Pathogenic SCN2A variants cause early-stage dysfunction in patient-derived neurons.

Pathogenic heterozygous variants in SCN2A, which encodes the neuronal sodium channel NaV1.2, cause different types of epilepsy or intellectual disability (ID)/autism without seizures. Previous studies using mouse models or heterologous systems suggest that NaV1.2 channel gain-of-function typically causes epilepsy, whereas loss-of-function leads to ID/autism. How altered channel biophysics translate into patient neurons remains unknown. Here, we investigated iPSC-derived early-stage cortical neurons from ID patients harboring diverse pathogenic SCN2A variants [p.(Leu611Valfs*35); p.(Arg937Cys); p.(Trp1716*)] and compared them with neurons from an epileptic encephalopathy (EE) patient [p.(Glu1803Gly)] and controls. ID neurons consistently expressed lower NaV1.2 protein levels. In neurons with the frameshift variant, NaV1.2 mRNA and protein levels were reduced by ~ 50%, suggesting nonsense-mediated decay and haploinsufficiency. In other ID neurons, only protein levels were reduced implying NaV1.2 instability. Electrophysiological analysis revealed decreased sodium current density and impaired action potential (AP) firing in ID neurons, consistent with reduced NaV1.2 levels. In contrast, epilepsy neurons displayed no change in NaV1.2 levels or sodium current density, but impaired sodium channel inactivation. Single-cell transcriptomics identified dysregulation of distinct molecular pathways including inhibition of oxidative phosphorylation in neurons with SCN2A haploinsufficiency and activation of calcium signaling and neurotransmission in epilepsy neurons. Together, our patient iPSC-derived neurons reveal characteristic sodium channel dysfunction consistent with biophysical changes previously observed in heterologous systems. Additionally, our model links the channel dysfunction in ID to reduced NaV1.2 levels and uncovers impaired AP firing in early-stage neurons. The altered molecular pathways may reflect a homeostatic response to NaV1.2 dysfunction and can guide further investigations.

The effects of short-term, progressive exercise training on disease activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance: a single-arm pilot study.

BACKGROUND: High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity. METHODS: In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation. RESULTS: Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0 g/L, P =.903), involved FLC (+ 1.8 ± 16.8 mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6 mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged. CONCLUSIONS: A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM). REGISTRATION: https://www.isrctn.com/ISRCTN65527208 (14/05/2018).

Genitourinary symptoms and sexual function in women with primary ovarian insufficiency.

OBJECTIVE: There are limited studies on urogenital symptoms in women who experience menopause before the age of 40 years due to primary ovarian insufficiency (POI) or bilateral oophorectomy (surgical POI). This study aimed to compare the urogenital symptoms, including sexuality, of women with POI to those without the condition. METHODS: This cross-sectional study conducted was in seven Latin American countries, in which postmenopausal women (with POI and non-POI) were surveyed with a general questionnaire, the Menopause Rating Scale (MRS) and the six-item Female Sexual Function Index (FSFI-6). The association of premature menopause with more urogenital symptoms and lower sexual function was evaluated with logistic regression analysis. RESULTS: Women with POI experience more urogenital symptoms (MRS urogenital score: 3.54 ± 3.16 vs. 3.15 ± 2.89, p < 0.05) and have lower sexual function (total FSFI-6 score: 13.71 ± 7.55 vs. 14.77 ± 7.57 p < 0.05) than women who experience menopause at a normal age range. There were no significant differences in symptoms when comparing women based on the type of POI (idiopathic or surgical). After adjusting for covariates, our logistic regression model determined that POI is associated with more urogenital symptoms (odds ratio [OR]: 1.38, 95% confidence interval [CI] 1.06-1.80) and lower sexual function (OR: 1.67, 95% CI 1.25-2.25). CONCLUSION: POI, whether idiopathic or secondary to bilateral oophorectomy, is associated with symptoms that affect vaginal and sexual health.

Applicability of the Barcelona scale to assess the quality of cleanliness of mucosa at esophagogastroduodenoscopy.

BACKGROUND AND OBJECTIVES: There are few scales with prospective validation for the assessment of the upper gastrointestinal mucosal cleanliness during an esophagogastroduodenoscopy (EGD). The aim of this study was to develop a valid and reproducible cleanliness scale for use during an EGD. METHODS: We developed a cleanliness scale (Barcelona scale) with a score (0-2 points) of five segments of the upper gastrointestinal tract with thorough cleaning techniques (esophagus, fundus, body, antrum, and duodenum). First, 125 photos (25 of each area) were assessed, and a score was assigned to each image by consensus among 7 experts endoscopists. Subsequently, 100 of the 125 images were selected and the inter- and intra-observer variability of 15 previously trained endoscopists was evaluated using the same images at two different times. RESULTS: In total, 1500 assessments were performed. In 1336/1500 observations (89%) there was agreement with the consensus score, with a mean kappa value of 0.83 (0.45-0.96). In the second evaluation, in 1330/1500 observations (89%) there was agreement with the consensus score, with a mean kappa value of 0.82 (0.45-0.93). The intra-observer variability was 0.89 (0.76-0.99). CONCLUSIONS: The Barcelona cleanliness scale is a valid measure and reproducible with minimal training. Its application in clinical practice is a significant step to standardize the quality of the EGD.

Psychometric validation and responder definition of the sleep disturbance numerical rating scale in moderate-to-severe atopic dermatitis.

BACKGROUND: Sleep disturbance (SD) is an important part of the burden of atopic dermatitis (AD), but patient-reported outcomes that are easy to understand and interpret in the target population have been lacking. A daily, single-item, self-reported SD 11-point numerical rating scale (NRS) was recently developed to assess SD for patients with moderate-to-severe AD, but its psychometric properties have not yet been described. OBJECTIVES: To assess the psychometric properties of the SD NRS in patients with moderate-to-severe AD. METHODS: The psychometric properties of the SD NRS were assessed using data from a phase IIb clinical trial in 218 adults with moderate-to-severe AD. RESULTS: Test-retest reliability of the SD NRS was substantial to almost perfect (interclass correlation 0·66-1·00) in participants who had stable SD or stable pruritus scores over 1 week. Baseline correlations were moderate to large (r > 0·30) between SD NRS and pruritus or sleep loss scores, but were small (r = -0·11 to 0·17) between SD NRS and EQ-5D-3L index and visual analogue scores, Hospital Anxiety and Depression Scale, Scoring Atopic Dermatitis, and Investigator's Global Assessment. The SD NRS could discriminate groups of participants in the expected direction according to different quality-of-life scores but not according to different clinician-reported disease severity scores. SD NRS scores significantly decreased as sleep loss, itch and quality-of-life scores improved. Analysis of meaningful change suggested a 2-5-point improvement as the initial range of responder definition in the SD NRS score. CONCLUSIONS: The SD NRS is a reliable, valid and responsive measure of SD in adults with moderate-to-severe AD.

Characterizing Determinants of Near-Road Ambient Air Quality for an Urban Intersection and a Freeway Site.

INTRODUCTION: Near-road ambient air pollution concentrations that are affected by vehicle emissions are typically characterized by substantial spatial variability with respect to distance from the roadway and temporal variability based on the time of day, day of week, and season. The goal of this work is to identify variables that explain either temporal or spatial variability based on case studies for a freeway site and an urban intersection site. The key hypothesis is that dispersion modeling of near-road pollutant concentrations could be improved by adding estimates or indices for site-specific explanatory variables, particularly related to traffic. Based on case studies for a freeway site and an urban intersection site, the specific aims of this project are to (1) develop and test regression models that explain variability in traffic-related air pollutant (TRAP) ambient concentration at two near-roadway locations; (2) develop and test refined proxies for land use, traffic, emissions and dispersion; and (3) prioritize inputs according to their ability to explain variability in ambient concentrations to help focus efforts for future data collection and model development.The key pollutants that are the key focus of this work include nitrogen oxides (NOx), carbon monoxide (CO), black carbon (BC), fine particulate matter (PM2.5; PM ≤ 2.5 µm in aerodynamic diameter), ultrafine particles (UFPs; PM ≤ 0.1 µm in aerodynamic diameter), and ozone (O3). NOx, CO, and BC are tracers of vehicle emissions and dispersion. PM2.5 is influenced by vehicle table emissions and regional sources. UFPs are sensitive to primary vehicle emissions. Secondary particles can form near roadways and on regional scales, influencing both PM2.5 and UFP concentrations. O3 concentrations are influenced by interaction with NOx near the roadway. Nitrogen dioxide (NO2), CO, PM2.5, and O3 are regulated under the National Ambient Air Quality Standards (NAAQS) because of demonstrated health effects. BC and UFPs are of concern for their potential health effects. Therefore, these pollutants are the focus of this work. METHODS: The methodological approach includes case studies for which variables are identified and assesses their ability to explain either temporal or spatial variability in pollutant ambient concentrations. The case studies include one freeway location and one urban intersection. The case studies address (1) temporal variability at a fixed monitor 10 meters from a freeway; (2) downwind concentrations perpendicular to the same location; (3) variability in 24-hour average pollutant concentrations at five sites near an urban intersection; and (4) spatiotemporal variability along a walking path near that same intersection.The study boundary encompasses key factors in the continuum from vehicle emissions to near-road exposure concentrations. These factors include land use, transportation infrastructure and traffic control, vehicle mix, vehicle (traffic) flow, on-road emissions, meteorology, transport and evolution (transformation) of primary emissions, and production of secondary pollutants, and their resulting impact on measured concentrations in the near-road environment. We conducted field measurements of land use, traffic, vehicle emissions, and near-road ambient concentrations in the vicinity of two newly installed fixed-site monitors. One is a monitoring station jointly operated by the U.S. Environmental Protection Agency (U.S. EPA) and the North Carolina Department of Environmental Quality (NC DEQ) on I-40 between Airport Boulevard and I-540 in Wake County, North Carolina. The other is a fixed-site monitor for measuring PM2.5 at the North Carolina Central University (NCCU) campus on E. Lawson Street in Durham, North Carolina. We refer to these two locations as the freeway site and the urban site, respectively. We developed statistical models for the freeway and urban sites. RESULTS: We quantified land use metrics at each site, such as distances to the nearest bus stop. For the freeway site, we quantified lane-by-lane total vehicle count, heavy vehicle (HV) count, and several vehicle-activity indices that account for distance from each lane to the roadside monitor. For the urban site, we quantified vehicle counts for all 12 turning movements through the intersection. At each site, we measured microscale vehicle tailpipe emissions using a portable emission measurement system.At the freeway site, we measured the spatial gradient of NOx, BC, UFPs, and PM, quantified particle size distributions at selected distances from the roadway and assessed partitioning of particles as a function of evolving volatility. We also quantified fleet-average emission factors for several pollutants.At the urban site, we measured daily average concentrations of nitric oxide (NO), NOx, O3, and PM2.5 at five sites surrounding the intersection of interest; we also measured high resolution (1-second to 10-second averages) concentrations of O3, PM2.5, and UFPs along a pedestrian transect. At both sites, the Research LINE-source (R-LINE) dispersion model was applied to predict concentration gradients based on the physical dispersion of pollution.Statistical models were developed for each site for selected pollutants. With variables for local wind direction, heavy-vehicle index, temperature, and day type, the multiple coefficient of determination (R2) was 0.61 for hourly NOx concentrations at the freeway site. An interaction effect of the dispersion model and a real-time traffic index contributed only 24% of the response variance for NOx at the freeway site. Local wind direction, measured near the road, was typically more important than wind direction measured some distance away, and vehicle-activity metrics directly related to actual real-time traffic were important. At the urban site, variability in pollutant concentrations measured for a pedestrian walk-along route was explained primarily by real-time traffic metrics, meteorology, time of day, season, and real-world vehicle tailpipe emissions, depending on the pollutant. The regression models explained most of the variance in measured concentrations for BC, PM, UFPs, NO, and NOx at the freeway site and for UFPs and O3 at the urban site pedestrian transect. CONCLUSIONS: Among the set of candidate explanatory variables, typically only a few were needed to explain most of the variability in observed ambient concentrations. At the freeway site, the concentration gradients perpendicular to the road were influenced by dilution, season, time of day, and whether the pollutant underwent chemical or physical transformations. The explanatory variables that were useful in explaining temporal variability in measured ambient concentrations, as well as spatial variability at the urban site, were typically localized real-time traffic-volume indices and local wind direction. However, the specific set of useful explanatory variables was site, context (e.g., next to road, quadrants around an intersection, pedestrian transects), and pollutant specific. Among the most novel of the indicators, variability in real-time measured tailpipe exhaust emissions was found to help explain variability in pedestrian transect UFP concentrations. UFP particle counts were very sensitive to real-time traffic indicators at both the freeway and urban sites. Localized site-specific data on traffic and meteorology contributed to explaining variability in ambient concentrations. HV traffic influenced near-road air quality at the freeway site more so than at the urban site. The statistical models typically explained most of the observed variability but were relatively simple. The results here are site-specific and not generalizable, but they are illustrative that near-road air quality can be highly sensitive to localized real-time indicators of traffic and meteorology.

Effects of progesterone concentrations and follicular wave during growth of the ovulatory follicle on conceptus and endometrial transcriptome in dairy cows.

Objectives were to evaluate the effects of follicular wave and progesterone concentration on growth of the ovulatory follicle, conceptus elongation, uterine IFN-τ concentration, and transcriptome of conceptus and endometrium of pregnant cows on d 17 of gestation. Nonlactating nonpregnant Holstein cows were assigned randomly to one of 3 treatments: ovulation of a first-wave follicle (FW, n = 15); ovulation of a first-wave follicle and progesterone supplementation (FWP4, n = 12); and ovulation of a second-wave follicle (SW, n = 19). Ovulation of a first- or second-wave follicle was achieved by initiating the Ovsynch protocol (d -9 GnRH, d -2 and -1 PGF2α, d 0 GnRH and artificial insemination, d 0.7 artificial insemination) on d 0 or 6 of a presynchronized estrous cycle, respectively. Cows in FWP4 received 3 intravaginal inserts containing progesterone at 12, 24, and 48 h after the first GnRH injection that were removed on d -2. Cows were killed on d 17 for collection of the reproductive tract. Transcriptome was evaluated by microarray using the Affymetrix Bovine Array. Orthogonal contrasts were built to assess the effects of progesterone concentration during follicle growth (FW vs. FWP4 + SW) and follicular wave (FWP4 vs. SW). Progesterone concentrations (LSM ± SEM) from d -9 to -2 were greater for SW, followed by FWP4 and FW (5.38 ± 0.24, 4.26 ± 0.28, and 1.17 ± 0.27 ng/mL). Diameter of the ovulatory follicle (FW = 19.6 ± 0.6; FWP4 = 15.6 ± 0.6; SW = 15.2 ± 0.5 mm) and concentrations of estradiol from d -2 to 1 (FW = 4.05 ± 0.33; FWP4 = 2.73 ± 0.35; SW = 2.48 ± 0.30 pg/mL) were greater for FW compared with FWP4 and SW. Progesterone concentrations from d 3 to 16 were greater for FW compared with FWP4 and SW. A total of 28 singleton conceptuses were collected (FW, n = 8; FWP4, n = 8; SW, n = 12) and only intact conceptuses were included in the analyses of length (FW, n = 8; FWP4, n = 6; SW, n = 12). Although conceptuses were longer for FW compared with FWP4 and SW (FW = 16.6 ± 2.3; FWP4 = 9.8 ± 2.2; SW = 9.6 ± 2.0 cm), treatment did not affect the amount of IFN-τ in uterine flushing. Transcriptome of conceptuses and endometrium of pregnant cows was not extensively affected by follicular wave (8 and 1 differentially expressed transcripts) or concentration of progesterone during follicle growth (0 and 3 differentially expressed transcripts), showing that these factors did not affect conceptuses and endometrium transcriptome in pregnancies that are maintained to d 17.

Methods for Gastrointestinal Endoscopy Quantification: A Focus on Hands and Fingers Kinematics.

Gastrointestinal endoscopy is a complex procedure requiring the mastery of several competencies and skills. This procedure is in increasing demand, but there exist important management and ethical issues regarding the training of new endoscopists. Nowadays, this requires the direct involvement of real patients and a high chance of the endoscopists themselves suffering from musculoskeletal conditions. Colonoscopy quantification can be useful for improving these two issues. This paper reviews the literature regarding efforts to quantify gastrointestinal procedures and focuses on the capture of hand and finger kinematics. Current technologies to support the capture of data from hand and finger movements are analyzed and tested, considering smart gloves and vision-based solutions. Manus VR Prime II and Stretch Sense MoCap reveal the main problems with smart gloves related to the adaptation of the gloves to different hand sizes and comfortability. Regarding vision-based solutions, Vero Vicon cameras show the main problem in gastrointestinal procedure scenarios: occlusion. In both cases, calibration and data interoperability are also key issues that limit possible applications. In conclusion, new advances are needed to quantify hand and finger kinematics in an appropriate way to support further developments.

Efficacy and Safety of Tranexamic Acid for the Control of Surgical Bleeding in Patients Under Liposuction.

Liposuction remains one of the most frequently performed cosmetic surgical procedures and its popularity is increasing every year. However, since its inception, justified concerns regarding patient safety have placed limits on the volume of fat that can be aspirated, influenced by hemodynamic fluctuations and blood loss during liposuction. Tranexamic acid (TXA) is an antifibrinolytic agent that competitively inhibits the conversion of plasminogen to plasmin, thus preventing the binding and degradation of fibrin. Despite the existence of evidence of the effectiveness of TXA in orthopedic and cardiac surgeries, there is little evidence of its use in liposuction. The objective of this study was to evaluate the efficacy and safety of tranexamic acid in the control of surgical bleeding in patients undergoing liposuction, through a prospective, open, randomized and controlled clinical trial. Two groups of 25 participants each were formed to whom the application of TXA in a tumescent solution prior to liposuction or liposuction with the traditional technique was randomly assigned. The results showed a decrease in blood loss reflected by the differences in the final hematocrit values, as well as decrease in the same per aspirated volume (p = 0.003). No adverse events were found related with the TXA application and no blood transfusions were required in this group, in contrast to the control group where the need for blood transfusion was present in 20% of the intervened participants. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

[Factors associated with intrahospital mortality in older patients with COVID-19 in Belgium : The COVID-AgeBru study]. / Face à la COVID-19. Mortalité intra-hospitalière chez les patients âgés de plus de 70 ans avec COVID-19 dans un hôpital universitaire en Belgique :l'étude COVID-AgeBru.

OBJECTIVE: We aimed at assessing the association between demographical and clinical data and the intrahospital mortality in older patients with COVID-19 in Belgium. METHODS: Descriptive, retrospective study of consecutive patients admitted to Brugmann university hospital, Brussels (Belgium) due to COVID-19 (Mars-September-2020). INCLUSION CRITERIA: Patients aged ≥ 70 years admitted to acute care with a positive PCR-RT test, or a highly indicative computed tomography scan. EXCLUSION CRITERIA: Patients transferred to another institution during hospitalization. OUTCOME MEASURE: All-cause intrahospital mortality. Demographic, clinical data, presence of comordibidties and comprehensive geriatric assessment were collected. Adjusted and unadjusted logistic regression were performed. RESULTS: From the 226 eligible patients, 160 (82.7 ± 6.5-year-old; 57.5 % females) met inclusion criteria, from which 67 (42 %) died during hospital stay. The adjusted logistic regression showed an association between intrahospital mortality and increasing age [OR = 1.09 per every year increase (95 % CI 1.02-1.16); p <0.001], type 2 diabetes [OR = 2.75 ( 1.17-6.46); p = 0.021], and acute respiratory distress syndrome (ARDS) [OR = 8.67 ( 3.48-21.61); p < 0.01]. CONCLUSIONS: A higher positive association between intrahospital mortality and increasing age, type 2 diabetes, and ARDS was found. The prognosis value of the comprehensive geriatric assessment in older people with COVID-19 in Belgium requires further studies.

INTRODUCTION: Les études sur l'impact de la pandémie en Belgique sont rares. L'objectif est d'évaluer l'association de l'âge et des comorbidités à la mortalité intra-hospitalière de toutes causes chez les patients âgés ? 70 ans avec COVID-19 dans un hôpital universitaire à Bruxelles, Belgique. Méthodes : Etude rétrospective descriptive des patients admis au CHU Brugmann pour cause de maladie COVID-19 (mars-septembre 2020). Critères d'inclusion : âge ≥ 70 ans admis avec PCR-RT positif ou haute probabilité d'infection au CT-scan thoracique. Critères d'exclusion : transfert dans un autre hôpital. Critère de jugement : toute cause de mortalité intra-hospitalière. Variables collectées : démographiques, cliniques et gériatriques [Katz, Lawton, MMSE, MNA, MNA-SF]. Une régression logistique non ajustée et ajustée a été réalisée. Résultats : Parmi les 226 patients éligibles, 160 (82,7 ± 6,5 ans; 57,5 % femmes) ont rempli les critères d'inclusion. Au total, 67 (42 %) sont décédés durant l'hospitalisation. La régression logistique a montré une association augmentée entre la mortalité et l'âge [odds ratio ou OR = 1,09/année en plus (IC 95 % 1,02-1,16) ; p< 0,001], le diabète de type 2 [OR = 2,75 (1,17-6,46); p = 0,021], l'ARDS [OR = 8,67 (3,48-21,61); p < 0,01]. CONCLUSION: L'âge, le diabète de type 2 et le syndrome de détresse respiratoire aiguë (ARDS) sont associés à une augmentation de la mortalité chez les patients âgés hospitalisés avec COVID-19 en Belgique.

Ce, Eu incorporation through doping of ALD-ZnO thin films for enhancing their photoluminescent properties.

Nanostructured ZnO nanoarrays deposited on silicon oriented substrates is a very promising area in the study of the control of physicochemical properties, in which photoluminescence plays a crucial role. This optical property inherent to ZnO, can be favorably modified through the inclusion of doping elements, with the purpose of appropriately modifying their optical absorption and luminescence. Following this objective, in the present work we present the development of Zn(1-x-y)Ce(x)Eu(y)O nanostructured thin films. The samples were produced in two steps process by atomic layer deposition technique followed by a solvothermal synthesis. The purpose of Cerium and Europium incorporation into the ZnO compound is to enhance the photoluminescence in ZnO thin films. In a first stage textured thin films were obtained from diethylzinc at a temperature of 190 °C and a pressure of 3.29 × 10-4 atm, on silicon substrates (111). Subsequently, the perpendicular growth of nanostructures was induced under a solvothermal process, where Zn(NO3)2 was used as Zn precursor and hexamethylene-tetramine operating as a dual-ligand to promote the linking of Zn2+ ions. The growth of cerium-europium ZnO nanostructures was promoted with Ce(C2H3O2)3·H2O and Eu(NO3)3·5H2O. The obtained Zn(1-x-y)Ce(x)Eu(y)O nanostructured thin films, were examined through SEM-microscopy, x-ray diffraction, x-ray photoelectron spectroscopy and photoluminescence studies. The attained results show that it is feasible to produce Ce-Eu-doped ZnO nanostructures with tailored photoluminescence and crystal size. Interestingly the Ce-Eu doping induces a strong shift in comparison to the typical UV emission of ZnO; an effect that can be related with the increase of lattice defects in ZnO.

Self-collected versus clinician-collected cervical samples for the detection of HPV infections by 14-type DNA and 7-type mRNA tests.

