Association of Plasma Amyloid, P-Tau, GFAP, and NfL With CSF, Clinical, and Cognitive Features in Patients With Dementia With Lewy Bodies.

BACKGROUND AND OBJECTIVES: Plasma ß-amyloid-1-42/1-40 (Aß42/40), phosphorylated-tau (P-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) have been widely examined in Alzheimer disease (AD), but little is known about their reflection of copathologies, clinical importance, and predictive value in dementia with Lewy bodies (DLB). We aimed to evaluate associations of these biomarkers with CSF amyloid, cognition, and core features in DLB. METHODS: This cross-sectional multicenter cohort study with prospective component included individuals with DLB, AD, and healthy controls (HCs), recruited from 2002 to 2020 with an annual follow-up of up to 5 years, from the European-Dementia With Lewy Bodies consortium. Plasma biomarkers were measured by single-molecule array (Neurology 4-Plex E kit). Amyloid status was determined by CSF Aß42 concentrations, and cognition was assessed by Mini-Mental State Examination (MMSE). Biomarker differences across groups, associations with amyloid status, and clinical core features were assessed by analysis of covariance. Associations with cognitive impairment and decline were assessed by linear regression and linear mixed-effects models. RESULTS: In our cohort consisting of 562 individuals (HC n = 89, DLB n = 342, AD n = 131; 250 women [44.5%], mean [SD] age of 71 [8] years), sex distribution did not differ between groups. Patients with DLB were significantly older, and had less years of education and worse baseline cognition than HC, but not AD. DLB participants stratified for amyloid status differed significantly in plasma Aß42/40 ratio (decreased in amyloid abnormal: ß = -0.008, 95% CI -0.016 to -0.0003, p = 0.01) and P-tau (increased in amyloid abnormal, P-tau181: ß = 0.246, 95% CI 0.011-0.481; P-tau231: ß = 0.227, 95% CI 0.035-0.419, both p < 0.05), but not in GFAP (ß = 0.068, 95% CI -0.018 to 0.153, p = 0.119), and NfL (ß = 0.004, 95% CI -0.087 to 0.096, p = 0.923) concentrations. Higher baseline GFAP, NfL, and P-tau concentrations were associated with lower MMSE scores in DLB, and GFAP and NfL were associated with a faster cognitive decline (GFAP: annual change of -2.11 MMSE points, 95% CI -2.88 to -1.35 MMSE points, p < 0.001; NfL: annual change of -2.13 MMSE points, 95% CI -2.97 to -1.29 MMSE points, p < 0.001). DLB participants with parkinsonism had higher concentrations of NfL (ß = 0.08, 95% CI 0.02-0.14, p = 0.006) than those without. DISCUSSION: Our study suggests a possible utility of plasma Aß42/40, P-tau181, and P-tau231 as a noninvasive biomarkers to assess amyloid copathology in DLB, and plasma GFAP and NfL as monitoring biomarkers for cognitive symptoms in DLB.

Bat-borne H9N2 influenza virus evades MxA restriction and exhibits efficient replication and transmission in ferrets.

Influenza A viruses (IAVs) of subtype H9N2 have reached an endemic stage in poultry farms in the Middle East and Asia. As a result, human infections with avian H9N2 viruses have been increasingly reported. In 2017, an H9N2 virus was isolated for the first time from Egyptian fruit bats (Rousettus aegyptiacus). Phylogenetic analyses revealed that bat H9N2 is descended from a common ancestor dating back centuries ago. However, the H9 and N2 sequences appear to be genetically similar to current avian IAVs, suggesting recent reassortment events. These observations raise the question of the zoonotic potential of the mammal-adapted bat H9N2. Here, we investigate the infection and transmission potential of bat H9N2 in vitro and in vivo, the ability to overcome the antiviral activity of the human MxA protein, and the presence of N2-specific cross-reactive antibodies in human sera. We show that bat H9N2 has high replication and transmission potential in ferrets, efficiently infects human lung explant cultures, and is able to evade antiviral inhibition by MxA in transgenic B6 mice. Together with its low antigenic similarity to the N2 of seasonal human strains, bat H9N2 fulfils key criteria for pre-pandemic IAVs.

The Repellent Capacity against Sitophilus zeamais (Coleoptera: Curculionidae) and In Vitro Inhibition of the Acetylcholinesterase Enzyme of 11 Essential Oils from Six Plants of the Caribbean Region of Colombia.

