bluuebunny/crossref_metadata_2025 huggingface dataset:
LARAI portal provides a safe method for lateral meniscus repair: three-dimensional computed tomography and cadaveric assessment
Authors: Long Yi , Zhang Zhengzheng , Zhou Min , Hou Jingyi , Zhou Yunfeng , Jiang Liang , Xu Xiaoding , Yang Rui
Published: September 2023

Background

Lateral, All-Round and All-Inside (LARAI) portal is a viewing or working portal for observing and repairing the lesions of the lateral meniscus. However, there are safety concerns about popliteal artery (PA) injuries during the procedure. This study aimed to assess the safe distance between the trajectory of the LARAI portal and PA.

Materials and methods

Both three-dimensional computed tomography (3D-CT) and cadavers were used to simulate the LARAI portal trajectory. In the 3D-CT study, between January 2020 and September 2020, 45 participants who underwent computed tomography angiography were included in the study. The shortest distance from the PA to the simulated trajectory needle (PS) was measured using 3D-CT. Mean −3SD −2 was calculated to assess the safety of the LARAI portal trajectory. If this value was more than zero, the trajectory was considered “safe.” In the cadaveric study, lower limbs from seven fresh-frozen cadavers were used to establish the “safe” trajectories of the LARAI portal, and the PS was measured.

Results

In the 3D-CT study, the longest PS (P < 0.001) was found 20 mm lateral to the edge of the patellar tendon trajectory at 0 mm from the posterior cruciate ligament (PCL). Safe trajectories were also found 10 mm, 15 mm, and 20 mm lateral to the edge of the patellar tendon at 0 mm from the PCL, as well as the 20 mm lateral to the edge of the patellar tendon at 3 mm from the PCL. The cadaveric study showed that the average PS of all safe trajectories closely adjoined to PCL was greater than 14 mm.

Conclusions

The LARAI portal trajectory in the “figure of four” is safe, and the optimal insertion point is 10–20 mm lateral to the edge of the patellar tendon and closely adjoined to the posterolateral margin of the PCL at knee joint line level.

Level of evidence

Level IV.
Multimodal imaging and photothermal/chemodynamic therapy of cervical cancer using GSH-responsive MoS2@MnO2 theranostic nanoparticles
Authors: Shao Runrun , Qiao Xiaofang , Cao Linlin , Man Jianliang , Guo Lingyun , Li Lanlan , Liu Wen , Li Lihong , Wang Bin , Guo Lixia , Ma Sufang , Zhang Boye , Wang Haojiang , Yan Lili
Published: September 2023

The development of nanoparticles capable of inducing reactive oxygen species (ROS) formation has become an important strategy for cancer therapy. Simultaneously, the preparation of multifunctional nanoparticles that respond to the tumor microenvironment is crucial for the diagnosis and treatment of tumors. In this study, we designed a Molybdenum disulfide (MoS2) core coated with Manganese dioxide (MnO2), which possessed a good photothermal effect and could produce Fenton-like Mn2+ in response to highly expressed glutathione (GSH) in the tumor microenvironment, thereby generating a chemodynamic therapy (CDT). The nanoparticles were further modified with Methoxypoly(Ethylene Glycol) 2000 (mPEG-NH2) to improve their biocompatibility, resulting in the formation of MoS2@MnO2-PEG. These nanoparticles were shown to possess significant Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) imaging capabilities, making them useful in tumor diagnosis. In vitro and in vivo experiments demonstrated the antitumor ability of MoS2@MnO2-PEG, with a significant killing effect on tumor cells under combined treatment. These nanoparticles hold great potential for CDT/photothermal therapy (PTT) combined antitumor therapy and could be further explored in biomedical research.
Current status and influencing factors of self-management in knee joint discomfort among middle-aged and elderly people: a cross-sectional study
Authors: Guo Yabin , Zhao Peipei , Zeng Biyun , Su Manman , Zhou Yang , Liu Xiaotong , Zhou Yang
Published: September 2023

Background

This study aims to identify the current status and factors influencing self-management of knee discomfort in middle-aged and elderly people in China.

Methods

A stratified multistage cluster sampling method was used to select participants from communities in China from January 15 to May 31, 2020. A cross-sectional survey was conducted using the general information questionnaire and the Knee Joint Discomfort Self-management Scale. Univariate analysis and a generalized linear model were used to analyze the factors influencing self-management.

Results

The prevalence of knee discomfort was 77%. Moderate to severe discomfort accounted for 30.5%. The average item score of self-management in 9640 participants was 1.98 ± 0.76. The highest and lowest levels were: ‘daily life management’ and ‘information management’. Gender, ethnicity, education level, economic source, chronic disease, knee pain in the past month, and the degree of self-reported knee discomfort were significant predictors of self-management.

Conclusion

The self-management of knee discomfort in middle-aged and elderly people is poor, and the degree of discomfort is a significant predictor. Healthcare providers should consider socioeconomic demographic and clinical characteristics to help these individuals improve their self-management skills. Attention should also be given to improving their ability to access health information and making them aware of disease risks.
Online decision tools for personalized survival prediction and treatment optimization in elderly patients with lung squamous cell carcinoma: a retrospective cohort study
Authors: Shao Chen-ye , Luo Jing , Ju Sheng , Li Chu-ling , Ding Cheng , Chen Jun , Liu Xiao-long , Zhao Jun , Yang Li-qin
Published: September 2023

Background

Despite major advances in cancer therapeutics, the therapeutic options of Lung Squamous Cell Carcinoma (LSCC)-specific remain limited. Furthermore, the current staging system is imperfect for defining a prognosis and guiding treatment due to its simplicity and heterogeneity. We sought to develop prognostic decision tools for individualized survival prediction and treatment optimization in elderly patients with LSCC.

Methods

Clinical data of 4564 patients (stageIB-IIIB) diagnosed from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database for prognostic nomograms development. The proposed models were externally validated using a separate group consisting of 1299 patients (stage IB-IIIB) diagnosed from 2012–2015 in China. The prognostic performance was measured using the concordance index (C-index), calibration curves, the average time-dependent area under the receiver operator characteristic curves (AUC), and decision curve analysis.

Results

Eleven candidate prognostic variables were identified by the univariable and multivariable Cox regression analysis. The calibration curves showed satisfactory agreement between the actual and nomogram-estimated Lung Cancer-Specific Survival (LCSS) rates. By calculating the c-indices and average AUC, our nomograms presented a higher prognostic accuracy than the current staging system. Clinical usefulness was revealed by the decision curve analysis. User-friendly online decision tools integrating proposed nomograms were created to estimate survival for patients with different treatment regimens.

Conclusions

The decision tools for individualized survival prediction and treatment optimization might facilitate clinicians with decision-making, medical teaching, and experimental design. Online tools are expected to be integrated into clinical practice by using the freely available website (https://loyal-brand-611803.framer.app/).
Spatio-temporal analysis of childhood vaccine uptake in Nigeria: a hierarchical Bayesian Zero-inflated Poisson approach
Authors: Lawal Temitayo Victor , Atoloye Kehinde Adebola , Adebowale Ayo Stephen , Fagbamigbe Adeniyi Francis
Published: September 2023

Background

Globally, child mortality and morbidity remain a serious health challenge and infectious diseases are the leading causes. The use of count models together with spatial analysis of the number of doses of childhood vaccines taken is limited in the literature. We used a Bayesian zero-inflated Poisson regression model with spatio-temporal components to assess the number of doses of childhood vaccines taken among children aged 12–23 months and their associated factors.

Methods

Data of 19,564 children from 2003, 2008, 2013 and 2018 population-based cross-sectional Nigeria Demographic and Health Survey were used. The childhood vaccines include one dose of Bacillus-Calmette-Guérin; three doses of Diphtheria-Pertussis-Tetanus; three doses of Polio and one dose of Measles. Uptake of all nine vaccines was regarded as full vaccination. We examined the multilevel factors associated with the number of doses of childhood vaccines taken using descriptive, bivariable and multivariable Bayesian models. Analysis was conducted in Stata version 16 and R statistical packages, and visualization in ArcGIS.

Results

The prevalence of full vaccination was 6.5% in 2003, 14.8% in 2008, 21.8% in 2013 and 23.3% in 2018. Full vaccination coverage ranged from 1.7% in Sokoto to 51.9% in Anambra. Factors associated with the number of doses of childhood vaccines taken include maternal age (adjusted Incidence “risk” Ratio (aIRR) = 1.05; 95% Credible Interval (CrI) = 1.03–1.07) for 25–34 years and (aIRR = 1.07; 95% CrI = 1.05–1.10) for 35–49 years and education: (aIRR = 1.11, 95% CrI = 1.09–1.14) for primary and (aIRR = 1.16; 95% CrI = 1.13–1.19) for secondary/tertiary education. Other significant factors are wealth status, antenatal care attendance, working status, use of skilled birth attendants, religion, mother’s desire for the child, community poverty rate, community illiteracy, and community unemployment.

Conclusion

Although full vaccination has remained low, there have been improvements over the years with wide disparities across the states. Improving the uptake of vaccines by educating women on the benefits of hospital delivery and vaccines through radio jingles and posters should be embraced, and state-specific efforts should be made to address inequality in access to routine vaccination in Nigeria.
Clinicians’ views of prescribing oral and intravenous bisphosphonates for osteoporosis: a qualitative study
Authors: Bishop Simon , Narayanasamy Melanie Jay , Paskins Zoe , Corp Nadia , Bastounis Anastasios , Griffin Jill , Gittoes Neil , Leonardi-Bee Jo , Langley Tessa , Sahota Opinder
Published: September 2023

Background

Bisphosphonate medications, including alendronate, ibandronate and risedronate administered orally and zoledronate, administered intravenously, are commonly prescribed for the treatment of osteoporosis based on evidence that, correctly taken, bisphosphonates can improve bone strength and lead to a reduction in the risk of fragility fractures. However, it is currently unclear how decisions to select between bisphosphonate regimens, including intravenous regimen, are made in practice and how clinicians support patients with different treatments.

Methods

This was an interpretivist qualitative study. 23 semi-structured telephone interviews were conducted with a sample of general practitioners (GPs), secondary care clinicians, specialist experts as well as those providing and leading novel treatments including participants from a community intravenous (IV) zoledronate service. Data analysis was undertaken through a process of iterative categorisation.

Results

The results report clinicians varying experiences of making treatment choices, as well as wider aspects of osteoporosis care. Secondary care and specialist clinicians conveyed some confidence in making treatment choices including on selecting IV treatment. This was aided by access to diagnostic testing and medication expertise. In contrast GPs reported a number of challenges in prescribing bisphosphonate medications for osteoporosis and uncertainty about treatment choice. Results also highlight how administering IV zoledronate was seen as an opportunity to engage in broader care practices.

Conclusion

Approaches to making treatment decisions and supporting patients when prescribing bisphosphonates for osteoporosis vary in practice. This study points to the need to co-ordinate osteoporosis treatment and care across different care providers.
Physicians’ attitudes and experiences about withholding/withdrawing life-sustaining treatments in pediatrics: a systematic review of quantitative evidence
Authors: Zhong Yajing , Cavolo Alice , Labarque Veerle , Gastmans Chris
Published: September 2023

Background

One of the most important and ethically challenging decisions made for children with life-limiting conditions is withholding/withdrawing life-sustaining treatments (LST). As important (co-)decision-makers in this process, physicians are expected to have deeply and broadly developed views. However, their attitudes and experiences in this area remain difficult to understand because of the diversity of the studies. Hence, the aim of this paper is to describe physicians’ attitudes and experiences about withholding/withdrawing LST in pediatrics and to identify the influencing factors.

Methods

We systematically searched Pubmed, Cinahl®, Embase®, Scopus®, and Web of Science™ in early 2021 and updated the search results in late 2021. Eligible articles were published in English, reported on investigations of physicians’ attitudes and experiences about withholding/withdrawing LST for children, and were quantitative.

Results

In 23 included articles, overall, physicians stated that withholding/withdrawing LST can be ethically legitimate for children with life-limiting conditions. Physicians tended to follow parents’ and parents-patient’s wishes about withholding/withdrawing or continuing LST when they specified treatment preferences. Although most physicians agreed to share decision-making with parents and/or children, they nonetheless reported experiencing both negative and positive feelings during the decision-making process. Moderating factors were identified, including barriers to and facilitators of withholding/withdrawing LST. In general, there was only a limited number of quantitative studies to support the hypothesis that some factors can influence physicians’ attitudes and experiences toward LST.

Conclusion

Overall, physicians agreed to withhold/withdraw LST in dying patients, followed parent-patients’ wishes, and involved them in decision-making. Barriers and facilitators relevant to the decision-making regarding withholding/withdrawing LST were identified. Future studies should explore children’s involvement in decision-making and consider barriers that hinder implementation of decisions about withholding/withdrawing LST.
Health, wealth, and medical expenditures among the elderly in rural Tanzania: experiences from Nzega and Igunga districts
Authors: Tungu Malale M. , Mujinja Phares G. , Amani Paul J. , Mwangu Mughwira A. , Kiwara Angwara D. , Lindholm Lars
Published: September 2023

Background

The per capita health expenditure (HE) and share of gross domestic product (GDP) spending on elderly healthcare are expected to increase. The gap between health needs and available resources for elderly healthcare is widening in many developing countries, like Tanzania, leaving the elderly in poor health. These conditions lead to catastrophic HEs for the elderly. This study aimed to analyse the association between measures of health, wealth, and medical expenditure in rural residents aged 60 years and above in Tanzania.

Methods

The data of this study were collected through a cross-sectional household survey to residents aged 60 years and above living in Nzega and Igunga districts using a standardised World Health Organization (WHO) Study on Global Ageing and Adult Health (SAGE) and European Quality of Life Five Dimension (EQ-5D) questionnaires. The quality of life (QoL) was estimated using EQ-5D weights. The wealth index was generated from principal component analysis (PCA). The linear regression analyses (outpatient/inpatient) were performed to analyse the association between measures of health, wealth, medical expenditure, and socio-demographic variables.

Results

This study found a negative and statistically significant association between QoL and HE, whereby HE increases with the decrease of QoL. We could not find any significant relationship between HE and social gradients. In addition, age influences HE such that as age increases, the HE for both outpatient and inpatient care also increases.

Conclusion

The health system in these districts allocate resources mainly according to needs, and social position is not important. We thus conclude that the elderly of lower socio-economic status (SES) was subjected to similar health expenditure as those of higher socio-economic status. Health, not wealth, determines the use of medical expenditures.
Five-year results of a treatment program for chronic hepatitis B in Ethiopia
Authors: Desalegn Hailemichael , Orlien Stian Magnus Staurung , Aberra Hanna , Mamo Eyerusalem , Grude Sine , Hommersand Kristina , Berhe Nega , Gundersen Svein Gunnar , Johannessen Asgeir
Published: September 2023

Background

In sub-Saharan Africa, less than 1% of treatment-eligible chronic hepatitis B (CHB) patients receive antiviral therapy. Experiences from local CHB programs are needed to inform treatment guidelines and policies on the continent. Here, we present 5-year results from one of the first large-scale CHB treatment programs in sub-Saharan Africa.

Methods

Adults with CHB were enrolled in a pilot treatment program in Addis Ababa, Ethiopia, in 2015. Liver enzymes, viral markers, and transient elastography were assessed at baseline and thereafter at 6-month intervals. Tenofovir disoproxil fumarate was initiated based on the European Association for the Study of the Liver (EASL) criteria, with some modifications. Survival analysis was performed using the Kaplan–Meier method.

Results

In total, 1303 patients were included in the program, of whom 291 (22.3%) started antiviral therapy within the initial 5 years of follow-up. Among patients on treatment, estimated 5-year hepatocellular carcinoma-free survival was 99.0% in patients without cirrhosis at baseline, compared to 88.8% in patients with compensated cirrhosis, and 54.2% in patients with decompensated cirrhosis (p < 0.001). The risk of death was significantly higher in patients with decompensated cirrhosis at baseline (adjusted hazard ratio 44.6, 95% confidence interval 6.1–328.1) and in patients older than 40 years (adjusted hazard ratio 3.7, 95% confidence interval 1.6–8.5). Liver stiffness declined significantly after treatment initiation; the median change from baseline after 1, 3, and 5 years of treatment was − 4.0 kPa, − 5.2 kPa, and − 5.6 kPa, respectively.

Conclusions

This pilot program demonstrates the long-term benefits of CHB therapy in a resource-limited setting. The high mortality in patients with cirrhosis underscores the need for earlier detection of CHB and timely initiation of antiviral treatment in sub-Saharan Africa.

Trial registration

The study was registered at ClinicalTrials.gov (NCT02344498) on January 26, 2015.
Toxoplasma gondii in small mammals in Romania: the influence of host, season and sampling location
Authors: Kalmár Zsuzsa , Sándor Attila D. , Balea Anamaria , Borşan Silvia-Diana , Matei Ioana Adriana , Ionică Angela Monica , Gherman Călin Mircea , Mihalca Andrei Daniel , Cozma-Petruț Anamaria , Mircean Viorica , Györke Adriana
Published: September 2023

Background

Toxoplasma gondii is a protozoan parasite that infects a large spectrum of warm-blooded animals, including humans. Small rodents and insectivores play an important role in the epidemiology of T. gondii and may serve as a source of infection for both, domestic and wild definitive felid hosts. Factors influencing the occurrence of T. gondii in wild small mammals are unknown, despite the fact that many intermediate host species are identified. We have used small mammals (Rodentia and Lipotyphla) captured over two years in various habitats, both in urbanised and in natural landscapes. We assessed the importance of land-use, season and host ecology on T. gondii infection.

Results

We examined 471 individuals belonging to 20 small mammal species, collected at 63 locations spread over wide altitude, habitat and land-use ranges from Romania. Heart tissue samples were individually analysed by PCR targeting the 529 bp repetitive DNA fragment of T. gondii. The overall prevalence of infection was 7.3%, with nine species of rodents and two species of shrews being found to carry T. gondii DNA. Five species showed high frequency of infection, with the highest prevalence found in Myodes glareolus (35.5%), followed by Spermophilus citellus (33.3%), Sorex minutus (23.1%), S. araneus (21.7%) and Micromys minutus (11.1%). Adults seemed more often infected than young, however when controlling for season, the difference was not significant, as in spring both adults and young showed higher infection rates, but more adults were sampled. Contrary to our expectations, urban/rural areas (with their implicit high density of domestic feline presence) had no effect on infection prevalence. In addition, neither habitat, nor land-use at sampling sites was important as only geographical location and host species were contributing factors to the infection risk.

Conclusions

High prevalence of T. gondii infection showed a highly localised, patchy occurrence, with long living and higher mobility host species being the most common carriers, especially during autumn.
Association of triglyceride-glucose index trajectory and frailty in urban older residents: evidence from the 10-year follow-up in a cohort study
Authors: Yuan Yin , Chen Simiao , Lin Chunjin , Huang Xiaoming , Lin Siyang , Huang Feng , Zhu Pengli
Published: September 2023

Background

Frailty is an age-related geriatric syndrome that leads to a series of clinically negative events. A better understanding of the factors associated with frailty assists in preventing its progression. The triglyceride-glucose (TyG) index, a simple alternative index of insulin resistance, has not yet been proven to be associated with frailty. The present study aimed to investigate the association between the TyG index and its trajectory with frailty from a cross-sectional, retrospective and prospective level based on an ongoing cohort.

Methods

This longitudinal study included 1,866 older residents from the “Fujian prospective aging cohort” (ChiCTR 2,000,032,949). The TyG index was calculated as ln [fasting triglyceride (mg/dL) ╳ fasting plasma glucose (mg/dL)/2] and group-based trajectory model (GBTM) was applied to identify the trajectory of TyG index. The association between different trajectory groups of TyG index with frailty risk were estimated using multinomial logistic regression analysis.

Results

In the cross-sectional analysis, the highest quartile of the TyG index was associated with an increased risk of frailty (TyG index Q4 vs. Q1, OR = 1.50, 95% CI 1.00–2.25, P = 0.048). Restricted cubic splines demonstrated an increasing trend for TyG index and frailty risk. During a follow-up of ten years, three distinct trajectories of the TyG index were identified: low-stable (n = 697, 38.3%), moderate-stable (n = 910, 50.0%) and high-stable (n = 214, 11.7%). Compared with those in the stable-low group of TyG index trajectory, the ORs (95% CI) of prefrailty and frailty risk were 1.79 (95% CI 1.11–2.88) and 2.17 (95% CI 1.01–3.88) for the high-stable group, respectively (P = 0.017 and P = 0.038). In the subgroup analysis, the association of the high-stable trajectory of TyG and frailty status were only observed in subjects with BMI ≥ 24 kg/m2. Prospectively, the highest quartile of the TyG index was associated with a 2.09-fold significantly increased risk of one-year ADL/IADL decline (P = 0.045).

