bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the effect of capsaicin on gene expression and chemotherapy sensitization in gastric cancer cells
Authors: Meng Weijian , Xie Sophia , Zhang Rui , Shen Jie
Published: September 2024

Purpose

Capsaicin has previously been demonstrated to exhibit anti-tumor effect in various cancer type. However, the effect of capsaicin on gene expression and its potential mechanism on chemotherapy sensitization were still uncertain.

Method

Human AGS gastric cancer cell line was treated with different concentrations of capsaicin, 5-fluorouracil and oxaliplatin. Cell viability was assessed using cell viability assay. High throughput RNA sequencing was used to screen differentially expressed genes triggered by capsaicin in AGS cells. qPCR and Western blotting were used to detect the expression of mRNAs and proteins induced by capsaicin.

Result

Capsaicin could significantly inhibit cell viability at a dose-depend manner in AGS gastric cancer cell line. Through high-throughput RNA sequencing, genes regulating DNA repair, DNA replication and chromosome assemble pathways were analyzed to be down-regulated by capsaicin. qPCR and western blot assay demonstrated that capsaicin could inhibit expression of the key enzymes (FEN1, LIG1 and PARP1) which play critical roles in DNA damage response and chemotherapy resistance. In vitro assay demonstrated that capsaicin could significantly induce chemo-sensitivity of 5-FU and Oxaliplatin at low dose.

Conclusion

Capsaicin could inhibit DNA repair pathway, which might contribute to cell growth inhibition and improvement of chemotherapy sensitization. These results revealed a novel function of capsaicin in DNA damage repair and provided new potential targets in cancer therapy.
Control of alveolar bone development, homeostasis, and socket healing by salt inducible kinases
Authors: Tokavanich Nicha , Chan Byron , Strauss Katelyn , Castro Andrade Christian D. , Arai Yuki , Nagata Mizuki , Foretz Marc , Brooks Daniel J. , Ono Noriaki , Ono Wanida , Wein Marc N.
Published: September 2024

Alveolar bone supports and anchors teeth. The parathyroid hormone-related protein (PTHrP) pathway plays a key role in alveolar bone biology. Salt inducible kinases (SIKs) are important downstream regulators of PTH/PTHrP signaling in the appendicular skeleton where SIK inhibition increases bone formation and trabecular bone mass. However, the function of these kinases in alveolar bone remains unknown. Here, we report a critical role for SIK2/SIK3 in alveolar bone development, homeostasis, and socket healing after tooth extraction. Inducible SIK2/SIK3 deletion led to dramatic alveolar bone defects without changes in tooth eruption. Ablating these kinases impairs alveolar bone formation due to disrupted osteoblast maturation, a finding associated with ectopic periostin expression by fibrous cells in regions of absent alveolar bone at steady state and following molar extraction. Distinct phenotypic consequences of SIK2/SIK3 deletion in appendicular versus craniofacial bones prompted us to identify a specific transcriptomic signature in alveolar versus long bone osteoblasts. Thus, SIK2/SIK3 deletion illuminates a key role for these kinases in alveolar bone biology and highlights the emerging concept that different osteoblast subsets utilize unique genetic programs.

Summary statement

SIK2/SIK3 deletion in alveolar bone reduces bone formation and mass by impairing osteoblast maturation, unlike in long bones, where it increases bone formation and mass.
The Pax transcription factor EGL-38 links EGFR signaling to assembly of a cell-type specific apical extracellular matrix in theCaenorhabditis elegansvulva
Authors: Schmidt Helen F. , Darwin Chelsea B. , Sundaram Meera V.
Published: September 2024

The surface of epithelial tissues is covered by an apical extracellular matrix (aECM). The aECMs of different tissues have distinct compositions to serve distinct functions, yet how a particular cell type assembles the proper aECM is not well understood. We used the cell-type specific matrix of theC. elegansvulva to investigate the connection between cell identity and matrix assembly. The vulva is an epithelial tube composed of seven cell types descending from EGFR/Ras-dependent (1°) and Notch-dependent (2°) lineages. Vulva aECM contains multiple Zona Pellucida domain (ZP) proteins, which are a common component of aECMs across life. ZP proteins LET-653 and CUTL-18 assemble on 1° cell surfaces, while NOAH-1 assembles on a subset of 2° surfaces. All three ZP genes are broadly transcribed, indicating that cell-type specific ZP assembly must be determined by features of the destination cell surface. The paired box (Pax) transcription factor EGL-38 promotes assembly of 1° matrix and prevents inappropriate assembly of 2° matrix, suggesting that EGL-38 promotes expression of one or more ZP matrix organizers. Our results connect the known signaling pathways and various downstream effectors to EGL-38/Pax expression and the ZP matrix component of vulva cell fate execution. We propose that dedicated transcriptional networks may contribute to cell-appropriate assembly of aECM in many epithelial organs.

Highlights

C. elegansvulva apical extracellular matrix is cell-type specific

Broadly transcribed Zona Pellucida domain proteins assemble in specific matrices

The Pax2/5/8 homolog EGL-38 promotes assembly of the 1° vulva cell matrix

EGL-38 expression and 1° cell matrix assembly depend on EGFR signaling
Lifestyle Profiling Using Wearables and Prediction of Glucose Metabolism in Individuals with Normoglycemia or Prediabetes
Authors: Park Heyjun , Metwally Ahmed A. , Delfarah Alireza , Wu Yue , Perelman Dalia , Rodgar Majid , Mayer Caleb , Celli Alessandra , McLaughlin Tracey , Mignot Emmanuel , Snyder Michael
Published: September 2024

This study examined the relationship between lifestyles (diet, sleep, and physical activity) and glucose responses at a personal level. 36 healthy adults in the Bay Area were monitored for their lifestyles and glucose levels using wearables and continuous glucose monitoring (NCT03919877). Gold-standard metabolic tests were conducted to phenotype metabolic characteristics. Through the lifestyle data (2,307 meals, 1,809 nights, and 2,447 days) and 231,206 CGM readings from metabolically-phenotyped individuals with normoglycemia or prediabetes, we found: 1) eating timing was associated with hyperglycemia, muscle insulin resistance (IR), and incretin dysfunction, whereas nutrient intakes were not; 2) timing of increased activity in muscle IS and IR participants was associated with differential benefits of glucose control; 3) Integrated ML models using lifestyle factors predicted distinct metabolic characteristics (muscle, adipose IR or incretin dysfunction). Our data indicate the differential impact of lifestyles on glucose regulation among individuals with different metabolic phenotypes, highlighting the value of personalized lifestyle modifications.
Neuroligin fragments as blood-based biomarkers for early detection of Alzheimer’s disease
Authors: Forestieri Fernandes Milton Guilherme , Pinard Maxime , Sokullu Esen , Gagnon Jean-François , Calon Frédéric , Coulombe Benoit ,   the Consortium for the early identification of Alzheimer’s disease-Quebec (CIMA-Q), Brouillette Jonathan
Published: September 2024

INTRODUCTION

Biomarkers for early detection of Alzheimer’s disease (AD) are essential for improving treatments. Fragments of the synaptic protein neuroligins (NLGNs) are released into the blood due to synaptic degeneration, which occurs in the early stages of AD.

METHODS

We used MS2-targeted mass spectrometry on blood samples from the CIMA-Q cohort to assess the potential of NLGN fragments as blood-based biomarkers for amnestic mild cognitive impairment (aMCI), a prodromal stage of AD.

RESULTS

We found higher blood levels of certain NLGN fragments in both aMCI and AD patients compared to healthy subjects. Within these same samples, the levels of Tau phosphorylated at various epitopes were higher in AD subjects but not in aMCI individuals.

DISCUSSION

Synaptic proteins such as NLGNs could serve as effective biomarkers for detecting the disease in its prodromal stage. This early detection could accelerate diagnosis and therapeutic intervention before neurodegeneration leads to irreversible brain damage.
Dissecting causal relationships between cortical morphology and neuropsychiatric disorders: a bidirectional Mendelian randomization study
Authors: Lin Bochao Danae , Li Yunzhi , Goula Anastasia A. , Chang Xiao , Grasby Katrina L. , Medland Sarah , Andreassen Ole A. , Rutten Bart P. F. , Guloksuz Sinan , van der Meer Dennis , Luykx Jurjen J.
Published: September 2024

Brain cortical morphology, indexed by its surface area and thickness, is known to be highly heritable. Previous research has suggested a relationship of cortical morphology with several neuropsychiatric phenotypes. However, the multitude of potential confounders makes it difficult to establish causal relationships. Here, we employ Generalized Summary-data-based Mendelian Randomization and a series of sensitivity analyses to investigate causal links between 70 cortical morphology measures and 199 neuropsychiatric, behavioral, and metabolic phenotypes. We show that total brain cortical surface area (TSA) has significant positive causal effects on 18 phenotypes. The strongest effects include TSA positively influencing cognitive performance, while reverse analyses reveal small effects of cognitive performance on TSA. Global mean cortical thickness (MTH) exhibits significant causal effects on five phenotypes, including schizophrenia. MTH reduces schizophrenia risk and bidirectional causality is found between MTH and smoking initiation. Finally, in regional analyses we detect positive influences of the transverse temporal surface area on cognitive performance and negative influences of transverse temporal thickness on schizophrenia risk. Overall, our results highlight bidirectional associations between TSA, MTH, and neuropsychiatric traits. These insights offer potential avenues for intervention studies aimed at improving brain health.
Dynamic cerebral autoregulation during and 3 months after endovascular treatment in large-vessel occlusion stroke
Authors: Heiberg Adam Vittrup , Lukassen Troels Gil , Truelsen Thomas Clement , Borgwardt Henrik Gutte , Benndorf Goetz , Sølling Christine , Schytz Henrik Winther , Møller Kirsten , Hansen Klaus , Iversen Helle Klingenberg
Published: September 2024

Acute ischemic stroke caused by large-vessel occlusion is effectively treated by endovascular treatment (EVT). However, treatment could be further refined by improved understanding of the pathophysiology, including dynamic cerebral autoregulation (dCA). Near-infrared spectroscopy (NIRS) requires virtually no setup time and enables dCA investigation during EVT by measuring dynamic concentration in cortical oxygenated hemoglobin (OxyHb). We aimed to investigate dCA during EVT, before and after recanalization, and at follow-up (FU) after 24 hours and 90 days. We applied interhemispheric transfer function analysis (TFA) of low-frequency (LF) oscillations (0.07-0.2 Hz) in OxyHb that yields the dCA measures, gain and phase shift. We found higher LF gain in patients with favorable outcome. While dCA was stable for most patients during EVT, LF phase shift increased immediately after recanalization for patients with milder symptom severity and at 24-hour FU for patients with more severe symptoms. Adjusted for age, infarct size before EVT, and recanalization success, average LF gain predicted independent functional outcome, symptom severity and mortality at 90-day FU. In conclusion, interhemispheric TFA based on NIRS provides insights into dCA during EVT that could potentially be applied in the development of individualized treatment. The method relies on intact contralateral dCA which needs further investigation.

Clinical Trial Registration

ClinicalTrial.gov:NCT03738644.Https://clinicaltrials.gov/study/NCT03738644.
The isoniazid analog IQG-607 is not a direct substrate for theMycobacterium tuberculosiscatalase-peroxidase KatG
Authors: Barsé Laísa Quadros , Roth Candida Deves , da Silva Dadda Adilio , Rambo Raoní Scheibler , Dalberto Pedro Ferrari , Pissinate Kenia , Nunes José Eduardo Sacconi , Etchart Renata Jardim , Machado Pablo , Basso Luiz Augusto , Bizarro Cristiano Valim
Published: September 2024

Tuberculosis (TB) is an infectious disease caused mainly byMycobacterium tuberculosis(Mtb) and is responsible for millions of deaths. New Mtb strains resistant to TB drugs are emerging and spreading. The first-line TB drug, isoniazid (INH), must be activated inside mycobacterial cells by the catalase-peroxidase enzyme KatG to exert its antimicrobial activity, and mutations on thekatGgene are a significant cause of INH resistance in clinics. The metal-containing compound IQG-607 is an INH analog developed to inhibit the target of INH, the FASII enzyme enoyl-ACP-reductase (InhA), without requiring KatG. However, we recently showed that inside mycobacterial cells, IQG-607 activity depends on KatG. Hence, this compound might also be activated by KatG to inhibit InhA. We evaluated whether recombinant MtKatG uses IQG-607 as a substrate in oxidation reactions and adduct formation with NAD+. A recombinant MtKatG was produced inE. coliand purified in a 3-step protocol to obtain a homogeneous protein. An HPLC method was optimized to monitor both oxidation and adduct products, and our assay system was validated by performing control reactions using INH as a substrate. We found that the metal-based compound IQG-607 is not a substrate for recombinant MtKatG under all conditions tested.
Molecular insights into the stimulation of SNM1A nuclease activity by CSB during interstrand crosslink processing
Authors: Roddan Rebecca , Nathan William J. , Newman Joseph A. , El-Sagheer Afaf , Wilson David M. , Brown Tom , Schofield Christopher J. , McHugh Peter J.
Published: September 2024

The SNM1A exonuclease plays a key role in repair of interstrand crosslinks (ICLs) which represent a particularly toxic class of DNA damage. Previous work suggests that the SWI/SNF family ATP-dependent, chromatin remodeler, Cockayne Syndrome B protein (CSB) interacts with SNM1A, during transcription-coupled DNA interstrand crosslink repair (TC-ICL repair). Here, we validate this interaction using purified proteins and demonstrate that the ubiquitin-binding and winged-helix domains of CSB are required for interaction with the catalytic domain of SNM1A. The winged helix domain is essential for binding, although high-affinity SNM1A binding requires the entire CSB C-terminal region (residues 1187-1493), where two copies of the C-terminal domain of CSB are necessary for a stable interaction with SNM1A. CSB stimulates SNM1A nuclease activity on varied model DNA repair intermediate substrates. Importantly, CSB was observed to stimulate digestion through ICLsin vitro, implying a key role of the interaction in ‘unhooking’ during TC-ICL repair. AlphaFold3 models of CSB constructs complexed with the SNM1A catalytic domain enabled mapping of the molecular contacts required for the CSB-SNM1A interaction. This identified specific protein-protein interactions necessary for CSB’s stimulation of SNM1A’s activity that we confirmed experimentally. Additionally, our studies reveal the C-terminal region of CSB as a novel DNA binding region that also is involved in stimulation of SNM1A-mediated ICL repair. Moreover, targeting protein-protein interactions that are vital for specific nuclease activities, such as CSB’s stimulation of SNM1A’s nuclease activity, may be a productive alternative therapeutic strategy to nuclease active site inhibition.
Structural Basis for Dimerization and Activation of UvrD-family Helicases
Authors: Chadda Ankita , Nguyen Binh , Lohman Timothy M. , Galburt Eric A.
Published: September 2024

UvrD-family helicases are superfamily 1A motor proteins that function during DNA replication, recombination, repair, and transcription. UvrD family monomers translocate along single stranded (ss) DNA but need to be activated by dimerization to unwind DNA in the absence of force or accessory factors. However, prior structural studies have only revealed monomeric complexes. Here, we report the first structures of a dimeric UvrD-family helicase,Mycobacterium tuberculosisUvrD1, both free and bound to a DNA junction. In each structure, the dimer interface occurs between the 2B subdomains of each subunit. The apo UvrD1 dimer is observed in symmetric compact and extended forms indicating substantial flexibility. This symmetry is broken in the DNA-bound dimer complex with leading and trailing subunits adopting distinct conformations. Biochemical experiments reveal that theE. coliUvrD dimer shares the same 2B-2B interface. In contrast to the dimeric structures, an inactive, auto-inhibited UvrD1 DNA-bound monomer structure reveals 2B subdomain-DNA contacts that are likely inhibitory. The major re-orientation of the 2B subdomains that occurs upon UvrD1 dimerization prevents these duplex DNA interactions, thus relieving the auto-inhibition. These structures reveal that the 2B subdomain serves a major regulatory role rather than participating directly in DNA unwinding.
Structural characterization of Mpn444, an essential lipoprotein ofMycoplasma pneumoniae
Authors: Keles Irem , Manger Sina , Mantanya Mbuso S. , Frangakis Achilleas S.
Published: September 2024

Mycoplasma pneumoniaeis a human pathogen causing atypical community-acquired pneumonia. It is a model for a minimal cell, known for its non-canonical use of surface proteins for host-cell adhesion through ectodomain shedding and antigenic variation to evade the host cell immune response. Mpn444 is an essential mycoplasma surface protein implicated in both processes. It is one of 46 lipoproteins ofM. pneumoniae, none of which have been structurally or functionally characterized. Here, we report the structure of Mpn444 at 3.04 Å as well as the molecular architecture of the trimeric Mpn444 complex. Our experimental structure displays striking similarity to structure predictions of several other essential lipoproteins inM. pneumoniaeand other relatedMycoplasmaspecies, suggesting it to have a specialized and conserved function. The essentiality and involvement of Mpn444 in host immune evasion makes our structure a target for the development of new treatment strategies against mycoplasma infections.
Widespread occurrence of benzimidazole resistance single nucleotide polymorphisms in the canine hookworm,Ancylostoma caninum, in Australia
Authors: Abdullah Swaid , Stocker Thomas , Kang Hyungsuk , Scott Ian , Hayward Douglas , Jaensch Susan , Ward Michael P. , Jones Malcolm K. , Kotze Andrew C. , Šlapeta Jan
Published: September 2024

Canine hookworm (Ancylostoma caninum), a gastrointestinal nematode of domestic dogs, principally infects the small intestine of dogs and has the potential to cause zoonotic disease. In greyhounds and pet dogs in the USA,A. caninumhas been shown to be resistant to multiple anthelmintics. We conducted a molecular survey of benzimidazole resistance inA. caninumfrom dogs at veterinary diagnostic centers in Australia and New Zealand. First, we implemented an internal transcribed spacer (ITS)-2 rDNA deep amplicon metabarcoding sequencing approach to ascertain the species of hookworms infecting dogs in the region. Then, we evaluated the frequency of the canonical F167Y and Q134H isotype-1 β-tubulin mutations, which confer benzimidazole resistance, using the same sequencing approach. The most detected hookworm species in diagnostic samples wasA. caninum(90%; 83/92); the related Northern hookworm (Uncinaria stenocephala) was identified in 11% (10/92) of the diagnostic samples. There was a single sample with coinfection byA. caninumandU. stenocephala. Both isotype-1 β-tubulin mutations were present inA. caninum, 49% and 67% for Q134H and F167Y, respectively. Mutation F167Y in the isotype-1 β-tubulin mutation was recorded inU. stenocephalafor the first known time. Canonical benzimidazole resistance codons 198 and 200 mutations were absent. Egg hatch assays performed on a subset of theA. caninumsamples showed significant correlation between 50% inhibitory concentration (IC50) to thiabendazole and F167Y, with an increased IC50for samples with >75% F167Y mutation. We detected 14% of dogs with >75% F167Y mutation inA. caninum. Given that these samples were collected from dogs across various regions of Australia, the present study suggests that benzimidazole resistance inA. caninumis widespread. Therefore, to mitigate the risk of resistance selection and further spread, adoption of a risk assessment-based approach to limit unnecessary anthelmintic use should be a key consideration for future parasite control.
Signatures of omicron-like adaptation in early SARS-CoV-2 variants and chronic infection
Authors: Cheng Mark Tsz Kin , Altaf Mazharul , Castin Jesu , Reuschl Ann-Kathrin , Sievers Benjamin L. , Kamelian Kimia , Mesner Dejan , Morse Rebecca B. , Abdullahi Adam , Meng Bo , Csiba Kata ,   Cambridge NIHR Bioresource, Kemp Steven A. , Martin Darren P. , Jolly Clare , Ruis Christopher , Thukral Lipi , Gupta Ravindra K
Published: September 2024

Omicron emergence represented a seismic event in the COVID-19 pandemic, demonstrating what was essentially antigenic shift in a virus that cannot reassort its genome as influenza can. Understanding the success of Omicron is essential, and yet we have little understanding of the biological underpinnings of its ability to accommodate diverse mutations and bring together deleterious mutations to generate a highly successful new serotype. Persistent SARS-CoV-2 infections are a likely source of new variants and may provide valuable insight into past and future evolutionary trajectories, in particular those involving allosteric interactions that defy genotype to phenotype prediction. Here we observe upper airway specific evolution of SARS-CoV-2 demonstrating fusion peptide (FP) domain mutation S:P812S adjacent to the S2' cleavage site that emerged during a chronic infection in an immunocompromised individual. Indeed, this mutation had previously emerged in an ancestral B lineage as well as the delta variant lineage and transmitted successfully in populations globally, though remains uncharacterised. P812S in spike pseudotyped virus particles did not impact entry efficiency across cell lines expressing endogenous ACE2 and TMPRSS2. However, efficiency of spike cleavage at S1/S2 was reduced and molecular dynamics simulation demonstrated altered S1/S2 loop conformations that possibly impacted furin mediated cleavage. Consistent with impaired S1/S2 cleavage, and reminiscent of Omicron BA.1, cell-cell fusogenicity was severely impaired by introduction of P812S. The mutation also introduced significant perturbations to the FP region and also affected protomer-protomer packing. P812S conferred evasion of a neutralising monoclonal antibody targeting the fusion peptide, consistent with significant structural rearrangements in the FP region. Finally, P812S bearing viruses showed evasion of polyclonal neutralising antibodies in sera from vaccinated individuals at 32°C (simulating upper respiratory tract) and to a lesser extent at 37°C. Thus we report a novel mutational adaptation to the upper airway allowing enhanced immune evasion to fusion peptide targeting neutralising antibodies that also incurs a defect in ability to induce syncytia. These data shed light on the balance between upper airway adaptation/immune evasion by SARS-CoV-2, ability to induce syncytia formation, and disease severity given the established link between syncytia and severe COVID-19.
A simple immunohistochemical method for perinatal mammalian ovaries revealed different kinetics of oocyte apoptosis caused by DNA damage and asynapsis
Authors: Kogo Hiroshi , Iizuka-Kogo Akiko , Yamamoto Hanako , Ikezawa Maiko , Tajika Yukiko , Matsuzaki Toshiyuki
Published: September 2024

Oocytes having meiotic defects are assumed to be eliminated by apoptosis in perinatal period. However, the oocyte apoptosis caused by meiotic defects has not been well analyzed, partly due to the great technical demands for tissue sectioning of perinatal ovaries. In the present study, we applied a squash method for immunohistochemical analysis of perinatal mouse ovaries as a substitute for tissue sectioning. As a result, we could show different kinetics of apoptosis caused by DMC1- and SPO11-deficiencies, indicating that DNA damage-induced apoptosis precedes asynapsis-induced apoptosis in mouse oocytes. Double mutant analysis revealed that only asynapsis-induced apoptosis was significantly dependent on HORMAD2. The present method is simple, easy, and able to analyze a sufficient number of oocytes for detecting infrequent events in a single specimen, accelerating detailed immunohistochemical analyses of mammalian ovaries during the fetal and perinatal periods.
Divergent inflammatory and neurology-related plasma protein profiles in individuals with long COVID following primary and breakthrough SARS-CoV-2 infections
Authors: Bansal Amit , Olechnowicz Sam W.Z. , Kiernan-Walker Nicholas , Cumming Jacob , Mazhari Ramin ,   COVID PROFILE consortium, Cox Rebecca J. , Mueller Ivo , Bowden Rory , Eriksson Emily M.
Published: September 2024

Long COVID is a complex condition where symptoms persist for more than 3 months after SARS-CoV-2 infection and affects an estimated 5-30% of individuals. While the pathobiology of long COVID is still evolving, persistent inflammation has emerged as an important feature of this condition. However, it is unclear if immune responses from COVID-19 vaccination or SARS-CoV-2 re-infection exacerbate or mirror the initial inflammatory responses. To address this question, we quantified 182 inflammatory and neurology-related proteins in plasma using multiplexed affinity proteomics. Plasma samples were collected 6-9 months after first infection, but before COVID-19 vaccination from individuals who had recovered from COVID-19 (n=21) or from individuals with long COVID (n=12). This was benchmarked against plasma from unvaccinated, SARS-CoV-2 naive individuals (n=24). In addition to this cross-sectional analysis, we performed longitudinal analysis in a subset of individuals (n=34), where paired samples collected 2-4 weeks after a third COVID-19 vaccine dose and after SARS-CoV-2 breakthrough infection were available. Boruta feature selection and lasso regression models identified a distinct plasma profile in long COVID individuals, characterised by elevated IL-20, HAGH, NAAA, CLEC10A, LXN, and MCP-1 and reduced TRAIL, G-CSF, NBL1, and CCL23 protein concentrations. Notably, longitudinal analysis demonstrated that neither COVID-19 booster vaccination nor breakthrough infection replicated inflammatory and neurology-related plasma protein profiles observed after primary infection suggesting an altered immune response outcome in individuals with long COVID upon re-exposure.
Chyme Reinfusion Practices in the Neonatal Population
Authors: Lim Alexandria H , Tinawi Georges , Harrington Taylor , Ludlow Emma , Evans Helen , Bissett Ian , Keane Celia
Published: September 2024

Introduction

The utilisation of chyme reinfusion therapy (CRT) by returning the output from the proximal limb into the distal limb of double enterostomies is a safe and effective method to improve nutritional uptake and maintain intestinal integrity in adult populations. This technique is also particularly suitable for neonatal patients with life-threatening conditions such as congenital bowel abnormalities and necrotising enterocolitis (NEC). Despite its promise, it has only had irregular uptake in neonatal patients. We aimed to identify the frequency, methodology and adverse events associated with CRT in the appropriate neonatal population.

Methods

A ten-year retrospective cohort study was conducted using database searches at two major paediatric hospitals in New Zealand. All patients with suitable anatomy were identified, and data on CRT methodology and outcomes were recorded.

Results

Of the 49 neonates identified with double enterostomy 23 (47%) underwent CRT for high stoma output, risk of short gut syndrome or as a routine protocol before re-anastomosis. A nasogastric feeding tube was inserted into the distal limb and collected chyme was reinfused via manual bolus or automated syringe driver. The median (IQR) weight gain increased from 13.9 (3.50 - 22.89) to 24.37 (19.68 - 29.99) g/day during CRT (p = 0.04). 18 infections requiring medical intervention but unrelated to CRT occurred in 13 patients (56%). The rate of non-infectious adverse events was 24, with 7% remaining free from any adverse events.

Conclusion

Chyme reinfusion is an underutilised method of improving nutrition in neonates with intestinal failure. Premature neonates requiring double enterostomy formation are at high risk of infectious and non-infectious complications, but few of these are related to CRT. Standardised protocols providing clear eligibility criteria and detailed methodology for CRT are required to promote uniform utilisation of this practice.
The relationship between physical function and psychological symptoms in Parkinson’s: A Survey of People with Parkinson’s and Carers
Authors: Hodgson Philip , Jordan Alastair , Sinani Charikleia , Charura Divine
Published: September 2024

Background

People with Parkinson’s (PwP) can experience both physical and psychological symptoms, and understanding the perspectives of people affected is crucial for improved management, and clinical outcomes.

Objectives

This online survey sought to investigate whether individuals perceive a connection between physical and psychological symptoms, while also considering the influence of personal roles and past symptom experiences.

Methods

A UK-wide survey of 251 PwP and 61 family/carers was conducted. The survey focused on reported diagnosed and non-diagnosed psychological symptoms experienced, their onset, and the perceived impact of physical and psychological symptoms on one another. Responses were summarised using descriptive statistics.

Results

A substantial proportion of respondents reported at least one diagnosed psychological condition (38.5%) or undiagnosed psychological symptoms (44.6%) such as anxiety and depression. Half of respondents reported perceiving a bi-directional interaction between physical and psychological symptoms, with this perception most reported in people with prior experience of psychological symptoms. Our sample shows that while PwP and carers have similar views on the impact of psychological symptoms, carers perceive the impact of physical symptoms to be greater than PwP.

Conclusions

PwP and carers appear to perceive an interaction between physical and psychological symptoms in Parkinson’s, noting that psychological symptoms frequently precede Parkinson’s diagnosis but are often under-recognised. Improved awareness of the potential link between physical and psychological symptoms in PwP may help to improve assessment, and onward referral processes to enhance care. Further research may assist in identifying potential sub-groups and allow the prediction of changes in physical and psychological presentation.
The global pattern of centenarians highlights deep problems in demography
Authors: Newman Saul Justin
Published: September 2024

Accurate age data is fundamental to medicine, social sciences, epidemiology, and good government. However, recent and heavily disputed debates on data quality have raised questions on the accuracy of demographic data at older ages. Here, we catalogue late-life survival patterns of every country in the world from 1970-2021 using comprehensive estimates of old-age populations provided by global governments and curated by the United Nations. Analysis of 236 nations or states across 51 years reveals that late-life survival data is dominated by anomalies at all scales and in all time periods. Life expectancy at age 100 and late-life survival from ages 80 to 100+, which we term centenarian attainment rate, is highest in a seemingly random assortment of states. The top 10 ‘blue zone’ regions with the best survival to ages 100+ routinely includes Thailand, Kenya and Malawi – respectively now 212thand 202ndin the world for life expectancy, the non-self-governing territory of Western Sahara, and Puerto Rico where birth certificates are so unreliable they were recently declared invalid as a legal document. These anomalous rankings are conserved across long time periods and multiple non-overlapping cohorts, and do not seem to be sampling effects. Instead these patterns suggest a persistent inability, even for nation-states or global organisations, to detect or measure error rates in human age data, with troubling implications for epidemiology, demography, and medicine.
Online monitoring technology for deep phenotyping of cognitive impairment after stroke
Authors: Gruia Dragos-Cristian , Giunchiglia Valentina , Coghlan Aoife , Brook Sophie , Banerjee Soma , Kwan Jo , Hellyer Peter J. , Hampshire Adam , Geranmayeh Fatemeh
Published: September 2024

Background

Despite the high prevalence of disabling post-stroke cognitive sequalae, these impairments are often underdiagnosed and rarely monitored longitudinally. Provision of unsupervised remote online cognitive technology would provide a scalable solution to this problem. However, despite recent advances, such technology is currently lacking, with existing tools either not meeting the scalability challenge or not optimised for specific applications in post-stroke cognitive impairment. To address this gap, we designed and developed a comprehensive online battery highly optimised for detecting cognitive impairments in stroke survivors.

Method

The technology is optimised to allow both diagnosis and monitoring of post-stroke deficits, and for remote unsupervised administration. Participants performed 22 computerised tasks, and answered neuropsychiatric questionnaires and patient reported outcomes. 90 stroke survivors (Mean age = 62.1 years; 68% and 32% in the acute and subacute/chronic phase after stroke respectively) and over 6,000 age-matched healthy older adults were recruited. Patient outcome measures were derived from Bayesian Regression modelling of the large normative sample and validated against standard clinical scales.

Results

Our online technology has greater sensitivity to post-stroke cognitive impairment than pen-and-paper tests such as the MOCA (mean sensitivity 81.75% and 52.25% respectively, P<0.001). Further, our outcomes show a stronger correlation with post-stroke quality of life (r(78)=0.51, R2=0.26, P<0.001) when compared to MOCA, which only explains half of this variance (r(78)=0.38, R2=0.14, P< 0.001). An additional set of experiments confirm that the online tasks yield highly reliable outcomes, with consistent performance observed across supervised versus unsupervised settings, and minimal learning effects across multiple timepoints.

Conclusion

The current online cognitive monitoring technology is feasible, sensitive, and reliable when assessing patients with stroke. The technology offers an economical and scalable method for assessing post-stroke cognition in the clinical setting and sensitively monitoring cognitive outcomes in clinical trials for stroke.
Seroprevalence of chikungunya and o’nyong-nyong viruses in Senegal, West Africa
Authors: Tonto Prince Baffour , Sy Mouhamad , Ndiaye Ibrahima Mbaye , Toure Mariama , Gaye Amy , Aidara Mariama , Mbaye Amadou Moctar , Dia Abdoulaye Kane , Diallo Mamadou Alpha , Gomis Jules Francois , Yade Mamadou Samba , Diedhiou Younous , Dieye Baba , Diongue Khadim , Seck Mame Cheikh , Badiane Aida S. , Herrera Bobby Brooke , Ndiaye Daouda
Published: September 2024

Background

Arthritogenic alphaviruses such as chikungunya (CHIKV) and o’nyong-nyong (ONNV) viruses have shown capacity to cause widespread epidemics, with recurrent and sporadic outbreaks occurring throughout sub-Saharan Africa.

Methods

We analyzed the seroprevalence for CHIKV and ONNV in 470 non-febrile subjects from three regions in Senegal (Sindia, 2018; Thies, 2018; and Kedougou, 2022/2023) using retrospective samples. We assessed the presence of anti-CHIKV IgG and neutralizing antibody titers against CHIKV and ONNV via enzyme-linked immunosorbent assay (ELISA) and microneutralization tests, respectively, and determined risk factors of CHIKV and ONNV exposure by binary logistic regression.

Results

The overall alphavirus seroprevalence based on an anti-CHIKV viral like particle (VLP) IgG ELISA was 38.5%, with rates varying geographically: Kedougou (48.6%), Thies (31.9%), and Sindia (14.9%). Neutralizing antibody titers revealed CHIKV and ONNV seroprevalence rates of 7.4% and 9.8%, respectively, with significant variations by region and age group. Cross-reactivity analysis showed that 82.9% of CHIKV cases exhibited a neutralizing response to ONNV, while 71.7% of ONNV cases cross-neutralized CHIKV. Residents of Thies had significantly higher odds of CHIKV infection (aOR, 3.147; 95% CI: 1.164-8.510) while ONNV infection was more likely in Kedougou (aOR, 3.888; 95% CI: 1.319-11.466). Furthermore, older age (> 40 years) was a significant risk factor both CHIKV (aOR, 2.094; 95% CI: 0.846-5.185) and ONNV infection (aOR, 2.745; 95% CI: 1.212-6.216).

Conclusions

Our study confirms the co-circulation of CHIKV and ONNV in Senegal, highlighting their geographic and demographic distribution. These findings underscore the need for continued surveillance, alphavirus testing, and tailored public health strategies to mitigate their impact in Senegal.
Immunotoxic Effects in Children Resulting from Prenatal and Early Childhood Exposure to Pesticides: Protocol and Pilot Study of a Systematic Review and Meta-Analysis
Authors: Sherif Moustafa , Darwish Aya , Ádám Balázs
Published: September 2024

Background

Pesticides, commonly employed in both agricultural and domestic environments, have been associated with disturbing the balance of the immune system during prenatal and early childhood phases of development. This disturbance has the potential to result in various outcomes such as autoimmunity, immunosuppression, inflammation, hypersensitivity, tissue damage, and overall alterations in immune modulation. The escalating concern regarding the immunotoxic effects of pesticides necessitates a systematic review and potential meta-analysis to consolidate empirical evidence and address the knowledge gaps. This systematic review aims to comprehensively assess the immunotoxic impact of pesticide exposure on children, considering alterations in immune system function induced by specific types of pesticides.

Methods

Through a meticulous search of the literature and synthesis of findings, the review will scrutinize prevalence, effect size, mechanisms, vulnerable periods, and the role of pre-existing conditions. The submitted protocol to PROSPERO aligns with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement, ensuring methodological rigor. A preliminary exploration involved a systematic search in electronic databases based on a pre-defined Population, Exposure, Comparator, and Outcome (PECO) statement. Data extraction sheets and risk of bias assessment tools were piloted on eight eligible articles to ensure reliability and efficiency. Subsequently, a rerun of the search will be executed, and two independent reviewers will employ the systematic review tool Covidence for article screening and data extraction, and Excel for risk of bias assessment. The results will be synthetized narratively in summary tables, and, if findings allow, meta-analysis including subgroup and sensitivity analysis will be conducted.

Discussion

By elucidating the intricate relationship between pesticide exposure and immunotoxicity during prenatal and early childhood, this review will provide insights into immune response that can contribute to public health awareness and guide interventions.

PROSPERO Registration number

[CRD42024510916].

Impact Statement

This study will establish a high level of evidence to highlight the critical immunotoxic risks of prenatal and early childhood pesticide exposure, offering essential insights for public health policies and interventions to safeguard the infants during this vulnerable developmental periods.
Genome-wide association studies of Down syndrome associated congenital heart defects
Authors: Feldman Elizabeth R. , Li Yunqi , Cutler David J. , Rosser Tracie C. , Wechsler Stephanie B. , Sanclemente Lauren , Rachubinski Angela L. , Elliott Natalina , Vyas Paresh , Roberts Irene , Rabin Karen R. , Wagner Michael , Gelb Bruce D. , Espinosa Joaquin M. , Lupo Philip J. , de Smith Adam J. , Sherman Stephanie L. , Leslie Elizabeth J.
Published: September 2024

Congenital heart defects (CHDs) are the most common structural birth defect and are present in 40-50% of children born with Down syndrome (DS). To characterize the genetic architecture of DS-associated CHD, we sequenced genomes of a multiethnic group of children with DS and a CHD (n=886: atrioventricular septal defects (AVSD), n=438; atrial septal defects (ASD), n=122; ventricular septal defects (VSD), n=170; other types of CHD, n=156) and DS with a structurally normal heart (DS+NH, n=572). We performed four GWAS for common variants (MAF>0.05) comparing DS with CHD, stratified by CHD-subtype, to DS+NH controls. Although no SNP achieved genome-wide significance, multiple loci in each analysis achieved suggestive significance (p<2×10−6). Of these, the 1p35.1 locus (nearRBBP4) was specifically associated with ASD risk and the 5q35.2 locus (nearMSX2) was associated with any type of CHD. Each of the suggestive loci contained one or more plausible candidate genes expressed in the developing heart. While no SNP replicated (p<2×10−6) in an independent cohort of DS+CHD (DS+CHD: n=229; DS+NH: n=197), most SNPs that were suggestive in our GWASs remained suggestive when meta-analyzed with the GWASs from the replication cohort. These results build on previous work to identify genetic modifiers of DS-associated CHD.
Loon Lens 1.0 Validation: Agentic AI for Title and Abstract Screening in Systematic Literature Reviews
Authors: Janoudi Ghayath , Uzun Mara , Jurdana Mia , Fuzul Ena , Ivkovic Josip
Published: September 2024

Introduction

Systematic literature reviews (SLRs) are critical for informing clinical research and practice, but they are time-consuming and resource-intensive, particularly during Title and Abstract (TiAb) screening. Loon Lens, an autonomous, agentic AI platform, streamlines TiAb screening without the need for human reviewers to conduct any screening.

Methods

This study validates Loon Lens against human reviewer decisions across eight SLRs conducted by Canada’s Drug Agency, covering a range of drugs and eligibility criteria. A total of 3,796 citations were retrieved, with human reviewers identifying 287 (7.6%) for inclusion. Loon Lens autonomously screened the same citations based on the provided inclusion and exclusion criteria. Metrics such as accuracy, recall, precision, F1 score, specificity, and negative predictive value (NPV) were calculated. Bootstrapping was applied to compute 95% confidence intervals.

Results

Loon Lens achieved an accuracy of 95.5% (95% CI: 94.8–96.1), with recall at 98.95% (95% CI: 97.57–100%) and specificity at 95.24% (95% CI: 94.54–95.89%). Precision was lower at 62.97% (95% CI: 58.39–67.27%), suggesting that Loon Lens included more citations for full-text screening compared to human reviewers. The F1 score was 0.770 (95% CI: 0.734–0.802), indicating a strong balance between precision and recall.

Conclusion

Loon Lens demonstrates the ability to autonomously conduct TiAb screening with a substantial potential for reducing the time and cost associated with manual or semi-autonomous TiAb screening in SLRs. While improvements in precision are needed, the platform offers a scalable, autonomous solution for systematic reviews. Access to Loon Lens is available upon request athttps://loonlens.com/.
Impact of vaccination on SARS-CoV-2 transmission in the UK: a modelling study
Authors: Derqui Nieves , Mishra Swapnil , Hinsley Wes R , Bhatt Samir , Laydon Daniel J
Published: September 2024

Background

Efficacy and effectiveness of vaccines against SARS-CoV-2 infection, severe disease and death have been widely assessed. However, the impact of vaccination against SARS-CoV-2 transmission is far less well-characterized, and has major implications for public health, because it informs the indirect effects of vaccination in addition to its direct effects. Analysing the effects of SARS-CoV-2 vaccination on transmission is challenging, because they must be considered in tandem with the time-varying reproduction number (Rt), while also accounting for regional variability, for example due to the presence of more transmissible variants.

Methods

We fitted a Bayesian hierarchical model to previously obtained estimates ofRtto estimate the effectiveness of vaccination with one, two and three doses on SARS-CoV-2 transmission in the UK during 2021. Vaccine effectiveness is defined as the proportional reduction in the time-varying reproduction numberRt. The model accounts for transmission at national and Lower Tier Local Authority (LTLA)-level, and uses vaccination data provided by the UK Health Security Agency (UKHSA), detailing the LTLA-specific proportions of people who have received doses one, two and three. The model also incorporates data on the proportion of wild-type, Alpha and Delta SARS-CoV-2 variants over time in each LTLA, obtained from UKHSA and the COVID-19 Genomics UK (COG-UK) Consortium.

Results

We find that vaccination had moderate-to-large effectiveness against transmission for dose 1 (39.30%, 95% CrI 26.64% - 48.07%), and for dose 3 (48.69%, 95% CrI 27.97% - 71.30%), but negligible effects on dose 2, likely attributable to the coincident importation and dominance of the Delta variant in the UK. Nationally, our model fitted the previously estimated values of time-series ofRtvalues well, largely reproducing the reproduction number averaged across LTLAs for each timepoint. This lends support to our hypothesis that the extent of vaccination (or lack thereof) was a major determinant of transmission intensity. Our model fits further reproduced well the reproduction numbers at regional level, although outliers were less well captured, implying some degree of variation that is not explained by our model.

Conclusions

To our knowledge, our analysis is the first evidence of the effectiveness of SARS-CoV-2 vaccination against its transmission at population level. We find that vaccination is an effective tool for the control of SARS-CoV-2 transmission, in addition to its well-documented effects on disease burden and mortality. Our results allow future assessment of the impact of vaccination accounting for several circulating variants and sociodemographic factors.