The repellent capacity against Sitophilus zeamais and the in vitro inhibition on AChE of 11 essential oils, isolated from six plants of the northern region of Colombia, were assessed using a modified tunnel-type device and the Ellman colorimetric method, respectively. The results were as follows: (i) the degree of repellency (DR) of the EOs against S. zeamais was 20-68% (2 h) and 28-74% (4 h); (ii) the IC50 values on AChE were 5-36 µg/mL; likewise, the %inh. on AChE (1 µg/cm3 per EO) did not show any effect in 91% of the EO tested; (iii) six EOs (Bursera graveolens-bark, B. graveolens-leaves, B. simaruba-bark, Peperomia pellucida-leaves, Piper holtonii (1b*)-leaves, and P. reticulatum-leaves) exhibited a DR (53-74%) ≥ C+ (chlorpyrifos-61%), while all EOs were less active (8-60-fold) on AChE compared to chlorpyrifos (IC50 of 0.59 µg/mL). Based on the ANOVA/linear regression and multivariate analysis of data, some differences/similarities could be established, as well as identifying the most active EOs (five: B. simaruba-bark, Pep. Pellucida-leaves, P. holtonii (1b*)-leaves, B. graveolens-bark, and B. graveolens-leaves). Finally, these EOs were constituted by spathulenol (24%)/ß-selinene (18%)/caryophyllene oxide (10%)-B. simaruba; carotol (44%)/dillapiole (21%)-Pep. pellucida; dillapiole (81% confirmed by 1H-/13C-NMR)-P. holtonii; mint furanone derivative (14%)/mint furanone (14%)-B. graveolens-bark; limonene (17%)/carvone (10%)-B. graveolens-leaves.

Sex differences in brain atrophy in dementia with Lewy bodies.

INTRODUCTION: Sex influences neurodegeneration, but it has been poorly investigated in dementia with Lewy bodies (DLB). We investigated sex differences in brain atrophy in DLB using magnetic resonance imaging (MRI). METHODS: We included 436 patients from the European-DLB consortium and the Mayo Clinic. Sex differences and sex-by-age interactions were assessed through visual atrophy rating scales (n = 327; 73 ± 8 years, 62% males) and automated estimations of regional gray matter volume and cortical thickness (n = 165; 69 ± 9 years, 72% males). RESULTS: We found a higher likelihood of frontal atrophy and smaller volumes in six cortical regions in males and thinner olfactory cortices in females. There were significant sex-by-age interactions in volume (six regions) and cortical thickness (seven regions) across the entire cortex. DISCUSSION: We demonstrate that males have more widespread cortical atrophy at younger ages, but differences tend to disappear with increasing age, with males and females converging around the age of 75. HIGHLIGHTS: Male DLB patients had higher odds for frontal atrophy on radiological visual rating scales. Male DLB patients displayed a widespread pattern of cortical gray matter alterations on automated methods. Sex differences in gray matter measures in DLB tended to disappear with increasing age.

Development of a novel serological assay for the detection of mpox infection in vaccinated populations.

In 2022 the World Health Organization declared a Public Health Emergency for an outbreak of mpox, the zoonotic Orthopoxvirus (OPV) affecting at least 104 nonendemic locations worldwide. Serologic detection of mpox infection is problematic, however, due to considerable antigenic and serologic cross-reactivity among OPVs and smallpox-vaccinated individuals. In this report, we developed a high-throughput multiplex microsphere immunoassay using a combination of mpox-specific peptides and cross-reactive OPV proteins that results in the specific serologic detection of mpox infection with 93% sensitivity and 98% specificity. The New York State Non-Vaccinia Orthopoxvirus Microsphere Immunoassay is an important tool to detect subclinical mpox infection and understand the extent of mpox spread in the community through retrospective analysis.

Phenotypic and genotypic characterization of Colombian clinical isolates of Sporothrix spp. / Caracterización fenotípica y genotípica de aislamientos clínicos colombianos de Sporothrix spp.

INTRODUCTION: For over a century, Sporothrix schenckii was considered the sole species responsible for sporotrichosis. In 2007, scientific community confirmed the disease could be caused by various Sporothrix species. These species differed in their virulence factors and their antifungal sensitivity. OBJECTIVE: This study aims to characterize 42 Colombian clinical isolates of Sporothrix spp. phenotypically and genotypically. MATERIAL AND METHODS: Forty-two clinical isolates were characterized using phenotypic methods. It involved various culture media to determine their growth range at different temperatures and to assess the type and distribution of pigment and colony texture. Microscopic morphology was evaluated through microcultures, as well as the conidia diameter, type of sporulation, and morphology. Additionally, the assimilation of carbohydrates was selected as a physiological trait for species identification. Genotyping of 40 isolates was performed through partial amplification of the calmodulin gene, followed by sequence analysis. RESULTS: Molecular studies enabled the identification of 32 isolates of S. schenckii and 8 isolates of S. globosa. The combination of phenotypic and genotypic methods eased these species characterizations and the recognition keys development based on parameters such as growth diameter at 25 and 30 ºC, colony texture (membranous or velvety) on potato dextrose agar, and microscopic morphology with predominance of pigmented triangular, elongated oval globose, or subglobose conidia. CONCLUSIONS: Confirmation of the phenotypic characteristics and molecular analysis is crucial for identifying Sporothrix species and determining adequate treatment. This study represents the first phenotypical and genotypical characterization of clinical isolates of Sporothrix spp. reported in Colombia.

Introducción: Por más de un siglo se creyó que Sporothrix schenckii era la única especie responsable de la esporotricosis. Sin embargo, en el 2007, se consideró que podría ser causada por diferentes especies de Sporothrix, que difieren en sus factores de virulencia y su sensibilidad a los antifúngicos. Objetivo: Caracterizar fenotípica y genotípicamente 42 aislamientos clínicos colombianos de Sporothrix spp. Materiales y métodos: Se caracterizaron 42 aislamientos clínicos mediante métodos fenotípicos. Se usaron varios medios de cultivo para determinar el rango de crecimiento a diferentes temperaturas, el tipo y la distribución del pigmento, y la textura de las colonias. Se evaluó la morfología microscópica por microcultivos mediante la determinación del diámetro, el tipo de esporulación y la morfología de las conidias. La asimilación de carbohidratos se usó como una característica fisiológica para identificar las especies. La genotipificación de los 40 aislamientos se llevó a cabo mediante la amplificación parcial del gen que codifica para la calmodulina y se confirmó por secuenciación. Resultados: Mediante estudios moleculares, se identificaron 32 aislamientos de S. schenckii y ocho de S. globosa. La combinación de métodos fenotípicos y genotípicos permitió caracterizar las especies y construir claves para su reconocimiento, con base en parámetros como el diámetro de crecimiento a 25 y 30 ºC, la textura de las colonias (membranosa, aterciopelada) en agar papa dextrosa y la morfología microscópica con predominio de conidias (triangulares pigmentadas, ovales globosas elongadas, subglobosas). Conclusiones: La caracterización fenotípica y los análisis moleculares son necesarios para identificar las especies de Sporothrix y, de esta forma, elegir el tratamiento indicado. Esta es la primera caracterización fenotípica y genotípica reportada de aislamientos clínicos colombianos de Sporothrix spp.

Mpox vaccine and infection-driven human immune signatures: an immunological analysis of an observational study.

BACKGROUND: Monkeypox virus has recently infected more than 88 000 people, raising concerns about our preparedness against this emerging viral pathogen. Licensed and approved for mpox, the JYNNEOS vaccine has fewer side-effects than previous smallpox vaccines and has shown immunogenicity against monkeypox in animal models. This study aims to elucidate human immune responses to JYNNEOS vaccination compared with mpox-induced immunity. METHODS: Peripheral blood mononuclear cells and sera were obtained from ten individuals vaccinated with one or two doses of JYNNEOS and six individuals diagnosed with monkeypox virus infection. Samples were obtained from seven individuals before vaccination to serve as a baseline. We examined the polyclonal serum (ELISA) and single B-cell (heavy chain gene and transcriptome data) antibody repertoires and T-cell responses (activation-induced marker and intracellular cytokine staining assays) induced by the JYNNEOS vaccine versus monkeypox virus infection. FINDINGS: All participants were men between the ages of 21 and 60 years, except for one woman in the group of mpox-convalescent individuals, and none had previous orthopoxvirus exposure. All mpox cases were mild. Vaccinee samples were collected 6-33 days after the first dose and 5-40 days after the second dose. Mpox-convalescent samples were collected 20-102 days after infection. In vaccine recipients, gene-level plasmablast and antibody responses were negligible and sera displayed moderate binding to recombinant orthopoxviral proteins (A29L, A35R, E8L, A30L, A27L, A33R, B18R, and L1R) and native proteins from the 2022 monkeypox outbreak strain. By contrast, recent monkeypox virus infection (within 20-102 days) induced robust serum antibody responses to monkeypox virus proteins and to native monkeypox virus proteins from a viral isolate obtained during the 2022 outbreak. JYNNEOS vaccine recipients presented robust orthopoxviral CD4+ and CD8+ T-cell responses. INTERPRETATION: Infection with monkeypox virus resulted in robust B-cell and T-cell responses, whereas immunisation with JYNNEOS elicited more robust T-cell responses. These data can help to inform vaccine design and policies for preventing mpox in humans. FUNDING: National Cancer Institute (National Institutes of Health), National Institute of Allergy and Infectious Diseases (National Institutes of Health), and Icahn School of Medicine.

Development of a Novel Serological Assay for the Detection of Mpox Infection in Vaccinated Populations.

In 2022 the World Health Organization declared a Public Health Emergency for an outbreak of mpox, the zoonotic Orthopoxvirus (OPV) affecting at least 103 non-endemic locations world-wide. Serologic detection of mpox infection is problematic, however, due to considerable antigenic and serologic cross-reactivity among OPVs and smallpox-vaccinated individuals. In this report, we developed a high-throughput multiplex microsphere immunoassay (MIA) using a combination of mpox-specific peptides and cross-reactive OPV proteins that results in the specific serologic detection of mpox infection with 93% sensitivity and 98% specificity. The New York State Non-Vaccinia Orthopoxvirus Microsphere Immunoassay is an important diagnostic tool to detect subclinical mpox infection and understand the extent of mpox spread in the community through retrospective analysis.

Mpox vaccine and infection-driven human immune signatures.

Background: Mpox (formerly known as monkeypox) outbreaks outside endemic areas peaked in July 2022, infecting > 85,000 people and raising concerns about our preparedness against this emerging viral pathogen. Licensed and approved for mpox, the JYNNEOS vaccine has fewer side effects than previous smallpox vaccines and demonstrated efficacy against mpox infection in humans. Comparing JYNNEOS vaccine- and mpox-induced immunity is imperative to evaluate JYNNEOS' immunogenicity and inform vaccine administration and design. Methods: We examined the polyclonal serum (ELISA) and single B cell (heavy chain gene and transcriptome data) antibody repertoires and T cells (AIM and ICS assays) induced by the JYNNEOS vaccine as well as mpox infection. Findings: Gene-level plasmablast and antibody responses were negligible and JYNNEOS vaccinee sera displayed minimal binding to recombinant mpox proteins and native proteins from the 2022 outbreak strain. In contrast, recent mpox infection (within 20-102 days) induced robust serum antibody responses to A29L, A35R, A33R, B18R, and A30L, and to native mpox proteins, compared to vaccinees. JYNNEOS vaccine recipients presented comparable CD4 and CD8 T cell responses against orthopox peptides to those observed after mpox infection. Interpretation: JYNNEOS immunization does not elicit a robust B cell response, and its immunogenicity may be mediated by T cells. Funding: Research reported in this publication was supported, in part, by the National Cancer Institute of the National Institutes of Health under Award Number U54CA267776, U19AI168631(VS), as well as institutional funds from the Icahn School of Medicine.

Volatile Metabolites of Piper eriopodon (Miq.) C.DC. from Northern Region of Colombia and Assessment of In Vitro Bioactivities of the Leaf Essential Oil.

Piper eriopodon is one of the Piper species found in the Sierra Nevada de Santa Marta, and the species has been reported with different compositions of their essential oils (EO). In this study, the volatile fractions/essential oil (by HS-SPME/SDE/MWHD-GC-MS/1H-NMR) of different parts from the plant were characterized, and assessments of the in vitro bio-properties of the leaf EO were conducted. The results indicated the following: (i) in the volatile fractions were ß-caryophyllene (~23%)/myrcene (~20%) (inflorescences) and ß-caryophyllene (~43%)/ß-selinene (~20%) (leaves) using HS-SPME; myrcene (~31%)/ß-pinene (~23%) (inflorescences), gibbilimbol B (~60%) (fruits) and gibbilimbol B (~46%)/ß-caryophyllene (~11%) (leaves) through SDE; (ii) leaf EO contained gibbilimbol B (~72%), confirmed with 1H-NMR; (iii) the cytotoxic values (µg/mL) in erythrocytes/lymphocytes/Hep-2 were HC50: 115 ± 3 (eryth.), LC50: 71 ± 4 (lymph.) and LC50: 33 ± 2 (cell-line); (iv) the antibacterial susceptibilities (ϕ inh. zone, mm; 4-16 µg EO) were 22.5 ± 0.4-97 ± 4 (Staphylococcus aureus), 23 ± 2-77 ± 4 (Escherichia coli) and 17 ± 1-48 ± 3 (Listeria monocytogenes); (v) the TAA value was 2249 ± 130 mmol Trolox®/kg; (vi) the IC50 value was 13±1 µg/mL (AChE) with 20 ± 0-37 ± 6% repellency (2-4 h, Sitophilus zeamais). Thus, the EO of P. eriopodon leaves from northern Colombia could be a promising species for sustainable exploitation in the future due to its outstanding bioactivities.

Nefroprotección en frío para reparo de ectasia aórtica y aneurismas ilíacos bilaterales ante la presencia de riñón ectópico pélvico / Cold nephroprotection for repair of aortic ectasia and bilateral iliac aneurysms in the presence of pelvic ectopic kidney

Resumen Los riñones ectópicos pélvicos solitarios asociados a degeneración aneurismática de las arterias ilíacas y la aorta abdominal son eventos muy raros. Los enfoques quirúrgicos para la corrección de aneurismas con compromiso renal son un desafío por la falta de consenso actual, en especial cuando cursan con riñones ectópicos pélvicos solitarios funcionales asociados. Por tal motivo, una de las estrategias que ha demostrado buenos resultados a corto y mediano plazo es la nefroprotección en frío, la cual puede ser usada con seguridad en estos pacientes. En el caso que se presenta, se evidenció una ectasia aórtica con aneurismas ilíacos bilaterales asociados con un riñón ectópico pélvico solitario en un paciente masculino de 75 años, con hipertensión arterial y dislipidemia. Se realizó una reconstrucción aortoilíaca bilateral y una reconstrucción de la arteria hipogástrica, además de reimplante de la arteria renal ectópica bajo irrigación renal en frío, sin complicaciones y preservación de la función renal.

Abstract Solitary pelvic ectopic kidneys associated with aneurysmal degeneration of the iliac arteries and abdominal aorta are very rare events. Surgical approaches for the correction of aneurysms with renal involvement are challenging due to the lack of current consensus, especially when they are associated with functional solitary pelvic ectopic kidneys. For this reason, one of the strategies that has shown good results in the short and medium term is cold nephroprotection, which can be used safely in these patients. In the present case, aortic ectasia with bilateral iliac aneurysms associated with a solitary pelvic ectopic kidneys was evidenced in a 75-year-old male patient with arterial hypertension and dyslipidemia. Bilateral aortoiliac reconstruction was performed with hypogastric artery reconstruction and reimplantation of the ectopic renal artery under cold renal irrigation, without complications and preservation of renal function.

Exposición intrauterina a disruptores endocrinos (ftalatos): fuentes de exposición y cuantificación de metabolitos urinarios / Intrauterine exposure to endocrine disruptors (phthalates): sources of exposure and quantification of urinary metabolites

Introducción: Los ftalatos son disruptores endocrinos usados en la fabricación de múltiples productos de la industria, principalmente plásticos. El periodo fetal representa la principal ventana de vulnerabilidad, y la exposición a ftalatos en esta etapa de vida genera efectos adversos fetales y postnatales. El biomarcador más fiable para medición de ftalatos es la orina. Objetivo: Caracterizar las diferentes fuentes de exposición a disruptores endocrinos y cuantificar la concentración urinaria de ftalatos en gestantes. Materiales y métodos: Estudio transversal, observacional y descriptivo que incluye 400 gestantes que asistieron a control prenatal en las instituciones de salud Génesis y Metrosalud (Medellín-Colombia). Se caracterizaron fuentes de exposición, se recolectó muestras de orina de todas las gestantes, y cuantificó la concentración de ftalatos de 38 mujeres. Resultados: Las medias geométricas de ftalato Di(2-ethylhexyl)phthalate(DEHP), Mono-n-butyl phthalate(MnBP), Mono-2-ethyl-5-hydroxyhexyl phthalate(MEHHP) y Mono-2-ethyl-5-oxohexyl phthalate(MEOHP) fueron 162,72µg/L, 58,5 µg/L, 33,93µg/L y 31,63µg/L respectivamente. Conclusiones: La mayoría de las gestantes evaluadas han estado expuestas a lo largo de su vida a fuentes potenciales de disruptores endocrinos, presentes en químicos domésticos, tabaco y uso frecuente de cosméticos faciales y corporales. Las concentraciones de MnBP, MEHHP y MEOHP en orina de las participantes, fueron superiores a los hallazgos a nivel mundial.

Introduction: Phthalates are endocrine disruptors used in the manufacture of various industrial products, mainly plastics. The fetal period represents the principal window of vulnerability, and the exposure to Phthalates in this stage of life generates adverse fetal and post-natal effects. The most reliable biomarker for the assessment of Phthalates is urine. Objective: To characterize the different exposure sources of endocrine disruptors and quantify the urinary concentration of Phthalates in pregnant women. Materials and methods: A cross-sectional, observational, and descriptive study which included 400 pregnant women who received prenatal care in the Genesis and Metrosalud health institutions (Medellín-Colombia). Exposure sources were characterized and urine samples were collected from all pregnant women and the Phthalate concentration was quantified in 38 women. Results: The geometric measures of Phthalate Di(2-ethylhexyl)phthalate(DEHP), Mono-n-butyl phthalate(MnBP), Mono-2-ethyl-5-hydroxyhexyl phthalate(MEHHP) and Mono-2-ethyl-5-oxohexyl phthalate(MEOHP) were 162.72µg/L, 58.5 µg/L, 33.93µg/L and 31.63µg/L respectively. Conclusions: The majority of pregnant women that were evaluated were exposed to potential sources of endocrine disruptors throughout their life, which are present in household chemicals, tobacco, and frequent use of facial and body cosmetics. The concentrations of MnBP, MEHHP y MEOHP in urine of participants were higher than those found worldwide.

Immune profiles to distinguish hospitalized versus ambulatory COVID-19 cases in older patients.

A fraction of patients with COVID-19 develops severe disease requiring hospitalization, while the majority, including high-risk individuals, experience mild symptoms. Severe disease has been associated with higher levels of antibodies and inflammatory cytokines but often among patients with diverse demographics and comorbidity status. This study evaluated hospitalized vs. ambulatory patients with COVID-19 with demographic risk factors for severe COVID-19: median age of 63, >80% male, and >85% black and/or Hispanic. Sera were collected four to 243 days after symptom onset and evaluated for binding and functional antibodies as well as 48 cytokines and chemokines. SARS-CoV-2-specific antibody levels and functions were similar in ambulatory and hospitalized patients. However, a strong correlation between anti-S2 antibody levels and the other antibody parameters, along with higher IL-27 levels, was observed in hospitalized but not ambulatory cases. These data indicate that antibodies against the relatively conserved S2 spike subunit and immunoregulatory cytokines such as IL-27 are potential immune determinants of COVID-19.

Novel CHRDL1 mutation causing X-linked megalocornea in a family with mild anterior segment manifestations in carrier females.

PURPOSE: X-linked megalocornea (XMC) is a rare anterior segment malformation characterized by a nonprogressive enlargement of the cornea to 13 mm or greater in the setting of normal intraocular pressure. XMC is caused by mutations in the CHRDL1 gene and it is inherited as an X-linked recessive trait affecting only males. Here, we describe the results of phenotypic and genetic assessment in a novel XMC pedigree. METHODS: Three subjects (a father and his two daughters) underwent a complete clinical and imaging ocular examination including biomicroscopy, fundoscopy, tonometry, visual acuity, Pentacam Scheimpflug imaging, anterior segment Swept Source OCT, and ultrabiomicroscopy. Genetic analysis was performed through whole exome sequencing in 3 family members. Candidate variants were validated by sanger sequencing. RESULTS: The affected father exhibited megalocornea, very deep anterior chambers, retrocorneal pigmentation, iris atrophy, queer iris configuration, extremely open iridocorneal angles, and cataracts. Notably, both daughters showed queer iris configuration and abnormally widely open iridocorneal angles in both eyes. Genetic analysis identified a novel hemizygous c.207+1G>A splicing variant in CHRDL1 in the affected father. Both mildly affected daughters were heterozygous for the pathogenic variant. CONCLUSIONS: Here, we report an additional XMC family due to a novel mutation in the CHRDL1 gene. Mild anterior segment anomalies were observed in two heterozygous carriers demonstrating for the first time a CHRDL1-linked phenotype in females. A detailed comparison of the clinical and genetic features of this pedigree with those observed in previously published XMC cases is also presented.

Association of Plasma p-tau181 and p-tau231 Concentrations With Cognitive Decline in Patients With Probable Dementia With Lewy Bodies.

Importance: Plasma phosphorylated tau (p-tau) has proven to be an accurate biomarker for Alzheimer disease (AD) pathologic characteristics, offering a less expensive and less invasive alternative to cerebrospinal fluid (CSF) and positron emission tomography biomarkers for amyloid-ß and tau. Alzheimer disease comorbid pathologic characteristics are common and are associated with more rapid cognitive decline in patients with dementia with Lewy bodies (DLB); therefore, it is anticipated that plasma p-tau concentrations may have utility in assessing cognitive impairment in individuals with this disorder. Objective: To measure the concentrations of plasma p-tau (p-tau181 and p-tau231) and evaluate their associations with cognitive decline in individuals with probable DLB. Design, Setting, and Participants: This multicenter longitudinal cohort study included participants from the European-DLB (E-DLB) Consortium cohort enrolled at 10 centers with harmonized diagnostic procedures from January 1, 2002, to December 31, 2020, with up to 5 years of follow-up. A total of 1122 participants with plasma samples were available. Participants with acute delirium or terminal illness and patients with other previous major psychiatric or neurologic disorders were excluded, leaving a cohort of 987 clinically diagnosed participants with probable DLB (n = 371), Parkinson disease (n = 204), AD (n = 207), as well as healthy controls (HCs) (n = 205). Main Outcomes and Measures: The main outcome was plasma p-tau181 and p-tau231 levels measured with in-house single molecule array assays. The Mini-Mental State Examination (MMSE) was used to measure cognition. Results: Among this cohort of 987 patients (512 men [51.9%]; mean [SD] age, 70.0 [8.8] years), patients with DLB did not differ significantly regarding age, sex, or years of education from those in the AD group, but the DLB group was older than the HC group and included more men than the AD and HC groups. Baseline concentrations of plasma p-tau181 and p-tau231 in patients with DLB were significantly higher than those in the HC group but lower than in the AD group and similar to the Parkinson disease group. Higher plasma concentrations of both p-tau markers were found in a subgroup of patients with DLB with abnormal CSF amyloid-ß42 levels compared with those with normal levels (difference in the groups in p-tau181, -3.61 pg/mL; 95% CI, -5.43 to -1.79 pg/mL; P = .049; difference in the groups in p-tau231, -2.51 pg/mL; 95% CI, -3.63 to -1.39 pg/mL; P = .02). There was no difference between p-tau181 level and p-tau231 level across confirmed AD pathologic characteristcs based on reduced Aß42 level in CSF in individuals with DLB. In DLB, a significant association was found between higher plasma p-tau181 and p-tau231 levels and lower MMSE scores at baseline (for p-tau181, -0.092 MMSE points; 95% CI, -0.12 to -0.06 MMSE points; P = .001; for p-tau231, -0.16 MMSE points; 95% CI, -0.21 to -0.12 MMSE points; P < .001), as well as more rapid MMSE decline over time. Plasma p-tau181 level was associated with a decrease of -0.094 MMSE points per year (95% CI, -0.144 to -0.052 MMSE points; P = .02), whereas plasma p-tau231 level was associated with an annual decrease of -0.130 MMSE points (95% CI, -0.201 to -0.071 MMSE points; P = .02), after adjusting for sex and age. Conclusions and Relevance: This study suggests that plasma p-tau181 and p-tau231 levels may be used as cost-effective and accessible biomarkers to assess cognitive decline in individuals with DLB.

Incidencia, mortalidad y supervivencia por cáncer de endometrio en Manizales, Colombia 2003-2017 / Incidence, mortality and survival of endometrial cancer in Manizales, Colombia 2003-2017

RESUMEN Objetivo. Estimar la incidencia, mortalidad y supervivencia a cinco años por carcinoma endometrial en Manizales, para el periodo 2003-2017. Materiales y métodos. Estudio observacional, retrospectivo, de base poblacional, con alcance descriptivo. Se ajustaron tasas de incidencia y mortalidad mediante el método directo usando la población mundial Segi como referencia. Se realizó seguimiento pasivo y activo de los casos hasta completar 60 meses o hasta la fecha de cierre de seguimiento. La supervivencia fue estimada mediante funciones de Kaplan-Meier y modelos de regresión de Cox. Resultados. Se observaron 210 casos incidentes en una población de 214 928 mujeres. La edad promedio al diagnóstico fue de 61 años. El tipo histológico más frecuente fue el endometrioide, bien diferenciado. La mayoría de las pacientes estaban afiliadas al régimen contributivo y pertenecían al nivel socioeconómico medio. La tasa de incidencia ajustada por edad fue de 5,7 casos nuevos por cada 100 000 mujeres-año. Se identificaron 75 defunciones con mayor mortalidad entre los 64 y los 79 años. La supervivencia global fue de 95,1% a los 12 meses y de 83,8% a los 60 meses. Se encontraron diferencias estadísticamente significativas en la supervivencia a favor de la histología epitelial, los estadios tempranos al momento del diagnóstico y la edad al diagnóstico menor a 60 años. Conclusiones. La mortalidad es similar a la reportada en otros países de la región. En Manizales, la sobrevida al cáncer de endometrio fue mayor en pacientes con diagnóstico temprano, con edad menor de 60 años y con histología endometrioide.

ABSTRACT Objective. To estimate the incidence, mortality and five-year survival of endometrial carcinoma in Manizales for the period 2003-2017. Materials and methods. Observational, retrospective, population-based study, descriptive in scope. Incidence and mortality rates were adjusted by the direct method using the Segi world population as reference. Passive and active follow-up of the cases was carried out until completing 60 months or until the follow-up closing date. Survival was estimated using Kaplan-Meier functions and Cox models. Results. 210 incident cases were observed in a population of 214.928 women. The average age at diagnosis was 61 years. The most frequent histological type was endometrioid, well differentiated. Most of the patients were affiliated to the contributory health insurance scheme and belonged to the middle socioeconomic level. The age-adjusted incidence rate was 5.7 new cases per 100,000 woman-years. Seventy-five deaths were identified, with greater mortality between 65-69 and 75-79 age groups. Overall survival was 95.1% at 12 months and 83.8% at 60 months. Statistically significant differences were found in survival in favor of epithelial histology, early stages at the time of diagnosis, and age at diagnosis less than 60 years. Conclusions. Manizales follows the global pattern of rise in the age-adjusted incidence rate. Mortality is like that reported in other countries in the region. In Manizales, endometrial cancer survival was higher in patients with early diagnosis, less than 60 years of age, and with endometrioid histology.

Incidence, mortality and survival of endometrial cancer in Manizales, Colombia 2003-2017. / Incidencia, mortalidad y supervivencia por cáncer de endometrio en Manizales, Colombia 2003-2017.

OBJECTIVE.: To estimate the incidence, mortality and five-year survival of endometrial carcinoma in Manizales for the period 2003-2017. MATERIALS AND METHODS.: Observational, retrospective, population-based study, descriptive in scope. Incidence and mortality rates were adjusted by the direct method using the Segi world population as reference. Passive and active follow-up of the cases was carried out until completing 60 months or until the follow-up closing date. Survival was estimated using Kaplan-Meier functions and Cox models. RESULTS.: 210 incident cases were observed in a population of 214.928 women. The average age at diagnosis was 61 years. The most frequent histological type was endometrioid, well differentiated. Most of the patients were affiliated to the contributory health insurance scheme and belonged to the middle socioeconomic level. The age-adjusted incidence rate was 5.7 new cases per 100,000 woman-years. Seventy-five deaths were identified, with greater mortality between 65-69 and 75-79 age groups. Overall survival was 95.1% at 12 months and 83.8% at 60 months. Statistically significant differences were found in survival in favor of epithelial histology, early stages at the time of diagnosis, and age at diagnosis less than 60 years. CONCLUSIONS.: Manizales follows the global pattern of rise in the age-adjusted incidence rate. Mortality is like that reported in other countries in the region. In Manizales, endometrial cancer survival was higher in patients with early diagnosis, less than 60 years of age, and with endometrioid histology.

OBJETIVO.: Estimar la incidencia, mortalidad y supervivencia a cinco años por carcinoma endometrial en Manizales, para el periodo 2003-2017. MATERIALES Y MÉTODOS.: Estudio observacional, retrospectivo, de base poblacional, con alcance descriptivo. Se ajustaron tasas de incidencia y mortalidad mediante el método directo usando la población mundial Segi como referencia. Se realizó seguimiento pasivo y activo de los casos hasta completar 60 meses o hasta la fecha de cierre de seguimiento. La supervivencia fue estimada mediante funciones de Kaplan-Meier y modelos de regresión de Cox. RESULTADOS.: Se observaron 210 casos incidentes en una población de 214 928 mujeres. La edad promedio al diagnóstico fue de 61 años. El tipo histológico más frecuente fue el endometrioide, bien diferenciado. La mayoría de las pacientes estaban afiliadas al régimen contributivo y pertenecían al nivel socioeconómico medio. La tasa de incidencia ajustada por edad fue de 5,7 casos nuevos por cada 100 000 mujeres-año. Se identificaron 75 defunciones con mayor mortalidad entre los 64 y los 79 años. La supervivencia global fue de 95,1% a los 12 meses y de 83,8% a los 60 meses. Se encontraron diferencias estadísticamente significativas en la supervivencia a favor de la histología epitelial, los estadios tempranos al momento del diagnóstico y la edad al diagnóstico menor a 60 años. CONCLUSIONES.: La mortalidad es similar a la reportada en otros países de la región. En Manizales, la sobrevida al cáncer de endometrio fue mayor en pacientes con diagnóstico temprano, con edad menor de 60 años y con histología endometrioide.

The effect of an online exercise programme on bone health in paediatric cancer survivors (iBoneFIT): study protocol of a multi-centre randomized controlled trial.

BACKGROUND: New approaches on paediatric cancer treatment aim to maintain long-term health. As a result of radiotherapy, chemotherapy or surgery, paediatric cancer survivors tend to suffer from any chronic health condition. Endocrine dysfunction represents one of the most common issues and affects bone health. Exercise is key for bone mass accrual during growth, specifically plyometric jump training. The iBoneFIT study will investigate the effect of a 9-month online exercise programme on bone health in paediatric cancer survivors. This study will also examine the effect of the intervention on body composition, physical fitness, physical activity, calcium intake, vitamin D, blood samples quality of life and mental health. METHODS: A minimum of 116 participants aged 6 to 18 years will be randomized into an intervention (n = 58) or control group (n = 58). The intervention group will receive an online exercise programme and diet counselling on calcium and vitamin D. In addition, five behaviour change techniques and a gamification design will be implemented in order to increase the interest of this non-game programme. The control group will only receive diet counselling. Participants will be assessed on 3 occasions: 1) at baseline; 2) after the 9 months of the intervention; 3) 4 months following the intervention. The primary outcome will be determined by dual energy X-ray absorptiometry (DXA) and the hip structural analysis, trabecular bone score and 3D-DXA softwares. Secondary outcomes will include anthropometry, body composition, physical fitness, physical activity, calcium and vitamin D intake, blood samples, quality of life and mental health. DISCUSSION: Whether a simple, feasible and short in duration exercise programme can improve bone health has not been examined in paediatric cancer survivors. This article describes the design, rationale and methods of a study intended to test the effect of a rigorous online exercise programme on bone health in paediatric cancer survivors. If successful, the iBoneFIT study will contribute to decrease chronic health conditions in this population and will have a positive impact in the society. TRIAL REGISTRATION: Prospectively registered in isrctn.com: isrctn61195625 . Registered 2 April 2020.