bluuebunny/crossref_metadata_2025 huggingface dataset:
High-risk factors associated with refractory childhood bacterial meningitis in Southwest China
Authors: Wu JinFeng , Song XiaoJie , Hu Yue , Chen Jin , Jiang Li
Published: May 2023

Background

Refractory bacterial meningitis is acute, develops rapidly, and has higher mortality and morbidity than common bacterial meningitis. This study was undertaken to investigate the high-risk factors related to refractory bacterial meningitis in children with positive pathogens.

Methods

We retrospectively analyzed the clinical data of 109 patients who had bacterial meningitis. The patients were divided into a refractory group (96 patients) and nonrefractory group (13 patients) based on the classification criteria. Seventeen clinical variables on risk factors were extracted and evaluated by univariate and multivariate logistic regression analyses.

Results

There were 64 males and 45 females. The onset age ranged from 1 month old to 12 years old, and the median age was 181 days old. The pathogenic bacteria included 67 cases of gram-positive (G+) bacteria (61.5%) and 42 cases of gram-negative (G-) bacteria. In patients who were 1 to 3 months old, E. coli was the most common (47.5%), followed by Streptococcus agalactiae and Staphylococcus hemolyticus (10.0%); in patients > 3 months old, S. pneumoniae was the most common (55.1%), followed by E. coli (8.7%). The multivariate analysis indicated that consciousness disorder (odds ratio [OR] = 13.050), peripheral blood C-reactive protein (CRP) ≥ 50 mg/L (OR = 29.436), and the isolate bacteria being gram-positive bacteria (OR = 8.227) were independent risk factors for predicting who would progress to refractory bacterial meningitis in this group.

Conclusion

For patients who have pathogenic positive bacterial meningitis along with consciousness disorder, CRP ≥ 50 mg/L, and/or have an isolate bacteria that is a G + bacteria, it is important to be alert to the potential for progression to refractory bacterial meningitis, which demands the physicians’ significant attention.
Intra-operative identification of a temporal bone fracture line during cochlear implant surgery: a case report
Authors: Vofo Gaelle , Shavit Sagit Stern , Eliashar Ron , Kaufmann Michal
Published: May 2023

Background

Temporal bone fractures are divided into otic capsule sparing and otic capsule involving fractures. In the latter, hearing loss, facial nerve paralysis, cerebrospinal fluid leak and meningitis have been reported to occur. The impact of hearing loss can be devastating, especially when occurring in children, with significant risk to speech development and sound localization. In the event of hearing loss, early rehabilitation is therefore of paramount importance. Identification of an intra-operative fracture line with available images and the outcome of such cases has not been reported.

Case presentation

We present the case of a 31-month-old male with an otic capsule involving temporal bone fracture, who presented with ipsilateral profound hearing loss. After all required work-up had been performed, he was admitted for a cochlear implant insertion. Per- operatively, a clear fracture line was seen at the round window niche, but a normal insertion was performed despite the anticipated potential ossification at the fracture line. The dreaded complications of cerebrospinal fluid otorrhea or non-auditory stimulation post-implant did not occur. The peculiarity of this case was its rarity, which was demonstrated by clear images that showed the fracture line on preoperative imaging and intraoperatively.

Conclusion

Cochlear implantation in the presence of a visible fracture line is feasible and the surgical procedure must not be aborted at its discovery. In these cases, post-operative bacterial meningitis can occur and should be treated aggressively with systemic antibiotics to avoid contralateral ossification of the labyrinth due to labyrinthitis.
Bulimia symptoms and anger and aggression among adolescents
Authors: Koposov Roman , Stickley Andrew , Sukhodolsky Denis , Ruchkin Vladislav
Published: May 2023

Background

Previous research has indicated that anger and aggression may be elevated in adolescents with a bulimia nervosa (BN) diagnosis. However, as yet, little is known about whether bulimia symptoms are linked to anger and aggression in adolescents in the general population. To address this deficit this study aimed to explore the associations between a clinical level of bulimia symptoms (CLBS) and anger, anger rumination and aggression in community-based adolescents, and determine whether gender is important in this context.

Methods

This study was conducted on a representative sample of youth from northwestern Russia (n = 2613, age 13–17 years old, 59.5% female) using self-report scales. A proxy variable for a CLBS was created using the Eating Disorder Diagnostic Scale. Aggression, anger and anger rumination were assessed by the Trait Anger Scale of the State Trait Anger Expression Inventory, the Anger Rumination Scale, and scales created to assess physically and verbally aggressive behavior. Multivariate analysis of covariance was used to examine the associations between the study variables.

Results

A CLBS was more prevalent in girls than in boys (13.4% vs. 3.5%). The association with anger and aggression was stronger in both genders with a CLBS, compared to those adolescents without a CLBS. In the CLBS group, boys as compared to girls scored higher on verbal and physical aggression, anger rumination and social aggression. In both the CLBS and Non-CLBS groups higher anger and aggression scores were associated with increasing age.

Conclusions

Findings suggest that aggression and anger rumination are elevated in adolescents with BN symptoms, and that the associations between anger, aggression and BN symptoms may be stronger in boys. As previous research has indicated that the presence of aggressive behaviors may affect the prognosis of BN and complicate management of the disorder, clinician screening for these behaviors in adolescents with BN symptoms may facilitate the provision of more effective treatment, especially among boys.
COVID-19 infection and vaccination uptake in men and gender-diverse people who have sex with men in the UK: analyses of a large, online community cross-sectional survey (RiiSH-COVID) undertaken November–December 2021
Authors: Ogaz Dana , Allen Hester , Reid David , Brown Jack R. G. , Howarth Alison R. , Pulford Caisey V. , Mercer Catherine H. , Saunders John , Hughes Gwenda , Mohammed Hamish
Published: May 2023

Background

Men and gender-diverse people who have sex with men are disproportionately affected by health conditions associated with increased risk of severe illness due to COVID-19 infection.

