bluuebunny/crossref_metadata_2025 huggingface dataset:
Mortality and cancer incidence in UK military veterans involved in human experiments at Porton Down: 48-year follow-up
Authors: Archer Gemma , Keegan Thomas J , Carpenter Lucy M , Venables Katherine M , Fear Nicola T
Published: May 2023

Background

We investigated whether military personnel involved in chemical warfare agent research at Porton Down had increased rates of mortality or cancer incidence.

Methods

This was a historical cohort study comprising male UK veterans who participated in the ‘Service Volunteer Programme’, 1941–89, identified from Porton Down experiment books, and a comparison group of similar ‘non-Porton Down’ veterans identified from military personnel files. Of 19 233 records retrieved for each group, 18 133 (94%) Porton Down and 17 591 (92%) non-Porton Down were included in our analytical sample. Mortality and cancer incidence data were obtained from national registries up to December 2019.

Results

Over a median follow-up of 48.1 years, 10 935 Porton Down veterans (60.3%) and 10 658 non-Porton Down veterans (60.6%) had died. After adjustment for age, year of birth and military service characteristics, overall, Porton Down veterans had a 6% higher rate of all-cause mortality compared with non-Porton Down veterans [hazard ratio (HR) = 1.06, 95% confidence interval (CI) 1.03–1.09]. For cause-specific mortality, Porton Down veterans had higher rates of death from genitourinary diseases (HR = 1.34, 95% CI 1.05–1.70) and deaths attributable to alcohol (HR = 1.44, 95% CI 1.07–1.94), with weaker associations observed for deaths from infectious and parasitic diseases (HR = 1.32, 95% CI 0.99–1.78), lung cancer (HR = 1.10, 95% CI 1.01–1.20) and external causes (HR = 1.15, 95% CI 1.00–1.32). Associations with all-cause mortality were stronger for veterans who attended Porton Down between 1960 and 1964 (HR = 1.34, 95% CI 1.19–1.50); likelihood-ratio test, P = 0.006. There was no association between attendance at Porton Down and overall cancer incidence (HR = 1.00, 95% CI 0.95–1.03).

Conclusions

Overall, mortality rates were slightly higher in Porton Down veterans, but there was no difference in cancer incidence. Associations for mortality were stronger in Porton Down veterans who attended in the early 1960s.
Mapping tuberculosis prevalence in Ethiopia using geospatial meta-analysis
Authors: Alene Kefyalew Addis , Python Andre , Weiss Daniel J , Elagali Ahmed , Wagaw Zeleke Alebachew , Kumsa Andargachew , Gething Peter W , Clements Archie C A
Published: May 2023

Background

Reliable and detailed data on the prevalence of tuberculosis (TB) with sub-national estimates are scarce in Ethiopia. We address this knowledge gap by spatially predicting the national, sub-national and local prevalence of TB, and identifying drivers of TB prevalence across the country.

Methods

TB prevalence data were obtained from the Ethiopia national TB prevalence survey and from a comprehensive review of published reports. Geospatial covariates were obtained from publicly available sources. A random effects meta-analysis was used to estimate a pooled prevalence of TB at the national level, and model-based geostatistics were used to estimate the spatial variation of TB prevalence at sub-national and local levels. Within the MBG Plugin Framework, a logistic regression model was fitted to TB prevalence data using both fixed covariate effects and spatial random effects to identify drivers of TB and to predict the prevalence of TB.

Results

The overall pooled prevalence of TB in Ethiopia was 0.19% [95% confidence intervals (CI): 0.12%–0.28%]. There was a high degree of heterogeneity in the prevalence of TB (I2 96.4%, P <0.001), which varied by geographical locations, data collection periods and diagnostic methods. The highest prevalence of TB was observed in Dire Dawa (0.96%), Gambela (0.88%), Somali (0.42%), Addis Ababa (0.28%) and Afar (0.24%) regions. Nationally, there was a decline in TB prevalence from 0.18% in 2001 to 0.04% in 2009. However, prevalence increased back to 0.29% in 2014. Substantial spatial variation of TB prevalence was observed at a regional level, with a higher prevalence observed in the border regions, and at a local level within regions. The spatial distribution of TB prevalence was positively associated with population density.

Conclusion

The results of this study showed that TB prevalence varied substantially at sub-national and local levels in Ethiopia. Spatial patterns were associated with population density. These results suggest that targeted interventions in high-risk areas may reduce the burden of TB in Ethiopia and additional data collection would be required to make further inferences on TB prevalence in areas that lack data.
Fine and coarse particulate air pollution and hospital admissions for a wide range of respiratory diseases: a nationwide case-crossover study
Authors: Lei Jian , Chen Renjie , Liu Cong , Zhu Yixiang , Xue Xiaowei , Jiang Yixuan , Shi Su , Gao Ya , Kan Haidong , Xuan Jianwei
Published: May 2023

Background

The associations between fine and coarse particulate matter (PM2.5 and PM2.5–10) air pollution and hospital admissions for full-spectrum respiratory diseases were rarely investigated, especially for age-specific associations. We aim to estimate the age-specific associations of short-term exposures to PM2.5 and PM2.5–10 with hospital admissions for full-spectrum respiratory diseases in China.

Methods

We conducted an individual-level case-crossover study based on a nationwide hospital-based registry including 153 hospitals across 20 provincial regions in China in 2013–20. We applied conditional logistic regression models and distributed lag models to estimate the exposure- and lag-response associations.

Results

A total of 1 399 955 hospital admission records for various respiratory diseases were identified. The associations of PM2.5 and PM2.5–10 with total respiratory hospitalizations lasted for 4 days, and an interquartile range increase in PM2.5 (34.5 μg/m3) and PM2.5–10 (26.0 μg/m3) was associated with 1.73% [95% confidence interval (95% CI): 1.34%, 2.12%)] and 1.70% (95% CI: 1.31%, 2.10%) increases, respectively, in total respiratory hospitalizations over lag 0–4 days. Acute respiratory infections (i.e. pneumonia, bronchitis and bronchiolitis) were consistently associated with PM2.5 or PM2.5–10 exposure across different age groups. We found the disease spectrum varied by age, including rarely reported findings (i.e. acute laryngitis and tracheitis, and influenza) among children and well-established associations (i.e. chronic obstructive pulmonary disease, asthma, acute bronchitis and emphysema) among older populations. Besides, the associations were stronger in females, children and older populations.

Conclusions

This nationwide case-crossover study provides robust evidence that short-term exposure to both PM2.5 and PM2.5–10 was associated with increased hospital admissions for a wide range of respiratory diseases, and the spectra of respiratory diseases varied by age. Females, children and older populations were more susceptible.
Development of resource treatment technology for fracturing backflow fluids of tight sandstone
Authors: Gao Feng , Yang Chunpeng , Zhao Rui , Sang Junqiang , Meng Fanbin , Ren Liming , Ji Yaxiong , Yang Yuning
Published: May 2023

Fracturing is an important means to realize the development value of tight sandstone unconventional reservoirs, which consumes serious water resources and generates high viscosity of backflow fluid with petroleum and suspended matter pollutants. Therefore, it is of great significance to recycle fracturing fluid from tight sandstone with low-carbon and environmental protection. In this study, the fracturing fluid of tight sandstone in a block of a certain oilfield was collected as the research object, and a comprehensive water quality analysis was carried out. The combined process technology for resource treatment of fracturing flowback fluid in tight sandstone were formed by studying on the influence factors of oxidation gel breaking, flocculation sedimentation, ion removal, filtration and process optimization. After treatment, the mass concentration of iron ion in fracturing flowback fluid was less than 5 mg/L, the mass concentration of suspended matter was less than 10 mg/L, and the mass concentration of oil was less than 5 mg/L, which could meet the water quality requirements of fluid distribution and reuse, and avoid the environmental pollution risk of flowback fluid effectively, while the consumption level of water resources in fracturing construction also was greatly reduced. This paper will have positive significance for the resource treatment technology and development of tight sandstone fracturing fluid.
Combiningin silicoandin vitroapproaches to understand the involvement of methylerythritol 4-phosphate and shikimate pathways inAgrobacterium tumefaciensfor enhanced coenzyme Q10 production
Authors: Yadav Karuna , Arora Devender , Jatain Indu , Dubey Kashyap Kumar , Dhaka Namrata , Kaur Inderjeet , Adlakha Nidhi
Published: May 2023

Aims

To perform an integrated comparative analysis of metabolic pathway to understand coenzyme Q10 (CoQ10) production in Agrobacterium tumefaciens.

Methods and results

Comparative analysis of the CoQ10 metabolic pathway in 10 organisms using a genome to KEGG orthology program (G2KO) and the KEGG database elucidated the completeness of the production pathway in A. tumefaciens. The specific roles of the key precursors and the enzymes in the metabolic network were subsequently confirmed using pathway inhibitors and enhancers. While the use of fosmidomycin and glyphosate was found to inhibit CoQ10 production by 54.54% to 99%, the supplementation of polyprenyl pyrophosphate of the methylerythritol 4-phosphate pathway and 4-hydroxybenzoate precursor of the shikimate pathway did increse the production of CoQ10 by 2.3-fold.

Conclusions

The present study provides a comprehensive understanding of the CoQ10 biosynthetic pathway in A. tumefaciens, which would assist rational metabolic engineering strategies for augmenting CoQ10 biosynthesis.
Effects of starch sources varying in particle sizes on ruminal fermentation, nutrient flow, starch digestibility, and lactation performance of dairy cows
Authors: Shipandeni Maria N T , Paula Eduardo M , Esposito Giulia , Faciola Antonio P , Raffrenato Emiliano
Published: May 2023

Cereal grains are the predominant starch source (SS) for dairy cows; however, starch digestibility varies greatly depending on source, grain processing, and potentially interactions between these factors. The objective was to study the effects of the interactions between SS, and particle sizes (PS) on ruminal fermentation, nutrient flow, starch digestibility, and lactation performance of dairy cows. Four ruminally cannulated multiparous Holstein cows were used in a 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments. Two SS (corn or sorghum) used in this study were either finely or coarsely ground (using a 1- or 4-mm screen sieve). Digesta flow was quantified using the reticular sampling technique, applying the triple-marker method. Data were analyzed using the GLIMMIX procedure of SAS version 9.3 (SAS Institute Inc., Cary, NC, USA). For ruminal pH, data were analysed with time as repeated measure. There were no interactions between SS and PS on production or intake, flow, and digestibility of nutrients. Dry matter intake was greater for the corn diet compared to the sorghum diet (25.15 vs. 21.98 kg/d), which consequently affected nutrient intake, however, PS did not affect intake. Milk yield was not affected by SS; however, it was greater for cows fed fine grains than cows fed coarser grains (25.32 vs. 23.16 kg/d). Milk fat and milk protein were not affected by SS or PS. Interactions (SS × PS) were observed for ruminal pH, reticular pH, and volatile fatty acids (VFA) concentrations but not for ruminal NH3–N concentration. Ruminal and reticular pH were greater for sorghum when coarsely ground and the total VFA concentration was decreased, compared to coarse corn and fine sorghum; however, coarsely grinding corn did not affect ruminal or reticular pH nor VFA concentration. Acetate concentration was lower for corn when finely ground; however, finely grinding sorghum did not affect acetate. Decreasing PS increased ruminal digestibility of starch (87.18% vs. 83.43%), reduced the flow of starch to the reticulum (0.79 vs. 0.96 kg/d) but decreased neutral detergent fiber digestibility in the rumen (30.23% vs. 34.88%). Although SS were differently affected by processing, the effects of PS on production, intake, flow, and digestibility of nutrients were observed regardless of the SS. Furthermore, the effects of decreasing PS on pH and VFA concentrations were more pronounced in sorghum compared to corn.
Children, Sexual Abuse and the Emotions of the Community Health Practitioner in England and Wales, 1970-2000
Authors: Beecher Ruth
Published: May 2023

