Tree rings reveal the transient risk of extinction hidden inside climate envelope forecasts.

Given the importance of climate in shaping species' geographic distributions, climate change poses an existential threat to biodiversity. Climate envelope modeling, the predominant approach used to quantify this threat, presumes that individuals in populations respond to climate variability and change according to species-level responses inferred from spatial occurrence data-such that individuals at the cool edge of a species' distribution should benefit from warming (the "leading edge"), whereas individuals at the warm edge should suffer (the "trailing edge"). Using 1,558 tree-ring time series of an aridland pine (Pinus edulis) collected at 977 locations across the species' distribution, we found that trees everywhere grow less in warmer-than-average and drier-than-average years. Ubiquitous negative temperature sensitivity indicates that individuals across the entire distribution should suffer with warming-the entire distribution is a trailing edge. Species-level responses to spatial climate variation are opposite in sign to individual-scale responses to time-varying climate for approximately half the species' distribution with respect to temperature and the majority of the species' distribution with respect to precipitation. These findings, added to evidence from the literature for scale-dependent climate responses in hundreds of species, suggest that correlative, equilibrium-based range forecasts may fail to accurately represent how individuals in populations will be impacted by changing climate. A scale-dependent view of the impact of climate change on biodiversity highlights the transient risk of extinction hidden inside climate envelope forecasts and the importance of evolution in rescuing species from extinction whenever local climate variability and change exceeds individual-scale climate tolerances.

A species' response to spatial climatic variation does not predict its response to climate change.

The dominant paradigm for assessing ecological responses to climate change assumes that future states of individuals and populations can be predicted by current, species-wide performance variation across spatial climatic gradients. However, if the fates of ecological systems are better predicted by past responses to in situ climatic variation through time, this current analytical paradigm may be severely misleading. Empirically testing whether spatial or temporal climate responses better predict how species respond to climate change has been elusive, largely due to restrictive data requirements. Here, we leverage a newly collected network of ponderosa pine tree-ring time series to test whether statistically inferred responses to spatial versus temporal climatic variation better predict how trees have responded to recent climate change. When compared to observed tree growth responses to climate change since 1980, predictions derived from spatial climatic variation were wrong in both magnitude and direction. This was not the case for predictions derived from climatic variation through time, which were able to replicate observed responses well. Future climate scenarios through the end of the 21st century exacerbated these disparities. These results suggest that the currently dominant paradigm of forecasting the ecological impacts of climate change based on spatial climatic variation may be severely misleading over decadal to centennial timescales.

Adding Tree Rings to North America's National Forest Inventories: An Essential Tool to Guide Drawdown of Atmospheric CO2.

Tree-ring time series provide long-term, annually resolved information on the growth of trees. When sampled in a systematic context, tree-ring data can be scaled to estimate the forest carbon capture and storage of landscapes, biomes, and-ultimately-the globe. A systematic effort to sample tree rings in national forest inventories would yield unprecedented temporal and spatial resolution of forest carbon dynamics and help resolve key scientific uncertainties, which we highlight in terms of evidence for forest greening (enhanced growth) versus browning (reduced growth, increased mortality). We describe jump-starting a tree-ring collection across the continent of North America, given the commitments of Canada, the United States, and Mexico to visit forest inventory plots, along with existing legacy collections. Failing to do so would be a missed opportunity to help chart an evidence-based path toward meeting national commitments to reduce net greenhouse gas emissions, urgently needed for climate stabilization and repair.

Ecological forecasting of tree growth: Regional fusion of tree-ring and forest inventory data to quantify drivers and characterize uncertainty.

Robust ecological forecasting of tree growth under future climate conditions is critical to anticipate future forest carbon storage and flux. Here, we apply three ingredients of ecological forecasting that are key to improving forecast skill: data fusion, confronting model predictions with new data, and partitioning forecast uncertainty. Specifically, we present the first fusion of tree-ring and forest inventory data within a Bayesian state-space model at a multi-site, regional scale, focusing on Pinus ponderosa var. brachyptera in the southwestern US. Leveraging the complementarity of these two data sources, we parsed the ecological complexity of tree growth into the effects of climate, tree size, stand density, site quality, and their interactions, and quantified uncertainties associated with these effects. New measurements of trees, an ongoing process in forest inventories, were used to confront forecasts of tree diameter with observations, and evaluate alternative tree growth models. We forecasted tree diameter and increment in response to an ensemble of climate change projections, and separated forecast uncertainty into four different causes: initial conditions, parameters, climate drivers, and process error. We found a strong negative effect of fall-spring maximum temperature, and a positive effect of water-year precipitation on tree growth. Furthermore, tree vulnerability to climate stress increases with greater competition, with tree size, and at poor sites. Under future climate scenarios, we forecast increment declines of 22%-117%, while the combined effect of climate and size-related trends results in a 56%-91% decline. Partitioning of forecast uncertainty showed that diameter forecast uncertainty is primarily caused by parameter and initial conditions uncertainty, but increment forecast uncertainty is mostly caused by process error and climate driver uncertainty. This fusion of tree-ring and forest inventory data lays the foundation for robust ecological forecasting of aboveground biomass and carbon accounting at tree, plot, and regional scales, including iterative improvement of model skill.

Climate-driven, but dynamic and complex? A reconciliation of competing hypotheses for species' distributions.

Estimates of the percentage of species "committed to extinction" by climate change range from 15% to 37%. The question is whether factors other than climate need to be included in models predicting species' range change. We created demographic range models that include climate vs. climate-plus-competition, evaluating their influence on the geographic distribution of Pinus edulis, a pine endemic to the semiarid southwestern U.S. Analyses of data on 23,426 trees in 1941 forest inventory plots support the inclusion of competition in range models. However, climate and competition together only partially explain this species' distribution. Instead, the evidence suggests that climate affects other range-limiting processes, including landscape-scale, spatial processes such as disturbances and antagonistic biotic interactions. Complex effects of climate on species distributions-through indirect effects, interactions, and feedbacks-are likely to cause sudden changes in abundance and distribution that are not predictable from a climate-only perspective.

Preterm Birth Is Associated With Immune Dysregulation Which Persists in Infants Exposed to Histologic Chorioamnionitis.

Introduction: Preterm infants are at increased risk of exposure to histologic chorioamnionitis (HCA) when compared to term-born controls, and this is associated with several neonatal morbidities involving brain, lungs and gut. Preterm infants could benefit from immunomodulatory therapies in the perinatal period, but development of rational treatment strategies requires improved characterization of the perinatal response to HCA. We had two objectives: The first, to characterize the umbilical cord blood immune profile in preterm infants compared to term-born controls; the second, to investigate the postnatal immune response in preterm infants exposed to HCA versus those who were not. Population: For objective one 59 term infants [mean gestational age (GA) 39+4 (37+3 to 42+0)] and 55 preterm infants [mean GA29+0(23+3 to 32+0)] with umbilical cord samples available were included; for objective two we studied 96 preterm infants [mean GA29+1(23+2 to 32+0)] for whom placental histology and postnatal blood samples were available. Methods: Placental histopathology was used to identify reaction patterns indicative of HCA, and a customized immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group. Results: The umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242x10-14. Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 8 immune proteins on postnatal day 5 (BDNF, C3, C5a, C9, IL-8, MCP-1, MIP-1ß and MMP-9) when compared to preterm infants who were not exposed. Conclusion: Preterm birth is associated with a distinct immune profile in umbilical cord blood and preterm infants exposed to HCA with evidence of a fetal inflammatory response have specific alterations in immune function that are apparent on day 5 of postnatal life.

Perinatal determinants of neonatal hair glucocorticoid concentrations.

Adult hair glucocorticoid concentrations reflect months of hypothalamic-pituitary-adrenal axis activity. However, little is known about the determinants of neonatal hair glucocorticoids. We tested associations between perinatal exposures and neonatal hair glucocorticoids. Cortisol and cortisone were measured by LC-MS/MS in paired maternal and infant hair samples collected within 10 days of birth (n = 49 term, n = 47 preterm), with neonatal samples collected at 6-weeks in n = 54 preterm infants. We demonstrate cortisol accumulation in hair increases with fetal maturity, with hair cortisol being higher in term than preterm born infants after delivery (median 401 vs 106 pg/mg; p < 0.001). In term born infants, neonatal hair cortisol is positively associated with maternal hair cortisol concentration (ß = 0.240, p = 0.045) and negatively associated with birthweight z-score (ß = -0.340, p = 0.006). Additionally, being born without maternal labour is associated with lower hair cortisol concentrations (ß = -0.489, p < 0.001) and a lower ratio of cortisol to cortisone (ß = -0.484, p = 0.001). In preterm infants, histological chorioamnionitis is associated with a higher cortisol to cortisone ratio in hair (ß = 0.459, p = 0.001). In samples collected 6 weeks after preterm birth, hair cortisol concentration is associated with cortisol hair concentrations measured after birth (ß = 0.523, p < 0.001), chorioamnionitis (ß = 0.250, p = 0.049) and postnatal exposures including intravenous hydrocortisone therapy (ß = 0.343, p < 0.007) and neonatal sepsis (ß = 0.290, p = 0.017). In summary, neonatal hair cortisol is associated with birth gestation, maternal hair cortisol concentration and fetal growth. Additionally, exposures at delivery are important determinants of hair cortisol, and should be considered in the design of future research investigating how neonatal hair cortisol relates to prenatal exposures or fetal development.

Interleukin-8 dysregulation is implicated in brain dysmaturation following preterm birth.

BACKGROUND: Preterm birth is associated with dysconnectivity of structural brain networks, impaired cognition and psychiatric disease. Systemic inflammation contributes to cerebral dysconnectivity, but the immune mediators driving this association are poorly understood. We analysed information from placenta, umbilical cord and neonatal blood, and brain MRI to determine which immune mediators link perinatal systemic inflammation with dysconnectivity of structural brain networks. METHODS: Participants were 102 preterm infants (mean gestational age 29+1 weeks, range 23+3-32+0). Placental histopathology identified reaction patterns indicative of histologic chorioamnionitis (HCA), and a customized immunoassay of 24 inflammation-associated proteins selected to reflect the neonatal innate and adaptive immune response was performed from umbilical cord (n = 55) and postnatal day 5 blood samples (n = 71). Brain MRI scans were acquired at term-equivalent age (41+0 weeks [range 38+0-44+4 weeks]) and alterations in white matter connectivity were inferred from mean diffusivity and neurite density index across the white matter skeleton. RESULTS: HCA was associated with elevated concentrations of C5a, C9, CRP, IL-1ß, IL-6, IL-8 and MCP-1 in cord blood, and IL-8 concentration predicted HCA with an area under the receiver operator curve of 0.917 (95% CI 0.841 - 0.993, p < 0.001). Fourteen analytes explained 66% of the variance in the postnatal profile (BDNF, C3, C5a, C9, CRP, IL-1ß, IL-6, IL-8, IL-18, MCP-1, MIP-1ß, MMP-9, RANTES and TNF-α). Of these, IL-8 was associated with altered neurite density index across the white matter skeleton after adjustment for gestational age at birth and at scan (ß = 0.221, p = 0.037). CONCLUSIONS: These findings suggest that IL-8 dysregulation has a role in linking perinatal systemic inflammation and atypical white matter development in preterm infants.

Statistical age determination of tree rings.

Dendrochronology, the study of annual rings formed by trees and woody plants, has important applications in research of climate and environmental phenomena of the past. Since its inception in the late 19th century, dendrochronology has not had a way to quantify uncertainty about the years assigned to each ring (dating). There are, however, many woody species and sites where it is difficult or impossible to delimit annual ring boundaries and verify them with crossdating, especially in the lowland tropics. Rather than ignoring dating uncertainty or discarding such samples as useless, we present for the first time a probabilistic approach to assign expected ages with a confidence interval. It is proven that the cumulative age in a tree-ring time series advances by an amount equal to the probability that a putative growth boundary is truly annual. Confidence curves for the tree stem radius as a function of uncertain ages are determined. A sensitivity analysis shows the effect of uncertainty of the probability that a recognizable boundary is annual, as well as of the number of expected missing boundaries. Furthermore, we derive a probabilistic version of the mean sensitivity of a dendrochronological time series, which quantifies a tree's sensitivity to environmental variation over time, as well as probabilistic versions of the autocorrelation and process standard deviation. A computer code in Mathematica is provided, with sample input files, as supporting information. Further research is necessary to analyze frequency patterns of false and missing boundaries for different species and sites.

Continental-scale tree-ring-based projection of Douglas-fir growth: Testing the limits of space-for-time substitution.

A central challenge in global change research is the projection of the future behavior of a system based upon past observations. Tree-ring data have been used increasingly over the last decade to project tree growth and forest ecosystem vulnerability under future climate conditions. But how can the response of tree growth to past climate variation predict the future, when the future does not look like the past? Space-for-time substitution (SFTS) is one way to overcome the problem of extrapolation: the response at a given location in a warmer future is assumed to follow the response at a warmer location today. Here we evaluated an SFTS approach to projecting future growth of Douglas-fir (Pseudotsuga menziesii), a species that occupies an exceptionally large environmental space in North America. We fit a hierarchical mixed-effects model to capture ring-width variability in response to spatial and temporal variation in climate. We found opposing gradients for productivity and climate sensitivity with highest growth rates and weakest response to interannual climate variation in the mesic coastal part of Douglas-fir's range; narrower rings and stronger climate sensitivity occurred across the semi-arid interior. Ring-width response to spatial versus temporal temperature variation was opposite in sign, suggesting that spatial variation in productivity, caused by local adaptation and other slow processes, cannot be used to anticipate changes in productivity caused by rapid climate change. We thus substituted only climate sensitivities when projecting future tree growth. Growth declines were projected across much of Douglas-fir's distribution, with largest relative decreases in the semiarid U.S. Interior West and smallest in the mesic Pacific Northwest. We further highlight the strengths of mixed-effects modeling for reviving a conceptual cornerstone of dendroecology, Cook's 1987 aggregate growth model, and the great potential to use tree-ring networks and results as a calibration target for next-generation vegetation models.

Impact of sociodemographic and clinical factors on offer and parental consent to postmortem following stillbirth or neonatal death: a UK population-based cohort study.

OBJECTIVE: To identify factors associated with the offer of and consent to perinatal post-mortem. DESIGN: National population-based cohort study SETTING: The UK. POPULATION: 26 578 perinatal deaths born between 1 January 2013 and 31 December 2017. MAIN OUTCOME MEASURES: Postmortem offer by clinical staff; parental consent to post-mortem. RESULTS: Postmortem offer rates were high but varied significantly with time of death from 97.8% for antepartum deaths to 88.4% for neonatal deaths following neonatal admission. Offer rates did not significantly vary by gestation, year of birth, mother's socioeconomic deprivation, ethnicity or age. Only 44.5% of parents consented to a postmortem. Mothers from the most deprived areas were less likely to consent than those from the least deprived areas (relative risk (RR)=0.76, 95% CI 0.71 to 0.80). Consent rates were similar for mothers of white, mixed, Asian Indian, black Caribbean and black African ethnicity (43%-47%), but significantly lower for mothers of Asian Pakistani (20%) and Asian Bangladeshi (18%) ethnicity. Consent increased with increasing gestation (p<0.001) and was lower for deaths following neonatal unit admission than for antepartum death (RR 0.71, 95% CI 0.67 to 0.75). CONCLUSIONS: The current profile of cause of perinatal deaths in the UK is likely to be biased with less postmortem information available for babies dying in the neonatal period and those born to mothers from deprived areas and of Asian Pakistani or Asian Bangladeshi ethnicity. Such bias severely limits the design of effective strategies for reducing mortality in these high-risk groups. These findings have implications for high-income countries seeking to explore and improve the understanding of perinatal deaths.

Non-typeable Haemophilus influenzae-associated early pregnancy loss: an emerging neonatal and maternal pathogen.

OBJECTIVES: There is increasing evidence indicating an association between invasive non-typeable Haemophilus influenzae (NTHi) infection in pregnancy and early pregnancy loss. As the diagnosis relies on microbiological investigation of post-mortem placental and foetal samples, a significant proportion of NTHi-related pregnancy loss remains unrecognised. To better characterise NTHi in septic abortion, we report NTHi cases associated with early pregnancy loss. METHODS: We reviewed all post-mortems at <24 weeks gestation with histologically proven acute chorioamnionitis on placental histology and enrolled cases with at least one matched foetal and placental sample culture positive for NTHi. The study was approved by the NHS Lothian Caldicott Guardian. RESULTS: In our cohort, invasive NTHi has accounted for 20% of infections associated with early pregnancy loss prior to 24 weeks gestation. All patients were young and healthy pregnant women at < 20 weeks' gestation who presented with abdominal pain, PV bleed /discharge and were septic at the time of presentation. One patient with previous history of miscarriage who presented with cervical incompetence had more severe pathology suggestive of early intrauterine pneumonia. CONCLUSION: The burden of invasive NTHi disease in early pregnancy loss is likely to be much larger than currently recognised. NTHi should be considered in pregnant women presenting with abdominal pain and PV bleed/discharge in whom clinical signs of sepsis are present. Active surveillance should be considered in this patient group including septic abortion to capture the true prevalence of this emerging pathogen to inform preventative and therapeutic approaches.

Noncardiac genetic predisposition in sudden infant death syndrome.

PURPOSE: Sudden infant death syndrome (SIDS) is the commonest cause of sudden death of an infant; however, the genetic basis remains poorly understood. We aimed to identify noncardiac genes underpinning SIDS and determine their prevalence compared with ethnically matched controls. METHODS: Using exome sequencing we assessed the yield of ultrarare nonsynonymous variants (minor allele frequency [MAF] ≤0.00005, dominant model; MAF ≤0.01, recessive model) in 278 European SIDS cases (62% male; average age =2.7 ± 2 months) versus 973 European controls across 61 noncardiac SIDS-susceptibility genes. The variants were classified according to American College of Medical Genetics and Genomics criteria. Case-control, gene-collapsing analysis was performed in eight candidate biological pathways previously implicated in SIDS pathogenesis. RESULTS: Overall 43/278 SIDS cases harbored an ultrarare single-nucleotide variant compared with 114/973 controls (15.5 vs. 11.7%, p=0.10). Only 2/61 noncardiac genes were significantly overrepresented in cases compared with controls (ECE1, 3/278 [1%] vs. 1/973 [0.1%] p=0.036; SLC6A4, 2/278 [0.7%] vs. 1/973 [0.1%] p=0.049). There was no difference in yield of pathogenic or likely pathogenic variants between cases and controls (1/278 [0.36%] vs. 4/973 [0.41%]; p=1.0). Gene-collapsing analysis did not identify any specific biological pathways to be significantly associated with SIDS. CONCLUSIONS: A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible.

Sampling bias overestimates climate change impacts on forest growth in the southwestern United States.

Climate-tree growth relationships recorded in annual growth rings have recently been the basis for projecting climate change impacts on forests. However, most trees and sample sites represented in the International Tree-Ring Data Bank (ITRDB) were chosen to maximize climate signal and are characterized by marginal growing conditions not representative of the larger forest ecosystem. We evaluate the magnitude of this potential bias using a spatially unbiased tree-ring network collected by the USFS Forest Inventory and Analysis (FIA) program. We show that U.S. Southwest ITRDB samples overestimate regional forest climate sensitivity by 41-59%, because ITRDB trees were sampled at warmer and drier locations, both at the macro- and micro-site scale, and are systematically older compared to the FIA collection. Although there are uncertainties associated with our statistical approach, projection based on representative FIA samples suggests 29% less of a climate change-induced growth decrease compared to projection based on climate-sensitive ITRDB samples.

Exome-Wide Rare Variant Analyses in Sudden Infant Death Syndrome.

OBJECTIVE: To determine whether a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. STUDY DESIGN: A cohort of 427 unrelated cases of SIDS (257 male; average age = 2.7 ± 1.9 months) underwent whole-exome sequencing. Exome-wide rare variant analyses were carried out with 278 SIDS cases of European ancestry (173 male; average age = 2.7 ± 1.98 months) and 973 ethnic-matched controls based on 6 genetic models. Ingenuity Pathway Analysis also was performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St George's University of London, United Kingdom, and Mayo Clinic, Rochester, Minnesota. Whole-exome sequencing was performed at the Genomic Laboratory, Kings College London, United Kingdom, or Mayo Clinic's Medical Genome Facility, Rochester, Minnesota. RESULTS: Although no exome-wide significant (P < 2.5 × 10-6) difference in burden of ultra-rare variants was detected for any gene, 405 genes had a greater prevalence (P < .05) of ultra-rare nonsynonymous variants among cases with 17 genes at P < .005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (P = .01). CONCLUSIONS: The lack of exome-wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence-based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS-associated biological pathway for future SIDS investigative research.

Expression of the candidate fat taste receptors in human fungiform papillae and the association with fat taste function.

Significant experimental evidence supports fat as a taste modality; however, the associated peripheral mechanisms are not well established. Several candidate taste receptors have been identified, but their expression pattern and potential functions in human fungiform papillae remain unknown. The aim of this study is to identify the fat taste candidate receptors and ion channels that were expressed in human fungiform taste buds and their association with oral sensory of fatty acids. For the expression analysis, quantitative RT-PCR (qRT-PCR) from RNA extracted from human fungiform papillae samples was used to determine the expression of candidate fatty acid receptors and ion channels. Western blotting analysis was used to confirm the presence of the proteins in fungiform papillae. Immunohistochemistry analysis was used to localise the expressed receptors or ion channels in the taste buds of fungiform papillae. The correlation study was analysed between the expression level of the expressed fat taste receptors or ion channels indicated by qRT-PCR and fat taste threshold, liking of fatty food and fat intake. As a result, qRT-PCR and western blotting indicated that mRNA and protein of CD36, FFAR4, FFAR2, GPR84 and delayed rectifying K+ channels are expressed in human fungiform taste buds. The expression level of CD36 was associated with the liking difference score (R -0·567, ß=-0·04, P=0·04) between high-fat and low-fat food and FFAR2 was associated with total fat intake (ρ=-0·535, ß=-0·01, P=0·003) and saturated fat intake (ρ=-0·641, ß=-0·02, P=0·008).

Trends in late-onset sepsis in a neonatal intensive care unit following implementation of infection control bundle: A 15-year audit.

AIM: Late-onset sepsis (LOS) is a frequent and important cause of morbidity and mortality in newborn infants admitted to neonatal intensive care units (NICUs). The objective of this study is to evaluate the impact of various infection control quality measures introduced as a bundle on the trends of the LOS in a NICU. METHODS: This was a prospective quality improvement study involving all neonates admitted to a NICU over a 15-year period between 2002 and 2016. The main focus areas of the bundle included collaborative team effort, hand hygiene, education, central line insertion and maintenance bundles and parenteral nutrition. The main outcome measures were LOS and central line-associated bloodstream infections. RESULTS: Yearly admissions increased during study period, from 776 in 2002 to 952 in 2016. There was a progressive decrease in LOS rate, from 4.3 to 1.6 per 1000 patient days (B coefficient -0.17, 95% confidence interval -0.25, -0.09; P < 0.001), and the central line-associated bloodstream infection rate dropped from 25 in 2003 to 5 in 2016 per 1000 central line days (B coefficient -1.20, 95% confidence interval -1.84, -0.56; P = 0.001). Hand hygiene compliance rates remained consistent, over 80%. During the study period, coagulase-negative staphylococcus caused 56% and Gram-negative organisms 18% of the total infections. CONCLUSION: Multifaceted infection control bundle practices with a concerted team effort in the implementation, with continuing education, feedback and reinforcement of best infection control practices, can sustain the gains achieved by infection control for a long period of time.

Biomineralization of osteoblasts on DLC coated surfaces for bone implants.

Diamond like carbon (DLC) films were deposited onto Ti6Al4V and Si wafer substrates by RF plasma enhanced chemical vapor deposition. The influence of dopants such as fluorine (F), silicon (Si), and nitrogen (N) on composition, structure, and biocompatibility was investigated. Ion scattering spectroscopy analysis revealed the presence of dopant atoms in the outer-most layers of the films. Raman studies showed that the position of the G-band shifts to higher frequencies with the fluorine and nitrogen content in the DLC film, whereas the incorporation of Si into DLC induces a decrease of the position of the G peak. The corrosion behavior was studied in simulated body fluid. A higher charge transfer resistance (Rct) was observed for the doped DLC films. The indirect cytotoxicity was performed using L929 fibroblast cells. The coated surfaces were hemocompatible when tested with red blood cells. DLC films were noncytotoxic to L929 cells over a 24 h exposure. Saos-2 osteoblast cell response to the doped and undoped DLC coated surfaces was studied in adhesion, proliferation, differentiation, and mineralization assays. The production of calcium and phosphate by cells on doped DLC, particularly, nitrogen doped DLC, was higher than that on undoped DLC.

Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study.

BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS. METHODS: We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system. FINDINGS: Four (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057). INTERPRETATION: Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths. FUNDING: UK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.