Deep cutaneous fungal infections in solid-organ transplant recipients.

BACKGROUND: Deep cutaneous fungal infections (DCFIs) are varied in immunosuppressed patients, with few data for such infections in solid-organ transplant recipients (s-OTRs). OBJECTIVE: To determine DCFI diagnostic characteristics and outcome with treatments in s-OTRs. METHODS: A 20-year retrospective observational study in France was conducted in 8 primary dermatology-dedicated centers for s-OTRs diagnosed with DCFIs. Relevant clinical data on transplants, fungal species, treatments, and outcomes were analyzed. RESULTS: Overall, 46 s-OTRs developed DCFIs (median delay, 13 months after transplant) with predominant phaeohyphomycoses (46%). Distribution of nodular lesions on limbs and granulomatous findings on histopathology were helpful diagnostic clues. Treatments received were systemic antifungal therapies (48%), systemic antifungal therapies combined with surgery (28%), surgery alone (15%), and modulation of immunosuppression (61%), leading to complete response in 63% of s-OTRs. LIMITATIONS: Due to the retrospective observational design of the study. CONCLUSIONS: Phaeohyphomycoses are the most common DCFIs in s-OTRs. Multidisciplinary teams are helpful for optimal diagnosis and management.

Livedoid Vasculopathy: A French Observational Study Including Therapeutic Options.

Livedoid vasculopathy is a rare thrombotic cutaneous disease. This observational study aimed to assess the clinical and biological features of livedoid vasculopathy and the efficacy of treatments. Patients enrolled had typical livedoid vasculopathy both clinically and histologically. Investigation of thrombophilia was performed. Electromyography was undertaken in the presence of symptoms suggesting peripheral neuropathy. Eighteen women and 8 men were included, with a mean age of 35.5 years at onset. Twenty patients had at least one thrombophilia factor. Ten patients had a peripheral neuropathy with 2 of these patients demonstrating a specific thrombo-occlusive vasculopathy on muscle biopsy. Anticoagulation with low molecular weight heparin was the most prescribed therapy and was associated with the best outcome (effective in 14 patients). Eight patients had severe disease refractory to anticoagulation and required intravenous immunoglobulins, producing a good response in 6 patients.

Cutaneous manifestations of Erdheim-Chester disease (ECD): Clinical, pathological, and molecular features in a monocentric series of 40 patients.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis with possible cutaneous-specific involvement. OBJECTIVES: We sought to describe the clinical, pathological, and molecular features of the cutaneous manifestations of 40 patients with ECD identified from a cohort of 123 patients. METHODS: Confirmed cases of patients with ECD were included in a single-center retrospective observational study. Clinical and pathological cutaneous features were analyzed and BRAF(V600E) mutation was determined. RESULTS: The most frequent ECD cutaneous manifestations were xanthelasma-like lesions (XLL), which occurred in 31 (25%) patients. Other ECD cutaneous lesions were patches or papulonodular lesions. Mixed form of ECD and cutaneous Langerhans cell histiocytosis presented with crusty papules of the folds in some patients. Compared with classic xanthelasma palpebrarum, ECD XLL pathology more frequently involved the reticular dermis, displayed more multinucleated or Touton cells, and showed less extensive fibrosis. BRAF(V600E) mutation was more frequently detected in patients with cutaneous involvement than in those without (76% vs 52%; P = .005) and constantly found in 10 XLL. LIMITATIONS: Some clinical data were not available because of the retrospective design of the study. CONCLUSIONS: XLL are the most frequent cutaneous ECD manifestations and might be targeted both for pathology and determination of BRAF mutational status.

Proliferative Verrucous Leukoplakia Presenting as a Ring Around the Collar and Cancer: A Case Report.

Proliferative verrucous leukoplakia (PVL) is an oral mucosa lesion with a high rate of malignant transformation. The diagnosis is often difficult, especially when the initial lesion is a simple homogeneous white leukoplakia, and when located only on the gingiva or palate. Moreover, the anatomopathological analysis is non-specific in the initial stages. The gingival PVL localisation (gPVL) is described as the most aggressive form with the highest rate of malignant transformation. Cases with a unique gingival localisation are rare, described with a "ring around the collar" clinical form. Considering the difficulty of early diagnosis of gPVL, we report the case of a 72-year-old woman, who presented "white lesions on her gingiva" with a slight discomfort in February 2019. The lesion was initially limited to the buccal part of the mandibular right gingiva, but rapidly extended to all the lingual and buccal mandibular gingiva during follow-up, leading to a diagnosis of gPVL. Two biopsies were performed, which concluded a verrucous hyperplasia and papilloma with a lichenoid part. The diagnosis of gPVL was made after a six-month follow-up based on clinical and anatomopathological factors. The gPVL transformed into a squamous cell carcinoma (SCC) after 18 months of follow-up. A surgical right mandibular bone excision with an autologous left fibula graft associated with radiotherapy was performed. Three years after the surgery, the patient remains under monitoring, with several gPVL and SCC recurrences treated. This case highlights that gPVL is a rare and aggressive form of PVL, with a high risk of fast malignant transformation. Knowledge about its aetiology, anatomic pathology, and biological markers is highly needed to speed up the diagnosis and develop specific follow-up and treatment.

Furan fatty acid extracted from Hevea brasiliensis latex increases muscle mass in mice.

Skeletal muscle is essential for locomotion and plays a crucial role in energy homeostasis. It is regulated by nutrition, genetic factors, physical activity and hormones. Furan fatty acids (FuFAs) are minor fatty acids present in small quantities in food from plants and animals origin. Recently, we showed that a preventive nutritional supplementation with furan fatty acid in a DIO mouse model reduces metabolic disorders. The present study was designed to determine the influence of FuFA-F2 extracted from Hevea brasiliensis latex on skeletal muscle phenotype. In C2C12 myotubes we found that FuFA-F2 whatever the concentration used increased protein content. We revealed that in C2C12 myotubes FuFA-F2 (10 µM) increases protein synthesis as shown by the stimulation of mTOR phosphorylation. Next, to confirm in vivo our results C57Bl6 mice were supplemented by oral gavage with vehicle or FuFA-F2 (20 mg/kg) for 3 and a half weeks. We found that mice supplemented with FuFA-F2 had a greater lean mass than the control mice. In line with this observation, we revealed that FuFA-F2 increased muscle mass and promoted more oxidative muscle metabolism in mice as attested by cytochrome c oxidase activity. In conclusion, we demonstrated that FuFA-F2 stimulates muscle anabolism in mice in vitro and in vivo, mimicking in part physical activity. This study highlights that in vivo FuFA-F2 may have health benefits by increasing muscle mass and oxidative metabolism.

9-PAHPA long term intake in DIO and db/db mice ameliorates insulin sensitivity but has few effects on obesity and associated metabolic disorders.

Branched fatty acid esters of hydroxy fatty acids are endogenous lipids reported to have antidiabetic and anti-inflammatory effects. Recently, we showed that 9-palmitic acid esters of hydroxypalmitic acid (9-PAHPA) and 9-oleic acid esters of hydroxypalmitic acid increased insulin sensitivity in mice when incorporated to a chow diet or to a high fat and high sucrose diet. However, preventive supplementation with 9-PAHPA and 9-oleic acid esters of hydroxypalmitic acid in high fat and high sucrose diet mice did not impair significant weight gain or the development of hyperglycemia. The aim of this work was therefore to study whether in two animal models of obesity, namely the classical diet-induced obesity (DIO) and the db/db mice, 9-PAHPA may have beneficial effects against obesity and liver and skeletal muscle metabolic dysfunction. In DIO mice, we observed that 9-PAHPA increased body weight and fat mass. In line with this observation, we found that 9-PAHPA supplementation decreased energy expenditure. In liver and in skeletal muscle, mitochondrial activities and oxidative stress parameters were not modified by 9-PAHPA supplementation. In db/db mice, 9-PAHPA had no effect on the dramatic weight gain and hyperglycemia. In addition, 9-PAHPA supplementation did not correct either the hepatomegaly and hepatic steatosis or the severe muscle atrophy recorded compared with db/+ animals. Likewise, supplementation with 9-PAHPA did not impact the different metabolic parameters analyzed, either in the liver or in the skeletal muscles. However, it decreased insulin resistance in DIO and db/db mice. In conclusion, our study indicated that a long-term intake of 9-PAHPA in DIO and db/db mice improved insulin sensitivity but had only few effects on obesity and associated metabolic disorders.

