A Single Administration of OC-01 (Varenicline Solution) Nasal Spray Induces Short-Term Alterations in Conjunctival Goblet Cells in Patients with Dry Eye Disease.

INTRODUCTION: Dry eye disease is characterized by a persistently unstable or deficient tear film causing discomfort or visual impairment. Varenicline is a small-molecule nicotinic acetylcholine receptor agonist recently approved for use as a preservative-free nasal spray (OC-01 [varenicline solution] nasal spray [OC-01 VNS]) to treat signs and symptoms of dry eye disease, but its effect on conjunctival goblet cells has not been studied. METHODS: In this phase 2, single-center, vehicle-controlled study, patients aged 18 years or more with a diagnosis of dry eye disease and Ocular Surface Disease Index© score of at least 23 were randomized 2:1 to receive a 50-µL single dose of OC-01 0.06 mg VNS or vehicle nasal spray in each nostril. Image assessments for area and perimeter were performed pre and 10 min post treatment for goblet cells by in vivo confocal microscopy and for meibomian glands by infrared meibography. Non-parametric Wilcoxon signed-rank test compared pre- and post-treatment measurements for each treatment group. Treatment-emergent adverse events (TEAEs) were assessed. RESULTS: The study randomized 18 patients (mean age 61 years); 6 received vehicle (3/6 [50%] female) and 12 patients received OC-01 VNS (11/12 [92%] female). OC-01 VNS treatment decreased mean goblet cell area (pre-treatment, 106.4 µm2; post-treatment, 67.6 µm2; p = 0.02) and perimeter (pre-treatment, 38.9 µm; post-treatment, 31.2 µm; p = 0.03) but not vehicle did not (p = 0.25). There were no significant changes in mean meibomian gland area with either treatment (p ≥ 0.05). All TEAEs were non-ocular, non-serious, and mild. CONCLUSIONS: This study demonstrated that a single administration of OC-01 0.06 mg VNS in patients with dry eye disease reduced conjunctival goblet cell area and perimeter, suggesting goblet cell degranulation and associated release of lubricating mucin. By activating the natural tear film, OC-01 VNS may provide benefits over topical medications. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03688802.

Cutting Edge: Topical Recombinant Nerve Growth Factor for the Treatment of Neurotrophic Keratopathy-Biologicals as a Novel Therapy for Neurotrophic Keratopathy.

ABSTRACT: Ophthalmologists find management of neurotrophic keratopathy (NK) challenging because conventional therapy lacks efficacy and may result in permanent loss of vision. Recombinant nerve growth factor (cenegermin) targets the underlying pathogenesis of NK by regenerating corneal nerves and healing the corneal epithelium through promotion of proliferation, maturing corneal epithelial cells. It has been approved as Food Drug Association-approved treatment of NK. In this article, the background, clinical trials, and impact of recombinant nerve growth factor as the first neurotrophic factor for the restoration of corneal integrity, homeostasis, and corneal nerve regeneration are discussed.

Low-dose naltrexone is effective and well-tolerated for modulating symptoms in patients with neuropathic corneal pain.

PURPOSE: Neuropathic corneal pain (NCP) is caused by damage or disease of the somatosensory nervous system that innervates the cornea and presents with symptoms of pain or persistent unpleasant sensations, such as burning, dryness, or light sensitivity. This retrospective study aims to assess the efficacy and tolerability of low-dose naltrexone (LDN) in refractory NCP patients. METHODS: Fifty-nine NCP patients with a centralized component treated with oral LDN 4.5  mg at bedtime for at least four weeks were identified. Thirty out of 59 patients who had a baseline pain score ≥4 on the visual analogue scale had completed the ocular pain assessment survey (OPAS) and presented persistent pain, despite instillation of topical anesthetic drops, were included. Changes in pain scores, comorbidities, side effects, among others, were analyzed. Change in ocular pain scores (scale 0-10) and quality of life (QoL) scores (scale 0-100%) were the main endpoints. RESULTS: Mean age (years ± SD) was 45.60 ± 19.30 with a white (80.00%) female (73.33%) predominance. Duration of LDN use was 14.87 ± 11.25 months, and the duration of NCP before treatment was 17.53 ± 17.29 months. Eight patients used LDN as a monotherapy, whereas the remaining used it as an adjunct therapy. LDN resulted in a 49.22% decrease in mean pain score from 6.13 ± 1.93 to 3.23 ± 2.60 (p < 0.001). Mean QoL scores by the OPAS were 5.84 ± 2.57 at the first visit and improved to 3.77 ± 2.91 at the last visit (p = 0.023). Common side effects were vivid dreams, headaches, and stomachache. CONCLUSION: LDN was effective and well-tolerated for NCP treatment.

How can surgical continuity be maintained during the COVID-19 pandemic? A quality improvement study in the pre-vaccination period.

Objectives: During the COVID-19 pandemic, most of the elective surgeries had to be postponed. However, it is not possible to delay the surgical treat- ment of cancer patients for a long time. The aim of this study was to present how gastrointestinal system surgery operations are managed without delay and how employee safety is ensured , together with the results of the last five months. For this purpose, a preclinical and clinical screening system was created. Material and Methods: Data of the patients who presented to our outpatient clinic between April 1st 2020 and August 31st 2020 were retrospectively reviewed. Results: During the last five months of the pandemic, a total of 387 patients were hospitalized and 309 of these patients underwent surgical procedures. 165 of the patients who underwent surgery were newly diagnosed malignancy patients. All patients who were hospitalized were subjected to a screening for COVID-19 during the preclinical, clinical and surgical period. In the preclinical period, five patients were found positive and were directed to COVID-19 treatment without hospitalization. In the clinical period, six patients were isolated by showing symptoms during the hospitalization period. Only one of these patients received surgical treatment. The remaining five patients underwent endoscopic and interventional procedures. In this process, COVID-19 positivity was detected in a total of five healthcare workers. Conclusion: With this preclinical and clinical screening method, it is shown that a COVID-19 sterile environment can be provided by early detection of positive cases in both patients and healthcare workers. In this way, the possibility of surgical continuity was demonstrated.

Endoscopy in surgery.

In the last 20 years, there have been important developments in endoscopy. Initially, endoscopy was developed and used as a diagnostic tool. As new technology developed, these devices also became the basis for therapeutic maneuvers. In recent years, flexible endoscopes have been used to per- form procedures replacing traditional surgical approaches. Examples of this field are transanal minimally invasive surgery, natural orifice transluminal endoscopic surgery, endoscopic metabolic surgery and third space endoscopies. Throughout history, surgeons have played a vital role in the design and development of endoscopic techniques, procedures, and equipment. Surgeons continue to lead the advancement of endoscopy, make important contributions, and serve as role models for innovation.

The Effect of Bariatric Surgery on Exocrine Pancreatic Function.

INTRODUCTION: After bariatric surgery (BS), patients might suffer from nutrient maldigestion, malabsorption, and vitamin deficiencies. In this study, our aim was to assess pancreatic functions after BS using fecal elastase-1 assay (FE-1). MATERIAL AND METHODS: Sixty patients (21M) undergoing BS and 20 (6M) healthy controls were included into the study. Stool samples were collected 1 year after surgery. Ten patients from one anastomosis gastric bypass (OAGB) and single anastomosis duodenal switch (SADS) groups with the lowest value of FE-1 and GIQLI scores were given pancreatic enzyme replacement therapy (PERT). After PERT, FE-1, excess weight loss (EWL), BMI, GIQLI scores, and vitamin D levels were measured. RESULTS: Vitamin D levels were detected as 19.04 (9-46.5) pg/ml, 15.1 (8.4-23.6) pg/ml, 17.8 (5-30) pg/ml, and 21.79 (11-40.3) pg/ml after sleeve gastrectomy (SG), OAGB, SADS, and control groups, respectively (p = 0.04). GIQLI scores in the first year were found to have increased in all patients (p = 0.02). FE-1 levels were found as 642.35 (566.3-711.4) µg/g, 378.52 (183.5-561.1) µg/g, 458.88 (252.5-593, 5) µg/g, and 518.2 (351.6-691) µg/g for the SG, OAGB, SADS, and control groups, respectively. There was a strong inverse correlation between EWL and FE-1 levels at the end of the first year (Spearman's rho = - 0.688, p = 0.003). After having performed PERT for patients with the lowest FE-1 levels, the levels increased to 683.39 (615.5-720) µg/g in the OAGB and 691.5 (643.1-720) µg/g in the SADS groups (p = 0.011). CONCLUSION: FE-1 measurements demonstrated that many patients suffer from malabsorption after OAGB or SADS, whereas functions remain normal after SG. PERT corrects pancreatic functions without affecting weight loss and also contributes to the normal serum level of vitamin D.

Efficacy and tolerability of nortriptyline in the management of neuropathic corneal pain.

PURPOSE: Neuropathic corneal pain (NCP) is a recently acknowledged disease entity. However, there is no consensus in potential treatment strategies, particularly in patients with a centralized component of pain. This study aims to assess the efficacy and tolerability of the tricyclic antidepressant, nortriptyline, among NCP patients. METHODS: Patients with clinically diagnosed NCP and a centralized component of pain, treated with oral nortriptyline, who had recorded pain scores as assessed by the ocular pain assessment survey at the first and last visit were included. Patients were excluded if they had any other ocular pathology that might result in pain or had less than 4 weeks of nortriptyline use. Demographics, time between visits, concomitant medications, systemic and ocular co-morbidities, duration of NCP, side effects, ocular pain scores, and quality of life (QoL) assessment were recorded. RESULTS: Thirty patients with a mean age of 53.1 ± 18.5 were included. Male to female ratio was 8:22. Mean ocular pain in the past 24 h improved from 5.7 ± 2.1 to 3.6 ± 2.1 after 10.5 ± 9.1 months (p < 0.0001). Twelve patients (40.0%) had equal to or more than 50% improvement, 6 patients (20.0%) had 30-49% improvement, 6 patients (20.0%) had 1-29% improvement, 4 patients (13.3%) did not improve, while 2 patients (6.7%) reported increase in pain levels. Mean QoL improved from 6.0 ± 2.5 to 4.3 ± 2.4 (p = 0.019). Eight patients (26.6%) discontinued treatment due to persistent side effects, despite improvement by 22.4%. CONCLUSION: Nortriptyline was effective in relieving NCP symptoms in patients with centralized component and insufficient response to other systemic and topical therapies who tolerated the drug for at least 4 weeks. Nortriptyline may be used in the management of patients with NCP.

General Surgery Operating Room Practice in Patients with COVID-19.

The virus COVID-19, which emerged in China in December 2019, was announced by the World Health Organization as a pandemic in January 2020. It is known that infection is not severe and may even progress without symptoms in patients who have come into contact with COVID-19. Although various organizations have been informed about how to take measures to protect the patient and the surgeon in case of diseases requiring urgent or elective surgery in people infected with COVID-19 or in cases with high suspicion, there is still no definite judgment between patients, physicians and health authorities. In this study, which was prepared with the initiative of the Turkish Surgical Association, we tried to shed light on what should be done and how surgeons should act in patients whose operation is mandatory in light of the available data.

Comparison of clinical characteristics of post-refractive surgery-related and post-herpetic neuropathic corneal pain.

PURPOSE: To compare the clinical characteristics and in vivo confocal microscopy (IVCM) findings of patients with neuropathic corneal pain (NCP) due to refractive surgery (RS-NCP) and herpetic eye disease (H-NCP) to controls. METHODS: Sixteen patients with RS-NCP and 7 patients with H-NCP, and 37 healthy reference age- and sex-matched healthy controls were included to the study. The medical records were reviewed for demographic features, detailed disease history, ocular surface disease index (OSDI), ocular pain assessment survey (OPAS) scores. IVCM images of patients were analyzed and compared to reference controls by two masked observers. RESULTS: The mean pain intensity score for the last 24 h (5.1 ± 2.4 vs. 3.9 ± 1.2; p = 0.27), last 2 weeks (6.1 ± 2.5 vs. 4.8 ± 2.3; p = 0.13) for RS-NCP vs. H-NCP respectively, and quality of life scores (p = 0.23) were similar in both groups. Quality of life, especially mood (p = 0.06) and enjoying life/relations to others (p = 0.10) were affected in both groups, but were not statistically significant between groups. The mean total nerve density was lower in RS-NCP (5,702.4 ± 4,599.0 µm/mm2) compared to their respective controls (26,422.8 ± 4,491.0; p < 0.001) and in the H-NCP group (2,149.5 ± 2,985.9) compared to their respective controls (22,948.8 ± 3,169.0; p < 0.001). Alterations in DC density were similar between all groups (38.3 ± 48.0 cells/mm2 in RS-NCP, 61.0 ± 76.9 in H-NCP, p = 0.95). CONCLUSION: Neuropathic corneal pain patients due to refractive surgery show similar clinical characteristics, pain levels, quality of life impact, and IVCM findings as patients with NCP due to herpetic eye disease.

Changes in HOMA-IR index levels after bariatric surgery: Comparison of Single Anastomosis Duodenal Switch-proximal approach (SADS-p) and One Anastomosis Gastric Bypass-Mini Gastric Bypass (OAGB-MGB).

BACKGROUND: Bariatric surgery plays a major role in ameliorating metabolic abnormalities of type 2 diabetes (T2DM). The aim of this study was to evaluate the early effects of "Single Anastomosis Duodenal Switch-proximal approach" (SADS-p) and "One Anastomosis Gastric Bypass-Mini Gastric Bypass (OAGB-MGB) on the "homeostasis model assessment of insulin resistance" (HOMA-IR) index levels in morbidly obese patients with T2DM. METHODS: In this retrospective 3-year trial, outcomes of SADS-p and OAGB-MGB patients were compared considering the changes in HOMA-IR index levels. All bariatric procedures were performed by a single primary surgeon recognized as a surgeon of excellence by IFSO-EC with the assistance of one or two additional attending surgeons. SADS-p was performed on 60(10 males) patients, and 200(27 males) patients underwent OAGB-MGB. Forty-six patients (78%) in the SADS-p group and 125 (63%) in the OAGB-MGB group had T2DM. Patients were evaluated before surgery and 1,3,9,12 months after surgery. RESULTS: In both groups, the HOMA-IR index levels decreased significantly after surgery (p < 0.05), and both procedures markedly improved glycemic control. In the SADS-p group the HOMA-IR index levels significantly decreased from 6.2 to 1.4 after the 12th month of surgery (p < 0.05), in OAGB-MGB group HOMA-IR index levels significantly decreased from 5,9 to 1.7 after the 12th month of surgery (p < 0.05). CONCLUSION: Both procedures are promising operations which offer excellent control on weight, HOMA-IR index and diabetes.

A Review of Imaging Biomarkers of the Ocular Surface.

A biomarker is a "characteristic that is measured as an indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions." Recently, calls for biomarkers for ocular surface diseases have increased, and advancements in imaging technologies have aided in allowing imaging biomarkers to serve as a potential solution for this need. This review focuses on the state of imaging biomarkers for ocular surface diseases, specifically non-invasive tear break-up time (NIBUT), tear meniscus measurement and corneal epithelial thickness with anterior segment optical coherence tomography (OCT), meibomian gland morphology with infrared meibography and in vivo confocal microscopy (IVCM), ocular redness with grading scales, and cellular corneal immune cells and nerve assessment by IVCM. Extensive literature review was performed for analytical and clinical validation that currently exists for potential imaging biomarkers. Our summary suggests that the reported analytical and clinical validation state for potential imaging biomarkers is broad, with some having good to excellent intra- and intergrader agreement to date. Examples of these include NIBUT for dry eye disease, ocular redness grading scales, and detection of corneal immune cells by IVCM for grading and monitoring inflammation. Further examples are nerve assessment by IVCM for monitoring severity of diabetes mellitus and neurotrophic keratitis, and corneal epithelial thickness assessment with anterior segment OCT for the diagnosis of early keratoconus. However, additional analytical validation for these biomarkers is required before clinical application as a biomarker.

Evaluation of episcleral venous fluid wave during gonioscopy assisted transluminal trabeculotomy in patients with advanced glaucoma.

PURPOSE: To evaluate episcleral venous fluid wave (EVFW) during GATT surgery in patients with advanced stage open angle glaucoma and to investigate its relationship with the severity of glaucoma. METHODS: In all, 34 eyes of 28 open angle glaucoma patients who underwent GATT surgery were included into study. The extent of EVFW was evaluated using surgical records of patients and it was defined as number of clock hours. Correlations between the extent of EVFW and GAAT surgical outcomes as determined by intraocular pressures (IOP) and postoperative antiglaucoma medication needs were investigated. The impact of preoperative maximum IOP on EVFW was also evaluated. RESULTS: There was a significant correlation between IOPs and the extent of the EVFW at 1st, 3rd, 6th and 12th months follow-up visits. 10 of (%29.4) 34 eyes required antiglaucoma medications after the surgery. Mean extents of EVFW in patients who needed and did not need medications during follow-ups were 2.6 ± 1.0 (1-4) and 5.9 ± 1.5 (3-8) clock hours and the difference was statistically significant. Cutoff value of <4.5 clock hours for the EVFW (sensitivity 79.2%, specifity 100%) was found to be associated with the need for additional antiglaucoma medication. CONCLUSIONS: The extent of EVFW might be a valuable prognostic indicator for the surgical success of GATT since trabeculotomy is circumferential in this surgical technique making all collector channels accessible.

Firm strategy and consumer behaviour under a complex tobacco tax system: implications for the effectiveness of taxation on tobacco control.

BACKGROUND: The current tobacco taxation scheme in Turkey, a mix of high ad valorem tax and low specific tax, contains incentives for firms and consumers to change pricing and consumption patterns, respectively. The association between tax structure and price and tax revenue stability has not been studied in detail with micro data containing price segment information. OBJECTIVES: In this study, we analyse whether incentives for firms and consumers undermine the effectiveness of tax policy in reducing consumption. METHODS: We calculate alternative taxation scheme outcomes using differing ad valorem and specific tax rates through simulation analysis. We also estimate price elasticity of demand using detailed price and volume statistics between segments via regression analysis. FINDINGS: A very high ad valorem rate provides strong incentives to firms to reduce prices. Therefore, this sort of tax strategy may induce even more consumption despite its initial aim of discouraging consumption. While higher prices dramatically reduce consumption of economy and medium price segment cigarettes, demand for premium segment cigarettes is found to be highly price-inelastic. CONCLUSIONS: The current tax scheme, based on both ad valorem and specific components, introduces various incentives to firms as well as to consumers which reduce the effectiveness of the tax policy. Therefore, on the basis of our theoretical predictions, an appropriate tax scheme should involve a balanced combination of ad valorem and specific rates, away from extreme (ad valorem or specific dominant) cases to enhance the effectiveness of tax policy for curbing consumption.

Inhibition of VEGF mediated corneal neovascularization by anti-angiogenic peptide nanofibers.

