bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms underneathXanthomonas citrisubsp.citripromoting ofAgrobacterium-mediated transient expression in citrus
Authors: Lamichhane Tirtha , Wang Nian
Published: September 2023

Agrobacterium-mediated transient expression (TE) is an important tool in plant genetics study and biotechnology. Citrus is one of the top tree crops, butAgrobacterium-mediated TE remains problematic in citrus. Previous study has shown that pretreatment of citrus leaves withXanthomonas citrisubsp.citri(Xcc), which causes citrus canker in almost all citrus cultivars, significantly improves the TE efficacy. Here we have shown thatXccpromotesAgrobacterium-mediated TE via improvingAgrobacteriumgrowth, suppressing plant immune response, triggering cell division, and upregulating plant cell wall degrading enzymes. We demonstrate thatXccpromotesAgrobacterium-mediated TE via PthA and mutation ofpthA4abolishes the promoting effect ofXcc.PthA4 is known to trigger cell division of citrus. We have demonstrated the causative relationship between cell division andAgrobacterium-mediated TE using cell division inhibitor mimosine. Importantly, the differential effects of mimosine and colchicine onXccpromotingAgrobacterium-mediated TE indicate that S-phase is critical for agroinfiltration of citrus tissues. In addition, PthA4 is known to upregulate plant growth hormones auxin (IAA), gibberellin and cytokinin, as well as cell degrading enzymes (e.g., cellulase). Exogenous application of IAA, cytokinin, and cellulase but not gibberellin significantly improvedAgrobacterium-mediated TE in leaves of sweet orange, pummelo, Meiwa kumquat, lucky bamboo and rose mallow. Our study provides a mechanistic understanding regarding howXccpromotesAgrobacterium-mediated TE and identified two practical measures to improveAgrobacterium-mediated TE via pretreatment with plant hormones (i.e., auxin and cytokinin) and cellulase.
Protein expression profiles in brain organoids are more similar to those in human brain parenchyma than in mouse brain parenchyma
Authors: Wenzel Tyler J. , Mousseau Darrell D.
Published: September 2023

Human brain organoids are emerging as relevant models for the study of human brain health and disease. However, it has not been shown whether human brain organoids exhibit a proteoform profile similar to the human brain. Herein, we demonstrate that unguided brain organoids exhibit minimal batch-to-batch variability in cell composition and metabolism when generated from induced pluripotent stem cells (iPSCs) derived from male-female siblings. We then show that profiles of select proteins in these brain organoids are more similar to autopsied human cortical and cerebellar profiles than to those in mouse cortical samples. Brain organoids derived from sibling iPSCs do not exhibit any sex differences in protein proportions. By benchmarking human brain organoid proteoforms against human parenchymal tissue, we establish the foundation for future studies that could investigate, for example, how well brain organoids can model any of the known sex-dependent differences in cellular function, including responses of drug-receptor interactions.

Highlights

Brain organoids (BOs) display protein banding similar to human parenchymal lysates

Protein banding differs between mouse and human brain parenchyma lysates

Sibling-derived BOs have similar cell composition and metabolism at day 90

Sibling-derived BOs exhibit similar protein banding at day 90
Characterizing the blood stage antimalarial activity of pyronaridine in healthy volunteers experimentally infected withPlasmodium falciparum
Authors: Barber Bridget E. , Webster Rebecca , Potter Adam J. , Llewellyn Stacey , Sahai Nischal , Leelasena Indika , Mathison Susan , Kuritz Karsten , Flynn Julia , Chalon Stephan , Marrast Anne Claire , Gobeau Nathalie , Moehrle Joerg J.
Published: September 2023

Although pyronaridine has been used to successfully treat malaria for many years, its antimalarial activity in humans has not been completely characterized. This volunteer infection study aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) relationship of pyronaridine in healthy malaria naïve adults. Volunteers were inoculated withPlasmodium falciparum3D7-infected erythrocytes on day 0 and different single oral doses of pyronaridine were administered on day 8. Parasitemia, and concentrations of pyronaridine in whole blood were measured and standard safety assessments performed. Curative artemether-lumefantrine therapy was administered if parasite regrowth occurred, or on day 47±2. Outcomes were parasite clearance kinetics, PK and PK/PD parameters from modelling. Ten participants were inoculated and administered 360 mg (n=4), 540 mg (n=4), or 720 mg (n=1) pyronaridine. One participant was withdrawn without receiving pyronaridine. Time to maximum pyronaridine concentration after dosing was 1-2 hours and the elimination half-life was 8-9 days. A parasite clearance half-life of approximately 5 hours was calculated for all dose levels. Parasite regrowth occurred after dosing with 360 mg (4/4 participants) and 540 mg (2/4 participants). Key efficacy parameters of pyronaridine including the minimum inhibitory concentration (MIC: 5.5 ng/mL) and minimum parasiticidal concentration that leads to 90% of maximum effect (MPC90: 8 ng/mL) were derived from the final PK/PD model. Adverse events considered related to pyronaridine were predominantly mild to moderate gastrointestinal symptoms. There were no serious adverse events. Data obtained in this study will support the use of pyronaridine in new antimalarial combination therapies by informing partner drug selection and dosing considerations.
Leukocyte Telomere Length and Cardiac Structure and Function: A Mendelian Randomization Study
Authors: Salih Ahmed , Boscolo Galazzo Ilaria , Menegaz Gloria , Altmann André
Published: September 2023

