Mechanisms of iron homeostasis in Pseudomonas aeruginosa and emerging therapeutics directed to disrupt this vital process.

Pseudomonas aeruginosa is an opportunistic pathogen able to infect any human tissue. One of the reasons for its high adaptability and colonization of host tissues is its capacity of maintaining iron homeostasis through a wide array of iron acquisition and removal mechanisms. Due to their ability to cause life-threatening acute and chronic infections, especially among cystic fibrosis and immunocompromised patients, and their propensity to acquire resistance to many antibiotics, the World Health Organization (WHO) has encouraged the scientific community to find new strategies to eradicate this pathogen. Several recent strategies to battle P. aeruginosa focus on targeting iron homeostasis mechanisms, turning its greatest advantage into an exploitable weak point. In this review, we discuss the different mechanisms used by P. aeruginosa to maintain iron homeostasis and the strategies being developed to fight this pathogen by blocking these mechanisms. Among others, the use of iron chelators and mimics, as well as disruption of siderophore production and uptake, have shown promising results in reducing viability and/or virulence of this pathogen. The so-called 'Trojan-horse' strategy taking advantage of the siderophore uptake systems is emerging as an efficient method to improve delivery of antibiotics into the bacterial cells. Moreover, siderophore transporters are considered promising targets for the developing of P. aeruginosa vaccines.

Ocean oil spill detection from SAR images based on multi-channel deep learning semantic segmentation.

One of the major threats to marine ecosystems is pollution, particularly, that associated with the offshore oil and gas industry. Oil spills occur in the world's oceans every day, either as large-scale spews from drilling-rig or tanker accidents, or as smaller discharges from all sorts of sea-going vessels. In order to contribute to the timely detection and monitoring of oil spills over the oceans, we propose a new Multi-channel Deep Neural Network (M-DNN) segmentation model and a new and effective Synthetic Aperture Radar (SAR) image dataset, that enable us to emit forewarnings in a prompt and reliable manner. Our proposed M-DNN is a pixel-level segmentation model intended to improve previous DNN oil-spill detection models, by taking into account multiple input channels, complex oil shapes at different scales (dimensions) and evolution in time, and look-alikes from low wind speed conditions. Our methodology consists of the following components: 1) New Multi-channel SAR Image Database Development; 2) Multi-Channel DNN Model based on U-net and ResNet; and 3) Multi-channel DNN Training and Transfer Learning. Due to the lack of public oil spill databases guaranteeing a correct learning process of the M-DNN, we developed our own database consisting of 16 ENVISAT-ASAR images acquired over the Gulf of Mexico during the Deepwater Horizon (DWH) blowout, off the west coast of South Korea during the Hebei Spirit oil tanker collision, and over the Black Sea. These images were pre-processed to create a 3-channel input image IM = {IO, IW, IV}, to feed in and train our M-DNN. The first channel IO represents the radiometric values of the original SAR Images, the second and third channels are derived from IO; in particular, IW represents the output of the wind speed estimation using CMOD5 algorithm (Hersbach et al., 2003) and IV represents the variance of IO that incorporates texture information and at the same time encapsulates oil spill transition regions. IM channels were split and linearly transformed for data augmentation (rotation and reflection) to obtain a total of 80,772 sub-images of 224 × 224 pixels. From the entire database, 80 % of the sub-images were used in the DNN training process, the remaining (20 %) was used for testing our final architecture. Our experimental results show higher pixel-level classification accuracy when 2 or 3 channels are used in the M-DNN, reaching an accuracy of 98.56 % (the highest score reported in the literature for DNN models). Additionally, our M-DNN model provides fast training convergence rate (about 14 times better on the average than previous works), which proves the effectiveness of our proposed method. According to our knowledge, our work is the first multi-channel DNN based scheme for the classification of oil spills at different scales.

Zika virus noncoding RNA cooperates with the viral protein NS5 to inhibit STAT1 phosphorylation and facilitate viral pathogenesis.

All flaviviruses, including Zika virus, produce noncoding subgenomic flaviviral RNA (sfRNA), which plays an important role in viral pathogenesis. However, the exact mechanism of how sfRNA enables viral evasion of antiviral response is not well defined. Here, we show that sfRNA is required for transplacental virus dissemination in pregnant mice and subsequent fetal brain infection. We also show that sfRNA promotes apoptosis of neural progenitor cells in human brain organoids, leading to their disintegration. In infected human placental cells, sfRNA inhibits multiple antiviral pathways and promotes apoptosis, with signal transducer and activator of transcription 1 (STAT1) identified as a key shared factor. We further show that the production of sfRNA leads to reduced phosphorylation and nuclear translocation of STAT1 via a mechanism that involves sfRNA binding to and stabilizing viral protein NS5. Our results suggest the cooperation between viral noncoding RNA and a viral protein as a novel strategy for counteracting antiviral responses.

Reporter Flaviviruses as Tools to Demonstrate Homologous and Heterologous Superinfection Exclusion.

Binjari virus (BinJV) is a lineage II or dual-host affiliated insect-specific flavivirus previously demonstrated as replication-deficient in vertebrate cells. Previous studies have shown that BinJV is tolerant to exchanging its structural proteins (prM-E) with pathogenic flaviviruses, making it a safe backbone for flavivirus vaccines. Here, we report generation by circular polymerase extension reaction of BinJV expressing zsGreen or mCherry fluorescent protein. Recovered BinJV reporter viruses grew to high titres (107-8 FFU/mL) in Aedes albopictus C6/36 cells assayed using immunoplaque assays (iPA). We also demonstrate that BinJV reporters could be semi-quantified live in vitro using a fluorescence microplate reader with an observed linear correlation between quantified fluorescence of BinJV reporter virus-infected C6/36 cells and iPA-quantitated virus titres. The utility of the BinJV reporter viruses was then examined in homologous and heterologous superinfection exclusion assays. We demonstrate that primary infection of C6/36 cells with BinJVzsGreen completely inhibits a secondary infection with homologous BinJVmCherry or heterologous ZIKVmCherry using fluorescence microscopy and virus quantitation by iPA. Finally, BinJVzsGreen infections were examined in vivo by microinjection of Aedes aegypti with BinJVzsGreen. At seven days post-infection, a strong fluorescence in the vicinity of salivary glands was detected in frozen sections. This is the first report on the construction of reporter viruses for lineage II insect-specific flaviviruses and establishes a tractable system for exploring flavivirus superinfection exclusion in vitro and in vivo.

Structural analysis of 3'UTRs in insect flaviviruses reveals novel determinants of sfRNA biogenesis and provides new insights into flavivirus evolution.

Subgenomic flaviviral RNAs (sfRNAs) are virus-derived noncoding RNAs produced by pathogenic mosquito-borne flaviviruses (MBF) to counteract the host antiviral response. To date, the ability of non-pathogenic flaviviruses to produce and utilise sfRNAs remains largely unexplored, and it is unclear what role XRN1 resistance plays in flavivirus evolution and host adaptation. Herein the production of sfRNAs by several insect-specific flaviviruses (ISFs) that replicate exclusively in mosquitoes is shown, and the secondary structures of their complete 3'UTRs are determined. The xrRNAs responsible for the biogenesis of ISF sfRNAs are also identified, and the role of these sfRNAs in virus replication is demonstrated. We demonstrate that 3'UTRs of all classical ISFs, except Anopheles spp-asscoaited viruses, and of the dual-host associated ISF Binjari virus contain duplicated xrRNAs. We also reveal novel structural elements in the 3'UTRs of dual host-associated and Anopheles-associated classical ISFs. Structure-based phylogenetic analysis demonstrates that xrRNAs identified in Anopheles spp-associated ISF are likely ancestral to xrRNAs of ISFs and MBFs. In addition, our data provide evidence that duplicated xrRNAs are selected in the evolution of flaviviruses to provide functional redundancy, which preserves the production of sfRNAs if one of the structures is disabled by mutations or misfolding.

Safety and efficacy of repeat long-term incobotulinumtoxinA treatment for lower limb or combined upper/lower limb spasticity in children with cerebral palsy.

PURPOSE: The open-label phase 3 "Treatment with IncobotulinumtoxinA in Movement Open-Label" (TIMO) study investigated longer-term safety and efficacy of incobotulinumtoxin A in children/adolescents with cerebral palsy (CP). METHODS: Patients on standard treatment, with unilateral or bilateral lower limb (LL) or combined upper limb (UL)/LL spasticity received four incobotulinumtoxinA injection cycles (16 or 20 Units/kg bodyweight total [maximum 400 or 500 Units] per cycle depending on ambulatory status/clinical pattern treated), each followed by 12-16 weeks' observation. Treatment for pes equinus was mandatory; flexed knee or adducted thigh were options for unilateral treatment and/or ULs for unilateral/bilateral treatment. The primary endpoint was safety; changes in Ashworth Scale and Gross Motor Function Measure-66 scores, and Global Impression of Change Scale scores at week 4 of each injection cycle were also evaluated. RESULTS: IncobotulinumtoxinA (≤500 Units for ≤98 weeks) was safe, well-tolerated, and effective across all endpoints for multipattern treatment of LL and combined LL/UL spasticity in ambulant/nonambulant children/adolescents with CP. Treatment effects increased with each injection cycle. No new/unexpected safety concerns were identified. CONCLUSION: IncobotulinumtoxinA showed a good safety and tolerability profile, with efficacy over multiple clinical presentations. As an adjunct treatment, it offers an effective, individualized treatment option for pediatric CP-related spasticity.

A versatile reverse genetics platform for SARS-CoV-2 and other positive-strand RNA viruses.

The current COVID-19 pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that despite the large size of the viral RNA genome (~30 kb), infectious full-length cDNA is readily assembled in vitro by a circular polymerase extension reaction (CPER) methodology without the need for technically demanding intermediate steps. Overlapping cDNA fragments are generated from viral RNA and assembled together with a linker fragment containing CMV promoter into a circular full-length viral cDNA in a single reaction. Transfection of the circular cDNA into mammalian cells results in the recovery of infectious SARS-CoV-2 virus that exhibits properties comparable to the parental virus in vitro and in vivo. CPER is also used to generate insect-specific Casuarina virus with ~20 kb genome and the human pathogens Ross River virus (Alphavirus) and Norovirus (Calicivirus), with the latter from a clinical sample. Additionally, reporter and mutant viruses are generated and employed to study virus replication and virus-receptor interactions.

IncobotulinumtoxinA for the treatment of lower-limb spasticity in children and adolescents with cerebral palsy: A phase 3 study.

PURPOSE: Investigate the efficacy and safety of multipattern incobotulinumtoxinA injections in children/adolescents with lower-limb cerebral palsy (CP)-related spasticity. METHODS: Phase 3 double-blind study in children/adolescents (Gross Motor Function Classification System - Expanded and Revised I-V) with unilateral or bilateral spastic CP and Ashworth Scale (AS) plantar flexor (PF) scores ⩾ 2 randomized (1:1:2) to incobotulinumtoxinA (4, 12, 16 U/kg, maximum 100, 300, 400 U, respectively) for two 12- to 36-week injection cycles. Two clinical patterns were treated. Pes equinus (bilateral or unilateral) was mandatory; if unilateral, treatment included flexed knee or adducted thigh. ENDPOINTS: Primary: AS-PF change from baseline to 4 weeks; Coprimary: investigator-rated Global Impression of Change Scale (GICS)-PF at 4 weeks; Secondary: investigator's, patient's, and parent's/caregiver's GICS, Gross Motor Function Measure-66 (GMFM-66). RESULTS: Among 311 patients, AS-PF and AS scores in all treated clinical patterns improved from baseline to 4-weeks post-injection and cumulatively across injection cycles. GICS-PF and GICS scores confirmed global spasticity improvements. GMFM-66 scores indicated better motor function. No significant differences between doses were evident. Treatment was well-tolerated, with no unexpected treatment-related adverse events or neutralising antibody development. CONCLUSION: Children/adolescents with lower-limb spasticity experienced multipattern benefits from incobotulinumtoxinA, which was safe and well-tolerated in doses up to 16 U/kg, maximum 400 U.

Zika virus noncoding RNA suppresses apoptosis and is required for virus transmission by mosquitoes.

Flaviviruses, including Zika virus (ZIKV), utilise host mRNA degradation machinery to produce subgenomic flaviviral RNA (sfRNA). In mammalian hosts, this noncoding RNA facilitates replication and pathogenesis of flaviviruses by inhibiting IFN-signalling, whereas the function of sfRNA in mosquitoes remains largely elusive. Herein, we conduct a series of in vitro and in vivo experiments to define the role of ZIKV sfRNA in infected Aedes aegypti employing viruses deficient in production of sfRNA. We show that sfRNA-deficient viruses have reduced ability to disseminate and reach saliva, thus implicating the role for sfRNA in productive infection and transmission. We also demonstrate that production of sfRNA alters the expression of mosquito genes related to cell death pathways, and prevents apoptosis in mosquito tissues. Inhibition of apoptosis restored replication and transmission of sfRNA-deficient mutants. Hence, we propose anti-apoptotic activity of sfRNA as the mechanism defining its role in ZIKV transmission.

Longitudinal association between adiposity and inter-arm blood pressure difference.

This is the first longitudinal study evaluating whether adiposity is associated with inter-arm blood pressure difference. We evaluated 714 overweight/obese individuals aged 40-65 years over a 3-year follow-up. Systolic and diastolic blood pressures were measured in both arms simultaneously using an automated machine. Linear regression assessed the associations of body mass index, fat %, waist, neck, thigh, and arm circumferences (cm), with absolute inter-arm differences in systolic (IAS) and diastolic (IAD) blood pressure (mm Hg). Poisson regression was used for binary outcomes (IAS and IAD ≥ 10 mm Hg). All models were adjusted for age, gender, smoking, physical activity, and HOMA-IR. Adiposity measures were associated with increased IAS and IAD (ß range: 0.09-0.20 and 0.09-0.30). Neck circumference showed the strongest association with IAS (ß = 0.20, 95% CI: 0.03, 0.37) and IAD (ß = 0.30, 95% CI: 0.12, 0.47); arm circumference showed a similar association with IAS, but lower with IAD. Highest quartiles of BMI, thigh, and arm showed significant associations with IAS (IRR: 2.21, 2.46 and 2.70). Highest quartiles of BMI, waist, neck, and arm circumferences were significantly associated with IAD (IRR: 2.38, 2.68, 4.50 and 2.24). If the associations are corroborated in other populations, adiposity may be an important modifiable risk factor for inter-arm blood pressure difference with a large potential public health impact.

Determinants of Zika virus host tropism uncovered by deep mutational scanning.

Arboviruses cycle between, and replicate in, both invertebrate and vertebrate hosts, which for Zika virus (ZIKV) involves Aedes mosquitoes and primates1. The viral determinants required for replication in such obligate hosts are under strong purifying selection during natural virus evolution, making it challenging to resolve which determinants are optimal for viral fitness in each host. Herein we describe a deep mutational scanning (DMS) strategy2-5 whereby a viral cDNA library was constructed containing all codon substitutions in the C-terminal 204 amino acids of ZIKV envelope protein (E). The cDNA library was transfected into C6/36 (Aedes) and Vero (primate) cells, with subsequent deep sequencing and computational analyses of recovered viruses showing that substitutions K316Q and S461G, or Q350L and T397S, conferred substantial replicative advantages in mosquito and primate cells, respectively. A 316Q/461G virus was constructed and shown to be replication-defective in mammalian cells due to severely compromised virus particle formation and secretion. The 316Q/461G virus was also highly attenuated in human brain organoids, and illustrated utility as a vaccine in mice. This approach can thus imitate evolutionary selection in a matter of days and identify amino acids key to the regulation of virus replication in specific host environments.

Longitudinal association between periodontitis and development of diabetes.

BACKGROUND: Clinical trials have shown very modest short-term improvements in glycemic control among participants with diabetes after periodontitis treatment. Few longitudinal studies suggest that periodontitis may be related to prediabetes/diabetes risk. METHODS: We evaluated 1206 diabetes free participants in the San Juan Overweight Adults Longitudinal Study (SOALS) and 941 with complete 3-year follow-up data were included. The National Health and Nutrition Examination Survey (NHANES) methods were used to assess periodontitis. Diabetes and prediabetes were classified using American Diabetes Association cutoffs for fasting and 2-hour post-load glucose and HbA1c. We used Poisson regression adjusting for baseline age, gender, smoking, education, family history of diabetes, physical activity, waist circumference, and alcohol intake. RESULTS: Over the 3-year follow-up, 69 (7.3%) of the 941 individuals developed type 2 diabetes, and 142 (34.9%) of the 407 with normal glycemia at baseline developed prediabetes. In multivariable models, greater mean pocket depth and mean attachment loss at baseline were associated with lower risk of developing prediabetes/diabetes over the follow-up (IRR = 0.81; 95% CI: 0.67-0.99, and IRR = 0.86; 95% CI: 0.74-0.99, respectively). Increase in periodontal attachment loss from baseline to follow-up was associated with higher prediabetes/diabetes risk (multivariate IRR = 1.25; 95% CI: 1.09-1.42), and increase in pocket depth was associated with >20% fasting glucose increase (multivariate IRR = 1.43; 95% CI: 1.14-1.79). The inverse associations persisted after additionally adjusting for baseline income, sugar-sweetened beverages, number of teeth, oral hygiene, glycemia, or previous periodontal therapy. CONCLUSIONS: There is no association between periodontitis and risk of prediabetes/diabetes in this longitudinal study.

Insulin resistance predicts the risk of gingival/periodontal inflammation.

OBJECTIVES: Evaluate whether insulin resistance (IR) predicts the risk of oral inflammation, assessed as the number of sites with bleeding on probing (BOP) and number of teeth with probing pocket depths (PPD) ≥ 4 mm and BOP. METHODS: Data on 870 overweight/obese diabetes free adults, aged 40-65 years from the San Juan Overweight Adults Longitudinal Study over a three-year period, was analyzed. Baseline IR, assessed using the Homeostasis Model Assessment of IR (HOMA-IR) index, was divided into tertiles. BOP was assessed at buccal and lingual sites, and PPD at six sites per tooth. Negative binomial regression was used to estimate the risk ratios (RRs) for oral inflammation adjusted for baseline age, gender, smoking status, alcohol intake, education, physical activity, waist circumference, mean plaque index, and baseline number of sites with BOP, or number of teeth with PPD≥4 mm and BOP. The potential impact of tertiles of serum TNF-α and adiponectin on the IR-oral inflammation association was also assessed in a subsample of 597 participants. RESULTS: Participants in the highest HOMA-IR tertile at baseline had significantly higher numbers of sites with BOP [RR = 1.19, 95% confidence interval (CI): 1.03-1.36] and number of teeth with PPD ≥ 4 mm and BOP (RR = 1.39, 95% CI: 1.09-1.78) at follow-up, compared with individuals in the lower two HOMA-IR tertiles. Neither TNF-α nor adiponectin confounded the associations. CONCLUSION: IR significantly predicts gingival/periodontal inflammation in this population.

Correction: The carriage of interleukin-1B-31*C allele plus Staphylococcus aureus and Haemophilus influenzae increases the risk of recurrent tonsillitis in a Mexican population.

[This corrects the article DOI: 10.1371/journal.pone.0178115.].

Over-the-counter mouthwash use and risk of pre-diabetes/diabetes.

AIMS: Over-the-counter mouthwash comprises part of routine oral care for many; however, potential adverse effects of the long-term daily use have not been evaluated. Most mouthwash contain antibacterial ingredients, which could impact oral microbes critical for nitric oxide formation, and in turn predispose to metabolic disorders including diabetes. Our aim was to evaluate longitudinally the association between baseline over-the-counter mouthwash use and development of pre-diabetes/diabetes over a 3-year follow-up. MATERIALS AND METHODS: The San Juan Overweight Adults Longitudinal Study (SOALS) recruited 1206 overweight/obese individuals, aged 40-65, and free of diabetes and major cardiovascular diseases; 945 with complete follow-up data were included in the analyses. We used Poisson regression models adjusting for baseline age, sex, smoking, physical activity, waist circumference, alcohol consumption, pre-hypertension/hypertension status; time between visits was included in the models as an offset. RESULTS: Many participants (43%) used mouthwash at least once daily and 22% at least twice daily. Participants using mouthwash ≥ twice daily at baseline, had a significantly elevated risk of pre-diabetes/diabetes compared to less frequent users (multivariate IRR = 1.55, 95% CI: 1.21-1.99), or non-users of mouthwash (multivariate IRR = 1.49; 95% CI: 1.13-1.95). The effect estimates were similar after adding income, education, oral hygiene, oral conditions, sleep breathing disorders, diet (processed meat, fruit, and vegetable intake), medications, HOMA-IR, fasting glucose, 2hr post load glucose or CRP to the multivariate models. Both associations were also significant among never-smokers and obese individuals. Mouthwash use lower than twice daily showed no association, suggesting a threshold effect at twice or more daily. CONCLUSIONS: Frequent regular use of over-the-counter mouthwash was associated with increased risk of developing pre-diabetes/diabetes in this population.

Relationship between tooth loss and peripheral arterial disease among women.

AIM: We assessed the longitudinal association between tooth loss and peripheral arterial disease (PAD) within the Nurses' Health Study. MATERIALS AND METHODS: After excluding participants with prior cardiovascular diseases, 277 of 79,663 women were confirmed as PAD cases during 16 years of follow-up. Number of teeth and recent tooth loss were reported initially in 1992. Subsequent tooth loss was recorded in 1996 and in 2000. We evaluated the associations of baseline number of teeth and recent tooth loss with risk of PAD, adjusting for age, smoking, diabetes, hypertension, high cholesterol, aspirin use, family history of myocardial infarction, BMI, alcohol consumption, physical activity, postmenopausal hormone use, and use of vitamin E, vitamin D, multivitamin and calcium. RESULTS: Incident tooth loss during follow-up was significantly associated with higher hazard of PAD (HR = 1.31 95% CI: 1.00-1.71). However, the association appeared inverse among never smokers. There was no dose-response relationship between baseline number of teeth and PAD. CONCLUSIONS: Tooth loss showed a modest association with PAD, but no dose-response relationship was observed.

The carriage of interleukin-1B-31*C allele plus Staphylococcus aureus and Haemophilus influenzae increases the risk of recurrent tonsillitis in a Mexican population.

The aim of the present study was to estimate the relative contribution of immunogenetic and microbiological factors in the development of recurrent tonsillitis in a Mexican population. Patients (n = 138) with recurrent tonsillitis and an indication of tonsillectomy (mean age: 6.05 years ± 3.00; median age: 5 years, female: 58; age range: 1-15 years) and 195 non-related controls older than 18 years and a medical history free of recurrent tonsillitis were included. To evaluate the microbial contribution, tonsil swab samples from both groups and extracted tonsil samples from cases were cultured. Biofilm production of isolated bacteria was measured. To assess the immunogenetic component, DNA from peripheral blood was genotyped for the TNFA-308G/A single-nucleotide polymorphism (SNP) and for the IL1B -31C/T SNP. Normal microbiota, but no pathogens or potential pathogens, were identified from all control sample cultures. The most frequent pathogenic species detected in tonsils from cases were Staphylococcus aureus (48.6%, 67/138) and Haemophilus influenzae (31.9%, 44/138), which were found more frequently in patient samples than in samples from healthy volunteers (P < 0.0001). Importantly, 41/54 (75.9%) S. aureus isolates were biofilm producers (18 weak and 23 strong), whereas 17/25 (68%) H. influenzae isolates were biofilm producers (10 weak, and 7 strong biofilm producers). Patients with at least one copy of the IL1B-31*C allele had a higher risk of recurrent tonsillitis (OR = 4.03; 95% CI = 1.27-14.27; P = 0.013). TNFA-308 G/A alleles were not preferentially distributed among the groups. When considering the presence of IL1B-31*C plus S. aureus, IL1B-31*C plus S. aureus biofilm producer, IL1B-31*C plus H. influenzae or IL1B-31*C plus H. influenzae biofilm producer, the OR tended to infinite. Thus, the presence of IL1B-31*C allele plus the presence of S. aureus and/or H. influenzae could be related to the development of tonsillitis in this particular Mexican population.

Association between within-visit systolic blood pressure variability and development of pre-diabetes and diabetes among overweight/obese individuals.

Short-term blood pressure variability is associated with pre-diabetes/diabetes cross-sectionally, but there are no longitudinal studies evaluating this association. The objective of this study is to evaluate the association between within-visit systolic and diastolic blood pressure variability and development of pre-diabetes/diabetes longitudinally. The study was conducted among eligible participants from the San Juan Overweight Adults Longitudinal Study (SOALS), who completed the 3-year follow-up exam. Participants were Hispanics, 40-65 years of age, and free of diabetes at baseline. Within-visit systolic and diastolic blood pressure variability was defined as the maximum difference between three measures, taken a few minutes apart, of systolic and diastolic blood pressure, respectively. Diabetes progression was defined as development of pre-diabetes/diabetes over the follow-up period. We computed multivariate incidence rate ratios adjusting for baseline age, gender, smoking, physical activity, waist circumference, and hypertension status. Participants with systolic blood pressure variability ≥10 mmHg compared to those with <10 mmHg, showed higher progression to pre-diabetes/diabetes (RR = 1.77, 95% CI: 1.30-2.42). The association persisted among never smokers. Diastolic blood pressure variability ≥10 mmHg (compared to <10 mmHg) did not show an association with diabetes status progression (RR = 1.20, 95% CI: 0.71-2.01). Additional adjustment of baseline glycemia, C-reactive protein, and lipids (reported dyslipidemia or baseline HDL or triglycerides) did not change the estimates. Systolic blood pressure variability may be a novel independent risk factor and an early predictor for diabetes, which can be easily incorporated into a single routine outpatient visit at none to minimal additional cost.

A Morphological and Morphometric Study of Bite Marks Caused by Mice (Mus Musculus) on Different Baits for Forensic Purposes.

In animal bites, the dental attributes can be fundamental in identifying the marks made by various species on different matrices. Although rodent bite marks have been studied in the context of postmortem interference, little research has used different baits to analyze these marks linking not only specific behavior patterns but also the possibility of structural damage. Twenty mice (Mus musculus) were exposed to different baits to study their bite marks in a controlled model. The known pattern of parallel and multiple grooves has been seen in all baits, but polyvinyl chloride and fiber-optic cable were significantly different between each other and the other baits. Some baits showed patterns of anchorage of the upper incisors and space between the lower incisors when gnawing. This technical note represents a novel model of analysis where veterinarians and/or dentists may be asked to give an opinion on alleged animal bite marks.

Comparing glucose and hemoglobin A1c diagnostic tests among a high metabolic risk Hispanic population.

BACKGROUND: Compare glycated hemoglobin (HbA1c ) diagnostic tests for prediabetes and diabetes with plasma glucose criteria and compare the metabolic profiles of people classified by HbA1c versus by glucose levels. METHODS: Participants were recruited for the San Juan Overweight Adults Longitudinal Study. The participants were primarily Hispanic (98%), without previously diagnosed diabetes, and aged 40 to 65 years. Participants classified as normal glycemic, prediabetes, or diabetes on the basis of baseline HbA1c and plasma glucose criteria were compared with respect to baseline cardiometabolic factors. RESULTS: The 1342 participants had a mean age of 50.5 ± 6.8 years and 28% were men. Thirty-one percent were diagnosed with prediabetes by plasma glucose criteria and 53.4% by HbA1c , and 8.1% were diagnosed with diabetes by plasma glucose criteria and 6.3% by HbA1c ; overall concordance rate was 55.1%. The area under the receiver operating characteristic curve of HbA1c compared to plasma glucose criteria was 0.62 for impaired glucose and 0.76 for diabetes. A worse cardiometabolic profile was seen within subgroups that met HbA1c and plasma glucose criteria for diabetes or prediabetes. Those diagnosed with prediabetes by plasma glucose criteria had significantly higher systolic blood pressure and higher homeostatic model assessment than those diagnosed using HbA1c . Participants diagnosed with diabetes by plasma glucose criteria had lower body mass index, smaller waist circumference, and lower insulinogenic and disposition indices, but higher homeostatic model assessment of insulin resistance, than those diagnosed by HbA1c . CONCLUSIONS: Low concordance was seen between HbA1c and glucose measurements. The HbA1c is not a good test for prediabetes but shows reasonable validity for diabetes in this high-risk predominantly female Hispanic population. People classified by HbA1c , plasma glucose criteria, or both show different metabolic profiles; a combined test may be ideal.