Notes

Intraoperative general complications during 2278 cerebral endovascular processes using multimodality IONM: connection between signal change, problem, involvement as well as postoperative outcome.
In single-pollutant models, we found positive associations between the three exposures and all three outcomes, with the strongest associations detected for the estimated ROS. The associations of AMI and CHF were sensitive to indirect adjustment, but remained robust for CVD death in all sensitivity analyses. In multi-pollutant models, the associations of the three exposures generally remained unaltered. Interestingly, adjustment for ROS did not substantially change the associations between PM2.5 and CVD, but attenuated the associations of NO2.

Long-term exposure to Fe and Cu in PM2.5 and their combined impact on ROS were consistently associated with increased CVD death.
Long-term exposure to Fe and Cu in PM2.5 and their combined impact on ROS were consistently associated with increased CVD death.
Mass spectrometry methods are widely used for the analysis of biological and medical samples. Recently developed methods such as DESI, REIMS, NESI allow fast analyses without sample preparation at the cost of higher variability of spectra. In biology and medicine, MS profiles are often used with machine learning (classification, regression, etc.) algorithms and statistical analysis, which are sensitive to outliers and intraclass variability. Here we present SSM Display software, a tool for fast visual outlier detection and variance estimation in mass spectrometric profiles. The tool speeds up the process of manual spectra inspection, improves accuracy and explainability of outlier detection, and decreases the requirements to the operator experience. It was shown that the batch effect could be revealed through SSM analysis and that the SSM calculation can also be used for tuning novel ion sources concerning the quality of obtained mass spectra.

Source code, example datasets, binaries, and other information are available at https//github.com/EvgenyZhvansky/R_matrix.

Supplementary data are available at Bioinformatics online.
Supplementary data are available at Bioinformatics online.University students are at elevated risk for mental health problems. The COVID-19 pandemic and subsequent public health measures taken to combat it burdened the students' life with additional dramatic psychological impacts. The aim of this study was to investigate the psychological impacts that affected the university students in Egypt during the COVID-19 pandemic. An online survey was sent to the Egyptian university students via all means of online communication during the first week of May 2020 by using a non-probability snowball sampling. A survey included a short version Depression Anxiety Stress Scale-21 (DASS-21) and socio-demographic data. Overall, 70.5, 53.6 and 47.8% of Egyptian students had depression, anxiety and stress, respectively. Being a female, having a relative or acquaintance infected with COVID-19, having a preexisting chronic disease and lacking of psychological support from families, community and universities increase the risk of depression, anxiety and stress among Egyptian students. Being a medical student is associated with depression while, spending more time to follow news of COVID-19 pandemic is associated with increased anxiety. Egyptian students experience varying levels of psychological disturbance during COVID-19 pandemic. This study suggests that mental health of the university students should be carefully, monitored during the crisis and the universities should provide psychological-oriented services, adapted to these circumstances to mitigate its emotional impact on the students.
Antimicrobial resistance (AMR) of Neisseria gonorrhoeae has spread worldwide. Rapid and comprehensive methods are needed to describe N. gonorrhoeae AMR profiles accurately. A method based on multiplex amplicon sequencing was developed to simultaneously sequence 13 genes related to AMR in N. gonorrhoeae directly from clinical samples.

Nine N. gonorrhoeae strains were used for the establishment and validation of the method. Eleven urethral swabs and their corresponding cultured isolates were matched as pairs to determine the accuracy of the method. Mock samples with different dilutions were prepared to determine the sensitivity of the method. Five nongonococcal Neisseria strains and 24 N. gonorrhoeae negative clinical samples were used to evaluate the cross-reactivity. Finally, the method was applied to 64 clinical samples to assess its performance.

Using Sanger sequencing as a reference method, sequences recovered from amplicon sequencing had a base accuracy of over 99.5% and the AMR sites were correctly identified. The limit of detection (LOD) was lower than 31 copies/reaction. No significant cross-reactivity was observed. Furthermore, target genes were successfully recovered from 64 clinical samples including 9 urines, demonstrating this method could be used in different types of samples. For clinical samples, the results can be obtained within a time frame of 7 h 40 min to 10 h 40 min, while for isolates, the turnaround time was approximately 2 h shorter.

This method can serve as a versatile and convenient culture-free diagnostic method with the advantages of high sensitivity and accuracy.
This method can serve as a versatile and convenient culture-free diagnostic method with the advantages of high sensitivity and accuracy.
Protein orthologous group databases are powerful tools for evolutionary analysis, functional annotation, or metabolic pathway modeling across lineages. Sequences are typically assigned to orthologous groups with alignment-based methods, such as profile hidden Markov models, which has become a computational bottleneck.

We present DeepNOG, an extremely fast and accurate, alignment-free orthology assignment method based on deep convolutional networks. We compare DeepNOG against state-of-the-art alignment-based (HMMER, DIAMOND) and alignment-free methods (DeepFam) on two orthology databases (COG, eggNOG 5). DeepNOG can be scaled to large orthology databases like eggNOG, for which it outperforms DeepFam in terms of precision and recall by large margins. While alignment-based methods still provide the most accurate assignments among the investigated methods, computing time of DeepNOG is an order of magnitude lower on CPUs. Optional GPU usage further increases throughput massively. A command-line tool enables rapid adoption by users.

