bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical observation of bronchoscopy alveolar lavage combined with thoracoscopy in the treatment of empyema in children
Authors: Yue Fang , Yang Zhiguo , Yang Fan , Liu Yanfang , Zhao Ling , Chen Zhiguo , Gao Feifei
Published: December 2019

The objective of this study was to investigate the therapeutic effects of bronchoscopy alveolar lavage (BAL) combined with thoracoscopy in the treatment of empyema in children.

Retrospectively analyzed 174 cases of pediatric empyema treated with thoracoscopy combined with BAL from January 2010 to December 2016 in our hospital. All the cases, according to admission order, were randomly divided into 2 groups, the control group (group A), which contained 89 cases, was treated with thoracoscopy; and the experimental group (group B), which contained 85 cases, was treated with BAL combined with thoracoscopy. The results of BAL treatment, the inflammatory indexes including body temperature, total leukocyte count in peripheral blood and CRP, and the therapeutic effect and prognosis including the days of antibiotic use, hospital stay, the incidence of thoracotomy and lobectomy were compared between the 2 groups.

There was statistical difference in all the therapeutic indexes (P < .05).

Bronchoscopy alveolar lavage combined with thoracoscopy has a higher success rate in the treatment of pediatric empyema, and is more comprehensive, safe and effective in controlling inflammation.
Compound Kushen injection plus platinum-based chemotherapy for stage IIIB/IV non-small cell lung cancer
Authors: Chen Hongwei , Yao Xiaojun , Li Ting , Lam Christopher Wai-Kei , Zhang Huixia , Wang Jue , Zhang Wei , Leung Elaine Lai-Han , Wu Qibiao
Published: December 2019

Background:

Compound Kushen injection (CKI) is a commonly used anti-tumor Chinese patent medicine, which is extracted from Kushen (Radix Sophorae Flavescentis) and Baituling (Rhizoma Smilacis Glabrae) and has been widely prescribed as an add-on therapy to platinum-based chemotherapy (PBC) for advanced non-small cell lung cancer (NSCLC). However, the efficacy and safety of this combination therapy remain controversial.

Methods and analysis:

A systematic review and meta-analysis will be performed following the PRISMA (Preferred Reported Items for Systematic Review and Meta-analysis) guidelines. All randomized controlled trials (RCTs) comparing CKI in combination with PBC versus PBC alone will be retrieved and assessed for inclusion. Analyses will be performed using Review Manager 5.3, Comprehensive Meta-Analysis 3.0 and Trial Sequential Analysis software. The disease control rate (DCR) will be defined as the primary outcome, and the objective response rate (ORR), quality of life (QOL), survival rate, and toxicities will be the secondary outcomes.

Results:

This study will systematically evaluate the efficacy and safety of Compound Kushen injection combined with platinum-based chemotherapy in the treatment of stage III/IV NSCLC. The results of this study will be published in a peer-reviewed journal.

Conclusions:

This systematic review and meta-analysis of eligible randomized controlled trials will evaluate the effects of Compound Kushen injection as adjunctive therapy to platinum-based chemotherapy in patients with stage III/IV non-small cell lung cancer, thus providing evidence to the clinical use of this combination therapy for the specific subsets of patients.

PROSPERO registration number:

CRD42019134892
Mortality and cause of death in distal radius fracture patients
Authors: Lee Jung Woo , Lee Yong-Beom , Kwon Bong Cheol , Yoo Je-Hyun , Choi Hyo Geun
Published: December 2019

The various harmful impacts of distal radius fractures (DRFs) may cause adverse effects. Although previous studies have reported the adverse effects of DRFs on mortality, most studies were performed in adults of advanced age and paid little attention to confounding factors of mortality. Furthermore, most of these studies investigated the overall impact of DRFs on mortality without differentiating the specified causes of death.

The purpose of the present study was to estimate the risk of mortality in DRF patients according to the cause of death.

Data from the Korean National Health Insurance Service-National Sample Cohort (NHIS-NSC) from 2002 to 2013 were collected. A total of 27,295 DRF participants who were 50 years or older were 1:4 matched with control participants for age, sex, income, and region of residence. The causes of death were grouped into 12 classifications.

DRFs were not associated with increased overall mortality. The adjusted hazard ratio (HR) of mortality was 1.04 (95% confidence interval [CI] = 0.98–1.11, P = .237). The adjusted HR for mortality was not significantly different according to age. The odds ratio of overall mortality was 1.03 (95% CI = 0.97–1.11, P = .329).

DRFs were not associated with a significant increase in mortality.
Characteristics and Operational Performance of Hospital-affiliated Freestanding Emergency Departments
Authors: Baehr Avi , Ledbetter Caroline , Bookman Kelly J. , Wang Yang , Ginde Adit A. , Wiler Jennifer L.
Published: December 2019

Background:

As there has been increasing pressure on acute care services to redefine how their care is delivered, hospital-affiliated freestanding emergency departments (FREDs) have rapidly expanded in some markets. Little is known about the populations served or the quality of care provided by these facilities.

Objective:

The objective of this study was to compare patient visit characteristics, geographic catchment areas, and operational performance between hospital-affiliated FREDs and hospital-based emergency departments (HEDs).

Research Design:

This was a population-based retrospective observational analysis of 19 FREDs and 5 HEDs in a single health system over a 1-year period. We abstracted patient visit data from the electronic health record and supplemented catchment area data with the 2016 American Community Survey. We analyzed lengths of stay using generalized linear models adjusted for age, severity, and insurance status.

Results:

FREDs had lower proportions of visits from nonwhite patients and more visits from privately insured patients than HEDs, with similar proportions of uninsured patient visits. These trends were mirrored in catchment area analyses. FRED visits were lower acuity, with fewer imaging and laboratory tests performed. The adjusted mean length of stay for discharged patients was 109 minutes for FREDs compared with 169 minutes for HEDs. For admitted or transferred patients, adjusted lengths of stay were 213 minutes at FREDs and 287 minutes at HEDs.

Conclusions:

Hospital-affiliated FREDs serve more affluent and less diverse patient populations and geographic communities. Relative to HEDs, they have lower acuity patient visits with fewer tests, and they have shorter lengths of stay, even after adjustment for patient visit characteristics.
Do Residents Participating in Minnesota’s Return to Community Initiative Experience Similar Postdischarge Outcomes to Their Peers?
Authors: Hass Zachary , Woodhouse Mark , Arling Greg
Published: December 2019

Objective:

The objective of this study was to evaluate the impact of Minnesota’s Return to Community Initiative (RTCI) on postdischarge outcomes for nursing home residents transitioned through the program.

Data Sources:

Secondary data were from the Minimum Data Set and RTCI staff (January 2015 to December 2016), state Medicaid eligibility files and death records. The sample consisted of 29,201 nursing home discharges in Minnesota occurring in 2015.

Research Design:

Cox proportional hazard models were used to compare 1-year postdischarge outcomes of nursing home readmission, mortality, and Medicaid conversion for RTCI assisted community discharges and a propensity-matched sample of unassisted community discharges.

Results:

The majority (60%) of RTCI assisted discharges remained alive, in the community and not having converted at Medicaid at 1 year after discharge. Time to mortality was significantly lower for the assisted group than the unassisted group, but time to readmission and Medicaid conversion were similar.

Conclusion:

The RTCI assisted residents fared well postdischarge in their time to mortality, nursing home readmission, and Medicaid conversion; they lived longer than a propensity-matched sample of their peers.
“…Part of My Identity”
Authors: Clausi Laura , Schneider Margaret
Published: December 2019

Purpose:

The purpose of this study was to explore the lived experiences of young women with type 1 diabetes and the ways in which their self-management of their illness may influence their perceived sense of self.

Methods:

Semistructured interviews were conducted with 7 women aged 18 to 22 years who had been formally given a diagnosis of type 1 diabetes. Interviews were audiotaped and transcribed verbatim, and subsequent member checks were completed. Returned member checks and transcriptions were then analyzed using a form of thematic analysis.

Results:

Three main themes emerged from the data including (1) “I just want to be more free, I guess”; (2) “It's just, like another part of me”; and (3) “I just kind of want to be normal, like I don't even have diabetes.” A number of subthemes within each theme were also identified.

Discussion:

Findings indicated that many aspects of the young women's day-to-day illness management routine impacted the way in which they viewed themselves. Key aspects that were identified by these women included issues with wanting to feel more free in terms of how they self-manage, trying to stay positive, and wanting to be normal, yet feeling as though they are still different from their peers.
Anorectal and Urogenital Mycoplasma genitalium in Nigerian Men Who Have Sex With Men and Transgender Women: Prevalence, Incidence, and Association With HIV
Authors: Crowell Trevor A. , Lawlor John , Lombardi Kara , Nowak Rebecca G. , Hardick Justin , Odeyemi Sunday , Kokogho Afoke , Malia Jennifer , Stewart Catherine , Robb Merlin L. , Baral Stefan D. , Adebajo Sylvia , Charurat Manhattan E. , Ake Julie A. , Peel Sheila A. , Gaydos Charlotte A.
Published: December 2019

Among 413 Nigerian men who have sex with men and transgender women, retrospective testing for Mycoplasma genitalium revealed mostly asymptomatic infections of the anorectum (prevalence, 36.8%; incidence, 18.4 cases/100 person-years) and urogenital tract (12.4%, 4.0 cases/100 person-years). Risk factors included HIV and increasing number of sex partners.
An Assessment of Risk Factors for Herpes Simplex Virus Type 2 Infection in Malawian Women Using 2 Classifications for the HerpeSelect 2 Test
Authors: Chakraborty Payal , Norris Alison H. , Huber-Krum Sarah , Garver Sarah , Hood Robert B. , Banda Venson , Esber Allahna , Patricia Carr Reese , Krysiak Robert , Turner Abigail Norris
Published: December 2019

Background

The HerpeSelect 2 ELISA IgG test for herpes simplex virus type 2 (HSV-2) infection is widely used, convenient, and inexpensive. However, it has been shown to have lower specificity among populations in Sub-Saharan Africa compared with HSV-2 tests regarded as criterion standards.

Methods

In 2016, we collected blood and survey data from 248 women participating in a community-based cohort study in rural Malawi (the Umoyo wa Thanzi project). Using multinomial logistic regression accounting for village-level clustering, we examined unadjusted associations between select demographic and sexual risk factors and HSV-2 serostatus. Because increasing the index value cutpoint for a positive result improves specificity, we coded HSV-2 serostatus in 2 ways: the manufacturer's recommended cutpoints (<0.9, negative; 0.9–1.1, indeterminate; >1.1, positive) and modified cutpoints with improved specificity (<0.9, negative; 0.9–3.5, indeterminate; >3.5, positive). We aimed to investigate whether associations between select risk factors and HSV-2 serostatus varied under the 2 approaches.

