bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel optical sensor system for the automatic classification of mosquitoes by genus and sex with high levels of accuracy
Authors: González-Pérez María I. , Faulhaber Bastian , Williams Mark , Brosa Josep , Aranda Carles , Pujol Nuria , Verdún Marta , Villalonga Pancraç , Encarnação Joao , Busquets Núria , Talavera Sandra
Published: June 2022

Background

Every year, more than 700,000 people die from vector-borne diseases, mainly transmitted by mosquitoes. Vector surveillance plays a major role in the control of these diseases and requires accurate and rapid taxonomical identification. New approaches to mosquito surveillance include the use of acoustic and optical sensors in combination with machine learning techniques to provide an automatic classification of mosquitoes based on their flight characteristics, including wingbeat frequency. The development and application of these methods could enable the remote monitoring of mosquito populations in the field, which could lead to significant improvements in vector surveillance.

Methods

A novel optical sensor prototype coupled to a commercial mosquito trap was tested in laboratory conditions for the automatic classification of mosquitoes by genus and sex. Recordings of > 4300 laboratory-reared mosquitoes of Aedes and Culex genera were made using the sensor. The chosen genera include mosquito species that have a major impact on public health in many parts of the world. Five features were extracted from each recording to form balanced datasets and used for the training and evaluation of five different machine learning algorithms to achieve the best model for mosquito classification.

Results

The best accuracy results achieved using machine learning were: 94.2% for genus classification, 99.4% for sex classification of Aedes, and 100% for sex classification of Culex. The best algorithms and features were deep neural network with spectrogram for genus classification and gradient boosting with Mel Frequency Cepstrum Coefficients among others for sex classification of either genus.

Conclusions

To our knowledge, this is the first time that a sensor coupled to a standard mosquito suction trap has provided automatic classification of mosquito genus and sex with high accuracy using a large number of unique samples with class balance. This system represents an improvement of the state of the art in mosquito surveillance and encourages future use of the sensor for remote, real-time characterization of mosquito populations.

Graphical abstract
Semaphorin 3G exacerbates joint inflammation through the accumulation and proliferation of macrophages in the synovium
Authors: Shoda Jumpei , Tanaka Shigeru , Etori Keishi , Hattori Koto , Kasuya Tadamichi , Ikeda Kei , Maezawa Yuko , Suto Akira , Suzuki Kotaro , Nakamura Junichi , Maezawa Yoshiro , Takemoto Minoru , Betsholtz Christer , Yokote Koutaro , Ohtori Seiji , Nakajima Hiroshi
Published: June 2022

Objectives

Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA). However, the precise mechanisms by which MTX stalls RA progression and alleviates the ensuing disease effects remain unknown. The aim of the present study was to identify novel therapeutic target molecules, the expression patterns of which are affected by MTX in patients with RA.

Methods

CD4+ T cells from 28 treatment-naïve patients with RA before and 3 months after the initiation of MTX treatment were subjected to DNA microarray analyses. The expression levels of semaphorin 3G, a differentially expressed gene, and its receptor, neuropilin-2, were evaluated in the RA synovium and collagen-induced arthritis synovium. Collagen-induced arthritis and collagen antibody-induced arthritis were induced in semaphorin3G-deficient mice and control mice, and the clinical score, histological score, and serum cytokines were assessed. The migration and proliferation of semaphorin 3G-stimulated bone marrow-derived macrophages were analyzed in vitro. The effect of local semaphorin 3G administration on the clinical score and number of infiltrating macrophages during collagen antibody-induced arthritis was evaluated.

Results

Semaphorin 3G expression in CD4+ T cells was downregulated by MTX treatment in RA patients. It was determined that semaphorin 3G is expressed in RA but not in the osteoarthritis synovium; its receptor neuropilin-2 is primarily expressed on activated macrophages. Semaphorin3G deficiency ameliorated collagen-induced arthritis and collagen antibody-induced arthritis. Semaphorin 3G stimulation enhanced the migration and proliferation of bone marrow-derived macrophages. Local administration of semaphorin 3G deteriorated collagen antibody-induced arthritis and increased the number of infiltrating macrophages.

Conclusions

Upregulation of semaphorin 3G in the RA synovium is a novel mechanism that exacerbates joint inflammation, leading to further deterioration, through macrophage accumulation.
Complete genome sequences and genomic characterization of five plasmids harbored by environmentally persistent Cronobacter sakazakii strains ST83 H322 and ST64 GK1025B obtained from powdered infant formula manufacturing facilities
Authors: Negrete Flavia J. , Ko Katie , Jang Hyein , Hoffmann Maria , Lehner Angelika , Stephan Roger , Fanning Séamus , Tall Ben D. , Gopinath Gopal R.
Published: June 2022

Background

Cronobacter sakazakii is a foodborne pathogen that causes septicemia, meningitis, and necrotizing enterocolitis in neonates and infants. The current research details the full genome sequences of two extremely persistent C. sakazakii strains (H322 and GK1025B) isolated from powdered infant formula (PIF) manufacturing settings. In addition, the genetic attributes associated with five plasmids, pH322_1, pH322_2, pGK1025B_1, pGK1025B_2, and pGK1025B_3 are described.

Materials and Methods

Using PacBio single-molecule real-time (SMRT®) sequencing technology, whole genome sequence (WGS) assemblies of C. sakazakii H322 [Sequence type (ST)83, clonal complex [CC] 83) and GK1025B (ST64, CC64) were generated. Plasmids, also sequenced, were aligned with phylogenetically related episomes to determine, and identify conserved and missing genomic regions.