Source code and packages are freely available at https//github.com/univieCUBE/deepnog. Install the platform-independent Python program with $pip install deepnog.

Supplementary material is available at Bioinformatics online.
Supplementary material is available at Bioinformatics online.
Only few pathogens that cause lower respiratory tract infections (LRTIs) can be identified due to limitations of traditional microbiological methods and the complexity of the oropharyngeal normal flora. Metagenomic next-generation sequencing (mNGS) has the potential to solve this problem.

This prospective observational study sequentially enrolled 93 patients with LRTI and 69 patients without LRTI who visited Peking University People's Hospital in 2019. Pathogens in bronchoalveolar lavage fluid (BALF) specimens were detected using mNGS (DNA and RNA) and traditional microbiological assays. Human transcriptomes were compared between LRTI and non-LRTI, bacterial and viral LRTI, and tuberculosis and nontuberculosis groups.

Among 93 patients with LRTI, 20%, 35%, and 65% of cases were detected as definite or probable pathogens by culture, all microbiological tests, and mNGS, respectively. Our in-house BALF mNGS platform had an approximately 2-working-day turnaround time and detected more viruses and fungi than the other methods. Taking the composite reference standard as a gold standard, it had a sensitivity of 66.7%, specificity of 75.4%, positive-predictive value of 78.5%, and negative-predictive value of 62.7%. LRTI-, viral LRTI-, and tuberculosis-related differentially expressed genes were respectively related to immunity responses to infection, viral transcription and response to interferon-γ pathways, and perforin 1 and T-cell receptor B variable 9.

Metagenomic DNA and RNA-seq can identify a wide range of LRTI pathogens, with improved sensitivity for viruses and fungi. Our in-host platform is likely feasible in the clinic. Host transcriptome data are expected to be useful for the diagnosis of LRTIs.
Metagenomic DNA and RNA-seq can identify a wide range of LRTI pathogens, with improved sensitivity for viruses and fungi. Our in-host platform is likely feasible in the clinic. Host transcriptome data are expected to be useful for the diagnosis of LRTIs.
Clinical practice guidelines or recommendations often require timely and regular updating as new evidence emerges, because this can alter the risk-benefit trade-off. The scientific process of developing and updating guidelines accompanied by adequate implementation can improve outcomes. To promote better management of patients receiving vancomycin therapy, we updated the guideline for the therapeutic drug monitoring (TDM) of vancomycin published in 2015.

Our updated recommendations complied with standards for developing trustworthy guidelines, including timeliness and rigor of the updating process, as well as the use of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We also followed the methodology handbook published by the National Institute for Health and Clinical Excellence and the Spanish National Health System.

We partially updated the 2015 guideline. Apart from adults, the updated guideline also focuses on pediatric patients and neonates requiring intravenous vancomycin therapy. The guideline recommendations involve a broadened range of patients requiring TDM, modified index of TDM (both 24-hour area under the curve and trough concentration), addition regarding the necessity and timing of repeated TDM, and initial dose for specific subpopulations. Overall, 1 recommendation was deleted and 3 recommendations were modified. Eleven new recommendations were added, and no recommendation was made for 2 clinical questions.

We updated an evidence-based guideline regarding the TDM of vancomycin using a rigorous and multidisciplinary approach. The updated guideline provides more comprehensive recommendations to inform rational and optimized vancomycin use and is thus of greater applicability.
We updated an evidence-based guideline regarding the TDM of vancomycin using a rigorous and multidisciplinary approach. The updated guideline provides more comprehensive recommendations to inform rational and optimized vancomycin use and is thus of greater applicability.The Chinese guidelines for IAI presented here were developed by a panel that included experts from the fields of surgery, critical care, microbiology, infection control, pharmacology, and evidence-based medicine. All questions were structured in population, intervention, comparison, and outcomes format, and evidence profiles were generated. Recommendations were generated following the principles of the Grading of Recommendations Assessment, Development, and Evaluation system or Best Practice Statement (BPS), when applicable. The final guidelines include 45 graded recommendations and 17 BPSs, including the classification of disease severity, diagnosis, source control, antimicrobial therapy, microbiologic evaluation, nutritional therapy, other supportive therapies, diagnosis and management of specific IAIs, and recognition and management of source control failure. Recommendations on fluid resuscitation and organ support therapy could not be formulated and thus were not included. Accordingly, additional high-quality clinical studies should be performed in the future to address the clinicians' concerns.
Considering the increasing incidence of carbapenem-resistant Enterobacteriaceae in China, this study aimed to establish the in vitro effectiveness of imipenem/relebactam (IMI/REL) on clinical Enterobacteriaceae isolates derived from intra-abdominal infections (IAIs), respiratory tract infections (RTIs), and urinary tract infections (UTIs) in China between 2015 and 2018.