Atypical angiogenesis is one of the major symptoms of severe eye diseases, including corneal neovascularization, and the complex nature of abnormal vascularization requires targeted methods with high biocompatibility. The targeting of VEGF is the most common approach for preventing angiogenesis, and the LPPR peptide sequence is known to strongly inhibit VEGF activity by binding to the VEGF receptor neuropilin-1. Here, the LPPR epitope is presented on a peptide amphiphile nanofiber system to benefit from multivalency and increase the anti-angiogenic function of the epitope. Peptide amphiphile nanofibers are especially useful for ocular delivery applications due to their ability to remain on the site of interest for extended periods of time, facilitating the long-term presentation of bioactive sequences. Consequently, the LPPR sequence was integrated into a self-assembled peptide amphiphile network to increase its efficiency in the prevention of neovascularization. Anti-angiogenic effects of the peptide nanofibers were investigated by using both in vitro and in vivo models. LPPR-PA nanofibers inhibited endothelial cell proliferation, tube formation, and migration to a greater extent than the soluble LPPR peptide in vitro. In addition, the LPPR-PA nanofiber system led to the prevention of vascular maturation and the regression of angiogenesis in a suture-induced corneal angiogenesis model. These results show that the anti-angiogenic activity exhibited by LPPR peptide nanofibers may be utilized as a promising approach for the treatment of corneal angiogenesis.

Diagnosis and management of acute appendicitis. EAES consensus development conference 2015.

Unequivocal international guidelines regarding the diagnosis and management of patients with acute appendicitis are lacking. The aim of the consensus meeting 2015 of the EAES was to generate a European guideline based on best available evidence and expert opinions of a panel of EAES members. After a systematic review of the literature by an international group of surgical research fellows, an expert panel with extensive clinical experience in the management of appendicitis discussed statements and recommendations. Statements and recommendations with more than 70 % agreement by the experts were selected for a web survey and the consensus meeting of the EAES in Bucharest in June 2015. EAES members and attendees at the EAES meeting in Bucharest could vote on these statements and recommendations. In the case of more than 70 % agreement, the statement or recommendation was defined as supported by the scientific community. Results from both the web survey and the consensus meeting in Bucharest are presented as percentages. In total, 46 statements and recommendations were selected for the web survey and consensus meeting. More than 232 members and attendees voted on them. In 41 of 46 statements and recommendations, more than 70 % agreement was reached. All 46 statements and recommendations are presented in this paper. They comprise topics regarding the diagnostic work-up, treatment indications, procedural aspects and post-operative care. The consensus meeting produced 46 statements and recommendations on the diagnostic work-up and management of appendicitis. The majority of the EAES members supported these statements. These consensus proceedings provide additional guidance to surgeons and surgical residents providing care to patients with appendicitis.

STEAP4 and HIF-1α gene expressions in visceral and subcutaneous adipose tissue of the morbidly obese patients.

AIM AND BACKGROUND: Obesity is a multifactorial disease in which environmental and genetic factors play an integrated role. Determining such target genes will help to elucidate the mechanisms underlying complex diseases such as obesity and diabetes which are usually seen together. Present study investigates the expression levels of STEAP4 and HIF-1α in visceral and subcutaneous adipose tissue. PATIENTS AND METHODS: 30(6M) morbidly obese patients undergoing bariatric surgery were included in the study. The patients were grouped according to the BMI as Group I (BMI <50kg/m(2)) and Group II (BMI ≥50kg/m(2)). Samples from visceral (omentum) and subcutaneous adipose tissues were obtained from each patient and real-time PCR (qPCR) was carried out for STEAP4 and HIF-1α gene expressions. Correlations between expression levels and clinical parameters were analyzed. RESULTS: Mean age of the patients recruited to the study was 37.4 (18-64) years. Mean BMI was 46 (36-60) kg/m(2). STEAP4 expression in visceral adipose tissue was significantly higher than subcutaneous tissue. Visceral STEAP4 expression was also found to be reduced with increased BMI. It was also lower in patients with HbA1C over 6. Furthermore, expression of subcutaneous and visceral HIF-1α was significantly higher in Group II. There was a significant correlation between BMI, glycosylated hemoglobin, STEAP4 and HIF-1α gene expression. CONCLUSIONS: Obesity and related disease are linked with the fact that there is a low grade inflammation in the adipose tissue of the obese individuals. Counter-regulatory processes such as STEAP4 protein family are overwhelmed by the proinflammatory stimuli. HIF-1α expression is increased due to tissue hypoxia and pro-inflammatory stimuli in the obese individuals, which results in increased visceral STEAP4 expressions.