Results

A truncated ~ 13 Kbp type 6 secretion system (T6SS) gene cluster harbored on virulence plasmids pH322_2 and pGK1025B_2, and a second large deletion (~ 6 Kbp) on pH322_2, which included genes for a tyrosine-type recombinase/integrase, a hypothetical protein, and a phospholipase D was identified. Within the T6SS of pH322_2 and pGK1025B_2, an arsenic resistance operon was identified which is in common with that of plasmids pSP291_1 and pESA3. In addition, PHASTER analysis identified an intact 96.9 Kbp Salmonella SSU5 prophage gene cluster in pH322_1 and pGK1025B_1 and showed that these two plasmids were phylogenetically related to C. sakazakii plasmids: pCS1, pCsa767a, pCsaC757b, pCsaC105731a. Plasmid pGK1025B_3 was identified as a novel conjugative Cronobacter plasmid. Furthermore, WGS analysis identified a ~ 16.4 Kbp type 4 secretion system gene cluster harbored on pGK1025B_3, which contained a phospholipase D gene, a key virulence factor in several host–pathogen diseases.

Conclusion

These data provide high resolution information on C. sakazakii genomes and emphasizes the need for furthering surveillance studies to link genotype to phenotype of strains from previous investigations. These results provide baseline data necessary for future in-depth investigations of C. sakazakii that colonize PIF manufacturing facility settings and genomic analyses of these two C. sakazakii strains and five associated plasmids will contribute to a better understanding of this pathogen's survival and persistence within various “built environments” like PIF manufacturing facilities.
Oligometastatic deposits of prostate cancer found within the sigmoid pericolic fat that was resected for colonic adenocarcinoma: a case report
Authors: Naumann David N. , Hejmadi Rahul K. , Richardson Jonathan J. R.
Published: June 2022

Background

Prostate cancer may rarely metastasize to the colon and colonic lymph nodes, and local treatment of oligometastatic deposits may improve oncological outcomes. Immunohistochemical stains are used to determine the most likely source of metastatic deposits when they are seen within surgical specimens. The aim of this case report is to illustrate how such techniques were used to identify unexpected prostatic metastases within the pericolic fat of a sigmoid colon resection specimen following elective curative surgery for colorectal cancer. To our knowledge, this is the first report of complete excision of oligometastatic deposits of prostate cancer found incidentally within the specimen of another cancer.

Case report

An 89-year-old Caucasian man underwent sigmoid colectomy for an obstructing colorectal cancer in the sigmoid colon with some mesenteric lymphadenopathy. He had previously received radical radiotherapy for prostate cancer 10 years earlier. When the specimen was examined by the histopathologist, it was noted that the pericolic fat adjacent to the colorectal adenocarcinoma contained some metastatic deposits. Positive immunohistochemical staining for prostate-specific antigen and prostate-specific acid phosphatase with negative staining for CDX2 and CK20 revealed these to be prostatic metastases rather than colonic. Since these were completely excised, and there were no other metastases, this represented a serendipitous, curative excision of oligometastatic deposits of an additional cancer to the one that was being treated.

Conclusions

This case illustrates how immunohistochemical staining may be used to distinguish the source of metastatic deposits based on the likelihood of primary tumor from a careful and thorough patient history.
Risk factors for asthma exacerbation during pregnancy: protocol for a systematic review and meta-analysis
Authors: Bokern Marleen P. , Robijn Annelies L. , Jensen Megan E. , Barker Daniel , Baines Katherine J. , Murphy Vanessa E.
Published: June 2022

Background

Asthma is the most common medical condition to affect pregnancy. Asthma exacerbations occur in up to 45% of pregnant women and have been associated with adverse perinatal and infant outcomes. Conflicting literature exists regarding the risk factors for exacerbations, and no synthesis of the literature currently exists. Therefore, this systematic review and meta-analysis aims to determine risk factors for asthma exacerbations during pregnancy among pregnant women with asthma.

Methods

This protocol has been reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis protocols checklist. A systematic search will be conducted in the electronic MEDLINE, Embase, CINAHL and Cochrane Clinical Trials Register databases (from January 2000 onwards). Eligibility of each publication will be determined based on predefined selection criteria. Prospective cohort studies, retrospective cohort studies, case-control studies and randomised controlled trials (RCTs) will be included. Quality of included studies will be determined using the Newcastle Ottawa Scale and the Cochrane Risk of Bias tool. Pooled relative risk will be computed using random-effects meta-analyses. Heterogeneity will be assessed using the chi-squared test and the I2 parameter. Publication bias will be assessed by inspecting a funnel plot for asymmetry and with the Egger’s test of analyses including ten studies or more.

Discussion

The results of this systematic review and meta-analysis will discuss the potential risk factors for asthma exacerbations during pregnancy. This may aid healthcare professionals in early identification of pregnant women with asthma at risk of poor outcomes, providing the opportunity to implement early interventions in order to avoid deterioration of asthma symptoms during pregnancy.