Methods

An online cross-sectional survey of men and gender-diverse people who have sex with men in the UK recruited via social networking and dating applications from 22 November-12 December 2021. Eligible participants included self-identifying men, transgender women, or gender-diverse individuals assigned male at birth (AMAB), aged ≥ 16, who were UK residents, and self-reported having had sex with an individual AMAB in the last year. We calculated self-reported COVID-19 test-positivity, proportion reporting long COVID, and COVID-19 vaccination uptake anytime from pandemic start to survey completion (November/December 2021). Logistic regression was used to assess sociodemographic, clinical, and behavioural characteristics associated with SARS-CoV-2 (COVID-19) test positivity and complete vaccination (≥ 2 vaccine doses).

Results

Among 1,039 participants (88.1% white, median age 41 years [interquartile range: 31-51]), 18.6% (95% CI: 16.3%-21.1%) reported COVID-19 test positivity, 8.3% (95% CI: 6.7%-10.1%) long COVID, and 94.5% (95% CI: 93.3%-96.1%) complete COVID-19 vaccination through late 2021. In multivariable models, COVID-19 test positivity was associated with UK country of residence (aOR: 2.22 [95% CI: 1.26-3.92], England vs outside England) and employment (aOR: 1.55 [95% CI: 1.01-2.38], current employment vs not employed). Complete COVID-19 vaccination was associated with age (aOR: 1.04 [95% CI: 1.01-1.06], per increasing year), gender (aOR: 0.26 [95% CI: 0.09-0.72], gender minority vs cisgender), education (aOR: 2.11 [95% CI: 1.12-3.98], degree-level or higher vs below degree-level), employment (aOR: 2.07 [95% CI: 1.08-3.94], current employment vs not employed), relationship status (aOR: 0.50 [95% CI: 0.25-1.00], single vs in a relationship), COVID-19 infection history (aOR: 0.47 [95% CI: 0.25-0.88], test positivity or self-perceived infection vs no history), known HPV vaccination (aOR: 3.32 [95% CI: 1.43-7.75]), and low self-worth (aOR: 0.29 [95% CI: 0.15-0.54]).

Conclusions

In this community sample, COVID-19 vaccine uptake was high overall, though lower among younger age-groups, gender minorities, and those with poorer well-being. Efforts are needed to limit COVID-19 related exacerbation of health inequalities in groups who already experience a greater burden of poor health relative to other men who have sex with men.
Prevalence of depression, syndemic factors and their impact on viral suppression among female sex workers living with HIV in eThekwini, South Africa
Authors: Bhardwaj Anvita , Comins Carly A. , Guddera Vijay , Mcingana Mfezi , Young Katherine , Phetlhu Rene , Mulumba Ntambue , Mishra Sharmistha , Hausler Harry , Baral Stefan , Schwartz Sheree
Published: May 2023

Introduction

Over half of female sex workers (FSW) in South Africa are living with HIV and clinical depression has been frequently documented among FSW. Data characterizing structural determinants of depression and the role of syndemic theory, synergistically interacting disease states, on viral suppression among FSW in South Africa are limited.

Methods

Between July 2018-March 2020, non-pregnant, cisgender women (≥ 18 years), reporting sex work as their primary income source, and diagnosed with HIV for ≥ 6 months were enrolled into the Siyaphambili trial in eThekwini, South Africa. Using baseline data, robust Poisson regression models were used to assess correlates of depression and associations between depression and syndemic factors on viral suppression.

Results

Of 1,384 participants, 459 (33%) screened positive for depression, defined as a score of ≥ 10 on the PHQ-9. Physical and sexual violence, drug use, alcohol use, anticipated stigma and internalized stigma were univariately associated with depression (all p’s < 0.05) and included the multivariate model. In the multivariate regression, prevalence of depression was higher among participants experiencing sexual violence (PR = 1.47 95% CI:1.24,1.73), physical violence 5 times or more in < 6 months (PR = 1.38 95% CI:1.07, 1.80), using illicit drugs in the last month (PR = 1.23 95%:CI 1.04, 1.48), and reporting higher levels of internalized stigma (PR = 1.11, 95% CI:1.04,1.18). Depression in the absence of the Substance Abuse, Violence and AIDS SAVA syndemic factors was associated with increased prevalence of unsuppressed viral load (aPR 1.24; 95% CI:1.08,1.43), and the SAVA substance use and violence syndemic was associated with an increase in unsuppressed viral load among non-depressed FSW (aPR 1.13; 95% CI:1.01, 1.26). Compared to those experiencing neither factors, those jointly experiencing depression and the SAVA syndemics were at increased risk for unsuppressed viral load (aPR 1.15; 95% CI:1.02,1.28).

Conclusion

Substance use, violence, and stigma were all associated with depression. Depression and syndemic factors (substance use + violence) were related to unsuppressed viral load; we did not observe higher unsuppressed viral load amongst those experiencing both depression and syndemic factors. Our findings point to the need to understand the unmet mental health needs of FSW living with HIV.

Trial registration

Clinical Trial Number: NCT03500172.
MODILM: towards better complex diseases classification using a novel multi-omics data integration learning model
Authors: Zhong Yating , Peng Yuzhong , Lin Yanmei , Chen Dingjia , Zhang Hao , Zheng Wen , Chen Yuanyuan , Wu Changliang
Published: May 2023

Background

Accurately classifying complex diseases is crucial for diagnosis and personalized treatment. Integrating multi-omics data has been demonstrated to enhance the accuracy of analyzing and classifying complex diseases. This can be attributed to the highly correlated nature of the data with various diseases, as well as the comprehensive and complementary information it provides. However, integrating multi-omics data for complex diseases is challenged by data characteristics such as high imbalance, scale variation, heterogeneity, and noise interference. These challenges further emphasize the importance of developing effective methods for multi-omics data integration.

Results

We proposed a novel multi-omics data learning model called MODILM, which integrates multiple omics data to improve the classification accuracy of complex diseases by obtaining more significant and complementary information from different single-omics data. Our approach includes four key steps: 1) constructing a similarity network for each omics data using the cosine similarity measure, 2) leveraging Graph Attention Networks to learn sample-specific and intra-association features from similarity networks for single-omics data, 3) using Multilayer Perceptron networks to map learned features to a new feature space, thereby strengthening and extracting high-level omics-specific features, and 4) fusing these high-level features using a View Correlation Discovery Network to learn cross-omics features in the label space, which results in unique class-level distinctiveness for complex diseases. To demonstrate the effectiveness of MODILM, we conducted experiments on six benchmark datasets consisting of miRNA expression, mRNA, and DNA methylation data. Our results show that MODILM outperforms state-of-the-art methods, effectively improving the accuracy of complex disease classification.

Conclusions

Our MODILM provides a more competitive way to extract and integrate important and complementary information from multiple omics data, providing a very promising tool for supporting decision-making for clinical diagnosis.
Policy analysis of the protection of Iranian households against catastrophic health expenditures: a qualitative analysis
Authors: Hedayati Maryam , Masoudi Asl Iravan , Maleki Mohammadreza , Fazaeli Ali Akbar , Goharinezhad Salime
Published: May 2023

Background

Despite the adoption of various policies and strategies in recent decades, the Iranian health system has not succeeded in protecting households against catastrophic health expenditures (CHE) and impoverishment. Accordingly, this qualitative study aimed to critically analyze current policies for reducing CHE.

Methods

This qualitative study was conducted as a retrospective policy analysis based on a document review and semi-structured interviews with key informants between July to October 2022. Two theoretical frameworks were used, including the Analysis of Determinants of Policy Impact (ADEPT) model and Walt and Gilson’s “Policy Triangle framework.” The country's related documents were searched through databases. In total, 35 participants were interviewed. Interviews and documents were analyzed using directed content analysis in MAXQDA v12 software. Interobserver reliability, peer check, and member check were done to confirm the trustworthiness of the data.

Results

Twelve main themes and 42 sub-themes emerged from the data. The findings revealed that policy accessibility, policy background, and a clear statement of goals influenced the policy process. However, resources, monitoring and evaluation, opportunities, and obligations negatively affected the implementation process. In addition, a policy analysis based on the policy triangle framework demonstrated that the main factors affecting the policy on reducing CHE in Iran were “conflicts of interest,” “contextual factors,” “monitoring and evaluation,” and “intersectoral relationship” factors.

Conclusion

The present study reflected the multifaceted nature of the barriers to reducing CHE in Iran. The implementation of the policy on reducing CHE requires the political will to improve intersectoral collaboration, strengthen the stewardship role of the Ministry of Health, design monitoring and evaluation mechanisms, and prevent personal and organizational conflicts of interest.
A cross-sectional study of the prevalence of lameness and digital dermatitis in dairy cattle herds in Egypt
Authors: Salem Shebl E. , Mesalam Ayman , Monir Ahmed
Published: May 2023

Background

Lameness is a significant problem for the dairy industry worldwide. No previous studies have evaluated the prevalence of lameness or digital dermatitis (DD) in dairy cattle herds in Egypt. A total of 16,098 dairy cows from 55 dairy herds in 11 Egyptian governorates underwent visual locomotion scoring using a 4-point scoring system. Cows that had a lameness score ≥ 2 were considered clinically lame. Following manure removal with water and using a flashlight, the cows’ hind feet were examined in the milking parlour to identify DD lesions and classify with M-score. Furthermore, each cow was assigned a hock score (a 3-point scale) and a hygiene score (a 4-point scale). The cow-, within-and between-herd prevalence of lameness and DD and associated 95% confidence intervals (CI) were calculated. The prevalence of hock lesions and poor cow hygiene was also calculated.

Results

Of the examined cows, 6,883 were found to be clinically lame (42.8%, 95% CI = 42.0–43.5%). The average within-herd prevalence of lameness was 43.1% (95% CI = 35.9–50.3%). None of the dairy herds recruited into the study were found to be free from clinical lameness. The average within-herd prevalence of DD was 6.4% (95% CI = 4.9–8.0%). The herd-level prevalence of DD was 92.7% (95% CI = 85.9–99.6%). Active DD lesions (M1, M2, M4.1) were identified in 464 cows (2.9%) while inactive lesions (M3, M4) were identified in 559 cows (3.5%). The within-herd prevalence of hock lesions (score 2 or 3) was 12.6% (95% CI = 4.03–21.1%) while a severe hock lesion had within-herd prevalence of 0.31% (95% CI = 0.12–0.51%). Cow-level prevalence of hock lesions was 6.2% (n = 847, 95% CI = 5.8–6.2%). The majority of examined cows had a hygiene score of 4 (n = 10,814, prevalence = 70.3%, 95% CI = 69.5–71%).

Conclusions

The prevalence of lameness was higher than prevalence estimates reported for other countries which could be due to differing management and/or environmental factors. DD was identified at lower prevalence in most herds but with high herd-level prevalence. Poor cow hygiene was notable in most herds. Measures to reduce the prevalence of lameness and to improve cow hygiene in dairy cattle herds in Egypt are therefore needed.
First case report of pustules associated with Escherichia fergusonii in the chinese pangolin (Manis pentadactyla aurita)
Authors: An Fuyu , Wang Kai , Wei Shichao , Yan Hongmei , Xu Xuelin , Xu Jinqian , Sun Song , Zou Jiejian , Hou Fanghui , Hua Yan
Published: May 2023

Background

Escherichia fergusonii is a common conditionally pathogenic bacterium that infects humans and animals. E. fergusonii has been reported to cause diarrhea, respiratory disease, and septicemia, but it is rarely reported to cause skin infections in animals. E. fergusonii has been isolated from the skin and muscular tissue of Chinese pangolin (Manis pentadactyla aurita). To date, there have been no reports of Chinese pangolins with clinical signs of skin diseases.

Case presentation

This case report describes the clinical case of a subadult (bodyweight: 1.1 kg) female Chinese pangolin from wild rescue with pustules and subcutaneous suppurative infection due to E. fergusonii in the abdominal skin. Bacterial culture, Biochemical analysis, PCR and histopathology were utilized to identify the bacteria in the pustule puncture fluid and infected tissue. To the best of our knowledge, this is the first report of E. fergusonii-related pustules on a Chinese pangolin.

Conclusion

This case report presents the first observed skin infection in a Chinese pangolin. E. fergusonii infection should be considered as a possible differential diagnosis of pustules and subcutaneous suppurative skin conditions in Chinese pangolins, and we also provide several recommendations for the diagnosis and treatment of this disease.
The Warburg effect modulates DHODH role in ferroptosis: a review
Authors: Amos Alvan , Amos Alex , Wu Lirong , Xia He
Published: May 2023

Ferroptosis is an iron-dependent regulated cell death that suppresses tumor growth. It is activated by extensive peroxidation of membrane phospholipids caused by oxidative stress. GPX4, an antioxidant enzyme, reduces these peroxidized membrane phospholipids thereby inhibiting ferroptosis. This enzyme has two distinct subcellular localization; the cytosol and mitochondria. Dihydroorotate dehydrogenase (DHODH) complements mitochondrial GPX4 in reducing peroxidized membrane phospholipids. It is the rate-limiting enzyme in de novo pyrimidine nucleotide biosynthesis. Its role in ferroptosis inhibition suggests that DHODH inhibitors could have two complementary mechanisms of action against tumors; inhibiting de novo pyrimidine nucleotide biosynthesis and enhancing ferroptosis. However, the link between mitochondrial function and ferroptosis, and the involvement of DHODH in the ETC suggests that its role in ferroptosis could be modulated by the Warburg effect. Therefore, we reviewed relevant literature to get an insight into the possible effect of this metabolic reprogramming on the role of DHODH in ferroptosis. Furthermore, an emerging link between DHODH and cellular GSH pool has also been highlighted. These insights could contribute to the rational design of ferroptosis-based anticancer drugs.
The oncogenic role of NF1 in gallbladder cancer through regulation of YAP1 stability by direct interaction with YAP1
Authors: Zhang Lingxiao , Jiang Lin , Zeng Ling , Jin Zhaohui , Dong Xuanjia , Zhang Yuhan , Chen Litian , Shu Yijun , Liu Yingbin , Huang Ying
Published: May 2023

Background

Gallbladder cancer (GBC) is the most prevalent and invasive biliary tract malignancy. As a GTPase-activating protein, Neurofibromin 1 (NF1) is a tumor suppressor that negatively regulates the RAS signaling pathway, and its abnormality leads to neurofibromatosis type 1 (NF-1) disease. However, the role of NF1 playing in GBC and the underlying molecular mechanism has not been defined yet.

Methods

A combination of NOZ and EH-GB1 cell lines as well as nude mice, were utilized in this study. mRNA expression and protein levels of NF1 and YAP1 were evaluated by quantitative real-time PCR (qRT-PCR), western blot (WB), and immunohistochemistry (IHC). In vitro and in vivo assays were performed to explore the biological effects of NF1 in NOZ and EH-GB1 cells via siRNA or lv-shRNA mediated knockdown. Direct interaction between NF1 and YAP1 was detected by confocal microscopy and co-immunoprecipitation (Co-IP), and further confirmed by GST pull-down assay and isothermal titration calorimetry assay (ITC). The stability of proteins was measured by western blot (WB) in the presence of cycloheximide.

Results

This study showed that a higher level of NF1 and YAP1 was found in GBC samples than in normal tissues and associated with worse prognoses. The NF1 knockdown impaired the proliferation and migration of NOZ in vivo and in vitro by downregulating YAP1 expression. Moreover, NF1 co-localized with YAP1 in NOZ and EH-GB1 cells, and the WW domains of YAP1 specifically recognized the PPQY motif of NF1. The structural modeling also indicated the hydrophobic interactions between YAP1 and NF1. On the other hand, YAP1 knockdown also impaired the proliferation of NOZ in vitro, phenocopying the effects of NF1 knockdown. Overexpression of YAP1 can partially rescue the impaired proliferation in NF1 stably knockdown cells. In mechanism, NF1 interacted with YAP1 and increased the stability of YAP1 by preventing ubiquitination.

Conclusions

Our findings discovered a novel oncogenic function of NF1 by directly interacting with YAP1 protein and stabilizing YAP1 to protect it from proteasome degradation in NOZ cells. NF1 may serve as a potential therapeutic target in GBC.
Benefits of applying molecular barcoding systems are not uniform across different genomic applications
Authors: Bieler Jonathan , Kubik Slawomir , Macheret Morgane , Pozzorini Christian , Willig Adrian , Xu Zhenyu
Published: May 2023

Background

Despite the wide variety of Next Generation Sequencing (NGS)-based methods, it remains challenging to detect mutations present at very low frequencies. This problem is particularly relevant in oncology, where the limiting amount of input material, and its low quality, often limit the performance of the assays. Unique Molecular Identifiers (UMIs) are a molecular barcoding system often coupled with computational methods of noise suppression to improve the reliability of detection of rare variants. Although widely adopted, UMI inclusion imposes additional technical complexity and sequencing cost. Currently, there are no guidelines on UMI usage nor a comprehensive evaluation of their advantage across different applications.

Methods

We used DNA sequencing data generated by molecular barcoding and hybridization-based enrichment, from various types and quantities of input material (fresh frozen, formaldehyde-treated and cell-free DNA), to evaluate the performance of variant calling in different clinically relevant contexts.

Results

Noise suppression achieved by read grouping based on fragment mapping positions ensures reliable variant calling for many experimental designs even without exogenous UMIs. Exogenous barcodes significantly improve performance only when mapping position collisions occur, which is common in cell-free DNA.

Conclusions

We demonstrate that UMI usage is not universally beneficial across experimental designs and that it is worthwhile to critically consider the comparative advantage of UMI usage for a given NGS application prior to experimental design.
Neuroinflammatory CSF biomarkers MIF, sTREM1, and sTREM2 show dynamic expression profiles in Alzheimer’s disease
Authors: Hok-A-Hin Yanaika S. , del Campo Marta , Boiten Walter A. , Stoops Erik , Vanhooren Melanie , Lemstra Afina W. , van der Flier Wiesje M. , Teunissen Charlotte E.
Published: May 2023

Background

There is a need for novel fluid biomarkers tracking neuroinflammatory responses in Alzheimer’s disease (AD). Our recent cerebrospinal fluid (CSF) proteomics study revealed that migration inhibitory factor (MIF) and soluble triggering receptor expressed on myeloid cells 1 (sTREM1) increased along the AD continuum. We aimed to assess the potential use of these proteins, in addition to sTREM2, as CSF biomarkers to monitor inflammatory processes in AD.

Methods

We included cognitively unimpaired controls (n = 67, 63 ± 9 years, 24% females, all amyloid negative), patients with mild cognitive impairment (MCI; n = 92, 65 ± 7 years, 47% females, 65% amyloid positive), AD (n = 38, 67 ± 6 years, 8% females, all amyloid positive), and DLB (n = 50, 67 ± 6 years, 5% females, 54% amyloid positive). MIF, sTREM1, and sTREM2 levels were measured by validated immunoassays. Differences in protein levels between groups were tested with analysis of covariance (corrected for age and sex). Spearman correlation analysis was performed to evaluate the association between these neuroinflammatory markers with AD-CSF biomarkers (Aβ42, tTau, pTau) and mini-mental state examination (MMSE) scores.

Results

MIF levels were increased in MCI (p < 0.01), AD (p < 0.05), and DLB (p > 0.05) compared to controls. Levels of sTREM1 were specifically increased in AD compared to controls (p < 0.01), MCI (p < 0.05), and DLB patients (p > 0.05), while sTREM2 levels were increased specifically in MCI compared to all other groups (all p < 0.001). Neuroinflammatory proteins were highly correlated with CSF pTau levels (MIF: all groups; sTREM1: MCI, AD and DLB; sTREM2: controls, MCI and DLB). Correlations with MMSE scores were observed in specific clinical groups (MIF in controls, sTREM1 in AD, and sTREM2 in DLB).

Conclusion

Inflammatory-related proteins show diverse expression profiles along different AD stages, with increased protein levels in the MCI stage (MIF and sTREM2) and AD stage (MIF and sTREM1). The associations of these inflammatory markers primarily with CSF pTau levels indicate an intertwined relationship between tau pathology and inflammation. These neuroinflammatory markers might be useful in clinical trials to capture dynamics in inflammatory responses or monitor drug–target engagement of inflammatory modulators.
Armed conflict and household food insecurity: evidence from war-torn Tigray, Ethiopia
Authors: Weldegiargis Aregawi Weldegebreal , Abebe Haftom Temesgen , Abraha Hiluf Ebuy , Abrha Meron Micheale , Tesfay Tsegay Berihu , Belay Rieye Esayas , Araya Alemnesh Abraha , Gebregziabher Mengish Bahresilassie , Godefay Hagos , Mulugeta Afework
Published: May 2023

Background

Exposure to armed conflicts result in strongly adverse and often irreversible short- and long-term effects which may transmit across generations. Armed conflicts directly cause food insecurity and starvation by disruption and destruction of food systems, reduce farming populations, destroying infrastructure, reducing resilience, and increasing vulnerabilities, disruptions in access to market, increasing food price or making goods and services unavailable altogether. The objective of the present study was to determine the status of household food insecurity in the armed conflict affected communities of Tigray in terms of Access, Experience and Hunger scale.

Method

Community-based cross-sectional study was conducted to assess impact of armed conflict on household food insecurity among households with children with under one year. FHI 360 and FAO guidelines were used to quantify household food insecurity and Household hunger status.

Results

Three-fourth of the households had anxiety about food supply and eat undesired monotonous diet due to lack of resources. Households were obliged to eat few kinds of foods, eat smaller meals, eat foods they do not want to eat, or went a whole day without eating any food. Household food insecurity access, food insecurity experience, and hunger scales significantly increased by 43.3 (95% CI: 41.9–44.7), 41.9 (95% CI: 40.5–43.3) and 32.5 (95% CI: 31.0-33.9) percentage points from the prewar period.

Conclusions

Household food insecurity levels and household hunger status of the study communities was unacceptably high. The armed conflict has significant negative effect on food security in Tigray. It is recommended that the study communities need to be protected from the immediate and long-term consequences of conflict-induced household food insecurity.
Systematic screening identifies ABCG2 as critical factor underlying synergy of kinase inhibitors with transcriptional CDK inhibitors
Authors: van der Noord Vera E. , van der Stel Wanda , Louwerens Gijs , Verhoeven Danielle , Kuiken Hendrik J. , Lieftink Cor , Grandits Melanie , Ecker Gerhard F. , Beijersbergen Roderick L. , Bouwman Peter , Le Dévédec Sylvia E. , van de Water Bob
Published: May 2023

Background

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with limited treatment options and poor clinical prognosis. Inhibitors of transcriptional CDKs are currently under thorough investigation for application in the treatment of multiple cancer types, including breast cancer. These studies have raised interest in combining these inhibitors, including CDK12/13 inhibitor THZ531, with a variety of other anti-cancer agents. However, the full scope of these potential synergistic interactions of transcriptional CDK inhibitors with kinase inhibitors has not been systematically investigated. Moreover, the mechanisms behind these previously described synergistic interactions remain largely elusive.

Methods

Kinase inhibitor combination screenings were performed to identify kinase inhibitors that synergize with CDK7 inhibitor THZ1 and CDK12/13 inhibitor THZ531 in TNBC cell lines. CRISPR-Cas9 knockout screening and transcriptomic evaluation of resistant versus sensitive cell lines were performed to identify genes critical for THZ531 resistance. RNA sequencing analysis after treatment with individual and combined synergistic treatments was performed to gain further insights into the mechanism of this synergy. Kinase inhibitor screening in combination with visualization of ABCG2-substrate pheophorbide A was used to identify kinase inhibitors that inhibit ABCG2. Multiple transcriptional CDK inhibitors were evaluated to extend the significance of the found mechanism to other transcriptional CDK inhibitors.

Results

We show that a very high number of tyrosine kinase inhibitors synergize with the CDK12/13 inhibitor THZ531. Yet, we identified the multidrug transporter ABCG2 as key determinant of THZ531 resistance in TNBC cells. Mechanistically, we demonstrate that most synergistic kinase inhibitors block ABCG2 function, thereby sensitizing cells to transcriptional CDK inhibitors, including THZ531. Accordingly, these kinase inhibitors potentiate the effects of THZ531, disrupting gene expression and increasing intronic polyadenylation.

Conclusion

Overall, this study demonstrates the critical role of ABCG2 in limiting the efficacy of transcriptional CDK inhibitors and identifies multiple kinase inhibitors that disrupt ABCG2 transporter function and thereby synergize with these CDK inhibitors. These findings therefore further facilitate the development of new (combination) therapies targeting transcriptional CDKs and highlight the importance of evaluating the role of ABC transporters in synergistic drug–drug interactions in general.
Probing pathways by which rhynchophylline modifies sleep using spatial transcriptomics
Authors: Ballester Roig Maria Neus , Leduc Tanya , Dufort-Gervais Julien , Maghmoul Yousra , Tastet Olivier , Mongrain Valérie
Published: May 2023

Background

Rhynchophylline (RHY) is an alkaloid component of Uncaria, which are plants extensively used in traditional Asian medicines. Uncaria treatments increase sleep time and quality in humans, and RHY induces sleep in rats. However, like many traditional natural treatments, the mechanisms of action of RHY and Uncaria remain evasive. Moreover, it is unknown whether RHY modifies key brain oscillations during sleep. We thus aimed at defining the effects of RHY on sleep architecture and oscillations throughout a 24-h cycle, as well as identifying the underlying molecular mechanisms. Mice received systemic RHY injections at two times of the day (beginning and end of the light period), and vigilance states were studied by electrocorticographic recordings.

Results

RHY enhanced slow wave sleep (SWS) after both injections, suppressed paradoxical sleep (PS) in the light but enhanced PS in the dark period. Furthermore, RHY modified brain oscillations during both wakefulness and SWS (including delta activity dynamics) in a time-dependent manner. Interestingly, most effects were larger in females. A brain spatial transcriptomic analysis showed that RHY modifies the expression of genes linked to cell movement, apoptosis/necrosis, and transcription/translation in a brain region-independent manner, and changes those linked to sleep regulation (e.g., Hcrt, Pmch) in a brain region-specific manner (e.g., in the hypothalamus).

Conclusions

The findings provide support to the sleep-inducing effect of RHY, expose the relevance to shape wake/sleep oscillations, and highlight its effects on the transcriptome with a high spatial resolution. The exposed molecular mechanisms underlying the effect of a natural compound should benefit sleep- and brain-related medicine.

Graphical Abstract
Cartilage diversification and modularity drove the evolution of the ancestral vertebrate head skeleton
Authors: Root Zachary D. , Jandzik David , Gould Claire , Allen Cara , Brewer Margaux , Medeiros Daniel M.
Published: May 2023

The vertebrate head skeleton has evolved a myriad of forms since their divergence from invertebrate chordates. The connection between novel gene expression and cell types is therefore of importance in this process. The transformation of the jawed vertebrate (gnathostome) head skeleton from oral cirri to jointed jaw elements required a diversity of cartilages as well as changes in the patterning of these tissues. Although lampreys are a sister clade to gnathostomes, they display skeletal diversity with distinct gene expression and histologies, a useful model for addressing joint evolution. Specifically, the lamprey tissue known as mucocartilage has noted similarities with the jointed elements of the mandibular arch in jawed vertebrates. We thus asked whether the cells in lamprey mucocartilage and gnathostome joint tissue could be considered homologous. To do this, we characterized new genes that are involved in gnathostome joint formation and characterized the histochemical properties of lamprey skeletal types. We find that most of these genes are minimally found in mucocartilage and are likely later innovations, but we do identify new activity for gdf5/6/7b in both hyaline and mucocartilage, supporting its role as a chondrogenic regulator. Contrary to previous works, our histological assays do not find any perichondrial fibroblasts surrounding mucocartilage, suggesting that mucocartilage is non-skeletogenic tissue that is partially chondrified. Interestingly, we also identify new histochemical features of the lamprey otic capsule that diverge from normal hyaline. Paired with our new insights into lamprey mucocartilage, we propose a broader framework for skeletal evolution in which an ancestral soxD/E and gdf5/6/7 network directs mesenchyme along a spectrum of cartilage-like features.
Utilization of non-coherent accumulation for LTE TOA estimation in weak LOS signal environments
Authors: Tian Jin , Fangchi Li , Yafei Tian , Dongmei Liu
Published: May 2023

Ground localization systems based on cellular signals are vulnerable to the hazards of signal power attenuation and multipath propagation in urban environments. Non-coherent accumulation is an effective solution to this problem, but its application to cellular localization systems has not been properly discussed. In this paper, we propose two cellular time-of-arrival (TOA) estimation methods based on non-coherent accumulation: the “TOA estimation algorithm based on non-coherent accumulation of the channel impulse response” (nch-CIR) in the time domain and the “Super Resolution TOA Estimation Algorithm based on non-coherent accumulation of the covariance matrix” (nch-SRA) in the frequency domain. Among these two methods, the nch-CIR algorithm has a lower computational cost and better anti-noise performance, and the nch-SRA algorithm has better performance in terms of multipath delay estimation. Through theoretical analysis and extensive simulations, we also discuss the influence of mobility on these two methods. In addition, experiments are conducted to evaluate the performance of the proposed method using real collected cellular signals. The results show that both nch-CIR and nch-SRA can achieve a better performance compared with the conventional methods.
Efficacy and safety of different regimens in the treatment of patients with latent tuberculosis infection: a systematic review and network meta-analysis of randomized controlled trials
Authors: Assefa Dawit Getachew , Bedru Ahmed , Zeleke Eden Dagnachew , Negash Solomon Emiru , Debela Dejene Tolossa , Molla Wondowsen , Mengistu Nebiyu , Woldesenbet Tigist Tekle , Bedane Neway Fekede , Kajogoo Violet Dismas , Atim Mary Gorret , Manyazewal Tsegahun
Published: May 2023

Background

Treatment of latent tuberculosis infection (LTBI) is effective in preventing progression to TB disease. This study aimed to synthesize available evidence on the efficacy, adherence, and safety of LTBI treatment in order to assist policymakers to design appropriate national treatment policies and treatment protocols.

Method

The PRISMA-NMA was used to review and report this research. Randomized controlled trials which compared the efficacy and safety of LTBI treatments were included. A systematic literature search was done to identify relevant articles from online databases PubMed/ MEDLINE, Embase, and Cochrane Center for Clinical Trial database (CENTRAL). The network meta-analysis was done using R- studio Version 1.4.1103.

Result

In this review, 42 studies were included, which enrolled 46,022 people who had recent contact with patients with active tuberculosis, evidence radiological of previous tuberculosis, tuberculin test equal or greater than 5 mm, radiographs that indicated inactive fibrotic or calcified parenchymal and/or lymph node lesions, had conversion to positive results on a tuberculin skin test, participants living with HIV, chronic Silicosis, immigrants, prisoners, old people, and pregnant women who were at risk for latent TB were included.

The incidence of TB among people living with HIV who have taken 3RH as TPT was lower, followed by 48%,followed by 6H (41%). However, 3HP has also the potential to reduce the incidence of TB by 36% among HIV negative patients who had TB contact history. Patients’ adherence to TPT was higher among patients who have taken 4R (RR 1.38 95% CI 1.0,1.89) followed by 3RH (34%). The proportion of subjects who permanently discontinued a study drug because of an adverse event were three times higher in the 3RH treatment group. Furthermore, the risk of grade 3 and 4 liver toxicity was significantly higher in 9H followed by 1HP, and 6H.

Conclusion

From this review, it can be concluded 3RH and 6H has a significant impact on the reduction of TB incidence among PLWH and 3HP among HIV negative people who had TB contact history. However, combinations of rifampicin either with isoniazid were significantly associated with adverse events which resulted in permanent discontinuation among adult patients. Furthermore, grade 3 and 4 liver toxicity was more common in patents who have taken 9H, 1HP, and 6H. This may support the current recommended TPT regimen of 3HP, 3RH, and 6H.
Dietary fiber during gestation improves lactational feed intake of sows by modulating gut microbiota
Authors: Li Shuang , Zheng Jie , He Jiaqi , Liu Hao , Huang Yingyan , Huang Liansu , Wang Ke , Zhao Xilun , Feng Bin , Che Lianqiang , Fang Zhengfeng , Li Jian , Xu Shengyu , Lin Yan , Jiang Xuemei , Hua Lun , Zhuo Yong , Wu De
Published: May 2023

Background

The feed intake of sows during lactation is often lower than their needs. High-fiber feed is usually used during gestation to increase the voluntary feed intake of sows during lactation. However, the mechanism underlying the effect of bulky diets on the appetites of sows during lactation have not been fully clarified. The current study was conducted to determine whether a high-fiber diet during gestation improves lactational feed intake (LFI) of sows by modulating gut microbiota.

Methods

We selected an appropriate high-fiber diet during gestation and utilized the fecal microbial transplantation (FMT) method to conduct research on the role of the gut microbiota in feed intake regulation of sows during lactation, as follows: high-fiber (HF) diet during gestation (n = 23), low-fiber (LF) diet during gestation (n = 23), and low-fiber diet + HF-FMT (LFM) during gestation (n = 23).

Results

Compared with the LF, sows in the HF and LFM groups had a higher LFI, while the sows also had higher peptide tyrosine tyrosine and glucagon-like peptide 1 on d 110 of gestation (G110 d). The litter weight gain of piglets during lactation and weaning weight of piglets from LFM group were higher than LF group. Sows given a HF diet had lower Proteobacteria, especially Escherichia-Shigella, on G110 d and higher Lactobacillus, especially Lactobacillus_mucosae_LM1 and Lactobacillus_amylovorus, on d 7 of lactation (L7 d). The abundance of Escherichia-Shigella was reduced by HF-FMT in numerically compared with the LF. In addition, HF and HF-FMT both decreased the perinatal concentrations of proinflammatory factors, such as endotoxin (ET), lipocalin-2 (LCN-2), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β). The concentration of ET and LCN-2 and the abundance of Proteobacteria and Escherichia-Shigella were negatively correlated with the LFI of sows.

Conclusion

The high abundance of Proteobacteria, especially Escherichia-Shigella of LF sows in late gestation, led to increased endotoxin levels, which result in inflammatory responses and adverse effects on the LFI of sows. Adding HF during gestation reverses this process by increasing the abundance of Lactobacillus, especially Lactobacillus_mucosae_LM1 and Lactobacillus_amylovorus.
Graft failure and revision rate after ACL repair with dynamic intraligamentary stabilization. One‐year results of a prospective case series of 155 patients
Authors: Farid Ajmal , Gommers Sophie A. , Sierevelt Inger N. , van Eijk Floor , van Kampen Paulien M. , Haverkamp Daniël ,   Dutch A. C. L. repair study group
Published: May 2023

Purpose

The aim of this study was to assess graft failure, revision rate, and functional outcomes after treatment of acute ACL rupture with dynamic intraligamentary stabilization (DIS) Ligamys device one year post surgery. Additionally, differences in functional outcome between patients with and without anteroposterior laxity were assessed. It was hypothesized that the failure rate of DIS was non‐inferior to that of previously reported ACL reconstruction (10%).

Methods

In this prospectively designed multicenter study, including patients with an acute ACL rupture, DIS was performed within 21 days after rupture. Primary outcome was failure of the graft at 1 year post surgery, defined as 1) re‐rupture of the graft, 2) revision of DIS, or 3) a > 3 mm side‐to‐side difference in anterior tibial translation compared to the non‐operated knee (∆ATT), measured by the KT1000 device. Additional analysis was performed using a 5 mm threshold. The subjective International Knee Documentation Committee Score (IKDC) and Numerical Rating Scales (NRS) for pain and confidence were used to evaluate functional outcome.

Results

A total of 155 patients were included with a mean age at surgery of 27.8 years (SD 9.4). The mean interval from rupture to DIS was 16.4 days (SD 5.2). At a median follow‐up of 13 months (IQR 12–18) the failure rate of the graft was 30.2% (95%CI:22.0–39.4); 11 patients (7%) required secondary reconstructive surgery and of the 105 patients who attended ATT measurement, 24 patients (23%) had an ∆ATT > 3 mm. Secondary analysis, based on a 5 mm threshold, revealed a failure rate of 22.4% (95%CI: 15.2; 31.1). A total of 39 patients (25%) reported at least one complication, comprising mainly arthrofibrosis, traumatic re‐rupture and pain. In these patients, removal of the monoblock was performed in 21 cases (13.5%). At follow‐up no significant differences in functional outcomes between patients with ∆ATT > 3 mm and stable ATT were observed.

Conclusion

This prospective multicenter study found a high failure rate at one year follow‐up of 30% (7% revision surgery and 23% > 3 mm side‐to‐side difference in anterior tibial translation) in patients treated by primary repair of the ACL with DIS, and did therefore not demonstrate non‐inferiority to ACL reconstruction. For patients who did not require secondary reconstructive surgery, this study found good functional outcomes, also in case of persistent anteroposterior knee laxity (∆ATT > 3 mm).

Level of evidence

Level IV.