Does Dry Eye Disease Severity Impact Efficacy of Varenicline Solution Nasal Spray on Sign and Symptom Treatment Outcomes?

SIGNIFICANCE: There is a clinical necessity for dry eye disease treatments that perform across a broad range of presenting patient severities. Varenicline solution nasal spray (VNS), a unique cholinergic agonist ocular surface-sparing nasal spray therapy, demonstrated significant improvement in both signs and symptoms of dry eye disease in subjects with mild, moderate, and severe symptoms as the clinical studies enrolled a more real-world patient population. PURPOSE: This study evaluated efficacy outcomes for VNS in patients with mild-moderate and severe dry eye disease. METHODS: An analysis of integrated data from two randomized clinical trials, ONSET-1 (NCT03636061) and ONSET-2 (NCT04036292) (vehicle control [VC], n = 294; VNS 0.03 mg, n = 308), was performed. Adults 22 years or older with dry eye disease, Ocular Surface Disease Index score of ≥23, corneal fluorescein staining score of ≥2 in ≥1 regions/≥4 all regions, and Schirmer Test Score (STS) of ≤10 mm (no restrictions on Eye Dryness Score [EDS]) were included in this study. Efficacy was evaluated using analysis of covariance among pre-specified subgroups of mild-moderate and severe baseline disease severity defined by STS (≤5 vs. >5) and EDS (<60 vs. ≥60). Consistency of effect was evaluated by interaction tests. RESULTS: No treatment-subgroup interactions were observed for all end points ( P > .05). The odds of achieving a ≥10-mm improvement in STS for VNS versus VC for patients with baseline STS ≤5 and >5 were 3.4(95% confidence interval, 2.0 to 5.6) and 2.3(1.3 to 4.0) and for EDS of <60 and ≥60 were 3.4(1.9 to 6.1) and 2.5(1.5 to 4.0). Least-squares mean treatment/VC differences in change from baseline in EDS for patients with baseline STS ≤5 or >5 were -7.4(95% confidence interval, -12.5 to -2.4) and -2.8(-8.7 to 3.1); EDS of <60 and ≥60 were -2.9(-8.3 to 2.5) and -8.1(-13.6 to -2.6). CONCLUSIONS: Compared with VC, VNS improved tear production and patient-reported symptoms in patients with dry eye disease, demonstrating consistency of effect regardless of initial presenting severity.

Improved Yield Prediction of Winter Wheat Using a Novel Two-Dimensional Deep Regression Neural Network Trained via Remote Sensing.

In recent years, the use of remotely sensed and on-ground observations of crop fields, in conjunction with machine learning techniques, has led to highly accurate crop yield estimations. In this work, we propose to further improve the yield prediction task by using Convolutional Neural Networks (CNNs) given their unique ability to exploit the spatial information of small regions of the field. We present a novel CNN architecture called Hyper3DNetReg that takes in a multi-channel input raster and, unlike previous approaches, outputs a two-dimensional raster, where each output pixel represents the predicted yield value of the corresponding input pixel. Our proposed method then generates a yield prediction map by aggregating the overlapping yield prediction patches obtained throughout the field. Our data consist of a set of eight rasterized remotely-sensed features: nitrogen rate applied, precipitation, slope, elevation, topographic position index (TPI), aspect, and two radar backscatter coefficients acquired from the Sentinel-1 satellites. We use data collected during the early stage of the winter wheat growing season (March) to predict yield values during the harvest season (August). We present leave-one-out cross-validation experiments for rain-fed winter wheat over four fields and show that our proposed methodology produces better predictions than five compared methods, including Bayesian multiple linear regression, standard multiple linear regression, random forest, an ensemble of feedforward networks using AdaBoost, a stacked autoencoder, and two other CNN architectures.

Gut Microbiome and Its Influence On Ocular Surface and Ocular Surface Diseases.

ABSTRACT: The gut microbiome plays a substantial immunologic and pathophysiologic role in maintaining the health of the host, and dysregulation of this dynamic ecosystem has been associated with several inflammatory conditions. Many studies have explored the influence of gut microbiota on the ocular surface and whether gut microbiota impact the pathophysiology of ophthalmic conditions. These findings have highlighted the advantages of enhancing gut microbes through probiotics, prebiotics, diet, vitamin supplementations, and fecal microbial transplant in clinical practice. The purpose of this review article was to provide an up-to-date overview of the knowledge on this topic. Further exploration of this area of research is important to help guide new therapeutic targets to develop treatment and prevention of certain ocular surface diseases.

Emerging therapies for dry eye disease.

INTRODUCTION: Dry Eye Disease (DED) is defined as a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and a vicious cycle of inflammation on the ocular surface. Despite its high prevalence and standing as one of the most common eye conditions seen by practitioners, the current treatment options available to patients have not proven adequate. AREAS COVERED: This review will discuss the burden of DED, its pathophysiology, as well as emerging therapies. These therapies include immunosuppressants, immunomodulators, anti-inflammatory drugs, and corticosteroids. The mechanisms of these drugs will be discussed, as well as their phase of development and results from recent clinical trials. The literature search was performed using PubMed, Cochrane Library, Web of Science, ClinicalTrials.gov, and the Springer AdisInsight database. EXPERT OPINION: The optimal therapy for DED is associated with improved bioavailability, minimal ocular side effects, and effective dosing. The ideal treatment has not yet been established, but this paper outlines a number of promising therapies. Continued development of therapies targeting the inflammation cascade, as well as the establishment of objective markers to quantify DED severity, are important aspects in the progression of treatment.

Radiotherapy versus combination radiotherapy-bevacizumab for the treatment of recurrent high-grade glioma: a systematic review.

BACKGROUND: High-grade gliomas (HGG) comprise the most common primary adult brain cancers and universally recur. Combination of re-irradiation therapy (reRT) and bevacizumab (BVZ) therapy for recurrent HGG is common, but its reported efficacy is mixed. OBJECTIVE: To assess clinical outcomes after reRT ± BVZ in recurrent HGG patients receiving stereotactic radiosurgery (SRS), hypofractionated radiosurgery (HFSRT), or fully fractionated radiotherapy (FFRT). METHODS: We performed a systematic review of PubMed, Web of Science, Scopus, Embase, and Cochrane databases, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We identified studies reporting outcomes for patients with recurrent HGG treated via reRT ± BVZ. Cohorts were stratified by BVZ treatment status and re-irradiation modality (SRS, HFSRT, and FFRT). Outcome variables were overall survival (OS), progression-free survival (PFS), and radiation necrosis (RN). RESULTS: Data on 1399 patients was analyzed, with 954 patients receiving reRT alone and 445 patients receiving reRT + BVZ. All patients initially underwent standard-of-care therapy for their primary HGG. In a multivariate analysis that adjusted for median patient age, WHO grade, RT dosing, reRT fractionation regimen, time between primary and re-irradiation, and re-irradiation target volume, BVZ therapy was associated with significantly improved OS (2.51, 95% CI [0.11, 4.92] months, P = .041) but no significant improvement in PFS (1.40, 95% CI [- 0.36, 3.18] months, P = .099). Patients receiving BVZ also had significantly lower rates of RN (2.2% vs 6.5%, P < .001). CONCLUSIONS: Combination of reRT + BVZ may improve OS and reduce RN rates in recurrent HGG, but further controlled studies are needed to confirm these effects.

Intratumor injection of CCL21-coupled vault nanoparticles is associated with reduction in tumor volume in an in vivo model of glioma.

PURPOSE: Glioblastoma (GBM) is the most common and malignant primary adult brain tumor. Current care includes surgical resection, radiation, and chemotherapy. Recent clinical trials for GBM have demonstrated extended survival using interventions such as tumor vaccines or tumor-treating fields. However, prognosis generally remains poor, with expected survival of 20 months after randomization. Chemokine-based immunotherapy utilizing CCL21 locally recruits lymphocytes and dendritic cells to enhance host antitumor response. Here, we report a preliminary study utilizing CPZ-vault nanoparticles as a vehicle to package, protect, and steadily deliver therapy to optimize CCL21 therapy in a murine flank model of GBM. METHODS: GL261 cells were subcutaneously injected into the left flank of eight-week-old female C57BL/6 mice. Mice were treated with intratumoral injections of either: (1) CCL21-packaged vault nanoparticles (CPZ-CCL21), (2) free recombinant CCL21 chemokine empty vault nanoparticles, (3) empty vault nanoparticles, or 4) PBS. RESULTS: The results of this study showed that CCL21-packaged vault nanoparticle injections can decrease the tumor volume in vivo. Additionally, this study showed mice injected with CCL21-packaged vault nanoparticle had the smallest average tumor volume and remained the only treatment group with a negative percent change in tumor volume. CONCLUSIONS: This preliminary study establishes vault nanoparticles as a feasible vehicle to increase drug delivery and immune response in a flank murine model of GBM. Future animal studies involving an intracranial orthotopic tumor model are required to fully evaluate the potential for CCL21-packaged vault nanoparticles as a strategy to bypass the blood brain barrier, enhance intracranial immune activity, and improve intracranial tumor control and survival.

Current and Future Pharmacological Therapies for the Management of Dry Eye.

Dry eye disease (DED) is among the most common reasons for visiting eye care practitioners and represents a substantial health and cost burden. Disease prevalence ranges from 5% to 33% and is increasing in the younger population. The core mechanism of DED involves a vicious cycle where hyperosmolarity leads to an inflammatory cascade resulting in ocular surface damage. No cure is available for DED, and patients require ongoing disease management. Over-the-counter medications can provide temporary symptom relief but do not tackle the inflammatory pathophysiology of DED. A number of medications with anti-inflammatory activity are available, but there is a need for development of pharmacotherapies with novel delivery methods and targets to widen the variety of treatment options. This review discusses current anti-inflammatory pharmacotherapies approved in the United States and Europe for DED and highlights novel drugs that have been recently approved or are in development.

Efficacy and Safety of OTX-101, a Novel Nanomicellar Formulation of Cyclosporine A, for the Treatment of Keratoconjunctivitis Sicca: Pooled Analysis of a Phase 2b/3 and Phase 3 Study.

BACKGROUND: OTX-101 (CEQUA™) is approved in the United States for treatment of keratoconjunctivitis sicca (KCS). This pooled analysis of 2 studies (phase 2b/3 and phase 3) evaluates the efficacy and safety of OTX-101 0.09% in the intent-to-treat (ITT) population and the subgroup of patients with a baseline Schirmer score less than 10 mm. METHODS: In these randomized, multicenter, double-masked, vehicle-controlled studies, patients received 1 drop of either OTX-101 or vehicle in both eyes twice daily. A Schirmer's test was performed at baseline and day 84/early discontinuation. Symptom Assessment iN Dry Eye (SANDE) scores and adverse events were monitored at each visit. RESULTS: The pooled analysis included 523 and 525 patients randomized to OTX-101 0.09% and vehicle, respectively. In the ITT population, 16.6% of eyes receiving OTX-101 and 9.0% of eyes receiving vehicle showed a day 84 increase in Schirmer score ≥10 mm from baseline (P<0.0001). In the subgroup with Schirmer score less than 10 mm at baseline, 18.7% and 10.2% of eyes receiving OTX-101 and vehicle, respectively, exhibited this outcome (P=0.0001). The mean (SD) percent change from baseline in global SANDE scores on day 84 in the ITT population was -29.0% (39.0%) and -30.4% (39.5%) for OTX-101 and vehicle groups, respectively. In the subgroup, the mean (SD) percent change was -27.3% (39.7%) and -31.4% (38.3%) for OTX-101 and vehicle groups, respectively. Adverse events were mostly mild to moderate. CONCLUSIONS: OTX-101 improved tear production compared with vehicle. Both OTX-101 and vehicle showed improved SANDE scores over baseline. OTX-101 was well tolerated in patients with KCS.

A Phase 3, Randomized, Double-Masked Study of OTX-101 Ophthalmic Solution 0.09% in the Treatment of Dry Eye Disease.

PURPOSE: To evaluate the safety and efficacy of OTX-101, a novel aqueous nanomicellar formulation of cyclosporine (0.09%), in the treatment of patients with dry eye disease (DED). DESIGN: A randomized, multicenter, vehicle-controlled, double-masked, phase 3 clinical trial. PARTICIPANTS: Adults (18-90 years of age) with a history and clinical diagnosis of DED, a global symptom score of 40 or more (range, 0-100), and a lissamine green conjunctival staining score of 3 or more and 9 or less (range, 0-12) in at least 1 eye. METHODS: Eligible patients entered a run-in period of 14 to 20 days in which all patients administered vehicle twice daily. Patients who remained eligible at the baseline (day 0) visit were randomized in a 1:1 ratio to twice-daily treatment with OTX-101 0.09% or vehicle for 84 days. MAIN OUTCOME MEASURES: Efficacy assessments included signs (unanesthetized Schirmer tear test, corneal and conjunctival staining) and symptoms (global symptom score) of DED. The primary end point was the proportion of eyes with a clinically meaningful improvement (increase of ≥10 mm) in Schirmer test score at day 84. Safety evaluations included adverse events (AEs), visual acuity, and intraocular pressure monitoring, slit-lamp, dilated ophthalmoscopy, and fundus examinations. RESULTS: A total of 744 patients were randomized and received study medication (371 to OTX-101 0.09% and 373 to vehicle). The primary end point was achieved; a significantly greater percentage of eyes in the OTX-101 0.09% treatment group achieved an increase of 10 mm or more in the Schirmer test score at day 84 (OTX-101 0.09%, 16.6%; vehicle, 9.2%; P < 0.001). Significant improvements relative to vehicle also were observed for corneal (days 28, 56, and 84) and conjunctival (days 56 and 84) staining. The global symptom score was reduced from baseline in both treatment groups by approximately 30%; however, no significant separation between groups was observed. The OTX-101 0.09% formulation was well tolerated. Treatment-emergent AEs were primarily mild in intensity. CONCLUSIONS: Clinically and statistically significant improvements in tear production and ocular surface integrity were observed in patients treated with OTX-101 0.09% for DED.

Surgery versus stereotactic radiosurgery for the treatment of multiple meningiomas in neurofibromatosis type 2: illustrative case and systematic review.

Neurofibromatosis type 2 (NF2) is a genetic neoplastic disorder that presents with hallmark bilateral vestibular schwannomas and multiple meningiomas. Though the current standard of care for meningiomas includes surgery, the multiplicity of meningiomas in NF2 patients renders complete resection of all developing lesions infeasible. Stereotactic radiosurgery (SRS) may be a viable non-invasive therapeutic alternative to surgery. We describe a particularly challenging case in a 39-year-old male with over 120 lesions who underwent more than 30 surgical procedures, and review the literature. We also searched three popular databases and compared outcomes of SRS versus surgery for the treatment of multiple meningiomas in patients with NF2. A total of 50 patients (27 radiosurgical and 23 surgical) were identified. For patients treated with SRS, local tumor control was achieved in 22 patients (81.5%) and distal control was achieved in 14 patients (51.8%). No malignant inductions were observed at an average follow-up duration of 90 months. Complications in the SRS-treated cohort were reported in 9 patients (33%). Eight patients (29.6%) died due to disease progression. Six patients experienced treatment failure and required further management. For NF2 patients treated with surgery, 11 patients (48%) showed tumor recurrence and 10 patients (43.5%) died due to neurological complications. SRS may be a safe and effective alternative for NF2-associated meningiomas. Further studies are required to identify the ideal radiosurgical candidate.

Radiosurgery treatment is associated with improved facial nerve preservation versus repeat resection in recurrent vestibular schwannomas.

BACKGROUND: Vestibular schwannomas (VSs) are benign neoplasms of the Schwann cells of cranial nerve VIII, and treatment of VS typically involves surgical resection. However, tumor recurrence may necessitate reintervention, and secondary treatment modalities include repeat surgical resection or adjuvant radiosurgery. The purpose of this study is to examine the scientific literature in order to determine whether surgical resection or radiosurgery for recurrent VS results in better tumor control, hearing preservation, and preservation of facial nerve function. METHODS: The PubMed, Scopus, Embase, Cochrane, and Web of Science databases were searched for studies reporting on patients undergoing either radiosurgery or repeat surgical resection after primary surgical resection for recurrent VS. Statistical analyses were performed on the compiled data, primarily outcome data involving tumor control, hearing preservation, and preservation of facial nerve function. RESULTS: We analyzed the data of 15 individual studies involving 359 total patients, and our results reveal that tumor control rates are comparable between adjuvant radiosurgery (91%, CI: 88-94%) and secondary resection (92%, CI 75-98%). However, adjuvant radiosurgery was shown to preserve good facial nerve function better (94%, CI 84-98%) compared to secondary surgical resection (56%, CI 41-69%). CONCLUSION: With comparable tumor control rates and better preservation of good facial nerve function, this study suggests that secondary radiosurgery for recurrent VS is associated with both optimal tumor control and preservation of good facial nerve function.

Herpes Zoster Ophthalmicus Review and Prevention.

Varicella-zoster virus (VZV) is the etiologic agent of both chickenpox and Herpes zoster (HZ). In the United States, there are around one million cases of HZ per year. Ten percent of HZ cases are subtyped as herpes zoster ophthalmicus (HZO) specifically and involve the V1 distribution. Herpes zoster ophthalmicus is a significant cause of blindness in the United States. This article will provide a basic overview of VZV, HZ, and HZO with a focus on preventative measures in an effort to prevent blindness through improving clinician awareness and education. The differences in clinical effectiveness and duration of effectiveness of the live (Zostavax) and recombinant vaccines (Shingrix) are illustrated. There is now a trend toward using the recombinant vaccine as recommended by the Advisory Committee for Immunization Practices (ACIP) for healthy adults 50 or older.

Posterior Parietal Cortex Guides Visual Decisions in Rats.

Neurons in putative decision-making structures can reflect both sensory and decision signals, making their causal role in decisions unclear. Here, we tested whether rat posterior parietal cortex (PPC) is causal for processing visual sensory signals or instead for accumulating evidence for decision alternatives. We disrupted PPC activity optogenetically during decision making and compared effects on decisions guided by auditory versus visual evidence. Deficits were largely restricted to visual decisions. To further test for visual dominance in PPC, we evaluated electrophysiological responses after individual sensory events and observed much larger response modulation after visual stimuli than auditory stimuli. Finally, we measured trial-to-trial spike count variability during stimulus presentation and decision formation. Variability decreased sharply, suggesting that the network is stabilized by inputs, unlike what would be expected if sensory signals were locally accumulated. Our findings suggest that PPC plays a causal role in processing visual signals that are accumulated elsewhere.SIGNIFICANCE STATEMENT Defining the neural circuits that support decision making bridges a gap between our understanding of simple sensorimotor reflexes and our understanding of truly complex behavior. However, identifying brain areas that play a causal role in decision making has proved challenging. We tested the causal role of a candidate component of decision circuits, the rat posterior parietal cortex (PPC). Our interpretation of the data benefited from our use of animals trained to make decisions guided by either visual or auditory evidence. Our results suggest that PPC plays a causal role specifically in visual decision making and may support sensory aspects of the decision, such as interpreting the visual signals so that evidence for a decision can be accumulated elsewhere.

The ecology of insect-yeast relationships and its relevance to human industry.

Many species of yeast are integral to human society. They produce many of our foods, beverages and industrial chemicals, challenge us as pathogens, and provide models for the study of our own biology. However, few species are regularly studied and much of their ecology remains unclear, hindering the development of knowledge that is needed to improve the relationships between humans and yeasts. There is increasing evidence that insects are an essential component of ascomycetous yeast ecology. We propose a 'dispersal-encounter hypothesis' whereby yeasts are dispersed by insects between ephemeral, spatially disparate sugar resources, and insects, in turn, obtain the benefits of an honest signal from yeasts for the sugar resources. We review the relationship between yeasts and insects through three main examples: social wasps, social bees and beetles, with some additional examples from fruit flies. Ultimately, we suggest that over the next decades, consideration of these ecological and evolutionary relationships between insects and yeasts will allow prediction of where new yeast diversity is most likely to be discovered, particularly yeasts with traits of interest to human industry.

Neuroglial ectopia of the vestibular nerve masquerading as a vestibular schwannoma: A case report.

Neuroglial ectopia is a rare entity of undetermined clinical significance. Here, we report a unique case of neuroglial ectopia of the vestibular nerve. A 27-year-old pharmacy student with a previous radiological diagnosis of vestibular schwannoma presented to our clinic for surgical evaluation. Magnetic resonance imaging (MRI) of the brain revealed a 17-mm T1 hypo- to isointense, T2 iso- to hyperintense, poorly enhancing left cerebellopontine angle mass extending into the left internal auditory canal compatible by imaging with a vestibular schwannoma. The lesion was resected under MRI guidance. The frozen specimen came back as a benign hypocellular lesion. Histological assessment revealed a peripheral nerve engulfed by glial fibrillary acidic protein-positive, S-100-negative cells, suggestive of neuroglial ectopia. There was no evidence of schwannoma. The main concerns were benign neoplasm with potential for progression or sampling artifact. The patient had an uncomplicated hospital course. This case report demonstrates an unusual case of neuroglial ectopia of the vestibular nerve. The differential diagnoses for a poorly enhancing cerebellopontine angle mass should include neuroglial ectopia.

Middle cranial fossa approach for the repair of superior semicircular canal dehiscence is associated with greater symptom resolution compared to transmastoid approach.

BACKGROUND: Superior semicircular canal dehiscence (SSCD) is a disorder of the skull base that is gaining increasing recognition among neurosurgeons. Traditionally, the middle cranial fossa (MCF) approach has been used for the surgical repair of SSCD. However, the transmastoid (TM) approach is an alternative strategy that has demonstrated promising results. METHODS: We performed independent searches of a popular database to identify studies that described outcomes following the surgical repair of SSCD through MCF and TM approaches. The primary outcome was symptom resolution. RESULTS: Our analysis included 24 studies that described 230 patients that underwent either an MCF (n = 148, 64%) approach or a TM (n = 82, 36%) approach for primary surgical repair of SSCD. A greater percentage of patients in the MCF group experienced resolution of auditory symptoms (72% vs 59%, p = 0.012), aural fullness (83% vs 55%, p = 0.049), hearing loss (57% vs 31%, p = 0.026), and disequilibrium (75% vs 44%, p = 0.001) when compared to the TM group. The MCF approach was also associated with higher odds of symptom resolution for auditory symptoms (odds ratio [OR] 1.79, 95% confidence interval [CI] 1.14-2.82), aural fullness (OR 4.02, 95% CI 1.04-15.53), hearing loss (OR 2.91, 95% CI 1.14-7.42), and disequilibrium (OR 3.94, 95% CI 1.78-8.73). The mean follow-up was 9 months. CONCLUSIONS: The literature suggests that the MCF approach for the repair of SSCD is associated with greater symptom resolution when compared to the TM approach. This information could help facilitate patient discussions.

Adenovirus Ocular Infections: Prevalence, Pathology, Pitfalls, and Practical Pointers.

Adenoviral conjunctivitis comprises a large number of physician office visits in the United States and places a great financial burden on health care. It is estimated that the incidence of adenovirus infection to be as high as 20 million cases per year in the United States. There are multiple adenovirus serotypes, each associated with different types and severity of infection. Ocular manifestations of adenovirus include epidemic keratoconjunctivitis, pharyngoconjunctival fever, and nonspecific conjunctivitis. Adenoviral conjunctivitis is primarily a clinical diagnosis. Laboratory diagnosis is available although until recently rarely used. At present, there is no established or approved specific effective drug against adenovirus. Treatment is primarily supportive and includes artificial tears and cool compresses. Topical antibiotics are only indicated if a bacterial coinfection is suspected or in high-risk patients such as children. Prevention against this extremely contagious disease is of utmost importance. Although most cases are self-limited and have a relatively benign course, permanent visual disability can occur. For this reason, it is imperative that all eye care providers are capable of diagnosing and effectively treating these patients, and also preventing the spread of this contagious disease to others.

Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial.

BACKGROUND: Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. METHODS: We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10-35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov number NCT01124838. FINDINGS: Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77-357) in the placebo group and 245 days (119-564) in the adalimumab group. Treatment failure occurred in 61 (55%) of 111 patients in the placebo group compared with 45 (39%) of 115 patients in the adalimumab group. Time to treatment failure was significantly improved in the adalimumab group compared with the placebo group (median not estimated [>18 months] vs 8·3 months; hazard ratio 0·57, 95% CI 0·39-0·84; p=0·004). The 40th percentile for time to treatment failure was 4·8 months in the placebo group and 10·2 months in the adalimumab group. No patients in either group had opportunistic infections (excluding oral candidiasis and tuberculosis). No malignancies were reported in the placebo group whereas one (1%) patient in the adalimumab group reported non-serious squamous cell carcinoma. The most common adverse events were arthralgia (12 [11%] patients in the placebo group and 27 [23%] patients in the adalimumab group), nasopharyngitis (16 [17%] and eight [16%] patients, respectively), and headache (17 [15%] patients in each group). INTERPRETATION: Adalimumab significantly lowered the risk of uveitic flare or loss of visual acuity upon corticosteroid withdrawal in patients with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by systemic corticosteroids. No new safety signals were observed and the rate of adverse events was similar between groups. These findings suggest that adalimumab is well tolerated and could be an effective treatment option in this patient population. An open-label extension study (NCT01148225) is ongoing to provide long-term safety data for adalimumab in patients with non-infectious uveitis. FUNDING: AbbVie.

Use of near-infrared spectroscopy (NIRs) in the biopharmaceutical industry for real-time determination of critical process parameters and integration of advanced feedback control strategies using MIDUS control.

Control of biopharmaceutical processes is critical to achieve consistent product quality. The most challenging unit operation to control is cell growth in bioreactors due to the exquisitely sensitive and complex nature of the cells that are converting raw materials into new cells and products. Current monitoring capabilities are increasing, however, the main challenge is now becoming the ability to use the data generated in an effective manner. There are a number of contributors to this challenge including integration of different monitoring systems as well as the functionality to perform data analytics in real-time to generate process knowledge and understanding. In addition, there is a lack of ability to easily generate strategies and close the loop to feedback into the process for advanced process control (APC). The current research aims to demonstrate the use of advanced monitoring tools along with data analytics to generate process understanding in an Escherichia coli fermentation process. NIR spectroscopy was used to measure glucose and critical amino acids in real-time to help in determining the root cause of failures associated with different lots of yeast extract. First, scale-down of the process was required to execute a simple design of experiment, followed by scale-up to build NIR models as well as soft sensors for advanced process control. In addition, the research demonstrates the potential for a novel platform technology that enables manufacturers to consistently achieve "goldenbatch" performance through monitoring, integration, data analytics, understanding, strategy design and control (MIDUS control). MIDUS control was employed to increase batch-to-batch consistency in final product titers, decrease the coefficient of variability from 8.49 to 1.16%, predict possible exhaust filter failures and close the loop to prevent their occurrence and avoid lost batches.

Multicenter Study of a Novel Topical Interleukin-1 Receptor Inhibitor, Isunakinra, in Subjects With Moderate to Severe Dry Eye Disease.

OBJECTIVES: Isunakinra, formerly known as EBI-005, is a novel interleukin (IL)-1 receptor inhibitor developed for topical treatment of patients with dry eye disease (DED). This phase 1b/2a multicenter, double-masked, randomized, vehicle controlled environmental trial assessed the safety and biological activity of isunakinra in patients with moderate to severe DED. METHODS: Subjects (N=74) were randomized to vehicle (placebo) or isunakinra (5 or 20 mg/mL) 3×/daily for 6 weeks. Evaluations included safety, tolerability, biological activity for signs (corneal fluorescein staining [CFS]), symptoms (pain or sore eyes and total Ocular Surface Disease Index [OSDI]), and reduction in rescue artificial tear use. RESULTS: Topical administration of isunakinra (5 and 20 mg/mL) was safe and well tolerated and resulted in clinically relevant improvements in symptoms (OSDI score, painful/sore eye component of OSDI) and signs (total CFS) compared with baseline with no dose response. OSDI scores improved from baseline by 38% (18.9 points) at 6 weeks and CFS scores improved by 33% (3 points) in the isunakinra groups. These changes were not statistically significant compared with the vehicle. Use of artificial rescue tears was significantly reduced in the isunakinra treatment groups (mean=9 vials) compared with vehicle (mean=31 vials). The differences between isunakinra and vehicle treatments were more pronounced in subjects with OSDI scores less than 50 at baseline. CONCLUSIONS: Isunakinra was safe, well tolerated and showed clinically meaningful improvements in signs and symptoms of DED. These results encouraged the design of an adequately powered study to characterize the safety and efficacy of isunakinra in ocular surface diseases.