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Summary Background The WHO VISION 2020 global initiative against blindness, launched in 2000, prioritised childhood visual disability by aiming to end avoidable childhood blindness by 2020. However, progress has been hampered by the global paucity of epidemiological data concerning childhood visual disability. The British Childhood Visual Impairment and Blindness Study 2 (BCVIS2) was done to address this evidence gap. Methods BCVIS2 was a prospective UK-wide, cross-sectional, observational study to establish an inception cohort of children newly diagnosed with visual impairment. Ophthalmologists and paediatricians reported cases from 89 hospitals and community centres across the UK. We included children aged 18 years or younger who were newly diagnosed with any condition causing impaired visual acuity to a level of 0·5 logMAR or worse (worse than 6/18 Snellen) in each eye, or equivalent vision as assessed by standard qualitative measures, between Oct 1, 2015, and Nov 1, 2016. Eligible children were notified simultaneously but independently by their managing ophthalmologists and paediatricians via the two national active surveillance schemes, the British Ophthalmological Surveillance Unit and the British Paediatric Surveillance Unit. Standardised detailed demographic, socioeconomic, and clinical data about detection, management, and treatment were collected at diagnosis and 1 year later. We calculated incidence estimates and relative rates by key sociodemographic factors. We did descriptive analyses of underlying ophthalmic disorders and non-ophthalmic comorbidities. Findings 61 (7%) of 845 eligible children initially notified were ineligible at follow-up because of improved vision after treatment. Thus, the study sample comprised 784 children with permanent newly-diagnosed all-cause visual impairment, severe visual impairment, or blindness. 559 (72%) of 778 children had clinically significant non-ophthalmic impairments or conditions. 28 (4%) of 784 children died within a year after diagnosis of visual disability (all had underlying systemic disorders). Incidence of visual disability in the first year of life was 5·19 per 10 000 children (95% CI 4·71–5·72), almost ten times higher than among 1-to-4-year-olds and between 20 times and 100 times higher than in the older age groups. The overall cumulative incidence (or lifetime risk) of visual impairment, severe visual impairment, or blindness was 10·03 per 10 000 children (9·35–10·76). Incidence rates were higher for those from any ethnic minority group, the lowest quintile of socioeconomic status, and those born preterm or with low birthweight. 345 (44%) of 784 children had a single affected anatomical site. Disorders of the brain and visual pathways affected 378 (48%) of 784 children. Interpretation BCVIS2 provides a contemporary snapshot of the heterogeneity, multi-morbidity, and vulnerability associated with childhood visual disability in a high-income country. These findings could facilitate developing and delivering health care and planning of interventional research. Our findings highlight the importance of including childhood visual disability as a sentinel event and metric in global child health initiatives. Funding Fight for Sight, National Institute for Health Research, and Ulverscroft Foundation.

Epidermal growth factor receptor (EGFR) signaling is fundamentally important for tissue homeostasis through EGFR/ligand interactions that stimulate numerous signal transduction pathways. Aberrant EGFR signaling has been reported in inflammatory and malignant diseases, but thus far no primary inherited defects in EGFR have been recorded. Using whole-exome sequencing, we identified a homozygous loss-of-function missense mutation in EGFR (c.1283 G>A; p.Gly428Asp) in a male infant with lifelong inflammation affecting the skin, bowel, and lungs. During the first year of life, his skin showed erosions, dry scale, and alopecia. Subsequently, there were numerous papules and pustules--similar to the rash seen in patients receiving EGFR inhibitor drugs. Skin biopsy demonstrated an altered cellular distribution of EGFR in the epidermis with reduced cell membrane labeling, and in vitro analysis of the mutant receptor revealed abrogated EGFR phosphorylation and EGF-stimulated downstream signaling. Microarray analysis on the patient's skin highlighted disturbed differentiation/premature terminal differentiation of keratinocytes and upregulation of several inflammatory/innate immune response networks. The boy died at the age of 2.5 years from extensive skin and chest infections as well as electrolyte imbalance. This case highlights the major mechanism of epithelial dysfunction following EGFR signaling ablation and illustrates the broader impact of EGFR inhibition on other tissues.

Vascular birthmark classification was updated in 1996 ([Table 1][1])[1][2],[2][3] and has gained widespread recognition as a clinically useful framework. Haemangiomas are differentiated from vascular malformations by their clinical presentation, radiology and pathology, particularly by their

The purpose of this study was to evaluate whether the heart can induce high blood pressure by maintaining an inappropriately elevated cardiac output/body weight ratio during growth. Direct (femoral artery) mean arterial pressure (MAP), heart rate, cardiac output/body weight ratio (as defined by M-mode echocardiography), and total peripheral vascular resistance were measured and calculated every 2 months in nine conscious dogs during development from 2 to 10 months of age. In four dogs a J-shaped catheter for atrial pacing was chronically implanted at the age of 3 months, and their hearts were permanently paced at 130 beats/min until maturity. The aim of atrial pacing was to prevent the natural slowing of the heart rate and, consequently, to maintain a cardiac output/body weight ratio that was inappropriately high in relation to age during growth. Five dogs were studied as controls. No hemodynamic differences were observed until the age of 4 months. From the age of 5 to 10 months heart rate was kept at 130 beats/min by atrial pacing in the atrially paced group, and the mean cardiac output/body weight ratio did not decrease (196 +/- 24 vs 191 +/- 34 [SE] ml/min/kg). MAP rose from 62 +/- 4 to 116 +/- 8 mm Hg, and total peripheral resistance increased from 0.34 +/- 0.07 to to 0.61 +/- 0.09 mm Hg/ml/min/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of dopexamine on the renal circulation have been examined to show whether any augmentation of renal blood flow (RBF) was secondary to the effect of the drug on cardiac output (CO) or whether it had any additional direct renal vasodilator activity. Eight male patients with mild to moderate hypertension, who were undergoing renal vein catheterization for renin estimation, were studied. Dose related increments in RBF (baseline (B) = 504 ml X min-1; after treatment (D) = 605 ml X min-1), CO (B = 5.9 l X min-1; D = 6.7 l X min-1), heart rate (B = 77 beats/min; D = 100 beats/min) and systolic blood pressure (B = 143 mmHg; D = 166 mmHg) were observed on administration of dopexamine 3 micrograms X kg-1 X min-1, with insignificant changes in diastolic blood pressure (B = 84.4 mmHg; D = 90 mmHg) and total peripheral resistance (B = 17.85; D = 17.25 Units). There was a slight but significant reduction in renal vascular resistance (B = 20.59, D = 18.75). The ratio of RBF to CO (%) confirmed that the increase in RBF due to dopexamine hydrochloride was greater that attributable to the increase in CO or perfusion pressure alone (RBF/CO B = 8.5%, D = 9%), consistent with selective renal vasodilatation. The fall in renin activity and lack of systemic vasodilatation suggest that this was a DA1-receptor mediated effect.

Established methods for evaluating cardiac function in small animals involve surgical manoeuvres. We describe a method for evaluating left ventricular volume (LVV) and pressure (LVP) in anaesthetised adult rats. Under fluoroscopic control a 23 G needle was inserted into the left ventricular cavity of anaesthetised normotensive WKY rats. LVV was determined by biplane angiography and LVP was measured directly. Surface electrocardiograms were recorded throughout the procedure. In 8 animals the study was repeated three times, one week apart. Animals were then sacrificed and tissues harvested for histological examination. In 8 rats, the technique was found to be reproducible and there was no evidence of functional (ECG) or pathological myocardial damage following repeated measurements. In conclusion this technique provides a reproducible method of measuring LVV and LVP, allowing longitudinal haemodynamic studies in anaesthetised rats.

The effects of dopexamine hydrochloride on the renal circulation have been examined to discover whether augmentation of renal blood flow is secondary to the effect of the drug on cardiac output (CO) or whether there is an additional direct renal vasodilator activity. Eight male patients with mild to moderate hypertension, who were undergoing renal vein catheterization for renin estimation, were studied. Dose-related increments in renal blood flow (baseline [B] = 504 ml/min; after treatment [D] = 605 ml/min), CO (B = 5.9 liters/min; D = 6.7 liters/min), heart rate (B = 77 beats/min; D = 100 beats/min) and systolic blood pressure (B = 143 mm Hg; D = 166 mm Hg) were observed after administration of dopexamine hydrochloride (3 μg/kg/min), with insignificant changes in diastolic blood pressure (B = 84.4 mm Hg; D = 90 mm Hg) and total peripheral resistance (B = 17.85; D = 17.25 units). There was a small but significant reduction in renal vascular resistance (B = 20.59; D = 18.75 units). The ratio of renal blood flow to CO confirmed that the increase in renal blood flow due to dopexamine hydrochloride was greater than that attributable to the increase in CO or perfusion pressure alone (renal blood flow/CO B = 8.5%; D = 9%), and this is consistent with selective renal vasodilatation. The decrease in renin activity and lack of systemic vasodilatation suggest that this was a DA 1 receptor-mediated effect.