Conclusions

The present study suggests a potential role for a high and sustainable level of TyG index in the risk of frailty. The trajectories of the TyG index can help to identify older individuals at a higher risk of frailty who deserve primitive preventive and therapeutic approaches.
A microglial activity state biomarker panel differentiates FTD-granulin and Alzheimer’s disease patients from controls
Authors: Pesämaa Ida , Müller Stephan A. , Robinson Sophie , Darcher Alana , Paquet Dominik , Zetterberg Henrik , Lichtenthaler Stefan F. , Haass Christian
Published: September 2023

Background

With the emergence of microglia-modulating therapies there is an urgent need for reliable biomarkers to evaluate microglial activation states.

Methods

Using mouse models and human induced pluripotent stem cell-derived microglia (hiMGL), genetically modified to yield the most opposite homeostatic (TREM2-knockout) and disease-associated (GRN-knockout) states, we identified microglia activity-dependent markers. Non-targeted mass spectrometry was used to identify proteomic changes in microglia and cerebrospinal fluid (CSF) of Grn- and Trem2-knockout mice. Additionally, we analyzed the proteome of GRN- and TREM2-knockout hiMGL and their conditioned media. Candidate marker proteins were tested in two independent patient cohorts, the ALLFTD cohort (GRN mutation carriers versus non-carriers), as well as the proteomic data set available from the EMIF-AD MBD study.

Results

We identified proteomic changes between the opposite activation states in mouse microglia and CSF, as well as in hiMGL cell lysates and conditioned media. For further verification, we analyzed the CSF proteome of heterozygous GRN mutation carriers suffering from frontotemporal dementia (FTD). We identified a panel of six proteins (FABP3, MDH1, GDI1, CAPG, CD44, GPNMB) as potential indicators for microglial activation. Moreover, we confirmed three of these proteins (FABP3, GDI1, MDH1) to be significantly elevated in the CSF of Alzheimer’s (AD) patients. Remarkably, each of these markers differentiated amyloid-positive cases with mild cognitive impairment (MCI) from amyloid-negative individuals.

Conclusions

The identified candidate proteins reflect microglia activity and may be relevant for monitoring the microglial response in clinical practice and clinical trials modulating microglial activity and amyloid deposition. Moreover, the finding that three of these markers differentiate amyloid-positive from amyloid-negative MCI cases in the AD cohort suggests that these proteins associate with a very early immune response to seeded amyloid. This is consistent with our previous findings in the Dominantly Inherited Alzheimer’s Disease Network (DIAN) cohort, where soluble TREM2 increases as early as 21 years before symptom onset. Moreover, in mouse models for amyloidogenesis, seeding of amyloid is limited by physiologically active microglia further supporting their early protective role. The biological functions of some of our main candidates (FABP3, CD44, GPNMB) also further emphasize that lipid dysmetabolism may be a common feature of neurodegenerative disorders.
A loss-of-function mutation in human Oxidation Resistance 1 disrupts the spatial–temporal regulation of histone arginine methylation in neurodevelopment
Authors: Lin Xiaolin , Wang Wei , Yang Mingyi , Damseh Nadirah , de Sousa Mirta Mittelstedt Leal , Jacob Fadi , Lång Anna , Kristiansen Elise , Pannone Marco , Kissova Miroslava , Almaas Runar , Kuśnierczyk Anna , Siller Richard , Shahrour Maher , Al-Ashhab Motee , Abu-Libdeh Bassam , Tang Wannan , Slupphaug Geir , Elpeleg Orly , Bøe Stig Ove , Eide Lars , Sullivan Gareth J. , Rinholm Johanne Egge , Song Hongjun , Ming Guo-li , van Loon Barbara , Edvardson Simon , Ye Jing , Bjørås Magnar
Published: September 2023

Background

Oxidation Resistance 1 (OXR1) gene is a highly conserved gene of the TLDc domain-containing family. OXR1 is involved in fundamental biological and cellular processes, including DNA damage response, antioxidant pathways, cell cycle, neuronal protection, and arginine methylation. In 2019, five patients from three families carrying four biallelic loss-of-function variants in OXR1 were reported to be associated with cerebellar atrophy. However, the impact of OXR1 on cellular functions and molecular mechanisms in the human brain is largely unknown. Notably, no human disease models are available to explore the pathological impact of OXR1 deficiency.

Results

We report a novel loss-of-function mutation in the TLDc domain of the human OXR1 gene, resulting in early-onset epilepsy, developmental delay, cognitive disabilities, and cerebellar atrophy. Patient lymphoblasts show impaired cell survival, proliferation, and hypersensitivity to oxidative stress. These phenotypes are rescued by TLDc domain replacement. We generate patient-derived induced pluripotent stem cells (iPSCs) revealing impaired neural differentiation along with dysregulation of genes essential for neurodevelopment. We identify that OXR1 influences histone arginine methylation by activating protein arginine methyltransferases (PRMTs), suggesting OXR1-dependent mechanisms regulating gene expression during neurodevelopment. We model the function of OXR1 in early human brain development using patient-derived brain organoids revealing that OXR1 contributes to the spatial–temporal regulation of histone arginine methylation in specific brain regions.

Conclusions

This study provides new insights into pathological features and molecular underpinnings associated with OXR1 deficiency in patients.
Dominance is common in mammals and is associated with trans-acting gene expression and alternative splicing
Authors: Cui Leilei , Yang Bin , Xiao Shijun , Gao Jun , Baud Amelie , Graham Delyth , McBride Martin , Dominiczak Anna , Schafer Sebastian , Aumatell Regina Lopez , Mont Carme , Teruel Albert Fernandez , Hübner Norbert , Flint Jonathan , Mott Richard , Huang Lusheng
Published: September 2023

Background

Dominance and other non-additive genetic effects arise from the interaction between alleles, and historically these phenomena play a major role in quantitative genetics. However, most genome-wide association studies (GWAS) assume alleles act additively.

Results

We systematically investigate both dominance—here representing any non-additive within-locus interaction—and additivity across 574 physiological and gene expression traits in three mammalian stocks: F2 intercross pigs, rat heterogeneous stock, and mice heterogeneous stock. Dominance accounts for about one quarter of heritable variance across all physiological traits in all species. Hematological and immunological traits exhibit the highest dominance variance, possibly reflecting balancing selection in response to pathogens. Although most quantitative trait loci (QTLs) are detectable as additive QTLs, we identify 154, 64, and 62 novel dominance QTLs in pigs, rats, and mice respectively that are undetectable as additive QTLs. Similarly, even though most cis-acting expression QTLs are additive, gene expression exhibits a large fraction of dominance variance, and trans-acting eQTLs are enriched for dominance. Genes causal for dominance physiological QTLs are less likely to be physically linked to their QTLs but instead act via trans-acting dominance eQTLs. In addition, thousands of eQTLs are associated with alternatively spliced isoforms with complex additive and dominant architectures in heterogeneous stock rats, suggesting a possible mechanism for dominance.

Conclusions

Although heritability is predominantly additive, many mammalian genetic effects are dominant and likely arise through distinct mechanisms. It is therefore advantageous to consider both additive and dominance effects in GWAS to improve power and uncover causality.
Assessment of implementation methods in sepsis: study protocol for a cluster-randomized hybrid type 2 trial
Authors: Frank Hannah E. , Evans Laura , Phillips Gary , Dellinger RPhillip , Goldstein Jessyca , Harmon Lori , Portelli David , Sarani Nima , Schorr Christa , Terry Kathleen M. , Townsend Sean R. , Levy Mitchell M.
Published: September 2023

Background

Sepsis is the leading cause of intensive care unit (ICU) admission and ICU death. In recognition of the burden of sepsis, the Surviving Sepsis Campaign (SSC) and the Institute for Healthcare Improvement developed sepsis “bundles” (goals to accomplish over a specific time period) to facilitate SSC guideline implementation in clinical practice. Using the SSC 3-h bundle as a base, the Centers for Medicare and Medicaid Services developed a 3-h sepsis bundle that has become the national standard for early management of sepsis. Emerging observational data, from an analysis conducted for the AIMS grant application, suggest there may be additional mortality benefit from even earlier implementation of the 3-h bundle, i.e., the 1-h bundle.

Method

The primary aims of this randomized controlled trial are to: (1) examine the effect on clinical outcomes of Emergency Department initiation of the elements of the 3-h bundle within the traditional 3 h versus initiating within 1 h of sepsis recognition and (2) examine the extent to which a rigorous implementation strategy will improve implementation and compliance with both the 1-h bundle and the 3-h bundle. This study will be entirely conducted in the Emergency Department at 18 sites. A secondary aim is to identify clinical sepsis phenotypes and their impact on treatment outcomes.

Discussion

This cluster-randomized trial, employing implementation science methodology, is timely and important to the field. The hybrid effectiveness-implementation design is likely to have an impact on clinical practice in sepsis management by providing a rigorous evaluation of the 1- and 3-h bundles.

Funding

NHLBI R01HL162954.

Trial registration

ClinicalTrials.gov NCT05491941. Registered on August 8, 2022.
Inter- and intra-species conversion efficacies of Norwegian prion isolates estimated by serial protein misfolding cyclic amplification
Authors: Harpaz Erez , Vuong Tram Thu , Tran Linh , Tranulis Michael Andreas , Benestad Sylvie L. , Ersdal Cecilie
Published: September 2023

Prion diseases, including chronic wasting disease (CWD) in cervids, are fatal neurodegenerative disorders caused by the misfolding of cellular prion proteins. CWD is known to spread among captive and free-ranging deer in North America. In 2016, an outbreak of contagious CWD was detected among wild reindeer in Norway, marking the first occurrence of the disease in Europe. Additionally, new sporadic forms of CWD have been discovered in red deer in Norway and moose in Fennoscandia. We used serial protein misfolding cyclic amplification to study the ability of Norwegian prion isolates from reindeer, red deer, and moose (two isolates), as well as experimental classical scrapie from sheep, to convert a panel of 16 brain homogenates (substrates) from six different species with various prion protein genotypes. The reindeer CWD isolate successfully converted substrates from all species except goats. The red deer isolate failed to convert sheep and goat substrates but exhibited amplification in all cervid substrates. The two moose isolates demonstrated lower conversion efficacies. The wild type isolate propagated in all moose substrates and in the wild type red deer substrate, while the other isolate only converted two of the moose substrates. The experimental classical scrapie isolate was successfully propagated in substrates from all species tested. Thus, reindeer CWD and classical sheep scrapie isolates were similarly propagated in substrates from different species, suggesting the potential for spillover of these contagious diseases. Furthermore, the roe deer substrate supported conversion of three isolates suggesting that this species may be vulnerable to prion disease.
Changes in structure and assembly of a species-rich soil natural community with contrasting nutrient availability upon establishment of a plant-beneficial Pseudomonas in the wheat rhizosphere
Authors: Garrido-Sanz Daniel , Čaušević Senka , Vacheron Jordan , Heiman Clara M. , Sentchilo Vladimir , van der Meer Jan Roelof , Keel Christoph
Published: September 2023

Background

Plant-beneficial bacterial inoculants are of great interest in agriculture as they have the potential to promote plant growth and health. However, the inoculation of the rhizosphere microbiome often results in a suboptimal or transient colonization, which is due to a variety of factors that influence the fate of the inoculant. To better understand the fate of plant-beneficial inoculants in complex rhizosphere microbiomes, composed by hundreds of genotypes and multifactorial selection mechanisms, controlled studies with high-complexity soil microbiomes are needed.

Results

We analysed early compositional changes in a taxa-rich natural soil bacterial community under both exponential nutrient-rich and stationary nutrient-limited growth conditions (i.e. growing and stable communities, respectively) following inoculation with the plant-beneficial bacterium Pseudomonas protegens in a bulk soil or a wheat rhizosphere environment. P. protegens successfully established under all conditions tested and was more abundant in the rhizosphere of the stable community. Nutrient availability was a major factor driving microbiome composition and structure as well as the underlying assembly processes. While access to nutrients resulted in communities assembled mainly by homogeneous selection, stochastic processes dominated under the nutrient-deprived conditions. We also observed an increased rhizosphere selection effect under nutrient-limited conditions, resulting in a higher number of amplicon sequence variants (ASVs) whose relative abundance was enriched. The inoculation with P. protegens produced discrete changes, some of which involved other Pseudomonas. Direct competition between Pseudomonas strains partially failed to replicate the observed differences in the microbiome and pointed to a more complex interaction network.

Conclusions

The results of this study show that nutrient availability is a major driving force of microbiome composition, structure and diversity in both the bulk soil and the wheat rhizosphere and determines the assembly processes that govern early microbiome development. The successful establishment of the inoculant was facilitated by the wheat rhizosphere and produced discrete changes among other members of the microbiome. Direct competition between Pseudomonas strains only partially explained the microbiome changes, indicating that indirect interactions or spatial distribution in the rhizosphere or soil interface may be crucial for the survival of certain bacteria.
Effect of Eccentric Exercise on Metabolic Health in Diabetes and Obesity
Authors: Szűcs Gergő , Pipicz Márton , Szabó Márton Richárd , Csont Tamás , Török László , Csonka Csaba
Published: September 2023

There is a growing body of evidence showing the importance of physical activity against civilization-induced metabolic diseases, including type 2 diabetes (T2DM) and obesity. Eccentric contraction, when skeletal muscles generate force by lengthening, is a unique type of skeletal muscle activity. Eccentric contraction may lead to better power production characteristics of the muscle because eccentric contraction requires less energy and can result in higher tension. Therefore, it is an ideal tool in the rehabilitation program of patients. However, the complex metabolic effect (i.e., fat mass reduction, increased lipid oxidation, improvement in blood lipid profile, and increased insulin sensitivity) of the eccentric contraction alone has scarcely been investigated. This paper aims to review the current literature to provide information on whether eccentric contraction can influence metabolic health and body composition in T2DM or obesity. We also discussed the potential role of myokines in mediating the effects of eccentric exercise. A better understanding of the mechanism of eccentric training and particularly their participation in the regulation of metabolic diseases may widen their possible therapeutic use and, thereby, may support the fight against the leading global risks for mortality in the world.
Effect of averaging time and respiratory pause time on the measurement of acoustic respiration rate monitoring
Authors: Honda Jun , Murakawa Masahiro , Inoue Satoki
Published: September 2023

Background

Acoustic respiration rate (RRa) monitoring is a method of continuously measuring respiratory rate using a signal from an acoustic transducer placed over the airway. The purpose of the present study is to examine how the averaging time and respiratory pause time settings of an RRa monitor affect the detection time of sudden respiratory rate changes.

Methods

A total of 40 healthy adult volunteers were included in the study. First, we measured the apnea detection time (apnea test) by dividing them into two groups (N = 20 each), one with a respiratory pause time setting of 20 s and the other with 40 s. Each group performed two apnea tests with an averaging time setting of 10 and 30 s. Next, we measured the tachypnea detection time (tachypnea test) for half of the subjects (N = 20) with two averaging time settings of 10 and 30 s. For each test, three measurements were taken, and the average of the three measurements was recorded.

Results

There was no significant difference in the apnea detection time between the averaging time set at 10 and 30 s regardless of whether the respiratory pause time was set at 20 or 40 s. However, the apnea detection time was significantly shorter with the respiratory pause time of 20 s than 40 s, regardless of whether the averaging time was set at 10 or 30 s (p < 0.001). The tachypnea detection time was shorter with the averaging time of 10 s than 30 s (p < 0.001).

Furthermore, the apnea detection time and tachypnea detection time were much longer than the actual settings.

Conclusions

The results of the current study show that in the measurement of RRa, the apnea detection time is more affected by the respiratory pause time setting than the averaging time setting; however, the tachypnea detection time is significantly affected by the averaging time setting.
Work burnout and organisational commitment of medical professionals
Authors: Babatope Valerie Onyia , Okoye Jude , Adekunle Ibrahim Ayoade , Fejoh Johnson
Published: September 2023

While psychological, emotional, and physical exhaustion has contributed to unproductivity across various dimensions of work life, how work burnout has shaped the organisational commitment of medical professionals who are at the forefront of health and well-being remains underexplored and less understood. This study offers new and insightful perspectives on work burnout and variations in the commitment of medical professionals in Ogun State, Nigeria. This study evaluated the correlation and relative effect between work burnout, family commitment, and organisational commitment and optimal productivity using the product moment correlation and analysis of variance (ANOVA) estimation procedures. Items in the questionnaire were developed in line with the Maslach Burnout Inventory-General Survey, organisational commitment questionnaire, family commitment inventory questionnaire, Work Productivity and Activity Impairment, Employment Absence and Productivity Scale, and employee performance questionnaire. Findings revealed that handling multiple tasks simultaneously, shortage of staff, inadequate facilities or equipment, poor appraisal, lack of recognition and autonomy, and work overload are the most prevalent stressors to medical professionals (medical laboratory scientists, nurses, pharmacists, and technicians). The result further revealed that the effects include fatigue, frequent headache, sleeplessness and the lingering cold, low motivation, anxiety, and decreased output, among other symptoms. This study suggests that work burnout and work–family conflict are positively associated with high productivity at work and increased organisational commitment. The gender dimensions of the result revealed that females experience more work burnout and work–family conflict than males. Thus, policies and management practices should be implemented to mitigate their effects in the health sector for efficient patient care.
SimStr: A C++ program for offshore seismic towed-streamer positioning data simulation
Authors: Duan Chufeng , Zhang Haonan , Kuang Cuilin , Yu Wenkun , Yang Baocai
Published: September 2023

Offshore seismic exploration requires accurate positions of towed streamers and seismic receivers. Because the actual positions of underwater streamers cannot be accurately determined, few effective evaluation methods for streamer positioning algorithms/software have been developed, besides simulations. However, most simulated data used in streamer positioning research are static; they lack physical meaning and neglect to consider the complex motion characteristics of the streamers caused by the towing vessel and current. To address this limitation, we have developed a C++ program for simulating streamer positioning observations, called SimStr. Based on the motion equation of underwater streamers, we use the finite-difference method to obtain a dynamic streamer shape, for which a box method is used to discretize the streamer motion in space and time. The positioning data are then simulated based on the dynamic streamer shape. We elaborate the structure of the program, for which the code of core algorithms was implemented to have good extendibility, efficiency, and portability, while ensuring high performance. As an example, we determine the simulated streamers of a vessel turning around to demonstrate the effectiveness of the code. Furthermore, we input the simulated data into a self-developed streamer positioning program and a commercial software to evaluate their positioning results and ultimately validate the simulated data.
European madness 1910–1980: lessons for today from Alastair Morgan's Continental Philosophy of Psychiatry: The Lure of Madness
Authors: Ikkos George
Published: September 2023

In Continental Philosophy of Psychiatry: The Lure of Madness Alastair Morgan surveys the contributions of a loosely conceived school of psychiatrists, philosophers and social theorists to understanding and responding to madness during the years 1910–1980. Taking my cue from him, I highlight some of the contributors discussed in Morgan's book and reflect that although madness may be difficult or even impossible to articulate effectively in discourse it remains a ‘limit experience’ which demarcates and illuminates the contours of other thinking and being, including reason and activism. I discuss social and cultural factors that have dulled clinicians’ sensitivities to the sounds of madness in recent decades and advocate the need for a reappraisal of our expertise and for a new activism today. What may at first appear as a failed clinical-philosophical tradition remains of professional relevance in today's rapidly transforming circumstances of practice both as inspiration and as cautionary tale.
Systemic Therapy for Tumor Control in Well-Differentiated Metastatic Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline Q and A
Authors: Del Rivero Jaydira , Kennedy Erin B. , Perez Kimberley
Published: September 2023

ASCO recently published new guidance on systemic therapy for tumor control in well-differentiated metastatic gastrointestinal and pancreatic neuroendocrine tumors in the Journal of Clinical Oncology. A companion Q and A article in the JCO-OP addresses some of the questions that clinicians may face as they implement these recommendations into clinical practice, including the role of somatostatin receptors and observation, definition of terms used within the guideline, considerations related to therapy options for G3 NETs, and future direction in research and treatment. ASCO also plans to address recommendations on the topic of symptom control of GEP-NETs in a forthcoming guideline