Tukey's Depth for Object Data.

We develop a novel exploratory tool for non-Euclidean object data based on data depth, extending celebrated Tukey's depth for Euclidean data. The proposed metric halfspace depth, applicable to data objects in a general metric space, assigns to data points depth values that characterize the centrality of these points with respect to the distribution and provides an interpretable center-outward ranking. Desirable theoretical properties that generalize standard depth properties postulated for Euclidean data are established for the metric halfspace depth. The depth median, defined as the deepest point, is shown to have high robustness as a location descriptor both in theory and in simulation. We propose an efficient algorithm to approximate the metric halfspace depth and illustrate its ability to adapt to the intrinsic data geometry. The metric halfspace depth was applied to an Alzheimer's disease study, revealing group differences in the brain connectivity, modeled as covariance matrices, for subjects in different stages of dementia. Based on phylogenetic trees of 7 pathogenic parasites, our proposed metric halfspace depth was also used to construct a meaningful consensus estimate of the evolutionary history and to identify potential outlier trees.

Uncertainty analysis of contagion processes based on a functional approach.

The spread of a disease, product or idea in a population is often hard to predict. We tend to observe one or few realizations of the contagion process and therefore limited information can be obtained for anticipating future similar events. The stochastic nature of contagion generates unpredictable outcomes throughout the whole course of the dynamics. This might lead to important inaccuracies in the predictions and to the over or under-reaction of policymakers, who tend to anticipate the average behavior. Through an extensive simulation study, we analyze properties of the contagion process, focusing on its unpredictability or uncertainty, and exploiting the functional nature of the data. In particular, we define a novel non-parametric measure of variance based on weighted depth-based central regions. We apply this methodology to the susceptible-infected-susceptible epidemiological model and small-world networks. We find that maximum uncertainty is attained at the epidemic threshold. The density of the network and the contagiousness of the process have a strong and complementary effect on the uncertainty of contagion, whereas only a mild effect of the network's randomness structure is observed.

Characteristics associated with poor atrial fibrillation-related quality of life in adults with atrial fibrillation.

PURPOSE: Few studies have examined the relationship between poor atrial fibrillation-related quality of life (AFQoL) and a battery of geriatric factors. The objective of this study is to describe factors associated with poor AFQoL in older adults with atrial fibrillation (AF) with a focus on sociodemographic and clinical factors and a battery of geriatric factors. METHODS: Cross-sectional analysis of a prospective cohort study of participants aged 65+ with high stroke risk and AF. AFQoL was measured using the validated Atrial Fibrillation Effect on Quality of Life (score 0-100) and categorized as poor (<80) or good (80-100). Chi-square and t -tests evaluated differences in factors across poor AFQoL and significant characteristics ( P  < 0.05) were entered into a logistic regression model to identify variables related to poor AFQoL. RESULTS: Of 1244 participants (mean age 75.5), 42% reported poor AFQoL. Falls in the past 6 months, pre/frail and frailty, depression, anxiety, social isolation, vision impairment, oral anticoagulant therapy, rhythm control, chronic obstructive pulmonary disease and polypharmacy were associated with higher odds of poor AFQoL. Marriage and college education were associated with a lower odds of poor AFQoL. CONCLUSIONS: More than 4 out of 10 older adults with AF reported poor AFQoL. Geriatric factors associated with higher odds of reporting poor AFQoL include recent falls, frailty, depression, anxiety, social isolation and vision impairment. Findings from this study may help clinicians screen for patients with poor AFQoL who could benefit from tailored management to ensure the delivery of patient-centered care and improved well being among older adults with AF.

Gaps in Cystic Fibrosis Care Are Associated with Reduced Lung Function in the U.S. Cystic Fibrosis Foundation Patient Registry.

Rationale: Cystic fibrosis (CF) is a genetic disease leading to progressive lung function loss and early mortality. Many clinical and demographic variables are associated with lung function decline, but little is known about the effects of prolonged periods of missed care. Objectives: To determine if missed care in the Cystic Fibrosis Foundation Patient Registry (CFFPR) is associated with decreased lung function at follow-up visits. Methods: Deidentified CFFPR data for 2004-2016 were analyzed, with the exposure of interest being ⩾12-month gap in CFFPR data. We modeled percentage predicted forced expiratory volume in 1 second using longitudinal semiparametric modeling with natural cubic splines for age (knots at quantiles) and with subject-specific random effects, adjusted for sex and CFTR (cystic fibrosis transmembrane conductance regulator) genotype, race, and ethnicity and included time-varying covariates for gaps in care, insurance type, underweight body mass index, CF-related diabetes status, and chronic infections. Results: A total of 24,328 individuals with 1,082,899 encounters in the CFFPR met inclusion criteria. In the cohort, 8,413 (35%) individuals had at least a single ⩾12-month episode of discontinuity, whereas 15,915 (65%) had continuous care. Of the encounters preceded by a 12-month gap, 75.8% occurred in patients 18 years and older. Compared with those with continuous care, those with a discontinuous care episode had a lower follow-up percentage predicted forced expiratory volume in 1 second at the index visit (-0.81%; 95% confidence interval, -1.00, -0.61) after adjustment for other variables. The magnitude of this difference was much greater (-2.1%; 95% confidence interval, -1.5, -2.7) in young adult F508del homozygotes. Conclusions: There was a high rate of ⩾12-month gap in care, especially in adults, documented in the CFFPR. Discontinuous care identified in the CFFPR was strongly associated with decreased lung function, especially in adolescents and young adults homozygous for the F508del CFTR mutation. This may have implications for identifying and treating people with lengthy gaps in care and may have implications for CFF care recommendations.

Long-term impact of COVID-19 associated acute respiratory distress syndrome.

OBJECTIVES: To determine the health status, exercise capacity, and health related quality of life (HRQoL) of COVID-19 associated acute respiratory distress syndrome (ARDS) survivors, 8 months after diagnosis. METHODS: All eligible patients were interviewed and underwent a physical examination, chest X-ray, and 6 min walk test (6MWT). Scales to evaluate post-traumatic stress disorder, depression, anxiety, and HRQoL were applied. RESULTS: Of 1295 patients, 365 suffered ARDS and 166 survived to hospital discharge. Five died after discharge and 48 were lost to follow-up. Of the 113 remaining patients, 81% had persistent symptoms. More than 50% of patients completed less than 80% of the theoretical distance on the 6MWT, 50% had an abnormal X-ray and 93% of patients developed psychiatric disorders. Mean SF-36 scores were worse than in the general population. After multivariate regression analysis, female sex, non-Caucasian race, and Charlson index>2 were independent risk factors for a worse mental health component summary score on the SF-36, and age was associated with a better prognosis. Female sex and chronic obstructive pulmonary disease were independently associated with a worse physical component summary score. CONCLUSION: COVID-19 associated ARDS survivors have long-term consequences in health status, exercise capacity, and HRQoL. Strategies addressed to prevent these sequelae are needed.

Standardized Semistructured Psychosocial Evaluation Before Stem Cell Transplantation Predicts Delirium After Transplant.

BACKGROUND: Delirium affects many patients undergoing stem cell transplantation (SCT). Delirium is treatable, but prevention is a better goal, making it desirable to identify patients at heightened risk for delirium. A standardized pretransplant psychosocial assessment rating scale, the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT), has been demonstrated to predict outcomes in solid organ transplant recipients and nonadherence in patients with SCT. OBJECTIVES: In this study, we aimed to evaluate the association of SIPAT score and post-SCT incident delirium. METHODS: We retrospectively reviewed records of SCT recipients who had SIPAT evaluations before SCT, for indications of delirium in the 6 months after transplant. We tested the association between SIPAT score and delirium by logistic regression, controlling for relevant covariates such as transplant type (allogeneic vs autologous). RESULTS: Of 85 patients (median age of 49 years, range 18-74), 56 (66%) were men, and 43 (50.5%) were autologous SCT recipients. The median pretransplant SIPAT score was 8, range 0-40. There were 15 cases (17.6%) of delirium in the 6 months following transplant.  In univariate analyses, transplant type was significantly associated with incident delirium. In multivariate analyses, SIPAT score was significantly associated with incident delirium (odds ratio, 1.090; P = 0.021). CONCLUSIONS: Psychosocial risk as quantified by the SIPAT is associated with development of delirium in SCT recipients. This scale can therefore be integrated into medical risk models to anticipate which patients are at higher risk for delirium in their hospital course, enabling preventative measures tailored to the needs of the individual patient.

A depth-based global envelope test for comparing two groups of functions with applications to biomedical data.

Functional data are commonly observed in many emerging biomedical fields and their analysis is an exciting developing area in statistics. Numerous statistical methods, such as principal components, analysis of variance, and linear regression, have been extended to functional data. The statistical analysis of functions can be significantly improved using nonparametric and robust estimators. New ideas of depth for functional data have been proposed in recent years and can be extended to image data. They provide a way of ordering curves or images from center-outward, and of defining robust order statistics in a functional context. In this paper we develop depth-based global envelope tests for comparing two groups of functions or images. In addition to providing global P-values, the proposed envelope test can be displayed graphically and indicates the specific portion(s) of the functional data (eg, in pixels or in time) that may have led to rejection of the null hypothesis. We show in a simulation study the performance of the envelope test in terms of empirical power and size in different scenarios. The proposed depth-based global approach has good power even for small differences and is robust to outliers. The methodology introduced is applied to test whether children with normal and low birth weight have similar growth pattern. We also analyzed a brain image dataset consisting of positron emission tomography scans of severe depressed patients and healthy controls. The global envelope test was used to find and visualize differences between the two groups.

Standardized Semi-structured Psychosocial Evaluation before Hematopoietic Stem Cell Transplantation Predicts Patient Adherence to Post-Transplant Regimen.

In patients undergoing stem cell transplantation (SCT), nonadherence has potential for significant medical impact and potentially life-threatening complications. No study thus far has demonstrated an effective way to predict adherence in SCT recipients. A structured rating scale, the Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT), has been shown to predict psychosocial outcomes and medical morbidity in solid organ transplant recipients. We assessed the SIPAT in SCT recipients. We hypothesized that the SIPAT rating would be associated with nonadherence to the post-SCT regimen. We retrospectively studied SCT recipients who had psychiatric evaluations with the SIPAT before SCT. The primary outcome was nonadherence, defined a priori as at least 1 life-threatening nonadherence event in the first 6 months post-transplant. Association of the SIPAT with outcomes was evaluated by logistic regression, and an optimal cutoff score was determined using a receiver operating characteristic curve. Of 85 patients (mean age 47 years; range, 18 to 74 years), 56 (66%) were male, and 43 (50.5%) received autologous SCT. Eighteen (21%) patients were nonadherent. The SIPAT rating, treated as a continuous variable and controlling for autologous versus allogeneic SCT, was significantly associated with nonadherence (per 1 point; odds ratio [OR], 1.162; P< .0001). Allogeneic SCT also conferred a significantly increased risk of nonadherence (OR, 14.184; P= .005). Multivariate analysis stratifying for allogeneic versus autologous transplantation and controlling for age, sex, and disease confirmed an independent association between the SIPAT score and nonadherence. A cutoff score of 18 provided optimal specificity (89.6%) and sensitivity (55.6%) for nonadherence. Nonadherence rates were 58.8% and 11.8% for subjects with SIPAT ratings of 18 and above or 17 and below, respectively (relative risk = 4.98, P < .0001). Psychosocial risk as quantified by the SIPAT correlated with SCT recipients' adherence to the post-transplant regimen, suggesting that this instrument can contribute to medical risk stratification models. Further study should evaluate long-term mortality data and the effects of intervention on psychosocial risks.

Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle.

Patients with metastatic cancer experience a severe loss of skeletal muscle mass and function known as cachexia. Cachexia is associated with poor prognosis and accelerated death in patients with cancer, yet its underlying mechanisms remain poorly understood. Here, we identify the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14) as a critical mediator of cancer-induced cachexia. ZIP14 is upregulated in cachectic muscles of mice and in patients with metastatic cancer and can be induced by TNF-α and TGF-ß cytokines. Strikingly, germline ablation or muscle-specific depletion of Zip14 markedly reduces muscle atrophy in metastatic cancer models. We find that ZIP14-mediated zinc uptake in muscle progenitor cells represses the expression of MyoD and Mef2c and blocks muscle-cell differentiation. Importantly, ZIP14-mediated zinc accumulation in differentiated muscle cells induces myosin heavy chain loss. These results highlight a previously unrecognized role for altered zinc homeostasis in metastatic cancer-induced muscle wasting and implicate ZIP14 as a therapeutic target for its treatment.

Salt Taste Recognition in a Heart Failure Cohort.

BACKGROUND: Heart failure (HF) disproportionately affects older adults. Dietary sodium indiscretion is frequently implicated in HF decompensation. The affinity for and ability to taste salt in this process is unexplored. We sought to evaluate differences in salt taste by age and HF diagnosis and to map changes after hospitalization for acute decompensated heart failure (ADHF). METHODS: Seventy-two subjects underwent initial salt-taste testing during hospitalization for ADHF. Follow-up taste testing occurred at discharge and 1, 4, and 12 weeks after hospitalization. Three different groups were included as control subjects and underwent 1-time salt-taste testing: 10 patients with stable HF, 10 healthy older adults, and 10 healthy younger adults. Salt-taste testing was completed with the use of commercially available and validated Salsave test strips with increasing concentrations of NaCl (0.6-1.6 mg/cm2) to identify salt taste recognition threshold. Respectively, 2-sample t tests, multiple regression, and linear mixed-effects modeling were used for intergroup comparisons, to adjust for confounders, and to assess the effect of time after discharge from ADHF hospitalization. RESULTS: The baseline salt taste recognition threshold was lowest in the young healthy control group (0.62 [SD 0.05] mg/cm2 NaCl) compared with the healthy older control subjects (0.92 [SD 0.29] mg/cm2 NaCl), stable HF outpatients, (1.06 [SD 0.22] mg/cm2 NaCl), and ADHF subjects on admission (1.06 [SD 0.48] mg/cm2 NaCl). There was a strong trend toward higher recognition threshold in HF patients (P = .051) that was independent from age and other potential confounders. Serial salt-taste testing in the ADHF group demonstrated a decrease in recognition threshold that persisted over the 12 weeks after discharge (1.04 [SD 0.44] to 0.76 [SD 0.22] mg/cm2 NaCl; P = .003). DISCUSSION: When compared with young healthy control subjects, HF patients have impaired recognition of salt taste. The salt taste recognition threshold decreases after hospitalization for ADHF. This change demonstrates the first evidence of the phenomenon known as the "hedonic shift" in HF, in which the threshold to recognize salt taste decreases after prescribed sodium restriction.

Continuous positive airway pressure for children with undifferentiated respiratory distress in Ghana: an open-label, cluster, crossover trial.

BACKGROUND: In low-income and middle-income countries, invasive mechanical ventilation is often not available for children at risk of death from respiratory failure. We aimed to determine if continuous positive airway pressure (CPAP), a form of non-invasive ventilation, decreases all-cause mortality in children with undifferentiated respiratory distress in Ghana. METHODS: This open-label, cluster, crossover trial was done in two Ghanaian non-tertiary hospitals where invasive mechanical ventilation is not routinely available. Eligible participants were children aged from 1 month to 5 years with a respiratory rate of more than 50 breaths per min in children 1-12 months old, or more than 40 breaths per min in children older than 12 months, and use of accessory muscles or nasal flaring. CPAP machines were allocated to one hospital during each study block, while the other hospital served as the control site. The initial intervention site was randomly chosen using a coin toss. 5 cm of water pressure was delivered via CPAP nasal prongs. The primary outcome measure was all-cause mortality rate at 2 weeks after enrolment in patients for whom data were available after 2 weeks. We also did post-hoc regression analysis and subgroup analysis of children by malaria status, oxygen saturation, and age. This study is registered with ClinicalTrials.gov, number NCT01839474. FINDINGS: Between Jan 20, 2014, and Dec 5, 2015, 2200 children were enrolled: 1025 at the intervention site and 1175 at the control site. Final analysis included 1021 patients in the CPAP group and 1160 patients in the control group. 2 weeks after enrolment, 26 (3%) of 1021 patients in the CPAP group, and 44 (4%) of 1160 patients in the control group, had died (relative risk [RR] of mortality 0·67, 95% CI 0·42-1·08; p=0·11). In children younger than 1 year, all-cause mortality was ten (3%) of 374 patients in the CPAP group, and 24 (7%) of 359 patients in the control group (RR 0·40, 0·19-0·82; p=0·01). After adjustment for study site, time, and clinically important variables, the odds ratio for 2-week mortality in the CPAP group versus the control group was 0·4 in children aged up to 6 months, 0·5 for children aged 12 months, 0·7 for children aged 24 months, and 1·0 for those aged 36 months. 28 patients (3%) in the CPAP group and 24 patients (2%) in the control group had CPAP-related adverse events, such as vomiting, aspiration, and nasal, skin, or eye trauma. No serious adverse events were observed. INTERPRETATION: In the unadjusted analysis the use of CPAP did not decrease all-cause 2-week mortality in children 1 month to 5 years of age with undifferentiated respiratory distress. After adjustment for study site, time, and clinically important variables, 2-week mortality in the CPAP group versus the control group was significantly decreased in children 1 year of age and younger. CPAP is safe and improves respiratory rate in a non-tertiary setting in a lower-middle-income country. FUNDING: General Electric Foundation.

Can diffusion-weighted imaging serve as a biomarker of fibrosis in pancreatic adenocarcinoma?

PURPOSE: To assess the relationship between diffusion-weighted imaging (DWI) and intravoxel incoherent motion (IVIM)-derived quantitative parameters (apparent diffusion coefficient [ADC], perfusion fraction [f], Dslow , diffusion coefficient [D], and Dfast , pseudodiffusion coefficient [D*]) and histopathology in pancreatic adenocarcinoma (PAC). MATERIALS AND METHODS: Subjects with suspected surgically resectable PAC were prospectively enrolled in this Health Insurance Portability and Accountability Act (HIPAA)-compliant, Institutional Review Board-approved study. Imaging was performed at 1.5T with a respiratory-triggered echo planar DWI sequence using 10 b values. Two readers drew regions of interest (ROIs) over the tumor and adjacent nontumoral tissue. Monoexponential and biexponential fits were used to derive ADC2b , ADCall , f, D, and D*, which were compared to quantitative histopathology of fibrosis, mean vascular density, and cellularity. Two biexponential IVIM models were investigated and compared: 1) nonlinear least-square fitting based on the Levenberg-Marquardt algorithm, and 2) linear fit using a fixed D* (20 mm2 /s). Statistical analysis included Student's t-test, Pearson correlation (P < 0.05 was considered significant), intraclass correlation, and coefficients of variance. RESULTS: Twenty subjects with PAC were included in the final cohort. Negative correlation between D and fibrosis (Reader 2: r = -0.57 P = 0.01; pooled P = -0.46, P = 0.04) was observed with a trend toward positive correlation between f and fibrosis (r = 0.44, P = 0.05). ADC2b was significantly lower in PAC with dense fibrosis than with loose fibrosis ADC2b (P = 0.03). Inter- and intrareader agreement was excellent for ADC, D, and f. CONCLUSION: In PAC, D negatively correlates with fibrosis, with a trend toward positive correlation with f suggesting both perfusion and diffusion effects contribute to stromal desmoplasia. ADC2b is significantly lower in tumors with dense fibrosis and may serve as a biomarker of fibrosis architecture. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:393-402.

Monitoring Metastasis and Cachexia in a Patient with Breast Cancer: A Case Study.

Cachexia, a wasting syndrome associated with advanced cancer and metastasis, is rarely documented in breast cancer patients. However, the incidence of cachexia in breast cancer is now thought to be largely underestimated. In our case report of a breast cancer patient with bone metastasis monitored during the course of her treatment, we document the development of cachexia by image analysis in relation to her metastatic burden. Elucidation of the link between metastatic burden and cachexia could unveil a highly specific screening process for metastasis, by assessing true muscle mass loss. Our patient was a 49-year-old premenopausal woman, with metastatic invasive ductal breast carcinoma in the vertebral and iliac bones on presentation, which progressed with new metastases to her hips, thigh bones, and vertebrae. In the two-year period, that is between her diagnosis and death, she lost >10% of her baseline weight. During these two years, we retrospectively identified a decrease in paraspinal muscle (PM) at the third lumbar vertebra followed by a sharp decline in weight. The increased tumor burden over time in metastatic sites was accompanied by a decrease in abdominal muscle and visceral and subcutaneous fat and was followed by the patient's demise. The increasing tumor burden in the patient was correlated with the mass of other tissues to determine the tissue that could best serve as a surrogate marker to cachexia and tumor burden. We noted a strong negative correlation between PM area and metastatic tumor area at the third lumbar vertebral level, with PM loss correlating to increasing tumor burden. The monitoring of PM wasting may serve as a marker, and therefore a prognostic factor, for both cachexia and extent of metastatic disease, especially in breast cancer, where metastasis to bone is frequent. Based on our data and review of the literature in this case study, longitudinal monitoring of cachexia in the selected muscle groups can give clinicians early indications of the extent of cachexia in metastatic breast cancer patients.

Serial high sensitivity cardiac troponin T measurement in acute heart failure: insights from the RELAX-AHF study.

AIMS: Troponin elevation is common in acute heart failure (AHF) and may be useful for prognostication; however, available data are mixed and many previous studies used older, less sensitive assays. We examined the association between serial measurements of high-sensitivity cardiac troponin T (hs-cTnT) and outcomes in RELAX-AHF. METHODS AND RESULTS: Hs-cTnT was measured at baseline and days 2, 5, and 14. We assessed the relationship between baseline, peak and peak change hs-cTnT with dyspnoea relief by visual analogue scale, cardiovascular death, or HF/renal hospitalization to 60 days and cardiovascular mortality to 180 days. Models were adjusted for clinical variables and treatment assignment. Whether baseline troponin status affected the treatment effect of serelaxin was assessed using interactions terms. In 1074 patients, the median baseline troponin was 0.033 µg/L, and 90% of patients were above the 99th upper reference limit (URL). Patients with hs-cTnT >median were more likely to be men with ischaemic heart disease, worse renal function, and higher N-terminal pro-brain natriuretic peptide. Higher baseline or peak hs-cTnT and greater peak change were associated with worse outcomes independent of adjustment for covariates, but relationships were generally strongest for 180-day cardiovascular mortality (hazard ratio per doubling of baseline hs-cTnT = 1.36, 95% confidence interval 1.15-1.60). Troponin was most strongly associated with death from heart failure or from other cardiovascular causes. The treatment effect of serelaxin did not differ by baseline troponin levels. CONCLUSION: Hs-cTnT was elevated above the 99% URL in the majority of AHF patients. Baseline, peak, and peak change hs-cTnT were associated with worse outcomes, with the strongest relationship with 180-day cardiovascular mortality.

Multimodal Imaging of Central Retinal Disease Progression in a 2-Year Mean Follow-up of Retinitis Pigmentosa.

PURPOSE: To determine the rate of progression and optimal follow-up time in patients with advanced-stage retinitis pigmentosa (RP) comparing the use of fundus autofluorescence imaging and spectral-domain optical coherence tomography. DESIGN: Retrospective analysis of progression rate. METHODS: Longitudinal imaging follow-up in 71 patients with retinitis pigmentosa was studied using the main outcome measurements of hyperautofluoresent ring horizontal diameter and vertical diameter along with ellipsoid zone line width from spectral-domain optical coherence tomography. Test-retest reliability and the rate of progression were calculated. The interaction between the progression rates was tested for sex, age, mode of inheritance, and baseline measurement size. Symmetry of left and right eye progression rate was also tested. RESULTS: Significant progression was observed in >75% of patients during the 2-year mean follow-up. The mean annual progression rates of ellipsoid zone line and hyperautofluorescent ring horizontal diameter and vertical diameter were 0.45 degree (4.9%), 0.51 degree (4.1%), and 0.42 degree (4.0%), respectively. The ellipsoid zone line width and hyperautofluorescent ring horizontal diameter and vertical diameter had low test-retest variabilities of 8.9%, 9.5%, and 9.6%, respectively. This study is the first to demonstrate asymmetrical structural progression rate between right and left eye, which was found in 19% of patients. The rate of progression was significantly slower as the disease approached the fovea, supporting the theory that RP progresses in an exponential fashion. No significant interaction between progression rate and patient age, sex, or mode of inheritance was observed. CONCLUSIONS: Fundus autofluorescence and optical coherence tomography detect progression in patients with RP reliably and with strong correlation. These parameters may be useful alongside functional assessments as the outcome measurements for future therapeutic trials. Follow-up at 1-year intervals should be adequate to efficiently detect progression.

Ambulatory assessments of psychological and peripheral stress-markers predict birth outcomes in teen pregnancy.

OBJECTIVE: Pregnant adolescents have high rates of poor birth outcomes, but the causes are unclear. We present a prospective, longitudinal study of pregnant adolescents assessing associations between maternal psychobiological stress indices and offspring gestational age at birth and birthweight. METHOD: Healthy nulliparous pregnant adolescents were recruited (n=205) and followed during pregnancy. Ambulatory assessments over 24h of perceived psychological stress (collected every 30 min) and salivary cortisol (6 samples) and a summary questionnaire, the Perceived Stress Scale, were collected at three time points (13-16, 24-27, and 34-37 gestational weeks). Corticotropin-releasing hormone, C-reactive protein, and interleukin 6 were assayed from blood taken at the latter 2 sessions. A final sample of 119 participants was selected for analyses. RESULTS: The ambulatory assessment of perceived psychological stress was positively correlated with the Perceived Stress Scale (r=.20, p=.03) but neither was associated with any of the biological assays (all ps>.20). Based on backward selection regression models that included all stress variables and relevant covariates, the ambulatory assessments of perceived psychological stress and cortisol - though not the Perceived Stress Scale - were negatively associated with gestational age at birth (F(4, 107)=3.38, p=.01) while cortisol was negatively related to birthweight (F(5, 107)=14.83, p<.0001). CONCLUSIONS: Targeted interventions to reduce psychological and biological indicators of heightened stress during pregnancy may have positive public health benefits for the offspring given the associations of shortened gestation and lower birthweight with risk for poor mental and physical health outcomes.

Fast and persistent electrocatalytic water oxidation by Co-Fe Prussian blue coordination polymers.

The lack of an efficient, robust, and inexpensive water oxidation catalyst (WOC) is arguably the biggest challenge for the technological development of artificial photosynthesis devices. Here we report the catalytic activity found in a cobalt hexacyanoferrate (CoHCF) Prussian blue-type coordination polymer. This material is competitive with state-of-the-art metal oxides and exhibits an unparalleled long-term stability at neutral pH and ambient conditions, maintaining constant catalytic rates for weeks. In addition to its remarkable catalytic activity, CoHCF adds the typical properties of molecule-based materials: transparency to visible light, porosity, flexibility, processability, and low density. Such features make CoHCF a promising WOC candidate for advancement in solar fuels production.

DepthTools: an R package for a robust analysis of gene expression data.

BACKGROUND: The use of DNA microarrays and oligonucleotide chips of high density in modern biomedical research provides complex, high dimensional data which have been proven to convey crucial information about gene expression levels and to play an important role in disease diagnosis. Therefore, there is a need for developing new, robust statistical techniques to analyze these data. RESULTS: depthTools is an R package for a robust statistical analysis of gene expression data, based on an efficient implementation of a feasible notion of depth, the Modified Band Depth. This software includes several visualization and inference tools successfully applied to high dimensional gene expression data. A user-friendly interface is also provided via an R-commander plugin. CONCLUSION: We illustrate the utility of the depthTools package, that could be used, for instance, to achieve a better understanding of genome-level variation between tumors and to facilitate the development of personalized treatments.

Recovering gradients from sparsely observed functional data.

The recovery of gradients of sparsely observed functional data is a challenging ill-posed inverse problem. Given observations of smooth curves (e.g., growth curves) at isolated time points, the aim is to provide estimates of the underlying gradients (or growth velocities). To address this problem, we develop a Bayesian inversion approach that models the gradient in the gaps between the observation times by a tied-down Brownian motion, conditionally on its values at the observation times. The posterior mean and covariance kernel of the growth velocities are then found to have explicit and computationally tractable representations in terms of quadratic splines. The hyperparameters in the prior are specified via nonparametric empirical Bayes, with the prior precision matrix at the observation times estimated by constrained ℓ1 minimization. The infinitessimal variance of the Brownian motion prior is selected by cross-validation. The approach is illustrated using both simulated and real data examples.