The Effect of a Square-Stepping Exercise Intervention on Heart Rate Variability in Older Individuals with Type 2 Diabetes and Subjective Cognitive Complaints

Aging is associated with increased onset of diseases such as type 2 diabetes (T2D) and cognitive impairment. Heart rate variability (HRV), a measure of autonomic function, is reduced in T2D and may have the potential to indicate cognitive decline in this population. Square-stepping exercise (SSE) is a novel cognitive exercise recently implemented in cognitive research, which may have the potential to improve global cognitive function in T2D individuals. Participants with T2D (N=25, aged ≥ 50y) and self-reported cognitive complaints were randomized into either an SSE intervention or a wait-list (WL) control group for 24-weeks. HRV parameters (time and frequency domain) and GCF domains were assessed at baseline and 24-weeks. No significant differences were found in HRV parameters between groups at baseline and 24-weeks. However, heart rate was significantly reduced from baseline to 24-weeks in the SSE group, p = 0.046. Additionally, low and high frequency power were significantly decreased from baseline to 24-weeks in the WL group, p = 0.05 and p = 0.043 respectively. This study elucidates the impact of cognitive exercise training on HRV, however, it is inconclusive as to why a shift towards vagal modulation was observed in both the SSE and WL groups

Real-time in vivo optogenetic neuromodulation and multielectrode electrophysiologic recording with NeuroRighter

Optogenetic channels have greatly expanded neuroscience’s experimental capabilities, enabling precise genetic targeting and manipulation of neuron subpopulations in awake and behaving animals. However, many barriers to entry remain for this technology – including low-cost and effective hardware for combined optical stimulation and electrophysiologic recording. To address this, we adapted the open-source NeuroRighter multichannel electrophysiology platform for use in awake and behaving rodents in both open and closed-loop stimulation experiments. Here, we present these cost-effective adaptations, including commercially available LED light sources; custom-made optical ferrules; 3D printed ferrule hardware and software to calibrate and standardize output intensity; and modifications to commercially available electrode arrays enabling stimulation proximally and distally to the recording target. We then demonstrate the capabilities and versatility of these adaptations in several open and closed-loop experiments, demonstrate spectrographic methods of analyzing the results, as well as discuss artifacts of stimulation.Emory University. School of Medicine (Emory Neurosciences Initiative seed grant)American Epilepsy SocietyEpilepsy Foundation of America (Predoctoral fellowship)National Science Foundation (U.S.) (NSF GRFP Fellowship 08-593)National Science Foundation (U.S.) (NSF IGERT Fellowship DGE-0333411)National Science Foundation (U.S.) (NSF EFRI #1238097)National Institutes of Health (U.S.) (NIH 1R01NS079757-01)American Society for Engineering Education (SMART Fellowship

BpaB, a Novel Protein Encoded by the Lyme Disease Spirochete\u27s Cp32 Prophages, Binds to Erp Operator 2 DNA

Borrelia burgdorferi produces Erp outer surface proteins throughout mammalian infection, but represses their synthesis during colonization of vector ticks. A DNA region 5′ of the start of erp transcription, Operator 2, was previously shown to be essential for regulation of expression. We now report identification and characterization of a novel erp Operator 2-binding protein, which we named BpaB. erp operons are located on episomal cp32 prophages, and a single bacterium may contain as many as 10 different cp32s. Each cp32 family member encodes a unique BpaB protein, yet the three tested cp32-encoded BpaB alleles all bound to the same DNA sequence. A 20-bp region of erp Operator 2 was determined to be essential for BpaB binding, and initial protein binding to that site was required for binding of additional BpaB molecules. A 36-residue region near the BpaB carboxy terminus was found to be essential for high-affinity DNA-binding. BpaB competed for binding to erp Operator 2 with a second B. burgdorferi DNA-binding protein, EbfC. Thus, cellular levels of free BpaB and EbfC could potentially control erp transcription levels

BpaB, a novel protein encoded by the Lyme disease spirochete’s cp32 prophages, binds to erp Operator 2 DNA

Borrelia burgdorferi produces Erp outer surface proteins throughout mammalian infection, but represses their synthesis during colonization of vector ticks. A DNA region 5′ of the start of erp transcription, Operator 2, was previously shown to be essential for regulation of expression. We now report identification and characterization of a novel erp Operator 2-binding protein, which we named BpaB. erp operons are located on episomal cp32 prophages, and a single bacterium may contain as many as 10 different cp32s. Each cp32 family member encodes a unique BpaB protein, yet the three tested cp32-encoded BpaB alleles all bound to the same DNA sequence. A 20-bp region of erp Operator 2 was determined to be essential for BpaB binding, and initial protein binding to that site was required for binding of additional BpaB molecules. A 36-residue region near the BpaB carboxy terminus was found to be essential for high-affinity DNA-binding. BpaB competed for binding to erp Operator 2 with a second B. burgdorferi DNA-binding protein, EbfC. Thus, cellular levels of free BpaB and EbfC could potentially control erp transcription levels

Development and validation of a prediction model for fat mass in children and adolescents: Meta-analysis using individual participant data

© Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to. To develop and validate a prediction model for fat mass in children aged 4-15 years using routinely available risk factors of height, weight, and demographic information without the need for more complex forms of assessment. Design Individual participant data meta-analysis. Setting Four population based cross sectional studies and a fifth study for external validation, United Kingdom. Participants A pooled derivation dataset (four studies) of 2375 children and an external validation dataset of 176 children with complete data on anthropometric measurements and deuterium dilution assessments of fat mass. Main outcome measure Multivariable linear regression analysis, using backwards selection for inclusion of predictor variables and allowing non-linear relations, was used to develop a prediction model for fat-free mass (and subsequently fat mass by subtracting resulting estimates from weight) based on the four studies. Internal validation and then internal-external cross validation were used to examine overfitting and generalisability of the model\u27s predictive performance within the four development studies; external validation followed using the fifth dataset. Results Model derivation was based on a multi-ethnic population of 2375 children (47.8% boys, n=1136) aged 4-15 years. The final model containing predictor variables of height, weight, age, sex, and ethnicity had extremely high predictive ability (optimism adjusted R 2: 94.8%, 95% confidence interval 94.4% to 95.2%) with excellent calibration of observed and predicted values. The internal validation showed minimal overfitting and good model generalisability, with excellent calibration and predictive performance. External validation in 176 children aged 11-12 years showed promising generalisability of the model (R 2: 90.0%, 95% confidence interval 87.2% to 92.8%) with good calibration of observed and predicted fat mass (slope: 1.02, 95% confidence interval 0.97 to 1.07). The mean difference between observed and predicted fat mass was -1.29 kg (95% confidence interval -1.62 to -0.96 kg). Conclusion The developed model accurately predicted levels of fat mass in children aged 4-15 years. The prediction model is based on simple anthropometric measures without the need for more complex forms of assessment and could improve the accuracy of assessments for body fatness in children (compared with those provided by body mass index) for effective surveillance, prevention, and management of clinical and public health obesity

New challenges for verbal autopsy: considering the ethical and social implications of verbal autopsy methods in routine health information systems

Verbal autopsy (VA) methods are designed to collect cause-of-death information from populations where many deaths occur outside of health facilities and where death certification is weak or absent. A VA consists of an interview with a relative or carer of a recently deceased individual in order to gather information on the signs and symptoms the decedent presented with prior to death. These details are then used to determine and assign a likely cause-of-death. At a population level this information can be invaluable to help guide prioritisation and direct health policy and services. To date VAs have largely been restricted to research contexts but many countries are now venturing to incorporate VA methods into routine civil registration and vital statistics (CRVS) systems. Given the sensitive nature of death, however, there are a number of ethical, legal and social issues that should be considered when scaling-up VAs, particularly in the cross-cultural and socio-economically disadvantaged environments in which they are typically applied. Considering each step of the VA process this paper provides a narrative review of the social context of VA methods. Harnessing the experiences of applying and rolling out VAs as part of routine CRVS systems in a number of low and middle income countries, we identify potential issues that countries and implementing institutions need to consider when incorporating VAs into CRVS systems and point to areas that could benefit from further research and deliberation

