In-vivo anterior segment OCT imaging provides unique insight into cerulean blue-dot opacities and cataracts in Down syndrome

Down syndrome (DS) is frequently associated with cataract, but there remains scant information about DS cataract morphology. Supra-nuclear cataracts in DS have been proposed as indicative of betaamyloid (Aß) aggregation and thus potential biomarkers for Alzheimer’s (AD). This study employed anterior segment OCT (AS-OCT) and slit-lamp (SL) photography to image the crystalline lens in DS, compared with adult controls. Lens images were obtained post-dilation. Using MATLAB, AS-OCT images were analysed and lens opacities calculated as pixel intensity and area ratios. SL images were classifed using LOCS III. Subjects were n=28 DS (mean±SD 24.1±14.3years), and n=36 controls (54.0±3.4years). Forthe DS group,AS-OCT imaging revealed the frequent presence of small dot opacities (27 eyes, 50%) in the cortex and nucleus ofthe lens, covering an area ranging from 0.2–14%. There was no relation with age or visual acuity and these dot opacities (p>0.5) and they were not present in any control lenses. However, their location and morphology does not coincide with previous reports linking these opacities with Aß accumulation andAD. Four participants (14%) in the DS group had clinically signifcant age-related cataracts, butthere was no evidence of early onset of age-related cataracts in DS.Peer ReviewedPostprint (author's final draft

In-vivo anterior segment OCT imaging provides unique insight into cerulean blue-dot opacities and cataracts in Down syndrome

Down syndrome (DS) is frequently associated with cataract, but there remains scant information about DS cataract morphology. Supra-nuclear cataracts in DS have been proposed as indicative of beta-amyloid (Aβ) aggregation and thus potential biomarkers for Alzheimer’s (AD). This study employed anterior segment OCT (AS-OCT) and slit-lamp (SL) photography to image the crystalline lens in DS, compared with adult controls. Lens images were obtained post-dilation. Using MATLAB, AS-OCT images were analysed and lens opacities calculated as pixel intensity and area ratios. SL images were classified using LOCS III. Subjects were n = 28 DS (mean ± SD 24.1 ± 14.3years), and n = 36 controls (54.0 ± 3.4years). For the DS group, AS-OCT imaging revealed the frequent presence of small dot opacities (27 eyes, 50%) in the cortex and nucleus of the lens, covering an area ranging from 0.2–14%. There was no relation with age or visual acuity and these dot opacities (p > 0.5) and they were not present in any control lenses. However, their location and morphology does not coincide with previous reports linking these opacities with Aβ accumulation and AD. Four participants (14%) in the DS group had clinically significant age-related cataracts, but there was no evidence of early onset of age-related cataracts in DS

Habitual visual acuity and visual acuity threshold demands in Nigerian school classrooms

This study was designed to estimate the burden of blindness and vision impairment in school children, and to determine the proportion of students meeting the visual acuity (VA) demand for their classrooms. From 148 primary and secondary school classrooms in Edo State, Nigeria, the habitual distance and near VA of over 2000 students were measured. Values obtained were compared with the calculated distance VA demand and actual near VA demand for their classrooms. Measures used to calculate the VA demand were working distance and smallest text size on learning materials, at both distance and near. We also determined the relationship between age and calculated VA demand and the effect of factors such as school ownership and school type on the VA demand. Habitual distance vision impairment was found in 0.8% of pupils, including 2 (0.10%) who met the WHO criteria for blindness. The average VA demand at the furthest and nearest sitting position to the board was 0.21 ± 0.23 and 0.65 ± 0.33LogMAR, respectively. Near working distance of students ranged from 15.00 to 37.20 cm, and the near VA demand as well as actual near VA demand (using a 2.5 times acuity reserve) was 0.60 ± 0.17 and 0.20 ± 1.7LogMAR, respectively. LogMAR VA demand increased (size of print decreases) with increasing age, at both distance (r = − 0.549, p = 0.070) and near (r = − 0.921, p < 0.0001). The VA demand at maximum distance and the actual near VA demand differed significantly by school ownership and between primary and secondary schools. Most students had VA better, but up to 11% of students per class had VA poorer than their classroom demands. Although the majority of students had better VA than their classroom demands, for students with reduced vision, learning could be negatively impacted. It is important to continually screen students for vision impairment and ensure prompt referral and treatment. These findings have implications for managing vision problems in children, as well as enabling appropriate classroom arrangements for those with vision impairment