Results

The prevalence of HSV-2 in this sample was 67% under the manufacturer's cutpoint and 22% under the modified cutpoint. Under both cutpoints, age, household size, number of marriages, and number of pregnancies were associated with HSV-2–positive serostatus. Using modified cutpoints, current bacterial vaginosis (odds ratio [OR], 3.17; 95% confidence interval [CI], 1.35–7.47), partner concurrency (OR, 4.88; 95% CI, 2.54–9.37) and unsure about partner concurrency (OR, 1.91; 95% CI, 1.08–3.38) were associated with HSV-2 seropositivity. Household size, education, and marital status were the only variables significantly associated with indeterminate HSV-2 serostatus using the modified cutpoints.

Conclusion

HSV-2-focused interventions informed by identifying individuals likely to have or acquire HSV-2 must be aware that different target populations may emerge depending on which cutpoints are adopted.
Mapping Geographical Patterns and High Rate Areas for Sexually Transmitted Infections in Portugal: A Retrospective Study Based on the National Epidemiological Surveillance System
Authors: Jardim Santos Cláudia , Gomes Bernardo , Ribeiro Ana Isabel
Published: December 2019

Objective

Monitoring disease variation using finer scales to identify high-rate communities is a critical aspect for precision public health and for efficient resource allocation. This study aimed to map the spatial patterns of chlamydia, gonorrhea, and syphilis; identify high-rate areas across Portuguese municipalities; and determine the association of these sexually transmitted infections (STIs) with socioeconomic deprivation, urbanicity level, and population density.

Methods

The STI notifications at municipality level for the period 2015 to 2017 were obtained from Portugal's Epidemiologic Surveillance System (Sistema Nacional de Vigilância Epidemiológica). Spatial Bayesian models were used to calculate smoothed standardized notification rates, identify high- and low-rate areas and estimate associations (relative risk [RR], 95% credible intervals [95%CrI]).

Results

There were 4819 cases of chlamydia, gonorrhea, and syphilis reported, accounting for 15.3%, 33.2%, and 51.5% of the notifications, respectively. The STI notification rates were substantially higher in Porto and Lisbon Metropolitan Areas and concentrically disperse around those. Notification rates of the 3 STIs were strongly correlated (r > 0.8). Rates of gonorrhea (Q1—lowest density vs. Q5—highest RR, 2.10; 95% CrI, 1.08–4.25) and syphilis (RR, 3.16; 95% CrI, 2.00–5.13) were associated with population density. Notifications of chlamydia (Q1—least urban vs. Q5—most RR, 9.64; 95% CrI, 1.73–93.59) and syphilis (RR, 1.92; 95% CrI, 1.30–2.88) increased with urbanicity level. We also found that notification rates of gonorrhea were associated with socioeconomic deprivation (Q1—least vs. Q5—most deprived RR, 1.75; 95% CrI, 1.07–2.88).

Conclusions

Wide spatial inequalities in STI notification rates were observed, which were predominantly concentrated in the 2 metropolitan areas of the country. Our findings can help guide more targeted interventions to reduce STIs incidence.
Right Ventricle Rupture After Open Heart Surgery
Authors: Weyrauch Deland , Kemp Walter L. , Koponen Mark
Published: December 2019

The potential complications of cardiac surgery with sternotomy include mediastinitis and major bleeding, events that are infrequent but carry high mortality.

We report a unique complication of median sternotomy. A 71-year-old man underwent coronary artery bypass grafting complicated by sternal dehiscence on postoperative day 7. One week after discharge, he presented with purulent drainage from the sternal wound bed and was diagnosed as having mediastinitis. Irrigation, debridement, and sternal reconstruction were performed. Two days later, bleeding was observed in the wound, and during surgical exploration, a tear in the right ventricle was discovered, and the patient exsanguinated and died. Autopsy findings included focal adhesions connecting the posterior sternum to the right ventricle wall, as well as microscopic evidence of focally extensive fatty infiltration along the rupture margin of the myocardium.

Pertinent aspects of the case are reviewed, with particular attention to the possible microbial etiology of mediastinal infection and most likely mechanisms of injury contributing to the fatal right ventricular rupture.
Magnetic Resonance Kidney Parenchyma-T2 as a Novel Imaging Biomarker for Autosomal Dominant Polycystic Kidney Disease
Authors: Siedek Florian , Grundmann Franziska , Weiss Kilian , Pinto dos Santos Daniel , Arjune Sita , Haneder Stefan , Persigehl Thorsten , Müller Roman-Ulrich , Baessler Bettina
Published: December 2019

Objective

Autosomal dominant polycystic kidney disease (ADPKD) is a chronic progressive disorder with a significant disease burden leading to end-stage renal disease in more than 75% of the affected individuals. Although prediction of disease progression is highly important, all currently available biomarkers—including height-adjusted total kidney volume (htTKV)—have important drawbacks in the everyday clinical setting. Thus, the purpose of this study was to evaluate T2 mapping as a source of easily obtainable and accurate biomarkers, which are needed for improved patient counseling and selection of targeted treatment options.

Materials and Methods

A total of 139 ADPKD patients from The German ADPKD Tolvaptan Treatment Registry and 10 healthy controls underwent magnetic resonance imaging on a clinical 1.5-T system including acquisition of a Gradient-Echo-Spin-Echo T2 mapping sequence. The ADPKD patients were divided into 3 groups according to kidney cyst fraction (0%–35%, 36%–70%, >70%) as a surrogate marker for disease severity. The htTKV was calculated based on standard T2-weighted imaging. Mean T2 relaxation times of both kidneys (kidney-T2) as well as T2 relaxation times of the residual kidney parenchyma (parenchyma-T2) were measured on the T2 maps.

Results

Calculation of parenchyma-T2 was 6- to 10-fold faster than determination of htTKV and kidney-T2 (0.78 ± 0.14 vs 4.78 ± 1.17 minutes, P < 0.001; 0.78 ± 0.14 vs 7.59 ± 1.57 minutes, P < 0.001). Parenchyma-T2 showed a similarly strong correlation to cyst fraction (r = 0.77, P < 0.001) as kidney-T2 (r = 0.76, P < 0.001), the strongest correlation to the serum-derived biomarker copeptin (r = 0.37, P < 0.001), and allowed for the most distinct separation of patient groups divided according to cyst fraction. In contrast, htTKV showed an only moderate correlation to cyst fraction (r = 0.48, P < 0.001). These observations were even more evident when considering only patients with preserved kidney function.

Conclusions

The rapidly assessable parenchyma-T2 shows a strong association with disease severity early in disease and is superior to htTKV when it comes to correlation with renal cyst fraction.
Melatonin inhibits GABAergic neurons in the hypothalamus consistent with a reduction in wakefulness
Authors: Huang Yan , Li Yong , Leng Zhengwei
Published: December 2019

Although melatonin is necessary for circadian regulation of sleep, the mechanisms underlying this effect of melatonin are still unclear. In the present study, we showed that melatonin suppressed the activity of GABAergic neurons in the lateral hypothalamus, which has been reported to play a crucial role in maintaining wakefulness. The inhibitory effect of the melatonin was mediated by activation of melatonin 1 receptors and depended on the inhibition of hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels. At behavioral levels, infusion of melatonin into the lateral hypothalamus significantly decreased the locomotor and exploratory activities and increased the time of immobility in open filed. Additionally, using electroencephalogram (EEG) and electromyogram (EMG) recordings, we found that infusion of melatonin into the lateral hypothalamus decreased the time spent in wakefulness and increased the amount of sleep. Overall, these results suggest that melatonin inhibits GABAergic neurons in the lateral hypothalamus via melatonin 1 receptor-dependent inhibition of the HCN channels, which is consistent with a decrease in wakefulness. These findings provide a new mechanism underlying the hypnotic effect of the melatonin.
Over-expression of long noncoding RNA HOTAIRM1 promotes cell proliferation and invasion in human glioblastoma by up-regulating SP1 via sponging miR-137
Authors: Hao Yunfei , Li Xiaoli , Chen Hecheng , Huo Hongzhi , Liu Zongbao , Chai Erqing
Published: December 2019

Glioblastoma is the most aggressive malignant brain tumor in adults. Long noncoding RNA HOTAIRM1 (HOX antisense intergenic RNA myeloid 1) has been reported to participate in the progression of various cancers. However, the role of HOTAIRM1 in glioblastoma and its underlying mechanisms are largely unknown. The relative expression levels of HOTAIRM1, miR-137 and specificity protein 1 were detected by quantitative real-time PCR or western blot. The effects of HOTAIRM1 on cell proliferation and invasion were evaluated by Cell Counting Kit-8 assay and Transwell assay, respectively. The interactions among HOTAIRM1, miR-137 and specificity protein 1 were predicted by online softwares and confirmed by luciferase reporter assay and RNA immunoprecipitation assay. The levels of HOTAIRM1 and specificity protein 1 were significantly increased while miR-137 was significantly decreased in glioblastoma tissues and cells. Knockdown of HOTAIRM1 suppressed proliferation and invasion in glioblastoma cells. Moreover, miR-137 was bound to HOTAIRM1, and specificity protein 1 was identified as a target of miR-137. The protein level of specificity protein 1 was repressed by silencing the expression of HOTAIRM1, whereas the effect was restored by inhibiting the expression of miR-137. Downregulation of HOTAIRM1 expression suppressed the proliferation and invasion of glioblastoma cells by down-regulating specificity protein 1 expression via sponging miR-137, indicating a promising strategy for glioblastoma treatment.
Antagonistic muscle prefatigue weakens the functional corticomuscular coupling during isometric elbow extension contraction
Authors: Wang Lejun , Xie Zihang , Lu Aiyun , Lu Tianfeng , Zhang Shengnian , Zheng Fanhui , Niu Wenxin
Published: December 2019

Objective

During muscle fatigue, acute changes in the interaction between the sensorimotor cortex and peripheral neurons have been widely studied. However, it is still unclear about the effect of antagonist muscle prefatigue on corticomuscular coupling and central modulation. The purpose of this study was to investigate the changes in the magnitude of electroencephalogram-electromyography (EEG-EMG) coherence and phase synchronization index (PSI) induced by antagonistic muscle prefatigue.

Methods

Twelve young male volunteers conducted a 30-s long, nonfatiguing isometric elbow extension with a target force level of 20% maximum voluntary contraction (MVC) before and after a fatiguing sustained elbow flexion contraction at 20% MVC until task failure. Coherence and PSI between the EEG recorded over the sensorimotor cortex and the surface EMG of the triceps brachii (TB) muscle were quantified for the pre- and post-fatigue elbow extension contractions.

Results

Coherence and PSI in the gamma frequency band (35–60 Hz) were found significantly decreased in the postfatigue elbow extension contraction than the prefatigue contraction. The power of the EEG in the beta and gamma band were significantly increased, while the EMG power showed no significant changes when the antagonistic muscle was prefatigued. PSI in the gamma frequency band between the EMG of the TB muscle and the EEG were found significantly decreased during postfatigue elbow extension contraction compared with prefatigue contraction.

Conclusion

Antagonistic muscle prefatigue led to significantly lower gamma band corticomuscular coherence and phase coupling during an isometric elbow extension position task. The lower corticomuscular coupling may indicate a central modulation mechanism of antagonist muscle prefatigue that related to decreased descending common drive or joint instability compensation modulation mechanism.
RASmutations drive proliferative chronic myelomonocytic leukemia via activation of a novel KMT2A-PLK1 axis
Authors: Carr Ryan M. , Vorobyev Denis , Lasho Terra , Marks David L. , Tolosa Ezequiel J. , Vedder Alexis , Almada Luciana L. , Yurchenko Andrey , Padioleau Ismael , Alver Bonnie , Coltro Giacomo , Binder Moritz , Safgren Stephanie L. , Horn Isaac , You Xiaona , Droin Nathalie , Solary Eric , Balasis Maria E. , Berger Kurt , Pin Christopher , Witzig Thomas , Buradkar Ajinkya , Graf Temeida , Valent Peter , Mangaonkar Abhishek A. , Robertson Keith D. , Howard Matthew T. , Kaufmann Scott H. , Fernandez-Zapico Martin E. , Geissler Klaus , Padron Eric , Zhang Jing , Nikolaev Sergey , Patnaik Mrinal M.
Published: December 2019

ABSTRACT

Chronic myelomonocytic leukemia (CMML) is an aggressive hematological malignancy with limited treatment options. Whole exome (WES) and targeted sequencing of several independent cohorts of CMML patients, comparing dysplastic (dCMML) to proliferative (pCMML) CMML, as well as paired chronic phase disease and acute leukemic transformation (LT), associate acquisition of oncogenic RAS pathway mutations, the most common beingNRASG12D, with aggressive disease and with disease progression. Using patient derived progenitor colony assays and aNRASG12D-Vav-Cre mouse model, we further demonstrate the role of mutant RAS signaling in driving and maintaining pCMML phenotype. RNA-sequencing links RAS pathway mutations with an increased expression of genes encoding the mitotic checkpoint kinases PLK1 and WEE1. Further, we dmeoinstrated that non-mutated lysine methyltransferase KMT2A (MLL1) acts as mediator of NRAS-inducedPLK1andWEE1expression. Finally, we demonstrate the translational value of our findings by showing that pharmacological PLK1 inhibition decreases monocytosis and hepatosplenomegaly while improving hematopoiesis inRASmutant patient-derived xenografts. Hence, we define severe CMML as oncogenic RAS pathway-enriched malignancies, with a unique gene expression profile regulated byKMT2A, amenable to therapeutic intervention.
Single strain control of microbial consortia
Authors: Fedorec Alex J.H. , Karkaria Behzad D. , Sulu Michael , Barnes Chris P
Published: December 2019

The scale of the biological systems we can engineer is limited by the burden that host cells can bear. Division-of-labour can spread that burden across a community of cells but competitive exclusion inevitably leads to the removal of less fit community members over time. Here, we leverage amensalism and competitive exclusion to stabilise multi-species communities by engineering a strain ofEscherichia coliwhich secretes a toxin in response to competition. We show mathematically and experimentally that such a system can produce stable populations with a composition that is tunable by easily controllable parameters. This is the first system to use competitive exclusion to create a stable two-species consortia and the first to only require the engineering of a single strain.
Cross-validation of technologies for genotypingCYP2D6andCYP2C19
Authors: Henriques Beatriz Carvalho , Buchner Amanda , Hu Xiuying , Yavorskyy Vasyl , Wang Yabing , Martens Kristina , Carr Michael , Asl Bahareh Behroozi , Hague Joshua , Maier Wolfgang , Dernovsek Mojca Z. , Henigsberg Neven , Souery Daniel , Cattaneo Annamaria , Hauser Joanna , Mors Ole , Rietschel Marcella , Pfeffer Gerald , Bousman Chad , Aitchison Katherine J.
Published: December 2019

Background

CYP2D6 and CYP2C19 are cytochrome P450 enzymes involved in the metabolism of many medications from multiple therapeutic classes. Associations between patterns of variants (known as haplotypes) in the genes encoding them (CYP2D6andCYP2C19) and enzyme activities are well described. The genes in fact comprise 21% of biomarkers in drug labels. Despite this, genotyping is not common, partly attributable to its challenging nature (CYP2D6having >100 haplotypes, including those with sequence from an adjacent pseudogene, and gene duplications). We cross-validated different methodologies for identifying haplotypes in these genes against each other.

Methods

Ninety-two samples with a variety ofCYP2D6andCYP2C19genotypes according to prior AmpliChip CYP450 and TaqManCYP2C19*17data were selected from the Genome-based therapeutic drugs for depression (GENDEP) study. Genotyping was performed with TaqMan copy number variant (CNV) and single nucleotide variant (SNV) analysis, the next generation sequencing-based Ion S5 AmpliSeq Pharmacogenomics Panel, PharmacoScan, long-range polymerase chain reaction (L-PCR) followed by amplicon analysis, and Agena forCYP2C19. Variant pattern to haplotype translation was automated.

Results

The inter-platform concordance forCYP2C19was high (up to 100% for available data). ForCYP2D6, the IonS5-PharmacoScan concordance was 94% for a range of variants tested apart from those with at least one extra copy of aCYP2D6gene (occurring at a frequency of 3.8%, 33/853), or those with substantial sequence derived from pseudogene, known as hybrids (3%, 26/853).

Conclusions

Inter-platform concordance forCYP2C19was high, and, moreover, the Ion S5 and PharmacoScan data were 100% concordant with that from a TaqManCYP2C19*2assay. We have also demonstrated feasibility of using an NGS platform for genotypingCYP2D6andCYP2C19, with automated data interpretation methodology. This points the way to a method of makingCYP2D6andCYP2C19genotyping more readily accessible.
Artiphysiology reveals visual preferences underlying V4-like blur selectivity in a deep convolutional neural network
Authors: Entezari Saba , Bair Wyeth
Published: December 2019

Blurry visual scenes arise from many causes and image blur is known to be important for scene interpretation, yet there have been very few studies of the visual encoding of blur in biological visual systems or in artificial visual systems trained for object recognition. Recently, a study of single neurons in the visual cortex of macaque monkeys found that a significant fraction of neurons were more responsive to blurred visual stimuli than to sharply defined stimuli. This raises two questions: (1) what types of visual features in natural scenes might underlie blur selectivity in macaque cortex, and (2) can blur selectivity be found in artificial neural networks using the simple artificial stimuli previously applied in vivo? To answer these questions, we presented simple shape stimuli to the widely studied deep convolutional neural network (CNN) known as AlexNet and used deconv-net visualization to identify features that are critical for driving blur selective units. We found that a substantial number of units in the CNN were selective for blur and that several categories of blur selectivity emerged in early-to-middle processing stages. Prominent among these is a set of units selective for spatial boundaries defined by blur contrast. These blur-contrast boundary units may serve the important task of segmentation in natural photographic images and may relate to a large body of literature on second-order boundary detection. Our results lead to the prediction that such units could exist in the visual cortex but have yet to be well characterized and localized, and they provide direction for future neurophysiological tests of blur selectivity in vivo.
Human antimicrobial peptide, LL-37, induces non-inheritable reduced susceptibility to vancomycin inStaphylococcus aureus
Authors: Friberg Cathrine , Haaber Jakob , Vestergaard Martin , Fait Anaëlle , Perrot Veronique , Levin Bruce , Ingmer Hanne
Published: December 2019

Antimicrobial peptides (AMPs) are central components of the innate immune system providing protection against pathogens. Yet, serum and tissue concentrations vary between individuals and disease conditions. We demonstrate that the human AMP LL-37 lowers the susceptibility to vancomycin in the community-associated methicillin-resistant S. aureus (CA-MRSA) strain FPR3757 (USA300). Vancomycin is used to treat serious MRSA infections, but treatment failures occur despite MRSA strains being tested susceptible according to standard susceptibility methods. Exposure to physiologically relevant concentrations of LL-37 increased the minimum inhibitory concentration (MIC) of S. aureus towards vancomycin by 75% and resulted in shortened lag-phase and increased colony formation at sub-inhibitory concentrations of vancomycin. Computer simulations using a mathematical antibiotic treatment model indicated that a small increase in MIC might decrease the efficacy of vancomycin in clearing an S. aureus infection. This prediction was supported in a Galleria mellonella infection model, where exposure of S. aureus to LL-37 abolished the antimicrobial effect of vancomycin. Thus, physiologically relevant concentrations of LL-37 reduce susceptibility to vancomycin, indicating that tissue and host-specific variations in LL-37 concentrations may influence vancomycin susceptibility in vivo.
Multimodal DTI-TMS assessment of the motor system in patients with chronic ischemic stroke
Authors: Nazarova M. , Kulikova S. , Piradov M. , Limonova A. , Dobrynina L. , Konovalov R. , Novikov P. , Sehm B. , Villringer A. , Nikulin V.
Published: December 2019

Background and Purpose

Despite the continuing efforts in multimodal assessment of the motor system after stroke, conclusive findings on the complementarity of functional and structural metrics of the corticospinal tract (CST) integrity and the role of the contralesional hemisphere are still missing. The aim of this work was to find the best combination of the motor system parameters, allowing classification of patients into three predefined groups of upper limb motor recovery.

Methods

35 chronic ischemic stroke patients (47 [26–66] y.o., 29 [6–58] months post-stroke) with only supratentorial lesion and unilateral upper extremity weakness were enrolled. Patients were divided into three groups depending on the upper limb motor recovery. Non-parametric statistical tests and regression analysis were used to investigate the relationships among structural and functional motor system parameters, probed by diffusion tensor imaging (DTI) and transcranial magnetic stimulation (TMS). In addition, stratification rules were tested, using a decision tree classifier to identify parameters explaining motor recovery.

Results

Fractional anisotropy (FA) ratio in the internal capsule (IC) and absence/presence of motor evoked potentials (MEPs), were equally discriminative of the worst motor outcome group (96% accuracy). MEP presence diverged for two investigated hand muscles. Concurrently, for the three recovery groups’ classification, the best parameter combination was: IC FA ratio and Fréchet distance between the contralesional and ipsilesional CST FA profiles (91% accuracy). No other metrics had any additional value for patients’ classification.

Conclusions

This study demonstrates that IC FA ratio and MEPs absence are equally important markers for poor recovery. Importantly, we found that MEPs should be controlled in more than one hand muscle. Finally, we show that better separation between different motor recovery groups may be achieved when considering the whole CST FA profile.
VariantStore: A Large-Scale Genomic Variant Search Index
Authors: Pandey Prashant , Gao Yinjie , Kingsford Carl
Published: December 2019

