Abstract
Motivation
Microbiome datasets with taxa linked to the functions (e.g. genes) they encode are becoming more common as metagenomics sequencing approaches improve. However, these data are ...challenging to analyze due to their complexity. Summary metrics, such as the alpha and beta diversity of taxa contributing to each function (i.e. contributional diversity), represent one approach to investigate these data, but currently there are no straightforward methods for doing so.
Results
We addressed this gap by developing FuncDiv, which efficiently performs these computations. Contributional diversity metrics can provide novel insights that would be impossible to identify without jointly considering taxa and functions.
Availability and implementation
FuncDiv is distributed under a GNU Affero General Public License v3.0 and is available at https://github.com/gavinmdouglas/FuncDiv.
Supplementary information
Supplementary data are available at Bioinformatics online.
Genetic and genomic technologies can effectively diagnose numerous genetic disorders. Patients benefit when genetic counselling accompanies genetic testing and international guidelines recommend pre‐ ...and post‐test genetic counselling with genome‐wide sequencing. However, there is a gap in knowledge regarding the unique genetic counselling considerations with different types of genetic testing in the Neonatal Intensive Care Unit (NICU) and the Pediatric Intensive Care Unit (PICU). This scoping review was conducted to identify the gaps in care with respect to genetic counselling for infants/pediatric patients undergoing genetic and genomic testing in NICUs and PICUs and understand areas in need of improvement in order to optimize clinical care for patients, caregivers, and healthcare providers. Five databases (MEDLINE Ovid, Embase Ovid, PsycINFO Ebsco, CENTRAL Ovid, and CINHAL Ebsco) and grey literature were searched. A total of 170 studies were included and used for data extraction and analysis. This scoping review includes descriptive analysis, followed by a narrative account of the extracted data. Results were divided into three groups: pre‐test, post‐test, and comprehensive (both pre‐ and post‐test) genetic counselling considerations based on indication for testing. More studies were conducted in the NICU than the PICU. Comprehensive genetic counselling was discussed in only 31% of all the included studies demonstrating the need for both pre‐test and post‐test genetic counselling for different clinical indications in addition to the need to account for different cultural aspects based on ethnicity and geographic factors.
Considerations for optimizing genetic counselling (both pre‐ and post‐test) in intensive care settings.
The evolution of antimicrobial resistant pathogens constitutes a significant global public health threat. Combined with the lack of incentive for pharmaceutical companies to invest in developing new ...antibiotics, it is clear alternative treatments are needed. Bacteriophages present one possible avenue as they harness the diversity and specificity of a microorganism that has coevolved with bacteria. However, little is known about these bacterial viruses. The SEA-PHAGES program was designed to identify and characterize novel bacteriophages and their associated gene functions. Herein, we report the genome annotation of one such novel phage: Mycobacteriophage Blizzard (GenBank accession number MW712733). Blizzard’s gene content was functionally annotated using bioinformatic tools including DNA Master, Phamerator, and NCBI BLAST, to call start sites as well as predict gene function. Overall, 96 genes were identified, including a tRNA and a translational frameshift, using highly similar reference phages BEEST, Belladonna, and CREW. From the 96 genes identified, 46 were functionally annotated. The remaining 50 genes have unknown functions due to the lack of significant matches in the databases. Our results demonstrate a novel annotated phage, whose genome serves to expand the understanding of phage biology and potential implications as alternative treatment to antibiotics.
We developed an electrochemical and fluorescent dual-mode sensor for assessing acetylcholinesterase (AChE) activity and inhibition by taking advantage of the high redox sensitivity of surface-coated ...mesoporous MnO2@polymer dot (MnO2@PD) towards AChE. The following phenomena constitute the basis of the detection mechanism: fluorescence resonance energy transfer (FRET) effect between MnO2 and PD; catalytic hydrolysis of acetylthiocholine (ATCh) to thiocholine (TCh) by AChE expressed by PC-12 cells, inducing fluorescence restoration and change in the conductivity of the system due to MnO2 decomposition; the presence of the inhibitor neostigmine preventing the conversion of ATCh to TCh. The surface-coated biosensor presents both fluorescence-based and electrochemical approaches for effectively monitoring AChE activity and inhibition. The fluorescence approach is based on the fluorescent “on/off” property of the system caused by MnO2 breakdown after interaction with TCh and the subsequent release of PDs. The conductivity of the coated electrode decreased dramatically as AChE concentration increased, resulting in electrochemical sensing of AChE activity and inhibition screening. Real-time wireless sensing can be conducted using a smartphone to monitor the resistance change, investigating the potential use of MnO2@PD nanocomposites in biological studies, and offering a real-time redox-fluorescent test for AChE activity monitoring and inhibitor screening.
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•Electrochemical and fluorescent-based surface-coated MnO2@PD for AChE sensing.•Electronic/optical properties affected by breakdown of MnO2 in the presence of AChE.•In vitro assessment of AChE using PC-12 cells exhibiting high AChE expression.•Monitor neostigmine inhibition of AChE via fluorescence and electronic signals.•Real-time wireless sensing to facilitate the detection of AChE via a smartphone.
Allogeneic hematopoeitic cell transplantation (allo‐HCT) is the only curative treatment for myelofibrosis (MF). We evaluate the impact of various factors on survival outcomes post‐transplant in MF. ...Data of 89 consecutive MF patients (primary 47%) who underwent allo‐HCT between 2005 and 2018 was evaluated. Fifty‐four percent patients had received JAK1/2 inhibitors (JAKi) pre‐HCT. The median CD34 count was 7.1x106 cells/kg. Graft failure was seen in 10% of the patients. Grade 3‐4 acute GVHD (aGVHD) and moderate/severe chronic graft versus host disease (cGVHD) occurred in 24% and 40% patients, respectively. Two‐year overall survival (OS) and relapse free survival (RFS) were 51% and 43%, respectively. Cumulative incidence of relapse (CIR) and non‐relapse mortality (NRM) at 2 years were 11% and 46%, respectively. Higher CD34 cell dose (≤5 × 106 cells/kg vs 5‐9 or ≥9 × 106 cells/kg) and lower pre‐HCT ferritin (</=1000 ng/ml) were associated with better OS, RFS and lower NRM. Grade 3‐4 aGVHD was associated with higher NRM. Use of pre‐transplant JAKi was associated with lower incidence of grade 3‐4 aGVHD. In summary, higher CD34 cell dose is associated with better allo‐HCT outcomes in MF and pre‐HCT JAKi use is associated with reduced risk of severe aGVHD. These two modifiable parameters should be considered during allo‐HCT for MF.
We developed an electrochemical and fluorescent dual-mode sensor for assessing acetylcholinesterase (AChE) activity and inhibition by taking advantage of the high redox sensitivity of surface-coated ...mesoporous MnO
@polymer dot (MnO
@PD) towards AChE. The following phenomena constitute the basis of the detection mechanism: fluorescence resonance energy transfer (FRET) effect between MnO
and PD; catalytic hydrolysis of acetylthiocholine (ATCh) to thiocholine (TCh) by AChE expressed by PC-12 cells, inducing fluorescence restoration and change in the conductivity of the system due to MnO
decomposition; the presence of the inhibitor neostigmine preventing the conversion of ATCh to TCh. The surface-coated biosensor presents both fluorescence-based and electrochemical approaches for effectively monitoring AChE activity and inhibition. The fluorescence approach is based on the fluorescent "on/off" property of the system caused by MnO
breakdown after interaction with TCh and the subsequent release of PDs. The conductivity of the coated electrode decreased dramatically as AChE concentration increased, resulting in electrochemical sensing of AChE activity and inhibition screening. Real-time wireless sensing can be conducted using a smartphone to monitor the resistance change, investigating the potential use of MnO
@PD nanocomposites in biological studies, and offering a real-time redox-fluorescent test for AChE activity monitoring and inhibitor screening.
BACKGROUND:
Allogeneic hematopoeitic cell transplant (HCT) is potentially curative for a variety of hematological diseases. It is however associated with significant morbidity and mortality. Numerous ...pre-transplant risk scores have been developed to predict outcomes, such as the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). This study assesses the value of the HCT-CI and related scores on a single center population, in comparison with other potential parameters influencing outcomes. A similar methodology was later applied to a different cohort of patients' data from Oslo University Hospital, Norway.
METHODS:
Two experienced physicians prospectively calculated the HCT-CI score for all patients transplanted at our center. The age-adjusted HCT-CI score and the augmented HCT-CI score were calculated retrospectively. Prospective calculation was performed during the patient's pre-transplant assessment before transplant admission using a pre-prepared form. The HCT-CI/age and the augmented HCT-CI (which includes ferritin, albumin and platelet count) were calculated using additional data retrospectively collected from the electronic patient records (EPR). All other patient and transplant characteristics were retrospectively collected from the EPR. Non-Relapse Mortality (NRM) and Overall survival (OS) were calculated to assess the prognostic power of the scores. We also looked at the impact of major transplant and patient related parameters in our patient population. A similar methodology was later applied to a different cohort of patients' data from Oslo University Hospital, Norway.
RESULTS:
From August 2014 to April 2017, 299 patients underwent allogeneic HCT at the Princess Margaret Cancer Centre (PMCC), Toronto. A similar analysis was performed in a cohort of 455 patients from Oslo University Hospital who underwent HCT between 2012 and 2018. Comparative patient characteristics are described in Table 1.
On univariate analysis, 2-year OS of the PMCC cohort was 51% (95% CI 45-56%). For the HCT-CI scores 0-2 vs ≥3, 2-year OS was 53% vs 46% respectively (p=0.29). For the HCT-CI/age scores 0-2 vs ≥3, it was 56% vs 44% respectively (p=0.03). For the augmented HCT-CI scores 0-2 vs ≥3, it was 55% vs 46% respectively (p=0.05). Among other variables, age group (<50 vs 50-64 vs ≥65, p=0.02) and donor mismatch (p=0.01) were significant for OS. However, age (HR 1.48 and 1.75 for age 50-64 and ≥65 respectively, p=0.047) and donor mismatch (HR 1.60, p=0.02) alone were also prognostically significant in the multivariate analysis as well.
We then developed a weighted score that would better reflect risk groups in our population. Age <50 and full HLA matching received 0 point each, age 50-64 and any mismatch (except DQ alone) received 1 point each, while age ≥65 received 2 points. The patients were grouped into 3 groups of 0, 1 and ≥ 2 points. This new simple 3 tier score predicted OS and NRM at 2 years with better accuracy. The 2 yr OS was 62%, 53% and 38% for the 3 groups (p value =0.0004) and 2 year NRM was 24%, 34% and 43% respectively (p value=0.015) (Table 2 and Figure 1). The same scoring system was later applied to an independent cohort of allogeneic HCT patients from the Oslo HCT registry and was found to be similarly significantly predictive of OS and NRM. In the Oslo cohort, the 2 yr OS was 69%, 65% and 35% for the 3 groups according to the new weighted score (p value <0.001) and 2 year NRM was 15%, 20% and 45% respectively (p value=0.015)
CONCLUSION:
A simple, weighted score involving donor HLA mismatch and age predicts survival and NRM better than the HCT-CI score for patients transplanted at our center with good replicability as shown from Oslo data. Efforts should continue to strive for the development of a widely applicable pre-transplant outcome predictive scoring system.
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Mattsson:Gilead: Honoraria; Therakos: Honoraria; Celgene: Honoraria. Michelis:CSL Behring: Other: Financial Support.
Allogeneic hematopoietic cell transplantation (HCT) outcomes may be predicted by published risk scores; however, the ideal system has not been identified for acute leukemias.
We retrospectively ...examined the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), modified European Group for Blood and Marrow Transplantation (mEBMT), EBMT-Alternating Decision Tree (ADT), and others on 231 patients with acute leukemia.
Acute myeloid leukemia was diagnosed in 200 patients, and acute lymphocytic leukemia was diagnosed in 31 patients. For HCT-CI, patients were grouped as 0 to 1, 2 to 3, and > 3. For mEBMT, patients were grouped as 0 to 2, 3, and > 3. For EBMT-ADT, the 100-day mortality was calculated and grouped as ≤ 4.1%, 4.1% to 11.5%, and > 11.5%. Higher HCI-CI demonstrated inferior overall survival (P = .04; c-statistic, 0.57), whereas mEBMT and EBMT-ADT did not stratify well. A new weighted score was developed that assigned 1 point for age ≥ 60 years, acute lymphocytic leukemia diagnosis, mismatch unrelated or haploidentical donor, cardiovascular comorbidity, and pre-transplant diabetes, whereas arrhythmia received 2 points. The new weighted score assigned 0 points to 88 (38%), 1 to 2 points to 121 (52%) and ≥ 3 points to 22 (10%) patients, and demonstrated improved prognostic capability compared with the other scores (P = .0001; c-statistic, 0.61).
The HCT-CI stratifies patients with leukemia for overall survival but is inferior to our single-center score, which is influenced by cardiac comorbidity and arrhythmia. Differences in pre-transplant risk scores may be related to different transplant practices.
Allogeneic hematopoietic cell transplantation may provide a cure for acute leukemia where indicated. Multiple prognostic scoring systems for transplant have been developed, but their general relevance is not well-defined. We observed that the modified European Group for Blood and Marrow Transplantation and European Group for Blood and Marrow Transplantation-Alternating Decision Tree scores are inferior to the Hematopoietic Cell Transplantation-Comorbidity Index, which, however, is not a powerful predictor. New approaches in outcome prediction in allogeneic transplant are warranted.
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