The humanistic burden of vitiligo: a systematic literature review of quality-of-life outcomes.

Despite historical mischaracterization as a cosmetic condition, patients with the autoimmune disorder vitiligo experience substantial quality-of-life (QoL) burden. This systematic literature review of peer-reviewed observational and interventional studies describes comprehensive evidence for humanistic burden in patients with vitiligo. PubMed, EMBASE, Scopus and the Cochrane databases were searched through February 10, 2021, to qualitatively assess QoL in vitiligo. Two independent reviewers assessed articles for inclusion and extracted data for qualitative synthesis. A total of 130 included studies were published between 1996 and 2021. Geographical regions with the most studies were Europe (32.3%) and the Middle East (26.9%). Dermatology-specific instruments, including the Dermatology Life Quality Index (DLQI; 80 studies) and its variants for children (CDLQI; 10 studies) and families (FDLQI; 4 studies), as well as Skindex instruments (Skindex-29, 15 studies; Skindex-16, 4 studies), were most commonly used to measure humanistic burden. Vitiligo-specific instruments, including the Vitiligo-specific QoL (VitiQoL; 11 studies) instrument and 22-item Vitiligo Impact Scale (VIS-22; 4 studies), were administered in fewer studies. Among studies that reported total scores for the overall population, a majority revealed moderate or worse effects of vitiligo on patient QoL (DLQI, 35/54 studies; Skindex, 8/8 studies; VitiQoL, 6/6 studies; VIS-22, 3/3 studies). Vitiligo also had a significant impact on the QoL of families and caregivers; 4/4 studies reporting FDLQI scores indicated moderate or worse effects on QoL. In general, treatment significantly (P < 0.05) improved QoL, but there were no trends for types or duration of treatment. Among studies that reported factors significantly (P ≤ 0.05) associated with reduced QoL, female sex and visible lesions and/or lesions in sensitive areas were most common. In summary, vitiligo has clinically meaningful effects on the QoL of patients, highlighting that greater attention should be dedicated to QoL decrement awareness and improvement in patients with vitiligo.

International Initiative for Outcomes (INFO) for vitiligo: workshops with patients with vitiligo on repigmentation.

BACKGROUND: There is no cure or firm clinical recommendations for the treatment of vitiligo. One of the main issues is the heterogeneity of outcome measures used in randomized controlled trials for vitiligo. OBJECTIVES: To define successful repigmentation from the patients' point of view and to propose how and when repigmentation should be evaluated in clinical trials in vitiligo. METHODS: We conducted three workshops with patients with vitiligo and their parents or caregivers. Workshop 1 was held at World Vitiligo Day (Detroit, MI), workshop 2 at the University of Texas Southwestern Medical Center and workshop 3 at the Vitiligo and Pigmentation Institute of Southern California, University of California. RESULTS: Seventy-three participants were recruited. Consensus on the following questions was achieved unanimously: (i) the definition of 'successful repigmentation' was 80-100% of repigmentation of a target lesion and (ii) both an objective and a subjective scale to measure repigmentation should be used. CONCLUSIONS: This was the largest patients' outcomes workshop. We followed the guidance from the CSG-COUSIN and the Vitiligo Global Issues Consensus Group. Our recommendations to use percentage of repigmentation quartiles (0-25%, 26-50%, 51-79%, 80-100%) and the Vitiligo Noticeability Scale are based on the best available current evidence. A limitation of the research is that the workshops were conducted only in the U.S.A., due to pre-existing organisational support and the availability of funding.

Assessment of hydration biomarkers including salivary osmolality during passive and active dehydration.

BACKGROUND/OBJECTIVES: Hydration state can be assessed via body mass change (BMΔ), serum and urine osmolality (Sosm, Uosm), urine-specific gravity (Usg) and urine volume (Uvol). As no hydration index has been shown to be valid in all circumstances, value exists in exploring novel biomarkers such as salivary osmolality (Vosm). Utilizing acute BMΔ as the reference standard, this research examined the efficacy of Sosm, Vosm, Uosm, Uvol and Usg, during passive (PAS) and active (ACT) heat exposure. SUBJECTS/METHODS: Twenty-three healthy men (age, 22±3 years; mass, 77.3±12.8 kg; height, 179.9±8.8cm; body fat, 10.6±4.5%) completed two randomized 5-h dehydration trials (36±1 °C). During PAS, subjects sat quietly, and during ACT, participants cycled at 68±6% maximal heart rate. Investigators measured all biomarkers at each 1% BMΔ. RESULTS: Average mass loss during PAS was 1.4±0.3%, and 4.1±0.7% during ACT. Significant between-treatment differences at -1% BMΔ were observed for Sosm (PAS, 296±4; ACT, 301±4 mOsm/kg) and Uosm (PAS, 895±207; ACT, 661±192 mOsm/kg). During PAS, only Uosm, Uvol and Usg increased significantly (-1 and -2% BMΔ versus baseline). During ACT, Vosm most effectively diagnosed dehydration 2% (sensitivity=86%; specificity=91%), followed by Sosm (sensitivity=83%; specificity=83%). Reference change values were validated for Sosm, Usg and BMΔ. CONCLUSIONS: The efficacy of indices to detect dehydration 2% differed across treatments. At rest (PAS), only urinary indices increased in concert with body water loss. During exercise (ACT), Sosm and Vosm exhibited the highest sensitivity and specificity. Sosm, Usg and BMΔ exhibited validity in serial measurements. These findings indicate hydration biomarkers should be selected by considering daily activities.

Vitiligo: recent insights and new therapeutic approaches.

Vitiligo represents a selective destruction of the melanocytes. It is a relatively common, probably autoimmune disorder that affects people of all backgrounds and both genders. No particular group seems to be preferentially affected. Half of vitiligo patients have an onset before the age of 18 years. In regions where leprosy is endemic, individuals with vitiligo are often stigmatized due to similarities in appearance between the two diseases. We will review this important subject, emphasizing the latest therapeutic advances.

Small population size and extremely low levels of genetic diversity in island populations of the platypus, Ornithorhynchus anatinus.

Genetic diversity generally underpins population resilience and persistence. Reductions in population size and absence of gene flow can lead to reductions in genetic diversity, reproductive fitness, and a limited ability to adapt to environmental change increasing the risk of extinction. Island populations are typically small and isolated, and as a result, inbreeding and reduced genetic diversity elevate their extinction risk. Two island populations of the platypus, Ornithorhynchus anatinus, exist; a naturally occurring population on King Island in Bass Strait and a recently introduced population on Kangaroo Island off the coast of South Australia. Here we assessed the genetic diversity within these two island populations and contrasted these patterns with genetic diversity estimates in areas from which the populations are likely to have been founded. On Kangaroo Island, we also modeled live capture data to determine estimates of population size. Levels of genetic diversity in King Island platypuses are perilously low, with eight of 13 microsatellite loci fixed, likely reflecting their small population size and prolonged isolation. Estimates of heterozygosity detected by microsatellites (H(E)= 0.032) are among the lowest level of genetic diversity recorded by this method in a naturally outbreeding vertebrate population. In contrast, estimates of genetic diversity on Kangaroo Island are somewhat higher. However, estimates of small population size and the limited founders combined with genetic isolation are likely to lead to further losses of genetic diversity through time for the Kangaroo Island platypus population. Implications for the future of these and similarly isolated or genetically depauperate populations are discussed.

Neuropsychiatric symptomatology predicts seizure recurrence in newly treated patients.

OBJECTIVES: To test the hypothesis that neuropsychiatric symptomatology is predictive of the success of seizure control in patients newly treated with antiepileptic drugs (AEDs), and that this predictive value adds to that provided by other clinical, imaging, and genomic factors in a multivariate model. METHODS: One hundred seventy newly treated patients with epilepsy completed the A-B Neuropsychological Assessment Scale (ABNAS) before commencing AED therapy and were prospectively followed up for 12 months. Patients were classified as nonresponsive if they had at least 1 seizure not explained by medication noncompliance or other significant provoking factors. RESULTS: Of the 138 patients in whom a drug response phenotype at 12 months was able to be determined, nonresponsive patients (n = 45) had a higher pretreatment ABNAS score than patients whose seizures were controlled (n = 93) (p = 0.007). A lesion on MRI was also associated with a higher risk of seizure recurrence (p = 0.003). On multivariate logistic regression, the ABNAS score, the MRI results, and a genomic classifier were all independently predictive of treatment outcome. For AED pharmacoresponse, this multivariate model had diagnostic values of 91% sensitivity, 64% specificity, 84% positive predictive, and 78% negative predictive values. The predictive value of the ABNAS score was validated in a second prospective cohort of 74 newly treated patients with epilepsy (p = 0.005). CONCLUSIONS: The ABNAS provides prognostic information regarding successful seizure control in patients newly treated with AEDs. Furthermore, these results demonstrate the multifactorial nature of the determinants of AED response, with neuropsychological, structural, and genomic factors all contributing to the complex response phenotype.

Evaluation of the inhibition of egg laying, larvicidal effects, and bloodfeeding success of Aedes aegypti exposed to permethrin- and bifenthrin-treated military tent fabric.

Laboratory studies were conducted to evaluate the effects of treating military canvas tent fabric with bifenthrin and permethrin on the survival of the eggs and larvae of Aedes aegypti. Gravid female Ae. aegypti were able to oviposit on tent canvas treated with either bifenthrin or permethrin. However, none of the eggs laid on treated canvas hatched, and no larvae added to water in treated trays survived. Low residual concentrations of bifenthrin and permethrin on treated canvas prevented the development of eggs and larvae of Ae. aegypti. Inhibition of bloodfeeding was shown when Ae. aegypti adults were exposed to lower concentrations (10-50% of operational concentrations) of bifenthrin- and permethrin-treated canvas tent fabric. These experiments have shown that military tent canvas treated with either bifenthrin or permethrin can reduce the development of Ae. aegypti eggs and larvae and reduce bloodfeeding success of adults.

Vitiligo.

Vitiligo represents a selective destruction of the melanocytes. It is a relatively common, probably autoimmune disorder that affects people of all backgrounds and both genders. No particular group seems to be preferentially affected. Half of vitiligo patients have an onset before the age of 18 years. In regions where leprosy is endemic, individuals with vitiligo are often stigmatized due to similarities in appearance between the two diseases. We will review this important subject, emphasizing the latest therapeutic advances.

Hierarchical Bayes model for random haplotype and family effects in the transmission of fragile-X.

A model for the transmission of the CGG repeat sequence associated with the fragile-X dynamic mutation in the FMR1 gene is developed. The model incorporates both haplotype and family effects on the expansion rate of the sequence. The resulting random effects model is fitted to new data, using computer-intensive Markov chain Monte Carlo methods. The results demonstrate both the FRAXAC1-DXS458 haplotype and family effects on the transmission of CGG repeats from mother to offspring.

Effect of fragile X status categories and FMRP deficits on cognitive profiles estimated by robust pedigree analysis.

The effect of the fragile X pre-mutation and full mutation categories, and FMRP deficits in these categories, on neurocognitive status, have been assessed in fragile X individuals from 144 extended families, which included fragile X individuals, as well as their non-fragile X relatives. Neuropsychological status was assessed by the Wechsler summary and subtest test scores. A modification of the maximum likelihood estimators for pedigree data that is resistant to outliers was used to analyze the data. The results have demonstrated the effect of large expansions of CGG repeat in the FMR1 (fragile X mental retardation 1) gene (full mutation) in decreasing full scale IQ (FSIQ), as well as several FSIQ-adjusted subtest scores in the performance domain. Moreover, the results have demonstrated significant cognitive deficits in male individuals with pre-mutation. FMRP depletion correlates strongly with neurocognitive status in the full mutation subjects. Evidence for the effect of FMRP in smaller expansions (pre-mutation) in reducing FSIQ, Performance and Verbal scores, as well as subtest scores in males, has also been obtained. The results are also suggestive of factors other than FMRP deficit which may determine some specific cognitive deficits in fragile X pre-mutation carriers. Genetic variance estimated from the models accounts for less than half of the total variance in FSIQ, and it varies widely between individual Wechsler subtests.

Relationship of deficits of FMR1 gene specific protein with physical phenotype of fragile X males and females in pedigrees: a new perspective.

The effect of deficit of the FMR1-gene product (FMRP) on physical phenotype was investigated using a robust modification of the maximum likelihood estimators for pedigree data. The approach is a powerful method of examining genotype-phenotype relationships because it adjusts for intra-familial variation, and the robust modification allows violation of distributional assumptions in the data to be overcome by objectively down-weighting unusual observations. The data on 19 age- or height-adjusted physical measures including head, trunk and limb measures and height and weight from 110 extended fragile X families (including 185 fragile X males and females and 120 normal relatives) were related to the FMRP levels assessed in peripheral blood lymphocytes. A significant interaction between FMRP and age was also included in the models for some measures. The results have demonstrated a linear effect of progressively reducing levels of FMRP on the values of a majority of physical measures considered in the study. The most evident effect of FMRP deficit in sexes combined was in decreasing body height and limb length, and in increasing head height and the degree of connective tissue involvement (measured by the middle finger extension angle). Heritability estimated from the complex FMRP models showed the highest values for height and limb length, and the lowest for weight, finger extension angle and some facial measures. On the basis of the present data, a possible mechanism by which the FMRP deficit impacts physical phenotype is discussed.

Application of robust pedigree analysis in studies of complex genotype-phenotype relationships in fragile X syndrome.

Relationships between the fragile X dynamic mutation and palmar and finger epidermal ridge measures were assessed using a robust modification of the maximum likelihood estimators for pedigree data. A total of 34 extended families affected with fragile X syndrome were used. Phenotypic traits included ridge count on the thumb and ridge breadth measured in the second palmar interdigital area bilaterally. Genotypic measures were represented by the number of CGG repeats in the FMR1 gene, the levels of specific FMR1 protein (FMRP), fragile X category defined by the size of the CCG repeat, and methylation status of the gene. The results demonstrated a significant fragile X effect (related to the number of CGG repeats) in the thumb ridge count in males. This effect was more evident in ridge breadth and was found in both sexes. However, the relationship between both phenotypic traits and the level of FMRP was nonsignificant. The study makes a useful contribution to the development of methodologies for the analysis of genotype-phenotype relationships in dynamic mutations, especially in overcoming extensive variability in both the genotype and phenotype, and in approaching the statistical problems related to intergenerational changes in repeat size. The findings support the hypothesis that the fragile X mutation affects limb development during an early fetal period.

Analysis of longitudinal data from twins.

Longitudinal data from twin pairs may be used to determine how the genetic effects influencing a quantitative trait change with age. Here a model for mixed longitudinal data of Huggins and Loesch [1998] on unrelated individuals is extended to twin studies. The model is fitted using robust statistical methods and a bootstrap procedure is proposed to estimate the percentiles. The method is applied to longitudinal twin data on body mass index in male and female twin pairs aged 5-18 years.

Characterization of fine particulate matter produced by combustion of residual fuel oil.

Combustion experiments were carried out on four different residual fuel oils in a 732-kW boiler. PM emission samples were separated aerodynamically by a cyclone into fractions that were nominally less than and greater than 2.5 microns in diameter. However, examination of several of the samples by computer-controlled scanning electron microscopy (CCSEM) revealed that part of the PM2.5 fraction consists of carbonaceous cenospheres and vesicular particles that range up to 10 microns in diameter. X-ray absorption fine structure (XAFS) spectroscopy data were obtained at the S, V, Ni, Fe, Cu, Zn, and As K-edges and at the Pb L-edge. Deconvolution of the X-ray absorption near edge structure (XANES) region of the S spectra established that the dominant molecular forms of S present were sulfate (26-84% of total S) and thiophene (13-39% of total S). Sulfate was greater in the PM2.5 samples than in the PM2.5+ samples. Inorganic sulfides and elemental sulfur were present in lower percentages. The Ni XANES spectra from all of the samples agreed fairly well with that of NiSO4, while most of the V spectra closely resembled that of vanadyl sulfate (VO.SO4.xH2O). The other metals investigated (i.e., Fe, Cu, Zn, and Pb) also were present predominantly as sulfates. Arsenic was present as an arsenate (As+5). X-ray diffraction patterns of the PM2.5 fraction exhibit sharp lines due to sulfate compounds (Zn, V, Ni, Ca, etc.) superimposed on broad peaks due to amorphous carbons. All of the samples contain a significant organic component, with the loss on ignition (LOI) ranging from 64 to 87% for the PM2.5 fraction and from 88 to 97% for the PM2.5+ fraction. Based on 13C nuclear magnetic resonance (NMR) analysis, the carbon is predominantly condensed in graphitic structures. Aliphatic structure was detected in only one of seven samples examined.

Local estimation of age-dependent variance components from longitudinal twin data.

In the study of longitudinal twin and family data, interest is often in the covariance structure of the data and the decomposition of this covariance structure into genetic and environmental components rather than in estimating the mean function. Various parametric models for covariance structures have been proposed but, e.g., in studies of children where growth spurts occur at various ages, it is difficult to a priori determine an appropriate parametric model for the covariance structure. In particular, there is a general lack of the visualization procedures, such as lowess, that are invaluable in the initial stages of constructing a parametric model for a mean function. Here we use kernel smoothing to modify a cross-sectional approach based on the sample covariance matrices to obtain smoothed estimates of the genetic and environmental variances and correlations for longitudinal twin data. The methods are proposed to be exploratory as an aid to parametric modeling rather than inferential, although approximate asymptotic standard errors are derived in the Appendix.

Secular trend in body height and weight of Australian children and adolescents.

Secular changes in growth and maturation have been well documented in various world populations, with secular increase especially noticeable in the developed countries. To assess the trend in both adult size and tempo of growth we compared the data on stature and body weight obtained in 1992-1993 from 1,804 Melbourne school students aged 5 to 17 with historical data collected from white Australians during the last 100 years. We illustrate the age-dependent trend in stature and body weight by means of regression surfaces. These were constructed by fitting local regression models to historical data and by simple plots showing the overall, and per decade, secular increase in both these measures at peripubertal and adult ages. Because of limited information on sample sizes and variability provided by the historical data, statistical comparisons have been performed only between the present 1992-1993 survey and two earlier independent surveys conducted in 1985 and 1970. The results have shown secular increase in adult stature over the last century, with the rate of increase varying between 0.4 and 2.1 cm/decade in males and 0.01 and 1.6 cm/decade in females. While secular increase in stature has significantly slowed down during the last two decades, the increase in body weight is still continuing at a high rate, and this increase is more pronounced in females. The period of strong secular increase, especially in the tempo of growth, coincided both with the shift toward earlier menarche and the improvement of socioeconomic conditions of the Australian population. The need for further studies to identify factors determining the continuing increase in body weight is emphasized, and caution in using the existing national growth standards for stature and weight is recommended.

Melatonin profiles and sleep characteristics in boys with fragile X syndrome: a preliminary study.

Sleep patterns and endogenous melatonin profiles in 13 fragile X boys between the age of 4.7 and 11.0 years were compared to those of 8 age-matched, normal control boys. Parents recorded sleep patterns on a Sleep Diary Chart for 14 consecutive days. Twelve saliva samples were obtained from 8 fragile X participants and all of the controls over 48 hours for the assessment of salivary melatonin profiles. The results showed greater variability in total sleep time and difficulty in sleep maintenance in fragile X boys compared with the control participants. Nocturnal melatonin production, expressed as both peak level and area under the concentration-time curve between 20:00 h and 08:00 h, were found to be significantly larger in fragile X boys than in controls. Additionally, the mean of the minimum daytime melatonin levels recorded was significantly higher for the fragile X group. Elevated levels in some fragile X boys relative to the range seen in controls, occurring either during the day or at night, or in both segments of the secretory profile for some individuals, may be due in part to overactivity of the sympathetic nervous system. Alternative molecular mechanisms leading to changes in melatonin profiles in fragile X are also discussed.

Estimation of the size of an open population from capture-recapture data using weighted martingale methods.

A weighted martingale method, akin to a moving average, is proposed to allow the use of modified closed-population methods in the estimation of the size of a smoothly changing open population when there are frequent capture occasions. We concentrate here on modifications to martingale estimating functions for model Mt, but a wide range of closed-population estimators may be modified in this fashion. The method is motivated by and applied to weekly capture-recapture data from the Mai Po bird sanctuary in Hong Kong. Simulations show that the weighted martingale estimator compared well with the Jolly-Seber estimator when the conditions for the latter to be valid are met, and it performed far better when individuals were allowed to leave and reenter the population. Expressions are derived for the asymptotic bias and variance of the estimator in an appendix.

On the analysis of mixed longitudinal growth data.

Mixed longitudinal growth data consists of several observations on a characteristic over a limited age range for each individual in a study. This data is then combined to model growth over the total age range of all individuals in the study. The limited data collected on each individual precludes a subject-specific approach to modelling so that a population-based approach must be used. Here we propose a method for the analysis of mixed longitudinal data using linear models constructed from cubic splines to model both the mean and variance curves of an observed characteristic. The method is illustrated on growth in height and head circumference for children in a recently collected mixed longitudinal data set concerning the growth of Victorian schoolchildren, where particular concern was the timing of growth spurts and increases in variability.