Body Mass Index, Smoking, and Alcohol and Risks of Barrett’s Esophagus and Esophageal Adenocarcinoma: A UK Prospective Cohort Study

BACKGROUND: The timing of the risk factors cigarette smoking, alcohol and obesity in the development of Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC) is unclear. AIMS: To investigate these exposures in the aetiology of BE and EAC in the same population. METHODS: The cohort included 24,068 men and women, aged 39–79 years, recruited between 1993 and 1997 into the prospective EPIC-Norfolk Study who provided information on anthropometry, smoking and alcohol intake. The cohort was monitored until December 2008 and incident cases identified. RESULTS: One hundred and four participants were diagnosed with BE and 66 with EAC. A body mass index (BMI) above 23 kg/m(2) was associated with a greater risk of BE [BMI ≥23 vs. 18.5 to <23, hazard ratio (HR) 3.73, 95 % CI 1.37–10.16], and within a normal BMI, the risk was greater in the higher category (HR 3.76, 95 % CI 1.30–10.85, BMI 23–25 vs. 18.5 to >23 kg/m(2)). Neither smoking nor alcohol intake were associated with risk for BE. For EAC, all BMI categories were associated with risk, although statistically significant for only the highest (BMI >35 vs. BMI 18.5 to <23, HR 4.95, 95 % CI 1.11–22.17). The risk was greater in the higher category of a normal BMI (HR 2.73, 95 % CI 0.93–8.00, p = 0.07, BMI 23–25 vs. 18.5 to >23 kg/m(2)). There was an inverse association with ≥7 units alcohol/week (HR 0.51, 95 % CI 0.29–0.88) and with wine (HR 0.49, 95 % CI 0.23–1.04, p = 0.06, drinkers vs. non-drinkers). CONCLUSIONS: Obesity may be involved early in carcinogenesis and the association with EAC and wine should be explored. The data have implications for aetiological investigations and prevention strategies

The effect of dietary intake, physical activity and posture on pepsin concentrations detected in the saliva of free-living, healthy individuals

Introduction: Diet and lifestyle are believed to be major causes of gastric reflux. The occurrence of reflux is associated with a number of respiratory, oesophageal and airways conditions. Previous studies have used oesophageal monitoring to assess the occurrence of reflux events. Such measurements may only measure "bulk" rather than "microreflux" events. Such technology is also likely to impact on both habitual dietary intake and physical activity due to the nature of the assessment. Aim: To assess the impact of meal intake and physical activity on pepsin concentrations in saliva collected from free-living individuals throughout the day. Methods: Fifty-one participants (aged 18+, non-smokers with no current chronic or acute respiratory conditions, bloodborne diseases, or diagnosis of reflux disease) provided saliva samples before (< 30 min) and after (< 1 h) meals and physical activity bouts or before and after sleep. Dietary intake and physical activity were monitored by diary over this time. Dietary intake was analyzed using Windiets® software, while physical activity output was calculated from pre-existing tables of energy expenditure. Saliva samples were analyzed for pepsin content using a previously described ELISA methodology. Wilcoxon matched pairs rank sign tests were performed on before- and after-meal/physical activity/sleep samples. Results: Fifty-seven paired pre-and post-meal,48 paired pre- and post-physical activity samples and 168 pre- and post-sleep samples were analyzed. Mean(standard deviation) pepsin concentrations in saliva were significantly higher (P=0.037) in the pre-meal samples (44.2(42.2)) than the post-meal samples (32.8(29.6)). Post-sleep pepsin concentrations (196.4(323.4)) were significantly higher (P< 0.001) than pre-sleep (102.3(152.8)). There was no significant difference (P=0.491) between pre-(45.2(56.8)) and post-(40.8(38.6)) physical activity saliva samples. Conclusions: Analysis of pepsin in saliva is a useful method to assess the impact of lifestyle on reflux event occurrence. Increased preprandial salivary pepsin concentrations may be due to microreflux events driven by the cephalic phase of digestion

Storage stability of bevacizumab in polycarbonate and polypropylene syringes

Purpose To compare and examine the storage stability of compounded bevacizumab in polycarbonate (PC) and polypropylene (PP) syringes over a 6-month period. PC syringes have been used in a recent clinical study and bevacizumab stability has not been reported for this type of syringe. Methods Repackaged bevacizumab was obtained from Moorfields Pharmaceuticals in polycarbonate (PC) and polypropylene (PP) syringes. Bevacizumab from the stored syringes was analysed at monthly time points for a 6-month period and compared with bevacizumab from a freshly opened vial at each time point. SDS-PAGE electrophoresis and size-exclusion chromatography (SEC) was used to observe aggregation and degradation. Dynamic light scattering (DLS) provided information about the hydrodynamic size and particle size distribution of bevacizumab in solution. VEGF binding and the active concentration of bevacizumab was determined by surface plasmon resonance (SPR) using Biacore. Results SDS-PAGE and SEC analysis did not show any changes in the presence of higher molecular species (HMWS) or degradation products in PC and PP syringes from T0 to T6 compared to bevacizumab sampled from a freshly opened vial. The hydrodynamic diameter of bevacizumab in the PC syringe after six months of storage was not significantly different to bevacizumab taken from a freshly opened vial. Using SPR, the VEGF binding activity of bevacizumab in the PC syringe was comparable with bevacizumab taken from a freshly opened vial. Conclusion No significant difference over a 6-month period was observed in the quality of bevacizumab repackaged into prefilled PC polycarbonate and PP polypropylene syringes when compared to bevacizumab that is supplied from the vial

Gene Therapy for Glaucoma by Ciliary Body Aquaporin 1 disruption using CRISPR-Cas9

Glaucoma is a common cause of blindness, yet current therapeutic options are imperfect. Clinical trials have invariably shown that reduction in intraocular pressure (IOP) regardless of disease subtype prevents visual loss. Reducing ciliary body aqueous humor production can lower IOP, and the adeno-associated virus ShH10 serotype was identified as able to transduce mouse ciliary body epithelium following intravitreal injection. Using ShH10 to deliver a single vector CRISPR-Cas9 system disrupting Aquaporin 1 resulted in reduced IOP in treated eyes (10.4 ± 2.4 mm Hg) compared with control (13.2 ± 2.0 mm Hg) or non-injected eyes (13.1 ± 2.8 mm Hg; p < 0.001; n = 12). Editing in the aquaporin 1 gene could be detected in ciliary body, and no off-target increases in corneal or retinal thickness were identified. In experimental mouse models of corticosteroid and microbead-induced ocular hypertension, IOP could be reduced to prevent ganglion cell loss (32 ± 4 /mm2) compared with untreated eyes (25 ± 5/mm2; p < 0.01). ShH10 could transduce human ciliary body from post-mortem donor eyes in ex vivo culture with indel formation detectable in the Aquaporin 1 locus. Clinical translation of this approach to patients with glaucoma may permit long-term reduction of IOP following a single injection

Evaluating the feasibility of implementing a Telesleep pilot program using two-tiered external facilitation

Background: Obstructive sleep apnea (OSA) can negatively impact patients' health status and outcomes. Positive airway pressure (PAP) reverses airway obstruction and may reduce the risk of adverse outcomes. Remote monitoring of PAP (as opposed to in-person visits) may improve access to sleep medicine services. This study aimed to evaluate the feasibility of implementing a clinical program that delivers treatment for OSA through PAP remote monitoring using external facilitation as an implementation strategy. Methods: Participants included patients with OSA at a Veteran Affairs Medical Center (VAMC). PAP adherence and clinical disease severity on treatment (measured by the apnea hypopnea index [AHI]) were the preliminary effectiveness outcomes across two delivery models: usual care (in-person) and Telehealth nurse-delivered remote monitoring. We also assessed visit duration and travel distance. A prospective, mixed-methods evaluation examined the two-tiered external facilitation implementation strategy. Results: The pilot project included N = 52 usual care patients and N = 38 Telehealth nurse-delivered remote monitoring patients. PAP adherence and disease severity were similar across the delivery modalities. However, remote monitoring visits were 50% shorter than in-person visits and saved a mean of 72 miles of travel (median = 45.6, SD = 59.0, mode = 17.8, range 5.4-220). A total of 62 interviews were conducted during implementation with a purposive sample of 12 clinical staff involved in program implementation. Weekly external facilitation delivered to both front-line staff and supervisory physicians was necessary to ensure patient enrollment and treatment. Synchronized, "two-tiered" facilitation at the executive and coordinator levels proved crucial to developing the clinical and administrative infrastructure to support a PAP remote monitoring program and to overcome implementation barriers. Conclusions: Remote PAP monitoring had similar efficacy to in-person PAP services in this Veteran population. Although external facilitation is a widely-recognized implementation strategy in quality improvement projects, less is known about how multiple facilitators work together to help implement complex programs. Two-tiered facilitation offers a model well-suited to programs where innovations span disciplines, disrupt professional hierarchies (such as those between service chiefs, clinicians, and technicians) and bring together providers who do not know each other, yet must collaborate to improve access to care

The effectiveness of schemes that refine referrals between primary and secondary care - the UK experience with glaucoma referrals: the Health Innovation & Education Cluster (HIEC) Glaucoma Pathways Project

Objectives: A comparison of glaucoma referral refinement schemes (GRRS) in the UK during a time period of considerable change in national policy and guidance. Design: Retrospective multisite review. Setting: The outcomes of clinical examinations by optometrists with a specialist interest in glaucoma (OSIs) were compared with optometrists with no specialist interest in glaucoma (non-OSIs). Data from Huntingdon and Nottingham assessed non-OSI findings, while Manchester and Gloucestershire reviewed OSI findings. Participants: 1086 patients. 434 patients were from Huntingdon, 179 from Manchester, 204 from Gloucestershire and 269 from Nottingham. Results: The first-visit discharge rate (FVDR) for all time periods for OSIs was 14.1% compared with 36.1% from non-OSIs (difference 22%, CI 16.9% to 26.7%; p<0.001). The FVDR increased after the April 2009 National Institute for Health and Clinical Excellence (NICE) glaucoma guidelines compared with pre-NICE, which was particularly evident when pre-NICE was compared with the current practice time period (OSIs 6.2–17.2%, difference 11%, CI −24.7% to 4.3%; p=0.18, non-OSIs 29.2–43.9%, difference 14.7%, CI −27.8% to −0.30%; p=0.03). Elevated intraocular pressure (IOP) was the commonest reason for referral for OSIs and non-OSIs, 28.7% and 36.1%, respectively, of total referrals. The proportion of referrals for elevated IOP increased from 10.9% pre-NICE to 28.0% post-NICE for OSIs, and from 19% to 45.1% for non-OSIs. Conclusions: In terms of ‘demand management’, OSIs can reduce FVDR of patients reviewed in secondary care; however, in terms of ‘patient safety’ this study also shows that overemphasis on IOP as a criterion for referral is having an adverse effect on both the non-OSIs and indeed the OSIs ability to detect glaucomatous optic nerve features. It is recommended that referral letters from non-OSIs be stratified for risk, directing high-risk patients straight to secondary care, and low-risk patients to OSIs

Carbohydrate Intake in the Etiology of Crohn's Disease and Ulcerative Colitis

Background: Diet may have a role in the etiology of inflammatory bowel disease. In previous studies, the associations between increased intakes of carbohydrates, sugar, starch, and inflammatory bowel disease are inconsistent. However, few prospective studies have investigated the associations between these macronutrients and incident Crohn's disease (CD) or ulcerative colitis (UC). Methods: A total of 401,326 men and women were recruited between 1991 and 1998. At recruitment, dietary intakes of carbohydrate, sugar, and starch were measured using validated food frequency questionnaires. The cohort was monitored identifying participants who developed incident CD or UC. Cases were matched with 4 controls, and odds ratios were calculated for quintiles of total carbohydrate, sugar, and starch intakes adjusted for total energy intake, body mass index, and smoking. Results: One hundred ten participants developed CD, and 244 participants developed UC during follow-up. The adjusted odds ratio for the highest versus the lowest quintiles of total carbohydrate intake for CD was 0.87, 95% CI = 0.24 to 3.12 and for UC 1.46, 95% CI = 0.62 to 3.46, with no significant trends across quintiles for either (CD, Ptrend = 0.70; UC, Ptrend = 0.41). Similarly, no associations were observed with intakes of total sugar (CD, Ptrend = 0.50; UC, Ptrend = 0.71) or starch (CD, Ptrend = 0.69; UC, Ptrend = 0.17). Conclusions: The lack of associations with these nutrients is in agreement with many case–control studies that have not identified associations with CD or UC. As there is biological plausibility for how specific carbohydrates could have an etiological role in inflammatory bowel disease, future epidemiological work should assess individual carbohydrates, although there does not seem to be a macronutrient effect

Associations with photoreceptor thickness measures in the UK Biobank.

Spectral-domain OCT (SD-OCT) provides high resolution images enabling identification of individual retinal layers. We included 32,923 participants aged 40-69 years old from UK Biobank. Questionnaires, physical examination, and eye examination including SD-OCT imaging were performed. SD OCT measured photoreceptor layer thickness includes photoreceptor layer thickness: inner nuclear layer-retinal pigment epithelium (INL-RPE) and the specific sublayers of the photoreceptor: inner nuclear layer-external limiting membrane (INL-ELM); external limiting membrane-inner segment outer segment (ELM-ISOS); and inner segment outer segment-retinal pigment epithelium (ISOS-RPE). In multivariate regression models, the total average INL-RPE was observed to be thinner in older aged, females, Black ethnicity, smokers, participants with higher systolic blood pressure, more negative refractive error, lower IOPcc and lower corneal hysteresis. The overall INL-ELM, ELM-ISOS and ISOS-RPE thickness was significantly associated with sex and race. Total average of INL-ELM thickness was additionally associated with age and refractive error, while ELM-ISOS was additionally associated with age, smoking status, SBP and refractive error; and ISOS-RPE was additionally associated with smoking status, IOPcc and corneal hysteresis. Hence, we found novel associations of ethnicity, smoking, systolic blood pressure, refraction, IOPcc and corneal hysteresis with photoreceptor thickness

Estimating the global cost of vision impairment and its major causes: protocol for a systematic review

Introduction: Vision impairment (VI) places a burden on individuals, health systems and society in general. In order to support the case for investing in eye health services, an updated cost of illness study that measures the global impact of VI is necessary. To perform such a study, a systematic review of the literature is needed. Here we outline the protocol for a systematic review to describe and summarise the costs associated with VI and its major causes. Methods and analysis: We will systematically search in Medline (Ovid) and the Centre for Reviews and Dissemination database which includes the National Health Service Economics Evaluation Database. No language or geographical restriction will be applied. Additional literature will be identified by reviewing the references in the included studies and by contacting field experts. Grey literature will be considered. The review will include any study published from 1 January 2000 to November 2019 that provides information about costs of illness, burden of disease and/or loss of well-being in participants with VI due to an unspecified cause or due to one of the seven leading causes globally. Two reviewers will independently screen studies and extract relevant data from included studies. Methodological quality of economic studies will be assessed based on the British Medical Journal checklist for economic submissions adapted to costs of illness studies. This protocol has been prepared following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols and has been published prospectively in Open Science Framework. Ethics and dissemination Formal ethical approval is not required, as primary data will not be collected in this review. The findings of this study will be disseminated through peer-reviewed publications, stakeholder meetings and inclusion in the ongoing Lancet Global Health Commission on Global Eye Health. Registration details https://osf.io/9au3w (DOI 10.17605/OSF.IO/6F8VM)