bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional Analysis of an Intronic FBN1 Pathogenic Gene Variant in a Family With Marfan Syndrome
Authors: Hu Kui , Wan Yun , Lee Fu-Tsuen , Chen Jinmiao , Wang Hao , Qu Haonan , Chen Tao , Lu Wang , Jiang Zhenwei , Gao Lufang , Ji Xiaojuan , Sun Liqun , Xiang Daokang
Published: April 2022

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder that canonically affects the ocular, skeletal, and cardiovascular system, in which aortic tear and rupture is the leading cause of death for MFS patients. Genetically, MFS is primarily associated with fibrillin-1 (FBN1) pathogenic variants. However, the disease-causing variant in approximately 10% of patients cannot be identified, partly due to some cryptic mutations that may be missed using routine exonic sequencing, such as non-coding intronic variants that affects the RNA splicing process. We present a 32-year female with typical MFS systemic presentation that reached to a clinical diagnosis according to the revised Ghent nosology. We performed whole-exome sequencing (WES) but the report failed to identify known causal variants when analyzing the exonic sequence. However, further investigation on the exon/intron boundaries of the WES report revealed a candidate intronic variant of the fibrillin 1 (FBN1) gene (c.248-3 C>G) that predicted to affect the RNA splicing process. We conducted minigene splicing analyses and demonstrated that the c.248-3 C>G variant abolished the canonical splicing site of intron 3, leading to activation of two cryptic splicing sites and causing insertion (c.248-1_248-2insAG and c.248-1_248-282ins). Our study not only characterizes an intronic variant to the mutational spectrum of the FBN1 gene in MFS and its aberrant effect on splicing, but highlights the importance to not neglect the exon/intron boundaries when reporting and assessing WES results. We point out the need of conducting functional analysis to verify the pathogenicity of intronic mutation, and the opportunity to re-consider the standard diagnostic approaches in cases of clinically diagnosed MFS with normal or variant of unknown significance genetic results.
Differences in Circulating Extracellular Vesicle and Soluble Cytokines in Older Versus Younger Breast Cancer Patients With Distinct Symptom Profiles
Authors: Sass Dilorom , Fitzgerald Wendy , Wolff Brian S. , Torres Isaias , Pagan-Mercado Glorivee , Armstrong Terri S. , Miaskowski Christine , Margolis Leonid , Saligan Leorey , Kober Kord M.
Published: April 2022

Because extracellular vesicle (EV)-associated cytokines, both encapsulated and surface bound, have been associated with symptom severity, and may vary over the lifespan, they may be potential biomarkers to uncover underlying mechanisms of various conditions. This study evaluated the associations of soluble and EV-associated cytokine concentrations with distinct symptom profiles reported by 290 women with breast cancer prior to surgery. Patients were classified into older (≥60 years, n = 93) and younger (< 60 years, n = 197) cohorts within two previously identified distinct symptom severity profiles, that included pain, depressive symptoms, sleep disturbance, and fatigue (i.e., High Fatigue Low Pain and All Low). EVs were extracted using ExoQuick. Cytokine concentrations were determined using Luminex multiplex assay. Mann Whitney U test evaluated the differences in EV and soluble cytokine levels between symptom classes and between and within the older and younger cohorts adjusting for Karnofsky Performance Status (KPS) score, body mass index (BMI), and stage of disease. Partial correlation analyses were run between symptom severity scores and cytokine concentrations. Results of this study suggest that levels of cytokine concentrations differ between EV and soluble fractions. Several EV and soluble pro-inflammatory cytokines had positive associations with depressive symptoms and fatigue within both age cohorts and symptom profiles. In addition, in the older cohort with High Fatigue Low Pain symptom profile, EV GM-CSF concentrations were higher compared to the All Low symptom profile (p < 0.05). Albeit limited by a small sample size, these exploratory analyses provide new information on the association between cytokines and symptom profiles of older and younger cohorts. Of note, unique EV-associated cytokines were found in older patients and in specific symptom classes. These results suggest that EVs may be potential biomarker discovery tools. Understanding the mechanisms that underlie distinct symptom class profiles categorized by age may inform intervention trials and offer precision medicine approaches.
Integrated mRNA and Small RNA Sequencing Reveals microRNAs Associated With Xylem Development in Dalbergia odorifera
Authors: Zhao Wenxiu , Meng Xiangxu , Xu Jiahong , Liu Zijia , Hu Yangyang , Li Bingyu , Chen Jinhui , Cao Bing
Published: April 2022