Systematic review registration

PROSPERO CRD42020196190
Approximation method for monotone inclusion problems in real Banach spaces with applications
Authors: Adamu Abubakar , Kitkuan Duangkamon , Kumam Poom , Padcharoen Anantachai , Seangwattana Thidaporn
Published: June 2022

In this paper, we introduce an inertial Halpern-type iterative algorithm for approximating a zero of the sum of two monotone operators in the setting of real Banach spaces that are 2-uniformly convex and uniformly smooth. Strong convergence of the sequence generated by our proposed algorithm is established by means of some new geometric inequalities proved in this paper that are of independent interest. Furthermore, numerical simulations in image restoration and compressed sensing problems are also presented. Finally, the performance of the proposed method is compared with that of some existing methods in the literature.
Armigeres subalbatus is a potential vector for Zika virus but not dengue virus
Authors: Yang Wenqiang , Zhao Siyu , Xie Yugu , Liu Tong , Kong Ling , Guo Yijia , Xie Zhensheng , Liu Peiwen , Chen Xiao-Guang
Published: June 2022

Background

Zika virus (ZIKV) and dengue virus (DENV) are closely related flaviviruses primarily transmitted by Aedes mosquitoes. Armigeres subalbatus is an emerging and widely distributed mosquito, and ZIKV has been detected and isolated from it. However, it is not clear whether Ar. subalbatus could be a vector for ZIKV and DENV or not. In this study, we investigated the infection and transmission of Ar. subalbatus to ZIKV and DENV.

Methods

A line of Ar. subalbatus was isolated from Guangdong, China, and further identified by the mitochondrial cytochrome oxidase subunit 1 (COI) gene. The adults of Ar. subalbatus were fed with blood meal containing ZIKV or DENV-2. At 4, 7, 10, 14, and 21 days post-inoculation (dpi), the infections of ZIKV or DENV-2 in the midguts, ovaries and salivary glands were detected and quantified by RT-PCR and RT-qPCR. To assess the transmissibility, suckling mice were exposed to bites of ZIKV-infected mosquitoes, and ZIKV was detected in brain tissue by RT-qPCR and plaque assays. Furthermore, the larvae of Ar. subalbatus were reared in artificial urine containing ZIKV or DENV-2. The infection rates and viral titers of larvae and adults were analyzed by RT-PCR and RT-qPCR, and the viral distribution in larval tissues was observed by immunohistochemistry. Chi-square test and one-way ANOVA analysis were used for assessing the infection rate and viral titer in varied tissues and different time points, respectively.

Results

Following oral inoculation, ZIKV but not DENV-2 could be detected in Ar. subalbatus midguts at 4 dpi, ovaries at 7 dpi and salivary glands at 10 dpi. The highest infection rate (IR) of ZIKV was 27.8% in midgut at 7 dpi, 9.7% in ovary and 5.6% in salivary gland at 21 dpi. Eight days after being bitten by ZIKV-positive mosquitoes, ZIKV was detected in three brain tissues out of four suckling mice exposed to bites. ZIKV could be detected in the larvae reared in artificial urine contained ZIKV at a high concentration of 105 pfu/ml and various tissues of adults with a low infection rate (0.70–1.35%). ZIKV could be observed in anal papillae and midgut of larvae at 4 dpi under laboratory conditions.

Conclusions

ZIKV but not DENV-2 can infect Ar. subalbatus by blood meal and artificial urine, and the infected mosquitoes can transmit ZIKV to suckling mice by bite. From these findings, we can conclude that the Ar. subalbatus isolated from Guangdong province, China, is a potential vector for ZIKV and should therefore be considered in vector control programs to prevent and control of Zika virus disease.

Graphical Abstract
“Everything has changed”: detention officer roles and recreation time changes due to COVID-19 policies at a Southwest County Jail
Authors: Pinn Travis , Williamson Heather , Robinson Bethany , Shuman Sara , Evans Maria , Pro George , Camplain Ricky
Published: June 2022

Background

The COVID-19 pandemic responses in jails have forced detention officers to adjust how they approach the confinement and care of individuals while they are incarcerated. One aspect of incarceration affected was detention officers’ roles. The aims of this research project were to determine how the COVID-19 pandemic has affected the general duties of detention officers at a Southwest County Jail. Detention officers were recruited via email to participate in an online questionnaire from October to December 2020. Participants answered Likert scale and open-ended questions regarding how the COVID-19 pandemic has affected their job duties. Descriptive statistics and thematic analysis were used to identify themes and patterns in the responses.

Results

Among 24 detention officers, 87% indicated agreement that the COVID-19 pandemic has significantly changed the duties of detention officers at CCDF. The most discussed change was the introduction of a 14-day quarantine process for newly incarcerated individuals. The 14-day quarantine increased the workload of detention officers.

Conclusion

The COVID-19 pandemic responses in jail may have unintended negative consequences for the job duties of detention officers. Current and future pandemic response strategies in jails would benefit from taking staff perspectives into consideration as they are directly impacted by the COVID-19 response strategies put into place. Policy implications are discussed.
MicroRNAs as the critical regulators of cell migration and invasion in thyroid cancer
Authors: Hamidi Amir Abbas , Taghehchian Negin , Basirat Zahra , Zangouei Amir Sadra , Moghbeli Meysam
Published: June 2022

