ROCCO: a robust method for detection of open chromatin via convex optimization.

MOTIVATION: Analysis of open chromatin regions across multiple samples from two or more distinct conditions can determine altered gene regulatory patterns associated with biological phenotypes and complex traits. The ATAC-seq assay allows for tractable genome-wide open chromatin profiling of large numbers of samples. Stable, broadly applicable genomic annotations of open chromatin regions are not available. Thus, most studies first identify open regions using peak calling methods for each sample independently. These are then heuristically combined to obtain a consensus peak set. Reconciling sample-specific peak results post hoc from larger cohorts is particularly challenging, and informative spatial features specific to open chromatin signals are not leveraged effectively. RESULTS: We propose a novel method, ROCCO, that determines consensus open chromatin regions across multiple samples simultaneously. ROCCO employs robust summary statistics and solves a constrained optimization problem formulated to account for both enrichment and spatial dependence of open chromatin signal data. We show this formulation admits attractive theoretical and conceptual properties as well as superior empirical performance compared to current methodology. AVAILABILITY AND IMPLEMENTATION: Source code, documentation, and usage demos for ROCCO are available on GitHub at: https://github.com/nolan-h-hamilton/ROCCO. ROCCO can also be installed as a stand-alone binary utility using pip/PyPI.

Cryptic Chemical Variation in a Marine Red Alga as Revealed by Nontargeted Metabolomics.

Many marine algae occupy habitats that are dark, deep, or encrusted on other organisms and hence are frequently overlooked by natural product chemists. However, exploration of less-studied organisms can lead to new opportunities for drug discovery. Genetic variation at the individual, species, genus, and population levels as well as environmental influences on gene expression enable expansion of the chemical repertoire associated with a taxonomic group, enabling natural product exploration using innovative analytical methods. A nontargeted LC-MS and 1H NMR spectroscopy-based metabolomic study of 32 collections of representatives of the calcareous red algal genus Peyssonnelia from coral reef habitats in Fiji and the Solomon Islands revealed significant correlations between natural products' chemistry, phylogeny, and biomedically relevant biological activity. Hierarchical cluster analysis (HCA) of LC-MS data in conjunction with NMR profiling and MS/MS-based molecular networking revealed the presence of at least four distinct algal chemotypes within the genus Peyssonnelia. Two Fijian collections were prioritized for further analysis, leading to the isolation of three novel sulfated triterpene glycosides with a rearranged isomalabaricane carbon skeleton, guided by the metabolomic data. The discovery of peyssobaricanosides A-C (15-17) from two Fijian Peyssonnelia collections, but not from closely related specimens collected in the Solomon Islands that were otherwise chemically and phylogenetically very similar, alludes to population-level variation in secondary metabolite production. Our study reinforces the significance of exploring unusual ecological niches and showcases marine red algae as a chemically rich treasure trove.

Adaptation and the Mortality Effects of Temperature Across U.S. Climate Regions.

We estimate how the mortality effects of temperature vary across U.S. climate regions to assess local and national damages from projected climate change. Using 22 years of Medicare data, we find that both cold and hot days increase mortality. However, hot days are less deadly in warm places while cold days are less deadly in cool places. Incorporating this heterogeneity into end-of-century climate change assessments reverses the conventional wisdom on climate damage incidence: cold places bear more, not less, of the mortality burden. Allowing places to adapt to their future climate substantially reduces the estimated mortality effects of climate change.

In utero teratogen exposure and cardiometabolic risk in 5-year-old children: a prospective pediatric study.

BACKGROUND: Aorta and carotid intima-media thickness (IMT) is a measure of subclinical atherosclerosis and useful to assess cardiometabolic risk in the young. The in utero milieu may involve cardiometabolic programing and the development of cardiometabolic risk factors in children. Maternal smoking, alcohol consumption, and micronutrient deficiencies during pregnancy influence the development of the cardiovascular system through a process of DNA methylation. AIM: To explore an association between maternal smoking and alcohol consumption during pregnancy and intima media thickness in 5-year-old children for a low-income setting. METHODS: Data were collected from 500 mother-child pairs at antenatal clinic visit, at birth, and at age 5 years. Anthropometric measurements were collected at birth and again at age 5 years. As well as clinical and ultrasound measurements at age 5 years. Clinical measurements, at age 5 years, included blood pressure, mean arterial pressure, and heart rate. Ultrasound measurements of the aorta and carotid arteries IMT were performed at age 5 years. Main outcome of interest was effect of dual teratogen exposure on the ultrasound measures IMT as indication of cardiometabolic risk. RESULTS: cIMT was significantly higher in children exposed to both alcohol and nicotine during pregnancy compared to those not exposed (p = .008). In separate linear models, dual in utero exposure (beta = 0.12; p = .01) and male sex (beta = 0.14; p = .01) were associated with higher right cIMT values (F(6,445) = 5.20; R2 = 0.07, p < .01); male sex (beta = 0.13; p = .01) and low birth weight (beta = 0.07; p = .01) with higher left cIMT value (F(4,491) = 4.49; R2 = 0.04; p = .01); and males sex (beta = 0.11; p = .02) with higher aorta IMT (F(6,459) = 5.63; R2 = 0.07; p < .01). Significant positive correlations between maternal measures of adiposity, maternal MUAC (r = 0.10; p = .03), and maternal BMI (r = 0.12; p < .01) and right cIMT measurements adjusted for the BMI of the child at age 5 years as covariate. Blood pressure measurements at age 5 years were not significantly associated with IMT but, instead, correlated significantly and positively with the BMI of the child at age 5 years (p < .01). CONCLUSION: Children exposed to both maternal smoking and alcohol consumption during pregnancy presented with cardiometabolic risk factors 5 years after birth. In addition, maternal adiposity, male sex, and low birth weight were associated with higher IMT at age 5 years.

The effects of in utero exposure to teratogens on organ size: a prospective paediatric study.

In low-income countries, prospective data on combined effects of in utero teratogen exposure are lacking and necessitates new research. The aim of the present study was to explore the effect of in utero teratogen exposure on the size of the kidneys and pancreas 5 years after birth in a low-income paediatric population. Data was collected from 500 mother-child pairs from a low-income setting. Anthropometric measurements included body weight, (BW) body height, mid-upper arm and waist circumference (WC). Clinical measurements included blood pressure (BP), mean arterial pressure and heart rate. Ultrasound measurements included pancreas, and kidney measurements at age 5 years. The main outcome of interest was the effect of maternal smoking and alcohol consumption on ultrasound measurements of organ size at age 5 years. Left and right kidney length measurements were significantly lower in smoking exposed children compared to controls (p = 0.04 and p = 0.03). Pancreas body measurements were significantly lower in smoking exposed children (p = 0.04). Multiple regression analyses were used to examine the associations between the independent variables (IDVs), maternal age, body mass index (BMI), mid-upper arm circumference (MUAC) and BW of the child, on the dependent variables (DVs) kidney lengths and kidney volumes. Also, the association between in utero exposure to alcohol and nicotine and pancreas size. WC was strongest (r = 0.28; p < 0.01) associated with pancreas head [F (4, 454) = 13.44; R2 = 0.11; p < 0.01] and tail (r = 0.30; p < 0.01) measurements at age 5 years, with in utero exposure, sex of the child and BMI as covariates. Kidney length and pancreas body measurements are affected by in utero exposure to nicotine at age 5 years and might contribute to cardiometabolic risk in later life. Also, findings from this study report on ultrasound reference values for kidney and pancreas measurements of children at age 5 years from a low-income setting.

Refining the Definition of Polypharmacy and Its Link to Disability in Older Adults: Conceptualizing Necessary Polypharmacy, Unnecessary Polypharmacy, and Polypharmacy of Unclear Benefit.

The term polypharmacy in older adults is generally used in a pejorative context in the medical literature. Because of its link to geriatric syndromes and disability, the avoidance of polypharmacy is usually recommended in older adults as a strategy to optimize functional status. However, there are many polypharmacy regimens based on high-quality trials that clearly reduce the risk of disability in older adults. Other guidelines for older adults recommend the use of additional medications that may or may not be evidence based and that may or may not reduce disability. Therefore, we propose that, in the geriatric literature, polypharmacy now be categorized as "necessary polypharmacy," "unnecessary polypharmacy," or "polypharmacy of unclear benefit." In this article, we discuss the 3 categories of polypharmacy and give examples on each polypharmacy regimen and its potential relationship to disability in older adults.

The Mortality and Medical Costs of Air Pollution: Evidence from Changes in Wind Direction.

We estimate the causal effects of acute fine particulate matter exposure on mortality, health care use, and medical costs among the US elderly using Medicare data. We instrument for air pollution using changes in local wind direction and develop a new approach that uses machine learning to estimate the life-years lost due to pollution exposure. Finally, we characterize treatment effect heterogeneity using both life expectancy and generic machine learning inference. Both approaches find that mortality effects are concentrated in about 25 percent of the elderly population.

The association between antidepressant use and orthostatic hypotension in older people: a matched cohort study.

Orthostatic hypotension (OH) is often reported as a significant potential adverse effect of antidepressant use but the association between phasic blood pressure (BP) and antidepressants has not yet been investigated. This cross-sectional study compares continuously measured phasic BP and prevalence of OH in a cohort of antidepressant users ≥50 years compared with an age- and sex-matched cohort not taking antidepressants. OH was defined as a drop in systolic BP ≥ 20 mm Hg or in diastolic BP ≥ 10 mm Hg at 30 seconds after standing, measured using continuous beat-to-beat finometry. Multilevel time × group interactions revealed significantly greater systolic and diastolic BP drop in antidepressant users than nonusers at 30 seconds after stand. The prevalence of OH among antidepressant users was 31% (63/206), compared with 17% in nonusers (X2 = 9.7; P = .002). Unadjusted logistic regression models demonstrated that selective serotonin reuptake inhibitor use was associated with OH at an odds ratio of 2.11 (95% confidence interval: 1.25-3.57); P = .005, and this association was not attenuated when covariates including cardiac disease and depressive symptom burden were added. There was no statistically significant association between serotonin noradrenaline reuptake inhibitor or tricyclic antidepressant use and OH in unadjusted models although the study was not powered to detect changes within these subgroups. Older people taking antidepressants have a two-fold higher prevalence of OH than nonusers, highlighting the importance of screening the older antidepressant user for OH and dizziness and rationalizing medications to reduce the risk of falls within this vulnerable cohort.

Bioprospecting Deep-Sea Actinobacteria for Novel Anti-infective Natural Products.

The global prevalence of drug resistance has created an urgent need for the discovery of novel anti-infective drugs. The major source of antibiotics in current clinical practice is terrestrial actinobacteria; the less-exploited deep-sea actinobacteria may serve as an unprecedented source of novel natural products. In this study, we evaluated 50 actinobacteria strains derived from diverse deep water sponges and environmental niches for their anti-microbial activities against a panel of pathogens including Candida albicans, Clostridium difficile, Staphylococcus aureus, and methicillin-resistant S. aureus (MRSA), and Pseudomonas aeruginosa. More than half of the tested strains (27) were identified as active in at least one assay. The rare earth salt lanthanum chloride (LaCl3) was shown to be as an effective elicitor. Among the 27 strains, the anti-microbial activity of 15 were induced or enhanced by the addition of LaCl3. This part of study focused on one strain R818, in which potent antifungal activity was induced by the addition of LaCl3. We found that the LaCl3-activated metabolites in R818 are likely antimycin-type compounds. One of them, compound 1, has been purified. Spectroscopic analyses including HR-MS and 1D NMR indicated that this compound is urauchimycin D. The antifungal activity of compound 1 was confirmed with a minimal inhibitory concentration (MIC) of 25 µg/mL; the purified compound also showed a moderate activity against C. difficile. Additional notable strains are: strain N217 which showed both antifungal and antibacterial (including P. aeruginosa) activities and strain M864 which showed potent activity against C. difficile with an MIC value (0.125 µg/mL) lower than those of vancomycin and metronidazole. Our preliminary studies show that deep-sea actinobacteria is a promising source of anti-infective natural products.

Noninvasive beat-to-beat finger arterial pressure monitoring during orthostasis: a comprehensive review of normal and abnormal responses at different ages.

Over the past 30 years, noninvasive beat-to-beat blood pressure (BP) monitoring has provided great insight into cardiovascular autonomic regulation during standing. Although traditional sphygmomanometric measurement of BP may be sufficient for detection of sustained orthostatic hypotension, it fails to capture the complexity of the underlying dynamic BP and heart rate responses. With the emerging use of noninvasive beat-to-beat BP monitoring for the assessment of orthostatic BP control in clinical and population studies, various definitions for abnormal orthostatic BP patterns have been used. Here, age-related changes in cardiovascular control in healthy subjects will be reviewed to define the spectrum of the most important abnormal orthostatic BP patterns within the first 180 s of standing. Abnormal orthostatic BP responses can be defined as initial orthostatic hypotension (a transient systolic BP fall of >40 mmHg within 15 s of standing), delayed BP recovery (an inability of systolic BP to recover to a value of >20 mmHg below baseline at 30 s after standing) and sustained orthostatic hypotension (a sustained decline in systolic BP of ≥20 mmHg occurring 60-180 s after standing). In the evaluation of patients with light-headedness, pre(syncope), (unexplained) falls or suspected autonomic dysfunction, it is essential to distinguish between normal cardiovascular autonomic regulation and these abnormal orthostatic BP responses. The prevalence, clinical relevance and underlying pathophysiological mechanisms of these patterns differ significantly across the lifespan. Initial orthostatic hypotension is important for identifying causes of syncope in younger adults, whereas delayed BP recovery and sustained orthostatic hypotension are essential for evaluating the risk of falls in older adults.

Draft Genome Sequence of Deep-Sea Alteromonas sp. Strain V450 Isolated from the Marine Sponge Leiodermatium sp.

The proteobacterium Alteromonas sp. strain V450 was isolated from the Atlantic deep-sea sponge Leiodermatium sp. Here, we report the draft genome sequence of this strain, with a genome size of approx. 4.39 Mb and a G+C content of 44.01%. The results will aid deep-sea microbial ecology, evolution, and sponge-microbe association studies.

Structured care of diabetes in general practice: a qualitative study of the barriers and facilitators.

This qualitative study explored general practitioner's and practice nurse's perceptions of barriers and facilitators to the proposed transfer of diabetes care to general practice. Qualitative data were collected through five focus groups. Participants included GPs (n = 55) and practice nurses (n = 11) representing urban (44%), rural (29%) and mixed (27%) practices, in the Irish Mid-West region. Barriers and facilitators were mentioned 631 times (100%). Barriers were mentioned 461 times (73%), facilitators 170 times (27%). The most frequently identified barriers were lack of financial incentive (119/631; 19%), lack of access to secondary resources (93/631; 15%), lack of staff and increased workload (59/631; 9%) and time constraints (52/631; 8%). Identified facilitators were access to secondary care (49/631;7.8%), the holistic nature of general practice and continuity of care (48/631;7.6%). Although many are enthusiastic, there remains significant reluctance among GPs and practice nurses to take responsibility for diabetes care without addressing these barriers.

Neural correlates of oddball detection in self-motion heading: a high-density event-related potential study of vestibular integration.

The perception of self-motion is a product of the integration of information from both visual and non-visual cues, to which the vestibular system is a central contributor. It is well documented that vestibular dysfunction leads to impaired movement and balance, dizziness and falls, and yet our knowledge of the neuronal processing of vestibular signals remains relatively sparse. In this study, high-density electroencephalographic recordings were deployed to investigate the neural processes associated with vestibular detection of changes in heading. To this end, a self-motion oddball paradigm was designed. Participants were translated linearly 7.8 cm on a motion platform using a one second motion profile, at a 45° angle leftward or rightward of straight ahead. These headings were presented with a stimulus probability of 80-20 %. Participants responded when they detected the infrequent direction change via button-press. Event-related potentials (ERPs) were calculated in response to the standard (80 %) and target (20 %) movement directions. Statistical parametric mapping showed that ERPs to standard and target movements differed significantly from 490 to 950 ms post-stimulus. Topographic analysis showed that this difference had a typical P3 topography. Individual participant bootstrap analysis revealed that 93.3 % of participants exhibited a clear P3 component. These results indicate that a perceived change in vestibular heading can readily elicit a P3 response, wholly similar to that evoked by oddball stimuli presented in other sensory modalities. This vestibular-evoked P3 response may provide a readily and robustly detectable objective measure for the evaluation of vestibular integrity in various disease models.

Change in PASAT performance correlates with change in P3 ERP amplitude over a 12-month period in multiple sclerosis patients.

OBJECTIVE: To examine the correlation between the change in PASAT and the change in P3 event-related potentials (ERPs) over a 12-month period in multiple sclerosis (MS) patients, and to compare the 12-month change in the P3 ERP between MS patients and controls. METHODS: Forty-four subjects (27 MS patients, 17 controls) completed visual and auditory two-stimulus oddball and three-stimulus oddball tasks at Month 0 and Month 12. Data were recorded from a 128-scalp channel electroencephalography array. Data from scalp channels were converted into continuous interpolated images (incorporating the entire scalp and time). Amplitude, topographical differences and correlations were then tested using statistical parametric mapping. RESULTS: The change in visual and auditory P3a correlated significantly with the change in PASAT score (r=0.56, p<0.001 and r=0.48, p=0.003, respectively). Visual P3b and P3a showed greater decrease in 12 months in MS patients relative to controls. Visual P3b, auditory P3b and auditory P3a amplitudes had significantly decreased in MS patients after 12-month period. CONCLUSIONS: Change in visual and auditory P3a ERP amplitudes correlate with change in PASAT scores in MS patients. Visual modality is more sensitive to changes in P3 ERP amplitudes over 12-month period. SIGNIFICANCE: P3 ERPs may have utility in monitoring the change in cognitive functioning in MS.

DO CONSUMER PRICE SUBSIDIES REALLY IMPROVE NUTRITION?

Many developing countries use food-price subsidies or controls to improve nutrition. However, subsidizing goods on which households spend a high proportion of their budget can create large wealth effects. Consumers may then substitute towards foods with higher non-nutritional attributes (e.g., taste), but lower nutritional content per unit of currency, weakening or perhaps even reversing the subsidy's intended impact. We analyze data from a randomized program of large price subsidies for poor households in two provinces of China and find no evidence that the subsidies improved nutrition. In fact, it may have had a negative impact for some households. (JEL I38; O12; Q18).

Preliminary evidence for correlation between PASAT performance and P3a and P3b amplitudes in progressive multiple sclerosis.

BACKGROUND: The no-go P3a event-related potential (ERP) is a measure of attentional engagement and the P3b is a measure of context updating. The aim of this study was to compare ERP topographies: (i) to Paced Auditory Serial Addition Test (PASAT) results, (ii) of visual and auditory P3a and P3b of patients with primary progressive multiple sclerosis (PPMS) versus patients with secondary-progressive multiple sclerosis (SPMS) and (iii) of both progressive subtypes to healthy controls. METHODS: Thirty subjects (10 PPMS, 10 SPMS and 10 age-matched controls) completed visual and auditory no-go P3a and P3b tasks whilst data were recorded from a 128-scalp channel electroencephalography (EEG) array. Data from scalp channels were converted into continuous interpolated images (incorporating the entire scalp and time). Topographical differences and correlations were then tested using statistical parametric mapping. RESULTS: For the patients with multiple sclerosis (MS), PASAT score correlated significantly with parietal regions in the auditory P3b, auditory P3a and visual P3b conditions, and with central regions in the visual P3a condition. Patients with PPMS had significantly lower amplitude than patients with SPMS in the auditory P3b condition over the parietal area. The control group had greater amplitude than the patients with MS in all the P3 tasks, with the exception of the auditory P3b. CONCLUSIONS: These data suggest that PASAT performance and P3 ERPs correlate for MS progressive subtypes and that PPMS and SPMS differ in electrophysiological responses during auditory P3b tasks.

FASTER: Fully Automated Statistical Thresholding for EEG artifact Rejection.

Electroencephalogram (EEG) data are typically contaminated with artifacts (e.g., by eye movements). The effect of artifacts can be attenuated by deleting data with amplitudes over a certain value, for example. Independent component analysis (ICA) separates EEG data into neural activity and artifact; once identified, artifactual components can be deleted from the data. Often, artifact rejection algorithms require supervision (e.g., training using canonical artifacts). Many artifact rejection methods are time consuming when applied to high-density EEG data. We describe FASTER (Fully Automated Statistical Thresholding for EEG artifact Rejection). Parameters were estimated for various aspects of data (e.g., channel variance) in both the EEG time series and in the independent components of the EEG: outliers were detected and removed. FASTER was tested on both simulated EEG (n=47) and real EEG (n=47) data on 128-, 64-, and 32-scalp electrode arrays. FASTER was compared to supervised artifact detection by experts and to a variant of the Statistical Control for Dense Arrays of Sensors (SCADS) method. FASTER had >90% sensitivity and specificity for detection of contaminated channels, eye movement and EMG artifacts, linear trends and white noise. FASTER generally had >60% sensitivity and specificity for detection of contaminated epochs, vs. 0.15% for SCADS. FASTER also aggregates the ERP across subject datasets, and detects outlier datasets. The variance in the ERP baseline, a measure of noise, was significantly lower for FASTER than either the supervised or SCADS methods. ERP amplitude did not differ significantly between FASTER and the supervised approach.

A high-density ERP study reveals latency, amplitude, and topographical differences in multiple sclerosis patients versus controls.

OBJECTIVE: To quantify latency, amplitude and topographical differences in event-related potential (ERP) components between multiple sclerosis (MS) patients and controls and to compare ERP findings with results from the paced auditory serial addition test (PASAT). METHODS: Fifty-four subjects (17 relapsing remitting (RRMS) patients, 16 secondary progressive (SPMS) patients, and 21 controls) completed visual and auditory oddball tasks while data were recorded from 134 EEG channels. Latency and amplitude differences, calculated using composite mean amplitude measures, were tested using an ANOVA. Topographical differences were tested using statistical parametric mapping (SPM). RESULTS: In the visual modality, P2, P3 amplitudes and N2 latency were significantly different across groups. In the auditory modality, P2, N2, and P3 latencies and N1 amplitude were significantly different across groups. There were no significant differences between RRMS and SPMS patients on any ERP component. There were topographical differences between MS patients and controls for both early and late components for the visual modality, but only in the early components for the auditory modality. PASAT score correlated significantly with auditory P3 latency for MS patients. CONCLUSIONS: There were significant ERP differences between MS patients and controls. SIGNIFICANCE: The present study indicated that both early sensory and later cognitive ERP components are impaired in MS patients relative to controls.

Impaired information processing speed and attention allocation in multiple sclerosis patients versus controls: a high-density EEG study.

BACKGROUND: The no-go P3a is a variant of the P300 event-related potential (ERP) that indexes speed of information processing and attention allocation. The aim of this study was to compare ERP findings with results from the paced auditory serial addition test (PASAT) and to quantify latency, amplitude and topographical differences in P3a ERP components between multiple sclerosis (MS) patients and controls. PATIENTS AND METHODS: Seventy-four subjects (20 relapsing remitting (RRMS) patients, 20 secondary progressive (SPMS) patients and 34 controls) completed a three-stimulus oddball paradigm (target, standard, and non-target). Subjects participated in separate visual and auditory tasks while data were recorded from 134 EEG channels. Latency differences were tested using an ANCOVA. Topographical differences were tested using statistical parametric mapping. RESULTS: Visual P3a amplitude correlated with PASAT score in all MS patients over frontal and parietal areas. There were significant differences in latency, amplitude, and topography between MS patients and controls in the visual condition. RRMS and SPMS patients differed in visual P3a latency and amplitude at frontal and parietal scalp regions. In the auditory condition, there were latency differences between MS patients and controls only over the parietal region. CONCLUSION: The present results demonstrate that information processing speed and attention allocation are impaired in MS.