Dalbergia odorifera is a rare and precious rosewood specie, whose wood is a very high-quality material for valuable furniture and carving crafts. However, limited information is available about the process of wood formation in D. odorifera. To determine genes that might be closely associated with the xylem differentiation process, we analyzed the differentially expressed genes (DEGs) and microRNAs (miRNAs) from specific xylem tissues of D. odorifera by RNA sequencing (RNA-seq) and small RNA sequencing (small RNA-seq). In total, we obtained 134,221,955 clean reads from RNA-seq and 90,940,761 clean reads from small RNA-seq. By comparing the transition zone (Dotz) and sapwood (Dosw) samples, a total of 395 DEGs were identified. Further analysis revealed that DEGs encoded for WRKY transcription factors (eight genes), lignin synthesis (PER47, COMT, CCR2), cell wall composition (UXS2), gibberellin synthesis (KAO2, GA20OX1), jasmonic acid synthesis (OPR2, CYP74A), and synthesis of flavonoids (PAL2) and terpenoids (CYP71A1). Subsequently, a preliminary analysis by small RNA-seq showed that the expressions of 14 miRNAs (such as miR168a-5p, miR167f-5p, miR167h-5p, miR167e, miR390a, miR156g, novel_52, and novel_9) were significantly different between Dotz and Dosw. Further analysis revealed that the target genes of these differentially expressed miRNAs were enriched in the GO terms “amino acid binding,” “cellulase activity,” and “DNA beta-glucosyltransferase activity”. Further, KEGG pathway annotation showed significant enrichment in “fatty acid elongation” and “biosynthesis of unsaturated fatty acids”. These processes might be participating in the xylem differentiation of D. odorifera. Next, expression correlation analysis showed that nine differentially expressed miRNAs were significantly negatively associated with 21 target genes, which encoded for proteins such as pyrH, SPL6, SPL12, GCS1, and ARF8. Overall, this is the first study on miRNAs and their potential functions in the xylem development of D. odorifera, which provides a stepping stone for a detailed functional investigation of D. odorifera miRNAs.
Impact of Long Noncoding RNA LINC00673 Genetic Variants on Susceptibility to Diabetic Retinopathy
Authors: Chuang Chih-Chun , Yang Yi-Sun , Kornelius Edy , Huang Chien-Ning , Hsu Min-Yen , Lee Chia-Yi , Yang Shun-Fa
Published: April 2022

Long noncoding RNAs (lncRNAs) have been proven to play critical roles in diabetic retinopathy (DR). This study investigated whether the single nucleotide polymorphism (SNP) of long intergenic noncoding RNA 00673 (LINC00673) affects the clinical characteristics of diabetic retinopathy (DR). A total of three loci of LINC00673 SNPs (rs6501551, rs9914618, and rs11655237) were genotyped using TaqMan allelic discrimination in 276 and 454 individuals with and without DR, respectively. Our results revealed that LINC00673 SNP rs11655237 CT genotype (AOR: 1.592, 95% CI: 1.059–2.395, p = 0.026), CT + TT genotype (AOR: 1.255, 95% CI: 1.029–1.531, p = 0.025), and allele T (AOR: 1.185, 95% CI: 1.004–1.397, p = 0.044) yielded higher ratios in the non-proliferative diabetic retinopathy (NPDR) subgroup than in the non-DR group. Furthermore, the interval of diabetes mellitus (DM) was significantly shorter in the LINC00673 SNP rs11655237 CT + TT variant than that in the LINC00673 SNP rs11655237 wild type (10.44 ± 7.10 vs. 12.98 ± 8.34, p = 0.009). In conclusion, the LINC00673 SNP rs11655237 T allele is associated with a higher probability of NPDR development. Patients with the LINC00673 SNP rs11655237 CT + TT variant exhibited a short DM interval.
Exposing Obstetric Violence in the Eastern Mediterranean Region: A Review of Women's Narratives of Disrespect and Abuse in Childbirth
Authors: Khalil Merette , Carasso Kashi Barbara , Kabakian-Khasholian Tamar
Published: April 2022

Background

Obstetric violence (OV) threatens the provision of dignified, rights-based, high-quality, and respectful maternal care (RMC). The dearth of evidence on OV in the Eastern Mediterranean Region poses a knowledge gap requiring research to improve rights-based and respectful health practice and policy. While efforts to improve the quality of maternal health have long-existed, women's experiences of childbirth and perceptions of dignity and respect are not adequately or systematically recorded, especially in the said region.

Aim

This study centered on the experiences of women's mistreatment in childbirth to provide an overview of OV and offer recommendations to improve RMC.

Methods

A scoping review was conducted, and a total of 38 articles met the inclusion criteria and were analyzed using Bowser and Hill's framework of the seven typologies of Disrespect and Abuse (D&A) in childbirth. D&A in childbirth (or violations to RMC) is a manifestation of OV and served as a proxy to analyze its prevalence in the EMR.

Findings and Discussion

This study indicated that across the EMR, women experienced every type of D&A in childbirth. This happens regardless of health systems' strength or country's income, with 6 out of 7 types of D&A found in almost two-thirds of included countries. In the EMR, the most common types of D&A in childbirth are physical abuse (especially overused routine interventions) and non-dignified care (embedded in patriarchal socio-cultural norms). The intersections of these abuses enable the objectification of women's bodies and overuse of unconsented routine interventions in a hierarchical and patriarchal system that regards the power and autonomy of doctors above birthing women. If unchecked, the implications include acceptance, continuation, and underreporting of D&A in childbirth, as well as passivity toward human-rights violations, which all further cause the continuing the cycle of OV.

Conclusion

In order to eliminate OV, a paradigm shift is required involving infrastructure changes, education, empowerment, advocacy, a women-centered and gender-sensitive approach to health system strengthening, and policy development. Recommendations are given at individual, community, health systems, and policy levels to ensure that every woman achieves her right to health and birth in a dignified, respectful, and empowered manner.
Brief Research Report: Virus-Specific Humoral Immunity at Admission Predicts the Development of Respiratory Failure in Unvaccinated SARS-CoV-2 Patients
Authors: Tajuelo Ana , Carretero Octavio , García-Ríos Estéfani , López-Siles Mireia , Cano Olga , Vázquez Mónica , Más Vicente , Rodríguez-Goncer Isabel , Lalueza Antonio , López-Medrano Francisco , San Juan Rafael , Fernández-Ruiz Mario , Aguado José Mᵃ , McConnell Michael J. , Pérez-Romero Pilar
Published: April 2022

Introduction

There is robust evidence indicating that the SARS-CoV-2-specific humoral response is associated with protection against severe disease. However, relatively little data exist regarding how the humoral immune response at the time of hospital admission correlates with disease severity in unimmunized patients. Our goal was toidentify variables of the humoral response that could potentially serve as prognostic markers for COVID-19 progressionin unvaccinated SARS-CoV-2 patients.

Methods

A prospective cross-sectional study was carried out in a cohort of 160 unimmunized, adult COVID-19 patients from the Hospital Universitario 12Octubre. Participants were classified into four clinical groups based on disease severity: non-survivors with respiratory failure (RF), RF survivors, patients requiring oxygen therapy and those not receiving oxygen therapy. Serum samples were taken on admission and IgM, IgG, IgG subclass antibody titers were determined by ELISA, and neutralizing antibody titersusing a surrogate neutralization assay. The differences in the antibody titers between groups and the association between the clinical and analytical characteristics of the patients and the antibody titers were analyzed.

Results

Patients that developed RF and survived had IgM titers that were 2-fold higher than non-survivors (p = 0.001), higher levels of total IgG than those who developed RF and succumbed to infection (p< 0.001), and than patients who required oxygen therapy (p< 0.05), and had 5-fold higher IgG1 titers than RF non-survivors (p< 0.001) and those who needed oxygen therapy (p< 0.001), and 2-fold higher than patients that did not require oxygen therapy during admission (p< 0.05). In contrast, RF non-survivorshad the lowest neutralizing antibodylevels, which were significantly lower compared those with RF that survived (p = 0.03). A positive correlation was found between IgM, total IgG, IgG1 and IgG3 titers and neutralizing antibody titers in the total cohort (p ≤ 0.0036).

Conclusions

We demonstrate that patients with RF that survived infection had significantly higher IgM, IgG, IgG1 and neutralizing titers compared to patients with RF that succumb to infection, suggesting that using humoral response variables could be used as a prognostic marker for guiding the clinical management of unimmunized patients admitted to the hospital for SARS-CoV-2 infection.
Malignant Isolated Cortical Vein Thrombosis as the Initial Manifestation of Primary Antiphospholipid Syndrome: Lessons on Diagnosis and Management From a Case Report
Authors: Shen Jie , Tao Zi , Chen Wei , Sun Jing , Li Yan , Fu Fangwang
Published: April 2022

Background

Antiphospholipid syndrome (APS) with isolated cortical vein thrombosis (ICoVT) is an extremely rare but potentially malignant entity. It is particularly challenging to diagnose APS-related ICoVT because of the non-specific clinical manifestations and the frequent absence of typical neuroimaging. Moreover, there is currently limited knowledge on the clinical features and management strategies for the condition. Delays in diagnosis and treatment may lead to life-threatening consequences.

Case Presentation

We present a rare case of a 74-year-old Chinese woman who presented with sudden onset of headache and right arm weakness that mimicked acute ischemic stroke. Her initial computed tomography was unremarkable, and intravenous thrombolysis was performed. Serial neuroimages confirmed ICoVT 4 days after symptom onset, and low-molecular-weight heparin (LMWH) was started at a dose of 0.4 ml twice per day, according to the 2019 Chinese guidelines. The workup for the predisposing causes of ICoVT revealed triple positivity APS. LMWH dose was adjusted according to the anti-Xa chromogenic assay. However, the patient’s condition deteriorated rapidly, and there was a progressive enlargement of the venous infarction despite treatment with anticoagulants. Transtentorial herniation developed on day 12, and decompressive craniectomy was immediately performed. The patient’s symptoms did not improve significantly after surgery, and she remained aphasic and hemiplegic at the 3-month follow-up, with a modified Rankin Scale score of 5.

Conclusion

ICoVT is a rare yet potentially fatal manifestation of APS, and its diagnosis and treatment are extremely challenging. Timely diagnosis, prompt treatment, and close monitoring are essential to improve the clinical prognosis of patients with APS-related ICoVT.
Macrofauna Associated With a Rhodolith Bed at an Oceanic Island in the Eastern Tropical Pacific (Isla del Coco National Park, Costa Rica)
Authors: Solano-Barquero Alberto , Sibaja-Cordero Jeffrey A. , Cortés Jorge
Published: April 2022

Rhodoliths are round calcareous red algae that form extensive beds and associated with them are a diverse suite of species. Rhodolith beds are among the least known coastal–marine ecosystems, and even less is understood about their associated flora and fauna. Here, we present an evaluation of the biodiversity larger than 500 μm associated with rhodoliths at Isla del Coco National Park, Costa Rica, an oceanic island in the Eastern Tropical Pacific, 500 km offshore of the mainland. This research determined the influence of rhodolith degree of aggregation (distance among individual rhodolith) as well as rhodolith complexity, volume, and mass in relation to the diversity, composition, and biomass of the associated fauna. A total of 145 taxa were collected in 60 rhodolith samples. Arthropods, polychaetes, and mollusks were the dominant taxa in terms of richness, and crustaceans + acari represented >50% of the total abundance. Five potentially new species were collected in this study. Collections identified 31 new records, with 20 of them being newly reported genera for Isla del Coco. Many of the organisms found were juveniles as well as adult stages bearing eggs, demonstrating the importance of this ecosystem. The faunal composition changed along the gradient of rhodolith aggregation. Moderately aggregated rhodoliths (separated by 5 to 10 cm) had the highest diversity, with the highest averages of taxon richness and total numerical abundance and the highest faunal biomass. There were more organisms in more complex rhodoliths; nevertheless, the complexity of the rhodolith did not affect the number of taxa or total organism biomass. Larger rhodoliths, in size and mass, favored higher amounts of taxa and organisms. The rhodolith bed studied is an example of the intermediate disturbance hypothesis because the highest value of biodiversity of invertebrates was at the moderate aggregation level of rhodoliths. In this density of rhodoliths, the fauna was less exposed to hard environmental conditions and prevented dominant species.
Study on the Individual Coloring Mechanism of Iridescent Cells in the Mantle of the Boring Giant Clam, Tridacna crocea
Authors: Li Yunqing , Zhou Yinyin , Wei Jinkuan , Shi Gongpengyang , Liao Qingliang , Guo Shuming , Zhou Zihua , Li Jun , Qin Yanping , Ma Haitao , Yu Ziniu , Zhang Yuehuan
Published: April 2022

Giant clams are marine bivalves that inhabit Indo-Pacific coral reefs. The boring giant clam, Tridacna crocea, exhibits bright and conspicuous mantle coloration based on the specialized cells (iridocytes) that generate structural colors. In order to illustrate the coloring mechanism of individual iridocytes, the reflection spectra curve of iridocytes was obtained by a micro-hyperspectral imager. TEM images were obtained to show the inner nanostructures of iridocytes. FDTD simulation was conducted to analyze the relationship between the color of iridocytes and the unique lamellar structure. We found that the laminae in the regular arrangement within cells govern the coloration of individual iridocytes. With the gradual increase of lamellar thickness and spacing, the color of the structure varies from bright violet to orange-red, forming a full visible spectrum. This study provides a new understanding of the various colors produced by individual iridocytes.
Impacts of Sea Bottom Temperature on CPUE of European Lobster Homarus gammarus (Linnaeus, 1758; Decapoda, Nephropidae) in the Eastern Adriatic Sea
Authors: Matić-Skoko Sanja , Pavičić Mišo , Šepić Jadranka , Janeković Ivica , Vrdoljak Dario , Vilibić Ivica , Stagličić Nika , Šegvić-Bubić Tanja , Vujević Ante
Published: April 2022

The study describes recent decadal changes (2008–2017) in the landing biomass, fishing effort and CPUE (kg/day) data of European lobster Homarus gammarus in the eastern Adriatic Sea region, and relates these changes to increases of sea bottom temperatures detected at long-term in situ stations and modelled by an ocean numerical model (ROMS, Regional Ocean Modelling System). Modelling results were further used to quantify spatial and temporal differences of bottom temperature changes over different fishing zones. Trends of sea bottom temperature were positive and statistically significant between stations. Temporal trends of landing, effort and CPUE were also positive and significant for the northern Adriatic. Correlation analysis was used to test the relationship between winter and spring sea bottom temperatures and CPUE data of H. gammarus, separately for the northern and central Adriatic Sea, resulting in statistically significant correlations for both areas. Whether the increased CPUE in the northern Adriatic is due to increased abundance or catchability is discussed. The observed temperature changes likely reflect climate system changes recognised at the regional level and as such, lobster management measures will need to be revised and updated in the future.
Control Mechanism of Particle Flow in the Weak Liquid Metal Flow Field on Non-Uniform Curvature Surface Based on Lippmann Model
Authors: Zhang Li , Zheng Bingjun , Xie Yi , Ji Renquan , Li Yanbiao , Mao Wenbing
Published: April 2022

In order to realize the uniform distribution in the abrasive flow polishing of the titanium alloy workpiece with curved surface, a novel method based on the liquid metal-abrasive flow machining technology is proposed in this study. Based on the SST k-ω model, Preston model and fluid flow particle tracking model, the COMSOL software is employed to study the dynamic characteristics of liquid metal-abrasive flow under different AC electric field conditions, and the two-phase flow field is used to simulate the liquid state, the movement of liquid metal particles on the surface of the workpiece and the varitation of the Pv value in the near-wall region. It is found from numerical simulation results that the average Pv value in the strong flow field is 23,718.8 W/m2, and that in the weak flow field is 5,427.3 W/m2. By the assistance of the electric filed with the voltage of AC 36 V, the average Pv value of the liquid metal particles in the weak flow field is found to be 10,948.6 W/m2 with an increase of 101.7%. Therefore, to properly control the electric field strength, the movement of liquid metal in the flow field can be found to be controlled, and hence improving the uniformity of the turbulent kinetic energy on the workpiece surface and improving the processing quality.
Numerical Modeling and Experimental Study on the Material Removal Process Using Ultrasonic Vibration-Assisted Abrasive Water Jet
Authors: Cheng Zhichao , Qin Shikang , Fang Zhufang
Published: April 2022

Currently, micro-abrasive water jet machining has the problem of insufficient processing capacity in the central area. To assist with improving the processing efficiency, ultrasonic vibration is introduced. First, based on the computational fluid dynamics method, the mathematical model of the three-dimensional shape prediction of micro-holes is established using a mixed model, standard k-ε model, discrete phase model, and dynamic mesh model. The effects of the ultrasonic vibration on the static pressure, jet velocity field, abrasive particle motion state, and material erosion rate in the stagnation zone are studied. Then the accuracy of the prediction model is verified by comparing the two-dimensional section of the experimental data and the simulated data and calculating the three-dimensional mean square deviation. The established prediction model is used to further analyze the optimal frequency of the ultrasonic vibration and the specific influence of the optimal amplitude on the machining effect in micro-abrasive water jet machining. The above research results have profound guiding significance for determining how to use ultrasonic vibration in micro-abrasive water jet machining.
Technical Design Report for a Carbon-11 Treatment Facility
Authors: Penescu Liviu , Stora Thierry , Stegemann Simon , Pitters Johanna , Fiorina Elisa , Augusto Ricardo Dos Santos , Schmitzer Claus , Wenander Fredrik , Parodi Katia , Ferrari Alfredo , Cocolios Thomas E.
Published: April 2022

Particle therapy relies on the advantageous dose deposition which permits to highly conform the dose to the target and better spare the surrounding healthy tissues and organs at risk with respect to conventional radiotherapy. In the case of treatments with heavier ions (like carbon ions already clinically used), another advantage is the enhanced radiobiological effectiveness due to high linear energy transfer radiation. These particle therapy advantages are unfortunately not thoroughly exploited due to particle range uncertainties. The possibility to monitor the compliance between the ongoing and prescribed dose distribution is a crucial step toward new optimizations in treatment planning and adaptive therapy. The Positron Emission Tomography (PET) is an established quantitative 3D imaging technique for particle treatment verification and, among the isotopes used for PET imaging, the 11C has gained more attention from the scientific and clinical communities for its application as new radioactive projectile for particle therapy. This is an interesting option clinically because of an enhanced imaging potential, without dosimetry drawbacks; technically, because the stable isotope 12C is successfully already in use in clinics. The MEDICIS-Promed network led an initiative to study the possible technical solutions for the implementation of 11C radioisotopes in an accelerator-based particle therapy center. We present here the result of this study, consisting in a Technical Design Report for a 11C Treatment Facility. The clinical usefulness is reviewed based on existing experimental data, complemented by Monte Carlo simulations using the FLUKA code. The technical analysis starts from reviewing the layout and results of the facilities which produced 11C beams in the past, for testing purposes. It then focuses on the elaboration of the feasible upgrades of an existing 12C particle therapy center, to accommodate the production of 11C beams for therapy. The analysis covers the options to produce the 11C atoms in sufficient amounts (as required for therapy), to ionize them as required by the existing accelerator layouts, to accelerate and transport them to the irradiation rooms. The results of the analysis and the identified challenges define the possible implementation scenario and timeline.
Multi-Site Observational Study to Assess Biomarkers for Susceptibility or Resilience to Chronic Pain: The Acute to Chronic Pain Signatures (A2CPS) Study Protocol
Authors: Berardi Giovanni , Frey-Law Laura , Sluka Kathleen A. , Bayman Emine O. , Coffey Christopher S. , Ecklund Dixie , Vance Carol G. T. , Dailey Dana L. , Burns John , Buvanendran Asokumar , McCarthy Robert J. , Jacobs Joshua , Zhou Xiaohong Joe , Wixson Richard , Balach Tessa , Brummett Chad M. , Clauw Daniel , Colquhoun Douglas , Harte Steven E. , Harris Richard E. , Williams David A. , Chang Andrew C. , Waljee Jennifer , Fisch Kathleen M. , Jepsen Kristen , Laurent Louise C. , Olivier Michael , Langefeld Carl D. , Howard Timothy D. , Fiehn Oliver , Jacobs Jon M. , Dakup Panshak , Qian Wei-Jun , Swensen Adam C. , Lokshin Anna , Lindquist Martin , Caffo Brian S. , Crainiceanu Ciprian , Zeger Scott , Kahn Ari , Wager Tor , Taub Margaret , Ford James , Sutherland Stephani P. , Wandner Laura D.
Published: April 2022

Chronic pain has become a global health problem contributing to years lived with disability and reduced quality of life. Advances in the clinical management of chronic pain have been limited due to incomplete understanding of the multiple risk factors and molecular mechanisms that contribute to the development of chronic pain. The Acute to Chronic Pain Signatures (A2CPS) Program aims to characterize the predictive nature of biomarkers (brain imaging, high-throughput molecular screening techniques, or “omics,” quantitative sensory testing, patient-reported outcome assessments and functional assessments) to identify individuals who will develop chronic pain following surgical intervention. The A2CPS is a multisite observational study investigating biomarkers and collective biosignatures (a combination of several individual biomarkers) that predict susceptibility or resilience to the development of chronic pain following knee arthroplasty and thoracic surgery. This manuscript provides an overview of data collection methods and procedures designed to standardize data collection across multiple clinical sites and institutions. Pain-related biomarkers are evaluated before surgery and up to 3 months after surgery for use as predictors of patient reported outcomes 6 months after surgery. The dataset from this prospective observational study will be available for researchers internal and external to the A2CPS Consortium to advance understanding of the transition from acute to chronic postsurgical pain.
Use of a Serious Game to Teach Infectious Disease Management in Medical School: Effectiveness and Transfer to a Clinical Examination
Authors: Aster Alexandra , Scheithauer Simone , Middeke Angélina Charline , Zegota Simon , Clauberg Sigrid , Artelt Tanja , Schuelper Nikolai , Raupach Tobias
Published: April 2022

Purpose

Physicians of all specialties must be familiar with important principles of infectious diseases, but curricular time for this content is limited and clinical teaching requires considerable resources in terms of available patients and teachers. Serious games are scalable interventions that can help standardize teaching. This study assessed whether knowledge and skills acquired in a serious game translate to better performance in a clinical examination.

Methods

Fifth-year undergraduate medical students (n = 100) at Goettingen Medical School were randomized to three groups receiving different levels of exposure to virtual patients presenting with signs and symptoms of either infective endocarditis or community-acquired pneumonia in a serious game simulating an accident and emergency department. Student performance was assessed based on game logfiles and an objective standardized clinical examination (OSCE).

Results

Higher exposure to virtual patients in the serious game did not result in superior OSCE scores. However, there was good agreement between student performance in the OSCE and in game logfiles (r = 0.477, p = 0.005). An Item Response Theory analysis suggested that items from the serious game covered a wider range of ability, thus better differentiating between students within a given cohort.

Conclusion

Repeated exposure to virtual patients with infectious diseases in a serious game did not directly impact on exam performance but game logfiles might be good and resource-sparing indicators of student ability. One advantage of using serious games in medical education is standardized content, a lower inhibition threshold to learn, and a need of less staff time compared to small-group clinical teaching.
Patients With Infantile Nephropathic Cystinosis in Germany and Austria: A Retrospective Cohort Study
Authors: O'Connell Nina , Oh Jun , Arbeiter Klaus , Büscher Anja , Haffner Dieter , Kaufeld Jessica , Kurschat Christine , Mache Christoph , Müller Dominik , Patzer Ludwig , Weber Lutz T. , Tönshoff Burkhard , Weitz Marcus , Hohenfellner Katharina , Pape Lars
Published: April 2022

Background

Infantile nephropathic cystinosis (INC) is a rare lysosomal storage disorder resulting in progressive chronic kidney disease (CKD) and a variety of extrarenal manifestations. This orphan disease remains a challenge for patients, their families and health care providers. There is currently no comprehensive study on patients' clinical course in Germany and Austria.

Methods

A retrospective cohort study including 74 patients at eleven centers of care was conducted. Data on time of diagnosis, CKD stage, leukocyte cystine levels (LCL), extrarenal manifestations, and treatment was collected from medical charts and subsequently analyzed using explorative statistics. Age at initiation of kidney replacement therapy (KRT) was evaluated by Kaplan–Meier analyses for different groups of patients.

Results

Patients were diagnosed at a median age of 15 months (IQR: 10–29, range: 0–110), more recent year of birth was not associated with earlier diagnosis. Oral cystine-depleting therapy (i.e., cysteamine) was prescribed at a median dose of 1.26 g/m2 per day (IQR: 1.03–1.48, range: 0.22–1.99). 69.2% of all 198 LCL measurements of 67 patients were within the desired target range (≤ 1 nmol cystine/mg protein). Median time-averaged LCLs per patient (n = 65) amounted to 0.57 nmol cystine/mg protein (IQR: 0.33–0.98, range: 0.07–3.13) when considering only values at least 1 year after initiation of therapy. The overall median height of 242 measurements of 68 patients was at the 7th percentile (IQR: 1–25, range: 1–99). 40.5% of the values were ≤ the 3rd percentile. Patient sex and year of birth were not associated with age at initiation of KRT, but patients diagnosed before the age of 18 months required KRT significantly later than those patients diagnosed at the age of ≥ 18 months (p = 0.033): median renal survival was 21 years (95% CI: 16, -) vs. 13 years (95% CI, 10, -), respectively.

Conclusion

Early diagnosis and initiation of cystine depleting therapy is important for renal survival in children with INC. Cysteamine doses and LCL showed that treatment in this cohort met international standards although there is great interindividual variety. Patient growth and other aspects of the disease should be managed more effectively in the future.
Identification and Analysis of SARS-CoV-2 Alpha Variants in the Largest Taiwan COVID-19 Outbreak in 2021
Authors: Liu Li-Teh , Tsai Jih-Jin , Chang Ko , Chen Chun-Hong , Lin Ping-Chang , Tsai Ching-Yi , Tsai Yan-Yi , Hsu Miao-Chen , Chuang Wan-Long , Chang Jer-Ming , Hwang Shang-Jyh , Chong Inn-Wen
Published: April 2022

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is believed to have originated in Wuhan City, Hubei Province, China, in December 2019. Infection with this highly dangerous human-infecting coronavirus via inhalation of respiratory droplets from SARS-CoV-2 carriers results in coronavirus disease 2019 (COVID-19), which features clinical symptoms such as fever, dry cough, shortness of breath, and life-threatening pneumonia. Several COVID-19 waves arose in Taiwan from January 2020 to March 2021, with the largest outbreak ever having a high case fatality rate (CFR) (5.95%) between May and June 2021. In this study, we identified five 20I (alpha, V1)/B.1.1.7/GR SARS-CoV-2 (KMUH-3 to 7) lineage viruses from COVID-19 patients in this largest COVID-19 outbreak. Sequence placement analysis using the existing SARS-CoV-2 phylogenetic tree revealed that KMUH-3 originated from Japan and that KMUH-4 to KMUH-7 possibly originated via local transmission. Spike mutations M1237I and D614G were identified in KMUH-4 to KMUH-7 as well as in 43 other alpha/B.1.1.7 sequences of 48 alpha/B.1.1.7 sequences deposited in GISAID derived from clinical samples collected in Taiwan between 20 April and July. However, M1237I mutation was not observed in the other 12 alpha/B.1.1.7 sequences collected between 26 December 2020, and 12 April 2021. We conclude that the largest COVID-19 outbreak in Taiwan between May and June 2021 was initially caused by the alpha/B.1.1.7 variant harboring spike D614G + M1237I mutations, which was introduced to Taiwan by China Airlines cargo crew members. To our knowledge, this is the first documented COVID-19 outbreak caused by alpha/B.1.1.7 variant harboring spike M1237I mutation thus far. The largest COVID-19 outbreak in Taiwan resulted in 13,795 cases and 820 deaths, with a high CFR, at 5.95%, accounting for 80.90% of all cases and 96.47% of all deaths during the first 2 years. The high CFR caused by SARS-CoV-2 alpha variants in Taiwan can be attributable to comorbidities and low herd immunity. We also suggest that timely SARS-CoV-2 isolation and/or sequencing are of importance in real-time epidemiological investigations and in epidemic prevention. The impact of D614G + M1237I mutations in the spike gene on the SARS-CoV-2 virus spreading as well as on high CFR remains to be elucidated.
The Long-Term Outcome in a Cohort of 52 Patients With Symptomatic Intramedullary Spinal Cavernous Hemangioma After Microsurgery and Emergency Rescue Surgery
Authors: Duan Yu , Mao Renling , Qin Xuanfeng , Liao Yujun , Li Jian , Chen Gong
Published: April 2022

Background

Surgery is the mainstay treatment for patients with symptomatic intramedullary spinal cavernous hemangioma (ISCH), however the time of surgical intervention remains controversial. In this study, we proposed emergency rescue surgery (ERS) for patients in deteriorative type. The prognostic factors of patients with ISCH after microsurgery and the clinical effect of ERS were analyzed.

Methods

From January 2013 to November 2019, 52 patients with symptomatic ISCH treated by microsurgical treatment were collected, ranging in age from 17 to 66 years old (mean: 45.8 ± 13.5 years). The course of the disease ranged from 2 days to 20 years. Of 52 lesions, 17 lesions were in the cervical segment, 25 in the thoracic segment, and 10 in the lumbosacral segment; while seven cases were at the ventral surface, 25 cases at the dorsal surface, and 20 cases at the central spinal cord. The sagittal diameter ranged from 1 to 58 mm (median: 17.3 mm). The transverse diameter ratio ranged from 20 to 80% (median: 50.7%). Thirty-two patients were diagnosed as deteriorative type and 22 were treated by ERS.

Results

At 12 months after surgery, all patients were followed up, and no residual or recurrence was found in all patients. Twenty-five patients (48.1%) showed spinal cord functional improvement after surgery; 25 (48.1%) had no functional change; 2 (3.8%) got worse. For deteriorative patients, ERS group had a significantly higher improvement rate than the non-ERS group (χ2 = 5.393, P = 0.02); For all 52 patients, the factors as a lesion at the ventral surface (Z = 10.453, P = 0.015), or lumbosacral segment (χ2 = 9.259, P = 0.010) and longer course of disease (Z = −2.021, P = 0.043) were potential risks in functional recovery in univariate analysis; and in multiple-factor analysis, the lesion at the lumbosacral segment (OR = 4.004, 95% CI: 1.341~11.961, P = 0.013) was the independent risk factors for the functional recovery.

Conclusions

Microsurgical resection is safe and effective for symptomatic ISCH. The ERS is an effective way to improve deteriorative patients' spinal cord function at long-term follow-up. The lesion at the lumbosacral segment is one of the poor prognostic factors.
Effect of Psychological Intervention on Pelvic Floor Function and Psychological Outcomes After Hysterectomy
Authors: Xie Meilian , Huang Xin , Zhao Shan , Chen Yingtong , Zeng Xiuqun
Published: April 2022

Background

Hysterectomy is one of the most frequently performed operations worldwide. However, postoperative complications and body image changes may induce psychological distress after hysterectomy. The study aimed to evaluate the effect of psychological intervention on pelvic floor function and psychological outcomes following hysterectomy among patients with benign indications.

Methods

Ninety-nine patients underwent hysterectomy were randomly divided into intervention group (n = 50) and control group (n = 49). Patients in the control group received routine postoperative nursing care, while extra psychological intervention was provided to patients in the intervention group, including psychological support, regular lectures and family support. After 6 months, patient's psychological statuses were assessed by Generalized Anxiety Disorder scale (GAD-7) and Patient Health Questionnaire-9 (PHQ-9). The pelvic floor function of patients was evaluated using Pelvic Floor Impact Questionnaire (PFIQ-7) and Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). Furthermore, the incidence of postoperative complications, including uracratia, pelvic organ prolapses, sexual dysfunction and chronic pelvic pain, was evaluated.

Results

After 6-month intervention, the GAD-7 and PHQ-9 scores were significantly decreased in the intervention group (p < 0.001 and p = 0.018 respectively). Both scored were significantly lower than that in the control group (p < 0.001 and p < 0.001). Compared with control group, the incidence of uracratia, pelvic organ prolapse, sexual dysfunction and chronic pelvic pain for intervention group was significantly lower (p = 0.003, p = 0.027, p = 0.001, p = 0.002 respectively) and the pelvic floor muscle strength was significantly stronger (p = 0.001). Besides, the postoperative Urinary Incontinence Impact Questionnaire (UIQ-7), Pelvic Organ Prolapse Impact Questionnaire (POPIQ-7), and Colorectal-Anal Impact Questionnaire (CRAIQ-7) scores were significantly lower (p = 0.025, p = 0.04, p < 0.001) and PISQ-12 score was significantly higher in intervention group (p < 0.001).

Conclusion

Psychological intervention could effectively improve the psychological condition of patients with hysterectomy, which may facilitate patients' postoperative recovery in pelvic floor function. These findings emphasized the necessity of psychological intervention in routine postoperative nursing care.
Two-Round Treatment With Propidium Monoazide Completely Inhibits the Detection of Dead Campylobacter spp. Cells by Quantitative PCR
Authors: Okada Ayaka , Tsuchida Mizuki , Rahman Md. Matiur , Inoshima Yasuo
Published: April 2022

Campylobacter spp. are known as important foodborne gastroenteric pathogens worldwide. Campylobacter spp. can exist in a viable but non-culturable (VBNC) state under unsuitable environmental conditions, which is undetectable by conventional culture methods. Quantitative polymerase chain reaction (qPCR) can be used to detect VBNC Campylobacter spp.; however, both viable and dead bacteria are detected during qPCR and are indistinguishable. Propidium monoazide (PMA), which can only enter dead bacterial cells through a damaged cell wall/cell membrane, binds to DNA and inhibits qPCR. PMA treatment has been performed along with qPCR (PMA-qPCR) to detect viable bacteria. However, the efficacy of detection inhibition differed among studies, and PMA can potentially enter living cells after changes in cell membrane permeability. In this study, we optimized the PMA treatment method by conducting it before qPCR. Two-round PMA treatment completely inhibited the qPCR signals from dead cells, whereas single-round PMA treatment failed to facilitate this. An optimized PMA-qPCR method was developed using commercial chicken meat, and VBNC Campylobacter spp., which are undetectable using conventional culture-based methods, were successfully detected. In conclusion, this study presents a novel, efficient PMA treatment method for the detection of viable Campylobacter spp., including VBNC Campylobacter spp., in chicken meat. We believe that this method will aid the reliable risk assessment of commercial chicken meat.
Peptic Ulcer and Gastric Cancer: Is It All in the Complex Host–Microbiome Interplay That Is Encoded in the Genomes of “Us” and “Them”?
Authors: Nath Angitha N. , Retnakumar R. J. , Francis Ashik , Chhetri Prakash , Thapa Namrata , Chattopadhyay Santanu
Published: April 2022

It is increasingly being recognized that severe gastroduodenal diseases such as peptic ulcer and gastric cancer are not just the outcomes of Helicobacter pylori infection in the stomach. Rather, both diseases develop and progress due to the perfect storms created by a combination of multiple factors such as the expression of different H. pylori virulence proteins, consequent human immune responses, and dysbiosis in gastrointestinal microbiomes. In this mini review, we have discussed how the genomes of H. pylori and other gastrointestinal microbes as well as the genomes of different human populations encode complex and variable virulome–immunome interplay, which influences gastroduodenal health. The heterogeneities that are encrypted in the genomes of different human populations and in the genomes of their respective resident microbes partly explain the inconsistencies in clinical outcomes among the H. pylori-infected people.
From Metagenomics to Discovery of New Viral Species: Galium Leaf Distortion Virus, a Monopartite Begomovirus Endemic in Mexico
Authors: Guevara-Rivera Enrique A. , Rodríguez-Negrete Edgar A. , Aréchiga-Carvajal Elva T. , Leyva-López Norma E. , Méndez-Lozano Jesús
Published: April 2022

Begomoviruses (Family Geminiviridae) are a major group of emerging plant viruses worldwide. The knowledge of begomoviruses is mostly restricted to crop plant systems. Nevertheless, it has been described that non-cultivated plants are important reservoirs and vessels of viral evolution that leads to the emergence of new diseases. High-throughput sequencing (HTS) has provided a powerful tool for speeding up the understanding of molecular ecology and epidemiology of plant virome and for discovery of new viral species. In this study, by performing earlier metagenomics library data mining, followed by geminivirus-related signature single plant searching and RCA-based full-length viral genome cloning, and based on phylogenetic analysis, genomes of two isolates of a novel monopartite begomovirus species tentatively named Galium leaf distortion virus (GLDV), which infects non-cultivated endemic plant Galium mexicanum, were identified in Colima, Mexico. Analysis of the genetic structure of both isolates (GLDV-1 and GLDV-2) revealed that the GLDV genome displays a DNA-A-like structure shared with the new world (NW) bipartite begomoviruses. Nonetheless, phylogenetic analysis using representative members of the main begomovirus American clades for tree construction grouped both GLDV isolates in a clade of the monopartite NW begomovirus, Tomato leaf deformation virus (ToLDeV). A comparative analysis of viral replication regulatory elements showed that the GLDV-1 isolate possesses an array and sequence conservation of iterons typical of NW begomovirus infecting the Solanaceae and Fabaceae families. Interestingly, GLDV-2 showed iteron sequences described only in monopartite begomovirus from OW belonging to a sweepovirus clade that infects plants of the Convolvulaceae family. In addition, the rep iteron related-domain (IRD) of both isolates display FRVQ or FRIS amino acid sequences corresponding to NW and sweepobegomovirus clades for GMV-1 and GMV-2, respectively. Finally, the lack of the GLDV DNA-B segment (tested by molecular detection and biological assays using GLDV-1/2 infectious clones) confirmed the monopartite nature of GLDV. This is the first time that a monopartite begomovirus is described in Mexican ecosystems, and “in silico” geometagenomics analysis indicates that it is restricted to a specific region. These data revealed additional complexity in monopartite begomovirus genetics and geographic distribution and highlighted the importance of metagenomic approaches in understanding global virome ecology and evolution.