A survivor of child sexual abuse felt that doctors missed opportunities to notice her distress when, at fourteen, she had an unexplained illness that lasted for a year. The cause, she wrote, was “explained by Doctors as psychological, but nobody questioned further. WHY??? … If adults don’t listen[,] then we have no one to turn to.” For decades, community health practitioners have been identified as an important group in protecting children from maltreatment, but survivor testimony and agency statistics demonstrate that they rarely receive verbal disclosures or recognize the physical or behavioural warning signs of sexual abuse. The accounts we have of the 1980s tell of swiftly heightening professional awareness, followed by a visceral backlash in the latter part of the decade that discouraged practitioners from acting on their concerns. This article uses trade and professional journals, training materials, textbooks, and new oral histories to consider why community-based doctors and nurses have struggled to notice and respond to the sexually abused child. It will argue that the conceptual model of child sexual abuse that community health practitioners encountered in the workplace encouraged a mechanical and procedural response to suspicions of abuse. In a highly gendered and contested workplace, practitioners’ feelings about how survivors, non-abusing family members, and perpetrators should be understood were rarely debated in training or in practice. The emotional cost to the practitioners of engagement with sexual abuse, and their need for spaces of reflexivity and structures of support, were ignored.
Postoperative alpha angle seems to be important for the achievement of clinical significance at a minimum 5-year follow-up after primary hip arthroscopy
Authors: Gürsan Onur , Hapa Onur , Matsuda Dean K , Aydemir Selahaddin , Çeltik Mustafa , Cici Hakan , Acan Ahmet Emrah
Published: May 2023

The purpose of the present study was to clarify whether there is an association of postoperative alpha value with functional scores or progression of osteoarthritis at X-rays at the midterm after arthroscopic treatment of femoroacetabular impingement (FAI) syndrome with femoral osteoplasty, labral repair or debridement and rim trimming. A retrospective review of prospectively gathered data from 2013 to 2017 was performed. All patients who underwent first-time unilateral hip arthroscopy for FAI resection with 5-year follow-up were included. Patient-reported outcomes included the modified Harris Hip Score (mHHS) and Visual Analog Scale for Pain (Pain VAS). The progression of osteoarthritis (Tönnis grade) and radiological parameters (alpha angle, lateral center-edge angle [LCEA] and head-neck offset) were evaluated. A receiver operating characteristic (ROC) analysis was used to evaluate the correlation between significant variables and achievement of patient-acceptable symptomatic state (PASS) and degree of osteoarthritis. We identified 52 patients with a minimum 5-year follow-up (average, 6.7 years). The average patient age was 33.9 ± 11.5 years. There were 19 (36.5%) female patients. The mHHS improved from 60.1 ± 13.4 before surgery to 86.8 ± 14 after surgery (P < 0.001). The Pain VAS decreased from 6.21 before surgery to 2 after surgery (P < 0.001). Overall, 69% achieved the PASS for mHHS. The ROC curve for postoperative alpha angle demonstrated acceptable discrimination between patients achieving a fifth-year PASS value and those who did not have an area under the curve of 0.72. Patients having a postoperative alpha angle of ≤48.3° achieved the fifth-year PASS value at a significantly higher rate than patients having a postoperative alpha angle of >48.3° (P = 0.002). The postoperative alpha angle is a predictor of the achievement of the fifth-year PASS value for the mHHS. A threshold of ≤48.3° had a sensitivity of 0.75 and a specificity of 0.69 to predict positivity.

Level of evidence IV
High-resolution and analytical electron microscopy in a liquid flow cell via gas purging
Authors: Pivak Yevheniy , Park Junbeom , Basak Shibabrata , Eichel Rüdiger-Albert , Beker Anne , Rozene Alejandro , Pérez Garza Héctor Hugo , Sun Hongyu
Published: May 2023

Liquid-phase transmission electron microscopy (LPTEM) technique has been used to perform a wide range of in situ and operando studies. While most studies are based on the sample contrast change in the liquid, acquiring high qualitative results in the native liquid environment still poses a challenge. Herein, we present a novel and facile method to perform high-resolution and analytical electron microscopy studies in a liquid flow cell. This technique is based on removing the liquid from the observation area by a flow of gas. It is expected that the proposed approach can find broad applications in LPTEM studies.
Association of nativity with survival among adults with hepatocellular carcinoma
Authors: Zhou Kali , Song Ziwei , Rostomian Nairi , Dodge Jennifer L , Stern Mariana C , Setiawan V Wendy , Terrault Norah A , Cockburn Myles G , Liu Lihua
Published: May 2023

Introduction

Immigrants comprise a considerable proportion of those diagnosed with hepatocellular carcinoma (HCC) in the United States. Nativity or birthplace affects incidence and risk factors for HCC, but little is known about its influence on survival after diagnosis.

Methods

We identified 51 533 adults with HCC with available birthplace in the California Cancer Registry between 1988 and 2017. HCC cases were categorized as foreign born or US born and stratified by mutually exclusive race and ethnicity groups. Primary outcome was all-cause mortality. Race and ethnicity–specific Cox regression propensity score-weighted models evaluated the relationship between nativity and death as well as region of birth among foreign-born patients.

Results

A total of 40% of all HCC cases were foreign born, and 92.2%, 45.2%, 9.1%, and 5.8% of Asian/Pacific Islander (API), Hispanic, White, and Black patients were foreign born, respectively. Five-year survival rates were higher in foreign-born patients compared with US-born patients: 12.9% vs 9.6% for White patients, 11.7% vs 9.8% for Hispanic patients, 12.8% vs 8.1% for Black patients, and 16.4% vs 12.4% for API patients. Nativity was associated with survival, with better survival in foreign-born patients: White patients: hazard ratio (HR) = 0.86 (95% confidence interval [CI] = 0.81 to 0.90), Hispanic patients: HR = 0.90 (95% CI = 0.86 to 0.93), Black patients: HR = 0.89 (95% CI = 0.76 to 1.05), and API patients: HR = 0.94 (95% CI = 0.88 to 1.00). Among foreign-born patients, lower mortality was observed in those from Central and South America compared with Mexico for Hispanic patients, East Asia compared with Southeast Asia for API patients, and East Europe and Greater Middle East compared with West/South/North Europe for White patients.

Conclusion

Foreign-born patients with HCC have better survival than US-born patients. Further investigation into the mechanisms of this survival disparity by nativity is needed.
Tucatinib promotes immune activation and synergizes with programmed cell death–1 and programmed cell death–ligand 1 inhibition in HER2-positive breast cancer
Authors: Li Ran , Sant Sneha , Brown Emmaline , Caramia Franco , Nikolic Bronte , Clarke Kylie , Byrne Ann , Lara Gonzalez Luis E , Savas Peter , Luen Stephen J , Teo Zhi Ling , Virassamy Balaji , Neeson Paul J , Darcy Phillip K , Loi Sherene
Published: May 2023

Background

Programmed cell death–1 (PD-1) and programmed cell death–ligand 1 (PD-L1) inhibitors have poor efficacy in patients with trastuzumab-resistant advanced HER2-positive breast cancer. Tucatinib is a potent, selective anti-HER2 tyrosine kinase inhibitor with proven clinical benefit in the advanced setting in patients with trastuzumab resistance. We investigated if tucatinib can alter the tumor microenvironment and if this could be harnessed for therapeutic efficacy.

Methods

We investigated the antitumor efficacy and contribution of the immune response of tucatinib using 2 immunocompetent, HER2-positive murine breast cancer models (trastuzumab-sensitive H2N113; trastuzumab-resistant Fo5) and the efficacy of tucatinib with trastuzumab and PD-1 or PD-L1 checkpoint inhibitors.

Results

In both models, tucatinib statistically significantly inhibited tumor growth and demonstrated dose-dependent efficacy. Ex vivo analysis by flow cytometry of tumor-infiltrating lymphocytes in mice treated with tucatinib showed increased frequency, higher proliferation, and enhanced effector function of CD8+ effector memory T cells. Tucatinib treatment also increased frequency of CD8+PD-1+ and CD8+TIM3+ T cells, CD49+ natural killer cells, monocytes, and major histocompatibility complex II expression on dendritic cells and macrophages and a decrease in myeloid-derived suppressor cells. Gene expression analysis revealed statistically significant enrichment in pathways associated with immune activation, type I and II interferon response, adaptive immune response, and antigen receptor signaling. In vivo, tucatinib and α-PD-L1 or α-PD-1 demonstrated statistically significantly increased efficacy and improved survival of mice compared with tucatinib alone.

Conclusion

Tucatinib modulates the immune microenvironment favorably, and combination treatment with α-PD-L1 or α-PD-1 demonstrated increased efficacy in preclinical HER2-positive tumor models. These findings provide a rationale for investigation of tucatinib and immune checkpoint inhibition in the clinic.
Effect of Neonatal Abstinence Syndrome Treatment Status and Maternal Depressive Symptomatology on Maternal Reports of Infant Behaviors
Authors: Heller Nicole A , Logan Beth A , Shrestha Hira , Morrison Deborah G , Hayes Marie J
Published: May 2023

Objective

The objective of this study is to investigate the effects of maternal perinatal depression symptoms and infant treatment status for neonatal abstinence syndrome (NAS) on maternal perceptions of infant regulatory behavior at 6 weeks of age.

Methods

Mothers and their infants (N = 106; 53 dyads) were recruited from a rural, White cohort in Northeast Maine. Mothers in medication-assisted treatment (methadone) and their infants (n = 35 dyads) were divided based on the infant’s NAS pharmacological treatment (n = 20, NAS+ group; n = 15, NAS− group) and compared with a demographically similar, nonexposed comparison group (n = 18 dyads; COMP group). At 6 weeks postpartum, mothers reported their depression symptoms Beck Depression Inventory—2nd Edition) and infant regulatory behaviors [Mother and Baby Scales (MABS)]. Infant neurobehavior was assessed during the same visit using the Neonatal Network Neurobehavioral Scale (NNNS).

Results

Mothers in the NAS+ group showed significantly higher depression scores than the COMP group (p < .05) while the NAS− group did not. Across the sample, mothers with higher depression scores reported higher infant “unsettled-irregularity” MABS scores, regardless of group status. Agreement between maternal reports of infant regulatory behaviors and observer-assessed NNNS summary scares was poor in both the NAS+ and COMP groups.

Conclusions

Postpartum women in opioid recovery with infants requiring pharmacological intervention for NAS are more at risk for depression which may adversely influence their perceptions of their infants’ regulatory profiles. Unique, targeted attachment interventions may be needed for this population.
Association of Vaccine Pass policy and Omicron incidence with COVID vaccine uptakes in Hong Kong
Authors: Qiu Hong , Zhao Shi , Cheung Annie Wai-Ling , Yeoh Eng-Kiong , Wong Eliza Lai-Yi
Published: May 2023

We observed the association of vaccine coverage with the implementation of the Vaccine Pass policy and the intensity of the Omicron outbreak in Hong Kong. Vaccine policy and transparent information dissemination are indispensable interventions promoting vaccination uptake.
Auxin as an architect of the pectin matrix
Authors: Jobert François , Yadav Sandeep , Robert Stéphanie
Published: May 2023

Auxin is a versatile plant growth regulator that triggers multiple signalling pathways at different spatial and temporal resolutions. A plant cell is surrounded by the cell wall, a complex and dynamic network of polysaccharides. The cell wall needs to be rigid to provide mechanical support and protection and highly flexible to allow cell growth and shape acquisition. The modification of the pectin components, among other processes, is a mechanism by which auxin activity alters the mechanical properties of the cell wall. Auxin signalling precisely controls the transcriptional output of several genes encoding pectin remodelling enzymes, their local activity, pectin deposition, and modulation in different developmental contexts. This review examines the mechanism of auxin activity in regulating pectin chemistry at organ, cellular, and subcellular levels across diverse plant species. Moreover, we ask questions that remain to be addressed to fully understand the interplay between auxin and pectin in plant growth and development.
Safety and immunogenicity of a modified COVID-19 mRNA vaccine, SYS6006, as a fourth-dose booster following three doses of inactivated vaccines in healthy adults: an open-labeled Phase 1 trial
Authors: Gui Yuzhou , Cao Ye , He Jiajin , Zhao Chunyang , Zheng Wei , Qian Ling , Cheng Jie , Yu Chengyin , Yu Chen , Lou Kun , Liu Gangyi , Jia Jingying
Published: May 2023

The continuous emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants led to a rapid decline in protection efficacy and neutralizing titers even after three doses of COVID-19 vaccines. Here, we report an open-labeled Phase I clinical trial of a modified mRNA vaccine (SYS6006) as a fourth-dose booster in healthy adults. Eighteen eligible participants, who had completed three doses of inactivated COVID-19 vaccines, received a fourth boosting dose of SYS6006-20 μg. Eighteen convalescent COVID-19 patients were enrolled for the collection of serum samples as a comparator of immunogenicity. The primary endpoint of this trial was titers of anti-receptor binding domain of spike glycoprotein (RBD) antibodies of the Omicron strain (BA.2 and BA.4/5) in serum; titers of neutralizing antibodies against pseudovirus of the Omicron strain (BA.2 and BA.4/5). The secondary endpoint was the incidence of adverse events within 30 days after the boosting. The exploratory endpoint was the cellular immune responses (interferon gamma, IFN-γ). This trial was registered with the Chinese Clinical Trial Registry website. No serious adverse events were reported within 30 days after vaccination. No Grade 3 fever or serious adverse event was reported in the SYS6006 group. Notably, SYS6006 elicited higher titers and longer increases in anti-RBD antibodies and neutralizing antibodies (>90 days) compared with the convalescent group (P < 0.0001) against Omicron strain (BA.2 and BA.4/5). Besides, higher positive spots of T-cell-secreting IFN-γ were observed in the SYS6006 group than those in the convalescent group (P < 0.05). These data demonstrated that SYS6006 was well tolerated and highly immunogenic, generating a stronger and more durable immune response against different variants of SARS-CoV-2.
Testing super-eddington accretion on to a supermassive black hole: reverberation mapping of PG 1119+120
Authors: Donnan Fergus R , Hernández Santisteban Juan V , Horne Keith , Hu Chen , Du Pu , Li Yan-Rong , Xiao Ming , Ho Luis C , Aceituno Jesús , Wang Jian-Min , Guo Wei-Jian , Yang Sen , Jiang Bo-Wei , Yao Zhu-Heng
Published: May 2023

We measure the black hole mass and investigate the accretion flow around the local (z = 0.0502) quasar PG 1119+120. Spectroscopic monitoring with Calar Alto provides H β lags and linewidths from which we estimate a black hole mass of log (M•/M⊙) = 7.0, uncertain by ∼0.4 dex. High cadence photometric monitoring over 2 yr with the Las Cumbres Observatory provides light curves in seven optical bands suitable for intensive continuum reverberation mapping. We identify variability on two time-scales. Slower variations on a 100-d time-scale exhibit excess flux and increased lag in the u′ band and are thus attributable to diffuse bound-free continuum emission from the broad-line region. Faster variations that we attribute to accretion disc reprocessing lack a u′-band excess and have flux and delay spectra consistent with either τ ∝ λ4/3, as expected for a temperature structure of T(R) ∝ R−3/4 for a thin accretion disc, or τ ∝ λ2 expected for a slim disc. Decomposing the flux into variable (disc) and constant (host galaxy) components, we find the disc SED to be flatter than expected with $f_{\nu } \sim \rm {const}$. Modelling the SED predicts an Eddington ratio of λEdd > 1, where the flat spectrum can be reproduced by a slim disc with little dust extinction or a thin disc that requires more dust extinction. While this accretion is super-Eddington, the geometry is still unclear; however, a slim disc is expected due to the high radiation pressure at these accretion rates, and is entirely consistent with our observations.
MpoxRadar: a worldwide MPXV genomic surveillance dashboard
Authors: Nasri Ferdous , Kongkitimanon Kunaphas , Wittig Alice , Cortés Jorge Sánchez , Brinkmann Annika , Nitsche Andreas , Schmachtenberg Anna-Juliane , Renard Bernhard Y , Fuchs Stephan
Published: May 2023

The mpox virus (MPXV) is mutating at an exceptional rate for a DNA virus and its global spread is concerning, making genomic surveillance a necessity. With MpoxRadar, we provide an interactive dashboard to track virus variants on mutation level worldwide. MpoxRadar allows users to select among different genomes as reference for comparison. The occurrence of mutation profiles based on the selected reference is indicated on an interactive world map that shows the respective geographic sampling site in customizable time ranges to easily follow the frequency or trend of defined mutations. Furthermore, the user can filter for specific mutations, genes, countries, genome types, and sequencing protocols and download the filtered data directly from MpoxRadar. On the server, we automatically download all MPXV genomes and metadata from the National Center for Biotechnology Information (NCBI) on a daily basis, align them to the different reference genomes, generate mutation profiles, which are stored and linked to the available metainformation in a database. This makes MpoxRadar a practical tool for the genomic survaillance of MPXV, supporting users with limited computational resources. MpoxRadar is open-source and freely accessible at https://MpoxRadar.net.
Conformational dynamics of the RNA binding channel regulates loading and translocation of the DEAH-box helicase Prp43
Authors: Enders Marieke , Ficner Ralf , Adio Sarah
Published: May 2023

The DEAH-box helicase Prp43 has essential functions in pre-mRNA splicing and ribosome biogenesis, remodeling structured RNAs. To initiate unwinding, Prp43 must first accommodate a single-stranded RNA segment into its RNA binding channel. This allows translocation of the helicase on the RNA. G-patch (gp) factors activate Prp43 in its cellular context enhancing the intrinsically low ATPase and RNA unwinding activity. It is unclear how the RNA loading process is accomplished by Prp43 and how it is regulated by its substrates, ATP and RNA, and the G-patch partners. We developed single-molecule (sm) FRET reporters on Prp43 from Chaetomium thermophilum to monitor the conformational dynamics of the RNA binding channel in Prp43 in real-time. We show that the channel can alternate between open and closed conformations. Binding of Pfa1(gp) and ATP shifts the distribution of states towards channel opening, facilitating the accommodation of RNA. After completion of the loading process, the channel remains firmly closed during successive cycles of ATP hydrolysis, ensuring stable interaction with the RNA and processive translocation. Without Pfa1(gp), it remains predominantly closed preventing efficient RNA loading. Our data reveal how the ligands of Prp43 regulate the structural dynamics of the RNA binding channel controlling the initial binding of RNA.
Thermally controlled intein splicing of engineered DNA polymerases provides a robust and generalizable solution for accurate and sensitive molecular diagnostics
Authors: Wang You , Shi Yuqian , Hellinga Homme W , Beese Lorena S
Published: May 2023

DNA polymerases are essential for nucleic acid synthesis, cloning, sequencing and molecular diagnostics technologies. Conditional intein splicing is a powerful tool for controlling enzyme reactions. We have engineered a thermal switch into thermostable DNA polymerases from two structurally distinct polymerase families by inserting a thermally activated intein domain into a surface loop that is integral to the polymerase active site, thereby blocking DNA or RNA template access. The fusion proteins are inactive, but retain their structures, such that the intein excises during a heat pulse delivered at 70–80°C to generate spliced, active polymerases. This straightforward thermal activation step provides a highly effective, one-component ‘hot-start’ control of PCR reactions that enables accurate target amplification by minimizing unwanted by-products generated by off-target reactions. In one engineered enzyme, derived from Thermus aquaticus DNA polymerase, both DNA polymerase and reverse transcriptase activities are controlled by the intein, enabling single-reagent amplification of DNA and RNA under hot-start conditions. This engineered polymerase provides high-sensitivity detection for molecular diagnostics applications, amplifying 5–6 copies of the tested DNA and RNA targets with >95% certainty. The design principles used to engineer the inteins can be readily applied to construct other conditionally activated nucleic acid processing enzymes.
OnTarget: in silico design of MiniPromoters for targeted delivery of expression
Authors: Fornes Oriol , Av-Shalom Tamar V , Korecki Andrea J , Farkas Rachelle A , Arenillas David J , Mathelier Anthony , Simpson Elizabeth M , Wasserman Wyeth W
Published: May 2023