In total, 8781 Enterobacteriaceae isolates from IAI, RTI, and UTI samples were collected from 22 hospitals across 7 geographic regions of China. Susceptibility to antimicrobial drugs was tested using the Clinical and Laboratory Standards Institute broth microdilution and breakpoints, and IMI/REL activity was assessed using United States Food and Drug Administration guidelines.

In 2015-2018, the most frequently identified Enterobacteriaceae species was Escherichia coli (n = 4676 [53.3%]), followed by Klebsiella pneumoniae (n = 2949 [33.6%]) and Enterobacter cloacae (n = 542 [6.2%]). The Enterobacteriaceae isolates showed 95.2% overall susceptibility to IMI/REL, of which the susceptibility rates in isolates from IAI, RTI, and UTI were 95.8%, 91.4%, and 96.6%, respectively. Overall, the susceptibilities of both intensive care unit (ICU) and non-ICU Enterobacteriaceae isolates to colistin were 92.9%, followed by IMI/REL (90.7% [95.9%]) and amikacin (83.3% [92.3%]). In addition, IMI/REL restored 66.3% susceptibility in imipenem-nonsusceptible Enterobacteriaceae.

Given their high in vitro susceptibility, Enterobacteriaceae infections in China should be considered for IMI/REL treatment, especially with isolates that are not susceptible to carbapenems.
Given their high in vitro susceptibility, Enterobacteriaceae infections in China should be considered for IMI/REL treatment, especially with isolates that are not susceptible to carbapenems.More than 3 decades have passed since infection control was implemented nationwide in China in 1986. A comprehensive set of regulations and guidelines has been developed, and almost all hospitals have established infection control teams. However, compliance is variable and is usually suboptimal. The incidence of certain multidrug-resistant organisms (MDROs), including carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Klebsiella pneumoniae (CRKP), is increasing, and associated infections are mainly hospital-acquired in China. Carbapenem-resistant Pseudomonas aeruginosa has remained relatively stable, whereas methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterobacter faecium have been decreasing. The spread of CRAB and CRKP in China is largely mediated by dominant high-risk lineages, namely, clonal complex 92 for CRAB and sequence type 11 for CRKP. However, challenges owing to MDROs bring opportunities for rethinking, taking coordinated action, building capacity, changing behavior, and performing studies that reflect everyday situations in the Chinese healthcare system.
Handwashing sinks can become contaminated by carbapenem-resistant Klebsiella (CRK), including carbapenem-resistant Klebsiella pneumoniae (CRKP) and carbapenem-resistant Klebsiella oxytoca (CRKO), but whether they are major sources of CRK infections remains unknown.

We performed a prospective multicenter study in 16 intensive care units (ICUs) (9 general and 7 neonatal) at 11 hospitals. All sinks at these locations were sampled to screen CRK. All CRK clinical isolates recovered between 2 weeks before and 3 months after sampling in ICUs with CRK-positive sinks or other participating ICUs at the same hospital were collected. Whole-genome sequencing of all isolates was performed. Isolates of the same sequence type (ST) were assigned to clones by calling single-nucleotide polymorphisms.

Among 158 sinks sampled, 6 CRKP and 6 CRKO were recovered from 12 sinks in 7 ICUs, corresponding to a 7.6% CRK contamination rate. Twenty-eight clinical isolates were collected, and all were CRKP. The 34 CRKP isolates belonged to 7 STs, including ST789 (n = 14, all had blaNDM-5); ST11 (n = 12, 5 belonged to KL64 and 7 to KL47, all had blaKPC-2); ST709 (n = 4, all had blaNDM-5); and ST16, ST20, ST1027, and ST2407 (n = 1 each). One particular ST789 clone caused an outbreak and contaminated a sink. ST11_KL47 sink isolates were likely the source of a cluster of clinical isolates. Two ST11_KL64 isolates belonged to a common clone but were from 2 hospitals.

Contaminated sinks were not the major source of CRK in our local settings. ST789 blaNDM-5-carrying CRKP might represent an emerging lineage causing neonatal infections.
Contaminated sinks were not the major source of CRK in our local settings. ST789 blaNDM-5-carrying CRKP might represent an emerging lineage causing neonatal infections.This is the first report of ceftazidime-avibactam resistance caused by the blaKPC-33 mutation through the D179Y variant during the treatment of blaKPC-2-positive Klebsiella pneumoniae-related infections in China. The blaKPC-33-containing K. pneumoniae was susceptible to meropenem-vaborbactam, cefepime-zidebactam, tigecycline, and polymyxin B. The blaKPC-33 gene was located on a 77 551-bp transformable plasmid harboring qnrS1 and blaLAP-2. Detecting blaKPC-33-positive K. pneumoniae clinical strains is important for infection control.
Infectious disease is the leading cause of fever of unknown origin (FUO). Serum inflammatory markers historically used to diagnose bacterial infection have sufficient diagnostic sensitivity but low specificity. This study aimed to develop a simple scoring system for differentiating bacterial infections from other causes of early-stage FUO.