The ability to efficiently query genomic variants from thousands of samples is critical to achieving the full potential of many medical and scientific applications such as personalized medicine. Performing variant queries based on coordinates in the reference or sample sequences is at the core of these applications. Efficiently supporting variant queries across thousands of samples is computationally challenging. Most solutions only support queries based on the reference coordinates and the ones that support queries based on coordinates across multiple samples do not scale to data containing more than a few thousand samples. We present VariantStore, a system for efficiently indexing and querying genomic variants and their sequences in either the reference or sample-specific coordinate systems. We show the scalability of VariantStore by indexing genomic variants from the TCGA-BRCA project containing 8640 samples and 5M variants in 4 Hrs and the 1000 genomes project containing 2500 samples and 924M variants in 3 Hrs. Querying for variants in a gene takes between 0.002 – 3 seconds using memory only 10% of the size of the full representation.
The interplay between host genetics and the gut microbiome reveals common and distinct microbiome features for human complex diseases
Authors: Xu Fengzhe , Fu Yuanqing , Sun Ting-yu , Jiang Zengliang , Miao Zelei , Shuai Menglei , Gou Wanglong , Ling Chu-wen , Yang Jian , Wang Jun , Chen Yu-ming , Zheng Ju-Sheng
Published: December 2019

There is increasing interest about the interplay between host genetics and gut microbiome on human complex diseases, with prior evidence mainly derived from animal models. In addition, the shared and distinct microbiome features among human complex diseases remain largely unclear. We performed a microbiome genome-wide association study to identify host genetic variants associated with gut microbiome in a Chinese population with 1475 participants. We then conducted bi-directional Mendelian randomization analyses to examine the potential causal associations between gut microbiome and human complex diseases. We found thatSaccharibacteria(also known asTM7phylum) could potentially improve renal function by affecting renal function biomarkers (i.e., creatinine and estimated glomerular filtration rate). In contrast, atrial fibrillation, chronic kidney disease and prostate cancer, as predicted by the host genetics, had potential causal effect on gut microbiome. Further disease-microbiome feature analysis suggested that gut microbiome features revealed novel relationship among human complex diseases. These results suggest that different human complex diseases share common and distinct gut microbiome features, which may help re-shape our understanding about the disease etiology in humans.
TRPS1 acts as a context-dependent regulator of mammary epithelial cell growth/differentiation and breast cancer development
Authors: Cornelissen Lisette M. , Drenth Anne Paulien , van der Burg Eline , de Bruijn Roebi , Pritchard Colin E.J. , Huijbers Ivo J. , Zwart Wilbert , Jonkers Jos
Published: December 2019

The GATA-type zinc finger transcription factor TRPS1 has been implicated in breast cancer. However, its precise role remains unclear, as both amplifications and inactivating mutations in TRPS1 have been reported. Here, we used in vitro and in vivo loss-of-function approaches to dissect the role of TRPS1 in mammary gland development and invasive lobular breast carcinoma, which is hallmarked by functional loss of E-cadherin. We show that TRPS1 is essential in mammary epithelial cells, since TRPS1-mediated suppression of interferon signaling promotes in vitro proliferation and lactogenic differentiation. Similarly, TRPS1 expression is indispensable for proliferation of mammary organoids and in vivo survival of luminal epithelial cells during mammary gland development. However, the consequences of TRPS1 loss are dependent on E-cadherin status, as combined inactivation of E-cadherin and TRPS1 causes persistent proliferation of mammary organoids and accelerated mammary tumor formation in mice. Together, our results demonstrate that TRPS1 can function as a context-dependent tumor suppressor in breast cancer, while being essential for growth and differentiation of normal mammary epithelial cells.
Real‐world efficacy and safety data for dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma
Authors: Takahashi Akira , Namikawa Kenjiro , Nakano Eiji , Yamazaki Naoya
Published: December 2019

We conducted a retrospective investigation of the efficacy and safety of dabrafenib and trametinib combination therapy in Japanese patients with BRAF V600 mutation‐positive advanced melanoma in real‐world clinical practise. The study analyzed 50 patients who received dabrafenib and trametinib combination therapy for BRAF V600 mutation‐positive advanced melanoma in our hospital (26 men and 24 women, aged 21–86 years, inclusive; median age, 53 years). The response rate was 72.3%, with complete response (CR) achieved in eight cases (17.0%), partial response in 26 (55.3%), stable disease in nine (19.1%) and progressive disease in four (8.5%). Median progression‐free survival (PFS) was 12 months, and median overall survival (OS) was 23 months. Disease progression occurred in 29 of the 50 patients during the study period, and 25 patients died. Baseline lactate dehydrogenase and the number of organs with metastasis were important predictive factors for PFS and OS, and CR to combination therapy was a predictive factor for long‐term remission. Adverse events occurred in 88% of cases; 16% were grade 3 or worse. The adverse events observed in 50% of more of patients were rash (56%) and pyrexia (52%). The efficacy of dabrafenib and trametinib combination therapy in Japanese patients was similar to that reported in global studies, and the same adverse events were generally reported; however, rash tended to occur more frequently in the patients in our study.
Dysfunction of the endothelium and constriction of the isolated rat's middle cerebral artery in low sodium environment in the presence of vasopressin
Authors: Aleksandrowicz Marta , Klapczynska Katarzyna , Kozniewska Ewa
Published: December 2019

Hyponatraemia, a water–electrolyte disorder diagnosed in patients with subarachnoid haemorrhage (SAH), increases a risk of persistent vasospasm. In majority of cases, hyponatraemia results from inappropriate secretion of vasopressin (AVP). The effect of AVP‐associated hyponatraemia on cerebral vasculature is unknown. The present study aimed to elucidate the role of AVP in the response of the middle cerebral artery (MCA) of the rat to hyponatraemia. Isolated, cannulated, and pressurized rat MCAs were perfused/superfused with physiological (Na+ = 144 mmol/L) buffer or low‐sodium (Na+ = 121 mmol/L) buffer containing either AVP or angiotensin II (ANG II). ANG II was used to check if the effect of low plasma sodium concentration combined with AVP on the MCA tone is unique to vasopressin. At physiological Na+ concentration, vasopressin (1.4 × 10−11 mol/L) or angiotensin II (10−9 mol/L) resulted in relaxation of the MCA. Substitution of low‐sodium for the normal sodium buffer with the same concentration of AVP, resulted in the constriction of the MCA. This effect was absent after removal of the endothelium, administration of vasopressin V1 receptor antagonist or concomitant inhibition of endothelin‐1 receptors and synthesis of thromboxane A2. In contrast, no constriction of the MCA in low‐sodium buffer was observed when AVP was replaced with ANG II. Our data suggest that presence of vasopressin and low sodium ion concentration results in the change of endothelium phenotype from pro‐vasodilatory to pro‐vasoconstrictory. This phenomenon may be an overlooked factor contributing to vasospasm in SAH patients with hyponatraemia caused by inappropriate antidiuretic hormone secretion (SIADH).
Stem cell paracrine actions in tissue regeneration and potential therapeutic effect in human endometrium: a retrospective study
Authors: de Miguel‐Gómez L , Ferrero H , López‐Martínez S , Campo H , López‐Pérez N , Faus A , Hervás D , Santamaría X , Pellicer A , Cervelló I
Published: December 2019

Objective

Determining genetic and paracrine mechanisms behind endometrial regeneration in Asherman's syndrome and endometrial atrophy (AS/EA) patients after autologous CD133+ bone marrow‐derived stem cell (CD133+BMDSC) transplantation.

Design

Retrospective study using human endometrial biopsies and mouse models.

Setting

Fundación‐IVI, IIS‐La Fe, Valencia, Spain.

Samples

Endometrial biopsies collected before and after CD133+BMDSC therapy, from eight women with AS/EA (NCT02144987) from the uterus of five mice with only left horns receiving CD133+BMDSC therapy.

Methods

In human samples, haematoxylin and eosin (H&E) staining, RNA arrays, PCR validation, and neutrophil elastase (NE) immunohistochemistry (IHQ). In mouse samples, PCR validation and protein immunoarrays.

Main outcome measures

H&E microscopic evaluation, RNA expression levels, PCR, and growth/angiogenic factors quantification, NE IHQ signal.

Results

Treatment improved endometrial morphology and thickness for all patients. In human samples, Jun, Serpine1, and Il4 were up‐regulated whereas Ccnd1 and Cxcl8 were down‐regulated after treatment. The significant decrease of NE signal corroborated Cxcl8 expression. Animal model analysis confirmed human results and revealed a higher expression of pro‐angiogenic cytokines (IL18, HGF, MCP‐1, MIP2) in treated uterine horns.

Conclusions

CD133+BMDSC seems to activate several factors through a paracrine mechanism to help tissue regeneration, modifying endometrial behaviour through an immunomodulatory milieu that precedes proliferation and angiogenic processes. Insight into these processes could bring us one step closer to a non‐invasive treatment for AS/EA patients.

Tweetable abstract

CD133+BMDSC therapy regenerates endometrium, modifying the immunological milieu that precedes proliferation and angiogenesis.
Evaluation of treatments for Bartholin’s cyst or abscess: a systematic review
Authors: Illingworth BJG , Stocking K , Showell M , Kirk E , Duffy JMN
Published: December 2019

Background

No consensus on the management of symptomatic cysts or abscesses of the Bartholin’s gland exists.

Objectives

To assess the effectiveness and safety of surgical interventions for a symptomatic Bartholin’s cyst or abscess.

Search Strategy

We searched bibliographical databases from inception to April 2019.

Selection Criteria

Randomised trials evaluating a surgical intervention for the treatment of a symptomatic Bartholin’s cyst or abscess.

Data Collection and Analysis

Eight trials, reporting data from 699 women, were included. Study characteristics and methodological quality were recorded for each trial. Summary estimates were calculated using random‐effects methods.

Main Results

When considering the recurrence of a symptomatic Bartholin’s cyst or abscess, the evidence was consistent with notable effects in either direction (risk ratio [RR] 0.76; 95% confidence interval [CI] 0.41–1.40) when comparing marsupialisation with incision, drainage and insertion of a Word catheter. Limited inference could be made when comparing marsupialisation with incision, drainage and silver nitrate insertion (RR 1.00; 95% CI 0.57–1.75), and incision, drainage and cavity closure (RR 0.25; 95% CI 0.01–4.89). There was limited reporting of secondary outcomes, including haematoma, infectious morbidity and persistent dyspareunia.

Conclusions

Current randomised trial evidence does not support the use of any single surgical intervention for the treatment of a symptomatic cyst or abscess of the Bartholin’s gland.

Prospective Registration

PROSPERO: International Prospective Register of Systematic Reviews; CRD42018088553.

Tweetable Abstract

Further research is needed to identify an effective treatment for #Bartholin’s cyst or abscess. @jamesmnduffy
Endogeneity and the Dynamics of Voluntary Disclosure Quality: Is there Really an Effect on the Cost of Equity Capital?*
Authors: Eugster Florian
Published: December 2019

Research on the effects of voluntary disclosure quality on the cost of equity capital is often plagued by endogeneity concerns. In this paper, I use a dynamic panel system GMM estimator, which provides internal instruments from the firm's history that directly address endogeneity arising from unobserved heterogeneity and simultaneity. By using hand‐collected voluntary disclosure scores for firms listed in the Swiss stock exchange, I examine the dynamic relation between voluntary disclosure quality and the cost of equity capital in a panel over a period of 10 years. The results suggest that the relation between voluntary disclosure quality and the cost of equity capital becomes insignificant after controlling adequately for potential dynamic endogeneity, simultaneity, and unobserved heterogeneity.