bluuebunny/crossref_metadata_2025 huggingface dataset:
Long-term outcomes for ibrutinib–rituximab and chemoimmunotherapy in CLL: updated results of the E1912 trial
Authors: Shanafelt Tait D. , Wang Xin Victoria , Hanson Curtis A. , Paietta Elisabeth M. , O’Brien Susan , Barrientos Jacqueline , Jelinek Diane F. , Braggio Esteban , Leis Jose F. , Zhang Cong Christine , Coutre Steven E. , Barr Paul M. , Cashen Amanda F. , Mato Anthony R. , Singh Avina K. , Mullane Michael P. , Little Richard F. , Erba Harry , Stone Richard M. , Litzow Mark , Tallman Martin , Kay Neil E.
Published: April 2022

Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib–rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.
Cryo-EM structure of the prothrombin-prothrombinase complex
Authors: Ruben Eliza A. , Summers Brock , Rau Michael J. , Fitzpatrick James A. J. , Di Cera Enrico
Published: April 2022

The intrinsic and extrinsic pathways of the coagulation cascade converge to a common step where the prothrombinase complex, comprising the enzyme factor Xa (fXa), the cofactor fVa, Ca2+ and phospholipids, activates the zymogen prothrombin to the protease thrombin. The reaction entails cleavage at 2 sites, R271 and R320, generating the intermediates prethrombin 2 and meizothrombin, respectively. The molecular basis of these interactions that are central to hemostasis remains elusive. We solved 2 cryogenic electron microscopy (cryo-EM) structures of the fVa-fXa complex, 1 free on nanodiscs at 5.3-Å resolution and the other bound to prothrombin at near atomic 4.1-Å resolution. In the prothrombin-fVa–fXa complex, the Gla domains of fXa and prothrombin align on a plane with the C1 and C2 domains of fVa for interaction with membranes. Prothrombin and fXa emerge from this plane in curved conformations that bring their protease domains in contact with each other against the A2 domain of fVa. The 672ESTVMATRKMHDRLEPEDEE691 segment of the A2 domain closes on the protease domain of fXa like a lid to fix orientation of the active site. The 696YDYQNRL702 segment binds to prothrombin and establishes the pathway of activation by sequestering R271 against D697 and directing R320 toward the active site of fXa. The cryo-EM structure provides a molecular view of prothrombin activation along the meizothrombin pathway and suggests a mechanism for cleavage at the alternative R271 site. The findings advance our basic knowledge of a key step of coagulation and bear broad relevance to other interactions in the blood.
Platelet-monocyte interaction amplifies thromboinflammation through tissue factor signaling in COVID-19
Authors: Hottz Eugenio D. , Martins-Gonçalves Remy , Palhinha Lohanna , Azevedo-Quintanilha Isaclaudia G. , de Campos Mariana M. , Sacramento Carolina Q. , Temerozo Jairo R. , Soares Vinicius Cardoso , Dias Suelen S. Gomes , Teixeira Lívia , Castro Ícaro , Righy Cassia , Souza Thiago Moreno L. , Kurtz Pedro , Andrade Bruno B. , Nakaya Helder I. , Monteiro Robson Q. , Bozza Fernando A. , Bozza Patrícia T.
Published: April 2022

Accumulating evidence into the pathogenesis of COVID-19 highlights a hypercoagulability state with high risk of life-threatening thromboembolic complications. However, the mechanisms of hypercoagulability and their link to hyperinflammation remain poorly understood. Here, we investigate functions and mechanisms of platelet activation and platelet-monocyte interactions in inflammatory amplification during SARS-CoV-2 infection. We used a combination of immunophenotyping, single-cell analysis, functional assays, and pharmacological approaches to gain insights on mechanisms. Critically ill patients with COVID-19 exhibited increased platelet-monocyte aggregates formation. We identified a subset of inflammatory monocytes presenting high CD16 and low HLA-DR expression as the subset mainly interacting with platelets during severe COVID-19. Single-cell RNA-sequencing analysis indicated enhanced fibrinogen receptor Mac-1 in monocytes from patients with severe COVID-19. Monocytes from patients with severe COVID-19 displayed increased platelet binding and hyperresponsiveness to P-selectin and fibrinogen with respect to tumor necrosis factor-α and interleukin-1β secretion. Platelets were able to orchestrate monocyte responses driving tissue factor (TF) expression, inflammatory activation, and inflammatory cytokines secretion in SARS-CoV-2 infection. Platelet-monocyte interactions ex vivo and in SARS-CoV-2 infection model in vitro reciprocally activated monocytes and platelets, inducing the heightened secretion of a wide panel of inflammatory mediators. We identified platelet adhesion as a primary signaling mechanism inducing mediator secretion and TF expression, whereas TF signaling played major roles in amplifying inflammation by inducing proinflammatory cytokines, especially tumor necrosis factor-α and interleukin-1β. Our data identify platelet-induced TF expression and activity at the crossroad of coagulation and inflammation in severe COVID-19.
Effects of core stability training on older women with low back pain: a randomized controlled trial
Authors: Ge Le , Huang Huanjie , Yu Qiuhua , Li Yan , Li Xin , Li Zhicheng , Chen Xi , Li Le , Wang Chuhuai
Published: April 2022

Background

Studies have demonstrated that elderly people with low back pain (LBP) may have poor postural control compared to healthy older adults. Poor postural control is associated with poor balance performance and a high risk of serious falls. A variety of training strategies are proposed for LBP therapy, particularly core stabilization training. But this treatment for older people with LBP remains unclear.

