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Abstract Cuffless blood pressure (BP) measurements have long been anticipated, and the PPG (Photoplethysmography)-only method is the most promising one since already embedded in many wearable devices. To further meet the clinical accuracy requirements, PPG-only BP predictions with personalized modeling for overcoming personal deviations have been widely studied, but all required tens to hundreds of minutes of personal PPG measurements for training. Moreover, their accurate test periods without calibration practice were not reported. In this work, we collected records of PPG data from our recruited subjects in real-life scenarios instead of relying on the openly available MIMIC dataset obtained from intensive care unit (ICU) patients. Since our objective is commercial application and a substantial reduction in training data, we tailored our model training to closely mimic real-world usage. To achieve this, we developed a training approach that only requires 9-minutes of personal PPG signal recordings and mixed with other PPG data from our recruited 364 subjects. The modeling is conducted with two-channel paired inputs to the convolutional neural network (CNN)-based model, which we called Mixed Deduction Learning (MDL). The test results of 88 samples from 15 subjects, under testing period up to 30-plus days without extra calibration, revealed that MDL meets most of the standards of AAMI, BHS, and IEEE 1708–2014 (for static test only) for BP measurement devices, which indicates MDL’s long-term stability and consistency. Furthermore, we found that the model with two-channel inputs presents a trend of improving performance as the pool of mixed training data increased, while the conventional one-channel input revealed degraded performance. The outperformance of MDL is attributed to many significant features remained in the first CNN layer even when mixing personal 9-minutes data with the other 364 subjects. Consequently, PPG-only with MDL introduces a new avenue for overcoming challenges in training due to personal physiological variations. Given our consideration of real-life usage, this technology can be seamlessly translated to commercial applications.

Emerging and reemerging viral infections represent a major concern for human public health emergencies and there is an urgent need for the development of broad-spectrum antivirals and next generation vaccines.By using integrated system-wide approaches including genome-wide gene silencing profiling, miRNA profiling and proteomics via high-throughput techniques, combined with bio-imaging and computational biology, we attempt to understand the biological complexity of virus-host interactions and translating it into antiviral strategies against these viral pathogens. To address the urgent need for treatment options, we have evaluated an array of antiviral strategies from high throughput screening of small molecule compound libraries for potential antivirals against these viruses, to the utilization of molecular intervention as well as the development of DNA launched replicon based vaccines. In vivo efficacy of these antiviral approaches are also illustrated with murine models established for these viral infections. In this talk, I will illustrate with the human enteroviruses (EV-A71) that have important medical implications on the pediatric populations in Asia. Together, these studies have provided the basis for the development of effective antiviral approaches that can be clinically validated as viable antiviral strategies against these medically important viral pathogens.

Abstract Background De novo genome assembly is essential to modern genomics studies. As it is not biased by a reference, it is also a useful method for studying genomes with high variation, such as cancer genomes. De novo short-read assemblers commonly use de Bruijn graphs, where nodes are sequences of equal length k, also known as k-mers. Edges in this graph are established between nodes that overlap by $$k - 1$$ k - 1 bases, and nodes along unambiguous walks in the graph are subsequently merged. The selection of k is influenced by multiple factors, and optimizing this value results in a trade-off between graph connectivity and sequence contiguity. Ideally, multiple k sizes should be used, so lower values can provide good connectivity in lesser covered regions and higher values can increase contiguity in well-covered regions. However, current approaches that use multiple k values do not address the scalability issues inherent to the assembly of large genomes. Results Here we present RResolver, a scalable algorithm that takes a short-read de Bruijn graph assembly with a starting k as input and uses a k value closer to that of the read length to resolve repeats. RResolver builds a Bloom filter of sequencing reads which is used to evaluate the assembly graph path support at branching points and removes paths with insufficient support. RResolver runs efficiently, taking only 26 min on average for an ABySS human assembly with 48 threads and 60 GiB memory. Across all experiments, compared to a baseline assembly, RResolver improves scaffold contiguity (NGA50) by up to 15% and reduces misassemblies by up to 12%. Conclusions RResolver adds a missing component to scalable de Bruijn graph genome assembly. By improving the initial and fundamental graph traversal outcome, all downstream ABySS algorithms greatly benefit by working with a more accurate and less complex representation of the genome. The RResolver code is integrated into ABySS and is available at https://github.com/bcgsc/abyss/tree/master/RResolver .

Abstract Personalized modeling has long been anticipated to approach precise noninvasive blood glucose measurements, but challenged by limited data for training personal model and its unavoidable outlier predictions. To overcome these long-standing problems, we largely enhanced the training efficiency with the limited personal data by an innovative Deduction Learning (DL), instead of the conventional Induction Learning (IL). The domain theory of our deductive method, DL, made use of accumulated comparison of paired inputs leading to corrections to preceded measured blood glucose to construct our deep neural network architecture. DL method involves the use of paired adjacent rounds of finger pulsation Photoplethysmography signal recordings as the input to a convolutional-neural-network (CNN) based deep learning model. Our study reveals that CNN filters of DL model generated extra and non-uniform feature patterns than that of IL models, which suggests DL is superior to IL in terms of learning efficiency under limited training data. Among 30 diabetic patients as our recruited volunteers, DL model achieved 80% of test prediction in zone A of Clarke Error Grid (CEG) for model training with 12 rounds of data, which was 20% improvement over IL method. Furthermore, we developed an automatic screening algorithm to delete low confidence outlier predictions. With only a dozen rounds of training data, DL with automatic screening achieved a correlation coefficient ( $${R}_{P}$$ R P ) of 0.81, an accuracy score ( $${R}_{A}$$ R A ) of 93.5, a root mean squared error of 13.93 mg/dl, a mean absolute error of 12.07 mg/dl, and 100% predictions in zone A of CEG. The nonparametric Wilcoxon paired test on $${R}_{A}$$ R A for DL versus IL revealed near significant difference with p-value 0.06. These significant improvements indicate that a very simple and precise noninvasive measurement of blood glucose concentration is achievable.

To reduce the error induced by overfitting or underfitting in predicting non-invasive fasting blood glucose (NIBG) levels using photoplethysmography (PPG) data alone, we previously demonstrated that incorporating HbA1c led to a notable 10% improvement in NIBG prediction accuracy (the ratio in zone A of Clarke’s error grid). However, this enhancement came at the cost of requiring an additional HbA1c measurement, thus being unfriendly to users. In this study, the enhanced HbA1c NIBG deep learning model (blood glucose level predicted from PPG and HbA1c) was trained with 1494 measurements, and we replaced the HbA1c measurement (explicit HbA1c) with “implicit HbA1c” which is reversely derived from pretested PPG and finger-pricked blood glucose levels. The implicit HbA1c is then evaluated across intervals up to 90 days since the pretest, achieving an impressive 87% accuracy, while the remaining 13% falls near the CEG zone A boundary. The implicit HbA1c approach exhibits a remarkable 16% improvement over the explicit HbA1c method by covering personal correction items automatically. This improvement not only refines the accuracy of the model but also enhances the practicality of the previously proposed model that relied on an HbA1c input. The nonparametric Wilcoxon paired test conducted on the percentage error of implicit and explicit HbA1c prediction results reveals a substantial difference, with a p-value of 2.75 × 10–7.

Context: Abdominal pain after surgery can occur for numerous reasons. Postoperative radiographs may be indicated to evaluate for ileus or other reasons for the pain. Whether outcomes are significantly different based on whether patients get radiographs following lateral lumbar interbody fusion (LLIF) are unclear. Aims: To investigate the postoperative outcomes of patients experiencing abdominal pain after LLIF. Settings and Design: This retrospective cohort study included patients at a tertiary academic medical center and surrounding affiliated hospitals. Materials and Methods: Patients >18 years of age who underwent elective LLIF at a single institution were retrospectively identified. Patients were stratified into two groups depending on whether they received a postoperative abdominal radiograph or computed tomography (CT) scan for postoperative abdominal pain. Statistical Analysis: Patient demographics, surgical characteristics, and surgical outcomes were compared between groups utilizing independent t-tests or Mann–Whitney U-tests for continuous variables or Pearson's Chi-square tests for categorical variables. Results: A total of 153 patients (18 with abdominal scans, 135 without) were included. Patients who received a postoperative abdominal radiograph or CT scan were more likely to undergo exploratory laparotomy (11.1% vs. 0.00%, P = 0.013). Ultimately, patients with abdominal scans had a longer hospital length of stay (6.67 vs. 3.79 days, P = 0.002) and were discharged home less frequently (71.4% vs. 83.7%, P = 0.002). Conclusions: Patients who received abdominal imaging after LLIF were more likely to undergo exploratory laparotomy, experience longer hospital length of stay, and were discharged home less frequently. Intra-abdominal air on postoperative imaging without corresponding physical exam findings consistent with bowel injury is not an appropriate indication for surgical intervention.

Trial design: A randomised, parallel-group, double-blind, placebo-controlled multicentre study with health economic and nested qualitative studies to determine if mifepristone (Mifegyne®, Exelgyn, Paris, France) plus misoprostol is superior to misoprostol alone for the resolution of missed miscarriage. Methods: Women diagnosed with missed miscarriage in the first 14 weeks of pregnancy were randomly assigned (1 : 1 ratio) to receive 200 mg of oral mifepristone or matched placebo, followed by 800 μg of misoprostol 2 days later. A web-based randomisation system allocated the women to the two groups, with minimisation for age, body mass index, parity, gestational age, amount of bleeding and randomising centre. The primary outcome was failure to pass the gestational sac within 7 days after randomisation. The prespecified key secondary outcome was requirement for surgery to resolve the miscarriage. A within-trial cost-effectiveness study and a nested qualitative study were also conducted. Women who completed the trial protocol were purposively approached to take part in an interview to explore their satisfaction with and the acceptability of medical management of missed miscarriage. Results: A total of 711 women, from 28 hospitals in the UK, were randomised to receive either mifepristone plus misoprostol (357 women) or placebo plus misoprostol (354 women). The follow-up rate for the primary outcome was 98% (696 out of 711 women). The risk of failure to pass the gestational sac within 7 days was 17% (59 out of 348 women) in the mifepristone plus misoprostol group, compared with 24% (82 out of 348 women) in the placebo plus misoprostol group (risk ratio 0.73, 95% confidence interval 0.54 to 0.98; p = 0.04). Surgical intervention to resolve the miscarriage was needed in 17% (62 out of 355 women) in the mifepristone plus misoprostol group, compared with 25% (87 out of 353 women) in the placebo plus misoprostol group (risk ratio 0.70, 95% confidence interval 0.52 to 0.94; p = 0.02). There was no evidence of a difference in the incidence of adverse events between the two groups. A total of 42 women, 19 in the mifepristone plus misoprostol group and 23 in the placebo plus misoprostol group, took part in an interview. Women appeared to have a preference for active management of their miscarriage. Overall, when women experienced care that supported their psychological well-being throughout the care pathway, and information was delivered in a skilled and sensitive manner such that women felt informed and in control, they were more likely to express satisfaction with medical management. The use of mifepristone and misoprostol showed an absolute effect difference of 6.6% (95% confidence interval 0.7% to 12.5%). The average cost per woman was lower in the mifepristone plus misoprostol group, with a cost saving of £182 (95% confidence interval £26 to £338). Therefore, the use of mifepristone and misoprostol for the medical management of a missed miscarriage dominated the use of misoprostol alone. Limitations: The results from this trial are not generalisable to women diagnosed with incomplete miscarriage and the study does not allow for a comparison with expectant or surgical management of miscarriage. Future work: Future work should use existing data to assess and rank the relative clinical effectiveness and safety profiles for all methods of management of miscarriage. Conclusions: Our trial showed that pre-treatment with mifepristone followed by misoprostol resulted in a higher rate of resolution of missed miscarriage than misoprostol treatment alone. Women were largely satisfied with medical management of missed miscarriage and would choose it again. The mifepristone and misoprostol intervention was shown to be cost-effective in comparison to misoprostol alone. Trial registration: Current Controlled Trials ISRCTN17405024. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 68. See the NIHR Journals Library website for further project information.

Animal models are used in preclinical trials to test vaccines, antivirals, monoclonal antibodies, and immunomodulatory drug therapies against SARS-CoV-2. However, these drugs often do not produce equivalent results in human clinical trials. Here, we show how different animal models infected with some of the most clinically relevant SARS-CoV-2 variants, WA1/2020, B.1.617.2/Delta, B.1.1.529/Omicron, and BA5.2/Omicron, have independent outcomes. We show that in K18-hACE2 mice, B.1.617.2 is more pathogenic, followed by WA1, while B.1.1.529 showed an absence of clinical signs. Only B.1.1.529 was able to infect C57BL/6J mice, which lack the human ACE2 receptor. B.1.1.529-infected C57BL/6J mice had different T cell profiles compared to infected K18-hACE2 mice, while viral shedding profiles and viral titers in lungs were similar between the K18-hACE2 and the C57BL/6J mice. These data suggest B.1.1.529 virus adaptation to a new host and shows that asymptomatic carriers can accumulate and shed virus. Next, we show how B.1.617.2, WA1 and BA5.2/Omicron have similar viral replication kinetics, pathogenicity, and viral shedding profiles in hamsters, demonstrating that the increased pathogenicity of B.1.617.2 observed in mice is host-dependent. Overall, these findings suggest that small animal models are useful to parallel human clinical data, but the experimental design places an important role in interpreting the data. Importance: There is a need to investigate SARS-CoV-2 variant phenotypes in different animal models due to the lack of reproducible outcomes when translating experiments to the human population. Our findings highlight the correlation of clinically relevant SARS-CoV-2 variants in animal models with human infections. Experimental design and understanding of correct animal models are essential to interpreting data to develop antivirals, vaccines, and other therapeutic compounds against COVID-19.

Abstract Background Vitamin D deficiency has been associated with an increased risk of abnormal pregnancy implantation leading to obstetric complications such as pre-eclampsia and fetal growth restriction. However, the effect of vitamin D on reproductive treatment outcomes in couples undergoing assisted reproductive treatment is poorly understood. This study investigates the association between vitamin D and reproductive treatment outcomes in women undergoing assisted reproductive treatments? Methods A prospective cohort study conducted at a large tertiary teaching hospital, United Kingdom. Five hundred women undergoing assisted reproductive treatment were recruited between September 2013 and September 2015. All participants had their serum vitamin D measured and their reproductive treatment outcomes collated. Women were categorised in to three groups: vitamin D replete (> 75 nmol/L), insufficient (50-75 nmol/L) and deficient (

Atrial fibrillation (AFib) is a common type of arrhythmia that is often clinically asymptomatic, which increases the risk of stroke significantly but can be prevented with anticoagulation. The photoplethysmogram (PPG) has recently attracted a lot of attention as a surrogate for electrocardiography (ECG) on atrial fibrillation (AFib) detection, with its out-of-hospital usability for rapid screening or long-term monitoring. Previous studies on AFib detection via PPG signals have achieved good results, but were short of intuitive criteria like ECG p-wave absence or not, especially while using interval randomness to detect AFib suffering from conjunction with premature contractions (PAC/PVC). In this study, we newly developed a PPG flux (pulse amplitude) and interval plots-based methodology, simply comprising an irregularity index threshold of 20 and regression error threshold of 0.06 for the precise automatic detection of AFib. The proposed method with automated detection on AFib shows a combined sensitivity, specificity, accuracy, and precision of 1, 0.995, 0.995, and 0.952 across the 460 samples. Furthermore, the flux-interval plot configuration also acts as a very intuitive tool for visual reassessment to confirm the automatic detection of AFib by its distinctive plot pattern compared to other cardiac rhythms. The study demonstrated that exclusive 2 false-positive cases could be corrected after the reassessment. With the methodology’s background theory well established, the detection process automated and visualized, and the PPG sensors already extensively used, this technology is very user-friendly and convincing for promoted to in-house AFib diagnostics.

Abstract Background RNA-seq is a powerful and cost-effective technology for molecular diagnostics of cancer and other diseases, and it can reach its full potential when coupled with validated clinical-grade informatics tools. Despite recent advances in long-read sequencing, transcriptome assembly of short reads remains a useful and cost-effective methodology for unveiling transcript-level rearrangements and novel isoforms. One of the major concerns for adopting the proven de novo assembly approach for RNA-seq data in clinical settings has been the analysis turnaround time. To address this concern, we have developed a targeted approach to expedite assembly and analysis of RNA-seq data. Results Here we present our Targeted Assembly Pipeline (TAP), which consists of four stages: 1) alignment-free gene-level classification of RNA-seq reads using BioBloomTools, 2) de novo assembly of individual targets using Trans-ABySS, 3) alignment of assembled contigs to the reference genome and transcriptome with GMAP and BWA and 4) structural and splicing variant detection using PAVFinder. We show that PAVFinder is a robust gene fusion detection tool when compared to established methods such as Tophat-Fusion and deFuse on simulated data of 448 events. Using the Leucegene acute myeloid leukemia (AML) RNA-seq data and a set of 580 COSMIC target genes, TAP identified a wide range of hallmark molecular anomalies including gene fusions, tandem duplications, insertions and deletions in agreement with published literature results. Moreover, also in this dataset, TAP captured AML-specific splicing variants such as skipped exons and novel splice sites reported in studies elsewhere. Running time of TAP on 100–150 million read pairs and a 580-gene set is one to 2 hours on a 48-core machine. Conclusions We demonstrated that TAP is a fast and robust RNA-seq variant detection pipeline that is potentially amenable to clinical applications. TAP is available at http://www.bcgsc.ca/platform/bioinfo/software/pavfinder

Previously published photoplethysmography-(PPG) based non-invasive blood glucose (NIBG) measurements have not yet been validated over 500 subjects. As illustrated in this work, we increased the number subjects recruited to 2538 and found that the prediction accuracy (the ratio in zone A of Clarke’s error grid) reduced to undesirable 60.6%. We suspect the low prediction accuracy induced by larger sample size might arise from the physiological diversity of subjects, and one possibility is that the diversity might originate from medication. Therefore, we split the subjects into two cohorts for deep learning: with and without medication (1682 and 856 recruited subjects, respectively). In comparison, the cohort training for subjects without any medication had approximately 30% higher prediction accuracy over the cohort training for those with medication. Furthermore, by adding quarterly (every 3 months) measured glycohemoglobin (HbA1c), we were able to significantly boost the prediction accuracy by approximately 10%. For subjects without medication, the best performing model with quarterly measured HbA1c achieved 94.3% prediction accuracy, RMSE of 12.4 mg/dL, MAE of 8.9 mg/dL, and MAPE of 0.08, which demonstrates a very promising solution for NIBG prediction via deep learning. Regarding subjects with medication, a personalized model could be a viable means of further investigation.

The most common cause of the neurodegenerative diseases amyotrophic lateral sclerosis and frontotemporal dementia is a hexanucleotide repeat expansion in C9orf72. Here we report a study of the C9orf72 protein by examining the consequences of loss of C9orf72 functions. Deletion of one or both alleles of the C9orf72 gene in mice causes age-dependent lethality phenotypes. We demonstrate that C9orf72 regulates nutrient sensing as the loss of C9orf72 decreases phosphorylation of the mTOR substrate S6K1. The transcription factor EB (TFEB), a master regulator of lysosomal and autophagy genes, which is negatively regulated by mTOR, is substantially up-regulated in C9orf72 loss-of-function animal and cellular models. Consistent with reduced mTOR activity and increased TFEB levels, loss of C9orf72 enhances autophagic flux, suggesting that C9orf72 is a negative regulator of autophagy. We identified a protein complex consisting of C9orf72 and SMCR8, both of which are homologous to DENN-like proteins. The depletion of C9orf72 or SMCR8 leads to significant down-regulation of each other's protein level. Loss of SMCR8 alters mTOR signaling and autophagy. These results demonstrate that the C9orf72-SMCR8 protein complex functions in the regulation of metabolism and provide evidence that loss of C9orf72 function may contribute to the pathogenesis of relevant diseases.

Background and objectives: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted. Design and setting: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites). Participants and interventions: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan®, Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks). Main outcome measures: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6–8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use. Methods: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth. Results: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence’s threshold of £20,000–30,000 per quality-adjusted life-year as between 0.7145 and 0.7341. Conclusions: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM. Limitations: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle. Future work: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM. Trial registration: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.