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In partial onset epilepsy, seizures arise focally in the brain and often propagate. Patients frequently become refractory to medical management, leaving neurosurgery, which can cause neurologic deficits, as a primary treatment. In the cortex, focal seizures spread through horizontal connections in layers II/III, suggesting that severing these connections can block seizures while preserving function. Focal neocortical epilepsy is induced in mice, sub‐surface cuts are created surrounding the seizure focus using tightly‐focused femtosecond laser pulses, and electrophysiological recordings are acquired at multiple locations for 3–12 months. Cuts reduced seizure frequency in most animals by 87%, and only 5% of remaining seizures propagated to the distant electrodes, compared to 80% in control animals. These cuts produced a modest decrease in cortical blood flow that recovered and left a ≈20‐µm wide scar with minimal collateral damage. When placed over the motor cortex, cuts do not cause notable deficits in a skilled reaching task, suggesting they hold promise as a novel neurosurgical approach for intractable focal cortical epilepsy. [ABSTRACT FROM AUTHOR]

Metabolomic age models have been proposed for the study of biological aging, however, they have not been widely validated. We aimed to assess the performance of newly developed and existing nuclear magnetic resonance spectroscopy (NMR) metabolomic age models for prediction of chronological age (CA), mortality, and age‐related disease. Ninety‐eight metabolic variables were measured in blood from nine UK and Finnish cohort studies (N ≈31,000 individuals, age range 24–86 years). We used nonlinear and penalized regression to model CA and time to all‐cause mortality. We examined associations of four new and two previously published metabolomic age models, with aging risk factors and phenotypes. Within the UK Biobank (N ≈102,000), we tested prediction of CA, incident disease (cardiovascular disease (CVD), type‐2 diabetes mellitus, cancer, dementia, and chronic obstructive pulmonary disease), and all‐cause mortality. Seven‐fold cross‐validated Pearson's r between metabolomic age models and CA ranged between 0.47 and 0.65 in the training cohort set (mean absolute error: 8–9 years). Metabolomic age models, adjusted for CA, were associated with C‐reactive protein, and inversely associated with glomerular filtration rate. Positively associated risk factors included obesity, diabetes, smoking, and physical inactivity. In UK Biobank, correlations of metabolomic age with CA were modest (r = 0.29–0.33), yet all metabolomic model scores predicted mortality (hazard ratios of 1.01 to 1.06/metabolomic age year) and CVD, after adjustment for CA. While metabolomic age models were only moderately associated with CA in an independent population, they provided additional prediction of morbidity and mortality over CA itself, suggesting their wider applicability. [ABSTRACT FROM AUTHOR]

Introduction: Kidney disease is common after pediatric heart transplantation. Serum creatinine‐based glomerular filtration rate is the most frequently reported measure of kidney function. Albuminuria is an additional marker of kidney dysfunction and is not well described in this population. In this study, we evaluate the prevalence and degree of albuminuria and describe clinical factors associated with albuminuria in a cohort of pediatric heart transplant recipients. Methods: This was a cross‐sectional study of pediatric heart transplant recipients. Albuminuria was assessed using spot urine albumin‐to‐creatinine ratio collected at the most recent annual screening cardiac catheterization through August 2019. Results: In 115 patients at a median duration of 10.2 years post‐transplant, 39% had albuminuria. Stage 3 or greater chronic kidney disease was present in 6%. The immunosuppressive regimen at the time of measurement contained a calcineurin inhibitor (CNI) in 88% and a proliferation signal inhibitor (PSI) in 62%. In multivariable modeling, lower eGFR, PSI use, and younger age at transplant were associated with higher levels of albuminuria, whereas CNI use was associated with lower levels of albuminuria. Conclusion: Albuminuria is a prevalent finding in medium‐term follow up of pediatric heart transplant recipients, reflecting kidney injury, and is associated with other markers of kidney dysfunction, such as low eGFR. Younger age at transplant, lower eGFR, and PSI use were among the associations with albuminuria. [ABSTRACT FROM AUTHOR]

Aims: Pharmacogenomic testing has the potential to target medicines more effectively towards those who will benefit and avoid use in individuals at risk of harm. Health economies are actively considering how pharmacogenomic tests can be integrated into health care systems to improve use of medicines. However, one of the barriers to effective implementation is evaluation of the evidence including clinical usefulness, cost‐effectiveness, and operational requirements. We sought to develop a framework that could aid the implementation of pharmacogenomic testing. We take the view from the National Health Service (NHS) in England. Methods: We used a literature review using EMBASE and Medline databases to identify prospective studies of pharmacogenomic testing, focusing on clinical outcomes and implementation of pharmacogenomics. Using this search, we identified key themes relating to the implementation of pharmacogenomic tests. We used a clinical advisory group with expertise in pharmacology, pharmacogenomics, formulary evaluation, and policy implementation to review data from our literature review and the interpretation of these data. With the clinical advisory group, we prioritized themes and developed a framework to evaluate proposals to implement pharmacogenomics tests. Results: Themes that emerged from review of the literature and subsequent discussion were distilled into a 10‐point checklist that is proposed as a tool to aid evidence‐based implementation of pharmacogenomic testing into routine clinical care within the NHS. Conclusion: Our 10‐point checklist outlines a standardized approach that could be used to evaluate proposals to implement pharmacogenomic tests. We propose a national approach, taking the view of the NHS in England. Using this approach could centralize commissioning of appropriate pharmacogenomic tests, reduce inequity and duplication using regional approaches, and provide a robust and evidence‐based framework for adoption. Such an approach could also be applied to other health systems. [ABSTRACT FROM AUTHOR]