MiniPromoters, or compact promoters, are short DNA sequences that can drive expression in specific cells and tissues. While broadly useful, they are of high relevance to gene therapy due to their role in enabling precise control of where a therapeutic gene will be expressed. Here, we present OnTarget (http://ontarget.cmmt.ubc.ca), a webserver that streamlines the MiniPromoter design process. Users only need to specify a gene of interest or custom genomic coordinates on which to focus the identification of promoters and enhancers, and can also provide relevant cell-type-specific genomic evidence (e.g. accessible chromatin regions, histone modifications, etc.). OnTarget combines the provided data with internal data to identify candidate promoters and enhancers and design MiniPromoters. To illustrate the utility of OnTarget, we designed and characterized two MiniPromoters targeting different cell populations relevant to Parkinson Disease.
Enrichr-KG: bridging enrichment analysis across multiple libraries
Authors: Evangelista John Erol , Xie Zhuorui , Marino Giacomo B , Nguyen Nhi , Clarke Daniel J B , Ma’ayan Avi
Published: May 2023

Gene and protein set enrichment analysis is a critical step in the analysis of data collected from omics experiments. Enrichr is a popular gene set enrichment analysis web-server search engine that contains hundreds of thousands of annotated gene sets. While Enrichr has been useful in providing enrichment analysis with many gene set libraries from different categories, integrating enrichment results across libraries and domains of knowledge can further hypothesis generation. To this end, Enrichr-KG is a knowledge graph database and a web-server application that combines selected gene set libraries from Enrichr for integrative enrichment analysis and visualization. The enrichment results are presented as subgraphs made of nodes and links that connect genes to their enriched terms. In addition, users of Enrichr-KG can add gene-gene links, as well as predicted genes to the subgraphs. This graphical representation of cross-library results with enriched and predicted genes can illuminate hidden associations between genes and annotated enriched terms from across datasets and resources. Enrichr-KG currently serves 26 gene set libraries from different categories that include transcription, pathways, ontologies, diseases/drugs, and cell types. To demonstrate the utility of Enrichr-KG we provide several case studies. Enrichr-KG is freely available at: https://maayanlab.cloud/enrichr-kg.
Protecting workers in the temporary staffing industry
Authors: Forst L , Chaudhry A , Lopez A , McCarthy M , Hebert-Beirne J
Published: May 2023

Background

Workers hired through temporary staffing companies have a high rate of severe and fatal injuries despite the legally mandated, shared responsibility of the temporary staffing company and the host company to assure safe work.

Aims

The aim of this study was to elucidate the perspective of temporary staffing personnel on approaches to mitigating injury risk among the workers they hire.

Methods

Based on a conceptual model representing the interplay between work and health, we conducted a ‘brainstorm’ of temporary staffing personnel regarding perceived barriers to protecting temporary workers. A content/context analysis used standard qualitative methods, and the findings were triangulated with notes taken during the discussion.

Results

Temporary staffing employers describe loss of control of the working conditions once workers are placed at host/client companies. Further, they describe a contentious relationship between temporary staffing and host companies, where it is difficult to hold host companies to account. Other barriers to providing temporary workers with a safe work environment include the temp companies’ lack of knowledge of site-specific hazards, the poor quality of onsite Occupational Safety and Health training, and ignoring Occupational Safety and Health Administration (OSHA) requirements.

Conclusions

The perspective of temporary staffing companies should be considered to address the lack of cooperation and shifted responsibility described in this study. Policy and practice changes could include requiring contract language, implementing communication about safety, either sharing workers’ compensation purchase or removing exclusive remedy protections from hosts, and prescribing safety training, such as an OSHA 10-h programme. Suggested interventions need further study.
Antiviral Prescribing Among Patients at an Ambulatory Cancer Center With Laboratory-Confirmed Influenza
Authors: Sorey Woody , Krantz Elizabeth M , Morris Jessica , Klaassen John , Sweet Ania , Tverdek Frank , Escobar Zahra K , McCulloch Denise J , Pergam Steven A , Liu Catherine
Published: May 2023

Among 133 cancer outpatients diagnosed with influenza between 2016 and 2018, 110 (83%) were prescribed oseltamivir. Among 109 with a known symptom onset date, 53% presented for care and 31% were prescribed oseltamivir within 48 hours. Patient/provider education and rapid diagnostics are needed to improve early oseltamivir use among cancer patients with influenza.
Dalbavancin for the Treatment of Acute Bacterial Skin and Skin Structure Infection in Patients With Obesity or Diabetes: A Subgroup Analysis of Pooled Phase 3 Clinical Trials
Authors: Riccobene Todd , Lock John , Lyles Rosie D , Georgiades Benjamin , Nowak Michael , Gonzalez Pedro L , Park Jenny , Rappo Urania
Published: May 2023

Background

We assessed the efficacy and safety of dalbavancin, a long-acting lipoglycopeptide with activity against Gram-positive pathogens, for treatment of acute bacterial skin and skin structure infections (ABSSSI) in patients with high body mass index (BMI) and/or diabetes.

Methods

Data from two phase 3 trials of dalbavancin (1000 mg intravenous [IV], day 1; 500 mg IV, day 8) versus comparator and one phase 3b trial of single-dose (1500 mg IV, day 1) versus 2-dose (1000 mg IV, day 1; 500 mg IV, day 8) dalbavancin in adults with ABSSSI were pooled and summarized separately by baseline BMI and diabetes status. Clinical success at 48 to 72 hours (≥20% reduction in lesion size), end of treatment ([EOT] day 14), and day 28 was evaluated in the intent-to-treat (ITT) and microbiological ITT (microITT) populations. Safety data were reported in patients who received ≥1 dose of study drug.

Results

In the dalbavancin ITT population (BMI, n = 2001; diabetes, n = 2010), at 48 to 72 hours (and EOT) clinical success was achieved in 89.3% (EOT, 90.9%) of patients with normal BMI and 78.9% to 87.6% (EOT, 91.0% to 95.2%) of patients with elevated BMI. Clinical success after dalbavancin treatment was achieved in 82.4% (EOT, 90.8%) of patients with diabetes and 86.0% (EOT, 91.6%) of patients without diabetes. Similar trends were observed for infections due to methicillin-resistant Staphylococcus aureus or methicillin-susceptible S aureus (microITT population).

Conclusions

Dalbavancin is effective, with sustained clinical success rates in patients with obesity or diabetes, with a similar safety profile across patient groups.
Prevalence and Predictors of Physician-Patient Discordance in Prognostic Perceptions in Advanced Cancer
Authors: van der Velden Naomi Cornelia Anna , Han Paul K J , van Laarhoven Hanneke W M , de Vos Filip Y F L , Hendriks Lizza E L , Burgers Sjaak A , Dingemans Anne-Marie C , van Haarst Jan Maarten W , Dits Joyce , Smets Ellen M A , Henselmans Inge
Published: May 2023

Background

Discordance between physicians’ and patients’ prognostic perceptions in advanced cancer care threatens informed medical decision-making and end-of-life preparation, yet this phenomenon is poorly understood. We sought to: (1) describe the extent and direction of prognostic discordance, patients’ prognostic information preferences in cases of prognostic discordance, and physicians’ awareness of prognostic discordance; and (2) examine which patient, physician, and caregiver factors predict prognostic discordance.

Materials and Methods

Oncologists and advanced cancer patients (median survival ≤12 months; n = 515) from 7 Dutch hospitals completed structured surveys in a cross-sectional study. Prognostic discordance was operationalized by comparing physicians’ and patients’ perceptions of the likelihood of cure, 2-year mortality risk, and 1-year mortality risk.

Results

Prognostic discordance occurred in 20% (likelihood of cure), 24%, and 35% (2-year and 1-year mortality risk) of physician-patient dyads, most often involving patients with more optimistic perceptions than their physician. Among patients demonstrating prognostic discordance, the proportion who preferred not knowing prognosis varied from 7% (likelihood of cure) to 37% (1-year mortality risk), and 45% (2-year mortality risk). Agreement between physician-perceived and observed prognostic discordance or concordance was poor (kappa = 0.186). Prognostic discordance was associated with several patient factors (stronger fighting spirit, self-reported absence of prognostic discussions, an information source other than the healthcare provider), and greater physician-reported uncertainty about prognosis.

Conclusion

Up to one-third of the patients perceive prognosis discordantly from their physician, among whom a substantial proportion prefers not knowing prognosis. Most physicians lack awareness of prognostic discordance, raising the need to explore patients’ prognostic information preferences and perceptions, and to tailor prognostic communication.
The ATR–WEE1 kinase module promotes SUPPRESSOR OF GAMMA RESPONSE 1 translation to activate replication stress responses
Authors: Chen Hanchen , Pan Ting , Zheng Xueao , Huang Yongchi , Wu Chong , Yang Tongbin , Gao Shan , Wang Lili , Yan Shunping
Published: May 2023

DNA replication stress threatens genome stability and is a hallmark of cancer in humans. The evolutionarily conserved kinases ATR (ATM and RAD3-related) and WEE1 are essential for the activation of replication stress responses. Translational control is an important mechanism that regulates gene expression, but its role in replication stress responses is largely unknown. Here we show that ATR–WEE1 control the translation of SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1), a master transcription factor required for replication stress responses in Arabidopsis thaliana. Through genetic screening, we found that the loss of GENERAL CONTROL NONDEREPRESSIBLE 20 (GCN20) or GCN1, which function together to inhibit protein translation, suppressed the hypersensitivity of the atr or wee1 mutant to replication stress. Biochemically, WEE1 inhibits GCN20 by phosphorylating it; phosphorylated GCN20 is subsequently polyubiquitinated and degraded. Ribosome profiling experiments revealed that that loss of GCN20 enhanced the translation efficiency of SOG1, while overexpressing GCN20 had the opposite effect. The loss of SOG1 reduced the resistance of wee1 gcn20 to replication stress, whereas overexpressing SOG1 enhanced the resistance to atr or wee1 to replication stress. These results suggest that ATR–WEE1 inhibits GCN20–GCN1 activity to promote the translation of SOG1 during replication stress. These findings link translational control to replication stress responses in Arabidopsis.
Callose synthesis at the center point of plant development—An evolutionary insight
Authors: Ušák David , Haluška Samuel , Pleskot Roman
Published: May 2023

Polar callose deposition into the extracellular matrix is tightly controlled in time and space. Its presence in the cell wall modifies the properties of the surrounding area, which is fundamental for the correct execution of numerous processes such as cell division, male gametophyte development, intercellular transport, or responses to biotic and abiotic stresses. Previous studies have been invaluable in characterizing specific callose synthases (CalSs) during individual cellular processes. However, the complex view of the relationships between a particular CalS and a specific process is still lacking. Here we review the recent proceedings on the role of callose and individual CalSs in cell wall remodelling from an evolutionary perspective and with a particular focus on cytokinesis. We provide a robust phylogenetic analysis of CalS across the plant kingdom, which implies a 3-subfamily distribution of CalS. We also discuss the possible linkage between the evolution of CalSs and their function in specific cell types and processes.