bluuebunny/crossref_metadata_2025 huggingface dataset:
Building capacity: a cross-sectional evaluation of the US Training Institute for Dissemination and Implementation Research in Health
Authors: Vinson Cynthia A. , Clyne Mindy , Cardoza Nina , Emmons Karen M.
Published: November 2019

Background

In 2011, the National Institute of Health (NIH) initiated the Training in Dissemination and Implementation Research in Health (TIDIRH) program. Over its first 5 years, TIDIRH provided an in-person, week-long training to 197 investigators who were new to the dissemination and implementation (D&I) field. This paper evaluates the long-term impact of TIDIRH on trainees’ use of D&I methods, collaborations, and research funding.

Methods

Trainees were selected to participate through a competitive process. We compared the 197 trainees to 125 unselected applicants (UAs) whose application score was within one standard deviation of the mean for all trainees’ scores for the same application year. A portfolio analysis examined electronic applications for NIH peer-reviewed funding submitted by trainees and UAs between 2011 and 2019. A survey of trainees and UAs was conducted in 2016, as was a faculty survey among the 87 individuals who served as TIDIRH instructors.

Results

A major goal of TIDIRH was to build the field, at least in part through networking and collaboration. Thirty-eight percent of trainees indicated they had extensive contact with faculty following the training, and an additional 38% indicated they had at least limited contact. Twenty-four percent of trainees had extensive collaboration with other fellows post-TIDIRH, and 43% had at least limited contact. Collaborative activities included the full range of academic activities, including manuscript development, grant writing, and consultation/collaboration on research studies.

The portfolio analysis combining grant mechanisms showed that overall, TIDIRH trainees submitted more peer-reviewed NIH grants per person than UA and had significantly better funding outcomes (25% vs 19% funded, respectively). The greatest difference was for large research project, program/center, and cooperative agreement grants mechanisms.

Conclusions

Overall, this evaluation found that TIDIRH is achieving its three primary goals: (1) building a pipeline of D&I investigators, (2) creating a network of scholars to build the field, and (3) improving funding outcomes for D&I grants.
In silico comparison of the dosimetric impacts of a greater omentum spacer for abdominal and pelvic tumors in carbon-ion, proton and photon radiotherapy
Authors: Yamada Masayoshi , Sato Hiraku , Ieko Yoshiro , Miyasaka Yuya , Kanai Takayuki , Yano Natsuko , Ono Takashi , Akamatsu Hiroko , Harada Mayumi , Ichikawa Mayumi , Teranishi Yasushi , Kikuchi Yasuhiro , Nemoto Kenji
Published: November 2019

Purpose

The purpose of this study was to compare carbon-ion (C-ion), proton and photon radiotherapy (RT) plans with regard to dose reduction of the gastrointestinal (GI) tract by using a greater omentum spacer (GO spacer).

Methods

We retrospectively retrieved data for ten patients who received the GO spacer as surgical spacer placement for abdominal and pelvic tumors. Simulation plans were created on pre-spacer Computed Tomography (CT) and post-spacer CT for C-ion RT, proton RT and photon RT to compare the dose of the GI tract. The plans were normalized so that at least 95% of the planning target volume (PTV) received 70 Gy (relative biological effectiveness equivalent) delivered in 35 fractions. All plans were created with the lowest possible dose to the GI tract under conditions that meet the dose constraints for the PTV and spinal cord (maximum dose < 45 Gy). The part of the GI tract to be evaluated was defined as that most adjacent to the PTV. C-ion RT plans and proton RT plans were calculated by a spot scanning technique, and photon RT plans were calculated employing by fixed-field intensity-modulated radiation therapy.

Results

D2 cc and V10–70 of the GI tract were significantly lower on post-spacer plans than on pre-spacer plans for all three RT modalities. Regarding post-spacer plans, D2 cc of the GI tract was significantly lower on C-ion RT plans and proton RT plans than on photon RT plans (C-ion vs photonp = 0.001, proton vs photonp = 0.002). However, there was no significant difference between C-ion RT plans and proton RT plans for D2 cc of the GI tract (C-ion vs protonp = 0.992). In the photon RT plan for one patient, D2 cc of the GI tract did not meet < 50 Gy.

Conclusions

The GO spacer shows a significant dose reduction effect on the GI tract.
Infiltration tendency of internal mammary lymph nodes involvement in patients with breast cancer: anatomical characteristics and implications for target delineation
Authors: Wang Yujie , Qi Weixiang , Xu Haoping , Zhang Miao , Han Yimin , Chen Jiayi , Xu Cheng
Published: November 2019

Background

Despite increasing clinical data suggest that internal mammary node (IMN) irradiation would improve local-regional control and overall survival in breast cancer, its role remains controversial due to increased risk of cardiac and pulmonary toxicity. The current study aims to determine the high risk areas of IMN metastases by collecting and analyzing the axial imaging of IMN involvement, in order to optimize IMN delineation for breast cancer.

Methods

Breast cancer patients with IMN involvement were retrospectively identified from single-center database. All available imaging modalities including thoracic CT, breast MRI, ultrasound and PET/CT were used to diagnose IMN metastases. Anatomical characteristics from axial imaging, including distribution of involved ribs and distance from the internal mammary vessels (IMV), were collected for each metastatic IMN. What’s more,the natural infiltration tendency of IMNs from IMV was calculated in this study.

Results

In total, 83 metastatic IMNs from 70 breast cancer patients (initial diagnosed:34 and recurrence: 36) were located from axial CT image in this study. The second intercostal space was the most likely involved in patients with single(n = 35, 53.0%) and multiple intercostal space (n = 31, 47.0%) involvement. The percentage of including IMN with a 5 mm, 6 mm and 7 mm medial/lateral distance to the IMV were 75.9% (63/83), 89.2.6% (74/83) and 92.3% (77/83) respectively. While in maximal dorsal/ventral distance, nearly 95% of the nodes were encompassed into 6 mm depth to the IMV. Over 65% of IMN adenopathy (32/49,65.3%) were found to have a growth direction close to the sternum. By retrospective reviewing diagnostic reports, MRI demonstrated a high diagnostic performance in diagnosis of IMN disease (90.3%, 28/31), while CT had a higher misdiagnosis rate (22/63, 34.9%). The diagnostic efficiency of IMN could be improved if different methods were combined.

Conclusions

For patients with indications of prophylactic IMN irradiation, a 7 mm medial and 6 mm dorsal distance to the IMV on axial CT would be optimal to cover the clinical volume of IMN; and it would be reasonable to extend clinical tumor volume (CTV) coverage towards sternum for patients with evident IMN disease. Multi-imaging modalities are recommended to improve the diagnostic specificity and sensitivity of IMN metastases.
Chronic hepatitis B: dynamic change in Traditional Chinese Medicine syndrome by dynamic network biomarkers
Authors: Lu Yiyu , Fang Zhaoyuan , Zeng Tao , Li Meiyi , Chen Qilong , Zhang Hui , Zhou Qianmei , Hu Yiyang , Chen Luonan , Su Shibing
Published: November 2019

Background

In traditional Chinese medicine (TCM) clinical practice, TCM syndromes help to understand human homeostasis and guide individualized treatment. However, the TCM syndrome changes with disease progression, of which the scientific basis and mechanism remain unclear.

Methods

To demonstrate the underlying mechanism of dynamic changes in the TCM syndrome, we applied a dynamic network biomarker (DNB) algorithm to obtain the DNBs of changes in the TCM syndrome, based on the transcriptomic data of patients with chronic hepatitis B and typical TCM syndromes, including healthy controls and patients with liver-gallbladder dampness-heat syndrome (LGDHS), liver-depression spleen-deficiency syndrome (LDSDS), and liver-kidney yin-deficiency syndrome (LKYDS). The DNB model exploits collective fluctuations and correlations of the observed genes, then diagnoses the critical state.

Results

Our results showed that the DNBs of TCM syndromes were comprised of 52 genes and the tipping point occurred at the LDSDS stage. Meanwhile, there were numerous differentially expressed genes between LGDHS and LKYDS, which highlighted the drastic changes before and after the tipping point, implying the 52 DNBs could serve as early-warning signals of the upcoming change in the TCM syndrome. Next, we validated DNBs by cytokine profiling and isobaric tags for relative and absolute quantitation (iTRAQ). The results showed that PLG (plasminogen) and coagulation factor XII (F12) were significantly expressed during the progression of TCM syndrome from LGDHS to LKYDS.

Conclusions

This study provides a scientific understanding of changes in the TCM syndrome. During this process, the cytokine system was involved all the time. The DNBs PLG and F12 were confirmed to significantly change during TCM-syndrome progression and indicated a potential value of DNBs in auxiliary diagnosis of TCM syndrome in CHB.

Trial registration Identifier: NCT03189992. Registered on June 4, 2017. Retrospectively registered (http://www.clinicaltrials.gov)
Biliary tract large cell neuroendocrine carcinoma: current evidence
Authors: Raiker Riva , Chauhan Aman , Hasanein Hassan , Burkeen Grant , Horn Millicent , Veedu Janeesh , Vela Cory , Arnold Susanne , Kolesar Jill , Anthony Lowell , Evers B. Mark , Cavnar Michael
Published: November 2019

Background

Primary neuroendocrine carcinomas of the gallbladder and biliary tract are rare, with pure large cell neuroendocrine carcinomas (LCNEC) being exceedingly rare and with a particularly poor prognosis.

Methods

We performed a review of published data on biliary tract large cell neuroendocrine carcinomas in PubMed.

Results

Preliminary search revealed over 2000 results but we found only 12 cases of pure large cell neuroendocrine carcinomas of biliary tract noted in literature to date. Because it commonly presents with non-specific symptoms of abdominal pain and jaundice, diagnosis is made after resection with histo-pathological and immunohistochemical analysis. These cancers are particularly aggressive with high recurrence rates, most often presenting with metastasis to regional lymph nodes and/or the liver resulting in a poor prognosis. Overall, complete surgical excision with systemic chemotherapy is the treatment mainstay. If the cancer is unresectable due to multiple metastases, medical management with systemic chemotherapy is the primary treatment modality.

Conclusion

The prognosis of hepatobiliary LCNEC remains poor with median survival of only 11 months from initial diagnosis. Studies focusing on high grade neuroendocrine carcinoma are needed to enhance our understanding of biology and therapeutics in this rare but aggressive cancer.
Biallelic ERBB3 loss-of-function variants are associated with a novel multisystem syndrome without congenital contracture
Authors: Li Niu , Xu Yufei , Zhang Yi , Li Guoqiang , Yu Tingting , Yao Ruen , Zhou YunFang , Shen Yiping , Yin Lei , Wang Xiumin , Wang Jian
Published: November 2019

Background

Gain-of-function pathogenic variants of the Erb-B2 receptor tyrosine kinase 3 (ERBB3) gene contribute to the occurrence and development of a variety of human carcinomas through activation of phosphatidylinositol 3-kinase (PI3K)/AKT and extracellular signal-regulated kinase (ERK) signaling. ERBB3 gene homozygous germline variants, whose loss of function may cause autosomal recessive congenital contractural syndrome, were recently identified. This study aims to identify the disease-causing gene in a Chinese pedigree with variable phenotypes involving multiple systems, including developmental delay, postnatal growth retardation, transient lower limb asymmetry, facial malformations, atrioventricular canal malformation, bilateral nystagmus and amblyopia, feeding difficulties, immunodeficiency, anemia, and liver damage, but without congenital contracture.

Methods

Trio-whole exome sequencing (WES) was performed to identify the disease-causing gene in a 24-month-old Chinese female patient. The pathogenicity of the identified variants was evaluated using in silico tools and in vitro functional studies.

Results

Trio-WES revealed compound heterozygous variants of c.1253 T > C (p.I418T) and c.3182dupA (p.N1061Kfs*16) in theERBB3gene. Functional studies showed that p.I418T resulted in normal expression of ERBB3, which was capable of interacting with ERBB2. However, the variant impaired ERBB3 phosphorylation, consequently blocking ERBB2 phosphorylation and AKT and ERK activation. The truncated protein resulting from the c.3182dupA variant also lacked the capacity to activate downstream signaling pathways.

Conclusions

We report the first patient with a novel multisystem syndrome disorder without congenital contracture resulting from biallelic loss-of-function variants ofERBB3.
Comparison of zebrafish and mice knockouts for Megalencephalic Leukoencephalopathy proteins indicates that GlialCAM/MLC1 forms a functional unit
Authors: Pérez-Rius Carla , Folgueira Mónica , Elorza-Vidal Xabier , Alia A. , Hoegg-Beiler Maja B. , Eeza Muhamed N. H. , Díaz María Luz , Nunes Virginia , Barrallo-Gimeno Alejandro , Estévez Raúl
Published: November 2019

Background

Megalencephalic Leukoencephalopathy with subcortical Cysts (MLC) is a rare type of leukodystrophy characterized by astrocyte and myelin vacuolization, epilepsy and early-onset macrocephaly. MLC is caused by mutations in MLC1 or GLIALCAM, coding for two membrane proteins with an unknown function that form a complex specifically expressed in astrocytes at cell-cell junctions. Recent studies in Mlc1−/− or Glialcam−/− mice and mlc1−/− zebrafish have shown that MLC1 regulates glial surface levels of GlialCAM in vivo and that GlialCAM is also required for MLC1 expression and localization at cell-cell junctions.

Methods

We have generated and analysed glialcama−/− zebrafish. We also generated zebrafish glialcama−/−mlc1−/− and mice double KO for both genes and performed magnetic resonance imaging, histological studies and biochemical analyses.

Results

glialcama−/− shows megalencephaly and increased fluid accumulation. In both zebrafish and mice, this phenotype is not aggravated by additional elimination of mlc1. Unlike mice, mlc1 protein expression and localization are unaltered in glialcama−/− zebrafish, possibly because there is an up-regulation of mlc1 mRNA. In line with these results, MLC1 overexpressed in Glialcam−/− mouse primary astrocytes is located at cell-cell junctions.

Conclusions

This work indicates that the two proteins involved in the pathogenesis of MLC, GlialCAM and MLC1, form a functional unit, and thus, that loss-of-function mutations in these genes cause leukodystrophy through a common pathway.
Phylogeny and polymorphism in the E6 and E7 of human papillomavirus: alpha-9 (HPV16, 31, 33, 52, 58), alpha-5 (HPV51), alpha-6 (HPV53, 66), alpha-7 (HPV18, 39, 59, 68) and alpha-10 (HPV6, 44) in women from Shanghai
Authors: Zhao Junwei , Zhan Qin , Guo Junhan , Liu Min , Ruan Yetian , Zhu Tailin , Han Lingfei , Li Fang
Published: November 2019

Background

Persistent infection with human papillomaviruses (HPVs) has been associated with cervical intraepithelial neoplasia (CIN) and cervical cancer. However, why only a fraction of HPV cases progress to cancer is still unclear.

Methods

We focused on the heterogeneity, classification, evolution and dispersal of variants for 14 common HPV types in 262 HPV-positive patients with cervical lesions. The E6 and E7 genes of HPV were sequenced and compared with the HPV reference for sequence analysis. Phylogenetic trees were constructed using the neighbour-joining tree method with MEGA 7.0.

Results

In this study, 233 E6 and 212 E7 sequences were successfully amplified by PCR, and these sequences were divided into 5 species groups: alpha-9 (HPV16, 31, 33, 52, 58), alpha-5 (HPV51), alpha-6 (HPV53, 66), alpha-7 (HPV18, 39, 59, 68) and alpha-10 (HPV6, 44). The incidence of high-grade squamous intraepithelial lesion (HSIL) in patients infected with alpha-9 HPV was significantly increased compared with other groups (P < 0.0001), especially HPV16 (P < 0.0001). Strikingly, E7 had significantly fewer nonsynonymous variants in the HSIL compared to <HSIL groups (P = 3.17× 10− 4). The A388C (K93 N) variation in HPV58 E6 can significantly reduce the risk of HSIL (P = 0.015). However, T7220G (D32E) variation in HPV16 E6 and A7689G (N29S) in HPV16 E7 increased the incidence of HSIL compared to the <HSIL group (P = 0.036 and 0.022).

Conclusions

Strict conservation of E7 is important for HPV carcinogenicity, especially N29 of HPV16. The findings in this work provide preventative/therapeutic interventions for HPV infections and CIN.
Increased expression of protease-activated receptors 2 indicates poor prognosis in HBV related hepatocellular carcinoma
Authors: Chen Peng , Yang Na , Xu Li , Zhao Fangfang , Zhang Min
Published: November 2019

Objective

To investigate the potential role of protease-activated receptor 2 (PAR2) in the prognosis of hepatocellular carcinoma (HCC).

Methods

A total of 202 HCC patients who underwent liver resections were included. Tissue microarray was established with specimens of both HCC and paired adjacent liver tissues. PAR2 expression was detected by immunohistochemistry (IHC) assays.. A semi-quantification method was used to define the expression level of PAR2. The correlations between PAR2 expression and clinical features of patients with HCC was explored. The association of different PAR2 expressions with both overall survival and disease-free survival was analyzed.

Results

Results showed that the expression of PAR2 in HCC tissues was higher than that in paired para-cancerous liver tissues (4.12 ± 3.55 vs. 2.71 ± 2.56, P < 0.001). Higher expression of PAR2 was associated with poor differentiation (P < 0.001) and advanced tumor-node-metastasis stage (P = 0.015). Kaplan-Meier survival analysis indicated that HCC patients with high PAR2 expression had decreased overall survival (P = 0.033) and disease-free survival (P = 0.043) compared to patients with lower PAR2 expression. Multivariate analysis indicated that PAR2 expression (P = 0.032) was a significant independent prognostic factor for both overall survival and disease-free survival (P = 0.032; P = 0.032, respectively).

Conclusion

Our data revealed that PAR2 expression was increased in HCC. High PAR2 expression was correlated with both decreased overall survival and disease-free survival in patients with HCC. High PAR2 expression indicated a poor prognosis.
HMEJ-mediated efficient site-specific gene integration in chicken cells
Authors: Xie Long , Sun Juanjuan , Mo Lifen , Xu Tianpeng , Shahzad Qaisar , Chen Dongyang , Yang Wenhao , Liao Yuying , Lu Yangqing
Published: November 2019

Background

The production of transgenic chicken cells holds great promise for several diverse areas, including developmental biology and biomedical research. To this end, site-specific gene integration has been an attractive strategy for generating transgenic chicken cell lines and has been successfully adopted for inserting desired genes and regulating specific gene expression patterns. However, optimization of this method is essential for improving the efficiency of genome modification in this species.

Results

Here we compare gene knock-in methods based on homology-independent targeted integration (HITI), homology-directed repair (HDR) and homology mediated end joining (HMEJ) coupled with a clustered regularly interspaced short palindromic repeat associated protein 9 (CRISPR/Cas9) gene editing system in chicken DF-1 cells and primordial germ cells (PGCs). HMEJ was found to be a robust and efficient method for gene knock-in in chicken PGCs. Using this method, we successfully labeled the germ cell specific gene DAZL and the pluripotency-related gene Pou5f3 in chicken PGCs through the insertion of a fluorescent protein in the frame at the 3′ end of the gene, allowing us to track cell migration in the embryonic gonad. HMEJ strategy was also successfully used in Ovalbumin, which accounts for more than 60% of proteins in chicken eggs, suggested its good promise for the mass production of protein with pharmaceutical importance using the chicken oviduct system.

Conclusions

Taken together, these results demonstrate that HMEJ efficiently mediates site-specific gene integration in chicken PGCs, which holds great potential for the biopharmaceutical engineering of chicken cells.
Simultaneous targeting of XPO1 and BCL2 as an effective treatment strategy for double-hit lymphoma
Authors: Liu Yuanhui , Azizian Nancy G. , Dou Yaling , Pham Lan V. , Li Yulin
Published: November 2019

Double-hit lymphoma (DHL) is among the most aggressive and chemoresistant lymphoma subtypes. DHLs carry genomic abnormalities in MYC, BCL2, and/or BCL6 oncogenes. Due to the simultaneous overexpression of these driver oncogenes, DHLs are highly resistant to frontline therapies. Most DHLs overexpress both MYC and BCL2 driver oncogenes concurrently. We reasoned that simultaneous suppression of the two driver oncogenes would be more effective in eradicating DHLs than inactivation of single oncogene. XPO1 is a receptor for nuclear cytoplasmic transport of protein and RNA species. Recently, XPO1 inhibition was shown to downregulate MYC expression in several cancer cell lines. We therefore examined the role of XPO1 as a therapeutic target in suppressing MYC function and the potential synergistic effects of simultaneous suppression of XPO1 and BCL2 in the treatment of DHL. Here, we demonstrate that XPO1 inhibition abrogates MYC protein expression and induces massive tumor cell apoptosis. Combined use of XPO1 and BCL2 inhibitors is highly effective in eradicating DHL cells in cell culture. Notably, in a mouse model of DHL bearing primary tumor cells derived from lymphoma patients, combined treatment with XPO1 and BCL2 inhibitors blocks tumor progression, prevents brain metastasis, and extends host survival. Thus, our study confirms the simultaneous targeting of MYC and BCL2 driver oncogenes through the combined use of XPO1 and BCL2 inhibitors as a unique approach for the treatment of DHLs.
Effects of inspiratory flow on lung stress, pendelluft, and ventilation heterogeneity in ARDS: a physiological study
Authors: Santini Alessandro , Mauri Tommaso , Dalla Corte Francesca , Spinelli Elena , Pesenti Antonio
Published: November 2019

Background

High inspiratory flow might damage the lungs by mechanisms not fully understood yet. We hypothesized that increasing inspiratory flow would increase lung stress, ventilation heterogeneity, and pendelluft in ARDS patients undergoing volume-controlled ventilation with constant tidal volume and that higher PEEP levels would reduce this phenomenon.

Methods

Ten ARDS patients were studied during protective volume-controlled ventilation. Three inspiratory flows (400, 800, and 1200 ml/s) and two PEEP levels (5 and 15 cmH2O) were applied in random order to each patient. Airway and esophageal pressures were recorded, end-inspiratory and end-expiratory holds were performed, and ventilation distribution was measured with electrical impedance tomography. Peak and plateau airway and transpulmonary pressures were recorded, together with the airway and transpulmonary pressure corresponding to the first point of zero end-inspiratory flow (P1). Ventilation heterogeneity was measured by the EIT-based global inhomogeneity (GI) index. Pendelluft was measured as the absolute difference between pixel-level inflation measured at plateau pressure minus P1.

Results

Plateau airway and transpulmonary pressure was not affected by inspiratory flow, while P1 increased at increasing inspiratory flow. The difference between P1 and plateau pressure was higher at higher flows at both PEEP levels (p < 0.001). While higher PEEP reduced heterogeneity of ventilation, higher inspiratory flow increased GI (p = 0.05), irrespective of the PEEP level. Finally, gas volume undergoing pendelluft was larger at higher inspiratory flow (p < 0.001), while PEEP had no effect.

Conclusions

The present exploratory analysis suggests that higher inspiratory flow increases additional inspiratory pressure, heterogeneity of ventilation, and pendelluft while PEEP has negligible effects on these flow-dependent phenomena. The clinical significance of these findings needs to be further clarified.
Outcomes of Stenotrophomonas maltophilia hospital-acquired pneumonia in intensive care unit: a nationwide retrospective study
Authors:   AZUREA research network, Guerci Philippe , Bellut Hugo , Mokhtari Mokhtar , Gaudefroy Julie , Mongardon Nicolas , Charpentier Claire , Louis Guillaume , Tashk Parvine , Dubost Clément , Ledochowski Stanislas , Kimmoun Antoine , Godet Thomas , Pottecher Julien , Lalot Jean-Marc , Novy Emmanuel , Hajage David , Bouglé Adrien
Published: November 2019

Background

There is little descriptive data on Stenotrophomonas maltophilia hospital-acquired pneumonia (HAP) in critically ill patients. The optimal modalities of antimicrobial therapy remain to be determined. Our objective was to describe the epidemiology and prognostic factors associated with S. maltophilia pneumonia, focusing on antimicrobial therapy.

Methods

This nationwide retrospective study included all patients admitted to 25 French mixed intensive care units between 2012 and 2017 with hospital-acquired S. maltophilia HAP during intensive care unit stay. Primary endpoint was time to in-hospital death. Secondary endpoints included microbiologic effectiveness and antimicrobial therapeutic modalities such as delay to appropriate antimicrobial treatment, mono versus combination therapy, and duration of antimicrobial therapy.

Results

Of the 282 patients included, 84% were intubated at S. maltophilia HAP diagnosis for duration of 11 [5–18] days. The Simplified Acute Physiology Score II was 47 [36–63], and the in-hospital mortality was 49.7%. Underlying chronic pulmonary comorbidities were present in 14.1% of cases. Empirical antimicrobial therapy was considered effective on S. maltophilia according to susceptibility patterns in only 30% of cases. Delay to appropriate antimicrobial treatment had, however, no significant impact on the primary endpoint. Survival analysis did not show any benefit from combination antimicrobial therapy (HR = 1.27, 95%CI [0.88; 1.83], p = 0.20) or prolonged antimicrobial therapy for more than 7 days (HR = 1.06, 95%CI [0.6; 1.86], p = 0.84). No differences were noted in in-hospital death irrespective of an appropriate and timely empiric antimicrobial therapy between mono- versus polymicrobial S. maltophilia HAP (p = 0.273). The duration of ventilation prior to S. maltophilia HAP diagnosis and ICU length of stay were shorter in patients with monomicrobial S. maltophilia HAP (p = 0.031 and p = 0.034 respectively).

Conclusions

S. maltophilia HAP occurred in severe, long-stay intensive care patients who mainly required prolonged invasive ventilation. Empirical antimicrobial therapy was barely effective while antimicrobial treatment modalities had no significant impact on hospital survival.

Trial registration

clinicaltrials.gov, NCT03506191
Respective contribution of intensive care unit-acquired limb muscle and severe diaphragm weakness on weaning outcome and mortality: a post hoc analysis of two cohorts
Authors: Dres Martin , Jung Boris , Molinari Nicolas , Manna Federico , Dubé Bruno-Pierre , Chanques Gerald , Similowski Thomas , Jaber Samir , Demoule Alexandre
Published: November 2019

Background

Intensive care unit (ICU)-acquired weakness (ICU-AW) and ICU-acquired diaphragm dysfunction (ICU-DD) occur frequently in mechanically ventilated (MV) patients. It is unknown whether they have different risk factors and different impacts on outcome. This study was designed to (1) describe the respective risk factors associated with ICU-AW and severe ICU-DD and (2) evaluate the respective impact of ICU-AW and severe ICU-DD on outcome.

Methods

Post hoc analysis of two prospective cohort studies conducted in two ICUs. In patients mechanically ventilated for at least 24 h undergoing a first spontaneous breathing trial, severe ICU-DD was defined as diaphragm twitch pressure < 7 cmH2O and ICU-AW was defined as Medical Research Council Score < 48.

Results

One hundred sixteen patients were assessed. Factors independently associated with severe ICU-DD were age, longer duration of MV, and exposure to sufentanil, and those factors associated with ICU-AW were longer duration of MV and exposure to norepinephrine. Severe ICU-DD (OR 3.56, p = 0.008), but not ICU-AW, was independently associated with weaning failure (59%). ICU-AW (OR 4.30, p = 0.033), but not severe ICU-DD, was associated with ICU mortality. Weaning failure and mortality rate were higher in patients with both severe ICU-DD and ICU-AW (86% and 39%, respectively) than in patients with either severe ICU-DD (64% and 0%) or ICU-AW (63% and 13%).

Conclusion

Severe ICU-DD and ICU-AW have different risk factors and different impacts on weaning failure and mortality. The impact of the combination of ICU-DD and ICU-AW is more pronounced than their individual impact.
Host factors associated with Giardia duodenalis infection in dogs across multiple diagnostic tests
Authors: Uiterwijk Mathilde , Nijsse Rolf , Kooyman Frans N. J. , Wagenaar Jaap A. , Mughini-Gras Lapo , Ploeger Harm W.
Published: November 2019

Background

The aim of this study was to assess potential associations between Giardia duodenalis infection in dogs, as determined by three diagnostic tests, and dog’s group of origin, fecal consistency, age, sex, neuter status, and co-infections with other gastrointestinal parasites.

Methods

Fecal samples from 1291 dogs from four groups (household, shelter, hunting and clinical dogs) were tested with qPCR, rapid enzyme immunochromatographic assay (IDEXX SNAP®Giardia), and direct immunofluorescence (DFA, Merifluor) for presence of G. duodenalis. Moreover, fecal samples were tested with centrifugation sedimentation flotation (CSF) coproscopical analysis for presence of gastrointestinal parasites. Associations were expressed as odds ratios (ORs).

Results

Several significant associations were found, of which a few were consistent for all three tests and Giardia positivity in general (positive with at least one of these tests). Dogs older than one year were significantly less likely to test positive for Giardia than younger dogs. Group-housed dogs, especially hunting dogs, were significantly more likely to test positive for Giardia compared to household and clinical dogs. A consistently significant association with Trichuris appeared to be driven by the high prevalence in hunting dogs. Although there was no significant association between loose stool and Giardia infection in the overall population, household dogs were significantly more likely to test Giardia-positive when having loose stool. Overall, Giardia-positive dogs with loose stool shed significantly more cysts, both determined semi-quantitatively with CSF and quantitatively by qPCR, than positive dogs with no loose stool. When other gastrointestinal parasites were present, significantly fewer cysts were detected with CSF, but this was not confirmed with qPCR.

Conclusion

Giardia is the most common gastrointestinal parasite in Dutch dogs, except for hunting dogs, in which Trichuris and strongyle-type eggs (hookworms) prevailed. Giardia infection was not significantly associated with loose stool, except for household dogs. Young dogs and group-housed dogs were significantly more often Giardia-positive. These associations were consistent across diagnostic tests. Young dogs, clinical dogs and dogs with loose stool shed Giardia cysts in the highest numbers. If another gastrointestinal parasite was present lower numbers of cysts were observed by microscope (CSF), but not with a molecular method (qPCR).
Is ‘likely pathogenic’ really 90% likely? Reclassification data in ClinVar
Authors: Harrison Steven M. , Rehm Heidi L.
Published: November 2019

In 2015, professional guidelines defined the term ‘likely pathogenic’ to mean with a 90% chance of pathogenicity. To determine whether current practice reflects this definition, ClinVar classifications were tracked from 2016 to 2019. During that period, between 83.8 and 99.1% of likely pathogenic classifications were reclassified as pathogenic, depending on whether LP to VUS reclassifications are included and on how these classifications are categorized.
Physical, behavioral and sociodemographic determinants of hypertension among the adult population in Nekemte town, western Ethiopia: community based study
Authors: Geleta Gemechis Teshome , Cheme Melese Chego , Roro Elias Merdassa
Published: November 2019

Objectives

Hypertension is a growing public health problem in many developing countries. However, there is an insufficiency of scientific evidence on the prevalence of hypertension (HTN) at a community level in the study area. The aim of the study was exploring the prevalence and associated factors of hypertension among adults in Nekemte town, Ethiopia. A community-based cross-sectional study was conducted on 711 adults who were selected by the multistage sampling procedure. Height, weight, blood pressure and waist circumference were measured with standard procedures. Data were analyzed by statistical package for social sciences (SPSS) version 20, and multiple logistic regression model was used to determine the independent risk factors for hypertension.

Result

The overall prevalence of hypertension was 34.9% among the adult population. Of them, only 52.7% know their status, and 22.4% were on antihypertensive medication. The prevalence of hypertension was higher among the older aged; AOR 5.85 (95% CI 1.74–20), Obese and over-weighted; (AOR 1.71 (95% CI 1.09–2.67)), Khat chewers in the past year; AOR 2.44 (95% CI 1.05–5.68), and with higher formal education (college and above); AOR 2.75 (95% CI 1.26–6.03) than their respective counterparts. Community-level prevention and treatment of hypertension should get due attention.
Measles outbreak investigation in Artuma Fursi Woreda, Oromia Zone, Amhara Region, Ethiopia, 2018: a case control study
Authors: Tariku Mengistie Kassahun , Misikir Sewnet Wongiel
Published: November 2019

Objective

To confirm the existence of Outbreak, describe cases in person, place and time, and identify determinants of the outbreak. Unmatched case control study in the ratio of 1:4 (38 cases and 152 controls) was conducted in Artuma Fursi Woreda from July 13 to August 1/2018. Data were collected with standard questionnaires. Collected data were entered into Epi Info version 7 and exported to Statistical package for social science (SPSS) version 23 for analysis.

Results

A total of 38 cases and 1 death with attack rate and case fatality rate 11.8/100,000 and 2.6%, respectively. All study participants had not vaccination history. Females and age group 5–14 were more affected. Being 5–14 years old versus (vs) ≥ 15 years [adjusted odd ratio (AOR) = 3.53; 95% CI 1.52–8.45)], contact with cases vs no contact with cases [AOR = 2.78; 95% CI 1.23–8.67] and travel history 7–18 days prior onset of illness vs no travel history [AOR = 2.53; 95% CI 1.31–7.24] were significantly associated with contracting measles. Routine and supplement immunization should be strengthened to reduce future occurrence of outbreak.
Genetic variants in humanin nuclear isoform gene regions show no association with coronary artery disease
Authors: Eltermaa Mall , Jakobson Maili , Utt Meeme , Kõks Sulev , Mägi Reedik , Starkopf Joel
Published: November 2019

Objective

Coronary artery disease contributes to noncommunicable disease deaths worldwide. In order to make preventive methods more accurate, we need to know more about the development and progress of this pathology, including the genetic aspects. Humanin is a small peptide known for its cytoprotective and anti-apoptotic properties. Our study looked for genomic associations between humanin-like nuclear isoform genes and coronary artery disease using CARDIoGRAMplusC4D Consortium data.

Results

Lookup from meta-analysis datasets gave single nucleotide polymorphisms in all 13 humanin-like nuclear isoform genes with the lowest P value for rs6151662 from the MTRNR2L2 gene including the 50 kb flanking region in both directions (P-value = 0.0037). Within the gene region alone the top variant was rs78083998 from the MTRNR2L13 region (meta-analysis P-value = 0.042). None of the found associations were statistically significant after correction for multiple testing. Lookup for expression trait loci in these gene regions gave no statistically significant variants.
Whole blood vs PBMC: compartmental differences in gene expression profiling exemplified in asthma
Authors: He Daniel , Yang Chen Xi , Sahin Basak , Singh Amrit , Shannon Casey P. , Oliveria John-Paul , Gauvreau Gail M. , Tebbutt Scott J.
Published: November 2019

Background

Blood has proven to be a useful resource for molecular analysis in numerous biomedical studies, with peripheral blood mononuclear cells (PBMCs) and whole blood being the major specimen types. However, comparative analyses between these two major compartments (PBMCs and whole blood) are few and far between. In this study, we compared gene expression profiles of PBMCs and whole blood samples obtained from research subjects with or without mild allergic asthma.

Methods

Whole blood (PAXgene) and PBMC samples were obtained from 5 mild allergic asthmatics and 5 healthy controls. RNA from both sample types was measured for expression of 730 immune-related genes using the NanoString nCounter platform.

Results

We identified 64 uniquely expressed transcripts in whole blood that reflected a variety of innate, humoral, and adaptive immune processes, and 13 uniquely expressed transcripts in PBMCs which were representative of T-cell and monocyte-mediated processes. Furthermore, analysis of mild allergic asthmatics versus non-asthmatics revealed 47 differentially expressed transcripts in whole blood compared to 1 differentially expressed transcript in PBMCs (FDR < 0.25). Finally, through simultaneous measurement of PBMC proteins on the nCounter assay, we identified CD28 and OX40 (TNFRSF4), both of which are critical co-stimulatory molecules during T-cell activation, as significantly upregulated in asthmatics.

Conclusions

Whole blood RNA preserved in PAXgene tubes is excellent for producing gene expression data with minimal variability and good sensitivity, suggesting its utility in multi-centre studies requiring measurement of blood gene expression.
A novel mutation in NCF2 resulting in very-early-onset colitis and juvenile idiopathic arthritis in a patient with chronic granulomatous disease
Authors: AlKhater Suzan
Published: November 2019

Background

Chronic granulomatous disease (CGD) is a rare primary immunodeficiency disorder caused by a defect in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. The disease primarily presents with recurrent infections, and patients may also present with inflammatory conditions, including noninfectious colitis, and an increased frequency of autoimmunity. We report here a patient with CGD in whom the presentation, unlike the classical presentation of CGD, was predominantly of an inflammatory and autoimmune phenotype.

Case presentation

A 3-year-old Pakistani female presented with bloody diarrhea since the age of 7 days, followed by the development of perianal abscesses and fistula. There was no other history of recurrent infections. The patient subsequently developed joint pain and stiffness with persistently elevated inflammatory markers and elevated anti-cyclic citrullinate peptide (anti-CCP) antibody titer. She was diagnosed with oligoarticular juvenile idiopathic arthritis and colitis. The diagnosis of CGD was later made and was based on the absence of NADPH oxidase activity in the patient’s neutrophils upon phorbol myristate acetate (PMA) stimulation using the dihydrorhodamine-1,2,3 (DHR) flow cytometry test. Targeted next-generation sequencing revealed an unreported deletion mutation in exon 10 as a homozygous loss-of-function variant of the human neutrophil oxidase factor 2 (NCF2) (NCF2: NM_001190789, nucleotide change: c.855_856del:p.T285fs). The gene encodes a protein subunit, p67phox, in the NADPH enzyme complex.

Conclusions

The case emphasizes the importance of maintaining high clinical suspicion of immunodeficiency and CGD in patients with very-early-onset colitis and autoimmune disorders. This case is important due to its rarity and because it might represent a previously undiscovered mutation, which is possibly more common in the patient’s ethnic group. Other mutations inNCF2have been linked to inflammatory bowel disease and autoimmunity, but without CGD, suggesting similarities in the pathogenesis.
Association between methylation in nasal epithelial TSLP gene and chronic rhinosinusitis with nasal polyps
Authors: Li Jingyun , Jiao Jian , Gao Yunbo , Zhang Yuan , Zhang Luo
Published: November 2019

Background

This study was performed to determine whether there was any association between abnormal DNA methylation of a thymic stromal lymphopoietin (TSLP) locus and pathogenesis of chronic rhinosinusitis (CRS).

Methods

A total of 48 CRS patients with nasal polyps (CRSwNP), 28 CRS patients without nasal polyps (CRSsNP) and 21 control subjects were enrolled into the study; and evaluated for serum total IgE level, olfactory score and nasal resistance. Samples were obtained from nasal polyps of CRSwNP patients, ethmoid mucosae of CRSsNP patients and inferior turbinate (IT) mucosa of control subjects during surgery, and used to isolate purified primary human nasal epithelial cells (HNECs). Genomic DNA was extracted from purified primary HNECs of each subject and DNA methylation ratios for a selected region of the TSLP gene were screened the using MassARRAY EpiTYPER.

Results

A total of 17 CpG units were analyzed; of which two CpG units (CpG3 and 22:23:24) had increased methylation ratios in the CRSwNP patients compared to the CRSsNP and control subjects after correction for false discovery rate (FDR) (Q < 0.1). The methylation ratios at both CpG3 and CpG22:23:24 units were positively correlated with olfactory score (r = 0.41, P = 0.0001; r = 0.25, P = 0.021) and unilateral nasal resistance at 75 Pa (r = 0.24, P = 0.04; r = 0.24, P = 0.036) and 150 Pa (r = 0.34, P = 0.004; r = 0.25, P = 0.031). Total nasal resistance at 75 Pa/150 Pa or serum total IgE levels were not correlated with the methylation ratios at either CpG unit.

Conclusions

Increased DNA methylation at the TSLP locus is likely to be associated with CRSwNP pathogenesis; however these findings need to be confirmed in larger multicentre group studies.
lncRNAs: function and mechanism in cartilage development, degeneration, and regeneration
Authors: Zhu Jian , Yu Wei , Wang Yitian , Xia Kaishun , Huang Yuluan , Xu Ankai , Chen Qixin , Liu Bing , Tao Huimin , Li Fangcai , Liang Chengzhen
Published: November 2019

With the increasing incidence of cartilage-related diseases such as osteoarthritis (OA) and intervertebral disc degeneration (IDD), heavier financial and social burdens need to be faced. Unfortunately, there is no satisfactory clinical method to target the pathophysiology of cartilage-related diseases. Many gene expressions, signaling pathways, and biomechanical dysregulations were involved in cartilage development, degeneration, and regeneration. However, the underlying mechanism was not clearly understood. Recently, lots of long non-coding RNAs (lncRNAs) were identified in the biological processes, including cartilage development, degeneration, and regeneration. It is clear that lncRNAs were important in regulating gene expression and maintaining chondrocyte phenotypes and homeostasis. In this review, we summarize the recent researches studying lncRNAs’ expression and function in cartilage development, degeneration, and regeneration and illustrate the potential mechanism of how they act in the pathologic process. With continued efforts, regulating lncRNA expression in the cartilage regeneration may be a promising biological treatment approach.
Surgical vacuum filter-derived stromal cells are superior in proliferation to human bone marrow aspirate
Authors: Henze Katharina , Herten Monika , Haversath Marcel , Busch André , Brandau Sven , Hackel Alexander , Flohé Stefanie B. , Jäger Marcus
Published: November 2019

Background

During joint replacement, surgical vacuum suction guarantees a sufficient overview on the situs. We assume high concentrations of mesenchymal stromal cells (MSCs) on surgical vacuum filters.

We compared the in vitro proliferative and differentiation potency of cells from the following: (i) bone marrow (BM), (ii) cancellous bone (CB), (iii) vacuum filter (VF), and (iv) cell saver filtrate reservoir (SF) in 32 patients undergoing elective total hip replacement.

Methods

Mononuclear cells (MNC) were isolated, and cell proliferation and colony-forming units (CFU) were measured. Adherent cells were characterized by flow cytometry for MSC surface markers. Cells were incubated with osteogenic, adipogenic, and chondrogenic stimuli. Cells were cytochemically stained and osteoblastic expression (RUNX-2, ALP, and BMP-2) investigated via qPCR.

Results

Dependent on the source, initial MNC amount as well as CFU number was significantly different whereas generation time did not vary significantly. CFU numbers from VF were superior to those from SR, BM, and CB. The resulting amount of MSC from the respective source was highest in the vacuum filter followed by reservoir, aspirate, and cancellous bone. Cells from all groups could be differentiated into the three mesenchymal lines demonstrating their stemness nature. However, gene expression of osteoblastic markers did not differ significantly between the groups.

Conclusion

We conclude that surgical vacuum filters are able to concentrate tissue with relevant amounts of MSCs. A new potent source of autologous regeneration material with clinical significance is identified. Further clinical studies have to elucidate the regenerative potential of this material in an autologous setting.
A magic kick for regeneration: role of mesenchymal stromal cell secretome in spermatogonial stem cell niche recovery
Authors: Sagaradze Georgy , Basalova Nataliya , Kirpatovsky Vladimir , Ohobotov Dmitry , Nimiritsky Peter , Grigorieva Olga , Popov Vladimir , Kamalov Armais , Tkachuk Vsevolod , Efimenko Anastasia
Published: November 2019

Background

Injury of stem cell niches may disturb tissue homeostasis and regeneration coordinated by specific niche components. Yet, the mechanisms of stem cell niche restoration remain poorly understood. Herein, we examined the role of mesenchymal stromal cells (MSCs) as pivotal regulators of stem cell niche recovery focusing on the effects of their secretome.

Methods

The spermatogonial stem cell (SSC) niche was selected as a model. SSC niches were injured by inducing abdominal cryptorchidism in rats. Briefly, testes of anesthetized rats were elevated into the abdominal cavity through the inguinal canal for 14 days. After descent of testes, MSC or MSC secretome treatment was applied to the animals by local subtunical injections.

Results

Local administration of MSC or MSC secretome was sufficient to recover spermatogenesis and production of functional germ cells. The effects of MSC and their secreted components were comparable, leading to restoration of Sertoli cell pools and recovery of Leydig cell secretory functions.

Conclusion

Our data suggest that MSCs mimic the functions of lost supportive cells within the stem cell niche, transiently providing paracrine stimuli for target cells and triggering tissue regenerative processes after damage.