CALHM3 Is Essential for Rapid Ion Channel-Mediated Purinergic Neurotransmission of GPCR-Mediated Tastes

Binding of sweet, umami, and bitter tastants to G protein-coupled receptors (GPCRs) in apical membranes of type II taste bud cells (TBCs) triggers action potentials that activate a voltage-gated nonselective ion channel to release ATP to gustatory nerves mediating taste perception. Although calcium homeostasis modulator 1 (CALHM1) is necessary for ATP release, the molecular identification of the channel complex that provides the conductive ATP-release mechanism suitable for action potential-dependent neurotransmission remains to be determined. Here we show that CALHM3 interacts with CALHM1 as a pore-forming subunit in a CALHM1/CALHM3 hexameric channel, endowing it with fast voltage-activated gating identical to that of the ATP-release channel in vivo. Calhm3 is co-expressed with Calhm1 exclusively in type II TBCs, and its genetic deletion abolishes taste-evoked ATP release from taste buds and GPCR-mediated taste perception. Thus, CALHM3, together with CALHM1, is essential to form the fast voltage-gated ATP-release channel in type II TBCs required for GPCR-mediated tastes. Ma et al. identify a CALHM1/CALHM3 hetero-hexameric ion channel as the mechanism by which type II taste bud cells release ATP as a neurotransmitter to gustatory neurons in response to GPCR-mediated tastes, including sweet, bitter, and umami substances. © 2018 Elsevier Inc

Updated Clinical Guidelines for Diagnosing Fetal Alcohol Spectrum Disorders

The adverse effects of prenatal alcohol exposure constitute a continuum of disabilities (fetal alcohol spectrum disorders [FASD]). In 1996, the Institute of Medicine established diagnostic categories delineating the spectrum but not specifying clinical criteria by which diagnoses could be assigned. In 2005, the authors published practical guidelines operationalizing the Institute of Medicine categories, allowing for standardization of FASD diagnoses in clinical settings. The purpose of the current report is to present updated diagnostic guidelines based on a thorough review of the literature and the authors’ combined expertise based on the evaluation of >10 000 children for potential FASD in clinical settings and in epidemiologic studies in conjunction with National Institute on Alcohol Abuse and Alcoholism–funded studies, the Collaborative Initiative on Fetal Alcohol Spectrum Disorders, and the Collaboration on FASD Prevalence. The guidelines were formulated through conference calls and meetings held at National Institute on Alcohol Abuse and Alcoholism offices in Rockville, MD. Specific areas addressed include the following: precise definition of documented prenatal alcohol exposure; neurobehavioral criteria for diagnosis of fetal alcohol syndrome, partial fetal alcohol syndrome, and alcohol-related neurodevelopmental disorder; revised diagnostic criteria for alcohol-related birth defects; an updated comprehensive research dysmorphology scoring system; and a new lip/philtrum guide for the white population, incorporating a 45-degree view. The guidelines reflect consensus among a large and experienced cadre of FASD investigators in the fields of dysmorphology, epidemiology, neurology, psychology, developmental/behavioral pediatrics, and educational diagnostics. Their improved clarity and specificity will guide clinicians in accurate diagnosis of infants and children prenatally exposed to alcohol

The Impact of Delayed Treatment of Uncomplicated \u3ci\u3eP. falciparum\u3c/i\u3e Malaria on Progression to Severe Malaria: A Systematic Review and a Pooled Multicentre Individual-Patient Meta-Analysis

BACKGROUND: Delay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as \u27test-and-treat\u27 policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM. METHODS AND FINDINGS: A search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as \u27Good\u27, scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged \u3c15 years) SM patients and 5,780 (79.6% aged \u3c15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of \u3e24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p \u3c 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p \u3c 0.001) for a delay of \u3e7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] \u3e3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify. CONCLUSIONS: Our results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment