bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical efficacy of anti-vascular endothelial growth factor versus panretinal photocoagulation for patients with proliferative diabetic retinopathy
Authors: Lin Yuxian , Zheng Xiaowei , Chen QiuJie , Wu Ruibin
Published: April 2021

Background:

The argument on the optimal treatment for patients with proliferative diabetic retinopathy (PDR) remains to be resolved. Therefore, the primary objective of the present study was to evaluate the clinical efficacy of anti-vascular endothelial growth factor (anti-VEGF) therapy versus panretinal photocoagulation (PRP) for patients with PDR.

Methods:

Two independent investigators followed The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines and the recommendations of the Cochrane Collaboration to conduct this meta-analysis. The electronic databases of EMBASE, PubMed, Cochrane Library, and Web of Science were searched from the inception to April 2021 using the following key terms: “proliferative diabetic retinopathy,” “anti-vascular endothelial growth factor,” and “panretinal photocoagulation,” for all relevant studies. We identified literature that met the following inclusion criteria: patients with PDR; studies focusing on assessing anti-VEGF therapy and PRP; the following outcome measures must be shown: anatomical outcomes, including complete regression and recurrence of neovascularization, mean change in best corrected vision acuity from baseline to the end of follow-up period. The Cochrane risk of bias tool was used to evaluate the risk of bias of included randomized clinical trials by 2 independent reviewers.

Results:

This protocol will provide a reliable theoretical basis for the following research.

Trial registration number:

10.17605/OSF.IO/UHYDR.
Meta-analysis of association of microRNAs genetic variants with susceptibility to rheumatoid arthritis and systemic lupus erythematosus
Authors: Liu Fengzhen , Liang Yahang , Zhao Yu , Chen Lili , Wang Xiaolin , Zhang Chunquan
Published: April 2021

Background:

An increasing body of studies has investigated that genetic polymorphisms in microRNA (miRNA) may be related to susceptibility to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, some results remain controversial. Thus, a meta-analysis was embarked on assessing whether some miRNA polymorphisms are associated with the risk of RA and SLE.

Methods:

Relevant studies were acquired on PubMed, Web of Science, Cochrane Library, CNKI, and Embase electronic databases from inception to December 2019. The strength of the association of miRNA polymorphisms with the risk of RA and SLE was assessed by odds ratios (ORs) and 95% confidence intervals (CIs).

Results:

Eligible 20 articles (36 studies) involving 5 miRNAs were enrolled in the meta-analysis. For RA, the polled result showed that there was no significant relationship between miR-146a rs2910164 and RA, but subgroup analysis based on ethnicity demonstrated that CC genotype may be a genetic protect factor for RA in Caucasians (CC vs CG+GG, OR = 0.825, 95% CI: 0.684–0.996, Pz = .045, Ph = .166). Besides, statistical significance of miR-499 rs3746444 (T/C) with susceptibility to RA was observed as well in the overall population, and the association was only significant in Caucasians but not Asians. For SLE, the associations of miR-146a rs2431697 T allele/T-carrier with increased risk of SLE were observed.

Conclusions:

Our results highlight that miR-499 rs3746444 may contribute to RA susceptibility, particularly in Caucasians. In addition, CC genotype in miR-146a rs2910164 may act as a protector of RA in Caucasians. For SLE, miR-146a rs2431697 (C/T) is most likely to the increased the risk of SLE. These findings do not support the genetic association between miR-196a2 rs11614913 and RA/SLE susceptibility, as well as the association of miR-146a rs2910164, miR-146a rs57095329, miR-499 rs3746444 with SLE.
Noninvasive papillary urothelial carcinoma with pathological features in between low and high grades
Authors: Ma Shuang , Han Yang , Zhang Di , Li Qingchang , Wang Enhua , Wu Guangping , Zhao Huanyu
Published: April 2021

Rationale:

Urinary bladder urothelial carcinoma is the most common malignant tumor in the urinary system, and noninvasive papillary urothelial carcinoma (NIPUC) comprises most bladder malignancies. NIPUC grading is important for therapeutic and clinical protocol selection. Here, we report a case of NIPUC with pathological features in between low (LG-NIPUC) and high (HG-NIPUC) grades NIPUC.

Patient concerns:

A 72-year-old male, presenting with a 20-year history of hypertension and 5 months of hematuria.

Diagnoses:

Computed tomography examination revealed a tumor in the urinary bladder neck. Microscopic investigation revealed that most tumor tissue samples had a branching papillary architecture, with well-developed fibrous-vascular cores. Tumor cells were slightly crowded, with somewhat altered cell polarity and cell adhesion. Immunohistochemistry showed positive Ki67 staining, mostly in the basal layer, while p53 staining was rarely positive. These samples were diagnosed as LG-NIPUC. However, a few tumor tissue samples presented mildly fused papillary architectures without cell polarity or adhesion. Most nuclei stained intensely and were pleomorphic. All epithelial tissue layers were ki67 positive, and the p53 positive rate was higher than that in the LG samples. Therefore, these were classified as HG-NIPUC.

Interventions:

The tumor was completely resected during lithotomy postural surgery.

Outcomes:

The patient is alive with a good recovery during 3 months after the surgery.

Lessons:

We diagnosed this patient as having LG-NIPUC with local HG-NIPUC components. HG- and LG-HIPUC have different outcomes. This case is a new challenge for the pathological grading of NIPUC. An intermediate HIPUC grade might need to be added to the original NIPUC grading system.
Lumbosacral plexopathy due to pelvic hematoma after extracorporeal membrane oxygenation
Authors: Wilks Anson W. , Al-Lozi Muhammad T.
Published: April 2021

Rationale:

Peripheral nerve injury related to vascular complications associated with extracorporeal membrane oxygenation (ECMO) is perhaps underappreciated. Compared to the well-described central nervous system complications of ECMO, brachial plexopathy and lumbosacral plexopathy have rarely been reported. We report this case to heighten awareness of lumbosacral plexus injury due to pelvic hematoma formation after ECMO.

Patient concerns:

A 53-year-old woman developed a large pelvic hematoma with significant mass effect on intrapelvic structures after receiving lifesaving venoarterial ECMO for cardiogenic shock following a cardiac arrest. During her hospital course, she developed bilateral foot drop that was attributed to critical illness. Her lack of neurological recovery after 6 months prompted referral to neuromuscular medicine for consultation.

Diagnosis:

The patient was retrospectively diagnosed with bilateral lumbosacral plexopathy due to the large pelvic hematoma.

Intervention:

Electromyography/nerve conduction study (EMG/NCS) obtained at the time of referral to neuromuscular medicine localized her neurological deficits to the bilateral lumbosacral plexus and demonstrated no volitional motor unit action potentials in her lower leg muscles.

Outcomes:

The patient had minimal recovery of strength at the level of the ankles but was ambulatory with solid ankle–foot orthoses due to spared proximal lower extremity strength. Unfortunately, the absence of any volitionally activated motor unit action potentials in her lower leg muscles on EMG performed 6 months after the initial injury was a poor prognostic indicator for successful reinnervation and future neurological recovery.

Lessons:

Neurological deficits occurring during the course of administration of ECMO require accurate localization. Neurology consultation and/or EMG/NCS may be useful if localization is not clear. Lesions localizing to the lumbosacral plexus should prompt radiographic evaluation with computed tomography of the abdomen and pelvis. Hemostasis of a retroperitoneal hematoma may be achieved with embolization. However, if neurological deficits do not improve, surgical consultation for hematoma evacuation may be warranted.
Personalized three-dimensional printed polyether-ether-ketone prosthesis for reconstruction after subtotal removal of chronic clavicle osteomyelitis
Authors: Chen Chang , Yin Yiran , Xu Huan , Li Zhong , Wang Fuyou , Chen Ge
Published: April 2021

Rationale:

Three-dimensional (3D) printing has attracted wide attention for its potential and abilities in the assistance of surgical planning and the development of personalized prostheses. We herewith report a unique case of chronic clavicle osteomyelitis treated with a two-stage subtotal clavicle reconstruction using a 3D printed polyether-ether-ketone (PEEK) prosthesis.

Patient concerns:

A 23-year-old Chinese female presented to our clinic complaining about a progressive pain of her right clavicle for about 1 year.

Diagnoses:

Chronic clavicle osteomyelitis confirmed by percutaneous biopsy and lesion biopsy.

Interventions:

This patient accepted a long-term conservative treatment, which did not gain satisfactory outcomes. Thus, a subtotal removal and two-stage reconstruction of the right clavicle with a 3D-printed polyether-ether-ketone prosthesis stabilized by screw fixation system was performed.

Outcomes:

At 2-year follow-up, complete pain relief and satisfactory functional recovery of her right shoulder were observed.

Lessons:

Personalized 3D printed prosthesis is an effective and feasible method for reconstruction of complex bone defects.
Moxibustion for diarrhea in children
Authors: Li Peiling , Chi Zhenhai , You Jianyu , Deng Gen , Zhou Xingchen , Mao Qiangjian , Pan Zefeng
Published: April 2021

Background:

Infantile Diarrhea is a common and frequent digestive tract disease in children. The causes of this disease are relatively complex and the onset time is relatively long. At present, there is no specific treatment method in Western medicine. Moxibustion is a simple and painless external treatment. However, due to the lack of high-quality evidence to support the effectiveness and safety of moxibustion therapy for pediatric diarrhea. Therefore, the purpose of this study is to verify the effectiveness and safety of moxibustion in the treatment of pediatric diarrhea.

Methods:

We will use PubMed, Cochrane Library, Wan Fang Database, Web of Science, China National Knowledge Infrastructure Database, Chinese Science Journal Database, China Biomedical Literature Database to carry out a progressive search of diseases. The study will be screened according to eligibility criteria, and quality of the study will be assessed by using the Cochrane Risk of Bias Tool.

Results:

Through this study, we will systematically evaluate the effectiveness and safety of moxibustion in the treatment of pediatric diarrhea.

Conclusion:

The results of this study will provide reliable evidence of the safety and effectiveness of moxibustion in the treatment of infantile diarrhea, and provide a therapeutic basis for the future clinical application.

Ethics and dissemination:

Since this paper does not involve ethical issues, it does not need to pass the review of the ethics committee. It can only collect relevant literature and study.

INPLASY Registration number:

INPLASY202130091
Mining immune-related genes with prognostic value in the tumor microenvironment of breast invasive ductal carcinoma
Authors: He Qiang , Xue Shuyin , Wa Qingbiao , He Mei , Feng Shuang , Chen Zhibing , Chen Wei , Luo Xinrong
Published: April 2021

The tumor microenvironment (TME) plays an important role in the development of breast cancer. Due to limitations in experimental conditions, the molecular mechanism of TME in breast cancer has not yet been elucidated. With the development of bioinformatics, the study of TME has become convenient and reliable.

Gene expression and clinical feature data were downloaded from The Cancer Genome Atlas database and the Molecular Taxonomy of Breast Cancer International Consortium database. Immune scores and stromal scores were calculated using the Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data algorithm. The interaction of genes was examined with protein-protein interaction and co-expression analysis. The function of genes was analyzed by gene ontology enrichment analysis, Kyoto Encyclopedia of Genes and Genomes analysis and gene set enrichment analysis. The clinical significance of genes was assessed with Kaplan-Meier analysis and univariate/multivariate Cox regression analysis.

Our results showed that the immune scores and stromal scores of breast invasive ductal carcinoma (IDC) were significantly lower than those of invasive lobular carcinoma. The immune scores were significantly related to overall survival of breast IDC patients and both the immune and stromal scores were significantly related to clinical features of these patients. According to the level of immune/stromal scores, 179 common differentially expressed genes and 5 hub genes with prognostic value were identified. In addition, the clinical significance of the hub genes was validated with data from the molecular taxonomy of breast cancer international consortium database, and gene set enrichment analysis analysis showed that these hub genes were mainly enriched in signaling pathways of the immune system and breast cancer.

We identified five immune-related hub genes with prognostic value in the TME of breast IDC, which may partly determine the prognosis of breast cancer and provide some direction for development of targeted treatments in the future.
Comparison of severe pediatric complicated influenza patients with and without neurological involvement
Authors: Lin Chien-Heng , Chen Chieh-Ho , Hong Syuan-Yu , Lin Sheng-Shing , Chou I-Ching , Lin Hsiao-Chuan , Chang Jeng-Sheng
Published: April 2021

Although influenza is generally an acute, self-limited, and uncomplicated disease in healthy children, it can result in severe morbidity and mortality. The objectives of this study were to analyze and compare the clinical features and outcome of severe pediatric influenza with and without central nervous system (CNS) involvement.

We conducted a retrospective observational study of children admitted to the pediatric intensive care unit (PICU) of China Medical University Children's Hospital in Taiwan with a confirmed diagnosis of influenza. The demographic data, clinical and laboratory presentations, therapeutic strategies, and neurodevelopmental outcomes for these patients were analyzed. Furthermore, comparison of patients with and without CNS involvement was conducted.

A total of 32 children with severe influenza were admitted during the study periods. Sixteen children were categorized as the non-CNS (nCNS) group and 16 children were categorized as the CNS group. Nine of them had underlying disease. The most common complication in the nCNS group was acute respiratory distress syndrome, (n = 8/16), followed by pneumonia (n = 7/16, 44%). In the CNS group, the most lethal complication was acute necrotizing encephalopathy (n = 3/16) which led to 3 deaths. The overall mortality rate was higher in the CNS group (n = 6) than in the nCNS group (n = 1) (37.5% vs 6.25%,P = .03).

The mortality rate of severe complicated influenza was significantly higher with CNS involvement. Children with primary cardiopulmonary abnormalities were at high risk of developing severe complicated influenza, while previously healthy children exhibited risk for influenza-associated encephalitis/encephalopathy.
PRISMA: accuracy of response entropy and bispectral index to predict the transition of consciousness during sevoflurane anesthesia
Authors: Liang Tao , Wu Fan , Wang Baoguo , Mu Feng
Published: April 2021

Background:

Bispectral index (BIS) and response entropy (RE) are used to monitor the depth of anesthesia.

Objectives:

To collect published data and compare the accuracy of BIS and RE in detecting the transition of consciousness during sevoflurane anesthesia.

Data sources:

Studies indexed in the PubMed, Embase, or Cochrane databases.

Study eligibility criteria:

Participants:

Patients who need to use BIS and RE to monitor sevoflurane anesthesia depth simultaneously.

Interventions:

A random-effects model was fitted using RevMan 5.3. Subgroup analyses were performed on patient age. The Cochrane I

2
methodology was used to determine the heterogeneity of the statistical results, while GRADE Pro served to assess the quality of evidence.

Results:

Overall, 195 articles were identified, of which 7 were finally included. The meta-analysis results showed that BIS is more accurate than RE in predicting loss of consciousness (LOC) during sevoflurane anesthesia (MD, .06; 95% confidence interval [CI], .02–.09; P = .009; I

2
 = 92%). In contrast, there was no significant difference between BIS and RE for recovery of consciousness (ROC; MD, .01; 95% CI, .00–.02; P = .79; I

2
 = 83%). Subgroup analyses revealed no significant differences in LOC (MD, .02; 95% CI, .01–.05; P = .13; I

2
 = 60%) and ROC (MD, −.01; 95% CI, −.06–.04; P = .58; I

2
 = 95%) in children. However, the results in adults demonstrated that BIS is more accurate than RE in predicting LOC (MD, −.07; 95% CI, .05–.10; P = .002; I

2
 = 76%).

Limitations:

First, this meta-analysis was affected by a large study heterogeneity. Second, this analysis only included publications in English, therefore, some studies may have been omitted.

Conclusion:

BIS is more accurate than RE in predicting LOC during sevoflurane anesthesia in adults. However, no significant differences were identified in children.

Registration number (PROSPERO):

CRD42020163119
Early blood pH as an independent predictor of neurological outcome in patients with out-of-hospital cardiac arrest
Authors: Lin Chin-Han , Yu Shao-Hua , Chen Chih-Yu , Huang Fen-Wei , Chen Wei-Kung , Shih Hong-Mo
Published: April 2021

Metabolic acidosis is observed in 98% of patients with out-of-hospital cardiac arrest (OHCA). The longer the no-flow or low-flow duration, the more severe is the acidosis in these patients. This study explored whether blood pH in early stages of advanced life support (ALS) was an independent predictor of neurological prognosis in patients with OHCA.