BACKGROUND: HPV self-sampling has been widely supported by the scientific community following a strong body of literature on the subject. Self-sampling is important in cervical cancer screening as it has been shown to improve participation. It is well documented that HPV-testing has proven superior to cytology with regards to sensitivity in detection of CIN and cancer. The value of self-collected samples is reliant on the quality of the molecular testing performed, as well as the patients' preference in sampling procedure and compliance to follow up on positive test results. Due to the incompatibility of self-samples and cytology, triage of HPV-DNA positives by testing for molecular biomarkers is highly warranted. METHODS: Our objective was to compare the detection rate of genital Human Papillomavirus (HPV) infection in self- and clinician-collected samples by a 14-type HPV-DNA test and a 7-type mRNA E6/E7 test. RESULTS: Five hundred five women were recruited. Each study participant had two sample collection procedures performed upon the same visit, alternating order in execution of the self-collection or the clinician-taken procedure first or second, 1010 samples in total. HPV-DNA prevalence was 22.8% in self-collected versus 19.2% in clinician-collected samples (P = 0.19). Overexpression of mRNA E6/E7 from 7 HPV types was 7.1 and 6.3%, respectively (P = 0.71). The difference between HPV-DNA and HPV-mRNA positivity rates were statistically significant in both self-collected (22.8% versus 7.1%, P < 0.001) and clinician-collected samples (19.2% versus 6.3%, P < 0.001). Overall agreement between the two collection methods was fair, with a concordance rate of 78.2% (390/505), k = 0.34 (95% CI: 0.25-0.44), P < 0.001, for the HPV-DNA test and 92.5% (467/505), k = 0.40 (95% CI, 0.25-0.56), P < 0.001, for the mRNA test, respectively. 96.8% of the participants reported they felt confident carrying out the self-collection themselves, and 88.8% reported no discomfort at all performing the procedure. CONCLUSIONS: This comparative study of two sampling methods reports fair agreement of HPV positivity rates between the self-collected and clinician-collected specimens using Abbott hrHPV and PreTect HPV-Proofer'7 tests. Only one third of HPV-DNA positive women had overexpression of mRNA E6/E7. TRIAL REGISTRATION: ISRCTN77337300 .

Detrimental conditions affecting Xestospongia muta across shallow and mesophotic coral reefs off the southwest coast of Puerto Rico.

Sponges are fundamental components of coral reef communities and, unfortunately, like other major benthic members, they too have been impacted by epizootic and panzootic events. We report on the prevalence of disease-like conditions affecting populations of the giant barrel sponge Xestospongia muta across shallow and mesophotic coral reefs off La Parguera Natural Reserve (LPNR) and Mona Island Marine Reserve (MIMR) in Puerto Rico. Four different conditions affecting X. muta were observed during our surveys, of which 3 have been previously reported: cyclic spotted bleaching (CSB; apparently non-lethal), Xestospongia-tissue wasting disease (X-TWD; apparently lethal), and sponge orange band disease (SOB; sparsely associated with X-TWD infected individuals). Additionally, we describe a fourth condition, Xestospongia-tissue hardening condition (X-THC), a previously unreported disease recently observed along the insular shelf margin off LPNR and MIMR. Within LPNR, a total of 764 specimens of X. muta were inspected and measured. Of these, 590 sponges (72.2%) had CSB, 25 (3.27%) had signs of X-TWD, 7 (0.92%) had SOB, and the remaining 142 (18.6%) were apparently healthy. Three colonies inhabiting upper mesophotic depths on the LPNR insular shelf showed signs of CSB and X-TWD. At MIMR, video-transect surveys revealed a total of 514 colonies, of which 40 (7.78%) had signs of CSB and/or XTWD, 14 (2.72%) were affected by X-THC, while the remaining 460 (89.5%) showed no external signs of disease and appeared healthy. The presence of 4 concomitant disease-like conditions in barrel sponges of Puerto Rico is alarming, and indicative of the deteriorating status of Caribbean coral reefs.

360° video recording inside a GI endoscopy room: Technical feasibility and its potential use for the acquisition of gastrointestinal endoscopy skills. Pilot experience.

New advances in video processing, 3-dimensional designs, and augmented/virtual reality are exciting and evolving fields. These new tools can facilitate the learning phase of basic or advanced endoscopic procedures. Herein, we explain our initial experience, creating an immersive virtual reality (IVR) by using 360-degree recording videos from an interventional endoscopy room. Some common terms used around this technology, such as Augmented reality (AR), Virtual Reality (VR), Three hundred sixty videos, and Mixed Reality (MR), are discussed below. Three examples of VR 360 endoscopic room videos are included in this article.

[Lung transplant with ex vivo lung perfusion, Chilean and Latin American first experience]. / Trasplante pulmonar ex vivo . Primera experiencia en Chile y Latinoamérica.

BACKGROUND: The number of patients waiting for a lung transplant worldwide greatly exceeds the number of available donors. Ex vivo lung perfusion is a useful tool that allows marginal donor lungs to be evaluated and reconditioned for a successful lung transplantation. AIM: To describe the first Chilean and Latin American experience in ex vivo lung perfusion for marginal donor lungs before transplantation. MATERIAL AND METHODS: Descriptive analysis of all ex vivo lung perfusion conducted for marginal donor lungs at a private clinic, from April 2019 to October 2020. High risk donor lungs and rejected lungs from other transplantation centers were included. The "Toronto Protocol" was used for ex vivo lung perfusion. Donor lung characteristics and recipient outcomes were studied. RESULTS: During the study period, five ex vivo lung perfusions were performed. All lungs were reconditioned and transplanted. No complications were associated. There were no primary graft dysfunctions and only one chronic allograft dysfunction. There was no mortality during the first year. The median arterial oxygen partial pressure/fractional inspired oxygen ratio increased from 266 mm Hg in the donor lung to 419 after 3 hours of ex vivo lung perfusion (p = 0.043). CONCLUSIONS: ex vivo lung perfusion is a safe and useful tool that allows marginal donor lungs to be reconditioned and successfully transplanted.

Germline mutagenesis of Nasonia vitripennis through ovarian delivery of CRISPR-Cas9 ribonucleoprotein.

CRISPR/Cas9 gene editing is a powerful technology to study the genetics of rising model organisms, such as the jewel wasp Nasonia vitripennis. However, current methods involving embryonic microinjection of CRISPR reagents are challenging. Delivery of Cas9 ribonucleoprotein into female ovaries is an alternative that has only been explored in a small handful of insects, such as mosquitoes, whiteflies and beetles. Here, we developed a simple protocol for germline gene editing by injecting Cas9 ribonucleoprotein in adult N. vitripennis females using either ReMOT control (Receptor-Mediated Ovary Transduction of Cargo) or BAPC (Branched Amphiphilic Peptide Capsules) as ovary delivery methods. For ReMOT Control we used the Drosophila melanogaster-derived peptide 'P2C' fused to EGFP to visualize the ovary delivery, and fused to Cas9 protein for gene editing of the cinnabar gene using saponin as an endosomal escape reagent. For BAPC we optimized the concentrations of protein, sgRNA and the transfection reagent. We demonstrate delivery of protein cargo such as EGFP and Cas9 into developing oocytes via P2C peptide and BAPC. Additionally, somatic and germline gene editing were demonstrated. This approach will greatly facilitate CRISPR-applied genetic manipulation in this and other rising model organisms.

Deciphering the natural history of SCA7 in children.

BACKGROUND AND PURPOSE: Childhood-onset autosomal dominant cerebellar ataxia type 7 (SCA7) is a severe disease which leads to premature loss of ambulation and death. Early diagnosis of SCA7 is of major importance for genetic counselling and still relies on specific genetic testing, driven by clinical expertise. However, the precise phenotype and natural history of paediatric SCA7 has not yet been fully described. Our aims were to describe the natural history of SCA7 in a large multicentric series of children of all ages, and to find correlates to variables defining this natural history. METHODS: We collected and analysed clinical data from 28 children with proven SCA7. All had clinical manifestations of SCA7 and either a definite number of CAG repeats in ATXN7 or a long expansion > 100 CAG. RESULTS: We identified four clinical presentation patterns related to age at onset. Children of all age groups had cerebellar atrophy and retinal dystrophy. Our data, combined with those in the literature, suggest that definite ranges of CAG repeats determine paediatric SCA7 subtypes. The number of CAG repeats inversely correlated to all variables of the natural history. Age at gait ataxia onset correlated accurately to age at loss of walking ability and to age at death. CONCLUSION: SCA7 in children has four presentation patterns that are roughly correlated to the number of CAG repeats. Our depiction of the natural history of SCA7 in children may help in monitoring the effect of future therapeutic trials.

Clinically significant intra-day variability of serum progesterone levels during the final day of oocyte maturation: a prospective study with repeated measurements.

STUDY QUESTION: Is there significant variability in progesterone levels during the final day of oocyte maturation in women undergoing ovarian stimulation? SUMMARY ANSWER: Progesterone levels drop from the basal level up to 44% during the final day of oocyte maturation in women undergoing ovarian stimulation. WHAT IS KNOWN ALREADY: It has been suggested that elevated progesterone levels on the final day of ovarian stimulation may be related to poorer outcomes in in vitro fertilization fresh cycles due to a negative impact on the endometrium. However, despite conflicting results regarding the actual effect of progesterone on pregnancy rates and the lack of a well-established cut off, currently many IVF patients have their embryo transfer deferred when progesterone values surpass a threshold of 1.5 ng/ml on the day of ovulation triggering. STUDY DESIGN, SIZE, DURATION: This was a prospective cohort study conducted in 22 oocyte donors of a university-affiliated fertility centre between November 2017 and January 2018. We calculated the sample size to detect a difference of 15% between the first and last progesterone measurements with a 5% false-positive rate in a two-sided test with 80% statistical power and a 95% confidence interval (CI). PARTICIPANTS/MATERIALS, SETTING, METHODS: Progesterone circulating levels were evaluated at four different times during the final day of oocyte maturation (08:00, 12:00, 16:00 and 20:00) before ovulation triggering in healthy oocyte donors. A flexible antagonist protocol was used, and ovarian stimulation was achieved with recombinant follicle-stimulating hormone (FSH) in all cases. The pairwise percentage differences in progesterone levels for each patient were calculated. Univariate linear regression analysis was adopted in order to evaluate variables associated with progesterone levels on the first measurement. The intra-day variability of progesterone was analysed using mixed models. MAIN RESULTS AND THE ROLE OF CHANCE: Mean serum progesterone values at 08:00, 12:00, 16:00 and 20:00 were 1.75 ng/ml, 1.40 ng/ml, 1.06 ng/ml and 0.97 ng/ml. The progesterone difference between 08:00 and 20:00 was 0.77 (95% CI, 0.56-0.99), which is equivalent to a 44% decline in the mean progesterone values between the first (08:00) and the last determination (20:00; P < 0.001). Among those patients with basal (08:00) progesterone levels >1.5 ng/ml (n = 10), 70% (n = 7) showed levels reduced to <1.5 ng/ml on the last determination of the day (20:00). A mixed model analysis revealed that the progesterone reduction during the day was significantly associated with time and total recombinant FSH dose administered. LIMITATIONS, REASONS FOR CAUTION: Only young healthy oocyte donors stimulated with an antagonist protocol using recombinant FSH were included. Extrapolation to the general IVF population, with different stimulation protocols and gonadotropins, needs to be confirmed. WIDER IMPLICATIONS OF THE FINDINGS: This study suggests that a single progesterone determination on the final day of oocyte maturation is not reliable enough to make clinical decisions due to the enormous variation in progesterone during the day. Further studies are needed to better define the impact of the follicular progesterone rise on the endometrium of IVF cycles. STUDY FUNDING/COMPETING INTEREST(S): Funding was granted from Fundació Santiago Dexeus Font. N.P.P. received unrestricted grants and/or lectures fees from Roche Diagnostics, MSD, Merck, Ferring Pharmaceuticals, IBSA, Theramex and BESINS International, not associated with the current study. The remaining authors have no competing interests. TRIAL REGISTRATION NUMBER: Clinicaltrials.gov NCT03366025.

Hippocampal mechanisms in impaired spatial learning and memory in male offspring of rats fed a low-protein isocaloric diet in pregnancy and/or lactation.

Maternal nutritional challenges during fetal and neonatal development result in developmental programming of multiple offspring organ systems including brain maturation and function. A maternal low-protein diet during pregnancy and lactation impairs associative learning and motivation. We evaluated effects of a maternal low-protein diet during gestation and/or lactation on male offspring spatial learning and hippocampal neural structure. Control mothers (C) ate 20% casein and restricted mothers (R) 10% casein, providing four groups: CC, RR, CR, and RC (first letter pregnancy, second lactation diet). We evaluated the behavior of young adult male offspring around postnatal day 110. Corticosterone and ACTH were measured. Males were tested for 2 days in the Morris water maze (MWM). Stratum lucidum mossy fiber (MF) area, total and spine type in basal dendrites of stratum oriens in the hippocampal CA3 field were measured. Corticosterone and ACTH were higher in RR vs. CC. In the MWM acquisition test CC offspring required two, RC three, and CR seven sessions to learn the maze. RR did not learn in eight trials. In a retention test 24 h later, RR, CR, and RC spent more time locating the platform and performed fewer target zone entries than CC. RR and RC offspring spent less time in the target zone than CC. MF area, total, and thin spines were lower in RR, CR, and RC than CC. Mushroom spines were lower in RR and RC than CC. Stubby spines were higher in RR, CR, and RC than CC. We conclude that maternal low-protein diet impairs spatial acquisition and memory retention in male offspring, and that alterations in hippocampal presynaptic (MF), postsynaptic (spines) elements and higher glucocorticoid levels are potential mechanisms to explain these learning and memory deficits.

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients.

Although whole-exome sequencing (WES) is the gold standard for the diagnosis of neurodevelopmental disorders (NDDs), it remains expensive for some genetic centers. Commercialized panels comprising all OMIM-referenced genes called "medical exome" (ME) constitute an alternative strategy to WES, but its efficiency is poorly known. In this study, we report the experience of 2 clinical genetic centers using ME for diagnosis of NDDs. We recruited 216 consecutive index patients with NDDs in 2 French genetic centers, corresponded to the daily practice of the units and included non-syndromic intellectual disability (NSID, n = 33), syndromic ID (NSID = 122), pediatric neurodegenerative disorders (n = 7) and autism spectrum disorder (ASD, n = 54). We sequenced samples from probands and their parents (when available) with the Illumina TruSight One sequencing kit. We found pathogenic or likely pathogenic variants in 56 index patients, for a global diagnostic yield of 25.9%. The diagnosis yield was higher in patients with ID as the main diagnosis (32%) than in patients with ASD (3.7%). Our results suggest that the use of ME is a valuable strategy for patients with ID when WES cannot be used as a routine diagnosis tool.