The epidemiology of alopecia areata: a population-based cohort study in UK primary care.

BACKGROUND: There is a lack of population-based information on the disease burden and management of alopecia areata (AA). OBJECTIVES: To describe the epidemiology of AA, focusing on incidence, demographics and patterns of healthcare utilization. METHODS: Population-based cohort study of 4·16 million adults and children, using UK electronic primary care records from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network database, 2009-2018. The incidence and point prevalence of AA were estimated. Variation in AA incidence by age, sex, deprivation, geographical distribution and ethnicity was examined. Patterns of healthcare utilization were evaluated in people with incident AA. RESULTS: The AA incidence rate was 0·26 per 1000 person-years. AA point prevalence in 2018 was 0·58% in adults. AA onset peaked at age 25-29 years for both sexes, although the peak was broader in females. People of nonwhite ethnicity were more likely to present with AA, especially those of Asian ethnicity [incidence rate ratio (IRR) 3·32 (95% confidence interval 3·11-3·55)]. Higher AA incidence was associated with social deprivation [IRR most vs. least deprived quintile 1·47 (1·37-1·59)] and urban living [IRR 1·23 (1·14-1·32)]. People of higher social deprivation were less likely to be referred for specialist dermatology review. CONCLUSIONS: By providing the first large-scale estimates of the incidence and point prevalence of AA, our study helps to understand the burden of AA on the population. Understanding the variation in AA onset between different population groups may give insight into the pathogenesis of AA and its management.

Non-radiative healing assessment techniques for fractured long bones and osseointegrated implant.

The paper provides an overview of the fracture healing process of long bones, a review of work that proposed appropriate physical parameters for the assessment of healing and highlights some recent work that reported on the development of non-radiative technique for healing assessment. An overview of the development and monitoring of osseointegration for trans-femoral osseointegrated implant is also presented. The state of healing of a fractured long bone and the stability of osseointegrated implants can be seen as engineering structural components where the mechanical properties are restored to facilitate their desired function. To this end, this paper describes non-radiative techniques that are useful for healing assessment and the stability assessment of osseointegrated implants. The achievement of non-radiative quantitative assessment methodologies to determine the state of healing of fractured long bones and to assess the stability of osseointegrated implant will shorten the patient's rehabilitation time, allowing earlier mobility and return to normal activities. Recent work on the development of assessment techniques supported by the Office of Naval Research as part of the Monitoring of Osseointegrated Implant Prosthesis program is highlighted.

Correlation between kidney and peripheral nerve functions in Type 2 diabetes.

BACKGROUND: Although greater impairments in nerve functions parameters are most likely to occur with a lower kidney function, there is a paucity of information on the relationship between the kidney and peripheral nerve functions parameters in Type 2 diabetes. AIM: To address the impact of peripheral nerve functions in Type 2 diabetes patients in different stages of chronic kidney diseases (CKD). DESIGN: This prospective study enrolled 238 patients with Type 2 diabetes at a tertiary medical center. METHOD: We designed composite amplitude scores of nerve conductions (CAS) as a measure of severity of peripheral neuropathy (PN), and used estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) parameters to stage CKD in Type 2 diabetes patients. The intrapersonal mean, standard deviation and coefficient of variation of eGFR for 238 patients were obtained in the 3 years prior to the study. RESULTS: The patients who had lower eGFR and higher UACR were older, with longer diabetes duration, a greater percentage of retinopathy and PN and higher CAS. Multiple linear regression analysis revealed that diabetes duration and eGFR were independently associated with CAS, and a cut-off value of eGFR in the presence of PN was 65.3 ml/min/1.73 m2. CONCLUSION: We observed a close relationship between the severity of kidney and peripheral nerve function in patients with diabetes. If a patient's eGFR value is below 65.3 ml/min/1.73 m2 or the UACR value is above 98.6 mg/dl, caution is needed with the presence of PN even in diabetic patients who are asymptomatic.

