Evaluating the Effects of an Ophthalmic Solution of Coenzyme Q10 and Vitamin E in Open-Angle Glaucoma Patients: A Study Protocol Abstract Introduction The CoQun® study is a multicenter, controlled trial aimed to evaluate the neuroprotective effects of Coqun®, an ophthalmic solution of Coenzyme q10 (CoQ10) and Vitamin E (VitE), in patients affected by primary open-angle glaucoma (POAG). Pre-clinical studies and small non-controlled clinical trials have previously shown a potential role of CoQ10 and VitE in glaucoma neuroprotection, both in vitro and in vivo. Methods Randomized, parallel arm, multicenter, double-blind study. POAG patients with an IOP ranging from 17 to 21 mm Hg on monotherapy with a prostaglandin analogue (PGA) will be considered for study enrollment. Inclusion criteria will be visual field (VF) mean deviation between − 4 and − 10 dB and VF Pattern Standard Deviation between 4 and 10 dB. Eligible patients will be randomized to receive CoQun® (Arm A) or placebo (Arm B), in addition to PGA monotherapy. Planned Outcomes Primary outcome will be time to progression, defined as the time between the baseline visit and the visit with confirmed VF progression. A total of 612 patients are planned to be enrolled, to detect a hazard ratio of 0.65, with a power of 80% and an alpha error of 0.05 (two-sided). For study power calculation, 10% non-evaluable patients are assumed. This is the first study investigating, in a randomized, double-blind and controlled fashion, the neuroprotective effects of CoQ10 and VitE in POAG patients. Trial Registration ClinicalTrials.gov identifier, NCT03611530.

Reduced Environmental Impact of the Reusable Respimat ® Soft Mist™ Inhaler Compared with Pressurised Metered-Dose Inhalers Abstract Introduction Pressurised metered-dose inhalers (pMDIs) are associated with global warming potential values as they contain a hydrofluoroalkane (HFA) propellant, whereas the Respimat® Soft Mist™ inhaler is propellant-free. The original disposable Respimat has recently been updated to provide a reusable device that is similar in performance and use but is more convenient to patients and reduces environmental impact. This study compared the product carbon footprint (PCF) of Respimat (both disposable and reusable) and pMDIs to understand life cycle hotspots, and also to determine the potential quantitative environmental benefits of a reusable Respimat product. Methods PCFs of four inhalation products—tiotropium bromide (Spiriva®) Respimat, ipratropium bromide/fenoterol hydrobromide (Berodual®) Respimat, Berodual HFA pMDI and ipratropium bromide (Atrovent®) HFA pMDI—were assessed across their whole life cycle. Results Data show that Respimat inhalers have a lower PCF (carbon dioxide equivalent per kilogram) than HFA pMDIs: pMDI Atrovent 14.59; pMDI Berodual 16.48; disposable Spiriva Respimat 0.78; disposable Berodual Respimat 0.78. Approximately 98% of the pMDI life cycle total is due to HFA propellant emissions during use and end-of-life phases. The impact of the material used for the Respimat product outweighs the impact of the material used to make the empty cartridge. Furthermore, compared with the single-use device over 1 month, the PCF of Spiriva Respimat was further reduced by 57% and 71% using the device with refill cartridges over 3 and 6 months, respectively. Conclusion Together, these data suggest that Respimat inhalers, and in particular the new reusable inhaler, can reduce the environmental impact associated with inhaler use. Funding Boehringer Ingelheim.

Efficacy of Endovenous Laser Treatment Combined with Sclerosing Foam in Treating Varicose Veins of the Lower Extremities Abstract Introduction This study aims to investigate the efficacy of incision-free endovenous laser treatment (EVLT) combined with sclerosing foam in treating varicose veins of the lower extremities. Methods A total of 140 patients (186 limbs) who underwent laser closure of the great saphenous vein + injection sclerotherapy were included in the present study. Preoperative information, intraoperative conditions, duration of the operation, and length of hospital stay were recorded in detail. During the 6-month follow-up, the closure of the trunk and branches of the great saphenous vein, postoperative pain, the recovery of ulcer and dermatitis, and postoperative complications were traced. Results All patients were treated with laser closure of the great saphenous vein and lauromacrogol injection. Twenty-six stage C6 limbs (lower extremity with ulcer) healed within 6 months, and the postoperative subjective pain disappeared after 1 month. In six patients, pigmentation in the surgical site did not completely disappear at 6 months after the operation. Saphenous nerve injury was found in five patients within 3 months after the operation, and all healed at 6 months after the operation. Conclusion EVLT combined with sclerosing foam is effective for treating varicose great saphenous veins. Trial Registration This study was registered at http://www.chictr.org.cn (registration number: ChiCTR1900021409).

Assessment of Risk of Disease Progression in Pulmonary Arterial Hypertension: Insights from an International Survey of Clinical Practice Abstract Introduction Current guidelines for the management of pulmonary arterial hypertension (PAH) recommend regular multi-parametric assessment of a patient’s risk of clinical worsening or death, with the goal of achieving/maintaining a low-risk status. This international survey investigated how physicians currently assess risk and compared their clinical gestalt (judgement of risk) with the risk calculated using an algorithm based on the European Society of Cardiology (ESC)/European Respiratory Society (ERS) pulmonary hypertension guidelines and demonstrated to provide accurate mortality estimates. Methods PAH-treating physicians from Europe and the United States were surveyed on (1) how frequently they evaluated the recommended risk-assessment parameters and (2) to complete patient record forms (PRFs) with details on 5–7 recent adult PAH patients receiving treatment. For each PRF, physicians provided (1) their gestalt judgement of current risk and (2) details of the risk-assessment parameters measured. In accordance with the published method, measurements for ≥ 2 (of 6 selected) variables were required to calculate risk. Each variable was assigned a score of 1, 2 or 3 according to whether the measurement was within the thresholds for the low-, intermediate- or high-risk categories, as defined in the ESC/ERS guidelines. The average score represented the patient’s calculated risk. Results In total, 90 physicians (52 cardiologists, 38 pulmonologists) completed the survey, providing a total of 623 PRFs; of these, 365 (59%) included ≥ 2 measurements required to calculate risk. Among these patients, the percentages assigned to low-, intermediate- and high-risk categories based on gestalt/calculation were 32%/15%, 45%/68% and 22%/17%, respectively. Overall, there was concordance between the gestalt and calculated risk category for 45% of patients. The greatest level of disparity was for patients judged to be at low risk, where 80% were assigned to higher risk categories based on their calculated risk. Conclusions The results of this survey demonstrate that multi-parametric risk assessment is being performed in clinical practice, but not always to the extent recommended in the current guidelines. Further study on the utility of more regular measurement is required. Funding Actelion Pharmaceuticals Ltd.

An Evaluation of Longitudinal Measures of Anticholinergic Exposure for Application in Retrospective Administrative Data Analyses Abstract Introduction As continuous exposure to anticholinergics has been associated with adverse outcomes, accurately measuring exposure is important. However, no gold standard measure is available, and the performance of existing measures has not been compared. Our objective was to compare the properties of the Cumulative Anticholinergic Burden (CAB) measure against two existing measures of anticholinergic exposure and to assess their compatibility for use in observational studies based on claims data. Methods The average daily dose, cumulative dose and CAB measures were evaluated on: the applicability for use with anticholinergic burden scales, the ability to consider duration and/or accumulation of exposure, and consideration of anticholinergic dose, potency, and residual effect. To calculate each measure empirically, Truven MarketScan claims data from 2012 to 2015 were analyzed. Cumulative anticholinergic exposure over 1-year post-enrollment was calculated for each measure using Anticholinergic Cognitive Burden scale scores. Median [interquartile range (IQR)] and ranges of measure scores, and Spearman’s correlation coefficients between measures, were estimated. Due to the differing methods of calculation, the absolute values of each score cannot be compared. Results The properties of the different measures varied, with only the CAB considering both dose and theoretical potency. The cohort included 99,742 individuals (mean age = 73.1 years; 54.9% female). Among individuals prescribed anticholinergics (n = 55,969), 1-year median (IQR) scores based on average daily dose, cumulative dose and CAB measures were 0.9 (0.3–1.5), 16.9 (7.3–33.9) and 203 (68–500), respectively. Measures were highly inter-correlated (r2 = 0.74-0.83). Conclusions Considering both potency and dose, the CAB may prove a more comprehensive measure of anticholinergic burden; however, additional research is necessary to demonstrate whether it has any association with relevant health-related outcomes. Funding Astellas Pharma Global Development, Inc.

The Proteins of Keratoconus: a Literature Review Exploring Their Contribution to the Pathophysiology of the Disease Abstract Introduction Keratoconus (KC) is a complex, genetically heterogeneous multifactorial degenerative disorder characterized by corneal ectasia and thinning. Its incidence is approximately 1/2000–1/50,000 in the general population. KC is associated with moderate to high myopia and irregular astigmatism, resulting in severe visual impairment. KC structural abnormalities primarily relate to the weakening of the corneal collagen. Their understanding is crucial and could contribute to effective management of the disease, such as with the aid of corneal cross-linking (CXL). The present article critically reviews the proteins involved in the pathophysiology of KC, with particular emphasis on the characteristics of collagen that pertain to CXL. Methods PubMed, MEDLINE, Google Scholar and GeneCards databases were screened for relevant articles published in English between January 2006 and June 2018. Keyword combinations of the words “keratoconus,” “risk factor(s),” “genetics,” “genes,” “genetic association(s),” “proteins”, “collagen” and “cornea’’ were used. In total, 272 articles were retrieved, reviewed and selected, with greater weight placed on more recently published evidence. Based on the reviewed literature, an attempt was made to tabulate the up- and down-regulation of genes involved in KC and their protein products and to delineate the mechanisms involved in CXL. Results A total of 117 proteins and protein classes have been implicated in the pathogenesis and pathophysiology of KC. These have been tabulated in seven distinct tables according to their gene coding, their biochemistry and their metabolic control. Conclusion The pathogenesis and pathophysiology of KC remain enigmatic. Emerging evidence has improved our understanding of the molecular characteristics of KC and could further improve the success rate of CXL therapies.

Current Practices for Outpatient Initiation of Levodopa-Carbidopa Intestinal Gel for Management of Advanced Parkinson’s Disease in the United States Abstract In 2015, the US Food and Drug Administration approved levodopa-carbidopa intestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension in the US) for the treatment of motor fluctuations in patients with advanced Parkinson’s disease. LCIG provides a continuous infusion of levodopa and carbidopa by means of a portable pump and percutaneous endoscopic gastrojejunostomy tube. The delivery system has a two-fold pharmacokinetic advantage over orally administered carbidopa/levodopa. First, levodopa is delivered in a continuous rather than intermittent, pulsatile fashion. Second, delivery to levodopa’s site of absorption in the jejunum bypasses the stomach, thereby avoiding issues with erratic gastric emptying. In blinded prospective clinical trials and observational studies, LCIG has been shown to significantly decrease “off” time, increase “on” time without troublesome dyskinesia, and reduce dyskinesia. Consistent with procedures in previous studies, LCIG initiation and titration in the pivotal US clinical trial were performed in the inpatient setting and followed a standardized protocol. In clinical practice, however, initiation and titration of LCIG have a great degree of flexibility and, in the US, almost always take place in the outpatient setting. Nonetheless, there remains a significant amount of clinician uncertainty regarding titration in outpatient clinical practice. This review aims to shed light on and provide guidance as to the current methods of titration in the outpatient setting, as informed by the medical literature and the authors’ experiences. Funding AbbVie, Inc. Plain Language Summary Plain language summary available for this article.

Clinical Characteristics and Glycemic Outcomes of Patients with Type 2 Diabetes Requiring Maximum Dose Insulin Glargine/Lixisenatide Fixed-Ratio Combination or Insulin Glargine in the LixiLan-L Trial Abstract Introduction iGlarLixi is a titratable, fixed-ratio combination of insulin glargine (iGlar, 100 units/ml) and the glucagon-like peptide-1 receptor agonist lixisenatide for the treatment of patients with type 2 diabetes. This post hoc analysis of the phase 3 LixiLan-L trial (NCT02058160) investigated baseline characteristics, glycemic control, and safety outcomes in participants who received the study-specified maximum dose (60 units/day) of iGlarLixi or iGlar vs. those who received < 60 units/day. Methods Outcomes were compared for participants receiving 60 or < 60 units/day at week 30. Endpoints analyzed included change in A1C, fasting plasma glucose (FPG), 2-h postprandial glucose (2-h PPG), body weight, proportion of participants achieving A1C < 7.0%, proportion of participants receiving rescue therapy, documented symptomatic hypoglycemia, and gastrointestinal adverse event (GI AE) incidence. Results By week 30, 27% (iGlarLixi) and 31% (iGlar) of participants received the maximum dose. Participants on 60 vs. < 60 units/day were younger and had higher body weight, body mass index (BMI), FPG, and baseline insulin dose. In both dose groups, A1C change from baseline was significantly greater with iGlarLixi vs. iGlar, and more participants treated with iGlarLixi vs. iGlar achieved A1C < 7.0%. No significant differences were observed in change from baseline for A1C, FPG, 2-h PPG, or GI AE incidence between insulin dose groups, regardless of treatment. In both treatment arms, incidence of symptomatic hypoglycemia was lower in participants receiving 60 units/day vs. those receiving < 60 units/day. Participants treated with iGlarLixi (< 60 or 60 units/day) had modest weight loss over 30 weeks vs. an increase in weight compared with iGlar. Conclusions Maximum doses of iGlarLixi were required in participants with a more insulin-resistant clinical phenotype (younger, higher BMI, FPG, and insulin doses). Benefits were observed with iGlarLixi vs. iGlar, even at 60 units/day, with more participants achieving glycemic goals, no increase in symptomatic hypoglycemia, and a modest reduction in body weight. Funding Sanofi US, Inc.

A Comprehensive Update of Current Anesthesia Perspectives on Therapeutic Hypothermia Abstract Normal thermal regulation is a result of the integration of afferent sensory, central control, and efferent responses to temperature change. Therapeutic hypothermia (TH) is a technique utilized during surgery to protect vital organs from ischemia; however, in doing so leads to other physiological changes. Indications for inducing hypothermia have been described for neuroprotection, coronary artery bypass graft (CABG) surgery, surgical repair of thoracoabdominal and intracranial aneurysms, pulmonary thromboendarterectomy, and arterial switch operations in neonates. Initially it was thought that induced hypothermia worked exclusively by a temperature-dependent reduction in metabolism causing a decreased demand for oxygen and glucose. Induced hypothermia exerts its neuroprotective effects through multiple underlying mechanisms including preservation of the integrity and survival of neurons through a reduction of extracellular levels of excitatory neurotransmitters dopamine and glutamate, therefore reducing central nervous system hyperexcitability. Risks of hypothermia include increased infection risk, altered drug pharmacokinetics, and systemic cardiovascular changes. Indications for TH include ischemia-inducing surgeries and diseases. Two commonly used methods are used to induce TH, surface cooling and endovascular cooling. Core body temperature monitoring is essential during induction of TH and rewarming, with central venous temperature as the gold standard. The aim of this review is to highlight current literature discussing perioperative considerations of TH including risks, benefits, indications, methods, and monitoring.

Evaluation of Safety and Efficacy of Growth Hormone Therapy by IGF-1 Z Score in Children with Short Stature Abstract Introduction This study aims to explore the safety and efficacy of growth hormone (GH) therapy by retrospectively analyzing the changes of insulin-like growth factor-1 (IGF-1) Z-scores in children with short stature after treatment with GH. Methods The etiology of 104 children with short stature was classified according to the GH stimulation test and IGF-1 levels: (1) growth hormone deficiency (GHD); (2) mild growth hormone deficiency (M-GHD); (3) idiopathic short stature (ISS); (4) GH insensitivity syndrome (GHIS). In addition, all patients were treated with recombinant human growth hormone (rhGH) for 12 months, and the growth rate (Gv), height, body mass, bone age, height standard deviation scores (HtSDS), IGF-1 and adverse reactions were compared among these three groups before and after treatment. Results The height, body mass, Gv and HtSDS were significantly higher in each group compared with those before treatment. Furthermore, the Z-score of IGF-1 significantly increased after 1 month of GH treatment and was positively correlated with the dosage of GH. Moreover, the difference in standard deviation score was significantly positively correlated with the increase in standard deviation score of IGF-1. Conclusion The detection of the GH-IGF-1 axis function can be carried out for the etiologic diagnosis of short stature. IGF-1 increased after rhGH treatment, and IGF-1 level was correlated to the time of therapy and dosage of GH. IGF-1-based GH dosing targeted to age- and gender-adjusted means may save medical costs and offer a more dose-sparing and potentially safer mode of therapy compared with traditional weight-based dosing.