Increases in Vein Length Compensate for Leaf Area Lost to Lobing in Grapevine

Premise:Leaf lobing and leaf size vary considerably across and within species,including among grapevines (Vitisspp.), some of the best‐studied leaves. Weexamined the relationship between leaf lobing and leaf area across grapevinepopulations that varied in extent of leaf lobing.Methods:We used homologous landmarking techniques to measure 2632 leavesacross 2 years in 476 unique, genetically distinct grapevines fromfive biparentalcrosses that vary primarily in the extent of lobing. We determined to what extent leafarea explained variation in lobing, vein length, and vein to blade ratio.Results:Although lobing was the primary source of variation in shape across theleaves we measured, leaf area varied only slightly as a function of lobing. Rather, leafarea increases as a function of total major vein length, total branching vein length, andvein to blade ratio. These relationships are stronger for more highly lobed leaves, withthe residuals for each model differing as a function of distal lobing.Conclusions:For leaves with different extents of lobing but the same area, the morehighly lobed leaves have longer veins and higher vein to blade ratios, allowing themto maintain similar leaf areas despite increased lobing. Thesefindings show howmore highly lobed leaves may compensate for what would otherwise result in areduced leaf area, allowing for increasedphotosynthetic capacity through similarleaf siz

The inter-relationship of adolescent unhappiness and parental mental distress

Purpose Substantial evidence supports the hypothesis that parental well-being impacts upon child well-being and that this relationship is bidirectional. Here we explore how, in a large, nationally representative sample, both parents' mental distress relates over time to each other's mental distress and to their adolescent child's unhappiness, and vice versa. Methods Analyses were conducted using data from waves one to five (2009/10–2014/15) of Understanding Society, the UK Household Longitudinal Study. Understanding Society collects data on adults' mental distress (General Health Questionnaire), and on youths' (age: 10–15 years) unhappiness in relation to their school work, appearance, family, friends, school, and life as a whole. We use repeated-measures structural equation models to investigate the reciprocal relationships between both parents' distress and their child's unhappiness, using both longitudinal cross-lagged and nonrecursive contemporaneous specifications. The analytic sample is 1,883 triads (adolescent child, mother, and father) with data at two or more consecutive time points. Analyses are stratified by adolescent gender. Results Our results show that parental mental distress predicts unhappiness of girls but not that of boys. Reciprocal associations of maternal and paternal mental distress are evident in families with an adolescent daughter. Unhappiness of adolescents does not predict their parents' mental distress. Results are similar whether examined contemporaneously or over time. Conclusions Our findings support the suggestion that the family should be considered as a dynamic system, for instance when planning clinical interventions. This is particularly pertinent in families with an adolescent daughter present

Prevention of infections and fever to improve outcome in older patients with acute stroke (PRECIOUS): a randomised, open, phase III, multifactorial, clinical trial with blinded outcome assessment

BackgroundInfections and fever after stroke are associated with poor functional outcome or death. We assessed whether prophylactic treatment with anti-emetic, antibiotic, or antipyretic medication would improve functional outcome in older patients with acute stroke. MethodsWe conducted an international, 2∗2∗2-factorial, randomised, controlled, open-label trial with blinded outcome assessment in patients aged 66 years or older with acute ischaemic stroke or intracerebral haemorrhage and a score on the National Institutes of Health Stroke Scale ≥ 6. Patients were randomly allocated (1:1) to metoclopramide (oral, rectal, or intravenous; 10 mg thrice daily) vs. no metoclopramide, ceftriaxone (intravenous; 2000 mg once daily) vs. no ceftriaxone, and paracetamol (oral, rectal, or intravenous; 1000 mg four times daily) vs. no paracetamol, started within 24 h after symptom onset and continued for four days. All participants received standard of care. The target sample size was 3800 patients. The primary outcome was the score on the modified Rankin Scale (mRS) at 90 days analysed with ordinal logistic regression and reported as an adjusted common odds ratio (an acOR 1 harm). This trial is registered (ISRCTN82217627). FindingsFrom April 2016 through June 2022, 1493 patients from 67 European sites were randomised to metoclopramide (n = 704) or no metoclopramide (n = 709), ceftriaxone (n = 594) or no ceftriaxone (n = 482), and paracetamol (n = 706) or no paracetamol (n = 739), of whom 1471 were included in the intention-to-treat analysis. Prophylactic use of study medication did not significantly alter the primary outcome at 90 days: metoclopramide vs. no metoclopramide (adjusted common odds ratio [acOR], 1.01; 95% CI 0.81–1.25), ceftriaxone vs. no ceftriaxone (acOR 0.99; 95% CI 0.77–1.27), paracetamol vs. no paracetamol (acOR 1.19; 95% CI 0.96–1.47). The study drugs were safe and not associated with an increased incidence of serious adverse events. InterpretationWe observed no sign of benefit of prophylactic use of metoclopramide, ceftriaxone, or paracetamol during four days in older patients with a moderately severe to severe acute stroke. FundingThis project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No: 634809

Which outcomes are most important to measure in patients with COVID-19 and how and when should these be measured? Development of an international standard set of outcomes measures for clinical use in patients with COVID-19: a report of the International Consortium for Health Outcomes Measurement (ICHOM) COVID-19 Working Group.

Objectives: The COVID-19 pandemic has resulted in widespread morbidity and mortality with the consequences expected to be felt for many years. Significant variation exists in the care even of similar patients with COVID-19, including treatment practices within and between institutions. Outcome measures vary among clinical trials on the same therapies. Understanding which therapies are of most value is not possible unless consensus can be reached on which outcomes are most important to measure. Furthermore, consensus on the most important outcomes may enable patients to monitor and track their care, and may help providers to improve the care they offer through quality improvement. To develop a standardised minimum set of outcomes for clinical care, the International Consortium for Health Outcomes Measurement (ICHOM) assembled a working group (WG) of 28 volunteers, including health professionals, patients and patient representatives. Design: A list of outcomes important to patients and professionals was generated from a systematic review of the published literature using the MEDLINE database, from review of outcomes being measured in ongoing clinical trials, from a survey distributed to patients and patient networks, and from previously published ICHOM standard sets in other disease areas. Using an online-modified Delphi process, the WG selected outcomes of greatest importance. Results: The outcomes considered by the WG to be most important were selected and categorised into five domains: (1) functional status and quality of life, (2) mental functioning, (3) social functioning, (4) clinical outcomes and (5) symptoms. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, clinical factors and treatment-related factors. Conclusion: Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of care to patients with COVID-19. Their consistent definition and collection could also broaden the implementation of more patient-centric clinical outcomes research.</p

The Exstrophy-epispadias complex

Exstrophy-epispadias complex (EEC) represents a spectrum of genitourinary malformations ranging in severity from epispadias (E) to classical bladder exstrophy (CEB) and exstrophy of the cloaca (EC). Depending on severity, EEC may involve the urinary system, musculoskeletal system, pelvis, pelvic floor, abdominal wall, genitalia, and sometimes the spine and anus. Prevalence at birth for the whole spectrum is reported at 1/10,000, ranging from 1/30,000 for CEB to 1/200,000 for EC, with an overall greater proportion of affected males. EEC is characterized by a visible defect of the lower abdominal wall, either with an evaginated bladder plate (CEB), or with an open urethral plate in males or a cleft in females (E). In CE, two exstrophied hemibladders, as well as omphalocele, an imperforate anus and spinal defects, can be seen after birth. EEC results from mechanical disruption or enlargement of the cloacal membrane; the timing of the rupture determines the severity of the malformation. The underlying cause remains unknown: both genetic and environmental factors are likely to play a role in the etiology of EEC. Diagnosis at birth is made on the basis of the clinical presentation but EEC may be detected prenatally by ultrasound from repeated non-visualization of a normally filled fetal bladder. Counseling should be provided to parents but, due to a favorable outcome, termination of the pregnancy is no longer recommended. Management is primarily surgical, with the main aims of obtaining secure abdominal wall closure, achieving urinary continence with preservation of renal function, and, finally, adequate cosmetic and functional genital reconstruction. Several methods for bladder reconstruction with creation of an outlet resistance during the newborn period are favored worldwide. Removal of the bladder template with complete urinary diversion to a rectal reservoir can be an alternative. After reconstructive surgery of the bladder, continence rates of about 80% are expected during childhood. Additional surgery might be needed to optimize bladder storage and emptying function. In cases of final reconstruction failure, urinary diversion should be undertaken. In puberty, genital and reproductive function are important issues. Psychosocial and psychosexual outcome depend on long-term multidisciplinary care to facilitate an adequate quality of life

Antagonistic Regulation of Apoptosis and Differentiation by the Cut Transcription Factor Represents a Tumor-Suppressing Mechanism in Drosophila

Apoptosis is essential to prevent oncogenic transformation by triggering self-destruction of harmful cells, including those unable to differentiate. However, the mechanisms linking impaired cell differentiation and apoptosis during development and disease are not well understood. Here we report that the Drosophila transcription factor Cut coordinately controls differentiation and repression of apoptosis via direct regulation of the pro-apoptotic gene reaper. We also demonstrate that this regulatory circuit acts in diverse cell lineages to remove uncommitted precursor cells in status nascendi and thereby interferes with their potential to develop into cancer cells. Consistent with the role of Cut homologues in controlling cell death in vertebrates, we find repression of apoptosis regulators by Cux1 in human cancer cells. Finally, we present evidence that suggests that other lineage-restricted specification factors employ a similar mechanism to put the brakes on the oncogenic process

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases