Epidemiology of Non-Traumatic Lower Extremities Amputations in West Africa: Nationwide Data from Togo.

OBJECTIVE: Non-traumatic lower limb amputation (NT-LLA) has consequences at individual and public health levels. Population based studies in sub-Saharan Africa are scarce and often related to single centre series. This study aimed to estimate the incidence of NT-LLA (minor and major) and to describe epidemiological, clinical, and prognostic aspects in Togo. METHODS: This was a population based observational study conducted among all patients who underwent NT-LLA. Traumatic amputations were excluded. Sociodemographic, clinical, and work up data were collected from clinical files in any Togolese health centre from 1 January 2016 to 31 December 2021. Incidence rates were adjusted for age. RESULTS: Over the six year period, 352 patients (59% males) underwent NT-LLA (mean ± standard deviation age 60 ± 15.7 years). The average age adjusted incidence rate of NT-LLA was 8.5 per million/year (95% confidence interval [CI] 7.6 - 9.4). Men were 1.7 times more likely to undergo a NT-LLA than women. The relative risk of NT-LLA was 48 times higher in patients with diabetes than in patients without diabetes. Around 61.0% of the NT-LLAs occurred within the 50 - 74 age group and 54.3% had diabetes mellitus. Among amputees, 54.5% had a diagnosis of peripheral artery disease (PAD) and 52.8% had diabetic ulcers, with co-existence of several factors. Less than 5% of participants had a history of smoking tobacco. Average length of hospital stay was 12 days. The in hospital mortality rate was 8.8% (9.0% for major, 6.7% for minor amputations). Only 18.2% had duplex ultrasound performed and 1.7% angiography prior to amputation. No patient underwent vascular intervention prior to amputation. CONCLUSION: This is the first study to report nationwide and contemporary epidemiological data on NT-LLAs in West Africa, highlighting several specificities. Large scale interventions are needed to ameliorate the care of diabetes and PAD and improve facilities for optimal management of patients at risk of amputation in Africa.

Functional Imaging in Olfactory Disorders.

Purpose of Review: The aim was to synthesize key findings regarding the use of functional MRI (fMRI) to assess olfactory dysfunction (OD), and thus, to evaluate whether fMRI could be a reliable clinical diagnostic tool. Recent Findings: In response to olfactory stimulation, patients with quantitative OD display reduced activation in olfactory-related brain regions but also stronger activation in non-olfactory brain areas. Parosmic patients also seem to show both weaker and higher brain signals. As to trigeminal chemosensory system, fMRI suggests that central processing may be declined in patients with OD. Functional connectivity studies report a possible correlation between altered neuronal connections within brain networks and olfactory performances. Summary: fMRI emerges as a valuable and promising objective method in OD evaluation. Yet, its high inter-individual variability still precludes its routine clinical use for diagnostic purpose. Future research should focus on optimizing stimulation paradigms and analysis methods.

Combinatorial Herpes Simplex Vaccine Strategies: From Bedside to Bench and Back.

The development of vaccines against herpes simplex virus type 1 and type 2 (HSV1 and HSV-2) is an important goal for global health. In this review we reexamined (i) the status of ocular herpes vaccines in clinical trials; and (ii) discusses the recent scientific advances in the understanding of differential immune response between HSV infected asymptomatic and symptomatic individuals that form the basis for the new combinatorial vaccine strategies targeting HSV; and (iii) shed light on our novel "asymptomatic" herpes approach based on protective immune mechanisms in seropositive asymptomatic individuals who are "naturally" protected from recurrent herpetic diseases. We previously reported that phenotypically and functionally distinct HSV-specific memory CD8+ T cell subsets in asymptomatic and symptomatic HSV-infected individuals. Moreover, a better protection induced following a prime/pull vaccine approach that consists of first priming anti-viral effector memory T cells systemically and then pulling them to the sites of virus reactivation (e.g., sensory ganglia) and replication (e.g., eyes and vaginal mucosa), following mucosal administration of vectors expressing T cell-attracting chemokines. In addition, we reported that a combination of prime/pull vaccine approach with approaches to reverse T cell exhaustion led to even better protection against herpes infection and disease. Blocking PD-1, LAG-3, TIGIT and/or TIM-3 immune checkpoint pathways helped in restoring the function of antiviral HSV-specific CD8+ T cells in latently infected ganglia and increased efficacy and longevity of the prime/pull herpes vaccine. We discussed that a prime/pull vaccine strategy that use of asymptomatic epitopes, combined with immune checkpoint blockade would prove to be a successful herpes vaccine approach.

Antiviral CD19+CD27+ Memory B Cells Are Associated with Protection from Recurrent Asymptomatic Ocular Herpesvirus Infection.

Reactivation of herpes simplex virus 1 (HSV-1) from latently infected neurons of the trigeminal ganglia (TG) leads to blinding recurrent herpetic disease in symptomatic (SYMP) individuals. Although the role of T cells in herpes immunity seen in asymptomatic (ASYMP) individuals is heavily explored, the role of B cells is less investigated. In the present study, we evaluated whether B cells are associated with protective immunity against recurrent ocular herpes. The frequencies of circulating HSV-specific memory B cells and of memory follicular helper T cells (CD4+ Tfh cells), which help B cells produce antibodies, were compared between HSV-1-infected SYMP and ASYMP individuals. The levels of IgG/IgA and neutralizing antibodies were compared in SYMP and ASYMP individuals. We found that (i) the ASYMP individuals had increased frequencies of HSV-specific CD19+CD27+ memory B cells, and (ii) high frequencies of HSV-specific switched IgG+CD19+CD27+ memory B cells detected in ASYMP individuals were directly proportional to high frequencies of CD45R0+CXCR5+CD4+ memory Tfh cells. However, no differences were detected in the level of HSV-specific IgG/IgA antibodies in SYMP and ASYMP individuals. Using the UV-B-induced HSV-1 reactivation mouse model, we found increased frequencies of HSV-specific antibody-secreting plasma HSV-1 gD+CD138+ B cells within the TG and circulation of ASYMP mice compared to those of SYMP mice. In contrast, no significant differences in the frequencies of B cells were found in the cornea, spleen, and bone-marrow. Our findings suggest that circulating antibody-producing HSV-specific memory B cells recruited locally to the TG may contribute to protection from symptomatic recurrent ocular herpes. IMPORTANCE Reactivation of herpes simplex virus 1 (HSV-1) from latently infected neurons of the trigeminal ganglia (TG) leads to blinding recurrent herpetic disease in symptomatic (SYMP) individuals. Although the role of T cells in herpes immunity against blinding recurrent herpetic disease is heavily explored, the role of B cells is less investigated. In the present study, we found that in both asymptomatic (ASYMP) individuals and ASYMP mice, there were increased frequencies of HSV-specific memory B cells that were directly proportional to high frequencies of memory Tfh cells. Moreover, following UV-B-induced reactivation, we found increased frequencies of HSV-specific antibody-secreting plasma B cells within the TG and circulation of ASYMP mice compared to those of SYMP mice. Our findings suggest that circulating antibody-producing HSV-specific memory B cells recruited locally to the TG may contribute to protection from recurrent ocular herpes.

High Frequencies of PD-1+TIM3+TIGIT+CTLA4+ Functionally Exhausted SARS-CoV-2-Specific CD4+ and CD8+ T Cells Associated with Severe Disease in Critically ill COVID-19 Patients

SARS-CoV-2-specific memory T cells that cross-react with common cold coronaviruses (CCCs) are present in both healthy donors and COVID-19 patients. However, whether these cross-reactive T cells play a role in COVID-19 pathogenesis versus protection remain to be fully elucidated. In this study, we characterized cross-reactive SARS-CoV-2-specific CD4+ and CD8+ T cells, targeting genome-wide conserved epitopes in a cohort of 147 non-vaccinated COVID-19 patients, divided into six groups based on the degrees of disease severity. We compared the frequency, phenotype, and function of these SARS-CoV-2-specific CD4+ and CD8+ T cells between severely ill and asymptomatic COVID-19 patients and correlated this with -CCCs and {beta}-CCCs co-infection status. Compared with asymptomatic COVID-19 patients, the severely ill COVID-19 patients and patients with fatal outcomes: (i) Presented a broad leukocytosis and a broad CD4+ and CD8+ T cell lymphopenia; (ii) Developed low frequencies of functional IFN-{gamma}-producing CD134+CD138+CD4+ and CD134+CD138+CD8+ T cells directed toward conserved epitopes from structural, non-structural and regulatory SARS-CoV-2 proteins; (iii) Displayed high frequencies of SARS-CoV-2-specific functionally exhausted PD-1+TIM3+TIGIT+CTLA4+CD4+ and PD-1+TIM3+TIGIT+CTLA4+CD8+ T cells; and (iv) Displayed similar frequencies of co-infections with {beta}-CCCs strains but significantly fewer co-infections with -CCCs strains. Interestingly, the cross-reactive SARS-CoV-2 epitopes that recalled the strongest CD4+ and CD8+ T cell responses in unexposed healthy donors (HD) were the most strongly associated with better disease outcome seen in asymptomatic COVID-19 patients. Our results demonstrate that, the critically ill COVID-19 patients displayed fewer co-infection with -CCCs strain, presented broad T cell lymphopenia and higher frequencies of cross-reactive exhausted SARS-CoV-2-specific CD4+ and CD8+ T cells. In contrast, the asymptomatic COVID-19 patients, appeared to present more co-infections with -CCCs strains, associated with higher frequencies of functional cross-reactive SARS-CoV-2-specific CD4+ and CD8+ T cells. These findings support the development of broadly protective, T-cell-based, multi-antigen universal pan-Coronavirus vaccines. KEY POINTSO_LIA broad lymphopenia and lower frequencies of SARS-CoV-2-specific CD4+ and CD8+ T-cells were associated with severe disease onset in COVID-19 patients. C_LIO_LIHigh frequencies of phenotypically and functionally exhausted SARS-CoV-2-specific CD4+ and CD8+ T cells, co-expressing multiple exhaustion markers, and targeting multiple structural, non-structural, and regulatory SARS-CoV-2 protein antigens, were detected in severely ill COVID-19 patients. C_LIO_LICompared to severely ill COVID-19 patients and to patients with fatal outcomes, the (non-vaccinated) asymptomatic COVID-19 patients presented more functional cross-reactive CD4+ and CD8+ T cells targeting conserved epitopes from structural, non-structural, and regulatory SARS-CoV-2 protein antigens. C_LIO_LIThe cross-reactive SARS-CoV-2 epitopes that recalled the strongest CD4+ and CD8+ T cell responses in unexposed healthy donors (HD) were the most strongly associated with better disease outcomes seen in asymptomatic COVID-19 patients. C_LIO_LICompared to severely ill COVID-19 patients and to patients with fatal outcomes, the (non-vaccinated) asymptomatic COVID-19 patients presented higher rates of co-infection with the -CCCs strains. C_LIO_LICompared to patients with mild or asymptomatic COVID-19, severely ill symptomatic patients and patients with fatal outcomes had more exhausted SARS-CoV-2-speccific CD4+ and CD8+ T cells that preferentially target cross-reactive epitopes that share high identity and similarity with the {beta}-CCCs strains. C_LI

Healing of Ocular Herpetic Disease Following Treatment With an Engineered FGF-1 Is Associated With Increased Corneal Anti-Inflammatory M2 Macrophages.

Herpes simplex virus 1 (HSV-1) infects the cornea and caused blinding ocular disease. In the present study, we evaluated whether and how a novel engineered version of fibroblast growth factor-1 (FGF-1), designated as TTHX1114, would reduce the severity of HSV-1-induced and recurrent ocular herpes in the mouse model. The efficacy of TTHX1114 against corneal keratopathy was assessed in B6 mice following corneal infection with HSV-1, strain McKrae. Starting day one post infection (PI), mice received TTHX1114 for 14 days. The severity of primary stromal keratitis and blepharitis were monitored up to 28 days PI. Inflammatory cell infiltrating infected corneas were characterized up to day 21 PI. The severity of recurrent herpetic disease was quantified in latently infected B6 mice up to 30 days post-UVB corneal exposure. The effect of TTHX1114 on M1 and M2 macrophage polarization was determined in vivo in mice and in vitro on primary human monocytes-derived macrophages. Compared to HSV-1 infected non-treated mice, the infected and TTHX1114 treated mice exhibited significant reduction of primary and recurrent stromal keratitis and blepharitis, without affecting virus corneal replication. The therapeutic effect of TTHX1114 was associated with a significant decrease in the frequency of M1 macrophages infiltrating the cornea, which expressed significantly lower levels of pro-inflammatory cytokines and chemokines. This polarization toward M2 phenotype was confirmed in vitro on human primary macrophages. This pre-clinical finding suggests use of this engineered FGF-1 as a novel immunotherapeutic regimen to reduce primary and recurrent HSV-1-induced corneal disease in the clinic.

Chemical stability of caesium iodide deposits in air/steam atmosphere.

Iodine compounds that may be released in case of severe nuclear accident will have important radiotoxicity if they are disseminated in air. One of the most important iodine species is CsI that is deposited on the surfaces of the reactor coolant system. However, depending on the conditions, CsI can volatilize or react with oxidants to produce I2(g). Theoretical and experimental studies demonstrate that the oxidation of iodide depends on the temperature and in the presence of oxidants in the gas. It is also slightly influenced by the crystallinity of the CsI particles and the nature of the support. In case of a high temperature deposition, the iodine release started at temperature lower than 300 °C. For the CsI vapour and aerosol depositions, the iodine is detected only at temperature above 450 °C and become very important above 550 °C.

High Frequency of Gamma Interferon-Producing PLZFloRORγtlo Invariant Natural Killer 1 Cells Infiltrating Herpes Simplex Virus 1-Infected Corneas Is Associated with Asymptomatic Ocular Herpesvirus Infection.

Invariant natural killer (iNKT) cells are among the first innate immune cells to elicit early protective immunity that controls invading viral pathogens. The role of the iNKT cell subsets iNKT1, iNKT2, and iNKT17 in herpesvirus immunity remains to be fully elucidated. In this study, we examined the protective role of cornea-resident iNKT cell subsets using the mouse model of ocular herpesvirus infection and disease. Wild-type (WT) C57BL/6 (B6) mice and CD1d knockout (KO) mice were infected ocularly with herpes simplex virus 1 (HSV-1) (strain McKrae). Cornea, spleen, and liver were harvested at 0, 2, 5, 8, and 14 days postinfection (p.i.), and the frequency and function of the three major iNKT cell subsets were analyzed and correlated with symptomatic and asymptomatic corneal herpesvirus infections. The profiles of 16 major pro- and anti-inflammatory cytokines were analyzed in corneal lysates using Western blot and Luminex assays. Early during ocular herpesvirus infection (i.e., day 2), the gamma interferon (IFN-γ)-producing PLZFloRORγtlo (promyelocytic leukemia zinc finger, retinoic acid-related orphan receptor gT) iNKT1 cell subset was the predominant iNKT cell subset in infected asymptomatic corneas. Moreover, compared to the asymptomatic corneas of HSV-1-infected WT mice, the symptomatic corneas CD1d KO mice, with iNKT cell deficiency, had increased levels of the inflammatory cytokine interleukin-6 (IL-6) and decreased levels of IL-12, IFN-γ, and the JAK1, STAT1, NF-κB, and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways. Our findings suggest that IFN-γ-producing PLZFloRORγtlo iNKT1 cells play a role in the protective innate immune response against symptomatic ocular herpes.IMPORTANCE We investigated the protective role of iNKT cell subsets in asymptomatic ocular herpesvirus infection. We found that early during ocular herpesvirus infection (i.e., on day 2 postinfection), IFN-γ-producing PLZFloRORγtlo iNKT1 cells were the predominant iNKT cell subset in infected corneas of asymptomatic B6 mice (with little to no corneal herpetic disease), compared to corneas of symptomatic mice (with severe corneal herpetic disease). Moreover, compared to asymptomatic corneas of wild-type (WT) B6 mice, the symptomatic corneas of CD1d KO mice, which lack iNKT cells, showed (i) decreases in the levels of IFN-γ and IL-12, (ii) an increase in the level of the inflammatory cytokine IL-6; and (iii) downregulation of the JAK1, STAT1, NF-κB, and ERK1/2 pathways. The findings suggest that early during ocular herpesvirus infection, cornea-resident IFN-γ-producing PLZFloRORγtlo iNKT1 cells provide protection from symptomatic ocular herpes.

Human Epitopes Identified from Herpes Simplex Virus Tegument Protein VP11/12 (UL46) Recall Multifunctional Effector Memory CD4+ TEM Cells in Asymptomatic Individuals and Protect from Ocular Herpes Infection and Disease in "Humanized" HLA-DR Transgenic Mice.

While the role of CD8+ T cells in the control of herpes simplex virus 1 (HSV-1) infection and disease is gaining wider acceptance, a direct involvement of effector CD4+ T cells in this protection and the phenotype and function of HSV-specific human CD4+ T cell epitopes remain to be fully elucidated. In the present study, we report that several epitopes from the HSV-1 virion tegument protein (VP11/12) encoded by UL46 are targeted by CD4+ T cells from HSV-seropositive asymptomatic individuals (who, despite being infected, never develop any recurrent herpetic disease). Among these, we identified two immunodominant effector memory CD4+ TEM cell epitopes, amino acids (aa) 129 to 143 of VP11/12 (VP11/12129-143) and VP11/12483-497, using in silico, in vitro, and in vivo approaches based on the following: (i) a combination of the TEPITOPE algorithm and PepScan library scanning of the entire 718 aa of HSV-1 VP11/12 sequence; (ii) an in silico peptide-protein docking analysis and in vitro binding assay that identify epitopes with high affinity to soluble HLA-DRB1 molecules; and (iii) an ELISpot assay and intracellular detection of gamma interferon (IFN-γ), CD107a/b degranulation, and CD4+ T cell carboxyfluorescein succinimidyl ester (CFSE) proliferation assays. We demonstrated that native VP11/12129-143 and VP11/12483-497 epitopes presented by HSV-1-infected HLA-DR-positive target cells were recognized mainly by effector memory CD4+ TEM cells while being less targeted by FOXP3+ CD4+ CD25+ regulatory T cells. Furthermore, immunization of HLA-DR transgenic mice with a mixture of the two immunodominant human VP11/12 CD4+ TEM cell epitopes, but not with cryptic epitopes, induced HSV-specific polyfunctional IFN-γ-producing CD107ab+ CD4+ T cells associated with protective immunity against ocular herpes infection and disease.IMPORTANCE We report that naturally protected HSV-1-seropositive asymptomatic individuals develop a higher frequency of antiviral effector memory CD4+ TEM cells specific to two immunodominant epitopes derived from the HSV-1 tegument protein VP11/12. Immunization of HLA-DR transgenic mice with a mixture of these two immunodominant CD4+ T cell epitopes induced a robust antiviral CD4+ T cell response in the cornea that was associated with protective immunity against ocular herpes. The emerging concept of developing an asymptomatic herpes vaccine that would boost effector memory CD4+ and CD8+ TEM cell responses is discussed.

Serum fructosamine predicts macrosomia in well-controlled hyperglycaemic pregnant women: An observational cross-sectional study.

AIM: While serum fructosamine may be a good marker of glucose control in pregnant women with diabetes, its relationship with macrosomia is still uncertain. METHODS: In 130 hyperglycaemic women with singleton pregnancies (117 gestational diabetes mellitus, 13 pregestational diabetes), serum fructosamine and HbA1c levels were measured at 25±7 weeks of gestation. Levels in mothers of infants with and without macrosomic newborns (birth weight>4000g and/or large-for-gestational-age birth weight>90th percentile) were compared using logistic regression analysis adjusted for macrosomia risk factors. RESULTS: These 130 pregnant women were 33±5 years old; their BMI before pregnancy was 27.7±6.9kg/m2, and they gained 7.5±5.1kg during the first 6 months of gestation. Glucose control was good according to HbA1c levels (5.3±0.3%; 34±2mmol/mol), yet 17/130 (13%) newborns had macrosomia: 3900±227g vs 3057±512g (P<0.001) in the others. These mothers were older and had higher parity, whereas their BMI scores before pregnancy and gestational weight gains did not differ. Fructosamine levels were also higher at 221±40µmol/L vs 192±22µmol/l (P<0.001), respectively, and remained significant even after adjusting for maternal age, BMI, parity, type of diabetes, antecedents of macrosomia and excessive gestational weight gain. By contrast, HbA1c did not differ between the two groups. In fact, nearly two-thirds (64.7%) of the mothers of macrosomic newborns had fructosamine levels>200µmol/l vs 31.9% of mothers with non-macrosomic newborns (P<0.05). CONCLUSION: High fructosamine levels are associated with macrosomia in the newborns of well-controlled hyperglycaemic pregnant women.

Unique Type I Interferon, Expansion/Survival Cytokines, and JAK/STAT Gene Signatures of Multifunctional Herpes Simplex Virus-Specific Effector Memory CD8+ TEM Cells Are Associated with Asymptomatic Herpes in Humans.

A large proportion of the world population harbors herpes simplex virus 1 (HSV-1), a major cause of infectious corneal blindness. HSV-specific CD8+ T cells protect from herpesvirus infection and disease. However, the genomic, phenotypic, and functional characteristics of CD8+ T cells associated with the protection seen in asymptomatic (ASYMP) individuals, who, despite being infected, never experienced any recurrent herpetic disease, remains to be fully elucidated. In this investigation, we compared the phenotype, function, and level of expression of a comprehensive panel of 579 immune genes of memory CD8+ T cells, sharing the same HSV-1 epitope specificities, and freshly isolated peripheral blood from well-characterized cohorts of protected ASYMP and nonprotected symptomatic (SYMP) individuals, with a history of numerous episodes of recurrent herpetic disease, using the high-throughput digital NanoString nCounter system and flow cytometry. Interestingly, our results demonstrated that memory CD8+ T cells from ASYMP individuals expressed a unique set of genes involved in expansion and survival, type I interferon (IFN-I), and JAK/STAT pathways. Frequent multifunctional HSV-specific effector memory CD62Llow CD44high CD8+ TEM cells were detected in ASYMP individuals compared to more of monofunctional central memory CD62Lhigh CD44high CD8+ TCM cells in SYMP individuals. Shedding light on the genotype, phenotype, and function of antiviral CD8+ T cells from "naturally protected" ASYMP individuals will help design future T-cell-based ocular herpes immunotherapeutic vaccines.IMPORTANCE A staggering number of the world population harbors herpes simplex virus 1 (HSV-1) potentially leading to blinding recurrent herpetic disease. While the majority are asymptomatic (ASYMP) individuals who never experienced any recurrent herpetic disease, symptomatic (SYMP) individuals have a history of numerous episodes of recurrent ocular herpetic disease. This study elucidates the phenotype, the effector function, and the gene signatures of memory CD8+ T-cell populations associated with protection seen in ASYMP individuals. Frequent multifunctional HSV-specific effector memory CD8+ TEM cells were detected in ASYMP individuals. In contrast, nonprotected SYMP individuals had more central memory CD8+ TCM cells. The memory CD8+ TEM cells from ASYMP individuals expressed unique gene signatures characterized by higher levels of type I interferon (IFN), expansion and expansion/survival cytokines, and JAK/STAT pathways. Future studies on the genotype, phenotype, and function of antiviral CD8+ T cells from "naturally protected" ASYMP individuals will help in the potential design of T-cell-based ocular herpes vaccines.

Screening for retinopathy of prematurity by telemedicine in a tertiary level neonatal intensive care unit in France: Review of a six-year period.

PURPOSE: To analyze the prevalence and risk factors for retinopathy of prematurity (ROP) and severe (treatment-requiring) ROP. METHODS: A retrospective study was conducted in a level III neonatal unit in Bordeaux, France, from 2009 to 2015. Four hundred and nineteen preterm infants who were screened for ROP exclusively by RetCam were included. RESULTS: ROP of any degree was diagnosed in 27.68% of infants. Stages 1, 2, 3 and 4 ROP was found in 44%, 46%, 9% and 1% of subjects, respectively. No stage 5 ROP was observed. 28/419 infants (6.6%) were treated exclusively with laser photocoagulation. No intravitreal anti-VEGF injections or surgical treatments were performed. No infants born at>31 weeks or with BW>1110g required ROP treatment. On multivariate analysis, risk factors for ROP development were low birth weight, low gestational age at birth, high duration of invasive mechanical ventilation, shock or use of vasopressors. On multivariate analysis, risk factors for severe, treatment-requiring ROP were male gender, gestational age≤27 weeks and Apgar score at 5minutes≤7. CONCLUSION: In our 6-year series, ROP was successfully identified on screening exclusively by telemedicine, and no surgical treatment was required. This study identifies known ROP risk factors, but the Apgar score at 5minutes as a risk factor for severe ROP requires further studies in order to be confirmed.

Skin autofluorescence predicts major adverse cardiovascular events in patients with type 1 diabetes: a 7-year follow-up study.

BACKGROUND: Advanced glycation end-products play a role in diabetic vascular complications. Their optical properties allow to estimate their accumulation in tissues by measuring the skin autofluorescence (SAF). We searched for an association between SAF and major adverse cardiovascular events (MACE) incidence in subjects with Type 1 Diabetes (T1D) during a 7 year follow-up. METHODS: During year 2009, 232 subjects with T1D were included. SAF measurement, clinical [age, sex, body mass index (BMI), comorbidities] and biological data (HbA1C, blood lipids, renal parameters) were recorded. MACE (myocardial infarction, stroke, lower extremity amputation or a revascularization procedure) were registered at visits in the center or by phone call to general practitioners until 2016. RESULTS: The participants were mainly men (59.5%), 51.5 ± 16.7 years old, with BMI 25.0 ± 4.1 kg/m2, diabetes duration 21.5 ± 13.6 years, HbA1C 7.6 ± 1.1%. LDL cholesterol was 1.04 ± 0.29 g/L, estimated Glomerular Filtration Rates (CKD-EPI): 86.3 ± 26.6 ml/min/1.73 m2. Among these subjects, 25.1% were smokers, 45.3% had arterial hypertension, 15.9% had elevated AER (≥ 30 mg/24 h), and 9.9% subjects had a history of previous MACE. From 2009 to 2016, 22 patients had at least one new MACE: 6 myocardial infarctions, 1 lower limb amputation, 15 revascularization procedures. Their SAF was 2.63 ± 0.73 arbitrary units (AU) vs 2.08 ± 0.54 for other patients (p = 0.002). Using Cox-model, after adjustment for age (as the scale time), sex, diabetes duration, BMI, hypertension, smoking status, albumin excretion rates, statin treatment and a previous history of MACE, higher baseline levels of SAF were significantly associated with an increased risk of MACE during follow-up (HR = 4.13 [1.30-13.07]; p = 0.02 for 1 AU of SAF) and Kaplan-Meier curve follow-up showed significantly more frequent MACE in group with SAF upper the median (p = 0.001). CONCLUSION: A high SAF predicts MACE in patients with T1D.

Colour ornamentation in the blue tit: quantitative genetic (co)variances across sexes.

Although secondary sexual traits are commonly more developed in males than females, in many animal species females also display elaborate ornaments or weaponry. Indirect selection on correlated traits in males and/or direct sexual or social selection in females are hypothesized to drive the evolution and maintenance of female ornaments. Yet, the relative roles of these evolutionary processes remain unidentified, because little is known about the genetic correlation that might exist between the ornaments of both sexes, and few estimates of sex-specific autosomal or sex-linked genetic variances are available. In this study, we used two wild blue tit populations with 9 years of measurements on two colour ornaments: one structurally based (blue crown) and one carotenoid based (yellow chest). We found significant autosomal heritability for the chromatic part of the structurally based colouration in both sexes, whereas carotenoid chroma was heritable only in males, and the achromatic part of both colour patches was mostly non heritable. Power limitations, which are probably common among most data sets collected so far in wild populations, prevented estimation of sex-linked genetic variance. Bivariate analyses revealed very strong cross-sex genetic correlations in all heritable traits, although the strength of these correlations was not related to the level of sexual dimorphism. In total, our results suggest that males and females share a majority of their genetic variation underlying colour ornamentation, and hence the evolution of these sex-specific traits may depend greatly on correlated responses to selection in the opposite sex.

Disruptive viability selection on a black plumage trait associated with dominance.

Traits used in communication, such as colour signals, are expected to have positive consequences for reproductive success, but their associations with survival are little understood. Previous studies have mainly investigated linear relationships between signals and survival, but both hump-shaped and U-shaped relationships can also be predicted, depending on the main costs involved in trait expression. Furthermore, few studies have taken the plasticity of signals into account in viability selection analyses. The relationship between signal expression and survival is of particular interest in melanin-based traits, because their main costs are still debated. Here, we first determined the main factors explaining variability in a melanin-based trait linked to dominance: the bib size of a colonial bird, the sociable weaver Philetairus socius. We then used these analyses to obtain a measure representative of the individual mean expression of bib size. Finally, we used capture-recapture models to study how survival varied in relation to bib size. Variation in bib size was strongly affected by year and moderately affected by age, body condition and colony size. In addition, individuals bearing small and large bibs had higher survival than those with intermediate bibs, and this U-shaped relationship between survival and bib size appeared to be more pronounced in some years than others. These results constitute a rare example of disruptive viability selection, and point towards the potential importance of social costs incurred by the dominance signalling function of badges of status.

Association of advanced glycation end products and chronic kidney disease with macroangiopathy in type 2 diabetes.

AIMS: Accumulation of advanced glycation end-products (AGEs), may explain the major contribution of chronic kidney disease (CKD) to cardiovascular events in patients with type 2 diabetes (T2D) related to their impaired renal function. The aim of this study was to analyze the factors associated with AGE assessed by skin autofluorescence and their association with macroangiopathy in T2D. METHODS: We measured skin autofluorescence in patients hospitalized for T2D. Glomerular filtration rates were estimated (eGFR) by the EPI-CKD formula. Associations between skin autofluorescence, renal function and macroangiopathy were explored by multivariate analyses adjusting for diabetes duration and control. RESULTS: The 418 patients had T2D since 13.3 (SD 9.8) years on average, high mean HbA1C: 8.9%, (SD 1.8), (74 mmol/mol, (SD 15)) and often renal complications (49.4% with CKD). Their mean skin autofluorescence was 2.53 (SD 0.62) A.U. In multivariate linear regression, skin autofluorescence was significantly associated with age (+0.20 for ten more years, p<0.0001), renal insufficiency (-0.07 for less 10 mL/min/1.73 m² eGFR, p<0.0001) and smoking (+0.21, p=0.0004). Autofluorescence (p=0.01), but not CKD, was associated with macroangiopathy independent of diabetes duration and control. CONCLUSIONS: Accumulation of AGEs is independently associated with renal insufficiency and macroangiopathy in patients with T2D.

Granular Cell Tumor of the Pituitary Stalk: A Rare and Benign Entity.

Granular cell tumor of the pituitary stalk is an uncommon benign lesion that usually appears like a suprasellar mass with visual disturbances. This diagnosis should be considered with the discovery of neurohypophysis tumors. Histological confirmation remains essential. We describe one case of this rare entity and review the literature.

Impending Carotid Blowout Stabilization Using an LT-D Tube.

Adequate stabilization of a patient presenting with a carotid blowout is one of the most challenging issues an on-call ENT surgeon can be confronted with. Reducing the bleeding and securing the airway are essential before more definitive management. We present the case of a 72-year-old patient with head and neck cancer who arrived at the emergency room with a carotid blowout and who was successfully stabilized using a King LT-D ventilation tube.