We retrospectively enrolled patients with OHCA from January 2012 to June 2018 in a single-medical tertiary hospital in Taiwan. Patients with OHCA whose blood gas analyses within 5 minutes after receiving ALS at the emergency department (ED) were enrolled. Patients younger than 20 years old, with cardiac arrest resulting from traumatic or circumstantial causes, with return of spontaneous circulation (ROSC) before ED arrival, lacking record of initial blood gas analysis, and with do-not-resuscitate orders were excluded. The primary outcome of this study was neurological status at hospital discharge.

In total, 2034 patients with OHCA were enrolled. The majority were male (61.89%), and the average age was 67.8 ± 17.0 years. Witnessed OHCA was noted in 571 cases, cardiopulmonary resuscitation was performed before paramedic arrival in 512 (25.2%) cases, and a shockable rhythm was observed in 269 (13.2%). Blood pH from initial blood gas analysis remained an independent predictor of neurological outcome after multivariate regression.

Blood pH at early stages of ALS was an independent prognostic factor of post-OHCA neurological outcome. Blood gas analysis on arrival at the ED may provide additional information about the prognosis of patients with OHCA.
Sudden Death After Electroconvulsive Therapy in the Context of Coronavirus Disease 2019
Authors: Hillow Mohamed Aden , Kwobah Edith Kamaru , Gakinya Benson , Omari Felicita
Published: April 2021

Electroconvulsive therapy (ECT) has been demonstrated to be a safe and effective treatment modality for a range of psychiatric illnesses. It is shown to be useful in the management of psychotic disorders for decades, more so in the treatment of refractory schizophrenia when given with antipsychotic medications. We highlight a case of a 37-year-old lady who was on treatment for refractory schizophrenia for the past 10 years but had continued to exhibit residual psychotic symptoms of auditory hallucinations and persecutory delusions that resulted in numerous in-patient admissions. She was initiated on ECT but contracted the coronavirus disease 2019 (COVID-19) before she could receive her second session. After isolating for 2 weeks in a COVID-19–designated isolation ward and testing negative twice, she was rescheduled to continue with her ECT. Ten minutes after leaving theater upon successfully undergoing her second ECT session, she collapsed suddenly and died. An autopsy done later revealed pulmonary thromboembolism as the cause of death.

Conclusions

Although ECT is a safe procedure, caution should be exercised in the context of COVID-19, as it is now clear that patients who recovered from COVID-19 might have an undetected venous thromboembolism that can cause untoward outcomes.

Ethical Consideration

A written consent was obtained from the sister to the deceased patient.
Rapid macrolide and amikacin resistance testing for Mycobacterium abscessus in people with cystic fibrosis
Authors: Bordin Amanda , Pandey Sushil , Coulter Christopher , Syrmis Melanie , Pardo Carolyn , Hackett Hazel , Bell Scott C. , Wainwright Claire E. , Nimmo Graeme R. , Jennison Amy V. , Clark Julia E. , Whiley David M.
Published: April 2021

Introduction.

Mycobacterium abscessus

complex (MABSC) is an environmental organism and opportunistic pathogen. MABSC pulmonary infections in people with cystic fibrosis are of growing clinical concern. Resistance data guide the use of macrolides and amikacin in MABSC pulmonary disease treatment. MABSC can acquire resistance against macrolides or amikacin via 23S or 16S rRNA gene mutations, respectively.

Gap Statement. Current culture-based methods for MABSC detection and antibiotic resistance characterization are typically prolonged, limiting their utility to directly inform treatment or clinical trials. Culture-independent molecular methods may help address this limitation.

Aim. To develop real-time PCR assays for characterization of key 23S or 16S rRNA gene mutations associated with constitutive resistance in MABSC.

Methodology. We designed two real-time PCR assays to detect the key 23S and 16S rRNA gene mutations. The highly conserved nature of rRNA genes was a major design challenge. To reduce potential cross-reactivity, primers included non-template bases and targeted single-nucleotide polymorphisms unique to MABSC. We applied these assays, as well as a previously developed real-time PCR assay for MABSC detection, to 968 respiratory samples from people with cystic fibrosis. The results from the molecular methods were compared to those for gold standard culture methods and 23S and 16S rRNA gene sequencing.

Results.The real-time PCR MABSC detection assay provided a sensitivity of 83.8 % and a specificity of 97.8 % compared to culture. The results from the real-time PCR resistance detection assays were mostly concordant (>77.4 %) with cultured isolate sequencing. The real-time PCR resistance detection assays identified several samples harbouring both resistant and susceptible MABSC, while culture-dependent methods only identified susceptible MABSC in these samples.

Conclusion. Using the molecular methods described here, results for health care providers or researchers could be available days or weeks earlier than is currently possible via culture-based antibiotic susceptibility testing.
Implementation of Rapid and Frequent SARS-CoV2 Antigen Testing and Response in Congregate Homeless Shelters
Authors: Aranda-Díaz Andrés , Imbert Elizabeth , Strieff Sarah , Graham-Squire Dave , Evans Jennifer L , Moore Jamie , McFarland Willi , Fuchs Jonathan , Handley Margaret A , Kushel Margot
Published: April 2021

Background

People experiencing homelessness who live in congregate shelters are at high risk of SARS-CoV2 transmission and severe COVID-19. Current screening and response protocols using rRT-PCR in homeless shelters are expensive, require specialized staff and have delays in returning results and implementing responses.

Methods

We piloted a program to offer frequent, rapid antigen-based tests (BinaxNOW) to residents and staff of congregate-living shelters in San Francisco, California, from January 15th to February 19th, 2021. We used the Reach-Effectiveness-Adoption-Implementation-Maintenance (RE-AIM) framework to evaluate the implementation.

Results

Reach

We offered testing at ten of twelve eligible shelters. Shelter residents and staff had variable participation across shelters; approximately half of eligible individuals tested at least once; few tested consistently during the study.

Effectiveness

2.2% of participants tested positive. We identified three outbreaks, but none exceeded 5 cases. All BinaxNOW-positive participants were isolated or left the shelters.

Adoption

We offered testing to all eligible participants within weeks of the project’s initiation.

Implementation

Adaptations made to increase reach and improve consistency were promptly implemented.

Maintenance

San Francisco Department of Public Health expanded and maintained testing with minimal support after the end of the pilot.

Conclusion

Rapid and frequent antigen testing for SARS-CoV2 in homeless shelters is a viable alternative to rRT-PCR testing that can lead to immediate isolation of infectious individuals. Using the RE-AIM framework, we evaluated and adapted interventions to enable the expansion and maintenance of protocols.
Evolving Phenotypes of non-hospitalized Patients that Indicate Long Covid
Authors: Estiri Hossein , Strasser Zachary H , Brat Gabriel A , Semenov Yevgeniy R ,   The Consortium for Characterization of COVID-19 by EHR (4CE), Patel Chirag J , Murphy Shawn N
Published: April 2021

For some SARS-CoV-2 survivors, recovery from the acute phase of the infection has been grueling with lingering effects. Many of the symptoms characterized as the post-acute sequelae of COVID-19 (PASC) could have multiple causes or are similarly seen in non-COVID patients. Accurate identification of phenotypes will be important to guide future research and help the healthcare system focus its efforts and resources on adequately controlled age- and gender-specific sequelae of a COVID-19 infection. In this retrospective electronic health records (EHR) cohort study, we applied a computational framework for knowledge discovery from clinical data, MLHO, to identify phenotypes that positively associate with a past positive reverse transcription-polymerase chain reaction (RT-PCR) test for COVID-19. We evaluated the post-test phenotypes in two temporal windows at 3-6 and 6-9 months after the test and by age and gender. Data from longitudinal diagnosis records stored in EHRs from Mass General Brigham in the Boston metropolitan area was used for the analyses. Statistical analyses were performed on data from March 2020 to June 2021. Study participants included over 96 thousand patients who had tested positive or negative for COVID-19 and were not hospitalized. We identified 33 phenotypes among different age/gender cohorts or time windows that were positively associated with past SARS-CoV-2 infection. All identified phenotypes were newly recorded in patients’ medical records two months or longer after a COVID-19 RT-PCR test in non-hospitalized patients regardless of the test result. Among these phenotypes, a new diagnosis record for anosmia and dysgeusia (OR: 2.60, 95% CI [1.94 - 3.46]), alopecia (OR: 3.09, 95% CI [2.53 - 3.76]), chest pain (OR: 1.27, 95% CI [1.09 - 1.48]), chronic fatigue syndrome (OR 2.60, 95% CI [1.22-2.10]), shortness of breath (OR 1.41, 95% CI [1.22 - 1.64]), pneumonia (OR 1.66, 95% CI [1.28 - 2.16]), and type 2 diabetes mellitus (OR 1.41, 95% CI [1.22 - 1.64]) are some of the most significant indicators of a past COVID-19 infection. Additionally, more new phenotypes were found with increased confidence among the cohorts who were younger than 65. Our approach avoids a flood of false positive discoveries while offering a more robust probabilistic approach compared to the standard linear phenome-wide association study (PheWAS). The findings of this study confirm many of the post-COVID symptoms and suggest that a variety of new diagnoses, including new diabetes mellitus and neurological disorder diagnoses, are more common among those with a history of COVID-19 than those without the infection. Additionally, more than 63 percent of PASC phenotypes were observed in patients under 65 years of age, pointing out the importance of vaccination to minimize the risk of debilitating post-acute sequelae of COVID-19 among younger adults.
Performance Decay of Molecular Assays Near the Limit of Detection: Probabilistic Modeling using Real-World COVID-19 Data
Authors: Durant Thomas J.S. , Koch Christopher D. , Kerantzas Christopher A. , Peaper David R.
Published: April 2021

The gold standard for diagnosis of COVID-19 is detection of SARS-CoV-2 RNA by RT-PCR. However, the effect of systematic changes in specimen viral burden on the overall assay performance is not quantitatively described. We observed decreased viral burdens in our testing population as the pandemic progressed, with median sample Ct values increasing from 22.7 to 32.8 from weeks 14 and 20, respectively. We developed a method using computer simulations to quantify the implications of variable SARS-CoV-2 viral burden on observed assay performance. We found that overall decreasing viral burden can have profound effects on assay detection rates. When real-world Ct values were used as source data in a bootstrap resampling simulation, the sensitivity of the same hypothetical assay decreased from 97.59 (95% CI 97.3-97.9) in week 12, to 74.42 (95% CI 73.9-75) in week 20. Furthermore, simulated assays with a 3-fold or 10-fold reduced sensitivity would both appear to be >95% sensitive early in the pandemic, but sensitivity would fall to 85.55 (95% CI 84.9-86.2) and 74.38 (95% CI 73.6-75.1) later in the pandemic, respectively. Our modeling approach can be used to better quantitate the impact that specimen viral burden may have on the clinical application of tests and specimens.
The SARS-CoV2 pandemic explained via asymptomatic infection and susceptibility heterogeneity. Buenos Aires first wave
Authors: Bullo Manuela , Poy-Piñeiro Santiago , Cosatto-Ammann Pedro , Seoane Hernan , Picasso Emilio
Published: April 2021

Background

The rapid global spread of SARS-COV-2 forced governments to implement drastic interventions. The existence of a large but undetermined number of mild or non-symptomatic but infectious cases seems to be involved in the rapid spread, creating a high level of uncertainty due to the difficulty to measure them, and difficulty for epidemiologic modelling.

