A signal processing tool for extracting features from arterial blood pressure and photoplethysmography waveforms.

Arterial blood pressure (ABP) and photoplethysmography (PPG) waveforms contain valuable clinical information and play a crucial role in cardiovascular health monitoring, medical research, and managing medical conditions. The features extracted from PPG waveforms have various clinical applications ranging from blood pressure monitoring to nociception monitoring, while features from ABP waveforms can be used to calculate cardiac output and predict hypertension or hypotension. In recent years, many machine learning models have been proposed to utilize both PPG and ABP waveform features for these healthcare applications. However, the lack of standardized tools for extracting features from these waveforms could potentially affect their clinical effectiveness. In this paper, we propose an automatic signal processing tool for extracting features from ABP and PPG waveforms. Additionally, we generated a PPG feature library from a large perioperative dataset comprising 17,327 patients using the proposed tool. This PPG feature library can be used to explore the potential of these extracted features to develop machine learning models for non-invasive blood pressure estimation.

Examining the functional space of gut microbiome-derived peptides.

The human gut microbiome contains thousands of small, novel peptides that could play a role in microbe-microbe and host-microbe interactions, contributing to human health and disease. Although these peptides have not yet been systematically characterized, computational tools can be used to elucidate the bioactivities they may have. This article proposes probing the functional space of gut microbiome-derived peptides (MDPs) using in silico approaches for three bioactivities: antimicrobial, anticancer, and nucleomodulins. Machine learning programs that support peptide and protein queries are provided for each bioactivity. Considering the biases of an activity-centric approach, activity-agnostic tools using structural and chemical similarity and target prediction are also described. Gut MDPs represent a vast functional space that can not only contribute to our understanding of microbiome interactions but potentially even serve as a source of life-changing therapeutics.

A Computer-Assisted Diagnostic Method for Accurate Detection of Early Nondisplaced Fractures of the Femoral Neck.

Nondisplaced femoral neck fractures are sometimes misdiagnosed by radiographs, which may deteriorate into displaced fractures. However, few efficient artificial intelligent methods have been reported. We developed an automatic detection method using deep learning networks to pinpoint femoral neck fractures on radiographs to assist physicians in making an accurate diagnosis in the first place. Our proposed accurate automatic detection method, called the direction-aware fracture-detection network (DAFDNet), consists of two steps, namely region-of-interest (ROI) segmentation and fracture detection. The first step removes the noise region and pinpoints the femoral neck region. The fracture-detection step uses a direction-aware deep learning algorithm to mark the exact femoral neck fracture location in the region detected in the first step. A total of 3840 femoral neck parts in anterior-posterior (AP) pelvis radiographs collected from the China Medical University Hospital database were used to test our method. The simulation results showed that DAFDNet outperformed the U-Net and DenseNet methods in terms of the IOU value, Dice value, and Jaccard value. Our proposed DAFDNet demonstrated over 94.8% accuracy in differentiating non-displaced Garden type I and type II femoral neck fracture cases. Our DAFDNet method outperformed the diagnostic accuracy of general practitioners and orthopedic surgeons in accurately locating Garden type I and type II fracture locations. This study can determine the feasibility of applying artificial intelligence in a clinical setting and how the use of deep learning networks assists physicians in improving correct diagnoses compared to the current traditional orthopedic manual assessments.

The Need for Biosecurity Education in Biotechnology Curricula.

The growth of biotechnology in recent decades and the dual-use nature of most bioscience research are making their misuse, or accidental misuse or release, more likely and present as threats to biosecurity. A proactive approach is through educating the next generation of scientists to be more security conscious. However, current educational and professional programs in biosecurity are lacking. In this perspective, we recommend that biosecurity educational opportunities should be implemented and expanded for undergraduate and graduate students who will likely use one or more methods in the field of biotechnology. We then propose that biosecurity education is a key factor in a path toward sustainable and safe research. Finally, a set of 17 biosecurity competencies organized into 6 distinct themes is outlined.

Correlation between Multiparametric MR Imaging and Molecular Genetics in Pontine Pediatric High-Grade Glioma.

BACKGROUND AND PURPOSE: Molecular profiling is a crucial feature in the "integrated diagnosis" of CNS tumors. We aimed to determine whether radiomics could distinguish molecular types of pontine pediatric high-grade gliomas that have similar/overlapping phenotypes on conventional anatomic MR images. MATERIALS AND METHODS: Baseline MR images from children with pontine pediatric high-grade gliomas were analyzed. Retrospective imaging studies included standard precontrast and postcontrast sequences and DTI. Imaging analyses included median, mean, mode, skewness, and kurtosis of the ADC histogram of the tumor volume based on T2 FLAIR and enhancement at baseline. Histone H3 mutations were identified through immunohistochemistry and/or Sanger or next-generation DNA sequencing. The log-rank test identified imaging factors prognostic of survival from the time of diagnosis. Wilcoxon rank-sum and Fisher exact tests compared imaging predictors among groups. RESULTS: Eighty-three patients had pretreatment MR imaging and evaluable tissue sampling. The median age was 6 years (range, 0.7-17 years); 50 tumors had a K27M mutation in H3-3A, and 11, in H3C2/3. Seven tumors had histone H3 K27 alteration, but the specific gene was unknown. Fifteen were H3 wild-type. Overall survival was significantly higher in H3C2/3- compared with H3-3A-mutant tumors (P = .003) and in wild-type tumors compared with any histone mutation (P = .001). Lower overall survival was observed in patients with enhancing tumors (P = .02) compared with those without enhancement. H3C2/3-mutant tumors showed higher mean, median, and mode ADC_total values (P < .001) and ADC_enhancement (P < .004), with lower ADC_total skewness and kurtosis (P < .003) relative to H3-3A-mutant tumors. CONCLUSIONS: ADC histogram parameters are correlated with histone H3 mutation status in pontine pediatric high-grade glioma.

More than skin deep: cyclic peptides as wound healing and cytoprotective compounds.

The prevalence and cost of wounds pose a challenge to patients as well as the healthcare system. Wounds can involve multiple tissue types and, in some cases, become chronic and difficult to treat. Comorbidities may also decrease the rate of tissue regeneration and complicate healing. Currently, treatment relies on optimizing healing factors rather than administering effective targeted therapies. Owing to their enormous diversity in structure and function, peptides are among the most prevalent and biologically important class of compounds and have been investigated for their wound healing bioactivities. A class of these peptides, called cyclic peptides, confer stability and improved pharmacokinetics, and are an ideal source of wound healing therapeutics. This review provides an overview of cyclic peptides that have been shown to promote wound healing in various tissues and in model organisms. In addition, we describe cytoprotective cyclic peptides that mitigate ischemic reperfusion injuries. Advantages and challenges in harnessing the healing potential for cyclic peptides from a clinical perspective are also discussed. Cyclic peptides are a potentially attractive category of wound healing compounds and more research in this field could not only rely on design as mimetics but also encompass de novo approaches as well.

Ambulatory transcutaneous carbon dioxide monitoring for children with neuromuscular disease.

OBJECTIVE: Early screening and diagnosis of nocturnal hypoventilation can slow progression to diurnal hypercapnia and mortality in children with neuromuscular disease (NMD). However, gold standard, laboratory-based polysomnography (PSG) testing is a limited resource. Therefore, we evaluated the diagnostic accuracy of ambulatory transcutaneous carbon dioxide (tcCO2) monitoring used in the home compared to PSG in children with NMD. METHODS: Prospective, cross-sectional study in children 0-18 years old with a confirmed diagnosis of NMD and a clinically indicated need for PSG. Ambulatory tcCO2 was assessed by a respiratory therapist in participant's homes. Demographics, and PSG (including tcCO2). RESULTS: We enrolled 39 children with NMD; 3 had unusable ambulatory tcCO2 data because of failure of drift correction on the machine (n = 2) or an air bubble (n = 1). The remaining 36 patients aged 11 months to 16 years (median (IQR) 12.5 years (6.0-15.8)) had ambulatory tcCO2 and outpatient level 1 PSG data. Ambulatory tcCO2 monitoring had a sensitivity of 20.0% (95% confidence interval [CI] 0.5-71.6%) and a specificity of 93.5% (95% CI 78.6-99.2%). Almost all children and/or parents (34/36, 94%) preferred ambulatory monitoring over in-hospital PSG. CONCLUSIONS: Ambulatory transcutaneous carbon dioxide monitoring was not sufficiently accurate as a clinical tool for the diagnosis of nocturnal hypoventilation our cohort of children with neuromuscular disease despite being preferred over PSG by both children and parents.

VARIATION IN RADIATION DOSE RATES FROM RADIONUCLIDES DISCHARGED BY THE SPENT NUCLEAR FUEL REPROCESSING PLANT IN ROKKASHO UNDER DIFFERENT YEARLY WEATHER CONDITIONS.

The radiation dose rate from radionuclides released by the spent nuclear fuel reprocessing plant in Rokkasho, Japan, was assessed for a year specified in the safety review during which the weather conditions were not significantly different from those of the other 10 y. However, the actual year-by-year variation in annual radiation dose rate was not examined. A model system for evaluating the dose rate from the radionuclides released into the atmosphere was constructed. In this study, the radiation dose rate in the weather conditions of 24 weather bins was estimated for a standard year by the model. The annual maximum dose rate from 1959 to 2012 was estimated using a simplified method that integrated the dose rates of each weather bin in the standard year by estimating the annual frequency of the bin in the target year. We obtained ~1.3 as the maximum/minimum ratio of the annual maximum dose rate.

Gut bacterial nutrient preferences quantified in vivo.

Great progress has been made in understanding gut microbiomes' products and their effects on health and disease. Less attention, however, has been given to the inputs that gut bacteria consume. Here, we quantitatively examine inputs and outputs of the mouse gut microbiome, using isotope tracing. The main input to microbial carbohydrate fermentation is dietary fiber and to branched-chain fatty acids and aromatic metabolites is dietary protein. In addition, circulating host lactate, 3-hydroxybutyrate, and urea (but not glucose or amino acids) feed the gut microbiome. To determine the nutrient preferences across bacteria, we traced into genus-specific bacterial protein sequences. We found systematic differences in nutrient use: most genera in the phylum Firmicutes prefer dietary protein, Bacteroides dietary fiber, and Akkermansia circulating host lactate. Such preferences correlate with microbiome composition changes in response to dietary modifications. Thus, diet shapes the microbiome by promoting the growth of bacteria that preferentially use the ingested nutrients.

Randomized, Double-Blind, Placebo-Controlled Phase III Study of Paclitaxel ± Napabucasin in Pretreated Advanced Gastric or Gastroesophageal Junction Adenocarcinoma.

PURPOSE: To compare napabucasin (generator of reactive oxygen species) plus paclitaxel with paclitaxel only in patients with second-line advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. EXPERIMENTAL DESIGN: In the double-blind, phase III BRIGHTER study (NCT02178956), patients were randomized (1:1) to napabucasin (480 mg orally twice daily) plus paclitaxel (80 mg/m2 i.v. weekly for 3 of 4 weeks) or placebo plus paclitaxel. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. RESULTS: Overall, 714 patients were randomized (napabucasin plus paclitaxel, n = 357; placebo plus paclitaxel, n = 357). 72.1% were male, 74.6% had gastric adenocarcinoma, and 46.2% had peritoneal metastases. The study was unblinded following an interim analysis at 380 deaths. The final efficacy analysis was performed on 565 deaths (median follow-up, 6.8 months). No significant differences were observed between napabucasin plus paclitaxel and placebo plus paclitaxel for OS (6.93 vs. 7.36 months), PFS (3.55 vs. 3.68 months), ORR (16% vs. 18%), or DCR (55% vs. 58%). Grade ≥3 adverse events occurred in 69.5% and 59.7% of patients administered napabucasin plus paclitaxel and placebo plus paclitaxel, respectively, with grade ≥3 diarrhea reported in 16.2% and 1.4%, respectively. CONCLUSIONS: Adding napabucasin to paclitaxel did not improve survival in patients with pretreated advanced gastric or GEJ adenocarcinoma. Consistent with previous reports, the safety profile of napabucasin was driven by manageable gastrointestinal events; grade ≥3 diarrhea occurred at a higher frequency with napabucasin plus paclitaxel versus placebo plus paclitaxel.

Peptide Toxins as Biothreats and the Potential for AI Systems to Enhance Biosecurity.

Biological weapons have been used for thousands of years, but recent advances in synthesis technologies have made peptide and protein toxin production more accessible and pose a threat to biosecurity worldwide. Natural toxins such as conotoxins, certain hemolytic compounds, and enterotoxins are peptide agents that can be synthesized in an environment with weak biosecurity measures and rudimentarily weaponized for limited use against smaller targets for lethal or nonlethal effects. Technological advances are changing the threat landscape around biological weapons and potentially facilitating a shift from state sponsored to more micro-level threats stemming from terror cells, insider threats, and lone wolf attacks. Here, we present the reader with an overview of the threat of peptide and protein toxins, provide examples of potent peptide toxins, and introduce capabilities of a proposed biosecurity program utilizing artificial intelligence that unifies commercial nucleotide and peptide synthesis vendors.

An Overview of Antiviral Peptides and Rational Biodesign Considerations.

Viral diseases have contributed significantly to worldwide morbidity and mortality throughout history. Despite the existence of therapeutic treatments for many viral infections, antiviral resistance and the threat posed by novel viruses highlight the need for an increased number of effective therapeutics. In addition to small molecule drugs and biologics, antimicrobial peptides (AMPs) represent an emerging class of potential antiviral therapeutics. While AMPs have traditionally been regarded in the context of their antibacterial activities, many AMPs are now known to be antiviral. These antiviral peptides (AVPs) have been shown to target and perturb viral membrane envelopes and inhibit various stages of the viral life cycle, from preattachment inhibition through viral release from infected host cells. Rational design of AMPs has also proven effective in identifying highly active and specific peptides and can aid in the discovery of lead peptides with high therapeutic selectivity. In this review, we highlight AVPs with strong antiviral activity largely curated from a publicly available AMP database. We then compile the sequences present in our AVP database to generate structural predictions of generic AVP motifs. Finally, we cover the rational design approaches available for AVPs taking into account approaches currently used for the rational design of AMPs.

Synthetic Biology Medicine and Bacteria-Based Cancer Therapeutics.

Spontaneous tumor regression following bacterial infection has been observed for hundreds of years. These observations along with anecdotal medical findings in 1890s led to the development of Coley's "toxins," consisting of killed Streptococcus pyogenes and Serratia marcescens bacteria, as the first cancer immunotherapy. The use of this approach, however, was not widely accepted at the time especially after the introduction of radiation therapy as a treatment for cancer in the early 1900s. Over the last 30-40 years there has been renewed interest in the use of bacteria to treat human solid tumors. This is based on the observation that various nonpathogenic anaerobic bacteria can infiltrate and replicate within solid tumors when given intravenously. Bacteria tested as potential anticancer agents include the Gram-positive obligate anaerobes Bifidobacterium and Clostridium, as well as the gram-negative facultative anaerobe Salmonella. Recent advances in synthetic biology and clinical success in cancer immunotherapy provide renewed momentum for developing bacteria-based cancer immunotherapy for cancer treatment and should allow greater potential for the development of novel therapeutic approaches for this devastating disease.

Pediatric Case of Li-Fraumeni Syndrome in Honduras.

Li-Fraumeni syndrome is an inherited, autosomal dominant disease. It is categorized as a rare disease caused by mutations of the TP53 gene, which causes increased susceptibility of the patients and their children to many types of cancer. Choroid plexus tumor is rare, which occurs in 0.3 cases per 1,000,000 people, of which 40% turn out to be carcinomas. We present a 12-year-old boy with a history of worsening headaches of more than one month, gait disturbance, projectile vomiting, and right hemiparesis. An intraventricular tumor was identified in the occipital of the left lateral ventricle, which turned out to be a TP53-mutant choroidal plexus carcinoma.

Minimally invasive right colectomy with transrectal natural orifice extraction: could this be the next step forward?

BACKGROUND: The transvaginal natural orifice specimen extraction (NOSE) approach for right-side colon surgery has been proven to exhibit favorable short-term outcomes. However, thus far, no study has reported the advantages of transrectal NOSE for right-side colon surgery. The aim of this study was to compare the technical feasibility, safety, and short-term outcomes of minimally invasive right hemicolectomy using the transrectal NOSE method and those of conventional mini-laparotomy specimen extraction. METHODS: A study was conducted on consecutive patients who had minimally invasive right hemicolectomy either for malignancy or benign disease at Chang Gung Memorial Hospital, Linkou, Taiwan, between January 2017 and December 2018. The patients were divided into two groups: conventional surgery with specimen extraction using mini-laparotomy and NOSE surgery. Surgical outcomes, including complications, postoperative short-term recovery, and pain intensity, were analyzed. RESULTS: We enrolled 297 patients (151 males, mean age 64.9 ± 12.8 years) who had minimally invasive right hemicolectomy. Of these 297 patients, 272 patients had conventional surgery with specimen extraction through mini-laparotomy and 25 patients had NOSE surgery (23 transrectal, 2 transvaginal). The diagnosis of colon disease did not differ significantly between the conventional and NOSE groups. Postoperative morbidity and mortality rates were comparable. The postoperative hospital stay was significantly (p = 0.004) shorter in the NOSE group (median 5 days, range 3-17 days) than in the conventional group (median 7 days, range 3-45 days). Postoperative pain was significantly (p = 0.026 on postoperative day 1 and p = 0.002 on postoperative day 2) greater in the conventional group than in the NOSE group. CONCLUSIONS: NOSE was associated with acceptable short-term surgical outcomes that were comparable to those of conventional surgery. NOSE results in less postoperative wound pain and a shorter hospital stay than conventional surgery. Larger studies are needed.

Personalized Mapping of Drug Metabolism by the Human Gut Microbiome.

The human gut microbiome harbors hundreds of bacterial species with diverse biochemical capabilities. Dozens of drugs have been shown to be metabolized by single isolates from the gut microbiome, but the extent of this phenomenon is rarely explored in the context of microbial communities. Here, we develop a quantitative experimental framework for mapping the ability of the human gut microbiome to metabolize small molecule drugs: Microbiome-Derived Metabolism (MDM)-Screen. Included are a batch culturing system for sustained growth of subject-specific gut microbial communities, an ex vivo drug metabolism screen, and targeted and untargeted functional metagenomic screens to identify microbiome-encoded genes responsible for specific metabolic events. Our framework identifies novel drug-microbiome interactions that vary between individuals and demonstrates how the gut microbiome might be used in drug development and personalized medicine.

Neuroimaging Findings in Children with Constitutional Mismatch Repair Deficiency Syndrome.

BACKGROUND AND PURPOSE: Constitutional mismatch repair deficiency is a hereditary childhood cancer predisposition syndrome characterized by brain tumors and colorectal and hematologic malignancies. Our objective was to describe the neuroimaging findings in patients with constitutional mismatch repair deficiency. MATERIALS AND METHODS: This retrospective study included 14 children with genetically confirmed constitutional mismatch repair deficiency who were referred to 2 tertiary pediatric oncology centers. RESULTS: Fourteen patients from 11 different families had diagnosed constitutional mismatch repair deficiency. The mean age at presentation was 9.3 years (range, 5-14 years). The most common clinical presentation was brain malignancy, diagnosed in 13 of the 14 patients. The most common brain tumors were glioblastoma (n = 7 patients), anaplastic astrocytoma (n = 3 patients), and diffuse astrocytoma (n = 3 patients). Nonspecific subcortical white matter T2 hyperintensities were noted in 10 patients (71%). Subcortical hyperintensities transformed into overt brain tumors on follow-up imaging in 3 patients. Additional non-neoplastic brain MR imaging findings included developmental venous anomalies in 12 patients (85%) and nontherapy-induced cavernous hemangiomas in 3 patients (21%). CONCLUSIONS: On brain MR imaging, these patients have both highly characteristic intra-axial tumors (typically multifocal high-grade gliomas) and nonspecific findings, some of which might represent early stages of neoplastic transformation. The incidence of developmental venous anomalies is high in these patients for unclear reasons. Awareness of these imaging findings, especially in combination, is important to raise the suspicion of constitutional mismatch repair deficiency in routine diagnostic imaging evaluation or surveillance imaging studies of asymptomatic carriers because early identification of the phenotypic "gestalt" might improve outcomes.

Associations between acute glucose control and peripheral nerve structure and function in type 1 diabetes.

AIM: To examine the associations between continuous overlapping net glycaemic action (CONGA), percentage time in hyperglycaemia (%HG) or normoglycaemia (%NG) and peripheral nerve structure and function in type 1 diabetes. METHODS: Twenty-seven participants with type 1 diabetes underwent continuous glucose monitoring followed by corneal confocal microscopy and nerve excitability assessments. CONGA, %HG (> 10.0 mmol/l) and %NG (3.9-10.0 mmol/l) were correlated against corneal nerve fibre length and density in the central cornea and inferior whorl region, corneal microneuromas, and a nerve excitability score while controlling for age, sex, diabetes duration and HbA1c . RESULTS: An increase in CONGA [median 2.5 (2.0-3.1) mmol/l] or %HG (mean 46 ± 18%) was associated with a worse nerve excitability score (r = -0.433, P = 0.036 and r = -0.670, P = 0.0012, respectively). By contrast, greater %NG (51 ± 17%) correlated with better nerve excitability scores (r = 0.672, P = 0.0011). Logistic regression revealed that increasing %HG increased the likelihood of abnormal nerve function [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.01-1.23; P = 0.037). An increase in CONGA and %HG were associated with worsening nerve conduction measures, whereas longer %NG correlated with improved nerve conduction variables. CONGA and %HG were associated with inferior whorl corneal nerve fibre length (r = 0.483, P = 0.034 and r = 0.591, P = 0.021, respectively) and number of microneuromas (r = 0.433, P = 0.047 and r = 0.516, P = 0.020, respectively). CONCLUSIONS: Short-term measures of glucose control are associated with impaired nerve function and alterations in corneal nerve morphology.

Functional and metabolic imaging in transthoracic biopsies guided by computed tomography.

OBJECTIVES: CT-guided biopsy of indeterminate lung lesions sometimes provides insufficient histological results due to tumor necrosis. Functional and metabolic methods such as DWI-MR and PET-CT may help by directing sample collection to a lesion area of greater biological representativeness. The objective is to evaluate the histopathological results based on findings on ADC and SUV levels in lung lesions suspected for primary cancer. METHODS: Tissue samples were evaluated after undergoing biopsies guided by either DWI-MR or PET-CT findings. In each patient, sample collection from two lesion areas was guided by local ADC and SUV. Values were used to define areas of low vs. high suspicion for cancer. RESULTS: Patients who underwent DWI-MR had median lesion size of 78.0 mm. Areas of higher suspicion (HSA) had a median ADC of 1.1 × 10-3 mm2/s, while areas of lower suspicion (LSA) had median ADC of 1.8 × 10-3 mm2/s (p = 0.0001). All HSA samples and 71.43% of LSA samples were positive for cancer (p = 0.0184). Patients who performed PET-CT had median lesion size of 61.0 mm. Median SUV was 7.1 for HSA and 3.9 for LSA (p = 0.0002). Positivity for cancer was observed in 76.9% of samples for both HSA and LSA (p = 0.0522). CONCLUSION: Use of DWI-MR and PET-CT showed that tumors are functional and metabolically heterogeneous and that this heterogeneity has implications for histopathological diagnosis. KEY POINTS: • Lung cancer is heterogeneous regarding functional and metabolic imaging. • Tumor heterogeneity may have implications in histopathological diagnosis. • Intralesional lower levels of ADC target highly suspected areas with a significant improvement in lung cancer diagnosis.