to investigate the prevalence of disability and damage, and identify the factors associated with articular and extra-articular damage in children and adolescents with JIA in a resource-restricted setting in Thailand.

Methods

This cross-sectional study enrolled JIA patients during June 2019-June 2021. Disability was assessed using the Child Health Assessment Questionnaire (CHAQ) and Steinbrocker classification criteria. Damage was evaluated using the Juvenile Arthritis Damage Index (JADI) and the modified-JADI (mJADI) tools.

Results

There were 101 patients (50.5% female) with median age of 11.8 years. Median disease duration was 32.7 months. Enthesitis-related arthritis (ERA) was the most common subtype (33.7%), followed by systemic JIA (25.7%). Thirty-three (32.7%) patients had delayed diagnosis ≥ 6 months. Moderate to severe disability was found in 20 (19.8%) patients. Patients with Steinbrocker functional classification > class I were seen in 17.9%. Thirty-seven (36.6%) patients had articular damage. Extra-articular complications were observed in 24.8%. Growth failure and striae were the most common complications in 7.8%. Leg-length discrepancy was documented in 5.0%. Ocular damage was found in 1 patient with ERA. Multivariable logistic regression analysis revealed Steinbrocker functional classification > class I (aOR: 18.1, 95% CI: 3.9–84.6; p < 0.001), delayed diagnosis ≥ 6 months (aOR: 8.5, 95%CI: 2.7–27.0; p < 0.001), and ERA (aOR: 5.7, 95%CI: 1.8–18.3; p = 0.004) as independent predictors of articular damage. Systemic corticosteroids use was the independent predictor of extra-articular damage (aOR: 3.8, 95%CI: 1.3–11.1; p = 0.013).

Conclusions

Disability and disease-related damage was identified in one-fifth and one-third of JIA patients. Early detection and treatment are essential for preventing permanent damage.
Dexmedetomidine ameliorates diabetic cardiomyopathy by inhibiting ferroptosis through the Nrf2/GPX4 pathway
Authors: Li Fan , Hu Zhenfei , Huang Yidan , Zhan Haiting
Published: July 2023

Objective

Dexmedetomidine (DEX) has been shown to have anti-apoptotic effects in diabetes mellitus, but its role in mitigating diabetic cardiomyopathy (DCM) through ferroptosis regulation is unclear.

Methods

An in vitro DCM model was established using H9C2 cells induced with high glucose (HG) and treated with DEX at varying doses and a nuclear factor erythroid 2-realated factor 2 (Nrf2) specific inhibitor ML385. Cell viability was evaluated using the MTT method after treatment with DEX or mannitol (MAN), and the dosage of DEX used in subsequent experimentation was determined. The effects of HG-induced high osmotic pressure were assessed using MAN as a control. Cell apoptosis was evaluated using flow cytometry. Protein levels of Bcl2, Bax, nuclear Nrf2, and glutathione peroxidase 4 (GPX4) were measured using Western blot. Superoxide dismutase (SOD) activity, malondialdehyde (MDA) levels, Fe2+ concentration and reactive oxygen species (ROS) levels were measured using corresponding kits and dichlorodihydrofluorescein diacetate, respectively.

Results

Treatment with DEX or MAN had no effect on H9C2 cell viability. HG induction reduced H9C2 cell viability, increased cell apoptosis, upregulated levels of Bax, Fe2+, MDA, and ROS, and downregulated Bcl2 protein levels, SOD activity, and protein levels of nuclear Nrf2 and GPX4. DEX inhibited HG-induced H9C2 cell apoptosis, promoted Nrf2 nuclear translocation, and activated the Nrf2/GPX4 pathway. Inhibition of Nrf2 partially reversed the protective effects of DEX against HG-evoked H9C2 cell injury.

Conclusion

Our findings demonstrate that DEX attenuates HG-induced cardiomyocyte injury by inhibiting ferroptosis through the Nrf2/GPX4 pathway, providing potential therapeutic targets for DCM treatment.
Dual growth factor-modified microspheres nesting human-derived umbilical cord mesenchymal stem cells for bone regeneration
Authors: Song Wenzhi , Zhao Lanlan , Gao Yuqi , Han Chunyu , Gao Shengrui , Guo Min , Bai Jianfei , Wang Liqiang , Yin Wanzhong , Wu Feng , Zhang Peibiao
Published: July 2023

Background

Modular tissue engineering (MTE) is a novel “bottom-up” approach that aims to mimic complex tissue microstructural features. The constructed micromodules are assembled into engineered biological tissues with repetitive functional microunits and form cellular networks. This is emerging as a promising strategy for reconstruction of biological tissue.

Results

Herein, we constructed a micromodule for MTE and developed engineered osteon-like microunits by inoculating human-derived umbilical cord mesenchymal stem cells (HUMSCs) onto nHA/PLGA microspheres with surface modification of dual growth factors (BMP2/bFGF). By evaluating the results of proliferation and osteogenic differentiation ability of HUMSCs in vitro, the optimal ratio of the dual growth factor (BMP2/bFGF) combination was derived as 5:5. In vivo assessments showed the great importance of HUMSCs for osteogneic differentiation. Ultimately, direct promotion of early osteo-differentiation manifested as upregulation of Runx-2 gene expression. The vascularization capability was evaluated by tube formation assays, demonstrating the importance of HUMSCs in the microunits for angiogenesis.

Conclusions

The modification of growth factors and HUMSCs showed ideal biocompatibility and osteogenesis combined with nHA/PLGA scaffolds. The micromodules constructed in the current study provide an efficient stem cell therapy strategy for bone defect repair.
A user evaluation of speech/phrase recognition software in critically ill patients: a DECIDE-AI feasibility study
Authors: Musalia M. , Laha S. , Cazalilla-Chica J. , Allan J. , Roach L. , Twamley J. , Nanda S. , Verlander M. , Williams A. , Kempe I. , Patel I. I. , Campbell-West F. , Blackwood B. , McAuley D. F.
Published: July 2023

Objectives

Evaluating effectiveness of speech/phrase recognition software in critically ill patients with speech impairments.

Design

Prospective study.

Setting

Tertiary hospital critical care unit in the northwest of England.

Participants

14 patients with tracheostomies, 3 female and 11 male.

Main outcome measures

Evaluation of dynamic time warping (DTW) and deep neural networks (DNN) methods in a speech/phrase recognition application. Using speech/phrase recognition app for voice impaired (SRAVI), patients attempted mouthing various supported phrases with recordings evaluated by both DNN and DTW processing methods. Then, a trio of potential recognition phrases was displayed on the screen, ranked from first to third in order of likelihood.

Results

A total of 616 patient recordings were taken with 516 phrase identifiable recordings. The overall results revealed a total recognition accuracy across all three ranks of 86% using the DNN method. The rank 1 recognition accuracy of the DNN method was 75%. The DTW method had a total recognition accuracy of 74%, with a rank 1 accuracy of 48%.

Conclusion

This feasibility evaluation of a novel speech/phrase recognition app using SRAVI demonstrated a good correlation between spoken phrases and app recognition. This suggests that speech/phrase recognition technology could be a therapeutic option to bridge the gap in communication in critically ill patients.

What is already known about this topic

Communication can be attempted using visual charts, eye gaze boards, alphabet boards, speech/phrase reading, gestures and speaking valves in critically ill patients with speech impairments.

What this study adds

Deep neural networks and dynamic time warping methods can be used to analyse lip movements and identify intended phrases.

How this study might affect research, practice and policy

Our study shows that speech/phrase recognition software has a role to play in bridging the communication gap in speech impairment.
Randomized double-blind personalized N-of-1 clinical trial to test the safety and potential efficacy of TJ-68 for treating muscle cramps in amyotrophic lateral sclerosis (ALS): study protocol for a TJ-68 trial
Authors: Mitsumoto Hiroshi , Cheung Ken , Oskarsson Björn , Andrews Howard F. , Jang Grace E. , Andrews Jinsy A. , Shah Jaimin S. , Fernandes Joseph Americo , McElhiney Martin , Santella Regina M.
Published: July 2023

Introduction/aims

Muscle cramps are a common and often disabling symptom in amyotrophic lateral sclerosis (ALS), a devastating and incurable neurodegenerative disorder. To date, there are no medications specifically approved for the treatment of muscle cramps. Ameliorating muscle cramps in ALS may improve and sustain quality of life. A widely prescribed traditional Japanese (Kampo) medicine against muscle cramps, shakuyakukanzoto (TJ-68), has been studied in advanced liver disease, spinal stenosis, kidney failure, and diabetic neuropathy. The Japanese ALS Management Guideline mentions TJ-68 for difficult muscle cramps in ALS. Therefore, the rationale of our trial is to investigate the safety and effectiveness of TJ-68 in treating painful and disabling muscle cramps in people with ALS outside of Japan. Accordingly, we are conducting a randomized clinical trial to test the safety and efficacy of TJ-68 in participants with ALS reporting frequent muscle cramps using an innovative, personalized N-of-1 design. If successful, TJ-68 may be used for muscle cramps in a broader population of people with ALS.

Methods

This is a two-site, double-blind, randomized personalized N-of-1 early clinical trial with TJ-68. At least 22 participants with ALS and daily muscle cramps will receive drug or placebo for 2 weeks (one treatment period) followed by a 1-week washout in a four-period cross-over design. While the primary objective is to evaluate the safety of TJ-68, the study has 85% power to detect a one-point shift on the Visual Analog Scale for Muscle Cramps Affecting Overall Daily Activity of the Columbia Muscle Cramp Scale (MCS). Secondary outcomes include the full MCS score, a Cramp Diary, Clinical Global Impression of Changes, Goal Attainment Scale, quality of life scale and ALS functional rating scale-revised (ALSFRS-R).

Discussion

The study is underway. A personalized N-of-1 trial design is an efficient approach to testing medications that alleviate muscle cramps in rare disorders. If TJ-68 proves safe and efficacious then it may be used to treat cramps in ALS, and help to improve and sustain quality of life.

Trial registration

This clinical trial has been registered with ClinicalTrials.gov (NCT04998305), 8/9/2021.
Fatty acid- and retinol-binding protein 6 does not control worm fatty acid content in Caenorhabditis elegans but might play a role in Haemonchus contortus parasitism
Authors: Wu Fei , Wei Haidian , Chen Xueqiu , Du Zhendong , Huang Yan , Shi Hengzhi , Yang Yi , Du Aifang , Ma Guangxu
Published: July 2023

Background

Nematodes have lost the ability to synthesise necessary lipids de novo and have complementally evolved the capacity to acquire fatty acids and their derivatives from a diet or host animal. Nematode-specific fatty acid- and retinol-binding protein (FAR) family is one approach that facilitates lipid acquisition, representing an Achilles heel and potential target against roundworms of socioeconomic significance. However, little is known about their detailed functional roles in either free-living or parasitic nematodes.

Methods

A genome-wide identification and curation were performed to screen the FAR family members of Haemonchus contortus. Their transcription patterns in worms were also analysed to identify the targets. Ligand binding assay and molecular docking were conducted to verify the fatty acid binding activities of FAR proteins of interest. RNA interference (RNAi) and heterologous expression (rescuing) experiments were designed to explore the potential roles of the selected FAR protein in nematodes. Localisation of the protein was shown in sections of paraffin-embedded worms after an immunohistochemistry (IHC) assay.

Results

Here, an orthologue of far-6 in the model organism Caenorhabditis elegans (Ce-far-6) was functionally characterised in a parasitic nematode, H. contortus (Hc-far-6). It is demonstrated that knockdown of Ce-far-6 gene did not affect worm fat content, reproduction, or lifespan, but decreased worm body length at an early life stage of C. elegans. In particular, the Ce-far-6 mutant associated phenotype was completely rescued by Hc-far-6, suggesting a conserved functional role. Surprisingly, there were distinct tissue expression patterns of FAR-6 in the free-living C. elegans and parasitic H. contortus. High transcriptional level of Hc-far-6 and dominant expression of FAR-6 in the intestine of the parasitic stage of H. contortus link this gene/protein to nematode parasitism.

Conclusions

These findings substantially enhance our understanding of far genes and the associated lipid biology of this important parasitic nematode at a molecular level, and the approaches established are readily applicable to the studies of far genes in a broad range of parasites.

Graphical Abstract