Methods

We developed a compartmental model with deterministic equations, that accounts for clinical status, mobility, r heterogenous susceptibility and non-pharmaceutical interventions. The model was calibrated using data from different regions and we used it to predict the dynamic in Buenos Aires Metropolitan Area (AMBA).

Results

The model adjusted well to different geographical regions. In AMBA the model predicted 21400 deaths at 300 days, with 27% of the population in the region immunized after the first wave, partly due to the high incidence of asymptomatic cases. The mobility restriction is approximately linear, with any restriction bringing a positive effect. The other interventions have a combined effect of 27% reduction in infection rates.

Conclusion

Our research underlines the role of asymptomatic cases in the epidemics’ dynamic and introduces the concept of susceptibility heterogeneity as a potential explanation for otherwise unexplained outbreak dynamics. The model also shows the big role of non-pharmaceutical interventions both in slowing down the epidemic dynamics and in reducing the eventual number of deaths. The model results are closely compatible with observed data.
Resource sharing by outer membrane vesicles from a citrus pathogen
Authors: Araujo Gabriel G. , Conforte Matheus M. , Purificação Aline D. da , Todeschini Iris , Llontop Edgar E. , Angeli Claudia B. , Inague Alex , Yoshinaga Marcos Y. , de Souza Robson F. , Papai Rodrigo , Luz Maciel S. , Miyamoto Sayuri , Palmisano Giuseppe , Farah Chuck S. , Guzzo Cristiane R.
Published: April 2021

The causative agent of citrus canker disease,Xanthomonas citripv.citri, was found to produce copious amounts of outer membrane vesicles (OMVs), frequently forming long membranous tubes under different culture conditions. Lipidomic analysis revealed significant differences in lipid composition between purified vesicles in relation to whole cells. The results suggest an enrichment in saturated cardiolipins and a decrease in unsaturated lipids in the OMV samples, possibly granting them a more rigid structure while allowing their high degree of curvature caused by their small diameters. The vesicles’ proteome was found to be significantly enriched in TonB-dependent receptors related to the acquisition of different nutrients. These proteins are known to transport siderophores, which were evidenced to be present in purifiedX. citriOMVs, along with essential metals including iron, zinc, and manganese quantified by elemental analysis. The availability of vesicle-associated nutrients to be incorporated by cells was demonstrated by the use of OMVs as the sole carbon source for bacterial growth. At last, the vesicles also presented esterase and protease activities, which have been associated with virulence in phytopathogens. These evidences point thatX. citricells can use OMVs to share resources within microbial communities, which has potential implications for microbial interactions and plant colonization, affecting their survival and persistence on the host and in the environment.

Importance

The shedding of outer membrane vesicles appears to be universal in Gram-negative bacteria and effectively constitutes a unique secretion pathway for diverse molecules and proteins. To study their possible functions in the citrus pathogenXanthomonas citri, purified vesicles from this bacterium were studied by omics and functional approaches. Nutrient transporters were found associated to these structures, which were evidenced to contain siderophores and essential metals. The availability of these nutrients to be incorporated by cells was then demonstrated by showing that purified vesicles can be used as sole carbon sources for microbial growth. Additionally, the samples also presented esterase and protease activities which can contribute to the release of substrates from plant host tissues. These observations help to establish the developing idea of vesicles as shared bacterial resources which can participate in shaping host-associated microbial communities in contrast to other interactions such as bacterial competition.
Perceived and mentally rotated contents are differentially represented in cortical depth of V1
Authors: Iamshchinina Polina , Kaiser Daniel , Yakupov Renat , Haenelt Daniel , Sciarra Alessandro , Mattern Hendrik , Lüesebrink Falk , Duezel Emrah , Speck Oliver , Weiskopf Nikolaus , Cichy Radoslaw Martin
Published: April 2021

Primary visual cortex (V1) in humans is known to represent both veridically perceived external input and internally-generated contents underlying imagery and mental rotation. However, it is unknown how the brain keeps these contents separate thus avoiding a mixture of the perceived and the imagined which could lead to potentially detrimental consequences. Inspired by neuroanatomical studies showing that feedforward and feedback connections in V1 terminate in different cortical layers, we hypothesized that this anatomical compartmentalization underlies functional segregation of external and internally-generated visual contents, respectively. We used high-resolution layer-specific fMRI to test this hypothesis in a mental rotation task. We found that rotated contents were predominant at outer cortical depth bins (i.e. superficial and deep). At the same time perceived contents were represented stronger at the middle cortical bin. These results identify how through cortical depth compartmentalization V1 functionally segregates rather than confuses external from internally-generated visual contents. These results indicate that feedforward and feedback manifest in distinct subdivisions of the early visual cortex, thereby reflecting a general strategy for implementing multiple cognitive functions within a single brain region.
Heterogeneouspdgfrβ+cells regulate coronary vessel development and revascularization during heart regeneration
Authors: Kapuria Subir , Bai Haipeng , Fierros Juancarlos , Huang Ying , Ma Feiyang , Yoshida Tyler , Aguayo Antonio , Kok Fatma , Wiens Katie M. , Yip Joycelyn K. , McCain Megan L. , Pellegrini Matteo , Nagashima Mikiko , Hitchcock Peter F. , Lawson Nathan D. , Harrison Michael MR , Lien Ching-Ling
Published: April 2021

Endothelial cells emerge from the atrioventricular canal (AVC) to form nascent coronary blood vessels in the juvenile zebrafish heart. We found thatpdgfrβis first expressed in the epicardium around the AVC and later becomes localized mainly in the mural cells.pdgfrβmutant fish display severe defects in mural cell recruitment and coronary vessel development.pdgfrβ+mural cells are heterogeneous and those associated with coronary arteries also expresscxcl12b. Mural cells positive for bothpdgfrβandcxcl12btransgenic reporters had elevated expression of smooth muscle cell genes. Interestingly, these mural cells were associated with coronary arteries even in the absence of Pdgfrβ, although smooth muscle gene expression was downregulated in these cells. We found thatpdgfrβexpression dynamically changes in the epicardium derived cells, which we found to be a heterogeneous population.mdkawas identified as a gene upregulated in subpopulations ofpdgfrβ+ cells during heart regeneration. However,pdgfrβbut notmdkamutants showed defects in heart regeneration. Our results demonstrated thatpdgfrβ+cells and Pdgfrβ signaling are essential for coronary development and heart regeneration.

SUMMARY STATEMENT

Heterogeneouspdgfrβpositive cells are present in developing and regenerating zebrafish hearts and are required for development of mural cells and their association with the nascent coronary vessels during zebrafish heart development and regeneration.
Rab11 negatively regulates Wingless preventing JNK mediated apoptosis inDrosophilaepithelium during embryonic dorsal closure
Authors: Nandy Nabarun , Roy Jagat Kumar
Published: April 2021

Cell signaling pathways involved in epithelial wound healing, show a lot of complexities when it comes to their regulation. Remarkably, a large proportion of these signaling pathways are triggered at the time of morphogenetic events which usually involve epithelial sheet fusions during embryonic development, such as the event of dorsal cloure in Drosophila embryos. One such conserved pathway in the wound healing process is the JNK-Dpp signaling pathway. Recent observations suggest that one such upstream regulator of JNK mediated apoptosis could be Rab11, a small Ras like GTPase, which is functionally associated with the membrane and cortical cytoskeletal organization of epithelial cells. UsingDrosophilaembryonic dorsal closure as a model of wound healing, we observed that a targeted expression of aRab11loss of function mutant in the dorso-lateral epidermis of fly embryos (tissue which extends contra-laterally in order to fill the intervening gap) undergoing dorsal closure leads to an ectopic expression of Caspase-3 and a concomitant up-regulation of the JNK-Dpp signaling. This resulted in the death of the dorso-lateral epithelial cells with a consequent embryonic lethality due to dorsal closure defects. Interestingly, a simultaneous knockdown ofwingless(another developmentally conserved gene) inRab11mutants resulted in a rescue of the lethal phenotype and also a significant level of successful completion of the dorsal closure process. In our experiments we suggest Rab11 could promote cross talk between the JNK-Dpp pathway and the canonicalwinglesspathway in the regulation of apoptosis in the dorsolateral epithelium of fly embryos undergoing dorsal closure.

One Sentence Summary

Rab11 functions through a conserved Wingless mediated JNK-Dpp pathway during embryonic dorsal closure.
Lymphotoxin-alpha expression in the meninges causes lymphoid tissue formation and neurodegeneration
Authors: James Bates Rachel E , Browne Eleanor , Schalks Renee , Jacobs Heather , Tan Li , Parekh Puja , Magliozzi Roberta , Calabrese Massimiliano , Mazarakis Nicholas D. , Reynolds Richard
Published: April 2021

Lymphotoxin alpha (LTα) plays an important role in lymphoid organ development and cellular cytotoxicity in the immune system. LTα expression is increased in the cerebrospinal fluid of naïve and progressive multiple sclerosis (MS) patients and post-mortem meningeal tissue. Here we show that persistently increased levels of LTα in the cerebral meninges can give rise to lymphoid-like structures and underlying MS-like cortical pathology. Stereotaxic injections of recombinant LTα into the rat meninges leads to acute meningeal inflammation and subpial demyelination that resolves after 28 days. Injection of an LTα lentiviral vector induces lymphoid-like immune cell aggregates, maintained over 3 months, including T-cell rich zones containing podoplanin+ fibroblastic reticular stromal cells and B-cell rich zones with a network of follicular dendritic cells, together with expression of lymphoid chemokines and their receptors. Extensive microglial activation, subpial demyelination and marked neuronal loss occurs in the underlying cortical parenchyma. These results show that chronic LTα overexpression is sufficient to induce formation of meningeal lymphoid-like structures and subsequent neurodegeneration.

Increased release of lymphotoxin-alpha contributes to the pro-inflammatory milieu of the cerebrospinal fluid of MS patients. A persistent elevated expression of this cytokine in the meninges of rats gives rise to chronic inflammation with lymphoid tissue induction and accompanying neurodegenerative and demyelinating pathology in the underlying brain tissue.
Tryptophan derivatives regulate the seed germination and radicle growth of a root parasitic plant,Orobanche minor
Authors: Kuruma Michio , Suzuki Taiki , Seto Yoshiya
Published: April 2021

Root parasitic plant germination is induced by the host-derived chemical, strigolactone (SL). We found that a major microbial culture broth component, tryptone, inhibits the SL-inducible germination of a root parasitic plant,Orobanche minor. L-tryptophan (1a, L-Trp) was isolated as the active compound from tryptone. We further found that L-Trp related compounds (1b-11), such as a major plant hormone auxin (8, indole-3-acetic acid; IAA), also inhibit the germination and post-radicle growth ofO. minor. We designed a hybrid chemical (13), in which IAA is attached to a part of SL, and found that this synthetic analog induced the germination ofO. minor, and also inhibited post-radicle growth. Moreover, we found thatN-acetyl Trp (9) showed germination stimulating activity, and introduction of a substitution at C-5 position incresed its activity (12a-12f). Our data, in particular, the discovery of a structurally hybrid compound that has two activities that induce spontaneous germination and inhibit subsequent radical growth, would provide new types of germination regulators for root parasitic plants.
A simple, inexpensive and multi-scale 3-D fluorescent test sample for optical sectioning microscopies
Authors: Olevsko Ilya , Szederkenyi Kaitlin , Corridon Jennifer , Au Aaron , Delhomme Brigitte , Bastien Thierry , Fernandes Julien , Yip Christopher , Oheim Martin , Salomon Adi
Published: April 2021

Fluorescence standards allow for quality control and for the comparison of data sets across instruments and laboratories in applications of quantitative fluorescence. For example, users of microscopy core facilities expect a homogenous and time-invariant illumination and a uniform detection sensitivity, which are prerequisites for quantitative imaging analysis, particle tracking or fluorometric pH or Ca2+-concentration measurements. Similarly, confirming the three-dimensional (3-D) resolution of optical sectioning micro-scopes prior to volumetric reconstructions calls for a regular calibration with a standardised point source. Typically, the test samples required for such calibration measurements are different ones, and they depend much on the very microscope technique used. Also, the ever-increasing choice among these techniques increases the demand for comparison and metrology across instruments. Here, we advocate and demonstrate the multiple uses of a surprisingly versatile and simple 3-D test sample that can complement existing and much more expensive calibration samples: simple commercial tissue paper labelled with a fluorescent highlighter pen. We provide relevant sample characteristics and show examples ranging from the sub-µm to cm scale, acquired on epifluorescence, confocal, image scanning, two-photon (2P) and light-sheet microscopes.

Graphical abstract

Pyranine-labeled tissue paper, imaged upon 405-nm epifluorescence excitation through a 455LP LP dichroic and 465LP emission filter. Objective ×20/NA0.25. Overlaid are the normalised absorbance (dashed) and emission spectra (through line), respectively. In the present work we show that this “primitive” and inexpensive three-dimensional (3-D) test sample is a surprisingly versatile and powerful tool for quality assessment, comparison across microscopes as well as routine metrology for optical sectioning techniques, both for research labs and imaging core facilities.

Research highlights

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highlighter-pen marked tissue paper is a surprisingly powerful and versatile test sample for 3-D fluorescence microscopies

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standard tissue paper presents features ranging from 400 nm to centimetres

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our sample can simultaneously be used for testing intensity, field homogeneity, resolution, optical sectioning and image contrast

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it is easy to prepare, versatile, photostable and inexpensive
Cognitive impairment and metabolite profile alterations in the hippocampus and cortex of male and female mice exposed to a fat and sugar-rich diet are normalized by diet reversal
Authors: Garcia-Serrano Alba M. , Mohr Adélaïde A. , Spégel Peter , Duarte João M.N.
Published: April 2021

Diabetes impacts on brain metabolism, structure and function. Alterations in brain metabolism have been observed in obesity and diabetes models induced by exposure to diets rich in saturated fat and/or sugar, and have been linked to memory impairment. However, it remains to be determined whether brain dysfunction induced by obesogenic diets results from permanent brain alterations. We tested the hypothesis that an obesogenic diet (high-fat and high-sucrose diet; HFHSD) causes reversible changes in hippocampus and cortex metabolism and alterations in behavior. To test this hypothesis, mice were exposed to HFHSD for 24 weeks or for 16 weeks followed by 8 weeks of diet normalization. Development of the metabolic syndrome, changes in behavior, and brain metabolite profiles by1H magnetic resonance spectroscopy (MRS) were assessed longitudinally. Control mice were fed an ingredient-matched low-fat and low-sugar diet. Mice fed a HFHSD developed obesity, glucose intolerance and insulin resistance, with a more severe phenotype in male than female mice. Relative to controls, both male and female HFHSD-fed mice showed increased anxiety-like behavior, impaired memory in object recognition tasks, but preserved working spatial memory as evaluated by spontaneous alternation in a Y-maze. Alterations in the metabolite profiles were observed both in the hippocampus and cortex, but were more distinct in the former. HFHSD-induced metabolic changes included altered levels of lactate, glutamate, GABA, glutathione, taurine,N-acetylaspartate, creatine and choline. Notably, HFHSD-induced metabolic syndrome, anxiety, memory impairment, and brain metabolic alterations recovered upon diet normalization for 8 weeks. We conclude that cortical and hippocampal derangements induced by long-term HFHSD consumption are reversible rather than being the result of permanent tissue damage.