Hospital Universitario San Agustín

Abstract Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3–6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.

INTRODUCTION: Sepsis is a leading cause of admission to non-cardiological intensive care units (ICUs) and the second leading cause of death among ICU patients. We present the first extensive dataset on the epidemiology of severe sepsis treated in ICUs in Spain. METHODS: We conducted a prospective, observational, multicentre cohort study, carried out over two 3-month periods in 2002. Our aims were to determine the incidence of severe sepsis among adults in ICUs in a specific area in Spain, to determine the early (48 h) ICU and hospital mortality rates, as well as factors associated with the risk of death. RESULTS: A total of 4,317 patients were admitted and 2,619 patients were eligible for the study; 311 (11.9%) of these presented at least 1 episode of severe sepsis, and 324 (12.4%) episodes of severe sepsis were recorded. The estimated accumulated incidence for the population was 25 cases of severe sepsis attended in ICUs per 100,000 inhabitants per year. The mean logistic organ dysfunction system (LODS) upon admission was 6.3; the mean sepsis-related organ failure assessment (SOFA) score on the first day was 9.6. Two or more organ failures were present at diagnosis in 78.1% of the patients. A microbiological diagnosis of the infection was reached in 209 episodes of sepsis (64.5%) and the most common clinical diagnosis was pneumonia (42.8%). A total of 169 patients (54.3%) died in hospital, 150 (48.2%) of these in the ICU. The mortality in the first 48 h was 14.8%. Factors associated with early death were haematological failure and liver failure at diagnosis, acquisition of the infection prior to ICU admission, and total LODS score on admission. Factors associated with death in the hospital were age, chronic alcohol abuse, increased McCabe score, higher LODS on admission, DeltaSOFA 3-1 (defined as the difference in the total SOFA scores on day 3 and on day 1), and the difference of the area under the curve of the SOFA score throughout the first 15 days. CONCLUSIONS: We found a high incidence of severe sepsis attended in the ICU and high ICU and hospital mortality rates. The high prevalence of multiple organ failure at diagnosis and the high mortality in the first 48 h suggests delays in diagnosis, in initial resuscitation, and/or in initiating appropriate antibiotic treatment.

Novel species of microfungi described in the present study include the following from South Africa: Cercosporella dolichandrae from Dolichandra unguiscati, Seiridium podocarpi from Podocarpus latifolius, Pseudocercospora parapseudarthriae from Pseudarthria hookeri, Neodevriesia coryneliae from Corynelia uberata on leaves of Afrocarpus falcatus, Ramichloridium eucleae from Euclea undulata and Stachybotrys aloeticola from Aloe sp. (South Africa), as novel member of the Stachybotriaceae fam. nov. Several species were also described from Zambia, and these include Chaetomella zambiensis on unknown Fabaceae, Schizoparme pseudogranati from Terminalia stuhlmannii, Diaporthe isoberliniae from Isoberlinia angolensis, Peyronellaea combreti from Combretum mossambiciensis, Zasmidium rothmanniae and Phaeococcomyces rothmanniae from Rothmannia engleriana, Diaporthe vangueriae from Vangueria infausta and Diaporthe parapterocarpi from Pterocarpus brenanii. Novel species from the Netherlands include: Stagonospora trichophoricola, Keissleriella trichophoricola and Dinemasporium trichophoricola from Trichophorum cespitosum, Phaeosphaeria poae, Keissleriella poagena, Phaeosphaeria poagena, Parastagonospora poagena and Pyrenochaetopsis poae from Poa sp., Septoriella oudemansii from Phragmites australis and Dendryphion europaeum from Hedera helix (Germany) and Heracleum sphondylium (the Netherlands). Novel species from Australia include: Anungitea eucalyptorum from Eucalyptus leaf litter, Beltraniopsis neolitseae and Acrodontium neolitseae from Neolitsea australiensis, Beltraniella endiandrae from Endiandra introrsa, Phaeophleospora parsoniae from Parsonia straminea, Penicillifer martinii from Cynodon dactylon, Ochroconis macrozamiae from Macrozamia leaf litter, Triposporium cycadicola, Circinotrichum cycadis, Cladosporium cycadicola and Acrocalymma cycadis from Cycas spp. Furthermore, Vermiculariopsiella dichapetali is described from Dichapetalum rhodesicum (Botswana), Ophiognomonia acadiensis from Picea rubens (Canada), Setophoma vernoniae from Vernonia polyanthes and Penicillium restingae from soil (Brazil), Pseudolachnella guaviyunis from Myrcianthes pungens (Uruguay) and Pseudocercospora neriicola from Nerium oleander (Italy). Novelties from Spain include: Dendryphiella eucalyptorum from Eucalyptus globulus, Conioscypha minutispora from dead wood, Diplogelasinospora moalensis and Pseudoneurospora canariensis from soil and Inocybe lanatopurpurea from reforested woodland of Pinus spp. Novelties from France include: Kellermania triseptata from Agave angustifolia, Zetiasplozna acaciae from Acacia melanoxylon, Pyrenochaeta pinicola from Pinus sp. and Pseudonectria rusci from Ruscus aculeatus. New species from China include: Dematiocladium celtidicola from Celtis bungeana, Beltrania pseudorhombica, Chaetopsina beijingensis and Toxicocladosporium pini from Pinus spp. and Setophaeosphaeria badalingensis from Hemerocallis fulva. Novel genera of Ascomycetes include Alfaria from Cyperus esculentus (Spain), Rinaldiella from a contaminated human lesion (Georgia), Hyalocladosporiella from Tectona grandis (Brazil), Pseudoacremonium from Saccharum spontaneum and Melnikomyces from leaf litter (Vietnam), Annellosympodiella from Juniperus procera (Ethiopia), Neoceratosperma from Eucalyptus leaves (Thailand), Ramopenidiella from Cycas calcicola (Australia), Cephalotrichiella from air in the Netherlands, Neocamarosporium from Mesembryanthemum sp. and Acervuloseptoria from Ziziphus mucronata (South Africa) and Setophaeosphaeria from Hemerocallis fulva (China). Several novel combinations are also introduced, namely for Phaeosphaeria setosa as Setophaeosphaeria setosa, Phoma heteroderae as Peyronellaea heteroderae and Phyllosticta maydis as Peyronellaea maydis. Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa.

Novel species of fungi described in this study include those from various countries as follows: Australia , Chaetomella pseudocircinoseta and Coniella pseudodiospyri on Eucalyptus microcorys leaves, Cladophialophora eucalypti , Teratosphaeria dunnii and Vermiculariopsiella dunnii on Eucalyptus dunnii leaves, Cylindrium grande and Hypsotheca eucalyptorum on Eucalyptus grandis leaves, Elsinoe salignae on Eucalyptus saligna leaves, Marasmius lebeliae on litter of regenerating subtropical rainforest, Phialoseptomonium eucalypti (incl. Phialoseptomonium gen. nov.) on Eucalyptus grandis × camaldulensis leaves, Phlogicylindrium pawpawense on Eucalyptus tereticornis leaves, Phyllosticta longicauda as an endophyte from healthy Eustrephus latifolius leaves, Pseudosydowia eucalyptorum on Eucalyptus sp. leaves, Saitozyma wallum on Banksia aemula leaves, Teratosphaeria henryi on Corymbia henryi leaves. Brazil , Aspergillus bezerrae , Backusella azygospora , Mariannaea terricola and Talaromyces pernambucoensis from soil, Calonectria matogrossensis on Eucalyptus urophylla leaves, Calvatia brasiliensis on soil, Carcinomyces nordestinensis on Bromelia antiacantha leaves, Dendryphiella stromaticola on small branches of an unidentified plant, Nigrospora brasiliensis on Nopalea cochenillifera leaves, Penicillium alagoense as a leaf endophyte on a Miconia sp., Podosordaria nigrobrunnea on dung, Spegazzinia bromeliacearum as a leaf endophyte on Tilandsia catimbauensis , Xylobolus brasiliensis on decaying wood. Bulgaria , Kazachstania molopis from the gut of the beetle Molops piceus . Croatia , Mollisia endocrystallina from a fallen decorticated Picea abies tree trunk. Ecuador , Hygrocybe rodomaculata on soil. Hungary , Alfoldia vorosii (incl. Alfoldia gen. nov.) from Juniperus communis roots, Kiskunsagia ubrizsyi (incl. Kiskunsagia gen. nov.) from Fumana procumbens roots. India , Aureobasidium tremulum as laboratory contaminant, Leucosporidium himalayensis and Naganishia indica from windblown dust on glaciers. Italy , Neodevriesia cycadicola on Cycas sp. leaves, Pseudocercospora pseudomyrticola on Myrtus communis leaves, Ramularia pistaciae on Pistacia lentiscus leaves, Neognomoniopsis quercina (incl. Neognomoniopsis gen. nov.) on Quercus ilex leaves. Japan , Diaporthe fructicola on Passiflora edulis × P . edulis f. flavicarpa fruit, Entoloma nipponicum on leaf litter in a mixed Cryptomeria japonica and Acer spp. forest. Macedonia , Astraeus macedonicus on soil. Malaysia , Fusicladium eucalyptigenum on Eucalyptus sp. twigs, Neoacrodontiella eucalypti (incl. Neoacrodontiella gen. nov.) on Eucalyptus urophylla leaves. Mozambique , Meliola gorongosensis on dead Philenoptera violacea leaflets. Nepal , Coniochaeta dendrobiicola from Dendriobium lognicornu roots. New Zealand , Neodevriesia sexualis and Thozetella neonivea on Archontophoenix cunninghamiana leaves. Norway , Calophoma sandfjordenica from a piece of board on a rocky shoreline, Clavaria parvispora on soil, Didymella finnmarkica from a piece of Pinus sylvestris driftwood. Poland , Sugiyamaella trypani from soil. Portugal , Colletotrichum feijoicola from Acca sellowiana. Russia , Crepidotus tobolensis on Populus tremula debris, Entoloma ekaterinae , Entoloma erhardii and Suillus gastroflavus on soil, Nakazawaea ambrosiae from the galleries of Ips typographus under the bark of Picea abies. Slovenia , Pluteus ludwigii on twigs of broadleaved trees. South Africa , Anungitiomyces stellenboschiensis (incl. Anungitiomyces gen. nov.) and Niesslia stellenboschiana on Eucalyptus sp. leaves, Beltraniella pseudoportoricensis on Podocarpus falcatus leaf litter, Corynespora encephalarti on Encephalartos sp. leaves, Cytospora pavettae on Pavetta revoluta leaves, Helminthosporium erythrinicola on Erythrina humeana leaves, Helminthosporium syzygii on a Syzygium sp. barkcanker, Libertasomyces aloeticus on Aloe sp. leaves, Penicillium lunae from Musa sp. fruit, Phyllosticta lauridiae on Lauridia tetragona leaves, Pseudotruncatella bolusanthi (incl. Pseudotruncatellaceae fam. nov.) and Dactylella bolusanthi on Bolusanthus speciosus leaves. Spain , Apenidiella foetida on submerged plant debris, Inocybe grammatoides on Quercus ilex subsp. ilex forest humus, Ossicaulis salomii on soil, Phialemonium guarroi from soil. Thailand , Pantospora chromolaenae on Chromolaena odorata leaves. Ukraine , Cadophora helianthi from Helianthus annuus stems. USA , Boletus pseudopinophilus on soil under slash pine, Botryotrichum foricae , Penicillium americanum and Penicillium minnesotense from air. Vietnam , Lycoperdon vietnamense on soil. Morphological and culture characteristics are supported by DNA barcodes.