Child mortality estimation: a global overview of infant and child mortality age patterns in light of new empirical data.

BACKGROUND: The under-five mortality rate (the probability of dying between birth and age 5 y, also denoted in the literature as U5MR and (5)q(0)) is a key indicator of child health, but it conceals important information about how this mortality is distributed by age. One important distinction is what amount of the under-five mortality occurs below age 1 y ((1)q(0)) versus at age 1 y and above ((4)q(1)). However, in many country settings, this distinction is often difficult to establish because of various types of data errors. As a result, it is common practice to resort to model age patterns to estimate (1)q(0) and (4)q(1) on the basis of an observed value of (5)q(0). The most commonly used model age patterns for this purpose are the Coale and Demeny and the United Nations systems. Since the development of these models, many additional sources of data for under-five mortality have become available, making possible a general evaluation of age patterns of infant and child mortality. In this paper, we do a systematic comparison of empirical values of (1)q(0) and (4)q(1) against model age patterns, and discuss whether observed deviations are due to data errors, or whether they reflect true epidemiological patterns not addressed in existing model life tables. METHODS AND FINDINGS: We used vital registration data from the Human Mortality Database, sample survey data from the World Fertility Survey and Demographic and Health Surveys programs, and data from Demographic Surveillance Systems. For each of these data sources, we compared empirical combinations of (1)q(0) and (4)q(1) against combinations provided by Coale and Demeny and United Nations model age patterns. We found that, on the whole, empirical values fall relatively well within the range provided by these models, but we also found important exceptions. Sub-Saharan African countries have a tendency to exhibit high values of (4)q(1) relative to (1)q(0), a pattern that appears to arise for the most part from true epidemiological causes. While this pattern is well known in the case of western Africa, we observed that it is more widespread than commonly thought. We also found that the emergence of HIV/AIDS, while perhaps contributing to high relative values of (4)q(1), does not appear to have substantially modified preexisting patterns. We also identified a small number of countries scattered in different parts of the world that exhibit unusually low values of (4)q(1) relative to (1)q(0), a pattern that is not likely to arise merely from data errors. Finally, we illustrate that it is relatively common for populations to experience changes in age patterns of infant and child mortality as they experience a decline in mortality. CONCLUSIONS: Existing models do not appear to cover the entire range of epidemiological situations and trajectories. Therefore, model life tables should be used with caution for estimating (1)q(0) and (4)q(1) on the basis of (5)q(0). Moreover, this model-based estimation procedure assumes that the input value of (5)q(0) is correct, which may not always be warranted, especially in the case of survey data. A systematic evaluation of data errors in sample surveys and their impact on age patterns of (1)q(0) and (4)q(1) is urgently needed, along with the development of model age patterns of under-five mortality that would cover a wider range of epidemiological situations and trajectories. Please see later in the article for the Editors' Summary.

Estimating trends in the total fertility rate with uncertainty using imperfect data: Examples from West Africa.

BACKGROUND: Estimating the total fertility rate is challenging for many developing countries because of limited data and varying data quality. A standardized, reproducible approach to produce estimates that include an uncertainty assessment is desired. METHODS: We develop a method to estimate and assess uncertainty in the total fertility rate over time, based on multiple imperfect observations from different data sources, including surveys and censuses. We take account of measurement error in observations by decomposing it into bias and variance, and assess both by linear regression on a variety of data quality covariates. We estimate the total fertility rate using a local smoother, and assess uncertainty using the weighted likelihood bootstrap. RESULTS: We apply our method to data from seven countries in West Africa and construct estimates and uncertainty intervals for the total fertility rate. Based on cross-validation exercises, we find that accounting for differences in data quality between observations gives better calibrated confidence intervals and reduces bias. CONCLUSIONS: When working with multiple imperfect observations from different data sources to estimate the total fertility rate, or demographic indicators in general, potential biases and differences in error variance should be taken into account to improve the estimates and their uncertainty assessment.

Defining pathways to healthy sustainable urban development.

Goals and pathways to achieve sustainable urban development have multiple interlinkages with human health and wellbeing. However, these interlinkages have not been examined in depth in recent discussions on urban sustainability and global urban science. This paper fills that gap by elaborating in detail the multiple links between urban sustainability and human health and by mapping research gaps at the interface of health and urban sustainability sciences. As researchers from a broad range of disciplines, we aimed to: 1) define the process of urbanization, highlighting distinctions from related concepts to support improved conceptual rigour in health research; 2) review the evidence linking health with urbanization, urbanicity, and cities and identify cross-cutting issues; and 3) highlight new research approaches needed to study complex urban systems and their links with health. This novel, comprehensive knowledge synthesis addresses issue of interest across multiple disciplines. Our review of concepts of urban development should be of particular value to researchers and practitioners in the health sciences, while our review of the links between urban environments and health should be of particular interest to those outside of public health. We identify specific actions to promote health through sustainable urban development that leaves no one behind, including: integrated planning; evidence-informed policy-making; and monitoring the implementation of policies. We also highlight the critical role of effective governance and equity-driven planning in progress towards sustainable, healthy, and just urban development.

How to evaluate the cellular uptake of CPPs with fluorescence techniques: Dissecting methodological pitfalls associated to tryptophan-rich peptides.

Cell-penetrating peptides (CPP) are broadly recognized as efficient non-viral vectors for the internalization of compounds such as peptides, oligonucleotides or proteins. Characterizing these carriers requires reliable methods to quantify their intracellular uptake. Flow cytometry on living cells is a method of choice but is not always applicable (e.g. big or polarized cells), so we decided to compare it to fluorescence spectroscopy on cell lysates. Surprisingly, for the internalization of a series of TAMRA-labeled conjugates formed of either cationic or amphipathic CPPs covalently coupled to a decamer peptide, we observed important differences in internalization levels between both methods. We partly explained these discrepancies by analyzing the effect of buffer conditions (pH, detergents) and peptide sequence/structure on TAMRA dye accessibility. Based on this analysis, we calculated a correction coefficient allowing a better coherence between both methods. However, an overestimated signal was still observable for both amphipathic peptides using the spectroscopic detection, which could be due to their localization at the cell membrane. Based on several in vitro experiments modeling events at the plasma membrane, we hypothesized that fluorescence of peptides entrapped in the membrane bilayer could be quenched by the tryptophan residues of close transmembrane proteins. During cell lysis, cell membranes are disintegrated liberating the entrapped peptides and restoring the fluorescence, explaining the divergences observed between flow cytometry and spectroscopy on lysates. Overall, our results highlighted major biases in the fluorescently-based quantification of internalized fluorescently-labeled CPP conjugates, which should be considered for accurate uptake quantification.

Glomeruloid haemangioma: a possible consequence of elevated VEGF in POEMS and Erdheim-Chester disease.

Glomeruloid haemangioma (GH) is considered a specific marker of POEMS syndrome, despite some published GH cases unrelated to POEMS syndrome. To present two cases with GH and atypical presentations of Erdheim-Chester disease (ECD) or POEMS syndrome, as well as a retrospective monocentric study of histologically-confirmed GH. Clinical, biological and histological data of the patients is presented. In addition to the two presented cases, 11 GH histologically-confirmed cases were retrospectively identified. Six patients were female (46.2%; 95 CI: 12-64.9) and median age was 54 years (31-85). For 11 patients (84.6%; 95 CI: 65-104.2), a diagnosis of POEMS syndrome was retained, one patient had autoimmune hepatitis, and another had ECD. GH was localised to the trunk in 10 cases (76.9%; 95 CI: 54-99) and the legs in the other three. The median number of haemangiomas in the cohort was three (SD: 3.08). Median level of VEGF was 1,490 (610-12,000) ng/mL. All immunohistochemical staining for human herpesvirus 8 (HHV-8) was negative. Of the 13 cases of GH, of which two were not clear-cut POEMS syndrome, we report the first case of GH associated with ECD. In this cohort, all patients had high serum levels of VEGF but no in situ HHV-8 latent infection. We hypothesise that GH might be linked to a high level of VEGF in these two rare diseases.

Age patterns and sex ratios of adult mortality in countries with high HIV prevalence.

OBJECTIVE: To compare the 2016 United Nations Programme on HIV/AIDS (UNAIDS) modelled estimates of adult mortality in sub-Saharan Africa to empirical estimates. DESIGN: Age-specific mortality rates were obtained from nationally representative sibling survival data, recent household deaths and vital registration, and directly compared with UNAIDS estimates. Orphanhood prevalence derived from UNAIDS mortality estimates was compared with survey and census reports on the survival of children's parents. METHODS: Age-specific mortality rates for adults aged 15-59 years were calculated from Demographic and Health Surveys and deaths reported in censuses or vital registration, adjusted for underreporting, whenever possible. Proportions of orphans were extracted from censuses and surveys for children aged 5-9 years. RESULTS: UNAIDS estimates were significantly higher than sibling mortality estimates, except among men in countries with very high HIV prevalence. There was a better agreement between rates based on household deaths or vital registration and model outputs. Sex ratios (M/F) of adult mortality were lower in UNAIDS estimates. The modelled orphan prevalence was significantly higher than in surveys and censuses, again with the exception of paternal orphans in countries with very high HIV prevalence. Ratios of paternal-to-maternal orphans were lower in the UNAIDS model than surveys and censuses. Among women, increases in mortality due to AIDS were more concentrated in the age range 25-50 years in model outputs, as compared with empirical estimates. CONCLUSION: Discrepancies in levels, sex ratios and age patterns of adult mortality between empirical and UNAIDS estimates call for additional data quality assessments and improvements in estimation methods.

Vascular invasion and other invasive features in granular cell tumours of the skin: a multicentre study of 119 cases.

BACKGROUND: Incidental finding of vascular invasion has been described in some benign granular cell tumours. Malignancy in granular cell tumours is excessively rare and its assessment relies on necrosis and cytological criteria. AIMS: To assess histopathological invasive features, particularly vascular invasion, in a large series of granular cell tumours of the skin. METHODS: 119 granular cell tumours of the skin were collected in 114 patients between 2001 and 2011. Histopathological and epidemiological data were collected. Five step sections and one orcein staining were performed in all cases. RESULTS: Mean age of the patients was 43.7±18 years. Granular cell tumours were multiple in 7% of patients. They were classified as benign in 111 cases, and atypical in eight cases. No malignant granular cell tumour was present. Tumours had 1.48±1.3 cm mean diameter, showed peripheral invasive growth pattern in 71% of cases, had a mean depth of 8.8±4.7 mm, and reached the subcutis in 66% of cases. Infiltration of arrector pili muscle occurred in 23% (95% CI 16% to 32%), and perineural spread in 66% (95% CI 56% to 74%) of cases. Vascular invasion occurred in 23% (95% CI 16% to 32%) of cases, with subendothelial layers infiltration or vascular obliteration. No intraluminal embolus was found. No association was found between vascular invasion and clinical outcome. CONCLUSIONS: Histopathological features of local invasion are frequent in otherwise benign granular cell tumours. Vascular invasion consists of an infiltration of the subendothelial layers, without intraluminal cells, and may not be considered as a marker of adverse prognosis.

Probabilistic projections of the total fertility rate for all countries.

We describe a Bayesian projection model to produce country-specific projections of the total fertility rate (TFR) for all countries. The model decomposes the evolution of TFR into three phases: pre-transition high fertility, the fertility transition, and post-transition low fertility. The model for the fertility decline builds on the United Nations Population Division's current deterministic projection methodology, which assumes that fertility will eventually fall below replacement level. It models the decline in TFR as the sum of two logistic functions that depend on the current TFR level, and a random term. A Bayesian hierarchical model is used to project future TFR based on both the country's TFR history and the pattern of all countries. It is estimated from United Nations estimates of past TFR in all countries using a Markov chain Monte Carlo algorithm. The post-transition low fertility phase is modeled using an autoregressive model, in which long-term TFR projections converge toward and oscillate around replacement level. The method is evaluated using out-of-sample projections for the period since 1980 and the period since 1995, and is found to be well calibrated.

A Cohort approach to tobacco use and mortality: the case os Quebec

Cigarette smoking is the No.1 cause of premature death among Canadians. However, tobacco consumption dropped by 35% in Canada during the 1980s...

Skin metastases from unknown origin: role of immunohistochemistry in the evaluation of cutaneous metastases of carcinoma of unknown origin.

Determining the primary origin of skin metastases might be a challenging issue for pathologists, especially when there is no primary history or when this history is unavailable. The poor specificity of morphological appreciation is challenging, emphasizing the need for ancillary studies. We have retrieved 44 cases of skin metastases from our pathology files. Paraffin blocks were collected and homemade tissue arrays were made. We have tried to assess the primary origin based on morphological data alone, and then using 13 antibodies (cytokeratins (CK) 5/6, 7, 19, 20, thyroid transcription factor-1, carcinoembryonic antigen, PS100, tumor-associated glycoprotein 72, BerEP4, estrogen receptor (ER), progesterone receptor (PR), CD10, and E-cadherin). Most metastases in our series were from breast (13) and colorectal cancers (six) as they are the main clinical activity in our hospital. Only 44% of cases were correctly assessed based on the sole morphology, emphasizing the need for ancillary studies. CK 20, ER, and PR were the most helpful markers to determine the primary origin of skin metastases by highlighting colorectal origin and mammary origin, respectively. By far, clinical information and morphological evaluation are more reliable than the use of ancillary techniques, which have to be used in the absence of the former one and the poor differentiation of the latter ones. Azoulay S, Adem C, Le Pelletier F, Barete S, Francès C, Capron F. Skin metastases from unknown origin: role of immunohistochemistry in the evaluation of cutaneous metastases of carcinoma of unknown origin.

Dermatologic manifestations of the antiphospholipid syndrome: two hundred consecutive cases.

OBJECTIVE: To describe dermatologic manifestations of the antiphospholipid syndrome (APS) and to investigate possible correlations between livedo reticularis and other APS manifestations. METHODS: We conducted a single-center study of 200 consecutive patients with primary or systemic lupus erythematosus-related APS. To qualify for the study, patients had to fulfill clinical and laboratory criteria from the most recent international consensus statement on classification of definite APS. Dermatologic manifestations were systematically evaluated by a dermatologist. Only dermatologic lesions that may be related to APS were included in the analyses. Correlations between livedo reticularis and other APS manifestations were determined using Fisher's 2-tailed, chi-square, and nonparametric Mann-Whitney tests. RESULTS: Dermatologic manifestations were noted in 49% of the patients and were the presenting manifestations in 30.5%. Livedo reticularis was the most frequent manifestation, observed in 25.5% of the patients. Livedo reticularis was shown to be significantly associated with cerebral or ocular ischemic arterial events (odds ratio [OR] 10.8, 95% confidence interval [95% CI] 5.2-22.5), seizures (OR 6.5, 95% CI 2.6-16), all arterial events (OR 6, 95% CI 2.9-12.6), heart valve abnormalities detected on echocardiography (OR 7.3, 95% CI 3.6-14.7), and arterial systemic hypertension (>/=160/90 mm Hg) (OR 2.9, 95% CI 1.5-5.7). Conversely, it was observed with decreased frequency in patients with only venous thrombosis (OR 0.2, 95% CI 0.1-0.5). CONCLUSION: The dermatologic manifestations of APS are frequently the presenting feature of the syndrome, and livedo reticularis is significantly associated with the arterial subset of APS.