bluuebunny/crossref_metadata_2025 huggingface dataset:
GDP/GTP exchange factor MADD drives activation and recruitment of secretory Rab GTPases to Weibel-Palade bodies
Authors: Kat Marije , Bürgisser Petra E. , Janssen Hans , De Cuyper Iris M. , Conte Ianina L. , Hume Alistair N. , Carter Tom , Voorberg Jan , Margadant Coert , Bierings Ruben
Published: September 2021

von Willebrand factor (VWF) is an essential hemostatic protein that is synthesized and secreted by endothelial cells and stored in Weibel-Palade bodies (WPBs). The secretory Rab GTPases Rab27A, Rab3B, and Rab3D have been linked with WPB trafficking and secretion. How these Rabs are activated and recruited to WPBs remains elusive. In this study, we identified MAP kinase-activating death domain (MADD) as the guanine nucleotide exchange factor for Rab27A and both Rab3 isoforms in primary human endothelial cells. Rab activity assays revealed a reduction in Rab27A, Rab3B, and Rab3D activation upon MADD silencing. Rab activation, but not binding, was dependent on the differentially expressed in normal and neoplastic cells (DENN) domain of MADD, indicating the potential existence of 2 Rab interaction modules. Furthermore, immunofluorescent analysis showed that Rab27A, Rab3B, and Rab3D recruitment to WPBs was dramatically decreased upon MADD knockdown, revealing that MADD drives Rab membrane targeting. Artificial mistargeting of MADD using a TOMM70 tag abolished Rab27A localization to WPB membranes in a DENN domain–dependent manner, indicating that normal MADD localization in the cytosol is crucial. Activation of Rab3B and Rab3D was reduced upon Rab27A silencing, suggesting that activation of these Rabs is enhanced through previous activation of Rab27A by MADD. MADD silencing did not affect WPB morphology, but it did reduce VWF intracellular content. Furthermore, MADD-depleted cells exhibited decreased histamine-evoked VWF release, similar to Rab27A-depleted cells. In conclusion, MADD acts as a master regulator of VWF secretion by coordinating the activation and membrane targeting of secretory Rabs to WPBs.
Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML
Authors: Menghrajani Kamal , Gomez-Arteaga Alexandra , Madero-Marroquin Rafael , Zhang Mei-Jie , Bo-Subait Khalid , Sanchez Jonathan , Wang Hai-Lin , Aljurf Mahmoud , Assal Amer , Bacher Vera Ulrike , Badawy Sherif M. , Bejanyan Nelli , Bhatt Vijaya Raj , Bredeson Christopher , Byrne Michael , Castillo Paul , Cerny Jan , Chhabra Saurabh , Ciurea Stefan Octavian , DeFilipp Zachariah , Farhadfar Nosha , Gadalla Shahinaz , Gale Robert Peter , Ganguly Siddhartha , Gowda Lohith , Grunwald Michael R. , Hashmi Shahrukh , Hildebrandt Gerhard , Kanakry Christopher G. , Kansagra Ankit , Khimani Farhad , Krem Maxwell , Lazarus Hillard , Liu Hongtao , Martino Rodrigo , Michelis Fotios V. , Nathan Sunita , Nishihori Taiga , Olsson Richard , Reshef Ran , Rizzieri David , Rowe Jacob M. , Savani Bipin N. , Seo Sachiko , Sharma Akshay , Solh Melhem , Ustun Celalettin , Verdonck Leo F. , Hourigan Christopher , Sandmaier Brenda , Litzow Mark , Kebriaei Partow , Weisdorf Daniel , Zhang Yanming , Tallman Martin S. , Saber Wael
Published: September 2021

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.
Successful treatment and integrated genomic analysis of an infant with FIP1L1-RARA fusion–associated myeloid neoplasm
Authors: Miltiadous Oriana , Petrova-Drus Kseniya , Kaicker Shipra , Mathew Susan , Kluk Michael , Geyer Julia T. , Rodriguez-Sanchez Irene , Bouvier Nancy , Inghirami Giorgio , Stieglitz Elliot , Khedoudja Nafa , Benayed Ryma , Richardson Michelle , Anderson Wade , Benhamida Jamal , You Daoqi , Londono Dory , Kung Andrew L. , Prockop Susan E. , Roshal Mikhail , Zhang Yanming , Shukla Neerav
Published: September 2021

FIP1L1-RARA–a ssociated neoplasm is a very rare and aggressive disease, with only 3 previously reported cases in the literature. Here, we describe a 9-month-old boy who presented with a FIP1L1-RARA fusion–associated myelodysplastic/myeloproliferative neoplasm-like overlap syndrome, with similarities and distinct features to both acute promyelocytic leukemia and juvenile myelomonocytic leukemia. Using a combined approach of chemotherapy, differentiating agents, and allogeneic hematopoietic stem cell transplant (allo-HCT), this patient remains in remission 20 months after allo-HCT. To our knowledge, this is only the second published pediatric case involving this condition and the only case with a favorable long-term outcome. Given the aggressive disease described in the previously published case report, as well as the successful treatment course described, the combinatorial use of chemotherapy, differentiation therapy, and allo-HCT for treatment of FIP1L1-RARA fusion–associated myeloid neoplasms should be considered.
Daratumumab for immune thrombotic thrombocytopenic purpura
Authors: van den Berg Jana , Kremer Hovinga Johanna A. , Pfleger Claudia , Hegemann Inga , Stehle Gregor , Holbro Andreas , Studt Jan-Dirk
Published: September 2021

Immune thrombotic thrombocytopenic purpura (iTTP) is a life-threatening thrombotic microangiopathy. It is caused by a severe ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs, 13) deficiency due to circulating autoantibodies, and is associated with significant morbidity and mortality. Current treatment options include plasma exchange, immunosuppression, and caplacizumab. When remission is achieved, the risk of relapse is high, especially in patients with persistent ADAMTS13 deficiency. We report the eradication of persistent ADAMTS13 inhibitory autoantibodies and restoration of normal ADAMTS13 activity using the anti-CD38 antibody daratumumab in two patients with iTTP. One patient had a frequently relapsing course, and the other a treatment-refractory first episode. There were no relevant adverse drug reactions.
Tissue-resident macrophages promote early dissemination of multiple myeloma via IL-6 and TNFα
Authors: Akhmetzyanova Ilseyar , Aaron Tonya , Galbo Phillip , Tikhonova Anastasia , Dolgalev Igor , Tanaka Masato , Aifantis Iannis , Zheng Deyou , Zang Xingxing , Fooksman David
Published: September 2021

Multiple myeloma (MM) is a plasma cell malignancy characterized by the presence of multiple foci in the skeleton. These distinct tumor foci represent cycles of tumor growth and dissemination that seed new clusters and drive disease progression. By using an intratibial Vk*MYC murine myeloma model, we found that CD169+ radiation-resistant tissue-resident macrophages (MPs) were critical for early dissemination of myeloma and disease progression. Depletion of these MPs had no effect on tumor proliferation, but it did reduce egress of myeloma from bone marrow (BM) and its spread to other bones. Depletion of MPs as a single therapy and in combination with BM transplantation improved overall survival. Dissemination of myeloma was correlated with an increased inflammatory signature in BM MPs. It was also correlated with the production of interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) by tumor-associated MPs. Exogenous intravenous IL-6 and TNFα can trigger myeloma intravasation in the BM by increasing vascular permeability in the BM and by enhancing the motility of myeloma cells by reducing the adhesion of CD138. Moreover, mice that lacked IL-6 had defects in disseminating myeloma similar to those in MP-depleted recipients. Mice that were deficient in TNFα or TNFα receptor (TNFR) had defects in disseminating MM, and engraftment was also impaired. These effects on dissemination of myeloma required production of cytokines in the radiation-resistant compartment that contained these radiation-resistant BM MPs. Taken together, we propose that egress of myeloma cells from BM is regulated by localized inflammation in foci, driven in part by CD169+ MPs.
Pre-selection against a lethal recessive allele in breeding schemes with optimum-contribution selection or truncation selection
Authors: Hjortø Line , Henryon Mark , Liu Huiming , Berg Peer , Thomasen Jørn Rind , Sørensen Anders Christian
Published: September 2021

Background

We tested the hypothesis that breeding schemes with a pre-selection step, in which carriers of a lethal recessive allele (LRA) were culled, and with optimum-contribution selection (OCS) reduce the frequency of a LRA, control rate of inbreeding, and realise as much genetic gain as breeding schemes without a pre-selection step.

Methods

We used stochastic simulation to estimate true genetic gain realised at a 0.01 rate of true inbreeding (ΔFtrue) by breeding schemes that combined one of four pre-selection strategies with one of three selection strategies. The four pre-selection strategies were: (1) no carriers culled, (2) male carriers culled, (3) female carriers culled, and (4) all carriers culled. Carrier-status was known prior to selection. The three selection strategies were: (1) OCS in which $$\Delta {\text{F}}_{{{\text{true}}}}$$

Δ

F
true

was predicted and controlled using pedigree relationships (POCS), (2) OCS in which $$\Delta {\text{F}}_{{{\text{true}}}}$$

Δ

F
true

was predicted and controlled using genomic relationships (GOCS), and (3) truncation selection of parents. All combinations of pre-selection strategies and selection strategies were tested for three starting frequencies of the LRA (0.05, 0.10, and 0.15) and two linkage statuses with the locus that has the LRA being on a chromosome with or without loci affecting the breeding goal trait. The breeding schemes were simulated for 10 discrete generations (t = 1, …, 10). In all breeding schemes, ΔFtrue was calibrated to be 0.01 per generation in generations t = 4, …, 10. Each breeding scheme was replicated 100 times.

Results

We found no significant difference in true genetic gain from generations t = 4, …, 10 between breeding schemes with or without pre-selection within selection strategy. POCS and GOCS schemes realised similar true genetic gains from generations t = 4, …, 10. POCS and GOCS schemes realised 12% more true genetic gain from generations t = 4, …, 10 than truncation selection schemes.

Conclusions

We advocate for OCS schemes with pre-selection against the LRA that cause animal suffering and high costs. At LRA frequencies of 0.10 or lower, OCS schemes in which male carriers are culled reduce the frequency of LRA, control rate of inbreeding, and realise no significant reduction in true genetic gain compared to OCS schemes without pre-selection against LRA.
MDMX is essential for the regulation of p53 protein levels in the absence of a functional MDM2 C-terminal tail
Authors: Sanford Jack D. , Yang Jing , Han Jing , Tollini Laura A. , Jin Aiwen , Zhang Yanping
Published: September 2021

Background

MDM2 is an E3 ubiquitin ligase that is able to ubiquitinate p53, targeting it for proteasomal degradation. Its homologue MDMX does not have innate E3 activity, but is able to dimerize with MDM2. Although mouse models have demonstrated both MDM2 and MDMX are individually essential for p53 regulation, the significance of MDM2-MDMX heterodimerization is only partially understood and sometimes controversial. MDM2C462A mice, where the C462A mutation abolishes MDM2 E3 ligase activity as well as its ability to dimerize with MDMX, die during embryogenesis. In contrast, the MDM2Y487A mice, where the Y487A mutation at MDM2 C-terminus significantly reduces its E3 ligase activity without disrupting MDM2-MDMX binding, survive normally even though p53 is expressed to high levels. This indicates that the MDM2-MDMX heterodimerization plays a critical role in the regulation of p53. However, it remains unclear whether MDMX is essential for the regulation of p53 protein levels in the context of an endogenous MDM2 C-terminal tail mutation.

Results

Here, we studied the significance of MDM2-MDMX binding in an MDM2 E3 ligase deficient context using the MDM2Y487A mouse embryonic fibroblast (MEF) cells. Surprisingly, down-regulation of MDMX in MDM2Y487A MEFs resulted in a significant increase of p53 protein levels. Conversely, ectopic overexpression of MDMX reduced p53 protein levels in MDM2Y487A MEFs. Mutations of the RING domain of MDMX prevented MDMX-MDM2 binding, and ablated MDMX-mediated suppression of p53 protein expression. Additionally, DNA damage treatment and nuclear sequestration of MDMX inhibited MDMX activity to suppress p53 protein expression.

Conclusions

These results suggest that MDMX plays a key role in suppressing p53 protein expression in the absence of normal MDM2 E3 ligase activity. We found that the ability of MDMX to suppress p53 levels requires MDM2 binding and its cytoplasmic localization, and this ability is abrogated by DNA damage. Hence, MDMX is essential for the regulation of p53 protein levels in the context of an MDM2 C-terminal mutation that disrupts its E3 ligase activity but not MDMX binding. Our study is the first to examine the role of MDMX in the regulation of p53 in the context of endogenous MDM2 C-terminal mutant MEF cells.
Patterns of reproductive isolation in a haplodiploid mite, Amphitetranychus viennensis: prezygotic isolation, hybrid inviability and hybrid sterility
Authors: Sato Yukie , Fujiwara Satoshi , Egas Martijn , Matsuda Tomoko , Gotoh Tetsuo
Published: September 2021

Background

Evolution of reproductive isolation is an important process, generating biodiversity and driving speciation. To better understand this process, it is necessary to investigate factors underlying reproductive isolation through various approaches but also in various taxa. Previous studies, mainly focusing on diploid animals, supported the prevalent view that reproductive barriers evolve gradually as a by-product of genetic changes accumulated by natural selection by showing a positive relationship between the degree of reproductive isolation and genetic distance. Haplodiploid animals are expected to generate additional insight into speciation, but few studies investigated the prevalent view in haplodiploid animals. In this study, we investigate whether the relationship also holds in a haplodiploid spider mite, Amphitetranychus viennensis (Zacher).

Results

We sampled seven populations of the mite in the Palaearctic region, measured their genetic distance (mtDNA) and carried out cross experiments with all combinations. We analyzed how lack of fertilization rate (as measure of prezygotic isolation) as well as hybrid inviability and hybrid sterility (as measures of postzygotic isolation) varies with genetic distance. We found that the degree of reproductive isolation varies among cross combinations, and that all three measures of reproductive isolation have a positive relationship with genetic distance. Based on the mtDNA marker, lack of fertilization rate, hybrid female inviability and hybrid female sterility were estimated to be nearly complete (99.0–99.9% barrier) at genetic distances of 0.475–0.657, 0.150–0.209 and 0.145–0.210, respectively. Besides, we found asymmetries in reproductive isolation.

Conclusions

The prevalent view on the evolution of reproductive barriers is supported in the haplodiploid spider mite we studied here. According to the estimated minimum genetic distance for total reproductive isolation in parent population crosses in this study and previous work, a genetic distance of 0.15–0.21 in mtDNA (COI) appears required for speciation in spider mites. Variations and asymmetries in the degree of reproductive isolation highlight the importance of reinforcement of prezygotic reproductive isolation through incompatibility and the importance of cytonuclear interactions for reproductive isolation in haplodiploid spider mites.
SCReadCounts: estimation of cell-level SNVs expression from scRNA-seq data
Authors: Prashant N. M. , Alomran Nawaf , Chen Yu , Liu Hongyu , Bousounis Pavlos , Movassagh Mercedeh , Edwards Nathan , Horvath Anelia
Published: September 2021

Background

Recent studies have demonstrated the utility of scRNA-seq SNVs to distinguish tumor from normal cells, characterize intra-tumoral heterogeneity, and define mutation-associated expression signatures. In addition to cancer studies, SNVs from single cells have been useful in studies of transcriptional burst kinetics, allelic expression, chromosome X inactivation, ploidy estimations, and haplotype inference.

Results

To aid these types of studies, we have developed a tool, SCReadCounts, for cell-level tabulation of the sequencing read counts bearing SNV reference and variant alleles from barcoded scRNA-seq alignments. Provided genomic loci and expected alleles, SCReadCounts generates cell-SNV matrices with the absolute variant- and reference-harboring read counts, as well as cell-SNV matrices of expressed Variant Allele Fraction (VAFRNA) suitable for a variety of downstream applications. We demonstrate three different SCReadCounts applications on 59,884 cells from seven neuroblastoma samples: (1) estimation of cell-level expression of known somatic mutations and RNA-editing sites, (2) estimation of cell- level allele expression of biallelic SNVs, and (3) a discovery mode assessment of the reference and each of the three alternative nucleotides at genomic positions of interest that does not require prior SNV information. For the later, we applied SCReadCounts on the coding regions of KRAS, where it identified known and novel somatic mutations in a low-to-moderate proportion of cells. The SCReadCounts read counts module is benchmarked against the analogous modules of GATK and Samtools. SCReadCounts is freely available (https://github.com/HorvathLab/NGS) as 64-bit self-contained binary distributions for Linux and MacOS, in addition to Python source.

Conclusions

SCReadCounts supplies a fast and efficient solution for estimation of cell-level SNV expression from scRNA-seq data. SCReadCounts enables distinguishing cells with monoallelic reference expression from those with no gene expression and is applicable to assess SNVs present in only a small proportion of the cells, such as somatic mutations in cancer.
Transcriptional profiling reveals changes in gene regulation and signaling transduction pathways during temperature stress in wucai (Brassica campestris L.)
Authors: Yuan Lingyun , Zheng Yushan , Nie Libing , Zhang Liting , Wu Ying , Zhu Shidong , Hou Jinfeng , Shan Guo Lei , Liu Tong Kun , Chen Guohu , Tang Xiaoyan , Wang Chenggang
Published: September 2021

Background

Wucai (Brassica campestris L. ssp. chinensis var. rosularis Tsen) is a cold-tolerant plant that is vulnerable to high temperature. This study explored the response mechanism of wucai to low temperature. In this study, wucai seedlings were treated with different temperatures, including low temperature (LT), high temperature (HT), and a control.

Results

According to transcriptomics analysis, the number of differentially expressed genes (DEGs) in HT and LT was 10,702 and 7267, respectively, compared with the control. The key genes associated with the physiological response of wucai to the treatments were analyzed. The Kyoto Encyclopedia of Genes and Genomes and Gene Ontology annotations indicated the importance of the photosynthesis and photosynthetic-antenna protein pathways. We found that a high-temperature environment greatly inhibited the expression of important genes in the photosynthetic pathway (BrLhc superfamily members, PsaD, PsaE, PsaD, PsaD, PsbO, PsbP, PsbQ, PsbR, PsbS, PsbW, PsbY, Psb27, and Psb28), whereas low temperature resulted in the expression of certain key genes (BrLhc superfamily members, Psa F, Psa H, Psb S, Psb H, Psb 28). In addition, the wucai seedlings exhibited better photosynthetic performance under low-temperature conditions than high-temperature conditions.

Conclusions

Based on the above results, we speculate that upon exposure to low temperature, the plants developed higher cold tolerance by upregulating the expression of genes related to photosynthesis. Conversely, high-temperature stress inhibited the expression of pivotal genes and weakened the self-regulating ability of the plants.
Impact of epidural labor analgesia using sufentanil combined with low-concentration ropivacaine on maternal and neonatal outcomes: a retrospective cohort study
Authors: Zhang Le , Xu Chengjie , Li Yue
Published: September 2021

Background

Whether epidural administered sufentanil combined with low-concentration ropivacaine affected labor progress as well as maternal and neonatal outcomes still remained unknown. The aim of this study was to assess the impact of epidural sufentanil plus ropivacaine on maternal and neonatal outcomes.

Methods

This is a retrospective cohort study. Data of singleton full-term pregnancy women who received epidural labor analgesia for vaginal delivery from May 2018 to June 2020 were collected. Parturients were divided into two groups (the R group and the SR group) according to different medication regimens for epidural labor analgesia. The implementation of epidural analgesia during labor was performed with 0.167 % ropivacaine in the R group and 0.1 % ropivacaine in combination with 0.5 µg/ml sufentanil in the SR group. The primary outcome of our study included the duration of labor progress and the incidence of maternal fever, postpartum hemorrhage, fetal distress and neonatal Apgar scores less than 7 at 1 and 5 min. The secondary outcome included the incidence of episiotomy, instrumental delivery, caesarean section and grade III meconium-stained amniotic fluid.

Results

There were a total 3778 deliveries during the study period, 1994 and 1784 parturients were included in the R group and in the SR group, respectively. The length of the first stage of labor was remarkably shorter in the R group in comparison to the SR group (548.0 ± 273.0 vs. 570.9 ± 273.0, P = 0.013). No significant difference was found in the incidence of maternal fever, postpartum hemorrhage, fetal distress and in the neonatal Apgar scores less than 7 at 1 and 5 min between two groups. Other Maternal outcomes were comparable in the R group and the SR group.

Conclusions

0.5 µg/ml sufentanil plus 0.1 % ropivacaine for epidural labor analgesia prolonged the duration of the first stage of labor, but did not have additional impact on maternal and neonatal outcomes compared with the sole 0.167 % ropivacaine.

Trial registration

Clinical Research Information Service with registration number ChiCTR2100045162. Registered 7 April 2021.
Differences in radiation dose for computed tomography of the brain among pediatric patients at the emergency departments: an observational study
Authors: Tan Xi Min , Shah Mohammad Taufik Bin Mohamed , Chong Shu-Ling , Ong Yong-Kwang Gene , Ang Peck Har , Zakaria Nur Diana Bte , Lee Khai Pin , Pek Jen Heng
Published: September 2021

Background

Computed tomography (CT) is associated with a risk of cancer development. Strategies to reduce radiation doses vary between centers. We compared radiation doses of CT brain studies between pediatric and general emergency departments (EDs), and determine the proportion studies performed within the reference levels recommended by the International Commission on Radiological Protection (ICRP).

Methods

A retrospective review was carried out in a healthcare network consisting of one pediatric ED and three general hospital EDs. Pediatric patients less than 16 years old with CT brain studies performed between 1 January 2015 and 31 December 2018 were included. Information on demographic, diagnosis, volume-averaged computed-tomography dose index and dose length product (DLP) were collected. Effective dose was then calculated from DLP using conversion factors, termed k-coefficients which were derived using a 16 cm head CT dose phantom.

Results

Four hundred and seventy-nine CT brain studies were performed – 379 (79.1%) at the pediatric ED. Seizure (149, 31.1%), head injury (147, 30.7%) and altered mental status (44, 9.2%) were the top three ED diagnoses. The median effective dose estimates were higher in general than pediatric EDs, particularly for those aged > 3 to ≤6 years old [1.57 mSv (IQR 1.42–1.79) versus 1.93 mSv (IQR 1.51–2.28), p = 0.047], > 6 to ≤10 years old [1.43 mSv (IQR 1.27–1.67) versus 1.94 mSv (IQR 1.61–2.59), p = 0.002) and > 10 years old (1.68 mSv (IQR 1.32–1.72) versus 2.03 mSv (IQR 1.58–2.88), p < 0.001). Overall, 233 (48.6%) and 13 (2.7%) studies were within the reference levels recommended by ICRP 60 and 103 respectively.

Conclusions

Radiation doses for CT brain studies were significantly higher at general EDs and less than half of the studies were within the reference levels recommended by ICRP. The development of diagnostic reference levels (DRLs) as a benchmark and clinical justification for performing CT studies can help reduce the radiation risks in the pediatric population.
Team VA Video Connect (VVC) to optimize mobility and physical activity in post-hospital discharge older veterans: baseline assessment
Authors: Alexander Neil B. , Phillips Kristin , Wagner-Felkey Joleen , Chan Chiao-Li , Hogikyan Robert , Sciaky Alexandra , Cigolle Christine
Published: September 2021

Background

Telehealth is increasingly used for rehabilitation and exercise but few studies include older adult participants with comorbidities and impairment, particularly cognitive. Using Veterans Administration Video Connect (VVC), the aim of the present study is to present the screening, recruitment, baseline assessment, and initial telehealth utilization of post-hospital discharge Veterans in a VVC home-telehealth based program to enhance mobility and physical activity.

Methods

Older adult Veterans (n = 45, mean age 73), recently discharged from the hospital with physical therapy goals, were VVC-assessed in self-report and performance-based measures, using test adaptations as necessary, by a clinical pharmacy specialist and social worker team.

Results

Basic and instrumental ADL disabilities were common as were low mobility (Short Portable Performance Battery) and physical activity levels (measured by actigraphy). Half had Montreal Cognitive Assessment (MoCA) scores in the mild cognitive impairment range (< 24). Over 2/3 of the participants used VA-supplied tablets. While half of the Veterans were fully successful in VVC, 1/3 of these and an additional group with at least one failed connection requested in-person visits for assistance. One-quarter had no VVC success and sought help for tablet troubleshooting, and half of these eventually “gave up” trying to connect; difficulty with using the computer and physical impairment (particularly dexterity) were described prominently in this group. On the other hand, Veterans with at least mild cognitive impairment (based on MoCA scores) were present in all connectivity groups and most of these used caregiver support to facilitate VVC.

Conclusions

Disabled older post-hospital discharged Veterans with physical therapy goals can be VVC-assessed and enrolled into a mobility/physical activity intervention. A substantial proportion required technical support, including in-person support for many. Yet, VVC seems feasible in those with mild cognitive impairment, assuming the presence of an able caregiver. Modifications of assessment tools were needed for the VVC interface, and while appearing feasible, will require further study.

Trial registration

ClinicalTrials.gov NCT 04045054 05/08/2019.
High resolution melting assay as a reliable method for diagnosing drug-resistant TB cases: a systematic review and meta-analysis
Authors: Keikha Masoud , Karbalaei Mohsen
Published: September 2021

Background

Tuberculosis (TB) is one of the most contagious infectious diseases worldwide. Currently, drug-resistant Mycobacterium tuberculosis (Mtb) isolates are considered as one of the main challenges in the global TB control strategy. Rapid detection of resistant strains effectively reduces morbidity and mortality of world’s population. Although both culture and conventional antibiotic susceptibility testing are time-consuming, recent studies have shown that high resolution melting (HRM) assay can be used to determine the types of antibiotic resistance. In the present meta-analysis, we evaluated the discriminative power of HRM in detecting all drug-resistance cases of TB.

Methods

A systematic search was performed using databases such as Cochrane Library, Scopus, PubMed, Web of Science, and Google Scholar. Related studies on the effect of HRM in the diagnosis of drug-resistant (DR) TB cases were retrieved by April 2021. We used Meta-Disc software to evaluate the pooled diagnostic sensitivity and specificity of HRM for the detection of each type of drug-resistant cases. Finally, diagnostic value of HRM was characterized by summary receiver operating characteristic (SROC) curve and the area under the curve (AUC) method.

Results

Overall 47 studies (4,732 Mtb isolates) met our criteria and were included in the present meta-analysis. Sensitivity, specificity, and AUC of HRM were measured for antibiotics such as isoniazid (93%, 98%, 0.987), rifampin (94%, 97%, 0963), ethambutol (82%, 87%, 0.728), streptomycin (82%, 95%, 0.957), pyrazinamide (72%, 84%, 0.845), fluoroquinolones (86%, 99%, 0.997), MDR-TB (90%, 98%, 0.989), and pan-drug-resistant TB (89%, 95%, 0.973).

Conclusions

The HRM assay has high accuracy for the identification of drug-resistant TB, particularly firs-line anti-TB drugs. Therefore, this method is considered as an alternative option for the rapid diagnosis of DR-TB cases. However, due to heterogeneity of included studies, the results of HRM assays should be interpreted based on conventional drug susceptibility testing.
Radically open dialectical behaviour therapy adapted for adolescents: a case series
Authors: Baudinet Julian , Stewart Catherine , Bennett Eleanor , Konstantellou Anna , Parham Rhian , Smith Keren , Hunt Katrina , Eisler Ivan , Simic Mima
Published: September 2021

Background

Overcontrol is a transdiagnostic cluster of traits associated with excessive psychological, behavioural and social inhibitory control. It is associated with psychiatric diagnoses of depression, restrictive eating disorders and/or obsessive-compulsive personality disorder. Radically Open Dialectical Behaviour Therapy is a transdiagnostic treatment for maladaptive overcontrol. This case series evaluates an adolescent adaption (RO-A) for a transdiagnostic group of adolescents identified as overcontrolled.

Methods

Twenty-eight adolescents were consecutively referred for RO-A from two different National and Specialist Child and Adolescent Mental Health Services between June 2017 and February 2020. Baseline self-report measures assessed overcontrol characteristics, relationship and attachment quality and mental health symptoms of depression and eating disorders, which were repeated at discharge.

Results

Adolescents in this case series reported high rates of depression (78.6%), self-harm (64.3%) and eating disorders (78.6%). Most (85.7%) had two or more mental health diagnoses and all had previous mental health treatments before starting RO-A. The mean number of RO-A sessions attended was 18 group-based skills classes and 21 individual sessions over a mean period of 34 weeks. Significant improvements with medium and large effect sizes were reported in cognitive flexibility (d = 1.63), risk aversion (d = 1.17), increased reward processing (d = .79) and reduced suppression of emotional expression (d = .72). Adolescents also reported feeling less socially withdrawn (d = .97), more connected to others (d = 1.03), as well as more confident (d = 1.10) and comfortable (d = .85) in attachment relationships. Symptoms of depression (d = .71), eating disorders (d = 1.06) and rates of self-harm (V = .39) also significantly improved. Exploratory correlation analyses suggest improvements in overcontrol are moderately to strongly correlated with improvements in symptoms of depression and eating disorders.

Conclusions

This case series provides preliminary data that RO-A may be an effective new treatment for adolescents with overcontrol and moderate to severe mental health disorders like depression and eating disorders. RO-A led to improved management of overcontrol, improved relationship quality and reduced mental health symptoms. Further evaluation is indicated by this case series, particularly for underweight young people with eating disorders. More rigorous testing of the model is required as conclusions are only tentative due to the small sample size and methodological limitations.
The effects of removing dead bacteria by propidium monoazide on the profile of salivary microbiome
Authors: Ren Qidi , Wei Fangqiao , Yuan Chao , Zhu Ce , Zhang Qian , Quan Junkang , Sun Xiangyu , Zheng Shuguo
Published: September 2021

Background

Oral microbiome played an important role in maintaining healthy state and might exhibit certain changes under circumstances of diseases. However, current microbiological research using sequencing techniques did not regard dead bacteria as a separate part, causing findings based on subsequent analyses on dynamic equilibrium and functional pathways of microbes somewhat questionable. Since treatment by propidium monoazide (PMA) was able to remove dead bacteria effectively, it would be worth studying how the sequencing results after PMA treatment differed from those focusing on the whole microbiota.

Methods

Unstimulated whole saliva samples were obtained from 18 healthy people from 3 age groups (children, adults, and the elderly). After removal of dead bacteria by propidium monoazide (PMA), changes in the profile of salivary microbiome were detected using 16S rRNA sequencing technology, and differences among age groups were compared subsequently.

Results

Dead bacteria accounted for nearly a half of the whole bacteria flora in saliva, while freezing had little effect on the proportion of deaths. After treatment with PMA, the numbers of OTUs reduced by 4.4–14.2%, while the Shannon diversity indices decreased significantly (P < 0.01). Only 35.2% of positive and 6.1% of negative correlations were found to be shared by the whole microbiota and that with dead bacteria removed. Differences in significantly changed OTUs and functional pathways among different age groups were also observed between the group of PMA and the control.

Conclusions

It was necessary to take the influence of living state of bacteria into account in analytic studies of salivary microbiome.
Expectations and needs of socially vulnerable patients for navigational support of primary health care services
Authors: Ngo Bikoko Piemeu Carine Sandrine , Loignon Christine , Dionne Émilie , Paré-Plante Andrée-Anne , Haggerty Jeannie , Breton Mylaine
Published: September 2021

Background

Primary healthcare is the main entry to the health care system for most of the population. In 2008, it was estimated that about 26% of the population in Quebec (Canada) did not have a regular family physician. In early 2017, about 10 years after the introduction of a centralized waiting list for patients without a family physician, Québec had 25% of its population without a family physician and nearly 33% of these or 540,000, many of whom were socially vulnerable (SV), remained registered on the list. SV patients often have more health problems. They also face access inequities or may lack the skills needed to navigate a constantly evolving and complex healthcare system. Navigation interventions show promise for improving access to primary health care for SV patients. This study aimed to describe and understand the expectations and needs of SV patients.

Methods

A descriptive qualitative study rooted in a participatory study on navigation interventions implemented in Montérégie (Quebec) addressed to SV patients. Semi-structured individual face-to-face and telephone interviews were conducted with patients recruited in three primary health care clinics, some of whom received the navigation intervention. A thematic analysis was performed using NVivo 11 software.

Results

Sixteen patients living in socially deprived contexts agreed to participate in this qualitative study. Three main expectations and needs of patients for navigation interventions were identified: communication expectations (support to understand providers and to be understood by them, discuss about medical visit, and bridge the communication cap between patients and PHC providers); relational expectations regarding emotional or psychosocial support; and pragmatic expectations (information on available resources, information about the clinic, and physical support to navigate the health care system).

Conclusions

Our study contributes to the literature by identifying expectations and needs specified to SV patients accessing primary health care services, that relate to navigation interventions. This information can be used by decision makers for navigation interventions design and inform health care organizational policies.
Industrial odour pollution and human health: a systematic review and meta-analysis
Authors: Guadalupe-Fernandez Victor , De Sario Manuela , Vecchi Simona , Bauleo Lisa , Michelozzi Paola , Davoli Marina , Ancona Carla
Published: September 2021

Objective

To conduct a systematic review to evaluate the association between residential or occupational short- and long–term exposure to odour pollution from industrial sources and the health status of the exposed population.

Methods

The searches were conducted in Medline, EMBASE and Scopus in April 2021. Exposure to an environmental odour from industrial sources in population resident near the source or in workers was considered. We considered outcomes for which there was a biological plausibility, such as wheezing and asthma, cough, headache, nausea and vomiting (primary outcomes). We also included stress-related symptoms and novel outcomes (e.g. mood states). Risk of bias was evaluated using the OHAT tool.

For primary outcomes, when at least 3 studies provided effect estimates by comparing exposed subjects versus not exposed, we pooled the study-specific estimates of odour-related effect using random effects models. Heterogeneity was evaluated with Higgins I2.

Results

Thirty studies were eligible for this review, mainly cross-sectional (n = 23). Only one study involved school-age children and two studies involved workers. Only five studies reported odour effects on objective laboratory or clinical outcomes. Animal Feeding Operations and waste were the most common industrial sources.

The overall odds ratios in exposed versus not exposed population were 1.15 (95% CI 1.01 to 1.29) for headache (7 studies), 1.09 (95% CI 0.88 to 1.30) for nausea/vomiting (7 studies), and 1.27 (95% CI 1.10 to 1.44) for cough/phlegm (5 studies). Heterogeneity was a moderate concern. Overall, the body of evidence was affected by a definitely high risk of bias in exposure and outcome assessment since most studies used self-reported information.

Conclusions

Findings underline the public health importance of odour pollution for population living nearby industrial odour sources. The limited evidence for most outcomes supports the need for high quality epidemiological studies on the association between odour pollution and its effects on human health.
FoXA2 promotes esophageal squamous cell carcinoma progression by ZEB2 activation
Authors: Gao Hanjing , Yan Zheng , Sun Haiyan , Chen Yanfang
Published: September 2021

Background

It has been reported that Forkhead transcription family member (FOXA2) regulates esophageal squamous cell carcinoma (ESCC) progression. However, the specific mechanism, by which FOXA2 promotes ESCC malignant progression, remains unclear.

Materials and methods

QRT-PCR and western blotting were applied to measure FOXA2 expression in ESCC tissues, while CCK-8 assay and Transwell assays were used to investigate the effect of FOXA2 on ESCC. Luciferase reporter assay, followed by fast chromatin immunoprecipitation (ChIP) assay, was used to study the relationship between FOXA2 and ZEB2.

Results

FOXA2 was significantly increased in ESCC tissues, when compared to normal tissues. Moreover, high expression of FOXA2 was also found in ESCC cells. Knockdown of FOXA2 inhibited ESCC cell proliferation, invasion, and migration. Mechanically, FOXA2 was verified to regulate ZEB2 expression at transcription level. Moreover, ZEB2 reversed the inhibitory effect of FOXA2 on ESCC proliferation, invasion, and migration. The relationship between ZEB2 and FOXA2 in ESCC tissues was negative.

Conclusions

These results indicate that FOXA2 plays a critical role in ESCC progression and may become a potential candidate target for ESCC treatment.
Conducting decolonizing research and practice with Australian First Nations to close the health gap
Authors: Laird Pamela , Chang Anne B. , Jacky John , Lane Mary , Schultz André , Walker Roz
Published: September 2021

The purpose of this paper is to highlight a perspective for decolonizing research with Australian First Nations and provide a framework for successful and sustained knowledge translation by drawing on the recent work conducted by a research group, in five remote communities in North-Western Australia. The perspective is discussed in light of national and international calls for meaningful and dedicated engagement with First Nations people in research, policy and practice, to help close the health gap between First Nations and other Australians.
Avoiding health technology assessment: a global survey of reasons for not using health technology assessment in decision making
Authors: Teerawattananon Yot , Painter Chris , Dabak Saudamini , Ottersen Trygve , Gopinathan Unni , Chola Lumbwe , Chalkidou Kalipso , Culyer Anthony J.
Published: September 2021

Introduction

Despite the documented benefits of using health technology assessments (HTA) to inform resource allocation in health care systems, HTA remains underused, especially in low- and middle-income countries. A survey of global health practitioners was conducted to reveal the top reasons (“excuses”) that they had heard from colleagues, policymakers or other stakeholders for not using HTA in their settings.

Methods

There were 193 respondents to the survey. Most responses were from individuals in research organisations (37%), ministries of health (27%) and other government agencies (14%). Participants came from Southeast Asia (40%), the Western Pacific (30%), Africa (15%), Europe (7%), the Americas (7%) and the Eastern Mediterranean region (2%).

Results

The top five reasons encountered by respondents related to lack of data, lack of technical skills for HTA, the technocratic nature of the work, the lack of explicit decision rules and the perception that HTA puts a “price on life”.

Conclusions

This study aimed to understand and address the top reasons for not using HTA. They fall into three categories: (1) misconceptions about HTA; (2) feasibility issues; and (3) values, attitudes and politics. Previous literature has shown that these reasons can be addressed when identified, and even imperfect HTA analyses can provide useful information to a decision-maker.
Study protocol for a type III hybrid effectiveness-implementation trial of strategies to implement firearm safety promotion as a universal suicide prevention strategy in pediatric primary care
Authors: Beidas Rinad S. , Ahmedani Brian K. , Linn Kristin A. , Marcus Steven C. , Johnson Christina , Maye Melissa , Westphal Joslyn , Wright Leslie , Beck Arne L. , Buttenheim Alison M. , Daley Matthew F. , Davis Molly , Elias Marisa E. , Jager-Hyman Shari , Hoskins Katelin , Lieberman Adina , McArdle Bridget , Ritzwoller Debra P. , Small Dylan S. , Wolk Courtney Benjamin , Williams Nathaniel J. , Boggs Jennifer M.
Published: September 2021

Background

Insights from behavioral economics, or how individuals’ decisions and behaviors are shaped by finite cognitive resources (e.g., time, attention) and mental heuristics, have been underutilized in efforts to increase the use of evidence-based practices in implementation science. Using the example of firearm safety promotion in pediatric primary care, which addresses an evidence-to-practice gap in universal suicide prevention, we aim to determine: is a less costly and more scalable behavioral economic-informed implementation strategy (i.e., “Nudge”) powerful enough to change clinician behavior or is a more intensive and expensive facilitation strategy needed to overcome implementation barriers?

Methods

The Adolescent and child Suicide Prevention in Routine clinical Encounters (ASPIRE) hybrid type III effectiveness-implementation trial uses a longitudinal cluster randomized design. We will test the comparative effectiveness of two implementation strategies to support clinicians’ use of an evidence-based firearm safety practice,S.A.F.E. Firearm, in 32 pediatric practices across two health systems. All pediatric practices in the two health systems will receiveS.A.F.E. Firearmmaterials, including training and cable locks. Half of the practices (k= 16) will be randomized to receive Nudge; the other half (k= 16) will be randomized to receive Nudge plus 1 year of facilitation to target additional practice and clinician implementation barriers (Nudge+). The primary implementation outcome is parent-reported clinician fidelity to theS.A.F.E Firearmprogram. Secondary implementation outcomes include reach and cost. To understand how the implementation strategies work, the primary mechanism to be tested is practice adaptive reserve, a self-report practice-level measure that includes relationship infrastructure, facilitative leadership, sense-making, teamwork, work environment, and culture of learning.

Discussion

The ASPIRE trial will integrate implementation science and behavioral economic approaches to advance our understanding of methods for implementing evidence-based firearm safety promotion practices in pediatric primary care. The study answers a question at the heart of many practice change efforts: which strategies are sufficient to support change, and why? Results of the trial will offer valuable insights into how best to implement evidence-based practices that address sensitive health matters in pediatric primary care.

Trial registration

ClinicalTrials.gov,NCT04844021. Registered 14 April 2021.