Abstract BACKGROUND Concern has been raised about the quality of available biological variation (BV) estimates and the effect of their application in clinical practice. A European Federation of Clinical Chemistry and Laboratory Medicine Task and Finish Group has addressed this issue. The aim of this report is to (a) describe the Biological Variation Data Critical Appraisal Checklist (BIVAC), which verifies whether publications have included all essential elements that may impact the veracity of associated BV estimates, (b) use the BIVAC to critically appraise existing BV publications on enzymes, lipids, kidney, and diabetes-related measurands, and (c) apply metaanalysis to deliver a global within-subject BV (CVI) estimate for alanine aminotransferase (ALT). METHODS In the BIVAC, publications were rated as A, B, C, or D, indicating descending compliance for 14 BIVAC quality items, focusing on study design, methodology, and statistical handling. A D grade indicated that associated BV estimates should not be applied in clinical practice. Systematic searches were applied to identify BV studies for 28 different measurands. RESULTS In total, 128 publications were identified, providing 935 different BV estimates. Nine percent achieved D scores. Outlier analysis and variance homogeneity testing were scored as C in >60% of 847 cases. Metaanalysis delivered a CVI estimate for ALT of 15.4%. CONCLUSIONS Application of BIVAC to BV publications identified deficiencies in required study detail and delivery, especially for statistical analysis. Those deficiencies impact the veracity of BV estimates. BV data from BIVAC-compliant studies can be combined to deliver robust global estimates for safe clinical application.

BACKGROUND: Quality of life of stoma patients is increasingly being addressed in clinical trials. However, the instruments used in the majority of these studies have not been validated specifically for stoma patients. The aim of this paper is to describe the development and validation of a quality-of-life instrument, "Stoma-QOL", specifically for patients with colostomy or ileostomy. METHODS: Potential items were formulated in English on the basis of the results of a series of semi-structured interviews with 169 adult stoma patients. The process resulted in a preliminary 37-item version, which was translated into French, German, Spanish and Danish, and administered repeatedly to 182 patients with colostomy or ileostomy. A psychometric selection of items was performed through Rasch Analysis. The measurement properties of the final questionnaire version were subsequently tested. RESULTS: The 20 items in the final questionnaire covered four domains--sleep, sexual activity, relations to family and close friends, and social relations to other than family and close friends. These items were found to define a unidimensional variable according to Rasch specifications (Infit MNSQ < 1.3). Internal consistency reliability calculated as Cronbach's alpha was 0.92, i.e., highly reliable. Spearman's correlation coefficients of scores across times of administration was > 0.88 (p < 0.01), indicating a high test-retest reliability. Item calibrations by country calculated as ICC were 0.81 (0.67-0.91 95% CI), confirming cross-cultural comparability across the European countries included in the study. CONCLUSION: Given the adequacy of the metric properties of the Stoma-QOL suggested by the psychometric analyses, this study confirms the suitability of the instrument in clinical practice and in clinical research.

Vestibular migraine (VM) is a common disorder in which genetic, epigenetic, and environmental factors probably contribute to its development. The pathophysiology of VM is unknown; nevertheless in the last few years, several studies are contributing to understand the neurophysiological pathways involved in VM. The current hypotheses are mostly based on the knowledge of migraine itself. The evidence of trigeminal innervation of the labyrinth vessels and the localization of vasoactive neuropeptides in the perivascular afferent terminals of these trigeminal fibers support the involvement of the trigemino-vascular system. The neurogenic inflammation triggered by activation of the trigeminal-vestibulocochlear reflex, with the subsequent inner ear plasma protein extravasation and the release of inflammatory mediators, can contribute to a sustained activation and sensitization of the trigeminal primary afferent neurons explaining VM symptoms. The reciprocal connections between brainstem vestibular nuclei and the structures that modulate trigeminal nociceptive inputs (rostral ventromedial medulla, ventrolateral periaqueductal gray, locus coeruleus, and nucleus raphe magnus) are critical to understand the pathophysiology of VM. Although cortical spreading depression can affect cortical areas involved in processing vestibular information, functional neuroimaging techniques suggest a dysmodulation in the multimodal sensory integration and processing of vestibular and nociceptive information, resulting from a vestibulo-thalamo-cortical dysfunction, as the pathogenic mechanism underlying VM. The elevated prevalence of VM suggests that multiple functional variants may confer a genetic susceptibility leading to a dysregulation of excitatory-inhibitory balance in brain structures involved in the processing of sensory information, vestibular inputs, and pain. The interactions among several functional and structural neural networks could explain the pathogenic mechanisms of VM.

