Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics.

Psychosis occurs inside the brain, but may have external manifestations (peripheral molecular biomarkers, behaviors) that can be objectively and quantitatively measured. Blood biomarkers that track core psychotic manifestations such as hallucinations and delusions could provide a window into the biology of psychosis, as well as help with diagnosis and treatment. We endeavored to identify objective blood gene expression biomarkers for hallucinations and delusions, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We were successful in identifying biomarkers that were predictive of high hallucinations and of high delusions states, and of future psychiatric hospitalizations related to them, more so when personalized by gender and diagnosis. Top biomarkers for hallucinations that survived discovery, prioritization, validation and testing include PPP3CB, DLG1, ENPP2, ZEB2, and RTN4. Top biomarkers for delusions include AUTS2, MACROD2, NR4A2, PDE4D, PDP1, and RORA. The top biological pathways uncovered by our work are glutamatergic synapse for hallucinations, as well as Rap1 signaling for delusions. Some of the biomarkers are targets of existing drugs, of potential utility in pharmacogenomics approaches (matching patients to medications, monitoring response to treatment). The top biomarkers gene expression signatures through bioinformatic analyses suggested a prioritization of existing medications such as clozapine and risperidone, as well as of lithium, fluoxetine, valproate, and the nutraceuticals omega-3 fatty acids and magnesium. Finally, we provide an example of how a personalized laboratory report for doctors would look. Overall, our work provides advances for the improved diagnosis and treatment for schizophrenia and other psychotic disorders.

A Novel Conceptual Model for Human Heat Tolerance.

Human "heat tolerance" has no accepted definition or physiological underpinnings; rather, it is almost always discussed in relative or comparative terms. We propose to use environmental limits to heat balance accounting for metabolic rate and clothing, that is, the environments for which heat stress becomes uncompensable for a specified metabolic rate and clothing, as a novel metric for quantifying heat tolerance.

Sex differences in thermophysiological responses of elderly to low-intensity exercise during uncompensable heat strain.

PURPOSE: The rising frequency of extreme heat events poses an escalating threat of heat-related illnesses and fatalities, placing an additional strain on global healthcare systems. Whether the risk of heat-related issues is sex specific, particularly among the elderly, remains uncertain. METHODS: 16 men and 15 women of similar age (69 ± 5 years) were exposed to an air temperature of 39.1 ± 0.3 °C and a relative humidity (RH) of 25.1 ± 1.9%, during 20 min of seated rest and at least 40 min of low-intensity (10 W) cycling exercise. RH was gradually increased by 2% every 5 min starting at minute 30. We measured sweat rate, heart rate, thermal sensation, and the rise in gastrointestinal temperature (Tgi) and skin temperature (Tsk). RESULTS: Tgi consistently increased from minute 30 to 60, with no significant difference between females and males (0.012 ± 0.004 °C/min vs. 0.011 ± 0.005 °C/min; p = 0.64). Similarly, Tsk increase did not differ between females and males (0.044 ± 0.007 °C/min vs. 0.038 ± 0.011 °C/min; p = 0.07). Females exhibited lower sweat rates than males (0.29 ± 0.06 vs. 0.45 ± 0.14 mg/m2/min; p < 0.001) in particular at relative humidities exceeding 30%. No sex differences in heart rate and thermal sensation were observed. CONCLUSION: Elderly females exhibit significantly lower sweat rates than their male counterparts during low-intensity exercise at ambient temperatures of 39 °C when humidity exceeds 30%. However, both elderly males and females demonstrate a comparable rise in core temperature, skin temperature, and mean body temperature, indicating similar health-related risks associated with heat exposure.

Adverse heat-health outcomes and critical environmental limits (Pennsylvania State University Human Environmental Age Thresholds project).

BACKGROUND: The earth's climate is warming and the frequency, duration, and severity of heat waves are increasing. Meanwhile, the world's population is rapidly aging. Epidemiological data demonstrate exponentially greater increases in morbidity and mortality during heat waves in adults ≥65 years. Laboratory data substantiate the mechanistic underpinnings of age-associated differences in thermoregulatory function. However, the specific combinations of environmental conditions (i.e., ambient temperature and absolute/relative humidity) above which older adults are at increased risk of heat-related morbidity and mortality are less clear. METHODS: This review was conducted to (1) examine the recent (past 3 years) literature regarding heat-related morbidity and mortality in the elderly and discuss projections of future heat-related morbidity and mortality based on climate model data, and (2) detail the background and unique methodology of our ongoing laboratory-based projects aimed toward identifying the specific environmental conditions that result in elevated risk of heat illness in older adults, and the implications of using the data toward the development of evidence-based safety interventions in a continually-warming climate (PSU HEAT; Human Environmental Age Thresholds). RESULTS: The recent literature demonstrates that extreme heat continues to be increasingly detrimental to the health of the elderly and that this is apparent across the world, although the specific environmental conditions above which older adults are at increased risk of heat-related morbidity and mortality remain unclear. CONCLUSION: Characterizing the environmental conditions above which risk of heat-related illnesses increase remains critical to enact policy decisions and mitigation efforts to protect vulnerable people during extreme heat events.

Comprehensive cancer predisposition testing within the prospective MASTER trial identifies hereditary cancer patients and supports treatment decisions for rare cancers.

BACKGROUND: Germline variant evaluation in precision oncology opens new paths toward the identification of patients with genetic tumor risk syndromes and the exploration of therapeutic relevance. Here, we present the results of germline variant analysis and their clinical implications in a precision oncology study for patients with predominantly rare cancers. PATIENTS AND METHODS: Matched tumor and control genome/exome and RNA sequencing was carried out for 1485 patients with rare cancers (79%) and/or young adults (77% younger than 51 years) in the National Center for Tumor Diseases/German Cancer Consortium (NCT/DKTK) Molecularly Aided Stratification for Tumor Eradication Research (MASTER) trial, a German multicenter, prospective, observational precision oncology study. Clinical and therapeutic relevance of prospective pathogenic germline variant (PGV) evaluation was analyzed and compared to other precision oncology studies. RESULTS: Ten percent of patients (n = 157) harbored PGVs in 35 genes associated with autosomal dominant cancer predisposition, whereof up to 75% were unknown before study participation. Another 5% of patients (n = 75) were heterozygous carriers for recessive genetic tumor risk syndromes. Particularly, high PGV yields were found in patients with gastrointestinal stromal tumors (GISTs) (28%, n = 11/40), and more specifically in wild-type GISTs (50%, n = 10/20), leiomyosarcomas (21%, n = 19/89), and hepatopancreaticobiliary cancers (16%, n = 16/97). Forty-five percent of PGVs (n = 100/221) supported treatment recommendations, and its implementation led to a clinical benefit in 40% of patients (n = 10/25). A comparison of different precision oncology studies revealed variable PGV yields and considerable differences in germline variant analysis workflows. We therefore propose a detailed workflow for germline variant evaluation. CONCLUSIONS: Genetic germline testing in patients with rare cancers can identify the very first patient in a hereditary cancer family and can lead to clinical benefit in a broad range of entities. Its routine implementation in precision oncology accompanied by the harmonization of germline variant evaluation workflows will increase clinical benefit and boost research.

Nitric oxide-mediated cutaneous microvascular function is not altered in young adults following mild-to-moderate SARS CoV-2 infection.

Vascular dysfunction has been reported in adults who have recovered from COVID-19. To date, no studies have investigated the underlying mechanisms of persistent COVID-19-associated vascular dysfunction. Our purpose was to quantify nitric oxide (NO)-mediated vasodilation in healthy adults who have recovered from SARS-CoV-2 infection. We hypothesized that COVID-19-recovered adults would have impaired NO-mediated vasodilation compared with adults who have not had COVID-19. In methods, we performed a cross-sectional study including 10 (5 men/5 women, 24 ± 4 yr) healthy control (HC) adults who were unvaccinated for COVID-19, 11 (4 men/7 women, 25 ± 6 yr) healthy vaccinated (HV) adults, and 12 (5 men/7 women, 22 ± 3 yr) post-COVID-19 (PC, 19 ± 14 wk) adults. COVID-19 symptoms severity (survey) was assessed. A standardized 39°C local heating protocol was used to assess NO-dependent vasodilation via perfusion (intradermal microdialysis) of 15 mM NG-nitro-l-arginine methyl ester during the plateau of the heating response. Red blood cell flux was measured (laser-Doppler flowmetry) and cutaneous vascular conductance (CVC = flux/mmHg) was expressed as a percentage of maximum (28 mM sodium nitroprusside + 43°C). In results, the local heating plateau (HC: 61 ± 20%, HV: 60 ± 19%, PC: 67 ± 19%, P = 0.80) and NO-dependent vasodilation (HC: 77 ± 9%, HV: 71 ± 7%, PC: 70 ± 10%, P = 0.36) were not different among groups. Neither symptom severity (25 ± 12 AU) nor time since diagnosis correlated with the NO-dependent vasodilation (r = 0.46, P = 0.13; r = 0.41, P = 0.19, respectively). In conclusion, healthy adults who have had mild-to-moderate COVID-19 do not have altered NO-mediated cutaneous microvascular function.NEW & NOTEWORTHY Healthy young adults who have had mild-to-moderate COVID-19 do not display alterations in nitric oxide-mediated cutaneous microvascular function. In addition, healthy young adults who have COVID-19 antibodies from the COVID-19 vaccinations do not display alterations in nitric oxide-mediated cutaneous microvascular function.

Skin pigmentation is negatively associated with circulating vitamin D concentration and cutaneous microvascular endothelial function.

Darkly pigmented individuals are at the greatest risk of hypovitaminosis D, which may result in microvascular endothelial dysfunction via reduced nitric oxide (NO) bioavailability and/or increased oxidative stress and inflammation. We investigated the associations among skin pigmentation (M-index; skin reflectance spectrophotometry), serum vitamin D concentration [25(OH)D], circulating inflammatory cytokine (TNF-α, IL-6, and IL-10) concentrations, and the NO contribution to local heating-induced cutaneous vasodilation (%NO-mediated vasodilation) in a diversely pigmented cohort of young adults. An intradermal microdialysis fiber was placed in the forearms of 33 healthy adults (14 men/19 women; 18-27 yr; M-index, 30-81 AU) for local delivery of pharmacological agents. Lactated Ringer's solution was perfused through the fiber during local heating-induced (39°C) cutaneous vasodilation. After attaining stable elevated blood flow, 15 mM NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibiter) was infused to quantify %NO-mediated vasodilation. Red cell flux was measured (laser-Doppler flowmetry; LDF) and cutaneous vascular conductance (CVC = LDF/MAP) was normalized to maximal (%CVCmax; 28 mM sodium nitroprusside + 43°C). Serum [25(OH)D] and circulating cytokines were analyzed by ELISA and multiplex assay, respectively. M-index was negatively associated with [25(OH)D] (r = -0.57, P < 0.0001) and %NO-mediated vasodilation (r = -0.42, P = 0.02). Serum[25(OH)D] was positively related to %NO (r = 0.41, P = 0.02). Controlling for [25(OH)D] weakened the association between M-index and %NO-mediated dilation (P = 0.16, r = -0.26). There was a negative curvilinear relation between [25(OH)D] and circulating IL-6 (r = -0.56, P < 0.001), but not TNF-α or IL-10 (P ≥ 0.14). IL-6 was not associated with %NO-mediated vasodilation (P = 0.44). These data suggest that vitamin D insufficiency/deficiency may contribute to reduced microvascular endothelial function in healthy, darkly pigmented young adults.NEW & NOTEWORTHY Endothelial dysfunction, an antecedent to hypertension and overt CVD, is commonly observed in otherwise healthy Black adults, although the underlying causes remain unclear. We show that reduced vitamin D availability with increasing degrees of skin pigmentation is associated with reduced microvascular endothelial function, independent of race or ethnicity, in healthy young adults. Greater prevalence of vitamin D deficiency in more darkly pigmented individuals may predispose them to increased risk of endothelial dysfunction.

Analysis of the structure and function of the epidermal barrier in patients with ichthyoses-clinical and electron microscopical investigations.

BACKGROUND: Ichthyoses are pathogenetically characterized by a pronounced disorder of the epidermal barrier. Clinically, hyperkeratosis, severe scaling and erythroderma are present on the entire integument. The time-consuming therapy includes daily baths and the application of skin care products to restore the epidermal barrier. OBJECTIVES AND METHODS: To enhance the knowledge about the structure and function of the epidermal barrier in ichthyoses, we conducted clinical, biophysical and electron microscopical measurements on 46 patients with ichthyoses, including autosomal recessive ichthyoses, keratinopathic ichthyoses, X-chromosomal-recessive ichthyosis and Netherton syndrome. RESULTS: The patients displayed a significantly decreased skin hydration along with unexpectedly low transepidermal waterloss values. Electron microscopical examinations demonstrated a severe occlusion of the epidermis by lipid remnants of skin care products in the stratum corneum. We found decreased intercellular lipid lamellae and an increased undulation of the corneocyte membrane of all ichthyoses, mostly pronounced in Netherton syndrome. The lipid profiles of ichthyoses showed decreased esterified Ω-hydroxy-sphingosine (EOS) ceramide levels. CONCLUSIONS: The results demonstrate the extent of the epidermal barrier disruption in ichthyoses. In combination with the knowledge about pathogenetic causes, individually improved therapeutic options can be derived from our results. In the future, the analyses of the organization of intercellular lipid lamellae and corneocyte membrane undulation will enable improved investigations of the epidermal barrier in ichthyoses and may be used to study and evaluate possible effects of topical skin preparations.

Utility of the Heat Index in defining the upper limits of thermal balance during light physical activity (PSU HEAT Project).

Extreme heat events and consequent detrimental heat-health outcomes have been increasing in recent decades and are expected to continue with future climate warming. While many indices have been created to quantify the combined atmospheric contributions to heat, few have been validated to determine how index-defined heat conditions impact human health. However, this subset of indices is likely not valid for all situations and populations nor easily understood and interpreted by health officials and the public. In this study, we compare the ability of thresholds determined from the National Weather Service's (NWS) Heat Index (HI), the Wet Bulb Globe Temperature (WBGT), and the Universal Thermal Climate Index (UTCI) to predict the compensability of human heat stress (upper limits of heat balance) measured as part of the Pennsylvania State University's Heat Environmental Age Thresholds (PSU HEAT) project. While the WBGT performed the best of the three indices for both minimal activities of daily living (MinAct; 83 W·m-2) and light ambulation (LightAmb; 133 W·m-2) in a cohort of young, healthy subjects, HI was likewise accurate in predicting heat stress compensability in MinAct conditions. HI was significantly correlated with subjects' perception of temperature and humidity as well as their body core temperature, linking perception of the ambient environment with physiological responses in MinAct conditions. Given the familiarity the public has with HI, it may be better utilized in the expansion of safeguard policies and the issuance of heat warnings during extreme heat events, especially when access to engineered cooling strategies is unavailable.

[Methods for analysing spatial data : Using the example of skin cancer prevalence in Germany]. / Methoden zur Analyse räumlicher Daten : Beispiel der regionalen Hautkrebsprävalenz in Deutschland.

BACKGROUND: Studies show a spatial variation in skin cancer frequencies, but the causes have not been fully understood. When analysing spatial patterns and correlations, different approaches need to be considered, as the data have special features due to their spatial structure. AIM OF THE STUDY: Why the spatial consideration of skin cancer frequencies is important at all, and which methods of analysis are useful is considered in more detail in this article. The article provides an introduction and overview of statistical methods that are important for the spatial analysis of skin cancer frequencies. MATERIALS AND METHODS: At first it is shown which descriptive methods, such as statistical smoothing, can be applied. Next, spatial cluster and regression analyses will be discussed. Testing for spatial autocorrelation will be considered. RESULTS: In particular, the spatial dependence of the data on neighbouring regions, which if ignored can lead to biased estimates, is of particular importance in the analysis of spatial data and requires special spatial analysis methods. DISCUSSION: This article provides an introduction and overview of statistical methods relevant to the spatial analysis of skin cancers.

Heat exposure limits for young unacclimatized males and females at low and high humidity.

Little is known about the separate and combined influences of humidity conditions, sex, and aerobic fitness on heat tolerance in unacclimatized males and females. The purpose of the current study was to describe heat tolerance, in terms of critical WBGT (WBGTcrit), in unacclimatized young males and females in hot-dry (HD) and warm-humid (WH) environments. Eighteen subjects (9 M/9F; 21 ± 2 yr) were tested during exercise at 30% V̇O2max in a controlled environmental chamber. Progressive heat stress exposures were performed with either (1) constant dry-bulb temperature (Tdb) of 34 and 36 °C and increasing ambient water vapor pressure (Pa) (Pcrit trials; WH); or (2) constant Pa of 12 and 16 mmHg and increasing Tdb (Tcrit trials; HD). Chamber Tdb and Pa, and subject esophageal temperature (Tes), were continuously monitored throughout each trial. After a 30-min equilibration period, progressive heat stress continued until subject heat balance could no longer be maintained and a clear rise in Tes was observed. Absolute WBGTcrit and WBGTcrit adjusted to a metabolic rate of 300 W (WBGT300), and the difference between WBGTcrit and occupational exposure limits (OEL; ΔOEL) was assessed. WBGTcrit, WBGT300, and ΔOEL were higher in WH compared to HD (p < 0.0001) for females but were the same between environments for males (p ≥ 0.21). WBGTcrit was higher in females compared to males in WH (p < 0.0001) but was similar between sexes in HD (p = 0.44). When controlling for metabolic rate, WBGT300 and ΔOEL were higher in males compared to females in WH and HD (both p < 0.0001). When controlling for sex, V̇O2max was not associated with WBGT300 or ΔOEL for either sex (r ≤ 0.12, p ≥ 0.49). These findings suggest that WBGTcrit is higher in females compared to males in WH, but not HD, conditions. Additionally, the WBGTcrit is lower in females, but not males, in HD compared to WH conditions.

Metabolism- and sex-dependent critical WBGT limits at rest and during exercise in the heat.

Critical environmental limits are environmental thresholds above which heat gain exceeds heat loss and body core temperature (Tc) cannot be maintained at equilibrium. Those limits can be represented as critical wet-bulb globe temperature (WBGTcrit), a validated index that represents the overall thermal environment. Little is known about WBGTcrit at rest and during low-to-moderate intensity exercise, or sex differences in WBGTcrit, in unacclimated young adults. The following hypotheses were tested: 1) WBGTcrit progressively decreases as metabolic heat production (Mnet) increases, 2) no sex differences in WBGTcrit occur at rest, and 3) WBGTcrit is lower during absolute-intensity exercise but higher at relative intensities in women than in men. Thirty-six participants [19 men (M)/17 women (W); 23 ± 4 yr] were tested at rest, during light, absolute-intensity exercise (10 W), or during moderate, relative-intensity exercise [30% maximal oxygen consumption (V̇o2max)] in an environmental chamber. Dry-bulb temperature was clamped as relative humidity or ambient water vapor pressure was increased until an upward inflection was observed in Tc (rectal or esophageal temperature). Sex-aggregated WBGTcrit was lower during 10 W (32.9°C ± 1.7°C, P < 0.0001) and 30% V̇o2max (31.6°C ± 1.1°C, P < 0.0001) exercise versus at rest (35.3°C ± 0.8°C), and lower at 30% V̇o2max versus 10 W (P = 0.01). WBGTcrit was similar between sexes at rest (35.6°C ± 0.8°C vs. 35.0°C ± 0.8°C, P = 0.83), but lower during 10 W (31.9°C ± 1.7°C vs. 34.1°C ± 0.3°C, P < 0.01) and higher during 30% V̇o2max (32.4°C ± 0.8°C vs. 30.8°C ± 0.9°C, P = 0.03) exercise in women versus men. These findings suggest that WBGTcrit decreases as Mnet increases, no sex differences occur in WBGTcrit at rest, and sex differences in WBGTcrit during exercise depend on absolute versus relative intensities.

Field-effect silicon-plasmonic photodetector for coherent T-wave reception.

Plasmonic internal photoemission detectors (PIPED) have recently been shown to combine compact footprint and high bandwidth with monolithic co-integration into silicon photonic circuits, thereby opening an attractive route towards optoelectronic generation and detection of waveforms in the sub-THz and THz frequency range, so-called T-waves. In this paper, we further expand the PIPED concept by introducing a metal-oxide-semiconductor (MOS) interface with an additional gate electrode that allows to control the carrier dynamics in the device and the degree of internal photoemission at the metal-semiconductor interfaces. We experimentally study the behavior of dedicated field-effect (FE-)PIPED test structures and develop a physical understanding of the underlying principles. We find that the THz down-conversion efficiency of FE-PIPED can be significantly increased when applying a gate potential. Building upon the improved understanding of the device physics, we further perform simulations and show that the gate field increases the carrier density in the conductive channel below the gate oxide to the extent that the device dynamics are determined by ultra-fast dielectric relaxation rather than by the carrier transit time. In this regime, the bandwidth can be increased to more than 1 THz. We believe that our experiments open a new path towards understanding the principles of internal photoemission in plasmonic structures, leading to PIPED-based optoelectronic signal processing systems with unprecedented bandwidth and efficiency.

Skin pigmentation and vitamin D-folate interactions in vascular function: an update.

PURPOSE OF REVIEW: Vitamin D and folate promote vascular endothelial health and may therefore help mitigate the development of cardiovascular disease (CVD). Ultraviolet radiation (UVR) exposure stimulates cutaneous vitamin D synthesis but degrades the bioactive metabolite of folate, 5-methyltetrahydrofolate (5-MTHF). Skin melanin absorbs UVR, thereby modulating the impact of UVR exposure on vitamin D and 5-MTHF metabolism. This review presents recent findings regarding the inter-relations among UVR, skin pigmentation, folate and vitamin D, and endothelial function. RECENT FINDINGS: Evidence for roles of folic acid or vitamin D supplementation on CVD endpoints is inconsistent, although preclinical and clinical studies have demonstrated the efficacy of both micronutrients for improving endothelial function. Vitamin D deficiency is most prevalent in darkly pigmented individuals living in relatively low-UVR environments. Conversely, there is a negative relation between accumulated UVR exposure and serum folate concentration in lightly pigmented adults. The interactions among UVR and bioavailable folate and vitamin D differentially impact endothelial function in differently pigmented skin. SUMMARY: UVR exposure disparately impacts folate and vitamin D metabolism in differently pigmented skin depending upon regional UVR intensity and seasonality. These findings present new clinical research questions regarding the interactions among UVR, skin pigmentation, folate and vitamin D bioavailability, and endothelial health.

Cerebrovascular Autoregulation Monitoring in the Management of Adult Severe Traumatic Brain Injury: A Delphi Consensus of Clinicians.

BACKGROUND: Several methods have been proposed to measure cerebrovascular autoregulation (CA) in traumatic brain injury (TBI), but the lack of a gold standard and the absence of prospective clinical data on risks, impact on care and outcomes of implementation of CA-guided management lead to uncertainty. AIM: To formulate statements using a Delphi consensus approach employing a group of expert clinicians, that reflect current knowledge of CA, aspects that can be implemented in TBI management and CA research priorities. METHODS: A group of 25 international academic experts with clinical expertise in the management of adult severe TBI patients participated in this consensus process. Seventy-seven statements and multiple-choice questions were submitted to the group in two online surveys, followed by a face-to-face meeting and a third online survey. Participants received feedback on average scores and the rationale for resubmission or rephrasing of statements. Consensus on a statement was defined as agreement of more than 75% of participants. RESULTS: Consensus amongst participants was achieved on the importance of CA status in adult severe TBI pathophysiology, the dynamic non-binary nature of CA impairment, its association with outcome and the inadvisability of employing universal and absolute cerebral perfusion pressure targets. Consensus could not be reached on the accuracy, reliability and validation of any current CA assessment method. There was also no consensus on how to implement CA information in clinical management protocols, reflecting insufficient clinical evidence. CONCLUSION: The Delphi process resulted in 25 consensus statements addressing the pathophysiology of impaired CA, and its impact on cerebral perfusion pressure targets and outcome. A research agenda was proposed emphasizing the need for better validated CA assessment methods as well as the focused investigation of the application of CA-guided management in clinical care using prospective safety, feasibility and efficacy studies.

Agent-based modeling: Population limits and large timescales.

Modeling, simulation, and analysis of interacting agent systems is a broad field of research, with existing approaches reaching from informal descriptions of interaction dynamics to more formal, mathematical models. In this paper, we study agent-based models (ABMs) given as continuous-time stochastic processes and their pathwise approximation by ordinary and stochastic differential equations (SDEs) for medium to large populations. By means of an appropriately adapted transfer operator approach, we study the behavior of the ABM process on long time scales. We show that, under certain conditions, the transfer operator approach allows us to bridge the gap between the pathwise results for large populations on finite timescales, i.e., the SDE limit model, and approaches built to study dynamical behavior on long time scales like large deviation theory. The latter provides a rigorous analysis of rare events including the associated asymptotic rates on timescales that scale exponentially with the population size. We demonstrate that it is possible to reveal metastable structures and timescales of rare events of the ABM process by finite-length trajectories of the SDE process for large enough populations. This approach has the potential to drastically reduce computational effort for the analysis of ABMs.

Examining "race" in physiology.

Racial disparities in cardiovascular and cerebrovascular health outcomes are well described, and recent research has shed light on the mechanistic underpinnings of those disparities. However, "race" is a social construct that is poorly defined and continually evolving and is historically based on faulty premises. The continued categorization by race in physiological research suggests that there are inherent differences between races, rather than addressing the specific underlying factors that result in health disparities between groups. The purpose of this Perspectives article is to provide a brief history of the genesis of categorization by race, why such categorization should be reconsidered in physiology research, and offer recommendations to more directly investigate the underlying factors that result in group disparities in cardiovascular and cerebrovascular health.

Four weeks of vitamin D supplementation improves nitric oxide-mediated microvascular function in college-aged African Americans.

Reduced nitric oxide (NO)-mediated cutaneous vasodilation, secondary to increased oxidative stress, presents in young African American (AA) compared with European American (EA) adults and may be modulated by vitamin D status. We assessed cutaneous microvascular function in 18 young, healthy (21 ± 2 yr; 9 men, 9 women) subjects before (pre, 8 AA, 10 EA) 4 wk of 2,000 IU/day oral vitamin D supplementation and in 13 subjects after (post, 7 AA, 6 EA) 4 wk of 2,000 IU/day oral vitamin D supplementation. Serum vitamin D concentrations [25(OH)D] were measured at each visit. Three intradermal microdialysis fibers placed in the ventral forearm were randomized for treatment with 10 µM Tempol, 100 µM apocynin, or lactated Ringer's solution (control). Local heating (39°C) induced cutaneous vasodilation; red cell flux was measured at each site (laser-Doppler flowmetry), and cutaneous vascular conductance (CVC = flux/MAP) was expressed as a percentage of maximum (28 mM sodium nitroprusside, +43°C) for each phase of local heating. After stable elevated blood flow was attained, 15 mM NG-nitro-l-arginine methyl ester (l-NAME; NO synthase inhibitor) was perfused at all sites to quantify the NO contribution to cutaneous vasodilation (%NO), calculated as the difference between local heating and l-NAME plateaus. Serum [25(OH)D], the magnitude of the local heating response, and %NO were all lower in AAs versus EAs (P < 0.01). Tempol (P = 0.01), but not apocynin (P ≥ 0.19), improved the local heating response and %NO. Four weeks of supplementation improved serum [25(OH)D], the local heating response, and %NO in AAs (P ≤ 0.04) but not in EAs (P ≥ 0.41). Vitamin D supplementation mitigated endothelial dysfunction, an antecedent to overt cardiovascular disease (CVD), in otherwise healthy, young AA adults.NEW & NOTEWORTHY Endothelial dysfunction, an antecedent to overt cardiovascular disease (CVD), is observed earlier and more frequently in otherwise healthy African Americans (AAs) when compared with other ethnic groups. Vitamin D may modulate endothelial function, and darkened skin pigmentation increases risk of vitamin D deficiency. We show that 4 wk of 2,000 IU/day vitamin D supplementation improves microvascular responses to local heating in AAs. Ensuring adequate vitamin D status may mitigate development of cardiovascular dysfunction in this at-risk population.

[Insoles, knee braces and ankle-foot orthoses in the treatment of medial gonarthrosis : A literature review]. / Einlagen, Knie- und Unterschenkelorthesen in der Behandlung der medialen Gonarthrose : Eine aktuelle Literaturübersicht.

BACKGROUND: Osteoarthritis is the most common joint disease worldwide and mostly affects the knee joint (gonarthrosis). In treatment algorithms, technical aids in the form of laterally wedged insoles, valgizing knee braces and ankle-foot orthoses have an importance in the treatment of medial unicompartmental knee joint disease. However, national and international guidelines differ in their recommendations. INSOLES: Taking into account a great amount of scientific work, the measurable effect of laterally wedged insoles appears to be low, so that a justifying indication only exists at low gonarthrosis levels. KNEE BRACES: Valgizing knee braces have shown stronger biomechanical and clinical effects, but with a slightly increased complication potential and low compliance. Low to medium-grade arthrosis can be treated. ANKLE-FOOT ORTHOSES: Ankle-foot arthroses have not yet been conclusively examined. Initial work indicates biomechanical and clinical efficacy. The overall effects and indications appear comparable to knee braces, probably with less complication potential.

[Expert assessment of lower extremity prosthetics]. / Begutachtung von Prothesenversorgungen der unteren Extremität.

Although the number of major amputations is declining throughout Germany, more than 57,000 surgical procedures for amputation still take place. As a consequence of high prosthetic care costs, these often lead to disputes before the social court in which expert medical opinions are required. With knowledge of the legal norms, the remit of the expert opinion can be fulfilled. The expert begins with evaluation of the patient's file and a search of the contested parts. The investigation includes a medical history, in addition to a physical examination, in order to be able to comment on the disputed beneficial use of the therapeutic appliance and respond to questions of proof. Questionnaires may be helpful.