Methods

31 participants were randomly placed in a core stability training group (TG, n = 15) and a control group (CG, n = 16). The participants in the training group were required to complete 4 sets of core stability training and conventional physiotherapy 4 times per week for 4 weeks, whereas the participants in the control group only completed physiotherapy 4 times per week for 4 weeks. Ultrasound imaging was used to measure transverse abdominal muscle (TrA) thickness before and after the intervention. A 10-cm visual analog scale (VAS), the Oswestry Disability Index (ODI), and mobility functions were applied before and after the intervention. Data are reported as the median and range and were compared using two-way repeated-measures ANOVA,t-tests and chi-squared tests. P < 0.05 was considered significant in all statistical tests.

Results

After intervention, there was a statistically significant difference in scores in the intervention group, especially for VAS, ODI, timed up-and-go,10-m walking and the four-square step test. TrA thickness was increased after core stability training, which was not observed in the control group.

Conclusion

Core stability training is an effective intervention for older women with LBP.
Quantitative delimitation of radiant belt toward lake of lake-terrestrial ecotone
Authors: Cai Tian-yi , Ye Chun , Li Chun-hua , Zhang Fan , Wei Wei-wei
Published: April 2022

Background

Lake-terrestrial ecotone is a transition zone between terrestrial and aquatic ecosystems. Linking land and lake, it is thus highly sensitive and vulnerable to disturbances. It includes three parts, namely, radiant belt toward land, shoreline zone and radiant belt toward lake. Extending from multi-year average low water level line to open water, radiant belt toward lake is a key part of lake-terrestrial ecotone. However, the delimitation method for radiant belt toward is unsolved, which is a big obstacle to protecting lake-terrestrial ecotone effectively. Wave is a major hydrodynamic factor in lakes, especially large shallow lakes. For linking landward and waterward directions, the boundary of radiant belt toward lake may be affected by waves. Hence, exampled as Lake Taihu, this research was carried out from wave perspective.

Results

In July 2021, a total of 12 species aquatic macrophyte were collected, including 3 species of floating-leaved and 9 submerged macrophyte within radiant belt toward lake of Lake Taihu. Aquatic macrophyte were incorporated into calibrated wave models driven by constant winds via MIKE21 SW. Wave height attenuation was successfully simulated, ranging − 0.19% ~ 8.89% under eastern-wind condition and − 0.08% ~ 23.37% under western-wind condition. In general, wave height gradually attenuates from shore to water. The abrupt change point in relative wave height was used as the boundary of the radiant belt toward lake. A total of 26 sampling lines from bank to water around the whole lake of Lake Taihu were set, ranging 701 ~ 2155 m. Based on the setups of sampling lines, the delimitation range of Lake Taihu is about 1 ~ 2 km.

Conclusions

A novel approach was developed for quantitative delimitation of radiant belt toward lake. Both wind forcing and aquatic vegetation has slight impact on results of delimitation, indicating the feasibility of this approach. It determines a theoretical boundary of lake-terrestrial ecotone, which is helpful to a more precise protection and restoration of large shallow lakes. Moreover, it could provide a potential method for quantitative delimitation for large shallow lakes with similar conditions.
COVID-profiler: a webserver for the analysis of SARS-CoV-2 sequencing data
Authors: Phelan Jody , Deelder Wouter , Ward Daniel , Campino Susana , Hibberd Martin L. , Clark Taane G.
Published: April 2022

Background

SARS-CoV-2 virus sequencing has been applied to track the COVID-19 pandemic spread and assist the development of PCR-based diagnostics, serological assays, and vaccines. With sequencing becoming routine globally, bioinformatic tools are needed to assist in the robust processing of resulting genomic data.

Results

We developed a web-based bioinformatic pipeline (“COVID-Profiler”) that inputs raw or assembled sequencing data, displays raw alignments for quality control, annotates mutations found and performs phylogenetic analysis. The pipeline software can be applied to other (re-) emerging pathogens.

Conclusions

The webserver is available at http://genomics.lshtm.ac.uk/. The source code is available at https://github.com/jodyphelan/covid-profiler.
Enhancing predictions of antimicrobial resistance of pathogens by expanding the potential resistance gene repertoire using a pan-genome-based feature selection approach
Authors: Yang Ming-Ren , Wu Yu-Wei
Published: April 2022

Background

Predicting which pathogens might exhibit antimicrobial resistance (AMR) based on genomics data is one of the promising ways to swiftly and precisely identify AMR pathogens. Currently, the most widely used genomics approach is through identifying known AMR genes from genomic information in order to predict whether a pathogen might be resistant to certain antibiotic drugs. The list of known AMR genes, however, is still far from comprehensive and may result in inaccurate AMR pathogen predictions. We thus felt the need to expand the AMR gene set and proposed a pan-genome-based feature selection method to identify potential gene sets for AMR prediction purposes.

Results

By building pan-genome datasets and extracting gene presence/absence patterns from four bacterial species, each with more than 2000 strains, we showed that machine learning models built from pan-genome data can be very promising for predicting AMR pathogens. The gene set selected by the eXtreme Gradient Boosting (XGBoost) feature selection approach further improved prediction outcomes, and an incremental approach selecting subsets of XGBoost-selected features brought the machine learning model performance to the next level. Investigating selected gene sets revealed that on average about 50% of genes had no known function and very few of them were known AMR genes, indicating the potential of the selected gene sets to expand resistance gene repertoires.

Conclusions

We demonstrated that a pan-genome-based feature selection approach is suitable for building machine learning models for predicting AMR pathogens. The extracted gene sets may provide future clues to expand our knowledge of known AMR genes and provide novel hypotheses for inferring bacterial AMR mechanisms.
Celastrol mitigates staphyloxanthin biosynthesis and biofilm formation in Staphylococcus aureus via targeting key regulators of virulence; in vitro and in vivo approach
Authors: Yehia Fatma Al-zahraa A. , Yousef Nehal , Askoura Momen
Published: April 2022

Background

Staphylococcus aureus is a leading cause of human infections. The spread of antibiotic-resistant staphylococci has driven the search for novel strategies to supersede antibiotics use. Thus, targeting bacterial virulence rather than viability could be a possible alternative.

Results

The influence of celastrol on staphyloxanthin (STX) biosynthesis, biofilm formation, antibiotic susceptibility and host pathogenesis in S. aureus has been investigated. Celastrol efficiently reduced STX biosynthesis in S. aureus. Liquid chromatography-mass spectrometry (LC–MS) and molecular docking revealed that celastrol inhibits STX biosynthesis through its effect on CrtM. Quantitative measurement of STX intermediates showed a significant pigment inhibition via interference of celastrol with CrtM and accumulation of its substrate, farnesyl diphosphate. Importantly, celastrol-treated S. aureus was more sensitive to environmental stresses and human blood killing than untreated bacteria. Similarly, inhibition of STX upon celastrol treatment rendered S. aureus more susceptible to membrane targeting antibiotics. In addition to its anti-pigment capability, celastrol exhibits significant anti-biofilm activity against S. aureus as indicated by crystal violet assay and microscopy. Celastrol-treated cells showed deficient exopolysaccharide production and cell hydrophobicity. Moreover, celastrol markedly synergized the action of conventional antibiotics against S. aureus and reduced bacterial pathogenesis in vivo using mice infection model. These findings were further validated using qRT-PCR, demonstrating that celastrol could alter the expression of STX biosynthesis genes as well as biofilm formation related genes and bacterial virulence.

Conclusions

Celastrol is a novel anti-virulent agent against S. aureus suggesting, a prospective therapeutic role for celastrol as a multi-targeted anti-pathogenic agent.
Cryopreservation of vegetative cells and zygotes of the multicellular volvocine green alga Gonium pectorale
Authors: Nozaki Hisayoshi , Mori Fumi , Tanaka Yoko , Matsuzaki Ryo , Yamaguchi Haruyo , Kawachi Masanobu
Published: April 2022

Background

Colonial and multicellular volvocine green algae have been extensively studied recently in various fields of the biological sciences. However, only one species (Pandorina morum) has been cryopreserved in public culture collections.

Results

Here, we investigated conditions for cryopreservation of the multicellular volvocine alga Gonium pectorale using vegetative colonies or cells and zygotes. Rates of vegetative cell survival in a G. pectorale strain after two-step cooling and freezing in liquid nitrogen were compared between different concentrations (3% and 6%) of the cryoprotectant N,N-dimethylformamide (DMF) and two types of tubes (0.2-mL polymerase chain reaction tubes and 2-mL cryotubes) used for cryopreservation. Among the four conditions investigated, the highest rate of survival [2.7 ± 3.6% (0.54–10%) by the most probable number (MPN) method] was obtained when 2.0-mL cryotubes containing 1.0 mL of culture samples with 6% DMF were subjected to cryogenic treatment. Using these optimized cryopreservation conditions, survival rates after freezing in liquid nitrogen were examined for twelve other strains of G. pectorale and twelve strains of five other Gonium species. We obtained ≥ 0.1% MPN survival in nine of the twelve G. pectorale strains tested. However, < 0.1% MPN survival was detected in eleven of twelve strains of five other Gonium species. In total, ten cryopreserved strains of G. pectorale were newly established in the Microbial Culture Collection at the National Institute for Environmental Studies. Although the cryopreservation of zygotes of volvocine algae has not been previously reported, high rates (approximately 60%) of G. pectorale zygote germination were observed after thawing zygotes that had been cryopreserved with 5% or 10% methanol as the cryoprotectant during two-step cooling and freezing in liquid nitrogen.

Conclusions

The present study demonstrated that cryopreservation of G. pectorale is possible with 6% DMF as a cryoprotectant and 1.0-mL culture samples in 2.0-mL cryotubes subjected to two-step cooling in a programmable freezer.
Upregulation of GLRs expression by light in Arabidopsis leaves
Authors: Hebda Anna , Liszka Aleksandra , Lewandowska Aleksandra , Lyczakowski Jan J. , Gabryś Halina , Krzeszowiec Weronika
Published: April 2022

Background

Glutamate receptor-like (GLR) channels are plant homologs of iGluRs, animal ionotropic glutamate receptors which participate in neurotransmission. GLRs mediate plant adaptive processes and photomorphogenesis. Despite their contribution to light-dependent processes, signaling mechanisms that modulateGLRresponse to light remain unknown. Here we show that leaf expression of 7 out of 20 ArabidopsisGLRsis significantly up-regulated by monochromatic irradiation.

Results

Our data indicates that both red and blue light stimulate the expression of selectedAtGLRs. Using a photosynthesis inhibitor and different irradiation regimes, we demonstrated that retrograde signaling from photosystem II is unlikely to be involved in light-dependentGLRup-regulation. Analysis of transcriptional patterns in mutants of key photoreceptors allowed us to observe that both phytochromes and cryptochromes are likely to be involved in the control of light-dependent up-regulation ofAtGLRexpression, with phytochromes playing a clearly dominating role in this process.

Conclusions

In mature Arabidopsis leaves, phytochromes, assisted by cryptochromes, mediate light-driven transcriptional up-regulation of several genes encoding GLR proteins. Since GLRs are known to be involved in a wide range of plant developmental processes our results provide mechanistic insight into how light may influence plant growth and development.
Transcriptome profiling of flower buds of male-sterile lines provides new insights into male sterility mechanism in alfalfa
Authors: Xu Bo , Wu Rina , Shi Fengling , Gao Cuiping , Wang Jia
Published: April 2022

Background

The use of heterosis to produce hybrid seeds is a challenge to breeding for improved crop yield. In previous studies, we isolated a male sterile alfalfa hybrid and successfully obtained a genetically stable alfalfa male sterile line through backcrossing, henceforth named MS-4. In this study, we used RNA-seq technology to analyze the transcriptome profiles of the male sterile line (MS-4) and the male fertile line (MF) of alfalfa to elucidate the mechanism of male sterility.

Results

We screened a total of 11,812 differentially expressed genes (DEGs) from both MS-4 and MF lines at three different stages of anther development. Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that these DEGs are mainly involved in processes such as energy metabolism, lipid and amino acid metabolism, carbohydrate metabolism, in addition to cell synthesis and aging. The results from protein–protein interaction (PPI) network analysis showed that the ribosomal protein (MS.Gene25178) was the core gene in the network. We also found that transcriptional regulation was an influential factor in the development of anthers.

Conclusions

Our findings provide new insights into understanding of the fertility changes in the male sterile (MS-4) of alfalfa.
De novo transcriptome assembly and analysis of gene expression in different tissues of moth bean (Vigna aconitifolia) (Jacq.) Marechal
Authors: Suranjika Sandhya , Pradhan Seema , Nayak Soumya Shree , Parida Ajay
Published: April 2022

Background

The underutilized species Vigna aconitifolia (Moth Bean) is an important legume crop cultivated in semi-arid conditions and is valued for its seeds for their high protein content. It is also a popular green manure cover crop that offers many agronomic benefits including nitrogen fixation and soil nutrients. Despite its economic potential, genomic resources for this crop are scarce and there is limited knowledge on the developmental process of this plant at a molecular level. In the present communication, we have studied the molecular mechanisms that regulate plant development in V. aconitifolia, with a special focus on flower and seed development. We believe that this study will greatly enrich the genomic resources for this plant in form of differentially expressed genes, transcription factors, and genic molecular markers.

Results

We have performed the de novo transcriptome assembly using six types of tissues from various developmental stages of Vigna aconitifolia (var. RMO-435), namely, leaves, roots, flowers, pods, and seed tissue in the early and late stages of development, using the Illumina NextSeq platform. We assembled the transcriptome to get 150938 unigenes with an average length of 937.78 bp. About 79.9% of these unigenes were annotated in public databases and 12839 of those unigenes showed a significant match in the KEGG database. Most of the unigenes displayed significant differential expression in the late stages of seed development as compared with leaves. We annotated 74082 unigenes as transcription factors and identified 12096 simple sequence repeats (SSRs) in the genic regions of V.aconitifolia. Digital expression analysis revealed specific gene activities in different tissues which were validated using Real-time PCR analysis.

Conclusions

The Vigna aconitifolia transcriptomic resources generated in this study provide foundational resources for gene discovery with respect to various developmental stages. This study provides the first comprehensive analysis revealing the genes involved in molecular as well as metabolic pathways that regulate seed development and may be responsible for the unique nutritive values of moth bean seeds. Hence, this study would serve as a foundation for characterization of candidate genes which would not only provide novel insights into understanding seed development but also provide resources for improved moth bean and related species genetic enhancement.
Ropivacaine inhibits wound healing by suppressing the proliferation and migration of keratinocytes via the PI3K/AKT/mTOR Pathway
Authors: Wu Xiaoyang , Sun Quanyu , He Simeng , Wu Ya , Du Shihan , Gong Lirong , Yu Jianbo , Guo Haifeng
Published: April 2022

Background

After surgery, millions of people suffer from delayed healing or wound dehiscence with subsequent severe complications, even death. Previous studies have reported that ropivacaine exhibits anti-proliferative and anti-migratory activities on numerous cells. Whether ropivacaine is able to influence the proliferation and migration of keratinocytes is still unclear. This study aimed to investigate the effect of ropivacaine on keratinocytes and its underlying molecular mechanism.