This study included a retrospective cohort of patients presenting with FUO at the Huashan Hospital (January 2014 to June 2017). The diagnostic utility of serum inflammatory markers for bacterial infection was evaluated using the receiver operating characteristic (ROC) curve analysis. Relevant markers were subsequently measured prospectively in a separate cohort of FUO patients (December 2017 to May 2019). A scoring system was based on inflammatory markers and other test results.

Bacterial infection was identified in 34% of patients in the retrospective cohort. The area under the ROC curve (AUC) was 0.644 (95% confidence interval [CI], .595-.693) for C-reactive protein, 0.624 (95% CI, .573-.675) for procalcitonin, and 0.646 (95% CI, .595-.697) for serum ferritin (SF) in diagnosing bacterial infection. Bacterial infection was found in 29% of cases in the prospective cohort. A model based on serum amyloid A (SAA) and SF levels and neutrophil percentage yielded an AUC of 0.775 (95% CI, .695-.854). Validation analysis indicated lower probability (<15%) of bacterial infection for patients with a score <16.5 points.

A scoring system based on SAA and SF levels and neutrophil percentage can help distinguish bacterial infection from other causes of FUO, potentially reducing antibiotic use.
A scoring system based on SAA and SF levels and neutrophil percentage can help distinguish bacterial infection from other causes of FUO, potentially reducing antibiotic use.
Mechanical ventilation is crucial for acute respiratory distress syndrome (ARDS) patients and diagnosis of ventilator-associated pneumonia (VAP) in ARDS patients is challenging. Hence, an effective model to predict VAP in ARDS is urgently needed.

We performed a secondary analysis of patient-level data from the Early versus Delayed Enteral Nutrition (EDEN) of ARDSNet randomized controlled trials. Multivariate binary logistic regression analysis established a predictive model, incorporating characteristics selected by systematic review and univariate analyses. The model's discrimination, calibration, and clinical usefulness were assessed using the C-index, calibration plot, and decision curve analysis (DCA).

Of the 1000 unique patients enrolled in the EDEN trials, 70 (7%) had ARDS complicated with VAP. Mechanical ventilation duration and intensive care unit (ICU) stay were significantly longer in the VAP group than non-VAP group (P < .001 for both) but the 60-day mortality was comparable. Use of neuromuscular blocking agents, severe ARDS, admission for unscheduled surgery, and trauma as primary ARDS causes were independent risk factors for VAP. The area under the curve of the model was .744, and model fit was acceptable (Hosmer-Lemeshow P = .185). The calibration curve indicated that the model had proper discrimination and good calibration. DCA showed that the VAP prediction nomogram was clinically useful when an intervention was decided at a VAP probability threshold between 1% and 61%.

The prediction nomogram for VAP development in ARDS patients can be applied after ICU admission, using available variables. Potential clinical benefits of using this model deserve further assessment.
The prediction nomogram for VAP development in ARDS patients can be applied after ICU admission, using available variables. Potential clinical benefits of using this model deserve further assessment.
Pseudomonas aeruginosa (PA) bloodstream infection (BSI) is a common complication in patients with acute leukemia (AL), and the prevalence of antibiotic-resistant strains poses a serious problem. However, there is limited information regarding antibiotic resistance, clinical characteristics, and outcomes of PA BSI in AL patients. This study explored characteristics associated with the clinical outcomes of AL patients with PA BSI and analyzed factors associated with BSI caused by multidrug-resistant (MDR) or carbapenem-resistant strains.

This single-center retrospective study enrolled hospitalized AL patients who developed PA BSI during January 2014-December 2019. The Kaplan-Meier method was used to plot survival curves. Multivariate logistic regression analyses were also performed.

Of 293 eligible patients with PA BSI, 55 (18.8%) received inappropriate empirical antibiotic therapy within 48 hours of BSI onset, whereas up to 65.8% MDR-PA BSI patients received inappropriate empirical treatment. The 30-day important in MDR-PA BSI development. Rational antibiotic use based on local antimicrobial susceptibility and clinical characteristics can help reduce antibiotic resistance and mortality.
Antifungal prophylaxis may result in breakthrough infections in hematology patients with severe agranulocytosis, with few studies assessing risk factors and clinical outcomes of breakthrough candidemia. We described the distribution of Candida species, assessed risk factors for mortality in such patients, and determined differences in the incidence and mortality of breakthrough candidemia between patients who did or did not receive an allogeneic hematopoietic stem cell transplant.

We collected clinical and microbiological data of patients with hematologic malignancies and breakthrough candidemia from a single center. Seven-day and 30-day follow-up outcomes were recorded; the incidence and mortality of breakthrough candidemia between patients who did or did not undergo an allogeneic transplant were compared. Kaplan-Meier survival estimates were used to generate survival curves, and predictors were identified using Cox regression analyses.

Of 71 enrolled patients, 17 received allogeneic transplants. Incid Prompt and adequate antifungal treatment with catheter removal may reduce mortality.Mutations that increase the protein kinase activity of LRRK2 are one of the most common causes of familial Parkinson's disease. LRRK2 phosphorylates a subset of Rab GTPases within their Switch-II motif, impacting interaction with effectors. We describe and validate a new, multiplexed targeted mass spectrometry assay to quantify endogenous levels of LRRK2-phosphorylated Rab substrates (Rab1, Rab3, Rab8, Rab10, Rab35 and Rab43) as well as total levels of Rabs, LRRK2 and LRRK2-phosphorylated at the Ser910 and Ser935 biomarker sites. Exploiting this assay, we quantify for the first time the relative levels of each of the pRab proteins in different cells (mouse embryonic fibroblasts, human neutrophils) and mouse tissues (brain, kidney, lung and spleen). We define how these components are impacted by Parkinson's pathogenic mutations (LRRK2[R1441C] and VPS35[D620N]) and LRRK2 inhibitors. We find that the VPS35[D620N], but not LRRK2[R1441C] mutation, enhances Rab1 phosphorylation in a manner blocked by administration of an LRRK2 inhibitor, providing the first evidence that endogenous Rab1 is a physiological substrate for LRRK2. We exploit this assay to demonstrate that in Parkinson's patients with VPS35[D620N] mutations, phosphorylation of multiple Rab proteins (Rab1, Rab3, Rab8, Rab10 and Rab43) is elevated. We highlight the benefits of this assay over immunoblotting approaches currently deployed to assess LRRK2 Rab signalling pathway.
The long-term course of ulcerative colitis [UC] is difficult to predict. Mortality, colectomy, cancer, and hospitalisation represent hard outcomes of disease. Moreover, knowledge on the risk of relapses and need for potent medication add important information about living with UC. We aimed to evaluate the course and prognosis of UC during the first 20 years after diagnosis, and to identify early prognostic risk factors.

From 1990 to 1994, a population-based inception cohort of patients with inflammatory bowel disease was enrolled in South-Eastern Norway. A systematic follow-up [FU] was conducted at 1,5, 10, and 20 years after diagnosis. Clinical outcomes were recorded continuously, and possible relationships between early disease characteristics and outcomes were analysed using multiple regression analysis.

Among 519 UC patients, 119 died, 60 were lost to FU, and 340 were included in the FU cohort. The 20-year cumulative risk of colectomy was 13.0% (95% confidence interval [CI] [11.4-14.6]). Extensive colitis at diagnosis was independently associated with an increased risk of colectomy compared with proctitis (hazard ratio [HR] = 2].8, 95% CI [1.3-6.1]). In contrast, mucosal healing at 1-year FU was independently associated with reduced risk of colectomy [HR = 0.4, 95% CI [0.2-0.8]), and inversely associated with subsequent risk of relapse [adjusted HR = 0.5, 95% CI [0.3-0.7]).

The overall risk of colectomy in our cohort was lower than expected from previous studies, although considerable for patients with extensive colitis at diagnosis. Early mucosal healing was associated with better disease outcomes 20 years after diagnosis.
The overall risk of colectomy in our cohort was lower than expected from previous studies, although considerable for patients with extensive colitis at diagnosis. Early mucosal healing was associated with better disease outcomes 20 years after diagnosis.The provision of population-oriented, on-demand digital health services in many countries exemplifies the perceived utility of digital health services in supporting population health. Yet, limited knowledge exists regarding the equity of these services. Using mixed-method research, we recruited users of a health website and general practice patients to surveys (n = 441) and telephone interviews (n = 40). We contribute specific evidence investigating barriers to access, use and benefit from digital health services within an equity framework that incorporates social determinant factors, eHealth Literacy and trust. Our research highlights the foundational role of trust in predicting use, showcases which groups are unlikely to benefit from population-oriented digital health services, and proposes strategies to enhance the equity of these services. The theoretical framework we developed serves as a roadmap for future health promotion research and action by outlining the complex and interrelated pathways that can promote and threaten digital health equity.Enzyme catalysis is omnipresent in the cell. The mechanisms by which highly evolved protein folds enable rapid and specific chemical transformation of substrates belong to the marvels of structural biology. Targeting of enzymes with inhibitors has immediate application in drug discovery, from chemotherapeutics over antibiotics to antivirals. NMR spectroscopy combines multiple assets for the investigation of enzyme function. The non-invasive technique can probe enzyme structure and dynamics and map interactions with substrates, cofactors and inhibitors at the atomic level. With experiments performed at close to native conditions, catalytic transformations can be monitored in real time, giving access to kinetic parameters. The power of NMR in the solid state, in contrast with solution, lies in the absence of fundamental size limitations, which is crucial for enzymes that are either membrane-embedded or assemble into large soluble complexes exceeding hundreds of kilodaltons in molecular weight. Here we review recent progress in solid-state NMR methodology, which has taken big leaps in the past years due to steady improvements in hardware design, notably magic angle spinning, and connect it to parallel biochemical advances that enable isotope labelling of increasingly complex enzymes. We first discuss general concepts and requirements of the method and then highlight the state-of-the-art in sample preparation, structure determination, dynamics and interaction studies. We focus on examples where solid-state NMR has been instrumental in elucidating enzyme mechanism, alone or in integrative studies.Physiological assessment is challenging in patients with multivessel disease (MVD) with a chronic total occlusion (CTO) and may result in inappropriate treatment decisions. We report herein, for the first time to our knowledge, on the dynamic changes of the instantaneous wave-free ratio in the CTO collateral donor artery before and after coronary artery bypass grafting (CABG). Our case highlights the paramount importance of collateral circulation when interpreting invasive indices of coronary stenosis severity to guide decision-making for CABG in MVD patients with a CTO. This may be particularly relevant to reduce the risk of early graft failure in patients with MVD undergoing CABG.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) involves severe fatigue, unrefreshing sleep, and cognitive impairment, leading to functional difficulties; prior studies have not evaluated risk factors with behavioral and immune data collected prior to developing ME/CFS.. Up to 5% of university students develop infectious mononucleosis (IM) annually, and 9-12% meet criteria for ME/CFS six months later. We sought to determine predictors of ME/CFS.