BACKGROUND: Despite favorable meta-analyses, no study involving third-generation cephalosporins for the treatment of childhood bacterial meningitis has documented a benefit of adjuvant dexamethasone therapy if the outcomes are examined individually. METHODS: We conducted a prospective, randomized, double-blind trial comparing adjuvant dexamethasone or glycerol with placebo in children aged from 2 months through 16 years in Latin America. Ceftriaxone was administered to all children; children were randomized to also receive dexamethasone intravenously, glycerol orally, both agents, or neither agent. Primary end points were death, severe neurological sequelae, or deafness, with the first 2 end points forming a composite end point. A subgroup analysis for Haemophilus influenzae type b meningitis was undertaken. Intention-to-treat analysis was performed using binary logistic regression models. RESULTS: H. influenzae type b, pneumococci, and meningococci were the main agents found among 654 patients; dexamethasone was given to 166, dexamethasone and glycerol were given to 159, glycerol was given to 166, and placebo was given to 163. No adjuvant therapy significantly affected death or deafness. In contrast, glycerol and dexamethasone plus glycerol reduced severe neurological sequelae, compared with placebo; the odds ratios were 0.31 (95% confidence interval [95% CI], 0.13-0.76; P=.010) and 0.39 (95% CI, 0.17-0.93; P=.033), respectively. For neurological sequelae and death, the odds ratios were 0.44 (95% CI, 0.25-0.76; P=.003) and 0.55 (95% CI, 0.32-0.93; P=.027), respectively. Dexamethasone therapy prevented deafness in patients with H. influenzae type b meningitis only if patients were divided grossly into dexamethasone recipients and nonrecipients and if timing between dexamethasone and ceftriaxone administration was not taken into account (odds ratio, 0.27; 95% CI, 0.09-0.77; P=.014). CONCLUSION: Oral glycerol therapy prevents severe neurological sequelae in patients with childhood meningitis. Safety, availability, low cost, and oral administration also add to its usefulness, especially in resource-limited settings.

Triple negative breast cancer (TNBC) is a highly heterogeneous tumor. There is increasing evidence of the role of tumor lymphocytic immune infiltrates in this subtype of breast cancer. Robust levels of tumor infiltrating lymphocytes (TILs) have been associated with improved disease-free and overall survival rates in TNBC patients with and without any treatment. Recent efforts have been made to develop a standardized methodology for evaluating TILs. The presence of TILs in the breast tumor microenvironment can also predict responses not only to neoadjuvant but also to adjuvant chemotherapy treatments. High numbers of TILs correlate with increased pathological complete responses (pCR) in TNBC. TILs are prognostic and predictive of response to standard therapies; thus, the immune system appears to play an active role in a subgroup of breast cancer. There is an increasing interest in directly targeting the immune system as part of breast cancer therapy, mainly in patients with TNBC. New immune modulatory agents, including immune checkpoints inhibitors, have shown promising activity in a subgroup of metastatic TNBC. Increased programmed cell death protein 1 ligand (PD-L1) expression on the surface of TNBC provides the rationale for implementing therapeutic strategies targeting the PD-1/PD-L1 axis in TNBC. The programmed cell death protein 1 (PD-1) inhibitor pembrolizumab, and the PD-L1 inhibitor atezolizumab have shown promising results in clinical trials.

The introduction of trastuzumab therapy markedly improved the poor prognosis associated with HER2-amplified breast cancers. Despite this, the presence of primary and acquired resistance to trastuzumab treatment remains a significant common challenge. The identification of resistance mechanisms and the incorporation of new drugs that achieve a better blockade of HER family receptors signaling have resulted in improved outcomes. The phosphatidylinositol 3'-kinase/protein kinase B/mammalian target of rapamycin pathway, cross-talk with estrogen receptors, immune response, cell cycle control mechanisms, and other tyrosine kinase receptors such as insulin-like growth factor I receptor are potential pathways involved in trastuzumab resistance. Different therapeutic interventions targeting these pathways are currently under evaluation.

BACKGROUND: Adequate vitamin D status in mothers during pregnancy may influence the health status of the child later in life. We assessed whether maternal circulating 25-hydroxyvitamin D (25[OH]D) concentrations in pregnancy are associated with risk of lower respiratory tract infections, wheezing, and asthma in the offspring. METHODS: Data were obtained from 1724 children of the INfancia y Medio Ambiente (INMA) Project, a population-based birth cohort study. Maternal circulating 25(OH)D concentrations were measured in pregnancy (mean gestational age = 12.6 [SD = 2.5] weeks). When the child was age 1 year, parents were asked if their child had a physician-confirmed history of lower respiratory tract infections or a history of wheezing. The questions about wheezing were repeated annually thereafter. Asthma was defined as parental report of doctor diagnosis of asthma or receiving treatment at the age of 4-6 years or wheezing since the age of 4 years. RESULTS: The median maternal circulating 25(OH)D concentration in pregnancy was 29.5 ng/mL (interquartile range, 22.5-37.1 ng/mL). After multivariable adjustment, there was a trend for an independent association between higher levels of maternal circulating 25(OH)D levels in pregnancy and decreased odds of lower respiratory tract infections in offspring (for cohort- and season-specific quartile Q4 vs. Q1, odds ratio = 0.67 [95% confidence interval = 0.50-0.90]; test for trend, P = 0.016). We found no association between 25(OH)D levels in pregnancy and risk of wheezing at age 1 year or 4 years, or asthma at age 4-6 years. CONCLUSIONS: Higher maternal circulating 25(OH)D concentrations in pregnancy were independently associated with lower risk of lower respiratory tract infections in offspring in the first year of life but not with wheezing or asthma in childhood.

BACKGROUND: Colorectal tumors caused by failure of the DNA mismatch repair system commonly show microsatellite instability. Our goals were to compare the performance of two panels of markers (a panel previously recommended by the National Cancer Institute [NCI] and a pentaplex of mononucleotide repeats) and to devise the simplest diagnostic strategy for identification of patients with colorectal cancer characterized by defects in mismatch repair. METHODS: We recruited 1058 patients who were newly diagnosed with colorectal cancer. DNA from fresh-frozen and paraffin-embedded tumors was tested for microsatellite instability, using the NCI-recommended panel of microsatellite markers and the pentaplex panel of mononucleotide repeats, respectively, as templates for polymerase chain reactions (PCRs). Microsatellite instability in fresh-frozen tumors was also assessed using the pentaplex panel of mononucleotides in a crossover analysis. The expression of mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2) in the tumors was determined immunohistochemically. The sensitivity and specificity with which the marker panels identified tumors with deficiencies in the expression of mismatch repair proteins were calculated. All statistical tests were two-sided. RESULTS: The sensitivity and positive predictive value of the NCI panel were 76.5% (95% confidence interval [CI] = 61% to 92%) and 65.0% (95% CI = 49% to 81%), respectively; corresponding values for the mononucleotide pentaplex panel were 95.8% (95% CI = 89% to 103%) and 88.5% (95% CI = 79% to 98%), respectively. A panel consisting of the mononucleotide repeat markers BAT26 and NR24 alone had the same predictive value as the pentaplex panel of mononucleotide repeats. CONCLUSIONS: The pentaplex panel of mononucleotide repeats performs better than the NCI panel for the detection of mismatch repair-deficient tumors. Simultaneous assessment of the instability of BAT26 and NR24 is as effective as use of the pentaplex panel for diagnosing mismatch repair deficiency.

OBJECTIVES: To define clinical subgroups by cluster analysis in patients with unilateral Meniere disease (MD) and to compare them with the clinical subgroups found in bilateral MD. DESIGN: A cross-sectional study with a two-step cluster analysis. SETTINGS: A tertiary referral multicenter study. PARTICIPANTS: Nine hundred and eighty-eight adult patients with unilateral MD. MAIN OUTCOME MEASURES: best predictors to define clinical subgroups with potential different aetiologies. RESULTS: We established five clusters in unilateral MD. Group 1 is the most frequently found, includes 53% of patients, and it is defined as the sporadic, classic MD without migraine and without autoimmune disorder (AD). Group 2 is found in 8% of patients, and it is defined by hearing loss, which antedates the vertigo episodes by months or years (delayed MD), without migraine or AD in most of cases. Group 3 involves 13% of patients, and it is considered familial MD, while group 4, which includes 15% of patients, is linked to the presence of migraine in all cases. Group 5 is found in 11% of patients and is defined by a comorbid AD. We found significant differences in the distribution of AD in clusters 3, 4 and 5 between patients with uni- and bilateral MD. CONCLUSIONS: Cluster analysis defines clinical subgroups in MD, and it extends the phenotype beyond audiovestibular symptoms. This classification will help to improve the phenotyping in MD and facilitate the selection of patients for randomised clinical trials.

Background: Acetaminophen is extensively used during pregnancy. But there is a lack of population-representative cohort studies evaluating its effects on a range of neuropsychological and behavioural endpoints. We aimed to assess whether prenatal exposure to acetaminophen is adversely associated with neurodevelopmental outcomes at 1 and 5 years of age. Methods: This Spanish birth cohort study included 2644 mother-child pairs recruited during pregnancy. The proportion of liveborn participants evaluated at 1 and 5 years was 88.8% and 79.9%, respectively. Use of acetaminophen was evaluated prospectively in two structured interviews. Ever/never use and frequency of use (never, sporadic, persistent) were measured. Main neurodevelopment outcomes were assessed using Childhood Autism Spectrum Test (CAST), Conner's Kiddie Continuous Performance Test (K-CPT) and ADHD-DSM-IV form list. Regression models were adjusted for social determinants and co-morbidities. Results: Over 40% of mothers reported using acetaminophen. Ever-exposed offspring had higher risks of presenting more hyperactivity/impulsivity symptoms [incidence rate ratio (IRR) = 1.41, 95% confidence interval (CI) 1.01-1.98), K-CPT commission errors (IRR = 1.10, 1.03-1.17), and lower detectability scores (coefficient β = -0.75, -0.13--0.02). CAST scores were increased in ever-exposed males (β = 0.63, 0.09-1.18). Increased effect sizes of risks by frequency of use were observed for hyperactivity/impulsivity symptoms (IRR = 2.01, 0.95-4.24) in all children, K-CPT commission errors (IRR = 1.32, 1.05-1.66) and detectability (β = -0.18, -0.36-0.00) in females, and CAST scores in males (β = 1.91, 0.44-3.38). Conclusions: Prenatal acetaminophen exposure was associated with a greater number of autism spectrum symptoms in males and showed adverse effects on attention-related outcomes for both genders. These associations seem to be dependent on the frequency of exposure.

BACKGROUND: The fetus depends on maternal thyroid hormones during pregnancy for normal brain development. Little is known about the effects of subclinical hypothyroidism and mild hypothyroxinemia during pregnancy on neurodevelopment of the child. METHODS: We evaluated a population-based birth cohort in Spain. A total of 1761 children and their mothers were included in the main analyses. Serum levels of free thyroxine and thyrotropin were measured in pregnant women. Mental and psychomotor development of their children was assessed using the Bayley Scales of Infant Development during the second year of life. RESULTS: Low free thyroxine levels (<5th percentile) and self-reported prepregnancy thyroid disorder without medical treatment were associated with a decrease of mental scores (Beta = -3.4 [95% confidence interval= -6.7 to -0.2]) and -5.5 [-8.9 to -2.0], respectively). No association between thyrotropin levels and mental scores or psychomotor scores was observed. CONCLUSIONS: Low free thyroxine levels in healthy pregnant women are related to a moderate delay in child neurodevelopment. The impairment is similar in magnitude to that observed in mothers with untreated prepregnancy thyroid disorder. The value of screening pregnant women for thyroid function requires further assessment, particularly in mildly iodine-deficient areas.

BACKGROUND: Natural environments, including green spaces, may have beneficial impacts on brain development. However, longitudinal evidence of an association between long-term exposure to green spaces and cognitive development (including attention) in children is limited. OBJECTIVES: We evaluated the association between lifelong residential exposure to green space and attention during preschool and early primary school years. METHODS: This longitudinal study was based on data from two well-established population-based birth cohorts in Spain. We assessed lifelong exposure to residential surrounding greenness and tree cover as the average of satellite-based normalized difference vegetation index and vegetation continuous fields, respectively, surrounding the child's residential addresses at birth, 4-5 y, and 7 y. Attention was characterized using two computer-based tests: Conners' Kiddie Continuous Performance Test (K-CPT) at 4-5 y (n=888) and Attentional Network Task (ANT) at 7 y (n=987). We used adjusted mixed effects models with cohort random effects to estimate associations between exposure to greenness and attention at ages 4-5 and 7 y. RESULTS: Higher lifelong residential surrounding greenness was associated with fewer K-CPT omission errors and lower K-CPT hit reaction time-standard error (HRT-SE) at 4-5 y and lower ANT HRT-SE at 7 y, consistent with better attention. This exposure was not associated with K-CPT commission errors or with ANT omission or commission errors. Associations with residential surrounding tree cover also were close to the null, or were negative (for ANT HRT-SE) but not statistically significant. CONCLUSION: Exposure to residential surrounding greenness was associated with better scores on tests of attention at 4-5 y and 7 y of age in our longitudinal cohort. https://doi.org/10.1289/EHP694.

The aims of this study were to estimate the prevalence of familial cases in patients with Meniere's disease (MD) and to identify clinical differences between sporadic and familial MD. We recruited 1375 patients with definite MD according to the American Academy of Otolaryngology-Head and Neck Surgery criteria, obtaining the familial history of hearing loss or episodic vertigo by direct interview or a postal survey in 1245 cases in a multicenter study. Familial clustering was estimated by the recurrence risk ratio in siblings (λs ) and offspring (λo ) using intermediate and high prevalence values for MD in European population. A total of 431 patients (34%) reported a familial history of hearing loss or recurrent vertigo and 133 patients had a relative with possible MD. After clinical reevaluation, 93 relatives in 76 families were diagnosed of definite MD (8.4%), including three pairs of monozygotic twins. λs and λo were 16-48 and 4-12, respectively. We observed genetic heterogeneity, but most families had an autosomal dominant inheritance with anticipation. No clinical differences were found between sporadic and familial MD, except for an early onset in familial cases. We may conclude that MD has a strong familial aggregation and that sporadic and familial MDs are clinically identical.

OBJECTIVE: To investigate whether circulating 25-hydroxyvitamin D(3) [25(OH)D(3)] concentration in pregnancy is associated with neuropsychological development in infants. METHODS: The Spanish population-based cohort study INfancia y Medio Ambiente Project recruited pregnant women during the first trimester of pregnancy between November 2003 and February 2008. Completed data on 1820 mother-infant pairs were used. Maternal plasma 25(OH)D(3) concentration was measured by high-performance liquid chromatography in pregnancy (mean 13.5 ± 2.1 weeks of gestation). Offspring mental and psychomotor scores were assessed by trained psychologists at age 14 months (range, 11-23) by using the Bayley Scales of Infant Development. β-Coefficients with 95% confidence intervals (CIs) of mental and psychomotor scores associated with continuous or categorical concentrations of maternal plasma 25(OH)D(3) were calculated by using linear regression analysis. RESULTS: The median plasma value of 25(OH)D(3) in pregnancy was 29.6 ng/mL (interquartile range, 21.8-37.3). A positive linear relationship was found between circulating concentrations of maternal 25(OH)D(3) concentrations in pregnancy and mental and psychomotor scores in the offspring. After adjustment for potential confounders, infants of mothers with 25(OH)D(3) concentrations in pregnancy >30 ng/mL showed higher mental score (β = 2.60; 95% CI 0.63-4.56) and higher psychomotor score (β = 2.32; 95% CI 0.36-4.28) in comparison with those of mothers with 25(OH)D(3) concentrations <20 ng/mL. CONCLUSIONS: Higher circulating concentration of maternal 25(OH)D(3) in pregnancy was associated with improved mental and psychomotor development in infants.

Abstract Rationale Menopause is associated with changes in sex hormones, which affect immunity, inflammation, and osteoporosis and may impair lung function. Lung function decline has not previously been investigated in relation to menopause. Objectives To study whether lung function decline, assessed by FVC and FEV1, is accelerated in women who undergo menopause. Methods The population-based longitudinal European Community Respiratory Health Survey provided serum samples, spirometry, and questionnaire data about respiratory and reproductive health from three study waves (n = 1,438). We measured follicle-stimulating hormone and luteinizing hormone and added information on menstrual patterns to determine menopausal status using latent class analysis. Associations with lung function decline were investigated using linear mixed effects models, adjusting for age, height, weight, pack-years, current smoking, age at completed full-time education, spirometer, and including study center as random effect. Measurements and Main Results Menopausal status was associated with accelerated lung function decline. The adjusted mean FVC decline was increased by −10.2 ml/yr (95% confidence interval [CI], −13.1 to −7.2) in transitional women and −12.5 ml/yr (95% CI, −16.2 to −8.9) in post-menopausal women, compared with women menstruating regularly. The adjusted mean FEV1 decline increased by −3.8 ml/yr (95% CI, −6.3 to −2.9) in transitional women and −5.2 ml/yr (95% CI, −8.3 to −2.0) in post-menopausal women. Conclusions Lung function declined more rapidly among transitional and post-menopausal women, in particular for FVC, beyond the expected age change. Clinicians should be aware that respiratory health often deteriorates during reproductive aging.

The labia minora or nymphae of the vulva are two cutaneous-mucosal refolds located between the labia majora, the internal aspect of which is separated by the interlabial cleft. The enlargement of the labia minora may be attributable to several factors, most commonly congenital. Although some women require surgical reduction for functional reasons, most seek reduction of their labia minora because of psychological concerns. The authors describe a modified plastic surgery procedure for functional and aesthetic reduction of the labia minora.