Impact of COVID-19 on a real-world treat-and-extend regimen with aflibercept for neovascular age-related macular degeneration.

OBJECTIVE: To assess the effect of the COVID-19 pandemic on injection intervals among patients treated for neovascular age-related macular degeneration. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients treated at a single practice using a treat-and-extend regimen with intravitreal aflibercept between December 2018 and April 2021. METHODS: The primary outcome was the change in injection intervals. Secondary outcomes included differences in best-recorded visual acuity (BRVA) and central subfield thickness (CST). Associations were evaluated with linear mixed-effects modelling. RESULTS: This study included 1839 injections from 185 eyes (141 patients). The median (interquartile range) injection intervals in the pre-COVID-19 and COVID-19 periods were 60 (42-70) and 70 (49-90) days, respectively. The pandemic was associated with a mean injection interval lengthening of 7.2 days (P < 0.001), a decrease in BRVA of 3.1 Early Treatment Diabetic Retinopathy Study letters (P < 0.001), and a reduction in CST of 14.7 µm (P = 0.003). The presence of exudative intraretinal fluid was associated with a reduction in treatment intervals of 11.1 days (P < 0.001), a reduction in BRVA of 1.9 Early Treatment Diabetic Retinopathy Study letters (P < 0.001), and an increase in CST of 52.4 µm (P < 0.001). The presence of subretinal fluid was associated with a reduction in treatment intervals of 8.5 days (P < 0.001) and an increase in CST of 21.6 µm (P < 0.001). CONCLUSIONS: This real-world study estimated that the severe acute respiratory syndrome coronavirus 2 pandemic resulted in an injection extension of 7.2 days with associated decreases in BRVA and CST that are unlikely clinically significant on a population basis. This builds on evidence suggesting that long-term vascular endothelial growth factor suppression can facilitate meaningful interval extensions while maintaining visual acuity.

Development and Verification of a Novel Three-Dimensional Aqueous Outflow Model for High-Throughput Drug Screening.

Distal outflow bleb-forming procedures in ophthalmic surgery expose subconjunctival tissue to inflammatory cytokines present in the aqueous humor, resulting in impaired outflow and, consequently, increased intraocular pressure. Clinically, this manifests as an increased risk of surgical failure often necessitating revision. This study (1) introduces a novel high-throughput screening platform for testing potential anti-fibrotic compounds and (2) assesses the clinical viability of modulating the transforming growth factor beta-SMAD2/3 pathway as a key contributor to post-operative outflow reduction, using the signal transduction inhibitor verteporfin. Human Tenon's capsule fibroblasts (HTCFs) were cultured within a 3D collagen matrix in a microfluidic system modelling aqueous humor drainage. The perfusate was augmented with transforming growth factor beta 1 (TGFß1), and afferent pressure to the tissue-mimetic was continuously monitored to detect treatment-related pressure elevations. Co-treatment with verteporfin was employed to evaluate its capacity to counteract TGFß1 induced pressure changes. Immunofluorescent studies were conducted on the tissue-mimetic to corroborate the pressure data with cellular changes. Introduction of TGFß1 induced treatment-related afferent pressure increase in the tissue-mimetic. HTCFs treated with TGFß1 displayed visibly enlarged cytoskeletons and stress fiber formation, consistent with myofibroblast transformation. Importantly, verteporfin effectively mitigated these changes, reducing both afferent pressure increases and cytoskeletal alterations. In summary, this study models the pathological filtration bleb response to TGFß1, while demonstrating verteporfin's effectiveness in ameliorating both functional and cellular changes caused by TGFß1. These demonstrate modulation of the aforementioned pathway as a potential avenue for addressing post-operative changes and reductions in filtration bleb outflow capacity. Furthermore, the establishment of a high-throughput screening platform offers a valuable pre-animal testing tool for investigating potential compounds to facilitate surgical wound healing.

Randomised clinical trial: Faecal microbiota transplantation for irritable bowel syndrome with diarrhoea.

BACKGROUND: Faecal microbiota transplantation (FMT) has been shown to improve symptoms in a proportion of patients with irritable bowel syndrome (IBS). AIM: We performed a randomised trial to assess the efficacy of FMT in patients with IBS. METHODS: We randomised 56 patients with diarrhoea-predominant IBS 1:1 to FMT or placebo via the duodenal route at baseline and week 4. The primary outcome was > 50 points decrease in IBS severity scoring system (IBS-SSS) score at week 12. Secondary outcomes were improvement in bloating and change in gut microbiota at week 12. After 12-week follow-up, those in the placebo group were assigned to receive open-label FMT. RESULTS: At week 12, 57.1% in the FMT group and 46.4% in the placebo group achieved the primary endpoint (p = 0.42). More patients receiving FMT than placebo had improvement in bloating (72% vs 30%; p = 0.005). In an open-label extension, 65.2% and 82.4% of patients achieved, respectively, the primary endpoint and improvement in bloating. Faecal microbiome of patients in the FMT group showed a reduction in bacteria like Ruminococcus gnavus and enrichment of bacteria such as Lawsonibacter at week 12, while no change in the placebo group. Functional analyses showed that the hydrogen sulphide-producing pathway decreased in patients who had FMT (p < 0.05) accompanied by a reduction in contributing bacteria. There were no serious adverse events related to FMT. CONCLUSION: FMT performed twice at an interval of four weeks did not significantly reduce IBS-SSS score. However, more patients had improvement in abdominal bloating, which was associated with a reduction in hydrogen sulphide-producing bacteria. (ClinicalTrials.gov NCT03125564).

Systematic review and meta-analysis of cost-effectiveness of minimally invasive versus open pancreatic resections.

BACKGROUND: The systematic review is aimed to evaluate the cost-effectiveness of minimally invasive surgery (MIS) and open distal pancreatectomy and pancreaticoduodenectomy. METHOD: The MEDLINE, CENTRAL, EMBASE, Centre for Reviews and Dissemination, and clinical trial registries were systematically searched using the PRISMA framework. Studies of adults aged ≥ 18 year comparing laparoscopic and/or robotic versus open DP and/or PD that reported cost of operation or index admission, and cost-effectiveness outcomes were included. The risk of bias of non-randomised studies was assessed using the Newcastle-Ottawa Scale, while the Cochrane Risk of Bias 2 (RoB2) tool was used for randomised studies. Standardised mean differences (SMDs) with 95% confidence intervals (CI) were calculated for continuous variables. RESULTS: Twenty-two studies (152,651 patients) were included in the systematic review and 15 studies in the meta-analysis (3 RCTs; 3 case-controlled; 9 retrospective studies). Of these, 1845 patients underwent MIS (1686 laparoscopic and 159 robotic) and 150,806 patients open surgery. The cost of surgical procedure (SMD 0.89; 95% CI 0.35 to 1.43; I2 = 91%; P = 0.001), equipment (SMD 3.73; 95% CI 1.55 to 5.91; I2 = 98%; P = 0.0008), and operating room occupation (SMD 1.17, 95% CI 0.11 to 2.24; I2 = 95%; P = 0.03) was higher with MIS. However, overall index hospitalisation costs trended lower with MIS (SMD - 0.13; 95% CI - 0.35 to 0.06; I2 = 80%; P = 0.17). There was significant heterogeneity among the studies. CONCLUSION: Minimally invasive major pancreatic surgery entailed higher intraoperative but similar overall index hospitalisation costs.

Role of anti-vascular endothelial growth factor in the management of non-proliferative diabetic retinopathy without centre-involving diabetic macular oedema: a meta-analysis of trials.

This systematic review and meta-analysis investigated the impact of anti-vascular endothelial growth factor (VEGF) treatment in management of eyes with non-proliferative diabetic retinopathy (NPDR) without centre involving diabetic macular oedema (CI-DMO). We searched multiple databases for all randomised clinical trials (RCTs) that evaluated anti-VEGF treatment versus observation in eyes with NPDR without CI-DMO. Data was collected for six outcomes (best corrected visual acuity (BCVA) improvement, diabetic retinopathy severity score (DRSS), central subfield thickness, progression to vision threatening complications (VTCs), ocular adverse events and quality of life measures). Risk of bias was assessed using Cochrane risk-of-bias tool for randomised trials (RoB 2) and certainty of evidence was assessed using Grade of Recommendations, Assessment, Development and Evaluation (GRADE). We identified a total of 2 unique RCTs that compared aflibercept and sham to treat a total of 811 eyes. For BCVA change, there was a small, clinically insignificant benefit for aflibercept treatment at year 2 (MD 0.70, 95% CI 0.02-1.38, GRADE rating: MODERATE). DRSS demonstrated a statistically significant improvement with aflibercept use at year 2 (RR 3.76, 95% CI 2.75-5.13, GRADE rating: MODERATE). VTCs were significantly less in aflibercept arm at year 2 (RR 0.30, 95% CI 0.23-0.40, GRADE rating: MODERATE). In conclusion, aflibercept treatment versus observation in eyes with NPDR without CI-DMO can result in reduced risk of development of VTCs and regression of DRSS score over 2 years. Future trials are needed to increase the precision of the treatment effect and to provide data on quality-of-life metrics.PROSPERO Registration: CRD42021288608.

Impact of Inhaled and Intranasal Corticosteroids Exposure on the Risk of Ocular Hypertension and Glaucoma: A Systematic Review and Meta-Analysis.

Purpose: Starting in 2019, the Global Initiative for Asthma recommended the use of inhaled corticosteroids (ICS) as part of reliever combination therapy in patients 12 years of age and older, thus dramatically increasing the population exposure to ICS. ICS and intranasal corticosteroids (INS) are commonly used for a variety of respiratory diseases. Chronic steroid use is a well-known risk factor for elevated intraocular pressure (IOP) and glaucoma regardless of route of administration. This study aimed to determine the reported risk of glaucoma, ocular hypertension (OHT) and IOP elevation associated with ICS and INS use. Materials and Methods: Systematic literature search in MEDLINE, EMBASE, Cochrane, CINAHL, BIOSIS, and Web of Science databases from the date of inception identified studies that assess ocular outcomes related to glaucoma in ICS and INS users. Study selection, risk of bias assessment and data extraction were done independently in duplicate. Meta-analysis assessed glaucoma incidence, OHT incidence and IOP changes in patients using ICS and INS. Study adhered to PRISMA guidelines. Study protocol was registered with PROSPERO: CRD42020190241. Results: Qualitative and quantitative analyses included 65 and 41 studies, respectively. Incidence of glaucoma was not significantly different in either ICS or INS users compared to control over 45,457 person-years of follow-up. Similarly, no significant difference in OHT incidence over 4431 person-years was detected. In studies reporting IOP, a significantly higher IOP was observed (0.69 mmHg) in 857 ICS or INS users compared to 615 controls. However, no significant increase in IOP was observed within ICS or INS users when compared to pre-treatment baseline. Conclusion: Overall, use of ICS or INS does not significantly increase the incidence of glaucoma or OHT. However, ICS and INS patients had significantly higher IOPs compared to untreated patients. Awareness of these findings is significant in care of patients with additional risk factors for glaucoma.

Rapid visual field progression in a patient with glaucoma as the presenting manifestation of sarcoidosis.

PURPOSE: To report a case of accelerated visual field progression secondary to a new orbital apex lesion in a patient with a longstanding history of fatigue and cough. OBSERVATIONS: A 73-year-old myopic female with known open angle glaucoma presented with accelerated unilateral visual field progression. Maximally tolerated medical therapy was instituted over a period of 1-2 years with imminent discussions of surgical intervention. Around this time the patient reported worsening cough and fatigue, which were initially attributed to glaucoma medication side effects. Consideration of the patient's remote history of melanoma and the current asymmetry of the visual field progression triggered a computerized tomography (CT) scan of the orbits as part of the management. An orbital apex lesion was discovered, raising suspicion for metastatic melanoma, and restaging CT imaging uncovered renal, hepatic, and mediastinal masses. Unexpectedly, biopsies revealed non-necrotizing granulomatous inflammatory processes consistent with a diagnosis of sarcoidosis. It is perhaps noteworthy that the patient had received interferon therapy for management of her melanoma; previous reports have associated interferon exposure with subsequent sarcoid disease, regardless of duration of therapy or elapsed time since exposure. CONCLUSIONS AND IMPORTANCE: Although rare, sarcoidosis can occur virtually anywhere in the body, including the orbital apex. Its common early symptoms, fatigue and cough, are insidious and seen frequently in this patient's age group and medication side effect profile. It is important to maintain an appropriate index of suspicion when monitoring atypical visual field progression in a patient with glaucoma. In this case, imaging, subsequent biopsy, and a multi-specialty team were integral to this patient's diagnosis and management.

In a Time of Need: A Grassroots Initiative in Response to PPE Shortage in the COVID-19 Pandemic.