Racial difference in bioavailability of oral ibandronate between Caucasian and Taiwanese postmenopausal women.

Following 150 mg of oral ibandronate, Taiwanese females have greater serum and urine levels of this drug and bone resorption marker suppression than Caucasian women. These inter-ethnic differences seems to be partly explained by a 2.48-fold higher bioavailability of ibandronate in Taiwanese postmenopausal women. INTRODUCTION: Interethnic differences in the pharmacokinetics of oral ibandronate for osteoporosis are unknown. We compared the disposition of oral ibandronate between Caucasian and Taiwanese postmenopausal women. METHODS: Ibandronate 150 mg was administered to 35 Caucasian and 16 Taiwanese postmenopausal women in two separate phase 1 studies. Interethnic comparisons were performed to assess pharmacokinetic properties, including the area under the concentration-time curve (AUC), peak concentration (Cmax), elimination half-life, urinary drug recovery (Ae%), renal clearance (CLr), apparent total clearance (CL/F), and apparent volume of distribution (Vd/F). RESULTS: The mean AUC, Cmax, and Ae% were 2.41-, 1.69-, and 2.95-fold greater in the Taiwanese than in the Caucasian subjects, and the average CL/F and Vd/F were 2.48- and 2.46-fold smaller. There were no significant differences in mean CLr and half-life between both groups. As bisphosphonates are not biotransformed but are mainly excreted in the urine, the total body clearance is close to the CLr. These results suggested a larger bioavailability in the Taiwanese group which resulted in the differences in the CL/F and Vd/F. Multiple linear regression analysis demonstrated ethnicity influences of the pharmacokinetic properties after adjusting for the other variables. CONCLUSIONS: Bioavailability was largely responsible for the interethnic pharmacokinetic differences following oral administration of 150 mg ibandronate and seemed greater in the Taiwanese compared with the Caucasian subjects. Further dose-ranging studies are warranted to determine the optimal dosages of oral ibandronate in patients of Asian or Taiwanese ethnicity.

Stratum Corneum Sampling to Assess Bioequivalence between Topical Acyclovir Products.

PURPOSE: To examine the potential of stratum corneum (SC) sampling via tape-stripping in humans to assess bioequivalence of topical acyclovir drug products, and to explore the potential value of alternative metrics of local skin bioavailability calculable from SC sampling experiments. METHODS: Three acyclovir creams were considered in two separate studies in which drug amounts in the SC after uptake and clearance periods were measured and used to assess bioequivalence. In each study, a "reference" formulation (evaluated twice) was compared to the "test" in 10 subjects. Each application site was replicated to achieve greater statistical power with fewer volunteers. RESULTS: SC sampling revealed similarities and differences between products consistent with results from other surrogate bioequivalence measures, including dermal open-flow microperfusion experiments. Further analysis of the tape-stripping data permitted acyclovir flux into the viable skin to be deduced and drug concentration in that 'compartment' to be estimated. CONCLUSIONS: Acyclovir quantities determined in the SC, following a single-time point uptake and clearance protocol, can be judiciously used both to objectively compare product performance in vivo and to assess delivery of the active into skin tissue below the barrier, thereby permitting local concentrations at or near to the site of action to be determined.

Baseline data for distribution of contaminants by natural disasters: results from a residential Houston neighborhood during Hurricane Harvey flooding.

Hurricane Harvey made landfall in Texas August 25, 2017, bringing massive rains and flooding that impacted soils in a residential neighborhood in East Houston. Trace elements, organochlorine pesticides, polycyclic aromatic hydrocarbons (PAHs), polybrominated diphenyl ether fire retardants (PBDEs) and polychlorinated biphenyls (PCBs) were determined in 24 soil samples. The highest concentrations found in soils were total PAHs, which ranged from 1,310 µg/kg to 85,700 µg/kg with a mean of 12,600 µg/kg. Analysis of specific PAH ratios indicate the source of the PAHs were dominated by pyrogenic rather than petrogenic sources. Chlordanes were detectable in the area where the likely local source is for ant control. The trace metal concentrations were below any environmental health concern concentrations but As, Cd, Hg, Pb, Se, Ag, Zn were enriched over the crustal abundance. While Hurricane Harvey was responsible for the redistribution of many contaminants, the large volume of rain and floodwater likely transported contaminants from the land areas and into the Houston Ship Channel and Galveston Bay. The findings from this study will serve as baseline data for determining the mobilization of contaminants caused by natural disasters.

Epidemiology of respiratory syncytial virus infection and its effect on children with heart disease in Hong Kong: a multicentre review.

OBJECTIVES: There is no guideline in Hong Kong regarding respiratory syncytial virus (RSV) immunoprophylaxis for children with heart disease because of a lack of local data on RSV infection. Therefore, this study evaluated the epidemiology and impact of RSV infection on children with heart disease in Hong Kong, with the goal of providing recommendations regarding RSV immunoprophylaxis. METHODS: This multicentre retrospective case-control study on paediatric RSV infection was conducted in four local regional hospitals from 2013 to 2015. The patients' demographic and clinical data were retrieved and analysed. RESULTS: There were 3538 RSV hospitalisations during the study period, and the mortality rate was 0.14%. Some RSV seasonality was present in Hong Kong, primarily in spring and summer. Respiratory syncytial virus infection was positively correlated with relative humidity and negatively correlated with wind speed and atmospheric pressure. Patients with heart disease had a more severe outcome than those without, including longer median hospital stay (4 vs 2 days, P<0.001), higher complication rate (28.6% vs 9.8%, P<0.001), and higher rates of intensive care (11.6% vs 1.4%, P<0.001) and mechanical ventilation (3.6% vs 0.4%, P=0.003). Complications in non-cardiac patients included myocarditis and Kawasaki disease. Predictors of severe RSV infection in patients with heart disease were heart failure, pulmonary hypertension, and severe airway abnormalities associated with congenital heart disease. CONCLUSIONS: Respiratory syncytial virus infection occurs mainly in spring and summer in Hong Kong, and is related to meteorological conditions. Respiratory syncytial virus infection poses a heavy disease burden on children with heart disease. A local guideline on RSV immunoprophylaxis for these children is therefore needed.

Effects of mass loading on the viability of assessing the state of healing of a fixated fractured long bone.

INTRODUCTION: This paper aims to evaluate the effects of mass loading on the healing assessment of an internally fixated femur by vibrational means. The presence of soft tissue surrounding a femur increases damping and mass of a system, and hence affects the vibrational response of a mechanical structure by obscuring the coherent modes. This may compromise vibration-based monitoring strategies in identifying modes associated with fracture healing. METHODS: This paper presents a series of experimental works to address this issue. Two osteotomised composite femurs were internally fixated using a plate-screw system and an intramedullary nail. Soft tissue is approximated by surrounding an artificial Sawbone femur with modelling clay. The femur is excited by an instrumented impact hammer and instrumented with two accelerometers to record bending and torsion modes between 0 and 600 Hz. A 30-min epoxy was applied to simulate the healing of the fractured femur in the osteotomised region. The resonant frequencies and its modes are monitored while union is being formed and a healing index is calculated at various times to quantify the degree of healing. RESULTS: The results demonstrate that the effect of modelling clay compressed the natural modes along the frequency axis. It is observed that frequency bandwidth in the vicinity of 150 Hz and 500 Hz is sensitive to the state of healing of the fixated femurs, which is due to the increase in stiffness of the osteotomised region. These findings were used to formulate the healing index which assists in identifying the initial, later and complete healing stages in conjunction with the index derivative. CONCLUSION: In this study, a two-sensor measurement strategy to quantify fixated femur healing is investigated. It is shown that the mass loading effect did not affect this vibrational analysis method ability to assess the state of healing, and both coherent bending and twisting modes associated with healing were easily identified. The proposed healing index, its derivative, and the cross-spectra are a viable tool for quantitative healing assessment.

Pressure Effects on the 4f Electronic Structure of Light Lanthanides.

Using the satellite structure of the Lγ_{1} line in nonresonant x-ray emission spectra, we probe the high-pressure evolution of the bare 4f signature of the early light lanthanides at ambient temperature. For Ce and Pr the satellite peak experiences a sudden reduction concurrent with their respective volume collapse (VC) transitions. These new experimental results are supported by calculations using state-of-the-art extended atomic structure codes for Ce and Pr, and also for Nd, which does not exhibit a VC. Our work suggests that changes to the 4f occupation are more consistently associated with evolution of the satellite than is the reduction of the 4f moment. Indeed, we show that in the case of Ce, mixing of a higher atomic angular momentum state, driven by the increased hybridization, acts to obscure the expected satellite reduction. These measurements emphasize the importance of a unified study of a full set of microscopic observables to obtain the most discerning test of the underlying, fundamental f-electron phenomena at high pressures.

Charge Order in the Holstein Model on a Honeycomb Lattice.

The effect of electron-electron interactions on Dirac fermions, and the possibility of an intervening spin-liquid phase between the semimetal and antiferromagnetic (AF) regimes, has been a focus of intense quantum simulation effort over the last five years. We use determinant quantum Monte Carlo simulations to study the Holstein model on a honeycomb lattice and explore the role of electron- phonon interactions on Dirac fermions. We show that they give rise to charge-density-wave (CDW) order and present evidence that this occurs only above a finite critical interaction strength. We evaluate the temperature for the transition into the CDW which, unlike the AF transition, can occur at finite values owing to the discrete nature of the broken symmetry.

Phonon Dispersion and the Competition between Pairing and Charge Order.

The Holstein model describes the interaction between fermions and a collection of local (dispersionless) phonon modes. In the dilute limit, the phonon degrees of freedom dress the fermions, giving rise to polaron and bipolaron formation. At higher densities, the phonons mediate collective superconducting (SC) and charge-density wave (CDW) phases. Quantum Monte Carlo (QMC) simulations have considered both these limits but have not yet focused on the physics of more general phonon spectra. Here we report QMC studies of the role of phonon dispersion on SC and CDW order in such models. We quantify the effect of finite phonon bandwidth and curvature on the critical temperature T_{cdw} for CDW order and also uncover several novel features of diagonal long-range order in the phase diagram, including a competition between charge patterns at momenta q=(π,π) and q=(0,π) which lends insight into the relationship between Fermi surface nesting and the wave vector at which charge order occurs. We also demonstrate SC order at half filling in situations where a nonzero bandwidth sufficiently suppresses T_{cdw}.

Resistin facilitates breast cancer progression via TLR4-mediated induction of mesenchymal phenotypes and stemness properties.

Growing evidence indicates that resistin-an obesity-related cytokine-is upregulated in breast cancer patients, yet its impact on breast cancer behavior remains to be ascertained. Similarly, Toll-like receptor 4 (TLR4) has been implicated in breast cancer progression, however, its clinically relevant endogenous ligand remains elusive. In this study, we observed that high serum resistin levels in breast cancer patients positively correlated with tumor stage, size and lymph node metastasis. These findings were replicated in animal models of breast cancer tumorigenesis and metastasis. Resistin was found to promote epithelial-mesenchymal transition and stemness in breast cancer cells-mechanisms critical to tumorigenesis and metastasis-through a TLR4/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB)/signal transducer and activator of transcription 3 (STAT3) signaling pathway and negated by TLR4-specific antibody and antagonist. These findings provide clear evidence that resistin is a clinically relevant endogenous ligand for TLR4, which promotes tumor progression via TLR4/NF-κB/STAT3 signaling, providing insights into a novel therapeutic target in breast cancer.

Socio-economic variations in the mental health treatment gap for people with anxiety, mood, and substance use disorders: results from the WHO World Mental Health (WMH) surveys.

BACKGROUND: The treatment gap between the number of people with mental disorders and the number treated represents a major public health challenge. We examine this gap by socio-economic status (SES; indicated by family income and respondent education) and service sector in a cross-national analysis of community epidemiological survey data. METHODS: Data come from 16 753 respondents with 12-month DSM-IV disorders from community surveys in 25 countries in the WHO World Mental Health Survey Initiative. DSM-IV anxiety, mood, or substance disorders and treatment of these disorders were assessed with the WHO Composite International Diagnostic Interview (CIDI). RESULTS: Only 13.7% of 12-month DSM-IV/CIDI cases in lower-middle-income countries, 22.0% in upper-middle-income countries, and 36.8% in high-income countries received treatment. Highest-SES respondents were somewhat more likely to receive treatment, but this was true mostly for specialty mental health treatment, where the association was positive with education (highest treatment among respondents with the highest education and a weak association of education with treatment among other respondents) but non-monotonic with income (somewhat lower treatment rates among middle-income respondents and equivalent among those with high and low incomes). CONCLUSIONS: The modest, but nonetheless stronger, an association of education than income with treatment raises questions about a financial barriers interpretation of the inverse association of SES with treatment, although future within-country analyses that consider contextual factors might document other important specifications. While beyond the scope of this report, such an expanded analysis could have important implications for designing interventions aimed at increasing mental disorder treatment among socio-economically disadvantaged people.

Using reciprocity to derive the far field displacements due to buried sources and scatterers.

It is shown that elastodynamic reciprocity provides a simpler approach for deriving the far-field displacements due to buried (sub-surface) sources in a half-space, compared with integral transform techniques. The auxiliary fields employed in this approach are the fields associated with the reflection of plane waves of the three possible polarisations, and the required far field can be expressed in terms of these well-known auxiliary fields. The crucial step in this approach is to evaluate a surface integral involving cross-work terms between an outgoing spherical wavefront and the auxiliary fields consisting of incident and reflected plane waves. This integral can be evaluated by the stationary phase approximation for the two-dimensional case, or by a generalisation of this approximation for the three-dimensional case. Although this evaluation involves several distinct contributions, the final result is shown to be very simple, and it can be interpreted as a generalisation of a known result for the one-dimensional case, whereby the net contribution arises only from counter-propagating waves of the same mode. The results derived for a buried force are extended to the case of buried cracks by exploiting the body force equivalents for displacement discontinuities across a surface.

An evaluation of multiple algorithms for the measurement of the heart rate corrected JTpeak interval.

Interest in the effects of drugs on the heart rate-corrected JTpeak (JTpc) interval from the body-surface ECG has spawned an increasing number of scientific investigations in the field of regulatory sciences, and more specifically in the context of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. We conducted a novel initiative to evaluate the role of automatic JTpc measurement technologies by comparing their ability to distinguish multi- from single-channel blocking drugs. A set of 5232 ECGs was shared by the FDA (through the Telemetric and Holter ECG Warehouse) with 3 ECG device companies (AMPS, Mortara, and Philips). We evaluated the differences in drug-concentration effects on these measurements between the commercial and the FDA technologies. We provide a description of the drug-induced placebo-corrected changes from baseline for dofetilide, quinidine, ranolazine, and verapamil, and discuss the various differences across all technologies. The results revealed only small differences between measurement technologies evaluated in this study. It also confirms that, in this dataset, the JTpc interval distinguishes between multi- and single-channel (hERG) blocking drugs when evaluating the effects of dofetilide, quinidine, ranolazine, and verapamil. However, in the case of quinidine and dofetilide, we noticed a poor consistency across technologies because of the lack of standard definitions for the location of the peak of the T-wave (T-apex) when the T-wave morphology is abnormal.

The J to T-peak interval as a biomarker in drug safety studies: A method of accuracy assessment applied to two algorithms.

OBJECTIVES: To evaluate performance of J-to-T-peak (JTP) measurements of 12-lead ECGs, in a five-arm study using drugs with various levels of electrolyte channel block. METHODS: The novel evaluation method distinguishes between different aspects of measurement. "Random noise" is the variability among repeated measurements made without changing the conditions. "Context noise" is the variability of changes in context of the measurement, e.g. T-wave morphology, autonomic nervous system state. RESULTS: The average random noise of our RR-corrected JTPc measurements in standard deviations was 3.0 ms and not dependent on the drug. The average context noise was 4.0 ms for ranolazine, verapamil, and placebo, and 8.8 ms for dofetilide and quinidine. Measurement consistency is corroborated by linear fit confidence intervals of baseline- and placebo-corrected JTPc versus drug concentration. CONCLUSIONS: Systematic differences were found in JTPc drug response between the Mortara method and published data. Residual signal component in the context noise may influence future study design.

Topical bioavailability of diclofenac from locally-acting, dermatological formulations.

Assessment of the bioavailability of topically applied drugs designed to act within or beneath the skin is a challenging objective. A number of different, but potentially complementary, techniques are under evaluation. The objective of this work was to evaluate in vitro skin penetration and stratum corneum tape-stripping in vivo as tools with which to measure topical diclofenac bioavailability from three approved and commercialized products (two gels and one solution). Drug uptake into, and its subsequent clearance from, the stratum corneum of human volunteers was used to estimate the input rate of diclofenac into the viable skin layers. This flux was compared to that measured across excised porcine skin in conventional diffusion cells. Both techniques clearly demonstrated (a) the superiority in terms of drug delivery from the solution, and (b) that the two gels performed similarly. There was qualitative and, importantly, quantitative agreement between the in vitro and in vivo measurements of drug flux into and beyond the viable skin. Evidence is therefore presented to support an in vivo - in vitro correlation between methods to assess topical drug bioavailability. The potential value of the stratum corneum tape-stripping technique to quantify drug delivery into (epi)dermal and subcutaneous tissue beneath the barrier is demonstrated.

Using self-report surveys at the beginning of service to develop multi-outcome risk models for new soldiers in the U.S. Army.

BACKGROUND: The U.S. Army uses universal preventives interventions for several negative outcomes (e.g. suicide, violence, sexual assault) with especially high risks in the early years of service. More intensive interventions exist, but would be cost-effective only if targeted at high-risk soldiers. We report results of efforts to develop models for such targeting from self-report surveys administered at the beginning of Army service. METHODS: 21 832 new soldiers completed a self-administered questionnaire (SAQ) in 2011-2012 and consented to link administrative data to SAQ responses. Penalized regression models were developed for 12 administratively-recorded outcomes occurring by December 2013: suicide attempt, mental hospitalization, positive drug test, traumatic brain injury (TBI), other severe injury, several types of violence perpetration and victimization, demotion, and attrition. RESULTS: The best-performing models were for TBI (AUC = 0.80), major physical violence perpetration (AUC = 0.78), sexual assault perpetration (AUC = 0.78), and suicide attempt (AUC = 0.74). Although predicted risk scores were significantly correlated across outcomes, prediction was not improved by including risk scores for other outcomes in models. Of particular note: 40.5% of suicide attempts occurred among the 10% of new soldiers with highest predicted risk, 57.2% of male sexual assault perpetrations among the 15% with highest predicted risk, and 35.5% of female sexual assault victimizations among the 10% with highest predicted risk. CONCLUSIONS: Data collected at the beginning of service in self-report surveys could be used to develop risk models that define small proportions of new soldiers accounting for high proportions of negative outcomes over the first few years of service.