Thyroid cancer (TC) is one of the most frequent endocrine malignancies that is more common among females. Tumor recurrence is one of the most important clinical manifestations in differentiated TC which is associated with different factors including age, tumor size, and histological features. Various molecular processes such as genetic or epigenetic modifications and non-coding RNAs are also involved in TC progression and metastasis. The epithelial-to-mesenchymal transition (EMT) is an important biological process during tumor invasion and migration that affects the initiation and transformation of early-stage tumors into invasive malignancies. A combination of transcription factors, growth factors, signaling pathways, and epigenetic regulations affect the thyroid cell migration and EMT process. MicroRNAs (miRNAs) are important molecular factors involved in tumor metastasis by regulation of EMT-activating signaling pathways. Various miRNAs are involved in the signaling pathways associated with TC metastasis which can be used as diagnostic and therapeutic biomarkers. Since, the miRNAs are sensitive, specific, and non-invasive, they can be suggested as efficient and optimal biomarkers of tumor invasion and metastasis. In the present review, we have summarized all of the miRNAs which have been significantly involved in thyroid tumor cells migration and invasion. We also categorized all of the reported miRNAs based on their cellular processes to clarify the molecular role of miRNAs during thyroid tumor cell migration and invasion. This review paves the way of introducing a non-invasive diagnostic and prognostic panel of miRNAs in aggressive and metastatic TC patients.
Method to determine the statistical technical variability of SUV metrics
Authors: De Luca Giulia M. R. , Habraken Jan B. A.
Published: June 2022

Background

The Standardized Uptake Value (SUV) Max, SUVMean, and SUVPeak are metrics used to quantify positron emission tomography (PET) images. In order to assess the significance of a change in these metrics for diagnostic purposes, it is relevant to know their variation. The sources of variation can be biological or technical. In this study, we present a method to determine the statistical technical variation of SUV in PET images.

Results

This method was tested on a NEMA quality phantom with spheres of various diameters with a full-length acquisition time of 150 s per bed position and foreground-to-background activity ratio of F18-2-fluoro-2-deoxy-d-glucose (FDG) of 10:1. Our method divides the 150 s acquisition into subsets with statistically independent frames of shorter reconstruction length. SUVMax, Mean and Peak were calculated for each reconstructed image in a subset. The coefficient of variation of SUV within each subset has been used to estimate the expected coefficient of variation at 150 s reconstruction length. We report the largest coefficient of variation of the SUV metrics for the smallest sphere and the smallest variation for the largest sphere. The expected variation at 150 s reconstruction length does not exceed 6% for the smallest sphere and 2% for the largest sphere.

Conclusions

With the presented method, we aim to determine the statistical technical variation of SUV. The method enables the evaluation of the effect of SUV metric choice (Max, Mean, Peak) and lesion size on the technical variation and, therefore, to evaluate its relevance on the total variation of the SUV value between clinical studies.
The design and evaluation of a health education control for comparison with cognitive behavioural therapy for individuals with acquired brain injury
Authors: Ymer Lucy , McKay Adam , Wong Dana , Ponsford Jennie
Published: June 2022

Background

In psychological research, control conditions in the form of “treatment as usual” provide support for intervention efficacy, but do not allow the attribution of positive outcomes to the unique components of the treatment itself. Attentionally and structurally equivalent active control conditions, such as health education (HE), have been implemented in recent trials of cognitive behavioural therapy (CBT). However, descriptions and evaluations of these control conditions are limited. The aims of this paper were to (i) provide a detailed description and rationale for a novel HE active control condition and (ii) to evaluate the face validity, treatment integrity and feasibility of HE.

Method

We developed a HE active control similar in structure and duration to a CBT intervention for reducing sleep disturbance and fatigue (CBT-SF) in a pilot randomised controlled trial (n = 51). Face validity was measured using post-treatment participant satisfaction and helpfulness ratings for fatigue and sleep symptoms, treatment fidelity was measured with integrity monitoring ratings from an independent expert and feasibility was measured with completion and attrition rates. HE and CBT-SF groups were compared using Wilcoxon rank-sum tests and chi-square tests of independence.

Results

There were no significant differences in participant ratings of overall satisfaction between HE (n = 17) and CBT (n = 34) or in how helpful each intervention was for fatigue symptoms. Participants rated helpfulness for sleep symptoms higher in the CBT-SF group compared to HE. Integrity monitoring ratings were not significantly different for overall treatment delivery and therapist competency, but HE had greater module adherence than CBT-SF. There were no significant differences in completion or attrition rates between groups.

Conclusion

Our findings suggest that the HE control had adequate face validity, was delivered with fidelity and was feasible and suitable for use as a comparator for CBT-SF. In providing a real-world example of practical and theoretical issues we considered when designing this control condition, we aim to provide a framework and guidance for future investigators.

Trial registration

ACTRN12617000879369 (registered 15/06/2017) and ACTRN12617000878370 (registered 15/06/2017).
Recognizing patient partner contributions to health research: a mixed methods research protocol
Authors: Fox Grace , Fergusson Dean A. , Nicholls Stuart G. , Smith Maureen , Stacey Dawn , Lalu Manoj M.
Published: June 2022

Background

The overall aim of this program of research is to assess when/how patient partners are compensated financially for their contributions to health research. The research program consists of three studies to address the following questions: (1) What is the prevalence of reporting patient partner financial compensation? (2) What are researcher and institutional attitudes around patient partner financial compensation? (3) What are the current practices of patient partner financial compensation and what guidance exists to inform these practices?

Methods

In our first project, we will conduct a systematic review to assess the prevalence of reporting patient partner financial compensation and identify current financial compensation practices on an international scale. We will identify a cohort of published studies that have engaged patients as partners through a forward citation search of the Guidance for Reporting the Involvement of Patients and the Public (GRIPP I and II) checklists. We will extract details of financial compensation (type of financial compensation, amount, payment frequency etc.) and reported benefits, challenges, barriers and enablers to financially compensating patient partners. Quantitative data will be analyzed descriptively, and qualitative data will undergo thematic analysis. In our second project, we will conduct a cross-sectional survey of researchers who have engaged patient partners. We will also survey members of their affiliated institutions to gain further understanding of stakeholder experiences and attitudes with patient partner financial compensation. Survey responses will be analyzed by calculating prevalence. In our third project, we will conduct a scoping review to identify all published guidance and policy documents that guide patient partner financial compensation. Overton, the largest available online database of international policy documents, and the grey literature will be systematically searched. Data items will be extracted and presented descriptively. A comprehensive overview of guidance documents will be presented, which will represent a repository of resources that stakeholders can refer to when developing a financial compensation strategy.

Discussion

Our three studies will not only inform and assist patient partners and researchers by informing compensation strategies, but also support the inclusion of diverse perspectives. We will disseminate findings through traditional mediums (publications, conferences) as well as social media, non-technical summaries, and visual abstracts.
The effects of climate change on the livelihood of rural women: a case study of Ilorin South, Nigeria
Authors: Duru Jemima , Aro Joseph , Oladipo Rachael Ebunoluwa
Published: June 2022

Background

Globally, the increasing impacts of climate change continue to be seen in rising sea temperature, flooding, and fluctuation in weather patterns. Recently, the phenomenon has become a reality for poor communities whose livelihoods are being washed away by floods and children whose education is being truncated by the economic impacts of climate change. Therefore, this research aims to determine the effects of climate change on the livelihood of rural women who are said to be more vulnerable to the culminating effects of anthropogenically induced climate change disasters. To achieve the aim and objectives of this study, the research was conducted phenomenologically using questionnaires, interviews, and focus group discussions to access the assets required for improving the livelihood of rural women affected by climate change.

Results

The interpreted results of the data gathered using questionnaires showed that rural women in Ilorin South Local Government Area (LGA) of Kwara State, Nigeria, are impacted by the perils of anthropogenically induced climate change disasters that have impacts on their livelihood. These implications can be seen in the resilience of the methods used by these rural women to combat the continuing impact of climate change on their livelihood. The findings of the research also indicate that there are other factors making them vulnerable to the impacts of climate change such as lack of basic infrastructures, low capital base, and the use of crude farming methods.

Conclusion

From the suggestions in this study, we can conclude that climate change is already affecting the livelihood of rural women. However, a collective effort is required to implement the proactive measures required to improve rural women’s resilience to the impact of climate change on their livelihood.
Prevalence of severe acute respiratory syndrome coronavirus 2 spike antibodies in some healthcare settings in Egypt
Authors: El-Ghitany Engy Mohamed , Farghaly Azza Galal , Farag Shehata , Hashish Mona H. , Charl Fahmy , Omran Eman A.
Published: June 2022

Background

Healthcare workers (HCWs) are at the front line in battling infection transmission, such as that in coronavirus disease 19 (COVID-19). Additionally, they may act as potential carriers passing the virus on to others. Anti-spike (anti-S) antibodies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are formed either as a result of infection or vaccination with both indicating immunity against future COVID-19 infection.

Aim

This study aimed to identify the prevalence of COVID-19 seropositivity among HCWs.

Methods

This cross-sectional study included 559 HCWs from 39 hospitals with variable degrees of COVID-19 exposure risk (depending on the occupation, department, and hospital type). Demographic data were recorded as well as history of COVID-19 infection and vaccination. Serum samples were collected and tested for SARS-CoV-2 spike antibodies.

Results

Anti-S positivity was found in 59.0% of the participating 559 HCWs, indicating a high level of seroprotection. Of the 559 HCWs, 34.1% had reported previous infection with COVID-19. Following infection, only 46 (24.0%) of those affected received vaccination. Anti-S seropositivity was found in 39.1% of participants who were unvaccinated and had no history of infection. Physicians had the highest median anti-S titers (58.0 relative units (RU)/mL), whereas pharmacists and office staff had the lowest (25.7 and 38.2 RU/mL, respectively).

Conclusions

Overall, 59.0% of the 559 HCWs were anti-S positive, indicating a relatively high seroprotective status. Among those who were unvaccinated and had no history of infection, 39.1% were seropositive for anti-S, denoting a high rate of silent/asymptomatic infections. Screening of HCWs for SARS-CoV-2 anti-S is recommended, along with the vaccination of seronegative individuals.
Effect of antimicrobial administration on fecal microbiota of critically ill dogs: dynamics of antimicrobial resistance over time
Authors: Menard Julie , Goggs Robert , Mitchell Patrick , Yang Yufan , Robbins Sarah , Franklin-Guild Rebecca J. , Thachil Anil J. , Altier Craig , Anderson Renee , Putzel Gregory G. , McQueary Holly , Goodman Laura B.
Published: June 2022

Background

Multidrug resistance in companion animals poses significant risks to animal and human health. Prolonged antimicrobial drug (AMD) treatment in animals is a potential source of selection pressure for antimicrobial resistance (AMR) including in the gastrointestinal microbiota. We performed a prospective study of dogs treated for septic peritonitis, pyometra, or bacterial pneumonia and collected repeated fecal samples over 60 days. Bacterial cultures and direct molecular analyses of fecal samples were performed including targeted resistance gene profiling.

Results

Resistant Escherichia coli increased after 1 week of treatment (D1:21.4% vs. D7:67.9% P < 0.001) and returned to baseline proportions by D60 (D7:67.9% vs D60:42.9%, P = 0.04). Dogs with septic peritonitis were hospitalized significantly longer than those with pneumonia or pyometra. Based on genetic analysis, Simpson’s diversity index significantly decreased after 1 week of treatment (D1 to D7, P = 0.008), followed by a gradual increase to day 60 (D1 and D60, P = 0.4). Detection of CTX-M was associated with phenotypic resistance to third-generation cephalosporins in E. coli (OR 12.1, 3.3–68.0, P < 0.001). Lincosamide and macrolide-resistance genes were more frequently recovered on days 14 and 28 compared to day 1 (P = 0.002 and P = 0.004 respectively).

Conclusion

AMR was associated with prescribed drugs but also developed against AMDs not administered during the study. Companion animals may be reservoirs of zoonotic multidrug resistant pathogens, suggesting that veterinary AMD stewardship and surveillance efforts should be prioritized.

Graphical abstract
Meta-analysis and systematic literature review of COVID-19 associated bradycardia as a predictor of mortality
Authors: Umeh Chukwuemeka A. , Kumar Sabina , Wassel Elias , Barve Pranav
Published: June 2022

Background

Cardiac arrhythmias have been identified as independent predictors of mortality in Coronavirus disease 2019 (COVID-19) patients. While some studies have reported poor prognosis with bradycardia in COVID-19 patients, others have not found any association between bradycardia and mortality in COVID-19 patients. This study aims to assess the relationship between bradycardia and mortality in COVID-19 patients by reviewing existing literature.

Main body

Articles were obtained by systematically searching the PubMed and Google scholar databases. Qualitative and quantitative analyses of the studies on bradycardia and mortality in COVID-19 were done. A pooled estimate, with a sample size of 1320 patients, comparing the effect of patients that were bradycardic during their admission with those that were not on mortality showed that bradycardia did not lead to increased mortality in COVID-19 patients (OR 1.25, 95% CI 0.41–3.84, p = 0.7).

Conclusions

This meta-analysis showed that bradycardia was not significantly associated with mortality in COVID-19 patients. However, this study is limited by the few studies on bradycardia and mortality in COVID-19 patients. Therefore, future studies should investigate this relationship so that clinicians can prognostically triage and treat COVID-19 patients appropriately.
Mid-term follow-up and outcomes of patients with prosthetic heart valves: a single-centre experience
Authors: Bennett Sadie , Demetriades Polyvios , Banks Keely , Tafuro Jacopo , Oatham Rosie , Griffiths Timothy , Oxley Cheryl , Clews Sally , Heatlie Grant , Kwok Chun Shing , Duckett Simon
Published: June 2022

Background

Patients with prosthetic heart valves (PHV) require long-term follow-up, usually within a physiologist led heart valve surveillance clinic. These clinics are well established providing safe and effective patient care. The disruption of the COVID-19 pandemic on services has increased wait times thus we undertook a service evaluation to better understand the patients currently within the service and PHV related complications.

Methods

A clinical service evaluation of the heart valve surveillance clinic was undertaken to assess patient demographics, rates of complications and patient outcomes in patients who had undergone a PHV intervention at our institute between 2010 and 2020.

Results

A total of 294 patients (mean age at time of PHV intervention: 71 ± 12 years, 68.7% male) were included in this service evaluation. Follow-up was 5.9 ± 2.7 years (range: 10 years). 37.1% underwent baseline transthoracic echo (TTE) assessment and 83% underwent annual TTE follow-up. Significant valve related complications were reported in 20 (6.8%) patients. Complications included a change in patient functional status secondary to significant PHV regurgitation (0.3%) or stenosis (0.3%), PHV thrombosis (0.3%) or infective endocarditis (3.7%). Significant valve related complications resulted in ten hospital admission (3.4%), two re-do interventions (0.6%), and four deaths (1.3%).

Conclusions

This service evaluation highlights the large number of patients requiring ongoing surveillance. Only a small proportion of patients develop significant PHV related complications resulting in a low incidence of re-do interventions and deaths.
Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC).
Authors: Krop Ian E. , Masuda Norikazu , Mukohara Toru , Takahashi Shunji , Nakayama Takahiro , Inoue Kenichi , Iwata Hiroji , Toyama Tatsuya , Yamamoto Yutaka , Hansra Damien Mikael , Takahashi Masato , Osaki Akihiko , Koyama Kumiko , Inoue Tatsuya , Yonekura Takatoshi , Mostillo Joseph , Ohwada Shoichi , Tanaka Yoshimi , Sternberg David W. , Yonemori Kan
Published: June 2022

1002

Background: Patritumab deruxtecan (HER3-DXd) is a novel, investigational ADC composed of a human anti-HER3 monoclonal antibody covalently bound to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. Here we report updated safety and efficacy data from this ongoing study (U31402-A-J101; NCT02980341; JapicCTI-163401) of HER3-DXd in pts with previously treated MBC. Methods: U31402-A-J101 is a phase 1/2, multicenter, open-label, first-in-human study of HER3-DXd in pts with HER3-expressing MBC (N = 182). The study enrolled pts in dose-escalation (3.2-8.0 mg/kg IV Q3W) and dose-finding portions across molecular subtypes (n = 66; including HER2+ MBC, n = 14) followed by dose expansion in the following subtypes: HER3 high (4.8 mg/kg [n = 33] or 6.4 mg/kg [n = 31]), HER3 low (6.4 mg/kg [n = 21]) HR+/HER2− MBC or HER3-high TNBC (6.4 mg/kg [n = 31]). HER3-high and -low were defined as ≥75% and 25% ‒ < 75% membrane positivity. The primary objective was to assess safety and efficacy; secondary objectives included determining the relationship between efficacy and HER3 expression. Results: At data cutoff (16 Aug 2021), median study duration was 31.9 mo (range, 15-56). Median age was 57 y (range, 30-83); 132 (72.5%) and 50 (27.5%) pts had an ECOG PS of 0 or 1. Pts had a median of 5 (range, 1-13) prior lines of therapy for locally advanced/metastatic disease. Median treatment duration with HER3-DXd was 5.9 mo (range, 0.7-30.6). In a pooled evaluation of dose escalation/finding and expansion, efficacy is shown in pts with HR+/HER2− MBC, TNBC, and HER2+ MBC in the Table. Overall, 130 pts (71.4%) had grade ≥3 TEAEs; the most common (≥15%) were decreased neutrophil count (39.6%), decreased platelet count (30.8%), anemia (18.7%), and decreased white blood cell count (18.1%). 12 pts (6.6%) experienced treatment-related interstitial lung disease according to central adjudication, including 1 grade 5 event. Conclusions: A pooled analysis in this heavily pretreated population showed promising efficacy in pts with HR+/HER2− and HER2+ MBC as well as TNBC. The safety profile with longer follow-up is consistent with previous reports and showed adequate safety and tolerability. Studies are ongoing in MBC tumor types, with a focus on biomarkers associated with efficacy. Clinical trial information: NCT02980341. [Table: see text]
Update on phase 1 study of tazemetostat, an enhancer of zeste homolog 2 inhibitor, in pediatric patients with relapsed or refractory integrase interactor 1–negative tumors.
Authors: Chi Susan N. , Bourdeaut Franck , Casanova Michela , Kilburn Lindsay Baker , Hargrave Darren R. , McCowage Geoffrey Brian , Pinto Navin R. , Yang Jay , Chadha Raminder , Kahali Bhaskar , Tapia Coya , Nysom Karsten
Published: June 2022

10040

Background: A defining feature of malignant rhabdoid tumors (MRTs), epithelioid sarcoma (ES), and poorly differentiated chordomas (PDC) is loss of integrase interactor 1 (INI1) expression, which induces dependence on enhancer of zeste homolog 2 (EZH2). Tazemetostat (TAZ) is a selective EZH2 inhibitor approved by the US Food and Drug Administration for patients (pts) aged ≥16 y with metastatic or locally advanced ES ineligible for complete resection. Pediatric dose escalation and interim efficacy and safety data for the dose expansion were previously reported. Updated efficacy, safety, subgroup analyses, and translational results are reported here. Methods: NCT02601937 is a phase 1 multicenter study evaluating TAZ monotherapy ≤2400 mg/m2 daily in pediatric pts with relapsed or refractory INI1− tumors (MRT, atypical teratoid rhabdoid tumor [ATRT], select tumors with rhabdoid features, other INI1− tumors, and SS18-SSX synovial sarcoma). Primary endpoint for dose expansion was objective response rate (ORR). Secondary endpoints included safety/tolerability, duration of response (DOR), progression-free survival (PFS), and overall survival. Selected exploratory flow data using 250,000 cells from peripheral blood were available for up to 25 pts. Results: Phase 1 enrolled 109 pts (escalation, n=46; expansion, n=63; Table) with mean ages of 5.4 y in the dose escalation and 7.4 y in the dose expansion. ORRs were 7% (3/46) in the dose escalation and 14% (9/63) in the dose expansion. Per tumor category in the dose expansion, ORRs were 24% (5/21) ATRT, 33% (2/6) PDC, 22% (2/9) ES, and 0% in non–CNS RTs (n=21) and other tumors (n=6). ORR for pts with prior radiotherapy was 14% (11/80) vs 3% (1/29) with prior radiotherapy ( P>0.05). In the dose expansion, median PFS was 8 wk (95% CI: 8–13), OS was 21 wk (95% CI: 13–38), and DOR was 35 wk (95% CI: 24–121). Grade 3–4 treatment-related treatment-emergent adverse event rates were 15% (7/46) in the dose escalation and 22% (14/63) in dose expansion. Differences between responders (R) and nonresponders (NR) at C1D1 for neutrophil counts were significant ( P<0.05). All R (6/6) had <125,000 total neutrophils at C1D1 vs 42% (8/19) of NR; 50% (3/6) of R had >50,000 total CD3 T cells vs 0% (0/19) of NR. Conclusions: TAZ showed promising antitumor activity in ATRT, ES, and PDC. Potential synergism between prior radiotherapy and TAZ requires further investigation. TAZ was generally well tolerated. The biological/clinical significance of differences in peripheral blood cell counts between R and NR at C1D1 needs further investigation. Clinical trial information: NCT02601937. [Table: see text]
Clinical validation of a multicancer detection blood test by circulating cell-free DNA (cfDNA) methylation sequencing: The THUNDER study.
Authors: Gao Qiang , Zhang Yuzi , Xu Jiayue , Wang Guoqiang , Zhao Jing , Wen Xiaofang , Li Bingsi , Zhang Zhihong , Cai Shangli , Fan Jia , Su Jing
Published: June 2022

10544

Background: The development of ultra-sensitive genomic and epigenomic assays enables the early detection of multiple cancers in parallel. However, large-scale prospective clinical validation data are rare. Here, we report clinical validation data from the THUNDER (The Unintrusive Detection of EaRly-stage cancers, NCT04820868) study, which evaluates the performance of ELSA-seq among 6 cancer types in lung, colorectum, liver, esophagus, pancreas and ovary, which account for 50% of cancer morbidity and 62% of cancer mortality. Methods: This prospective case-control study consists of four stages: marker discovery, model training, validation, and independent validation. A customized panel covering 161,984 CpG sites was established using public data and in-house data. Cancer patients were pre-specified into the training and validation sets, and healthy controls (HC) were age-matched. Two multi-cancer detection blood test (MCDBT-1 and MCDBT-2) models with different cut-offs were established from the retrospectively collected training set and tested in the validation set. An independent validation set was enrolled prospectively, matched by age, and tested with the locked MCDBT-1/2 models. An interception model was then applied based on the model performance and China cancer incidence data to infer potential positive predictive value (PPV) and clinical utility in real-world practice. Results: In total, the training set consisted of 399 cases and 626 HC; the validation set consisted of 301 cases and 123 HC; and the independent validation set consisted of 505 cases and 505 HC. In the training set, the specificities were 98.9% (95% confidence interval [CI], 97.7%‒99.5%) and 99.7% (98.8%‒100.0%) for MCDBT-1/2 models, respectively. In the independent validation set ( n = 856, the rest to be sequenced and reported), MCDBT-1 and MCDBT-2 yielded sensitivity of 76.2% (72.0%‒80.0%) and 70.2% (65.8%‒74.4%) in 6 cancers with specificity of 96.3% (93.9%‒97.9%) and 99.3% (97.8%‒99.8%), respectively. Stage I‒III sensitivity was 68.5% (63.1%‒73.5%) and 60.8% (55.3%‒66.2%) for MCDBT-1/2 models, respectively. The prediction accuracy of top predicted origin was 79.1% (74.5%‒83.2%) and 83.0% (78.4%‒87.0%) for MCDBT-1/2, respectively. The interception model projected an estimated PPV of 3.1% and 12.4% for MCDBT-1/2 models, respectively. MCDBT-1 could reduce 5-year cancer mortality by 20.3%‒24.6% and reduce late-stage incidence by 51.7%‒61.7%, and MCDBT-2 could reduce 5-year cancer mortality by 15.9%‒19.9% and reduce late-stage incidence by 40.9%‒49.2%. Conclusions: cfDNA methylation-based MCDBT-1/2 models can effectively identify multiple cancers simultaneously at early stages with promising sensitivity, specificity, and accuracy of predicted origin. Their performances are to be further validated in a prospective interventional study (NCT05227534).
Comprehensive immune profiling unravels evolution of spatial distribution and immune repertoire in tumor microenvironment from primary to metastatic triple-negative breast cancer.
Authors: Guo Weihua , Egelston Colt A. , Hutchinson Katherine E. , Giltnane Jennifer M. , Ibarra-Lopez Veronica , Liu Bonnie , Yost Susan Elaine , Schmolze Daniel , Lee Peter P. , Yuan Yuan
Published: June 2022

1079

Background: Immune checkpoint inhibitors (ICI) have improved PFS and OS in metastatic triple-negative breast cancer (mTNBC), but benefit is limited to PD-L1 positive tumors. Metastatic tumors are notorious for deficient immune cell infiltration and immunosuppressive features that may limit responses to ICI in mTNBC. However, the underlying mechanisms for the weak immunogenicity of the metastatic tumor immune microenvironment (TIME) and related poor ICI responses are still not well understood. The current study was designed to investigate the evolution of the TIME between paired primary and metastatic TNBCs. Methods: Spatial distribution of 37 key immune regulators using the NanoString digital spatial profiling (DSP) platform was analyzed. 452 regions of interests (ROIs) from 33 primary tumors (PT) and 29 metastatic tumors (MT) including 28 paired specimens, were selected based on CD45+ immune hotspots, and the protein expression levels of the key immune regulators were quantified within pan-cytokeratin (panCK) and CD45 masked regions, respectively. In parallel, we examined the clonality of tumor infiltrating B cell receptors by reconstructing the immune repertoire from bulk RNA-seq data. Results: Using the DSP platform, we confirmed reduced immune infiltration (e.g., CD3 and CD20) in both panCK and CD45 masked regions of MT, while CD8A and CD11c (padj = 2.8×10-7 and 2.1×10-6) expression was only observed in panCK masked regions of MT compared with PT. A significant shift in myeloid composition between PT and MT as evidenced by increased CD68 signal (padj = 5.8×10-4) in CD45 masked regions of MT was identified. Within MT, PD-L1 signal was substantially higher (padj = 0.030) in CD45 masked regions only, while PD1 counts were lower (padj = 0.035) in panCK masked regions. This suggests the limited responses to ICI for MT may stem from relatively low expression of activated and targetable T cell subsets in MT islands. In support of the lower CD20 counts in MT, immune repertoire analysis revealed B cell receptor (BCR) repertoire diversity (represented by Gini index) was substantially lower in MT than PT (p = 0.041) suggesting that the ability of B cells to recognize a wide variety of tumor antigens in MT is greatly reduced in contrast to PT. Conclusions: Through comprehensive analysis of the TIME spatial organization within paired PT and MT, a significant reduction in dendritic cell/macrophage ratios (CD11c/CD68), reduced tumor localized T cell activation (CD8, PD1, PD-L1), and reduced B cell diversity (BCR clonality) are key features of the reduced immunogenicity of the metastatic TIME in TNBC. Further work to understand key mechanistic features driving the evolution of these differences in TIME between primary and metastatic tumors are ongoing.