Purpose: To explore the effects of cyclosporine A (CsA) in the management of atopic keratoconjunctivitis (AKC). Methods: Open single‐group interventional consecutive cohort study (case series) at a single eye care facility in the UK. We reviewed the electronic patient records of 99 children and young people (CYP) aged 3.4–18 years with AKC treated with topical CsA 1 mg/ml. Main outcome measures were number of prescriptions and hospital clinic visits over 12 months before and after the start of CsA and the proportion of CYP affected by adverse effects. Results: The median number of inflammatory episodes requiring treatment with topical corticosteroids (tCS) fell from 3 (interquartile range IQR 1–4) during the 12 months prior to CsA to 1 (IQR 0–3) during the 12 months after, excluding tCS prescriptions with the first CsA prescription (Wilcoxon signed ranks test, 2 tailed, p < 0.01). In the 12‐month period following initiation of CsA 1 mg/ml with concomitant prescription of tCS (n = 66), daily dosage of steroids was reduced in 62 CYP (93.9%), and they were discontinued in 43 (65.2%). The median number of hospital visits fell from 4 (IQR 3–6) to 3 (IQR 2–5; Wilcoxon p < 0.01). Adverse events leading to discontinuation of CsA were stinging (instillation site pain; 9/99, 9%) and a transient skin rash (1/99, 1%). Conclusions: Off‐label use of commercial preparations of CsA 1 mg/ml significantly reduces the need for concomitant topical corticosteroids and hospital clinic visits in CYP with AKC. Stinging and skin rash can lead to discontinuation. [ABSTRACT FROM AUTHOR]

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The Dalbergia sissoo leaves traditionally have medicinal values and are well known for current research on osteoporosis and bone health. The present research aims to develop and validate a simple, sensitive, and comprehensive analytical method to standardize Dalbergia sissoo leaves. An ultra‐high performance liquid chromatography method was developed for seven isoflavone glycosides, and isoflavone's identification, including bioactive caviunin and biochanin‐A based glycosides with genistein, pratensein, biochanin‐A, and biochanin‐A‐7‐O‐glucoside for simultaneous quantification in Dalbergia sissoo leaves. Also, a novel high‐performance thin‐layer chromatography‐based method has been developed for isoflavone glycosides as a visual quality control tool for Dalbergia sissoo. Further, seven isoflavonoids were also characterized using mass spectrometry in sample matrices. A qualitative high‐performance thin‐layer chromatography‐based method was found helpful in identifying four major isoflavone glycosides in leaves. The performance of the method and the validation data showed the ultra‐high performance liquid chromatography method was precise (relative standard deviation < 5.0%), accurate (recoveries 80%–110%), robust (relative standard deviation < 5.0%), and linear (r2 > 0.99) for quantification. This well‐separated novel and rapid determination of Dalbergia sissoo compounds in leaves will be helpful in the standardization of the quality assessment tool for Dalbergia sissoo. [ABSTRACT FROM AUTHOR]

Tinospora cordifolia is an important traditional botanical medicine used as an immunomodulator with diversified therapeutic potential. The present study used the systematic isolated Tinospora cordifolia compounds (tinosporide, 8‐hydroxy tinosporide, tinosporaside, cordifolioside A, 20‐β‐hydroxy ecdysone, and columbin) with four alkaloids (syringin, magnoflorine, tetrahydropalmatine, and jatrorrhizine) to develop and validate a high‐performance liquid chromatography method for simultaneous quantification of these multi‐class bioactive. This novel method showed good specificity with excellent linearity (r2 > 0.99), precision (relative standard deviation < 5.0%), and robust and accurate performance (93.68–99.76%) for 10 Tinospora cordifolia compounds as an effective strategy for quantification using the single and multi‐class standards approach. The rapid marker‐based qualitative high‐performance thin‐layer chromatography methods were also developed to analyze samples as a visual quality control tool. These methods were first applied to analyze 15 Tinospora cordifolia samples using the external standard method. By analyzing the results based on the multi‐class (%relative error 2.19–10.56) and single standard (%relative error 25.00–70.50) approach, the multi‐class standard assessment can be effectively adapted for Tinospora cordifolia samples. The quantitative‐qualitative analysis was further confirmed with mass spectroscopy characterization. This multi‐faceted analytical approach provides a unique solution for fingerprint, quality assurance, and identification of Tinospora cordifolia with tinosporide, 8‐hydroxy tinosporide, and tinosporaside as an authenticated marker. [ABSTRACT FROM AUTHOR]

Introduction: Plasma proteins affect biological processes and are common drug targets but their role in the development of Alzheimer's disease and related dementias remains unclear. We examined associations between 4953 plasma proteins and cognitive decline and risk of dementia in two cohort studies with 20‐year follow‐ups. Methods: In the Whitehall II prospective cohort study proteins were measured using SOMAscan technology. Cognitive performance was tested five times over 20 years. Linkage to electronic health records identified incident dementia. The results were replicated in the Atherosclerosis Risk in Communities (ARIC) study. Results: Fifteen non‐amyloid/non‐tau–related proteins were associated with cognitive decline and dementia, were consistently identified in both cohorts, and were not explained by known dementia risk factors. Levels of six of the proteins are modifiable by currently approved medications for other conditions. Discussion: This study identified several plasma proteins in dementia‐free people that are associated with long‐term risk of cognitive decline and dementia. [ABSTRACT FROM AUTHOR]

Genetic, environmental, and pharmacological interventions into the aging process can confer resistance to multiple age‐related diseases in laboratory animals, including rhesus monkeys. These findings imply that individual mechanisms of aging might contribute to the co‐occurrence of age‐related diseases in humans and could be targeted to prevent these conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation and found strong, non‐random associations between age‐related diseases and aging mechanisms in humans, confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age‐related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signaling pathway and activity of the ERK1/2 pathway were associated with multiple aging mechanisms and diverse age‐related diseases. Mechanisms of aging hence contribute both together and individually to age‐related disease co‐occurrence in humans and could potentially be targeted accordingly to prevent multimorbidity. [ABSTRACT FROM AUTHOR]

Objective: The primary objective was to investigate the relationship between periodontitis and hypertension in two independent large surveys. The secondary objective was to ascertain whether systemic inflammation had a mediation effect in the association. Methods: This cross‐sectional study analysed representative samples of the US (n = 3460; NHANES 2009/10) and Korean (n = 4539; 2015 KNHANES VI‐3) populations. The association between periodontitis (exposure), hypertension (outcome) and inflammatory markers [C‐reactive protein (CRP) and white blood cell counts (WBC)] (mediators) was assessed using multivariate linear and logistic regression models and mediation analysis. Results: Participants with periodontitis were more likely to have hypertension (NHANES: OR = 1.3, 95% CI: 1.0–1.6, P = 0.025; KNHANES: OR = 1.2, 95% CI: 1.0–1.4, P = 0.041) and actual systolic blood pressure ≥ 140 mmHg (NHANES: OR = 1.6, 95% CI: 1.1–2.3, P < 0.001; KNHANES: OR = 1.3, 95% CI :1.0–1.6, P < 0.031) than those without the disease. These associations were independent of age, gender, BMI, education level, smoking, alcohol consumption, creatinine, physical activity, presence of other comorbidities and confirmed in participants not taking antihypertensive medications. Diagnosis of periodontitis was directly associated with WBC (in both surveys: NHANES: β ± SE = 0.3 ± 0.1, P < 0.004; KNHANES: β ± SE = 0.3 ± 0.1, P < 0.001) and with CRP levels (in one survey: NHANES: β ± SE = 0.1 ± 0.03, P < 0.007; KNHANES: β ± SE = 0.1 ± 0.04, P > 0.213). Mediation analyses confirmed that CRP acted as a mediator in the association between periodontitis and hypertension in both populations (mediated effect: NHANES: β ± SE = 0.010 ± 0.003, P < 0.001; KNHANES: β ± SE = 0.003 ± 0.001, P = 0.015). WBC acted as a mediator in the KNHANES (mediated effect: β ± SE = 0.004 ± 0.001, P = 0.004) whilst in the NHANES, its effect was dependent of CRP inclusion in the model (mediated effect WBC + CRP: β ± SE = 0.002 ± 0.001, P = 0.001). Conclusions: These findings suggest that periodontitis is closely linked to hypertension and systemic inflammation is, in part, a mediator of this association. [ABSTRACT FROM AUTHOR]

Seeds of Blepharis persica, the extracts of which have various pharmacological activities, contain benzoxazinoid compounds. The present studies were aimed to isolate benzoxazinoid class of compound using chromatography, identify the isolated compound using spectroscopic methods, and development of a high‐performance liquid chromatography‐based analytical method for estimation of the constituent. The compound was isolated using HP‐20 and silica‐based column from n‐butanol fraction of Blepharis persica seeds and identified as blepharin from interpretation of spectra. An analytical method was developed using high‐performance liquid chromatography containing a photodiode‐array detector and validated as per ICH Q2(R1) guideline for estimation of blepharin. Blepharin was resolved using a C18 column, whereas the optimized mobile phase was water (pH 8): acetonitrile (90:10, %v/v). The linearity was established between 0.5 to 10.00 μg/mL. Limit of detection and limit of quantification were 0.015 and 0.046 μg/mL, respectively. The recovery was in the range of 100.9‐103.9%. The method was found to be selective, precise, and robust too. The content of blepharin was found (0.708 ± 0.02)% w/w of the dried weight basis of plant extract. [ABSTRACT FROM AUTHOR]

Background: Strategies to optimize management in rhabdomyosarcoma (RMS) include risk stratification to assign therapy aiming to minimize treatment morbidity yet improve outcomes. This analysis evaluated the relationship between complete metabolic response (CMR) as assessed by 18F‐fluorodeoxyglucose positron emission tomography‐computed tomography (FDG‐PET) imaging and event‐free survival (EFS) in intermediate‐risk (IR) and high‐risk (HR) RMS patients. Methods: FDG‐PET imaging characteristics, including assessment of CMR and maximum standard uptake values (SUVmax) of the primary tumor, were evaluated by central review. Institutional reports of SUVmax were used when SUVmax values could not be determined by central review. One hundred and thirty IR and 105 HR patients had FDG‐PET scans submitted for central review or had SUVmax data available from institutional report at any time point. A Cox proportional hazards regression model was used to evaluate the relationship between these parameters and EFS. Results: SUVmax at study entry did not correlate with EFS for IR (p = 0.32) or HR (p = 0.86) patients. Compared to patients who did not achieve a CMR, EFS was not superior for IR patients who achieved a CMR at weeks 4 (p = 0.66) or 15 (p = 0.46), nor for HR patients who achieved CMR at week 6 (p = 0.75) or 19 (p = 0.28). Change in SUVmax at week 4 (p = 0.21) or 15 (p = 0.91) for IR patients or at week 6 (p = 0.75) or 19 (p = 0.61) for HR patients did not correlate with EFS. Conclusion: Based on these data, FDG‐PET does not appear to predict EFS in IR or HR‐RMS. It remains to be determined whether FDG‐PET has a role in predicting survival outcomes in other RMS subpopulations. [ABSTRACT FROM AUTHOR]

Olaratumab is a monoclonal antibody that specifically binds to platelet‐derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21‐day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high‐dose ifosfamide by investigator choice for subsequent 21‐day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A‐C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose‐limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma‐glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment‐emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents. [ABSTRACT FROM AUTHOR]

Objective: This study evaluated the risk of subclinical atrial fibrillation (AF) in patients with central retinal artery occlusion (CRAO) compared to those with cryptogenic stroke using implantable loop recorders (ILR). Methods: We conducted a retrospective analysis of 273 consecutive patients who had ILRs inserted at our institution for either cryptogenic stroke (n = 227) or CRAO (n = 46). Our primary endpoint was a time to event analysis for the new diagnosis of AF by ILR. Univariable and multivariable Cox proportional hazard models were used to determine the predictors of time‐to‐AF. Results: A total of 64 patients were found to have newly diagnosed AF by remote monitoring of the ILR. AF was detected in 57 of 227 (25%) cryptogenic stroke patients by the end of a maximum 5.1 years follow‐up and in seven of 46 (15%) CRAO patients by the end of a maximum 3.6 years follow‐up (P =.215, log‐rank test). The Kaplan‐Meier estimates for freedom from AF was 59.4% for CRAO and 66.6% for cryptogenic stroke (P = NS, log‐rank test). Baseline variables predicting AF included older patients, higher CHADS2VASC score, longer PR interval on initial EKG evaluation, and mitral annular calcification on transthoracic echocardiogram. Conclusions: Patients with CRAO are at risk for subclinical AF, similar to those with cryptogenic stroke. Long‐term monitoring to detect AF may lead to changes in pharmacotherapy to reduce the risk for subsequent stroke. [ABSTRACT FROM AUTHOR]

Key content: Pregnancy may precipitate several physiological changes that can have ocular consequences; many of these are innocuous and require little more than reassurance for the patient.There are uncommon instances of new sight‐threatening pathology that necessitate a prompt approach.Pregnant women presenting to the ophthalmologist with ocular symptoms can cause concern because alternative differentials may need to be considered; and the potential teratogenic or fetotoxic effects of investigations or treatment mean that management decisions may, in some cases, differ to those of the nonpregnant patient. Learning objectives: To be aware of both physiological and pathological ocular changes that may occur during pregnancy.To develop a greater understanding of investigations and management of ophthalmic and neuro‐ophthalmic disorders in pregnancy.To develop an understanding of referral pathways, enabling an optimal outcome for both mother and baby. [ABSTRACT FROM AUTHOR]

Purpose: A bottleneck in developing cell therapies for cancer is assaying cell biodistribution, persistence, and survival in vivo. Ex vivo cell labeling using perfluorocarbon (PFC) nanoemulsions, paired with 19F MRI detection, is a non‐invasive approach for cell product detection in vivo. Lymphocytes are small and weakly phagocytic limiting PFC labeling levels and MRI sensitivity. To boost labeling, we designed PFC nanoemulsion imaging probes displaying a cell‐penetrating peptide, namely the transactivating transcription sequence (TAT) of the human immunodeficiency virus. We report optimized synthesis schemes for preparing TAT co‐surfactant to complement the common surfactants used in PFC nanoemulsion preparations. Methods: We performed ex vivo labeling of primary human chimeric antigen receptor (CAR) T cells with nanoemulsion. Intracellular labeling was validated using electron microscopy and confocal imaging. To detect signal enhancement in vivo, labeled CAR T cells were intra‐tumorally injected into mice bearing flank glioma tumors. Results: By incorporating TAT into the nanoemulsion, a labeling efficiency of ~1012 fluorine atoms per CAR T cell was achieved that is a >8‐fold increase compared to nanoemulsion without TAT while retaining high cell viability (~84%). Flow cytometry phenotypic assays show that CAR T cells are unaltered after labeling with TAT nanoemulsion, and in vitro tumor cell killing assays display intact cytotoxic function. The 19F MRI signal detected from TAT‐labeled CAR T cells was 8 times higher than cells labeled with PFC without TAT. Conclusion: The peptide‐PFC nanoemulsion synthesis scheme presented can significantly enhance cell labeling and imaging sensitivity and is generalizable for other targeted imaging probes. [ABSTRACT FROM AUTHOR]

Objective: To examine whether genetic variation affecting the expression or function of lipid-lowering drug targets is associated with Alzheimer disease (AD) risk, to evaluate the potential impact of long-term exposure to corresponding therapeutics.Methods: We conducted Mendelian randomization analyses using variants in genes that encode the protein targets of several approved lipid-lowering drug classes: HMGCR (encoding the target for statins), PCSK9 (encoding the target for PCSK9 inhibitors, eg, evolocumab and alirocumab), NPC1L1 (encoding the target for ezetimibe), and APOB (encoding the target of mipomersen). Variants were weighted by associations with low-density lipoprotein cholesterol (LDL-C) using data from lipid genetics consortia (n up to 295,826). We meta-analyzed Mendelian randomization estimates for regional variants weighted by LDL-C on AD risk from 2 large samples (total n = 24,718 cases, 56,685 controls).Results: Models for HMGCR, APOB, and NPC1L1 did not suggest that the use of related lipid-lowering drug classes would affect AD risk. In contrast, genetically instrumented exposure to PCSK9 inhibitors was predicted to increase AD risk in both of the AD samples (combined odds ratio per standard deviation lower LDL-C inducible by the drug target = 1.45, 95% confidence interval = 1.23-1.69). This risk increase was opposite to, although more modest than, the degree of protection from coronary artery disease predicted by these same methods for PCSK9 inhibition.Interpretation: We did not identify genetic support for the repurposing of statins, ezetimibe, or mipomersen for AD prevention. Notwithstanding caveats to this genetic evidence, pharmacovigilance for AD risk among users of PCSK9 inhibitors may be warranted. ANN NEUROL 2020;87:30-39. [ABSTRACT FROM AUTHOR]

The relatively high failure rates, with important consequences in many cases, suggest that the implicitly acceptable risk levels corresponding to temporary civil engineering structures and activities might exceed the bounds of normally acceptable levels associated with different societal activities. Among other reasons, this may be attributed to the lack of a rational approach for the assessment of risks associated with the different technologies supporting these activities in general, and for structures in particular. There is a need for establishing appropriate target reliability levels for structures under temporary use taking into account specific circumstances such as reduced risk exposure times. This issue is being addressed in this article. Acceptance criteria for building‐structure‐related risks to persons obtained in prior studies are adapted to the special circumstances of nonpermanent risk exposure. Thereby, the general principle followed is to maintain the same risk levels per time unit as for permanently occupied buildings. The adaptation is based on the statistical annual fatality rate, a life safety risk metric that allows for a consistent comparison of risks across different societal activities and technologies. It is shown that the target reliability indices taking account of the temporary use of buildings might be significantly higher than the values suggested for permanently used structures. [ABSTRACT FROM AUTHOR]

Whilst VKC only affects the eye surface, AKC is often accompanied by chronic blepharitis (lid margin inflammation) and systemic conditions such as eczema. As dermatitis frequently affects the eyelids, reports have emerged that tacrolimus skin ointment is well tolerated on the ocular surface and has a strong effect on dampening AKC/VKC inflammation. Yet surprisingly little high-quality evidence is available about efficacy and safety of topical and systemic treatments for AKC and VKC.2 WHY IS AKC/VKC IMPORTANT TO PRACTITIONERS OUTSIDE OF EYE CLINICS?. [Extracted from the article]

Purpose: To evaluate non‐contact infrared meibography and anterior segment optical coherence tomography (AS‐OCT) to detect meibomian gland (MG) and corneal changes in children with blepharokeratoconjunctivitis (BKC). Methods: We acquired infrared meibography images of upper and lower lids and AS‐OCT corneal scans. One masked observer graded meiboscore, full/partial MG dropout, and measured total corneal volume and differential corneal volume per quadrant and central corneal thickness (CCT). Results: We enrolled 63 children, 31 with BKC and 32 without ocular surface inflammation; median (interquartile range) age BKC 10.6 (7.2‐13.9) years, healthy volunteers (HV) 11.4 (9.5‐13.8) years. Likert scale scores for meibography and OCT indicate no to low discomfort. Meiboscores for upper and lower lids as well as the total meiboscore were significantly higher in children with BKC than in HV. Subscores for full and partial MG dropout were also significantly higher in children with BKC than in healthy volunteers. There was no statistically significant difference between upper and lower lid for meiboscore nor full/partial MG dropout scores. The corneal volume in the superior quadrant was significantly higher in children with BKC than in HV, whereas the corneal volume in the nasal and inferior quadrants was significantly lower. Conclusions: Non‐contact imaging technologies objectively demonstrate damage to meibomian glands and changes in corneal volume secondary to BKC. The tests are well tolerated by children with mild/moderate ocular surface inflammation and can detect changes without the requirement for routine eversion of the upper lid. These parameters may be useful both for clinical follow‐up and clinical trials. [ABSTRACT FROM AUTHOR]

Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care. Under the organization of the Bone Tumor Biology Committee of the Children's Oncology Group, a team of clinicians and scientists sought to define the state of the science and to identify questions that, if answered, have the greatest potential to drive fundamental clinical advances. Having discussed these questions in a series of meetings, each led by invited experts, we distilled these conversations into a series of seven Provocative Questions. These include questions about the molecular events that trigger oncogenesis, the genomic and epigenomic drivers of disease, the biology of lung metastasis, research models that best predict clinical outcomes, and processes for translating findings into clinical trials. Here, we briefly present each Provocative Question, review the current scientific evidence, note the immediate opportunities, and speculate on the impact that answered questions might have on the field. We do so with an intent to provide a framework around which investigators can build programs and collaborations to tackle the hardest problems and to establish research priorities for those developing policies and providing funding. [ABSTRACT FROM AUTHOR]

Intensive exercise of elite athletes can lead to physiological alterations in the cardiovascular system in response to increased stroke volume and blood pressure, known collectively as cardiovascular demand (CD). This study aimed to compare metabolic differences in elite athletes with high vs low/moderate CD and to reveal their underlying metabolic pathways as potential biomarker signatures for assessing health, performance, and recovery of elite athletes. Metabolic profiling of serum samples from 495 elite athletes from different sport disciplines (118 high CD and 377 low/moderate CD athletes) was conducted using non‐targeted metabolomics‐based mass spectroscopy combined with ultra‐high‐performance liquid chromatography. Results show that DAGs containing arachidonic were enriched in high CD together with branched‐chain amino acids, plasminogens, phosphatidylcholines, and phosphatidylethanolamines, potentially indicating increased risk of cardiovascular disease in the high CD group. Gamma‐glutamyl amino acids and glutathione metabolism were increased in low/moderate CD group, suggesting more efficient oxidative stress scavenging mechanisms than the high CD group. This first most comprehensive metabolic profiling of elite athletes provides an evidence that athletes with different CD show a unique metabolic signature that reflects energy generation and oxidative stress and potentially places the high CD group at a higher risk of cardiovascular disease. Further studies are warranted for confirmation and validation of findings in other sport groups in light of potential confounders related to limited available information about participants. [ABSTRACT FROM AUTHOR]

Bright long‐wavelength‐excitable semiconducting polymer dots (LWE‐Pdots) are highly desirable for in vivo imaging and multiplexed in vitro bioassays. LWE‐Pdots have been obtained by incorporating a near‐infrared (NIR) emitter into the backbone of a polymer host to develop a binary donor–acceptor (D–A) system. However, they usually suffer from severe concentration quenching and a trade‐off between fluorescence quantum yield (Φf) and absorption cross‐section (σ). Herein, we describe a ternary component (D1/D2–A) strategy to achieve ultrabright, green laser‐excitable Pdots with narrow‐band NIR emission by introducing a BODIPY‐based assistant polymer donor as D1. The D1/D2–A Pdots possess improved Φf and σ compared to corresponding binary D2–A Pdots. Their Φf is as high as 40.2 %, one of the most efficient NIR Pdots reported. The D1/D2–A Pdots show ultrahigh single‐particle brightness, 83‐fold brighter than Qdot 705 when excited by a 532 nm laser. When injected into mice, higher contrast in vivo tumor imaging was achieved using the ternary Pdots versus the binary D–A Pdots. [ABSTRACT FROM AUTHOR]

Objective Functional imaging of synovitis could improve both early detection of rheumatoid arthritis (RA) and long-term outcomes. Given the intersection of inflammation with coagulation protease activation, this study was undertaken to examine coagulation protease activities in arthritic mice with a dual-fluorescence ratiometric activatable cell-penetrating peptide (RACPP) that has a linker, norleucine (Nle)-TPRSFL, with a cleavage site for thrombin. Methods K/BxN-transgenic mice with chronic arthritis and mice with day 1 passive serum-transfer arthritis were imaged in vivo for Cy5:Cy7 emission ratiometric fluorescence from proteolytic cleavage and activation of RACPPNleTPRSFL. Joint thickness in mice with serum-transfer arthritis was measured from days 0 to 10. The cleavage-evoked release of Cy5-tagged tissue-adhesive fragments enabled microscopic correlation with immunohistochemistry for inflammatory markers. Thrombin dependence of ratiometric fluorescence was tested by ex vivo application of RACPPNleTPRSFL and argatroban to cryosections obtained from mouse hind paws on day 1 of serum-transfer arthritis. Results In chronic arthritis, RACPPNleTPRSFL fluorescence ratios of Cy5:Cy7 emission were significantly higher in diseased swollen ankles of K/BxN-transgenic mice than in normal mouse ankles. A high ratio of RACPPNleTPRSFL fluorescence in mouse ankles and toes on day 1 of serum-transfer arthritis correlated with subsequent joint swelling. Foci of high ratiometric fluorescence localized to inflammation, as demarcated by immune reactivity for citrullinated histones, macrophages, mast cells, and neutrophils, in soft tissue on day 1 of serum-transfer arthritis. Ex vivo application of RACPPNleTPRSFL to cryosections obtained from mice on day 1 of serum-transfer arthritis produced ratiometric fluorescence that was inhibited by argatroban. Conclusion RACPPNleTPRSFL activation detects established experimental arthritis, and the detection of inflammation by RACPPNleTPRSFL on day 1 of serum-transfer arthritis correlates with disease progression. [ABSTRACT FROM AUTHOR]

Regulatory agencies encourage sponsors to submit 24-hour ambulatory ECG data for assessing cardiac safety of new drugs, and some arrhythmias, hitherto considered rare, have been observed in some early-phase studies. Interpretation of these observations is difficult given the dearth of published data on the prevalence of cardiac arrhythmias seen during 24-hour continuous ECG monitoring in healthy volunteers (HV) from clinical trials. We analyzed drug-free ambulatory ECG recordings from 1273 HV (1000 males, 273 females; age 18-65 years) from 22 phase 1 studies that were analyzed in a core ECG laboratory; all subjects had normal screening ECGs. Supraventricular arrhythmias such as supraventricular premature complexes were observed in 60.8% of healthy volunteers, supraventricular tachycardia in 2.2%, and atrial fibrillation in 0.1%. Ventricular arrhythmias included premature ventricular complexes (PVCs) in 43.4%, >200 PVCs per 24 hours in 3.3%, multifocal PVCs in 5.3%, nonsustained ventricular tachycardia in 0.7%, and accelerated idioventricular rhythm in 0.3%. Bradyarrhythmias included sinus pause >3 seconds in 0.3%, and second-degree AV block in 2.4%. Complete heart block and torsades de pointes were not seen in any subject. Based on the observed incidence, we estimated the maximum number of healthy subjects in whom these arrhythmias may be seen as a matter of chance in studies with smaller sample sizes if the study drug has no arrhythmogenic effect. Our results and these estimates could help interpret whether cardiac arrhythmias observed in early-phase studies are due to chance or possibly are a drug effect. [ABSTRACT FROM AUTHOR]

In routine engineering practice, the risks associated with safety considerations addressed when designing new or assessing existing structures are not quantified and the corresponding acceptance criteria may diverge widely. Although the use of explicit risk analysis methods to quantify structural safety would therefore deliver significant benefits, the implementation of such methods is hindered by a series of technical and administrative obstacles. The present study explores methods and tools for the practical application of explicit risk analysis methods. Structure-related risks to persons are established on the grounds of the probability of structural failure and its consequences in terms of loss of human life. The procedure adopted is applied to a representative set of building structures. Acceptance criteria for risks to persons associated with such structures are deduced from the findings. These criteria provide a rational basis for decision-making in structural engineering. They may be used in explicit risk analysis or as a basis for the consistent calibration of simplified models for determining partial factors in the design of new or assessment of existing structures. [ABSTRACT FROM AUTHOR]

Aims To use Mendelian randomization to assess whether alcohol intake was causally associated with cognitive function. Design Mendelian randomization using a genetic variant related to alcohol intake (ADH1B rs1229984) was used to obtain unbiased estimates of the association between alcohol intake and cognitive performance. Setting Europe. Participants More than 34 000 adults. Measurements Any versus no alcohol intake and units of intake in the previous week was measured by questionnaire. Cognitive function was assessed in terms of immediate and delayed word recall, verbal fluency and processing speed. Findings Having consumed any versus no alcohol was associated with higher scores by 0.17 standard deviations (SD) [95% confidence interval (CI) = 0.15, 0.20] for immediate recall, 0.17 SD (95% CI = 0.14, 0.19) for delayed recall, 0.17 SD (95% CI = 0.14, 0.19) for verbal fluency and 0.12 SD (95% CI = 0.09, 0.15) for processing speed. The minor allele of rs1229984 was associated with reduced odds of consuming any alcohol (odds ratio = 0.87; 95% CI = 0.80, 0.95; P = 0.001; R2 = 0.1%; F-statistic = 47). In Mendelian randomization analysis, the minor allele was not associated with any cognitive test score, and instrumental variable analysis suggested no causal association between alcohol consumption and cognition: −0.74 SD (95% CI = −1.88, 0.41) for immediate recall, −1.09 SD (95% CI = −2.38, 0.21) for delayed recall, −0.63 SD (95% CI = −1.78, 0.53) for verbal fluency and −0.16 SD (95% CI = −1.29, 0.97) for processing speed. Conclusions The Mendelian randomization analysis did not provide strong evidence of a causal association between alcohol consumption and cognitive ability. [ABSTRACT FROM AUTHOR]

This review focuses on exogenous magnetic resonance imaging (MRI) contrast agents that are responsive to enzyme activity. Enzymes can catalyze a change in water access, rotational tumbling time, the proximity of a 19F-labeled ligand, the aggregation state, the proton chemical-exchange rate between the agent and water, or the chemical shift of 19F, 31P, 13C or a labile 1H of an agent, all of which can be used to detect enzyme activity. The variety of agents attests to the creativity in developing enzyme-responsive MRI contrast agents. [ABSTRACT FROM AUTHOR]

Morphological ECG abnormalities occur in 5-12% healthy adults participating in early phase clinical trials. We retrospectively analyzed 16,472 12-lead ECGs recorded at multiple time points in 420 volunteers (282 males, 138 females; aged 18-76 years) randomized to receive placebo from 19 Phase I studies to see if some baseline ECG abnormalities may disappear or new abnormalities may appear during the study. One hundred forty-four (34.3%) subjects had abnormal baseline ECGs, of which 66 (44.8%) reverted to normal during follow-up. Of 276 (65.7%) subjects with normal baseline ECGs, 118 (42.8%) developed ECG abnormalities over the next 6 weeks. Common baseline abnormalities included sinus bradycardia, R wave transition abnormalities, right axis deviation, non-specific T wave changes and atrial premature complexes. On follow-up ECGs, prolonged QT interval, first-degree AV block, sinus bradycardia, short PR interval, and R wave transition abnormalities reverted to normal. Common new-onset abnormalities in subjects with normal baseline ECGs included sinus bradycardia, prolonged QT interval, non-specific T wave changes, R wave transition abnormalities, and sinus tachycardia. Thus, transient morphological ECG changes may occur in healthy volunteers possibly due to diurnal variation, effect of food, hormones, or autonomic changes. This should be considered when interpreting 'treatment-emergent' ECG changes in clinical trials. [ABSTRACT FROM AUTHOR]

Oestrogen is mainly responsible for alterations in blood vessels and progesterone stimulates the production of inflammatory mediators. In females, during puberty, ovulation and pregnancy, there is an increase in the production of sex steroid hormones, which results in increased gingival inflammation, characterized by gingival enlargement, increased bleeding and crevicular fluid flow. This article presents a case of a patient who presented with a complaint of gingival swelling and spontaneous bleeding that persisted for more than two months. Her health history documented the recently diagnosed presence of polycystic ovarian syndrome. Clinical examination revealed enlarged painful gingival tissues, which bled when touched. After completion of Phase I therapy, the enlargement did not subside and a biopsy sample was taken. This was compared with another patient who had the same health condition but did not show any gingival enlargement. Testing of tissue samples for oestrogen and progesterone receptors showed the first patient to be positive for oestrogen receptors but negative for progesterone, whereas the control was negative for both. Positive oestrogen receptors suggest that polycystic ovarian syndrome has some effect on the periodontium. The dental consequences of this condition, highly prevalent among young females, are typically ignored. Further studies warrant establishment of a clinical association and future diagnosis. [ABSTRACT FROM AUTHOR]

Age-dependent renal length tables are routinely used when interpreting pediatric ultrasound. Standard renal length tables may not be accurate for HCT patients due to treatment effects on kidney size. The purpose of this study was to determine whether renal size changes from expected lengths based on age after HCT in the absence of other markers of renal disease. Four hundred and fifty renal measurements were made on 101 patients who underwent HCT between 2006 and 2010. Renal length was measured at 1-90 days pre- HCT and at 0-30, 31-90, 91-180, and 181+ days post- HCT. Values were compared with normal renal length tables. Average post- HCT renal lengths were greater than established normative renal length data within every age group. Age-adjusted average renal lengths measured at 0-30 and 31-90 days post-transplantation were significantly larger than pre- HCT renal lengths, with relative increases of 6.9% (4.5, 9.4; p < 0.001) and 3.9% (1.4, 6.4; p = 0.003), respectively. Average renal length did not differ significantly after 90 days post-transplantation. HCT patients may have larger kidneys in the absence of renal disease. Awareness of the potential phenomenon of transient renal enlargement following HCT can prevent misdiagnosis and eliminate unnecessary diagnostic evaluations, interventions, anxiety, resource allocation, and financial costs. [ABSTRACT FROM AUTHOR]

Adoptive T-cell therapy involves the isolation, expansion, and reinfusion of T lymphocytes with a defined specificity and function as a means to eradicate cancer. Our research has focused on specifying the requirements for tumor eradication with antigen-specific T cells and T cells transduced to express a defined T-cell receptor ( TCR) in mouse models and then translating these strategies to clinical trials. Our design of T-cell-based therapy for cancer has reflected efforts to identify the obstacles that limit sustained effector T-cell activity in mice and humans, design approaches to enhance T-cell persistence, develop methods to increase TCR affinity/T-cell functional avidity, and pursue strategies to overcome tolerance and immunosuppression. With the advent of genetic engineering, a highly functional population of T cells can now be rapidly generated and tailored for the targeted malignancy. Preclinical studies in faithful and informative mouse models, in concert with knowledge gained from analyses of successes and limitations in clinical trials, are shaping how we continue to develop, refine, and broaden the applicability of this approach for cancer therapy. [ABSTRACT FROM AUTHOR]

The matricellular protein periostin is strongly expressed in collagen-rich connective tissues such as periodontal ligaments (PDLs), skeletal muscle, adipose tissue, tendons, skin, and bone. It is prominent in tumorigenesis, angiogenesis, and cardiac repair. It is localized in the periosteum and PDL, where it is seen in the cytoplasmic extensions of the PDL fibroblasts. It plays a key role in morphogenesis, postnatal development, and maintenance of the tooth, and related structures. It mediates and augments collagen fibrillogenesis, cell migration, adhesion, response to mechanical stress, and wound healing. It has been shown to be an integral regulator of periodontal disease pathogenesis and repair. This review focuses on the various functional aspects of periostin in dental connective tissue development and maintenance. J. Cell. Physiol. 229: 1-5, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]