Existing research demonstrates association of shorter telomere length (TL) with increased risk of agerelated health outcomes including cardiovascular diseases. However, the direct causality of these relationships is not definitively established. Cardiovascular aging at an organ-level may be captured using image derived phenotypes (IDPs) of cardiac anatomy and function. In the current study, we use two-sample Mendelian Randomization (MR) to assess the causal link between TL and 54 cardiac magnetic resonance imaging (CMR) measures representing structure and function across the four cardiac chambers. Genetically predicted shorter TL was causally linked to smaller ventricular cavity sizes including left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), lower left ventricular mass (LVM) and pulmonary artery. The association with LVM (β= 0.217, PFDR= 0.016) remained significant after multiple testing adjustment, whilst other associations were attenuated. Our findings support a causal role for shorter TL and faster cardiac aging, with the most prominent relationship with LVM.
Cardiovascular Risks Among the Transgender Population in Rural United States: Spotlight on the Appalachian Region
Authors: Ezeh Ebubechukwu , Perdoncin Maddie , Ogbu Chukwuemeka , Akhigbe Esiemoghie , Al-Hiari Mohammed , Ramalingam Archana , Saunders Elizabeth , Mader Jason , Rodriguez Lozano Patricia F.
Published: September 2023

Background

Gender diverse populations have disproportionately worse cardiovascular (CV) outcomes. However, the data on the prevalence of cardiovascular risk factors among the transgender population in rural Appalachia remains limited. The purpose of this study was to determine the prevalence of CV risk factors among the transgender population in rural Appalachia.

Methods

This retrospective case-control study from an Appalachian university teaching hospital clinic matched transgender individuals with controls from the same clinic. Logistic regression model was performed to determine the prevalence of CV risk factors among the transgender population in comparison to their cisgender counterparts.

Results

The total number of transgender and cisgender individuals identified were 89 and 69, respectively. After adjusting for age and family history of atherosclerotic CV disease, transgender status remained independently associated with tobacco use (adjusted odds ratio [aOR] 6.64 [2.59-17.01]) and prediabetes/diabetes mellitus (aOR 3.98 [1.05-15.15]). Among the transgender population, there were increased odds of obesity (aOR 13.39 [3.30-54.30] and hyperlipidemia (aOR 3.46 [1.03-11.59]) in the transgender male group compared to the transgender female group. In another subgroup analysis, transgender individuals who underwent surgical and/or hormonal treatment had significantly higher odds of tobacco use (aOR 6.67 [2.80-15.98]), statin need (aOR 3.97 [1.14-13.81], and alcohol use (aOR 11.31 [1.34-95.53]). Increased statin use tends to be associated with normal LDL levels.

Conclusions

In rural Appalachia, transgender status is associated with disproportionately higher odds of tobacco use, elevated blood glucose and other CV risk factors.
Diagnostic Value of Carotid Ring Sign in Predicting Internal Carotid True Occlusion
Authors: Yi Tingyu , Sui Yi , Zheng Ding-huan , Ren Xinwen , Lin Xiao-hui , Wu Yan-min , Lin Ding-lai , Pan Zhi-nan , Zheng Xiu-fen , Hong Ganji , Wu Mei-hua , Zeng Lisan , Chen Wen-huo
Published: September 2023

BACKGROUND AND PURPOSE

To differentiate between pseudo-occlusion (PO) and true occlusion (TO) of internal carotid artery (ICA) is important in thrombectomy treatment planning for acute ischemic stroke (AIS) patients. Although delayed contrast filling has been differentiated carotid PO from TO, its application has been limited by the implementations of multiphasic computed tomography angiography (mCTA). In this study, we hypothesized that carotid ring sign, which is readily acquired from single-phasic CTA, can sufficiently differentiate carotid TO from PO.

METHODS

Two hundred patients with non-visualization of the proximal ICA were included. Diagnosis of PO or TO of the cervical segment of ICA was made based on digital subtraction angiography. Diagnostic performances of carotid ring sign on arterial-phasic CTA and delayed contrast filling on mCTA were evaluated and compared.

RESULTS

One-hundred-twelve patients had ICA PO and 88 had TO. Carotid ring sign was more common in TO patients (70.5% vs 6.3%, p<0.001), while delayed contrast filling was more common in PO (94.9% vs 7.7%, p<0.001). The sensitivity and specificity of carotid ring sign in diagnosing carotid TO was 0.70 and 0.94 respectively, while sensitivity and specificity of delayed contrast filling was 0.95 and 0.92 in judging carotid PO.

CONCLUSIONS

Carotid ring sign is a potent imaging marker in diagnosing ICA TO. Carotid ring sign could be complementary to delayed contrast filling sign in differentiating TO from PO, in particular in centers with only single-phasic CTA.
Factors associated with teenage pregnancies during the Covid-19 period in Pakwach district, Northern Uganda: a case-control study
Authors: Alunyo Jimmy Patrick , Mukunya David , Napyo Agnes , Matovu Joseph KB , Okia David , Wanume Benon , Okello Francis , Tuwa Ally Hassan , Wenani Daniel , Okibure Ambrose , Omara Godfrey , Olupot-Olupot Peter
Published: September 2023

Background

Teenage pregnancy rates have globally decreased over the years, but remain high, especially in low- and middle-income countries (LMICs). Among girls aged 15-19, teenage pregnancy remains the leading cause of death and a significant barrier to education and productivity. Its prevalence underscores concern about the sexual and reproductive health of youth. However, limited data exist regarding factors contributing to its rise during the COVID-19 pandemic in Uganda. This study explores the factors associated with teenage pregnancy in Pakwach district during this period.

Methods

We conducted a matched case-control study, enrolling 362 teenage girls aged 10-19 years, divided into two groups: 181 pregnant teenagers and 181 not pregnant teenagers. We collected exposure data from both groups using questionnaires to evaluate factors associated with teenage pregnancy. The study period covered March 2020 to January 2021, coinciding with lockdown measures.

Results

During the COVID-19 lockdown, teenage pregnancies were only associated with having exclusively female peers (AOR 3.0, 95% CI: 0.1-104.4). Conversely, having a Radio/TV at home (AOR 0.2, 95% CI: 0.1-0.6), age at first sexual encounter (AOR 0.1, 95% CI: 0.03-0.9), considering teenage pregnancy as sexual abuse (AOR 0.1, 95% CI: 0.02-0.4), feeling comfortable asking questions during consultations (AOR 0.5, 95% CI: 0.2-1.3), and ensuring sufficient privacy during consultations were protective against teenage pregnancy.

Conclusion

The factors contributing to increased teenage pregnancies during the COVID-19 pandemic were consistent with long-standing contextual factors associated with teenage pregnancy. The lockdown environment may have slightly exacerbated these factors, but no direct association was observed. Only having female peers was linked to teenage pregnancy during the lockdown. Conversely, having access to a radio/TV at home and other healthcare system-related factors offered protection. Therefore, interventions should prioritize providing comprehensive information on the risks of teenage pregnancy during any lockdown scenario.
The HOMEODOMAIN-Like protein HDL mediates chromatin organization and rewires leaf epidermal patterning
Authors: Ali Ansar , Kuan Chi , Hung Fu-Yu , Chen Tsai-Chen , Lee Hui-Chun , Yang Shao-Li , Feng Yun-Ru , Wu Keqiang , Ho Chin-Min Kimmy
Published: September 2023

TheArabidopsisleaf epidermis is comprised of trichomes, pavement cells, and stomata, originating from versatile precursor cells capable of dividing or differentiating to create unique epidermal patterns. The mechanism governing these transitions and the maintenance of cell heterogeneity remains unclear. In this study, we identified a novelhomeodomain-like superfamily protein, HDL, localized in chromocenters and playing a role in chromatin organization. HDL interacts withhistonedeacetylase 6 (HDA6) and methyltransferases, indicating its function in modulating chromatin accessibility. Inhdlmutants, we observed moderately increased chromatin accessibility in the promoter region of protein-coding genes, along with reduced stomatal density and elevated trichome numbers on leaf surfaces. Corresponding to these phenotypes, stomatal-related gene expression decreased, while a transcriptional reporter forGLABRA2, a trichome initiation gene, exhibited higher and more variable expression levels. These findings highlight how HDL-mediated chromatin organization influences epidermal cell fate by modulating gene expression and enhancing cell heterogeneity within the leaf epidermis.

One Sentence Summary

A homeodomain-like protein functions with histone modifiers to regulate chromatin and influence cell fate decisions.
Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19
Authors: Narasimhan Harish , Cheon In Su , Qian Wei , Hu Sheng’en , Parimon Tanyalak , Li Chaofan , Goplen Nick , Wu Yue , Wei Xiaoqin , Son Young Min , Fink Elizabeth , Santos Gislane , Tang Jinyi , Yao Changfu , Muehling Lyndsey , Canderan Glenda , Kadl Alexandra , Cannon Abigail , Young Samuel , Hannan Riley , Bingham Grace , Arish Mohammed , Chaudhari Arka Sen , Sturek Jeffrey , Pramoonjago Patcharin , Shim Yun Michael , Woodfolk Judith , Zang Chongzhi , Chen Peter , Sun Jie
Published: September 2023

The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+T cell-macrophage interactions in maintaining Krt8hitransitional and ectopic Krt5+basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.
Genetic tracing of market wildlife and viruses at the epicenter of the COVID-19 pandemic
Authors: Crits-Christoph Alexander , Levy Joshua I. , Pekar Jonathan E. , Goldstein Stephen A. , Singh Reema , Hensel Zach , Gangavarapu Karthik , Rogers Matthew B. , Moshiri Niema , Garry Robert F. , Holmes Edward C. , Koopmans Marion P. G. , Lemey Philippe , Popescu Saskia , Rambaut Andrew , Robertson David L. , Suchard Marc A. , Wertheim Joel O. , Rasmussen Angela L. , Andersen Kristian G. , Worobey Michael , Débarre Florence
Published: September 2023

Zoonotic spillovers of viruses have occurred through the animal trade worldwide. The start of the COVID-19 pandemic was traced epidemiologically to the Huanan Wholesale Seafood Market, the site with the most reported wildlife vendors in the city of Wuhan, China. Here, we analyze publicly available qPCR and sequencing data from environmental samples collected in the Huanan market in early 2020. We demonstrate that the SARS-CoV-2 genetic diversity linked to this market is consistent with market emergence, and find increased SARS-CoV-2 positivity near and within a particular wildlife stall. We identify wildlife DNA in all SARS-CoV-2 positive samples from this stall. This includes species such as civets, bamboo rats, porcupines, hedgehogs, and one species, raccoon dogs, known to be capable of SARS-CoV-2 transmission. We also detect other animal viruses that infect raccoon dogs, civets, and bamboo rats. Combining metagenomic and phylogenetic approaches, we recover genotypes of market animals and compare them to those from other markets. This analysis provides the genetic basis for a short list of potential intermediate hosts of SARS-CoV-2 to prioritize for retrospective serological testing and viral sampling.
Temporal Generative Models for Learning Heterogeneous Group Dynamics of Ecological Momentary Data
Authors: Kim Soohyun , Kim Young-geun , Wang Yuanjia
Published: September 2023

Summary

One of the goals of precision psychiatry is to characterize mental disorders in an individualized manner, taking into account the underlying dynamic processes. Recent advances in mobile technologies have enabled the collection of Ecological Momentary Assessments (EMAs) that capture multiple responses in real-time at high frequency. However, EMA data is often multi-dimensional, correlated, and hierarchical. Mixed-effects models are commonly used but may require restrictive assumptions about the fixed and random effects and the correlation structure. The Recurrent Temporal Restricted Boltzmann Machine (RTRBM) is a generative neural network that can be used to model temporal data, but most existing RTRBM approaches do not account for the potential heterogeneity of group dynamics within a population based on available covariates. In this paper, we propose a new temporal generative model, the Heterogeneous-Dynamics Restricted Boltzmann Machine (HDRBM), to learn the heterogeneous group dynamics and demonstrate the effectiveness of this approach on simulated and real-world EMA data sets. We show that by incorporating covariates, HDRBM can improve accuracy and interpretability, explore the underlying drivers of the group dynamics of participants, and serve as a generative model for EMA studies.
CellBoost: A pipeline for machine assisted annotation in neuroanatomy
Authors: Qian Kui , Friedman Beth , Takatoh Jun , Wang Fan , Kleinfeld David , Freund Yoav
Published: September 2023

One of the important yet labor intensive tasks in neuroanatomy is the identification of select populations of cells. Current high-throughput techniques enable marking cells with histochemical fluorescent molecules as well as through the genetic expression of fluorescent proteins. Modern scanning microscopes allow high resolution multi-channel imaging of the mechanically or optically sectioned brain with thousands of marked cells per square millimeter. Manual identification of all marked cells is prohibitively time consuming. At the same time, simple segmentation algorithms suffer from high error rates and sensitivity to variation in fluorescent intensity and spatial distribution. We present a methodology that combines human judgement and machine learning that serves to significantly reduce the labor of the anatomist while improving the consistency of the annotation. As a demonstration, we analyzed murine brains with marked premotor neurons in the brainstem. We compared the error rate of our method to the disagreement rate among human anatomists. This comparison shows that our method can reduce the time to annotate by as much as ten-fold without significantly increasing the rate of errors. We show that our method achieves significant reduction in labor while achieving an accuracy that is similar to the level of agreement between different anatomists.
Characterization of sinking and suspended microeukaryotic communities in spring Oyashio waters
Authors: Yang Qingwei , Yang Yanhui , Xia Jun , Fukuda Hideki , Okazaki Yusuke , Nagata Toshi , Ogata Hiroyuki , Endo Hisashi
Published: September 2023

Microeukaryotes are important components of sinking particles contributing to carbon export from the surface to deep oceans. The knowledge of the sinking microeukaryotic communities and their dynamics is limited. We applied 18S rDNA metabarcoding method to investigate the microeukaryotic communities in sinking and suspended particles distinguished by marine snow catchers (MSC) during spring in the Oyashio region. Sinking particles displayed distinct communities and lower diversity than did suspended particles. The community compositions of the sinking particles varied with depth, suggesting that microeukaryotes were selectively removed through disaggregation or decomposition during settling. Prymnesiophyceae and diatoms were effectively removed, as indicated by their decreased abundance in the sinking particles at increasing depths. Conversely, phototrophic dinoflagellates maintained a higher abundance in the sinking particles across depths, indicating resistance to disaggregation and decomposition. Heterotrophic dinoflagellates and Spirotrichea were enriched in sinking particles and marine stramenopiles (MAST) groups were enriched in suspended particles. Sinking heterotrophic protist communities in the deep layers were similar to those in the surface layers, whereas they differed from the suspended ones in the same layer. Therefore, heterotrophic protists in surface layers were transported to deeper layers. Overall, our results demonstrate the functional differences among microeukaryotes in the biological carbon pump.
Selection of Ethanol Tolerant Strains ofCandida albicansby Repeated Ethanol Exposure Results in Strains with Reduced Susceptibility to Fluconazole
Authors: Day Andrew W. , Kumamoto Carol A.
Published: September 2023

Candida albicansis a commensal yeast that has important impacts on host metabolism and immune function, and can establish life-threatening infections in immunocompromised individuals. Previously,C. albicanscolonization has been shown to contribute to the progression and severity of alcoholic liver disease. However, relatively little is known about howC. albicansresponds to changing environmental conditions in the GI tract of individuals with alcohol use disorder, namely repeated exposure to ethanol. In this study, we repeatedly exposedC. albicansto high concentrations (10% vol/vol) of ethanol—a concentration that can be observed in the upper GI tract of humans following consumption of alcohol. Following this repeated exposure protocol, ethanol small colony (Esc) variants ofC. albicansisolated from these populations exhibited increased ethanol tolerance, altered transcriptional responses to ethanol, and cross-resistance/tolerance to the frontline antifungal fluconazole. These Esc strains exhibited chromosomal copy number variations and carried polymorphisms in genes previously associated with the acquisition of fluconazole resistance during human infection. This study identifies a selective pressure that can result in evolution of fluconazole tolerance and resistance without previous exposure to the drug.
Hepatitis C Virus Infection and Risk of Non-Hodgkin’s Lymphoma: A Case-control Study in Mainland China
Authors: Hao Miao , Wang Wenjun , Lu Rui , Liu Yixin , Wu Fengping , Li Yaping , Jia Xiaoli , Dang Shuangsuo , Zhang Xin
Published: September 2023

In order to evaluate the association between hepatitis C virus (HCV) and non-Hodgkin’s lymphoma (NHL) in Mainland China, we conducted a hospital case-control study. Cases were newly diagnosed patients with NHL between 2009 and 2015 admitted to the Second Affiliated Hospital of Xi’an Jiaotong University. Controls were gender and age matched patients admitted to the same hospital due to acute conditions. A total of 694 cases and controls (1 : 1 ratio) were identified. Anti-HCV prevalence was 1.7% in NHL cases and 2.3% in controls (6/347vs. 8/347, OR = 0.75, 95% CI 0.26-2.17). Such prevalence in NHL cases (1.7%; 95% CI 0.6%-3.7%) does not differ from that in the Xi’an population (1.9%) or that in the general Chinese population (1.3%). HCV-RNA positivity was 0.9% in both NHL cases and controls using the available data (OR = 1.00, 95% CI 0.20-4.99). Subgroup analyses by histologic type of NHL or Epstein-Barr virus infection also showed no associations between anti-HCV and NHL. In conclusion, HCV is not associated with NHL risk in Mainland China, suggesting that the role of HCV in the occurrence of NHL is not significant in this population.
Estimating the population effectiveness of interventions against COVID-19 in France: a modelling study
Authors: Ganser Iris , Buckeridge David L , Heffernan Jane , Prague Mélanie , Thiébaut Rodolphe
Published: September 2023

Background

Non-pharmaceutical interventions (NPIs) and vaccines have been widely used to manage the COVID-19 pandemic. However, uncertainty persists regarding the effectiveness of these interventions due to data quality issues, methodological challenges, and differing contextual factors. Accurate estimation of their effects is crucial for future epidemic preparedness.

Methods

To address this, we developed a population-based mechanistic model that includes the impact of NPIs and vaccines on SARS-CoV-2 transmission and hospitalization rates. Our statistical approach estimated all parameters in one step, accurately propagating uncertainty. We fitted the model to comprehensive epidemiological data in France from March 2020 to October 2021. With the same model, we simulated scenarios of vaccine rollout.

Results

The first lockdown was the most effective, reducing transmission by 84% (95% confidence interval (CI) 83-85). Subsequent lockdowns had diminished effectiveness (reduction of 74% (69-77) and 11% (9-18), respectively). A 6 pm curfew was more effective than one at 8 pm (68% (66-69) vs. 48% (45-49) reduction), while school closures reduced transmission by 15% (12-18). In a scenario without vaccines before November 2021, we predicted 159,000 or 168% (95% prediction interval (PI) 70-315) more deaths and 1,488,000 or 300% (133-492) more hospitalizations. If a vaccine had been available after 100 days, over 71,000 deaths (16,507-204,249) and 384,000 (88,579-1,020,386) hospitalizations could have been averted.

Conclusion

Our results highlight the substantial impact of NPIs, including lockdowns and curfews, in controlling the COVID-19 pandemic. We also demonstrate the value of the 100 days objective of the Coalition for Epidemic Preparedness Innovations (CEPI) initiative for vaccine availability.
Genetic Variations in TrkB.T1 Isoform and Their Association with Somatic and Psychological Symptoms in Individuals with IBS
Authors: Hong H. , Mocci E. , Kamp K. , Zhu S. , Cain K.C. , Burr R. L. , Perry J. , Heitkemper M. M , Weaver-Toedtman K. R. , Dorsey S.G
Published: September 2023

Irritable bowel syndrome (IBS), a disorder of gut-brain interaction, is often comorbid with somatic pain and psychological disorders. Dysregulated signaling of brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), has been implicated in somatic-psychological symptoms in individuals with IBS. Thus, we investigated the association of 10 single nucleotide polymorphisms (SNPs) in the regulatory 3’ untranslated region (UTR) ofNTRK2(TrkB) kinase domain-deficient truncated isoform (TrkB.T1) and theBDNFVal66Met SNP with somatic and psychological symptoms and quality of life in a U.S. cohort (IBS n=464; healthy controls n=156). We found that the homozygous recessive genotype (G/G) of rs2013566 in individuals with IBS is associated with worsened somatic symptoms, including headache, back pain, joint pain, muscle pain, and somatization as well as diminished sleep quality, energy level and overall quality of life. Validation using U.K. BioBank (UKBB) data confirmed the association of rs2013566 with increased likelihood of headache. Several SNPs (rs1627784, rs1624327, rs1147198) showed significant associations with muscle pain in our U.S. cohort. Notably, these SNPs are predominantly located in H3K4Me1-enriched regions, suggesting their enhancer and/or transcription regulation potential. Together, our findings suggest that genetic variation within the 3’UTR region of the TrkB.T1 isoform may contribute to comorbid conditions in individuals with IBS, resulting in a spectrum of somatic and psychological symptoms that may influence their quality of life. These findings advance our understanding of the genetic interaction between BDNF/TrkB pathways and somatic-psychological symptoms in IBS, highlighting the importance of further exploring this interaction for potential clinical applications.
Qualitative exploration of patients’ experiences with Intrabeam targeted intraoperative radiotherapy (TARGIT-IORT) and External-Beam Radiotherapy Treatment (EBRT)
Authors: Bagga Sandeep , Swiderska Natalie , Hooker Charlotte , Royle Jenny , O’Connor Marie Ennis , Freeney Siobhan , Watson Dympna , Woolcock Robin
Published: September 2023

For patients with early breast cancer undergoing breast conserving surgery, radiotherapy is given either as a post-operative course of External-Beam RadioTherapy (EBRT), given daily for over a number of days and often weeks, or with TARGeted Intrabeam Intraoperative radioTherapy (TARGIT-IORT), which is delivered, during surgery under the same anaesthetic. Several studies have reported the quantitative Quality-of-Life (QoL) benefits of TARGIT-IORT over EBRT. This qualitative study was designed to gather a deep understanding of the benefits and impacts of receiving EBRT or TARGIT-IORT as perceived by patients. It also captured how differently the treatments affected the lived experience of the patient and their care partner through their treatment journey.

A patient-led Working Group was established to guide study design, delivery and to help validate findings. Patients with experience of receiving EBRT or TARGIT-IORT were first purposively sampled by Hampshire Hospitals NHS Foundation Trust after which a randomiser was applied to ensure the final selection process was free from bias. In February and March 2023, 29 semi-structured interviews (15 EBRT, 14 TARGIT-IORT) were conducted virtually via Zoom. Thematic analysis of verbatim interview transcripts was then carried out by two coders generating 11 themes related to either EBRT or TARGIT-IORT.

A number of procedural grievances were noted among EBRT patients. EBRT was perceived as being disruptive to a range of normal routines (work, home-life, and the burden of travel), and dissatisfying due to discomfort of side effects. TARGIT-IORT was perceived by patients and care partners as being efficient (given while they are asleep during surgery and without additional hospital visits) with minimal if any disruptions to QoL and that it was the safer option. The need for adequate, accessible information provision at the right time to reduce anxieties was noted in both cohorts. These new insights are valuable for healthcare staff and policy makers and could help incorporate the two treatments into routine practice. Further research is now needed to explore TARGIT-IORT in more diverse populations and in the 35 other countries where it is already a well- established treatment option.
Mechanisms for Integrating Real Data into Search Game Simulations: An Application to Winter Health Service Pressures and Preventative Policies
Authors: Chapman Martin , G-Medhin Abigail , Daneshi Kian , Bramwell Tom , Durbaba Stevo , Curcin Vasa , Parmar Divya , Boulding Harriet , Becares Laia , Morgan Craig , Molokhia Mariam , McBurney Peter , Harding Seeromanie , Wolfe Ingrid , Ashworth Mark , Poston Lucilla
Published: September 2023

While modelling and simulation are powerful techniques for exploring complex phenomena, if they are not coupled with suitable real-world data any results obtained are likely to require extensive validation. We consider this problem in the context of search game modelling, and suggest that both demographic and behaviour data are used to configure certain model parameters. We show this integration in practice by using a combined dataset of over 150,000 individuals to configure a specific search game model that captures the environment, population, interventions and individual behaviours relating to winter health service pressures. The presence of this data enables us to more accurately explore the potential impact of service pressure interventions, which we do across 33,000 simulations using a computational version of the model. We find government advice to be the best-performing intervention in simulation, in respect of improved health, reduced health inequalities, and thus reduced pressure on health service utilisation.
Are the rise in childhood obesity rates leading an increase in hospitalizations due to dengue?
Authors: Jeewandara Chandima , Karunananda Maneshka Vindesh , Fernando Suranga , Danasekara Saubhagya , Jayakody Gamini , Arulkumaran S. , Samaraweera N.Y. , Kumarawansha Sarathchandra , Sivaganesh Subramaniyam , Amarasinghe P. Geethika , Jayasinghe Chintha , Wijesekara Dilini , Marasinghe Manonath Bandara , Mambulage Udari , Wijayatilake Helanka , Senevirathne Kasun , Bandara A.D.P , Gallage C.P. , Colambage N.R. , Udayasiri A.A. Thilak , Lokumarambage Tharaka , Upasena Y. , Weerasooriya W.P.K.P. ,   seroprevalence study group, Ogg Graham S. , Malavige Gathsaurie Neelika
Published: September 2023

Background

Obesity and diabetes are known risk factors for severe dengue. The prevalence of obesity has markedly increased in many dengue endemic countries and the association of obesity with increased risk of hospitalization has not been previously been studied.

Methods and findings

Children aged 10 to 20 years (n=5207), were recruited from nine districts in Sri Lanka using a stratified multi-stage cluster sampling method. Details of previous admissions to hospital due to dengue and anthropometric measurements were recorded and seropositivity rates for dengue were assessed. The body mass index centile (BMI) in children aged 10 to 18, was derived by plotting the values on the WHO BMI-for-age growth charts, to acquire the percentile ranking. For participants aged >18 years of age, BMI was calculated and interpretated as for adults and a BMI of > 23.9 kg/m2were considered as obese.

Although the dengue seropositivity rates were similar in children of the different BMI centiles, 12/66 (18.2%) seropositive children with BMI centile >97th, had been hospitalized for dengue, compared to 103/1086 (9.48%) of children with a BMI centile of <97th. Therefore, those with a BMI centile of >97th, were twice as likely (odds ratio 2.1, 95% CI, 1.1 to 3.9, p=0.03) to have been hospitalized for dengue compared to children with a lower BMI. In those >18 years of age, obese individuals were again significantly more likely to have been hospitalized compared to leaner individuals (odds ratio 2.6, 95% CI, 1.0 to 6.1, p=0.04).

Conclusions

Obesity appears to increase the risk of hospitalization in those with dengue, highlighting the importance of creating awareness regarding obesity and risk of severe disease and hospitalization in dengue endemic countries.
Outbreak of severe community-acquired bacterial infections fromStreptococcus pyogenes, Streptococcus pneumoniae, Neisseria meningitidis, andHaemophilus influenzaeamong children in North Rhine-Westphalia (Germany), October to December 2022
Authors: Goretzki Sarah C. , van der Linden Mark , Itzek Andreas , Hühne Tom , Adelmann Roland O. , Ala Eldin Firas , Albarouni Mohamed , Becker Jan-Claudius , Berghäuser Michael A. , Boesing Thomas , Boeswald Michael , Brasche Milian , Brevis Francisco , Camara Rokya , Deibert Clara , Dohle Frank , Dolgner Jörg , Dziobaka Jan , Eifinger Frank , Elting Natalie , Endmann Matthias , Engelmann Guido , Frenzke Holger , Gappa Monika , Gharavi Bahman , Goletz Christine , Hahn Eva , Heidenreich Yvonne , Heimann Konrad , Hensel Kai O. , Hoffmann Hans-Georg , Hoppenz Marc , Horneff Gerd , Klassen Helene , Körner-Rettberg Cordula , Längler Alfred , Lenz Pascal , Lohmeier Klaus , Müller Andreas , Niemann Frank , Paulussen Michael , Pentek Falk , Perez Ruy , Pingel Markus , Repges Philip , Rothoeft Tobias , Rübo Jochen , Schade Herbert , Schmitz Robert , Schonhoff Peter , Schwade Jan N. , Schwarz Tobias , Seiffert Peter , Selzer Georg , Spille Uwe , Thiel Carsten , Thimm Ansgar , Urgatz Bartholomäus , van den Heuvel Alijda , van Hop Tan , Giesen Verena , Wirth Stefan , Wollbrink Thomas , Wüller Daniel , Felderhoff-Müser Ursula , Dohna-Schwake Christian , Lâm Thiên-Trí , Claus Heike , Bruns N.
Published: September 2023

Background

In late 2022, a surge of severe bacterial infections caused byS. pyogeneswas reported in several European countries, including Germany. This study assessed disease burden and severity of hospitalizations for community-acquired bacterial infections withS. pyogenes, S. pneumoniae, N. meningitidis, andH. influenzaeamong children in North Rhine-Westphalia (NRW), Germany, during the last quarter of 2022 compared to long-term incidences.

Methods

Hospital cases due to bacterial infections between October and December 2022 were collected from 59/62 (95 %) children’s hospitals in NRW and combined with surveillance data (2016 - 2023) from the national reference laboratories for streptococci,N. meningitidis, andH. influenzae. Total cases in NRW and incidence rates from January 2016 to March 2023 were estimated by capture-recapture analyses. Expected annual deaths from the studied pathogens were calculated from national death cause statistics.

Results

Between October and December 2022, 153 cases with high overall disease severity were reported with pneumonia being most common (59 %, n = 91). Incidence rates of bacterial infections declined at the beginning of the COVID-19 pandemic. In late 2022 and early 2023 a massive surge to levels unprecedented since 2016 was observed, mainly driven byS. pyogenesandS. pneumoniae. Observed deaths during the study period exceeded the expected number for the entire year in NRW by far (7 vs. 0.9).

Discussion

The unprecedented peak of bacterial infections in late 2022 and early 2023 was caused by various mechanisms intertwined that require close surveillance and improved precautionary measures for future outbreaks.
How COVID-19 continues to affect contraception in Scotland: a retrospective analysis of Scottish prescribing data between 2016 and 2023
Authors: Johnson-Hall Elliot
Published: September 2023

Background

In Scotland, the effects of the COVID-19 pandemic on women’s access to contraception are unknown. Globally, COVID-19 restrictions have led to a shift to telehealth service delivery alongside a reduction in contraceptive provision. Research into whether the effects of COVID-19 on contraception have abated after restrictions have been lifted is lacking.

Methods

This is a retrospective longitudinal study of prescribing data from the Scottish Health and Social Care Open Data repository (https://www.opendata.nhs.scot) between January 2016 and January 2023. Contraceptives were extracted and categorised using truncated British National Formulary codes and analysed using R. Contraceptive provision was compared across four periods: pre-COVID-19 (01/01/2016–23/03/2020), lockdown (24/03/2020–29/05/2020 & 05/01/2021–26/04/2021), restrictions (30/05/2020–04/01/2021 & 27/04/2021–30/04/2022), and post-COVID-19 (01/05/2022–01/01/2023).

Results

During lockdowns, contraceptive prescribing in Scotland decreased by 82.90% of pre-COVID-19 levels. This trend was more severe for long-acting reversible contraception which fell to 11.80% of pre-COVID-19 prescriptions. After COVID-19, the level of contraceptive prescribing has risen to 108.23% of its pre-pandemic level. Large increases in subcutaneous medroxyprogesterone acetate (499.05%), progestogen-only pills (125.07%), the patch (165.09%), levonorgestrel-IUS (112.54%), and ulipristal acetate emergency contraception prescribing (357.97%). Conversely, combined oral contraceptive pills (75.04%), Cu-IUD (83.63%), the implant (81.10%), and levonorgestrel emergency contraception (67.42%) prescribing has decreased.