SETTING: Primary care is the first line of defence in healthcare, particularly during the coronavirus disease 2019 (COVID-19) pandemic. In the London-Middlesex region of Ontario, a critical shortage of personal protective equipment (PPE) was identified among primary care physicians (PCPs). INTERVENTION: With the help of the London-Middlesex Primary Care Alliance, volunteer administrators, physicians and medical students coordinated the acquisition and redistribution of community-donated PPE to PCPs across London-Middlesex. Our scope evolved to include PPE reusability and stewardship and PCP wellness. OUTCOME: Beginning on March 16, 2020, our initial four-week operation provided PPE to over 200 PCPs. We received 60 donations, including over 118,000 gloves, 13,700 masks, 700 wellness kits and reusable cloth masks and gowns. Each delivery included educational pamphlets, and our online PPE stewardship session was attended by over 30 physicians. IMPLICATIONS: In response to the PPE shortage in COVID-19, our efforts evolved into a complex adaptive system, supported by an organizational body with a pre-existing communication infrastructure, to great success. Our scope extended beyond simple PPE provision to PCPs. Furthermore, our initiative established a framework for a centralized response to PPE shortage in Ontario Health West.

Analyzing 10 years of early awareness and alert activity in the United kingdom.

OBJECTIVES: The aim of this study was to assess the accuracy of the English National Horizon Scanning Centre (NHSC) in identifying and filtering pharmaceutical developments using end user and international collaborator databases of emerging technologies as proxies for new drugs of likely significance to health services and/or patients. METHODS: We used the NHSC information system and the list of National Institute for Health and Clinical Excellence (NICE) technology appraisals to estimate the false positive rate for NHSC identification, filtration, and reporting. We assessed the sensitivity of NHSC identification and filtration of pharmaceuticals for NICE technology appraisals from 1999 to the end of December 2010, and for pharmaceuticals entered into the EuroScan International Network database. RESULTS: We estimate that overall NHSC identification, filtration and reporting had a positive predictive value of 0.39 (95 percent CI, 0.36 to 0.43) and a false positive rate of 60 percent. Using NICE appraisals and EuroScan's database as proxies for pharmaceuticals of significance, we estimate the NHSC sensitivity over the 10-year period at 0.92 (95 percent CI, 0.89 to 0.95) and 0.89 (95 percent CI, 0.82 to 0.96) respectively. CONCLUSIONS: Our results suggest that the NHSC has performed well in terms of sensitivity over the past decade, but that the false positive rate of 60 percent may indicate that the filtration criteria for pharmaceuticals could be tightened for increased efficiency. Future evaluations of EAA systems should include an element of external review and explore the level of accuracy acceptable to funders and customers of such systems.

Identification of innovation in public health.

BACKGROUND: The National Horizon Scanning Centre provides national policy-makers in England with forewarning about emerging and new health technologies. This includes public health interventions (PHIs) but identification of these interventions is not always easy. OBJECTIVES: The aim of this study was to explore the meaning and define innovation in public health. METHODS: We used a quasi-Delphi method with questionnaire 1 sent to 106 public health and horizon scanning professionals and decision-makers in June 2008. Questionnaire 2 was developed based on answers to questionnaire 1 and sent to all respondents. RESULTS: A definition of innovative PHIs was developed: 'Innovative PHIs are generally new and different to established interventions. They should be equitable, applicable to all in a population, cost-effective and may address health determinants in the non-health sector of society. A good evidence base is ideal, but sometimes it may be necessary to consider PHIs lacking evidence'. Sources suggested for identifying innovative PHIs were similar to those used for other types of health technologies. CONCLUSION: Our findings should help early awareness and alert systems distinguish innovative from non-innovative PHIs, although its application in practice needs trialling.

The ATM tumour suppressor gene is down-regulated in EBV-associated nasopharyngeal carcinoma.

A micro-array analysis using biopsies from patients with EBV-positive undifferentiated nasopharyngeal carcinoma (NPC) and from cancer-free controls revealed down-regulation of tumour suppressor genes (TSG) not previously associated with this disease; one such gene was the ataxia telangiectasia mutated (ATM) gene. Q-PCR confirmed down-regulation of ATM mRNA and ATM protein expression in tumour cells was weak or absent in almost all cases. In NPC cell lines, however, ATM was down-regulated only in the EBV-positive line, C666.1, and in none of five EBV-negative lines. In vitro infection of EBV-negative NPC cell lines with a recombinant EBV was followed by the down-regulation of ATM mRNA and protein, and only EBV-positive cells showed a defective DNA damage response following gamma-irradiation. Our data suggest that loss of ATM function could be an important step in the pathogenesis of NPC, and may have implications for the treatment of this disease.