Methods

Adult male Sprague–Dawley rats were allocated to establish wound healing models with or without 0.75% ropivacaine treatment and assessed the epidermal thickness by HE staining. HaCaT cells were cultured to evaluate the effect of ropivacaine on wound healing. The cell proliferation, apoptosis status and migration were detected in vitro. Moreover, western blotting was used to examine expression to with PI3K/AKT/mTOR signaling pathways for molecular studies and the changes in inflammatory factors (IL-6, IL-10, TNF-α) were detected by ELISA.

Results

In the present study, we found that ropivacaine delayed wound closure in vivo. In vitro experiments, it was demonstrated that ropivacaine significantly inhibited the proliferation and migration of HaCaT cells via the suppression of PI3K/AKT/mTOR signaling pathway. Activation of PI3K/AKT/mTOR signaling pathway reversed the effects of ropivacaine on the proliferation and migration of HaCaT cells. Furthermore, ropivacaine contributed to the release of pro-inflammatory cytokines (IL-6 and TNF-α) and inhibited the secretion of anti-inflammatory cytokines of keratinocytes (IL-10).

Conclusions

Our research demonstrated that ropivacaine treatment showed a more decreased wound closure rate. Mechanistically, we found that ropivacaine suppressed the proliferation and migration of keratinocytes and altered the expression of cytokines by inhibiting PI3K/AKT/mTOR pathway.
How parents express their worry in calls to a medical helpline: a mixed methods study
Authors: Gren Caroline , Pedersen Maria Kjøller , Hasselager Asbjørn Børch , Folke Fredrik , Ersbøll Annette Kjær , Cortes Dina , Egerod Ingrid , Gamst-Jensen Hejdi
Published: April 2022

Background

Telephone triage is used globally in out-of-hours primary care, to prioritize who needs urgent assessment. Even though children rarely are severely ill, calls about sick children are among the most prevalent, mainly due to parental worry. Pediatric calls are considered challenging, as the call-handler must rely on parents’ second-hand information. We aimed to investigate if parents’ worry can be used as a predictor of severe illness, and if the content of the calls varies between different grades of worry.

Methods

In a convergent mixed methods study design we asked patients to rate their degree-of-worry before talking to a call-handler. We used quantitative data of degree-of-worry, triage- and patient outcome in pediatric calls (n = 2857), and the qualitative content from 54 calls with subsequent hospitalization ≥24 h.

Results

High degree-of-worry was associated with hospitalization ≥24 h (OR 3.33, 95% CI 1.53–7.21). Qualitative findings both confirmed and expanded knowledge of degree-of-worry. Worry was the predominant cause for contact overall, and was mainly triggered by loss-of-control. In calls with high degree-of-worry, the prevalence of loss-of-control was especially high, and the parents had additionally often contacted healthcare services recently. Parents with a foreign accent often rated their worry as high, and these callers were often ignored or interrupted. Calls with low degree-of-worry seemed to occur early during the disease.

Conclusion

High degree of parental worry was associated with severe illness. At the end of calls, call-handlers should ensure that the parent has regained control of the situation to reach increased reassurance and to prevent renewed unnecessary contact. Safety-netting is crucial, as many parents made contact early during the illness and deterioration may develop later. The scoring of parental degree-of-worry may be used as an indicator of potentially severe illness and can easily be implemented at out-of-hours call-centers globally.

Trial registration

Original study registered atclinicaltrials.gov(NCT02979457).
Combined impact of lifestyle-related factors on total mortality among the elder Chinese: a prospective cohort study
Authors: Lian Zhiwei , Zhu Chunsu , Yuan Haowen , Chen Ying
Published: April 2022

Background

The combined impact of healthy lifestyle factors on total mortality among elder Chinese is unclear. This study aimed to investigate the overall impact of lifestyle factors on total mortality in a senior Chinese population, and determine whether these associations were consistent in the presence of different characteristics, including physical comorbidities.

Methods

The Chinese Longitudinal Healthy Longevity Survey (CLHLS) is a large population-based prospective cohort study in 22 of 31 provinces from mainland China. We included 15,163 adults aged ≥65 years recruited from 1998- to 2002 and followed-up until 2014. A healthy lifestyle score was calculated considering five lifestyle factors (exercise, smoking, dietary diversity, body mass index and drinking). The scores ranged from zero to five points and were classified into the following three categories: unhealthy (0-1 point), intermediate (2-3 points) and healthy (4-5 points). Cox proportional hazards regression analyses were used to assess the associations between the combined healthy lifestyle score and total mortality, adjusting for demographic characteristics and physical comorbidities, as appropriate. Stratification analyses and interaction analyses were further performed.

Results

Among the 15,163 participants, the mean age (SD) was 86.2 (11.6) years. During an average follow-up period of 12.5 (SD = 3.9) years, 9655 deaths occurred. The adjusted hazard ratios (HRs) of total mortality decreased as the number of healthy lifestyle factors increased. Compared to the unhealthy lifestyle group, the healthy lifestyle group had a HR and 95% CI of 0.78 and 0.72-0.83. The population attributable risk of total death among those without a healthy lifestyle was 25.2%. A healthier lifestyle pattern was associated with a lower total mortality risk among individuals with different severities of physical comorbidities, although the associations were stronger among those with fatal physical comorbidities (p-interaction < .001).

Conclusions

In this large-scale study, a healthier lifestyle measured by regular exercise participation, never smoking, never drinking, good dietary diversity and normal weight, was inversely associated with total mortality, regardless of physical comorbidity status. These findings support the necessity of multiple lifestyle modifications to prevent premature death in both general elderly populations and those with physical comorbidities.
Cascade Immune Mechanisms of Protection against Mycobacterium tuberculosis (IMPAc-TB): study protocol for the Household Contact Study in the Western Cape, South Africa
Authors: Hiemstra Andriёtte M. , MacDonald Candice E. , van Rensburg Ilana C. , Stanley Kim , Maasdorp Elizna , Mc Anda Shirley , Tönsing Susanne , Shaw Jane Alexandra , Tromp Gerard , van der Spuy Gian D. , Urdahl Kevin B. , Lewinsohn David M. , Kuivaniemi Helena , Du Plessis Nelita , Malherbe Stephanus T. , Walzl Gerhard
Published: April 2022

Background

Natural immunity against Mycobacterium tuberculosis exists, and > 90% of those infected remain disease-free. Innate and adaptive immune responses required to mediate such protection against tuberculosis (TB) are, however, poorly understood.

Methods

This is an analytical study exploring protective and non-protective pathways of immunity against Mycobacterium tuberculosis. Adults without HIV infection are recruited at community healthcare clinics in high TB incidence areas of the Western Cape Province, South Africa. Data regarding participants’ medical, social and medication usage will be collected, and clinical examinations and point-of-care tests documented. Reference tests for TB (chest radiographs and sputum tests for GeneXpert MTB/RIF Ultra®, Auramine smear and liquid cultures) and investigations to classify infection states [interferon-gamma release assay (IGRA) and SARS-CoV-2 polymerase chain reaction (PCR) nasopharyngeal swab and IgG], are done on all participants who meet the inclusion criteria. 18F-Fluorodeoxyglucose positron emission tomography combined with computerized tomography will be done on all close contacts (contacts) and healthy control (controls) participants. Participants are divided into 12 study groups representing a spectrum of TB clinical phenotypes and prior SARS-CoV-2 infection based on their TB status, exposure history, results of IGRA test at baseline and 3 months, SARS-CoV-2 serology, and PCR results, and for contacts and controls, PET-CT imaging findings indicative of sub-clinical TB lesions. Samples for experimental assays include whole blood for isolation of peripheral blood mononuclear cells and blood in PAXgene® tubes for RNA isolation. All SARS-CoV-2 PCR negative study participants undergo bronchoscopy for collecting bronchoalveolar lavage samples.

Discussion

The paired blood and BAL samples will be used for comprehensive analyses of the tissue-specific and systemic immunity that will include e.g., cytometry by time-of-flight analyses, RNA-sequencing, multiplex immunoassays, epigenetic analysis, and mechanistic studies of control of infection by Mycobacterium tuberculosis. Results will be integrated with those from mice and non-human primate studies to provide a comprehensive analysis of protective pathways in natural and vaccine-induced immunity against Mycobacterium tuberculosis.
Determinants of measles vaccination dropout among 12 − 23 months aged children in pastoralist community of Afar, Ethiopia
Authors: Hailu Chekole , Fisseha Girmatsion , Gebreyesus Aregawi
Published: April 2022

Background

Measles is a viral disease and a leading vaccine-preventable childhood killer. More than 95% of measles deaths occur in countries with low incomes and weak health infrastructures. In response to this, Ethiopia prepared a measles elimination strategic plan to achieve by 2020. However, based on the Mini-Ethiopian demographic health survey 2019 the full coverage of immunization is 43% at the country level and it is lowest (20%) in the Afar region where this study was conducted. Therefore, this study aimed to identify the determinants of the measles vaccine dropout rate in Afar regional state which is one of the pastoralist communities in Ethiopia.

Methods

Community based unmatched case-control study design was used. The study was conducted in Awash district of Afar regional state, Ethiopia from June 1st -30th 2018. Data were collected from a study unit of 12–23 months old children. For this study, a sample of 166 cases and 331controls were selected by simple random sampling methods and the total sample size was 497. Data were collected using a pretested structured questionnaire by health workers using the local language. Data were entered into Epi-info − 7 and analyzed by SPSS version 20 software and logistic regression was used to assess the determinants measles dropout rate.

Results

A total of 487 children participated in this study with a response rate of 97.9%. More than half of the children were female (53.3%) and 113 (35.2%) children mothers’ were not attended formal education. Mother who had antenatal care ≤ 2 visits [AOR:=5.7(3.2–10.14)], being in the birth order of 1 − 3 [AOR = 4.47(1.63–12.29)], long waiting time > 60 min at nearby health facility for vaccine [AOR = 2.37(1.36–4.15)], households visit by health extension workers [AOR = 2.03(1.12–3.66)], pregnant women not participating with women development army [AOR = 3.5(1.94–6.18)], and poor maternal knowledge on vaccination [AOR = 3.30(1.9–5.73)] were significant determinants with measles vaccination dropout rate.

Conclusions

Health facility and mother characteristics were the determinants of the measles vaccine dropout rate. Therefore, tracing and strict follow up by the health extension works using home visits and women development army at the pastoralist community is necessary to reach them.
Ipsilateral blooming of microbleeds after Hyperintense Acute Reperfusion Marker sign in an ischemic Stroke patient, a case report
Authors: Saccaro Luigi Francesco , Bekri Imen , De Malherbe Maxime , Hmida Intissar , Pico Fernando
Published: April 2022

Background

Hyperintense Acute Reperfusion Marker (HARM) is a hyperintense subarachnoid signal on FLAIR MRI sequence caused by gadolinium contrast leakage into the subpial space. While, on FLAIR, HARM may mimic subarachnoid hemorrhage, it is differentiated from it on computed tomography (CT) and SWAN MRI sequences. Cerebral microbleeds are black, rounded spots on SWAN caused by blood-products deposition following red blood cell leakage from small cerebral vessels brain. Both microbleeds and HARM carry important prognostic implication as they are associated with blood-brain barrier disruption and an increased risk of intracerebral hemorrhage.

Case presentation

A 79-year-old man presented with aphasia and right hemiparesis due to ischemic stroke with left middle cerebral artery occlusion. Admission NIHSS score was 7, and he was successfully treated by intravenous thrombolysis and mechanical thrombectomy. On day 1, his clinical condition worsened, and he had an urgent gadolinium-enhanced MRI. There was no evidence of early recurrence, nor of hemorrhage on SWAN or on FLAIR. Left middle cerebral artery was permeable. The patient was anticoagulated for newly diagnosed atrial fibrillation, and a second MRI following a generalized tonic-clonic seizure showed multiple left hemispheric diffusion-weighted imaging (DWI) hyperintense spots and a left hemispheric sub-arachnoid hyperintensity on FLAIR, compatible with a subarachnoid hemorrhage. This diagnosis was excluded by SWAN MRI sequence and a normal cerebral CT the same day. The diagnosis of HARM was retained. At day 9, patient’s condition improved, and a control MRI did not show evidence of HARM. However, numerous microbleeds were detected in the left hemisphere only (ipsilateral with HARM and stroke).

Conclusions

This case highlights first of all the importance of differentiating HARM and subarachnoid hemorrhage, especially in an anticoagulated patient with clinical aggravation. Secondly, it is crucial to identify microbleeds and understand their pathophysiology, as they are associated with higher risk of hemorrhage and stroke recurrence in ischemic stroke patients. Finally, the mono-hemispheric appearance of microbleeds in this case suggests for the first time that, in some acute ischemic stroke patients, a relationship between HARM and cerebral microbleeds may exist.
Potential critical risks of pulmonary thromboembolism from an asymptomatic postpartum ovarian vein thrombosis: a case report
Authors: Murata Tsuyoshi , Yoshimoto Yuki , Shibano Yoshiaki , Owada Koji , Miyajima Masayuki , Nakamura Soichi , Yamauchi Ryuji
Published: April 2022

Background

Ovarian vein thrombosis (OVT) may cause maternal mortality by inducing pulmonary thromboembolism (PTE). However, the prevalence, etiology, risk factors, prognosis, and optimal treatments for asymptomatic OVT during and after pregnancies are unclear, which therefore requires a high clinical index of suspicion for certain diagnoses due to its vague presentation. We herein present a case of asymptomatic postpartum OVT that extended toward the inferior vena cava (IVC), resulting in a potential risk of PTE.

Case presentation

A 30-year-old postpartum woman presented with slight dyspnea after an uneventful vaginal delivery at 40 weeks of gestation. We checked her laboratory data to exclude lethal thrombosis; D-dimer levels were 85.6 μg/mL. We performed computed tomography (CT) to search the presence of PTE and deep vein thrombosis (DVT); although no signs of PTE and DVT in her legs were detected, CT and trans-abdominal ultrasonography (TAUS) revealed a right OVT. Heparin was administered, and D-dimer levels decreased; warfarin at a dose of 2 mg/day was subsequently administered to control anti-coagulopathy. However, D-dimer was re-elevated despite adequate anticoagulation treatment, and extension of the right OVT to the IVC was detected by CT and TAUS. With warfarin administration, CT and TAUS showed the disappearance of right OVT. The patient was discharged from the hospital 17 days after delivery.

Conclusions

Even asymptomatic postpartum OVT may lead to PTE. Universal screening guidelines and optimal treatment strategies for asymptomatic OVT in pregnant and postpartum women should be established through future studies.
Prenatal sonographic findings in confirmed cases of Wolf-Hirschhorn syndrome
Authors: Simonini Corinna , Hoopmann Markus , Kagan Karl Oliver , Schröder Torsten , Gembruch Ulrich , Geipel Annegret
Published: April 2022

Background

Wolf-Hirschhorn syndrome (WHS) is a common genetic condition and prenatal diagnosis is difficult due to heterogeneous expression of this syndrome and rather non-specific ultrasound findings. Objective of this study was to examine the prenatal ultrasound findings in fetuses with Wolf-Hirschhorn syndrome (WHS).

Methods

Retrospective assessment of 18 pregnancies that were seen at three tertiary referral centers (Universities of Bonn, Tuebingen and Nuernberg / Germany). Findings of prenatal ultrasound examinations, genetic results and outcome were compared. Additionally, findings of our study were compared to previous small case series from the literature and then compared to data on postnatal frequencies and abnormalities in affected patients.

Results

Median gestational age at the time of examination was 23 + 1 weeks’ (range: 13 + 4 to 29 + 1 weeks’) with female-to-male ratio of > 2.5:1. Most frequent ultrasound findings were facial abnormalities, symmetric IUGR and microcephaly that presented in 94.4, 83.3 and 72.2% of cases, respectively. The combination of microcephaly and hypoplastic nasal bone was a particularly characteristic finding. Growth retardation presented in all fetuses > 20 weeks, but not below. Other frequent abnormalities included cardiac anomalies in 50 and single umbilical artery (SUA) in 44.4% of fetuses.

Conclusion

WHS should be considered in the presence of symmetric IUGR together with microcephaly, hypoplastic nasal bone and facial abnormalities on prenatal ultrasound. Genetic testing by chromosomal microarray analysis (CMA) is strongly recommended in this context.
Racial disparities in caesarean delivery among nulliparous women that delivered at term: cross-sectional decomposition analysis of Nebraska birth records from 2005-2014
Authors: Hanson Corrine , Samson Kaeli , Anderson-Berry Ann L. , Slotkowski Rebecca A. , Su Dejun
Published: April 2022

Background

Previous studies suggest higher rates of caesarean section among women who identify as racial/ethnic minorities. The objective of this study was to understand factors contributing to differences in caesarean rates across racial and ethnic groups.

Methods

Data was collected from 2005 to 2014 Nebraska birth records on nulliparous, singleton births occurring on or after 37 weeks gestation (n = 87,908). Risk ratios (RR) and 95% confidence intervals (CI) for caesarean were calculated for different racial and ethnic categories, adjusting for maternal age, marital status, county of residence, education, insurance status, pre-pregnancy BMI, and smoking status. Fairlie decomposition technique was utilized to quantify the contribution of individual variables to the observed differences in caesarean.

Results

In the adjusted analysis, relative to non-Hispanic (NH) White race, both Asian-NH (RR 1.21, 95% CI 1.14, 1.28) and Black-NH races (RR 1.13, 95% CI 1.08, 1.19) were associated with a significantly higher risk for caesarean. The decomposition analysis showed that among the variables assessed, maternal age, education, and pre-pregnancy BMI contributed the most to the observed differences in caesarean rates across racial/ethnic groups.

Conclusion

This analysis quantified the effect of social and demographic factors on racial differences in caesarean delivery, which may guide public health interventions aimed towards reducing racial disparities in caesarean rates. Interventions targeted towards modifying maternal characteristics, such as reducing pre-pregnancy BMI or increasing maternal education, may narrow the gap in caesarean rates across racial and ethnic groups. Future studies should determine the contribution of physician characteristics, hospital characteristics, and structural determinants of health towards racial disparities in caesarean rates.
CA19-9 in combination with P-CRP as a predictive marker of immune-related adverse events in patients with recurrent or unresectable advanced gastric cancer treated with nivolumab
Authors: Matsunaga Tomoyuki , Saito Hiroaki , Kuroda Hirohiko , Osaki Tomohiro , Takahashi Sadamu , Iwamoto Akemi , Fukumoto Yoji , Taniguchi Kenjiro , Fukuda Kenji , Miyauchi Wataru , Shishido Yuji , Miyatani Kozo , Fujiwara Yoshiyuki
Published: April 2022

Background

Immune-check point inhibitors (ICPIs) for treatment of cancer patients sometimes induce potentially life-threatening immune-related adverse events (irAEs), which predict ICPIs treatment efficacy. Prediction of irAEs would be useful for management of irAEs and prediction of ICPIs efficacy. This study aimed to determine predictors of irAEs in patients with recurrent or unresectable advanced gastric cancer (RUGC) treated with nivolumab.

Methods

Seventy-eight RUGC patients treated with nivolumab at nine institutions between January 2017 and April 2020 were included in this study. The usefulness of specific blood test results as predictors of irAEs was evaluated.

Results

We observed irAEs in 15 (19.2%) patients. The disease control rate was significantly higher in the patients with irAEs than in those without (86.7% vs. 42.9%; P < 0.001). The median progression-free survival was significantly longer for patients with irAEs than for patients without (4.9 vs. 2.6 months; P = 0.018). The median survival time was longer for patients with irAEs than for those without (9.4 vs. 5.8 months; P = 0.041). The receiver operating characteristic (ROC) curves for irAEs indicated that the area under the curve (AUC) of carbohydrate antigen 19–9 (CA19-9) was highest (0.692; P = 0.022), followed by that for the platelet count × serum C-reactive protein (P-CRP) value (0.680; P = 0.032). The AUC for the CA19-9 + P-CRP combination was 0.782, which was more useful than that for either component and significantly associated with overall survival of nivolumab-treated RUGC patients.

Conclusions

The CA19-9 + P-CRP combination was predictive of irAEs and prognosis in RUGC patients.