Conclusions

COVID-19 vastly decreased contraceptive prescribing during lockdowns in Scotland. Post-COVID-19, changes in contraceptive prescribing within Scottish general practices are reported, with implications for health policy and service delivery planning.

Availability of Data & Code

All code and data used are fully available from Zenodo (doi:10.5281/zenodo.8310085)

The raw dataset used is also publicly available from the Scottish Health and Social Care Open Data repository (opendata.nhs.scot).
The impact of the COVID-19 pandemic on short-term cancer survival in the United Kingdom: a cohort analysis
Authors: Barclay Nicola L , Burkard Theresa , Burn Edward , Delmestri Antonella , Dominguez Andrea Miquel , Golozar Asieh , Guarner-Argente Carlos , Avilés-Jurado Francesc Xavier , Man Wai Yi , Serrano Àlvar Roselló , Rosen Andreas Weinberger , Tan Eng Hooi , Tietzova Ilona ,   OPTIMA Consortium, Alhambra Daniel Prieto , Newby Danielle
Published: September 2023

Objectives

The COVID-19 pandemic profoundly affected healthcare systems and patients. There is a pressing need to comprehend the collateral effects of the pandemic on noncommunicable diseases. Here we examined the impact of the COVID-19 pandemic on shortterm cancer survival in the United Kingdom (UK). We hypothesised that short-term survival from nine cancers would be reduced during the pandemic, particularly cancers that benefit from screening and early detection (e.g., breast and colorectal cancer).

Design

Population-based cohort study.

Setting

Electronic health records from UK primary care Clinical Practice Research Datalink (CPRD) GOLD database.

Participants

There were 12,259,744 eligible patients aged ≥18 years with ≥one year of prior history identified from January 2000 to December 2021.

Main outcome measures

We estimated age-standardised incidence rates (IR) and short-term (one- and two-year) survival of several common cancers (breast, colorectal, head and neck, liver, lung, oesophagus, pancreatic, prostate, and stomach cancer) from 2000 to 2019 (in five-year strata) compared to 2020 to 2021 using the Kaplan-Meier method.

Results

Apart from pancreatic cancer, IRs decreased for all cancers in 2020 and recovered to different extents in 2021. Short-term survival improved for most cancers between 2000 to 2019, but then declined for those diagnosed in 2020 to 2021.This was most pronounced for colorectal cancer, with one-year survival falling from 79.3% [95% confidence interval: 78.5%-80.1%] in 2015 to 2019 to 76.3% [74.6%-78.1%] for those diagnosed in 2020 to 2021.

Conclusion

Short-term survival for many cancers was impacted by the management of the COVID-19 pandemic in the UK. This decline was most prominent for colorectal cancer, with reductions in survivorship equivalent to returning to mortality seen in the first decade of the 2000s. These results illustrate the need for an immediate and well-funded investment in resolving the current backlog in cancer screening and diagnostic procedures in the UK National Health Service to improve patient outcomes.
Choice of Ultrafilter affects Recovery Rate of Bacteriophages
Authors: Larsen Frej , Offersen Simone Margaard , Li Viktoria Rose , Ling Deng , Nielsen Dennis Sandris , Rasmussen Torben Sølbeck
Published: September 2023

Studies into the viral fraction of complex microbial communities like in the mammalian gut have recently garnered much interest. Yet there is still no standardized protocol for extracting viruses from such samples, and the protocols that exist employ procedures that skew the viral community of the sample one way or another. The first step of the extraction pipeline often consists of basic filtering of macromolecules and bacteria, yet even this affects the viruses in a strain-specific manner. In this study we investigate a protocol for viral extraction based on ultrafiltration and6 how the choice of ultrafilter might influence the viral community. Clinical samples (feces, vaginal7 swabs, and tracheal suction samples) were spiked with a mock community of known phages (T4,8 c2, Φ6, Φ29, Φx174, and Φ2972), filtered, and quantified by spot and plaque assays to estimate the9 loss in recovery. Especially the enveloped Φ6 phage is severely affected by choice of filter, but also10 tailed phages such as T4 and c2 have a reduced infectivity after ultrafiltration. We conclude that11 the pore size of ultrafilters may affect the recovery of phages in a strain- and sample dependent12 manner, suggesting the need for greater thought when selecting filters for virus extraction.
The Dynamics of Synthesis and Localization of Jumbo Phage RNA Polymerases inside Infected Cells
Authors: Antonova Daria , Belousova Viktoriia V. , Zhivkoplyas Erik , Sobinina Mariia , Artamonova Tatyana , Vishnyakov Innokentii E. , Kurdyumova Inna , Arseniev Anatoly , Morozova Natalia , Severinov Konstantin , Khodorkovskii Mikhail , Yakunina Maria V.
Published: September 2023

A nucleus-like structure composed of phage-encoded proteins and containing replicating viral DNA is formed inPseudomonas aeruginosacells infected by jumbo bacteriophage phiKZ. The PhiKZ genes are transcribed independently from host RNA polymerase (RNAP) by two RNAPs encoded by the phage. The virion RNAP (vRNAP) transcribes early viral genes and must be injected into the cell with phage DNA. The non-virion RNAP (nvRNAP) is composed of early genes products and transcribes late viral genes. In this work, the dynamics of phage RNAPs localization during phage phiKZ infection was studied. We provide direct evidence of PhiKZ vRNAP injection in infected cells and show that it is excluded from the phage nucleus. The nvRNAP is synthesized shortly after the onset of infection and localizes in the nucleus. We propose that spatial separation of two phage RNAPs allows coordinated expression of phage genes belonging to different temporal classes.