We enrolled college students at the start of the school year (Time 1), identified those who developed IM (Time 2) and followed them for 6 months (Time 3), identifying three groups those who developed ME/CFS, those who developed severe ME/CFS (meeting >1 set of criteria) and those who were asymptomatic. We conducted 8 behavioral and psychological surveys and analyzed cytokines at three time points.

238 of the 4501 students (5.3%) developed IM; 6 months later, 55 of the 238 (23%) met criteria for ME/CFS and 157 (66%) were asymptomatic. 67 of the 157 asymptomatic students served as controls. Students with severe-ME/CFS were compared to students who were asymptomatic at three time points. The former group was not different from the latter group at Time 1 (prior to developing IM) in stress, coping, anxiety or depression, but were different in several behavioral measures and had significantly lower levels of IL-6 and IL-13. At Time 2 (when they developed IM), the two ME/CFS groups tended to have more autonomic complaints and behavioral symptoms while the severe- ME/CFS group had higher levels of IL-12 and lower levels of IL-13 than the recovered group.

At baseline, those who developed ME/CFS had more physical symptoms and immune irregularities, but not more psychological symptoms, than those who recovered.
At baseline, those who developed ME/CFS had more physical symptoms and immune irregularities, but not more psychological symptoms, than those who recovered.
To report the findings of the 2019 Society for Hematopathology/European Association for Haematopathology Workshop within the categories of reactive eosinophilia, hypereosinophilic syndrome (HES), germline disorders with eosinophilia (GDE), and myeloid and lymphoid neoplasms associated with eosinophilia (excluding entities covered by other studies in this series).

The workshop panel reviewed 109 cases, assigned consensus diagnosis, and created diagnosis-specific sessions.

The most frequent diagnosis was reactive eosinophilia (35), followed by acute leukemia (24). Myeloproliferative neoplasms (MPNs) received 17 submissions, including chronic eosinophilic leukemia, not otherwise specified (CEL, NOS). Myelodysplastic syndrome (MDS), MDS/MPN, and therapy-related myeloid neoplasms received 11, while GDE and HES received 12 and 11 submissions, respectively.

Hypereosinophilia and HES are defined by specific clinical and laboratory criteria. Eosinophilia is commonly reactive. An acute leukemic onset with eosintic and/or molecular clonality may distinguish CEL from HES. Molecular testing helps to better subclassify myeloid neoplasms with eosinophilia and to identify patients for targeted treatments.Levodopa is widely administered orally in clinical treatment of Parkinson's disease; however, due to levodopa various oral absorption and low bioavailability, intranasal delivery seems to be a suitable alternative route of administration. Pluronic F-127 is a thermosensitive polymer, which can form gel at nasal cavity temperature and increase drug residence time. In this study, a rapid High Performance Liquid Chromatography (HPLC) method was validated in presence of internal standard to determine pharmacokinetic parameters following levodopa administration to rats in three different intravenous solution, intranasal solution and intranasal thermosensitive gel groups. A precised (96.7%) and accurate (95.0%) HPLC method was validated at low UltraViolet (UV) wavelength of 208 nm that showed limit of detection and limit of quantitation of 59 and 177 ng/mL, respectively. Specificity results showed no interference for levodopa with endogenous serum materials, and serum extraction efficacy was 93%. Pharmacokinetic parameters including bioavailability of 75 and 85% with mean residence time of 78 and 94 min were estimated for intranasal solution and thermosensitive gel using the validated HPLC method, which indicated that levodopa nasal gel may be a good alternative with appropriate pharmacokinetic outcome. Therefore, the validated levodopa HPLC analysis method at low UV wavelength was efficiently applied in pharmacokinetic study.Infections of frozen elephant trunk hybrid prosthesis (HP) are not well documented in the literature and their management is not standardized yet. We report herein the case of a 59-year-old patient who benefited from a Thoraflex™ HP aortic arch replacement for an acute type A aortic dissection. He presented a year later with a Staphylococcus aureus infection of the proximal part of this prosthesis. We performed a replacement of the proximal compound of the HP accompanied by a complete debranching of the 3 supra-aortic vessels with an inter-carotidal retro-oesophageal bypass. As we left in situ the endovascular graft within the descending aorta, a life-long antibiotic therapy was introduced. The postoperative follow-up was uneventful, and the patient discharged home 2 weeks after his surgery. As an alternative to a more radical redo surgery with major risk, a hybrid medical and surgical treatment of infected frozen elephant trunk could be considered.Patient referral systems are fragile and overlooked components of the health system in Tanzania. Our study aims at exploring patient referral networks in two rural districts in Tanzania, Kilolo and Msalala. Firstly, we ask whether secondary-level facilities act as gatekeepers, mediating referrals from primary- to tertiary-level facilities. Secondly, we explore the facility and network-level determinants of patient referrals focusing on treatment of childhood illnesses and non-communicable diseases. We use data collected across all public health facilities in the districts in 2018. To study gatekeeping, we employ descriptive network analysis tools. To explore the determinants of referrals, we use exponential random graph models. In Kilolo, we find a disproportionate share of patients referred directly to the largest hospital due to geographical proximity. In Msalala, small and specialized secondary-level facilities seem to attract more patients. Overall, the results call for policies to increase referrals to secondary facilities avoiding expensive referrals to hospitals, improving timeliness of care and reducing travel-related financial burden for households.Agricultural workers often produce considerable excess heat due to the physically demanding nature of their activities, increasing their risk of thermal stress in even moderately warm conditions. Few studies have examined the physiological responses to heat load in agriculture. We aimed to assess the heat strain experienced by vineyard workers during canopy management in dry field conditions, and to disentangle the effects of the heat produced by the body and the thermal environment. Thirty workers from five Bordeaux vineyards of southern France were monitored during vine-lifting and trellising (June 2012). The mean heart rate, net cardiac cost, relative cardiac cost, and cardiac workload score were assessed during field activity. As the workers were nested within vineyards, multilevel linear regression models were used for correct inference. Skin temperature increased by an average of 1.0°C. Cardiac indices showed marked differences between individuals. The workload was evaluated as 'heavy' or 'very heavy' for more than one-third of the workers, of whom one experienced heat exhaustion. Above some individual characteristics, we highlighted a contextual effect (air temperature) for the mean heart rate (P = 0.03), the relative cardiac cost (P = 0.01) and, to a lesser extent, a cardiac workload score (P = 0.07). Canopy management by hand in vineyards causes considerable cardiac and thermoregulatory strain. Appropriate instruments should be developed to simultaneously evaluate work intensity, work quality, and productivity at the vineyard level to raise the awareness of both managers and employees about taking preventive measures.Lysophosphatidic acid (LPA) and its G-protein-coupled receptors (Lpar1-Lpar6) mediate a plethora of activities associated with cancer growth and progression. However, there is no systematic study about whether and how LPA promotes esophageal squamous cell carcinoma (ESCC). Here, we show that autotaxin (ATX), a primary LPA-producing enzyme, is highly expressed in ESCC, and overexpressed ATX is associated with the poor outcome of ESCC patients. Meanwhile, the expression of Lpar1 was much higher in ESCC cells compared with Het-1a (human esophagus normal epithelial cells). Functional experiments showed that LPA remarkably increased the proliferation and migration of ESCC cells. Furthermore, Lpar1 knockdown abolished the effect of LPA on ESCC cell proliferation and migration. Mechanistic studies revealed that LPA promoted ESCC cell lines proliferation and migration through PI3K/Akt pathway. Treatment of KYSE30 cell xenografts with Lpar1 inhibitor BMS-986020 significantly repressed tumor growth. Our results shed light on the important role of LPA in ESCC, and Lpar1 might be a potential treatment target for ESCC.
Evaluating morbidity and survival of patients operated on for a second primary non-small-cell lung cancer (NSCLC).

Retrospective collection of data from patients operated on for a second NSCLC between 2009 and 2018.

Fifty-two patients met the inclusion criteria. At the time of second pulmonary resection, the median time between the 2 surgeries was 25 months (5-44.5 months). Patients' median age was 65 years (61-68 years). Median tumour size was 16 mm (10-22 mm). Thoracoscopy was used in 75% of cases. The resection was a pneumonectomy (n = 1), bilobectomy (n = 1), lobectomy (n = 15), segmentectomy (n = 32) or wedge resection (n = 3). The length of stay was 7 days (5-9 days). Mortality was null and morbidity was 36.5%, mainly from grade I-II complications according to the Clavien-Dindo classification. The median follow-up was 28 months (13-50 months). The median overall survival was 67 months (95% confidence interval 60.8-73.1 months). Survival at 5 years and specific survival were 71.1% and 67.7%, respectively.

A second surgical resection of either synchronous or metachronous NSCLC has a morbidity that is not superior to the morbidity of the first operation. The new tumour is usually diagnosed at an early stage. An anatomical sublobar resection is most likely the best compromise. It might also be considered for the first operation when there is a suspicious synchronous lesion that may require surgery at a later stage.
A second surgical resection of either synchronous or metachronous NSCLC has a morbidity that is not superior to the morbidity of the first operation. The new tumour is usually diagnosed at an early stage. An anatomical sublobar resection is most likely the best compromise. It might also be considered for the first operation when there is a suspicious synchronous lesion that may require surgery at a later stage.
DNA methylation patterns in a cell are associated with gene expression and the phenotype of a cell, including disease states. Bisulphite PCR sequencing is commonly used to assess the methylation profile of genomic regions between different cells. Here we have developed MethPanel, a computational pipeline with an interactive graphical interface to rapidly analyse multiplex bisulphite PCR sequencing data. MethPanel comprises a complete analysis workflow from genomic alignment to DNA methylation calling and supports an unlimited number of PCR amplicons and input samples. MethPanel offers important and unique features, such as calculation of a epipolymorphism score and bisulphite PCR bias correction capabilities, and is designed so that the methylation data from all samples can be processed in parallel. The outputs are automatically forwarded to a shinyApp for convenient display, visualisation and remotely sharing data with collaborators and clinicians.

MethPanel is freely available at https//github.com/thinhong/MethPanel.

Supplementary data are available at Bioinformatics online.
Supplementary data are available at Bioinformatics online.The primary cause of morbidity and mortality in patients with multiple myeloma (MM) is an infection. Therefore, there is great concern about susceptibility to the outcome of COVID-19-infected patients with MM. This retrospective study describes the baseline characteristics and outcome data of COVID-19 infection in 650 patients with plasma cell disorders, collected by the International Myeloma Society to understand the initial challenges faced by myeloma patients during the COVID-19 pandemic. Analyses were performed for hospitalized MM patients. Among hospitalized patients, the median age was 69 years, and nearly all patients (96%) had MM. Approximately 36% were recently diagnosed (2019-2020), and 54% of patients were receiving first-line therapy. Thirty-three percent of patients have died, with significant geographic variability, ranging from 27% to 57% of hospitalized patients. Univariate analysis identified age, International Staging System stage 3 (ISS3), high-risk disease, renal disease, suboptimal myeloma control (active or progressive disease), and 1 or more comorbidities as risk factors for higher rates of death. Neither history of transplant, including within a year of COVID-19 diagnosis, nor other anti-MM treatments were associated with outcomes. Multivariate analysis found that only age, high-risk MM, renal disease, and suboptimal MM control remained independent predictors of adverse outcome with COVID-19 infection. The management of MM in the era of COVID-19 requires careful consideration of patient- and disease-related factors to decrease the risk of acquiring COVID-19 infection, while not compromising disease control through appropriate MM treatment. This study provides initial data to develop recommendations for the management of MM patients with COVID-19 infection.Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate.Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pretransplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pretransplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (P less then .001) because of a high risk of nonrelapse mortality (NRM; P = .001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ') fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ' fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ' fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ' fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ' fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ' fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ' fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.
To determine the effects of Salvianolic acid B (Sal B) on new bone formation in the orthopedically expanded premaxillary sutures in rats.

The sample consisting of Sprague Dawley rats (male, n = 14) was split in half by random selection the experiment group (Sal B) and the control group. The premaxillary suture of each rat was expanded by bonding an open-loop spring to two maxillary incisors, each end to one tooth. A 5-day expansion period followed by a 12-day retention period was conducted. The 17-day intraperitoneal administration of Sal B was performed daily for the experiment group at a dose of 40 mg/kilo. The trial was completed after sacrificing the rats and dissection of the premaxillae for histological analysis. The amount of new bone, quantity of capillaries and intensity of inflammatory cells were histomorphometrically determined while the quantities of osteoblasts and osteoclasts were determined immunohistochemically.

The Sal B group was significantly different from the control group and had greater quantities of new bone, capillaries, inflammatory cells, osteoblasts, and osteoclasts.

Salvianolic acid B displays a positive effect during premaxillary expansion with a greater number of capillaries potentially in association with higher bone formation and improved angiogenesis in rats.
Salvianolic acid B displays a positive effect during premaxillary expansion with a greater number of capillaries potentially in association with higher bone formation and improved angiogenesis in rats.In disease research, the study of gene-disease correlation has always been an important topic. With the emergence of large-scale connected data sets in biology, we use known correlations between the entities, which may be from different sets, to build a biological heterogeneous network and propose a new network embedded representation algorithm to calculate the correlation between disease and genes, using the correlation score to predict pathogenic genes. Then, we conduct several experiments to compare our method to other state-of-the-art methods. The results reveal that our method achieves better performance than the traditional methods.
Homepage: