Clinical Endpoint Studies Research Articles

Relationship Among Treatment, Pruritus, Investigator's Static Global Assessment, and Quality of Life in Patients with Atopic Dermatitis.

IntroductionThe Investigator’s Static Global Assessment (ISGA) is a 5-point rating scale that is recommended by the US Food and Drug Administration for assessing the severity of atopic dermatitis (AD), and ISGA success is a widely used endpoint in AD clinical studies. In this study, we seek to interpret the relationship of ISGA with treatment, pruritus, and quality of life (QoL) by conducting post hoc analyses of pooled data from two phase 3 crisaborole studies.MethodsPatients aged ≥ 2 years with baseline ISGA of 2 (mild) or 3 (moderate) were randomly assigned 2:1 to receive crisaborole or vehicle for 28 days. Disease severity, pruritus severity, and QoL were assessed with the ISGA, Severity of Pruritus Scale (SPS), and Dermatology Life Quality Index (DLQI; patients aged ≥ 16 years), or Children’s Dermatology Life Quality Index (CDLQI; patients aged 2–15 years), respectively. The effect of treatment on ISGA and the relationship between ISGA and QoL were analyzed using a longitudinal repeated-measures model. The interrelationship between treatment, disease severity, pruritus, and QoL was analyzed with a mediation model.ResultsOverall, 1522 patients (crisaborole, n = 1016; vehicle, n = 506) were included. Estimated longitudinal profiles indicated changes in ISGA by day 8 were large for crisaborole (effect size [ES]: − 0.68) and small for vehicle (ES: − 0.34). There was a direct relationship between ISGA and DLQI and CDLQI severity bands in the longitudinal repeated-measures model. For both QoL mediation models, treatment effects on QoL were mediated indirectly by reduction in pruritus (DLQI, 42.4%; CDLQI, 58.1%) and disease severity (DLQI, 12.2%; CDLQI, 33.1%).ConclusionsThese post hoc analyses suggest that ISGA success is a clinically meaningful endpoint associated with reduction in the severity of pruritus and improvement in QoL.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00506-y.

Physiologically-based pharmacokinetic modeling to support bioequivalence and approval of generic products: A case for diclofenac sodium topical gel, 1.

Establishing bioequivalence (BE) for dermatological drug products by conducting comparative clinical end point studies can be costly and the studies may not be sufficiently sensitive to detect certain formulation differences. Quantitative methods and modeling, such as physiologically‐based pharmacokinetic (PBPK) modeling, can support alternative BE approaches with reduced or no human testing. To enable PBPK modeling for regulatory decision making, models should be sufficiently verified and validated (V&V) for the intended purpose. This report illustrates the US Food and Drug Administration (FDA) approval of a generic diclofenac sodium topical gel that was based on a totality of evidence, including qualitative and quantitative sameness and physical and structural similarity to the reference product, an in vivo BE study with PK end points, and, more importantly, for the purposes of this report, a virtual BE assessment leveraging dermal PBPK modeling and simulation instead of a comparative clinical end point study in patients. The modeling approach characterized the relationship between systemic (plasma) and local (skin and synovial fluid) diclofenac exposure and demonstrated BE between the generic and reference products at the presumed site of action. Based on the fit‐for‐purpose modeling principle, the V&V process involved assessing observed data of diclofenac concentrations in skin tissues and plasma, and the overall performance of the modeling platform for relevant products. Using this case as an example, this report provides current scientific considerations on good practices for model V&V and the establishment of BE for dermatological drug products when leveraging PBPK modeling and simulation for regulatory decision making.

The association of histological progression with biochemical response to ursodeoxycholic acid in primary biliary cholangitis.

Primary biliary cholangitis (PBC) is currently diagnosed at an early stage; therefore, the number of patients with PBC without symptoms at the time of diagnosis is increasing. However, up to 30% of patients with PBC exhibit the suboptimal response to ursodeoxycholic acid (UDCA) and are at high risk of end-stage liver disease. Obeticholic acid is an approved second-line therapy for patients with PBC that are refractory to UDCA. Novel surrogate endpoints are required to identify individuals eligible for second-line therapies. An inadequate biochemical response to UDCA is a useful predictor of poor outcomes in patients with PBC. In addition to UDCA effects on biochemical parameters, histological outcomes could be considered as candidate surrogate endpoints. Alterations in liver histology are used as surrogate endpoints in clinical studies. However, current staging systems are insufficient to determine PBC disease severity and progression because of the pathological heterogeneity of the disease. Histological features at baseline and biochemical response to UDCA treatment can affect the disease course of PBC. Therefore, novel surrogate endpoints must be represented by parameters characterized by histological outcomes and treatment responses in PBC. In this review, we discuss the existing histological parameters and newly created factors to identify patients with PBC who are at a high risk of developing end-stage liver disease and, consequently, the potential need for additional treatments.

PIN161 Validation of a Sexual Quality of Life Questionnaire in HIV and Hepatitis C (PROQOL-SEXLIFE)

Existing tools for sexual life are focused on erectile dysfunction and do not measure other domains, such as stigma, fear of transmission, or satisfaction, that are important for people living with HIV/AIDS or Hepatitis C. A 46-item pilot questionnaire was created based on interviews and then validated. Subjects were included in 5 countries (Australia, Brazil, Canada, France, USA). Sociodemographic and clinical data were collected. Besides the PROQOL-Sexlife, subjects completed questionnaires on sexuality (MSHQ, SRQ, FSFI) and the generic SF-12. Analysis was performed according to 3 different language groups (English, French and Portuguese) and different population subgroups (HIV+, HCV+, women, men having sex with men (MSM) and heterosexual men. An analysis by hierarchical classification was performed to explain the differences of sexual orientation. 1164 subjects were included (Australia: 175; Brazil: 360; Canada: 102, France: 393; USA: 134). Their infections were: 673 HIV, 365 HCV, 126 co-infection HIV/HCV and 92 HIV/HBV. 63% were female. Mean age was 49. 639 subjects were heterosexual, 465 homosexual, and 57 bisexual. High floor/ceiling effect, inter-item correlation, cross-loading or no clear loading were reasons to delete 23 items. Confirmatory analyses revealed different structure according to sexual practice: 4-factor structure with 23 items for women, 5-factor (23 items) for heterosexual, and 6-factor (22) items for MSM. PROQOL-Sexlife and SF-12 and other scores were logically correlated according to the concepts captured. PROQOL-Sexlife analysis highlighted the impairment of sexual quality of life and different structure in sub-populations. The questionnaire specific to HIV and HCV is available for use as an endpoint in clinical trials and epidemiological studies.

Stages of Drusen-Associated Atrophy in Age-Related Macular Degeneration Visible via Histologically Validated Fundus Autofluorescence

To determine histologic correlates for stages of drusen-associated atrophy observed with fundus autofluorescence (FAF) and color fundus photography (CFP), of eyes with advanced age-related macular degeneration (AMD). Case study and clinicopathologic correlation. A white woman with AMD findings of inactive subretinal fibrosis (right eye) and untreated nonexudative type 1 macular neovascularization (left eye) was followed for 9 years before death at 90 years of age. Eyes preserved 6.25 hours after death were postfixed in osmium tannic acid paraphenylenediamine and were prepared for submicrometer epoxy resin sections (115 and 90 from the right and left eye, respectively), with 19 aligned to clinical B-scans. Drusen visible by CFP at the last visit were assigned to 4 stages ofFAF: stage 1, isoautofluorescence; stage 2, mildly uniform hyperautofluorescence; stage 3, a ring of hyperautofluorescence around a center of the hypoautofluorescence; and stage 4, uniform hypoautofluorescence. Light microscopic morphologic features at known FAF stages, including druse size, druse contents, and changes in overlying retinal pigment epithelium (RPE), photoreceptors, and external limiting membrane (ELM). Histologic examination of 166 drusen demonstrated that stage 1 isoautofluorescent drusen were visible on CFP. Hyperautofluorescence in stage 2 corresponded to short photoreceptors and complete coverage by RPE. Hypoautofluorescence in stages 3 and 4 corresponded to different extents of RPE atrophy (RPE gap and no RPE, respectively). Of stage 4 drusen, 67% showed no outer nuclear layer (ONL) and an undetectable ELM. Stage 4 included a high proportion of refractile drusen (82%) with many calcific nodules, visible on CFP. We present the first direct clinicopathologic correlation for FAF imaging of drusen-associated atrophy. Our data support 4 FAF stages of drusen-associated atrophy. Stage 2 is the earliest detected stage in which loss of screening by photoreceptor photopigment contributes to uniform hyperautofluorescence. Stages 3 and 4 comport with incomplete RPE and outer retinal atrophy as defined by the Classification of Atrophy Meetings group. Loss of RPE, ONL, and ELM in stage 4 indicates that atrophy can begin over individual drusen. Findings will help the identification of new therapeutic approaches and clinical study end points.

Time to Next Treatment as a Meaningful Endpoint for Trials of Primary Cutaneous Lymphoma.

Time to next treatment (TTNT) is an emerging endpoint in clinical studies of primary cutaneous T-cell lymphomas (CTCL), with utility as a surrogate marker for the “duration of clinical benefit”. TTNT provides a highly clinically meaningful endpoint that uniquely reflects not only the duration of treatment efficacy on disease and symptom control, but also incorporates the patient experience by accounting for patient compliance and tolerance to the studied therapy(s). Given the distinct challenges of pin-pointing the exact date of progression in patients with multi-compartmental CTCL, TTNT overcomes many of the shortcomings of conventional, disease-focused, clinical endpoints in primary CTCL research. Although widely accepted in clinical research for numerous other incurable malignancies, TTNT currently lacks a standardised definition. In this paper, we describe the value of TTNT as a clinical endpoint, review the applications of TTNT in primary CTCL research, and propose a standardised definition of TTNT to be applied in future clinical research of primary CTCL therapies.

Potentiality of Q3 characterization of nanosystem: Surrogate data for obtaining a biowaiver.

A tremendous increase in the entry of drug delivery systems (DDSs) based on nanotechnology has been observed as a result of the ability of pharmaceutical nanotechnology to overcome the various drawbacks related to the first generation DDS. The patent period of these proprietary branded drugs gives its manufacturers sole exclusivity of their product in the market. As the patent period of these products expire, the generic players will initiate their attempts to manufacture and bring generic versions of the reference listed drug product (RLD) into the market. The regulatory approval for a generic DDS based on nanotechnology requires proving the therapeutic equivalence of the generic product with that of the RLD via pharmacodynamics clinical endpoint study on healthy subjects or patients. These studies are extremely complex, expensive and time-consuming and may have uncertain outcomes. Furthermore, development, scale-up and manufacturing of generic versions of nanotechnology-based DDS involves complex steps and achieving an optimized formulation heavily depends on the process parameters during manufacturing. The information in this review addresses the said issues above and emphasizes on the possibility of using exhaustive in vitro characterization of the generic versions of nanotechnology-based DDSs in the current market to obtain a biowaiver. Various processes involved and their importance in obtaining an optimized formulation have been described to address the issue regarding manufacturing complexities.

Harmonization of Outcomes and Vision Endpoints in Vision Restoration Trials: Recommendations from the International HOVER Taskforce.

Translational research in vision prosthetics, gene therapy, optogenetics, stem cell and other forms of transplantation, and sensory substitution is creating new therapeutic options for patients with neural forms of blindness. The technical challenges faced by each of these disciplines differ considerably, but they all face the same challenge of how to assess vision in patients with ultra-low vision (ULV), who will be the earliest subjects to receive new therapies.Historically, there were few tests to assess vision in ULV patients. In the 1990s, the field of visual prosthetics expanded rapidly, and this activity led to a heightened need to develop better tests to quantify end points for clinical studies. Each group tended to develop novel tests, which made it difficult to compare outcomes across groups. The common lack of validation of the tests and the variable use of controls added to the challenge of interpreting the outcomes of these clinical studies.In 2014, at the bi-annual International “Eye and the Chip” meeting of experts in the field of visual prosthetics, a group of interested leaders agreed to work cooperatively to develop the International Harmonization of Outcomes and Vision Endpoints in Vision Restoration Trials (HOVER) Taskforce. Under this banner, more than 80 specialists across seven topic areas joined an effort to formulate guidelines for performing and reporting psychophysical tests in humans who participate in clinical trials for visual restoration. This document provides the complete version of the consensus opinions from the HOVER taskforce, which, together with its rules of governance, will be posted on the website of the Henry Ford Department of Ophthalmology (www.artificialvision.org).Research groups or companies that choose to follow these guidelines are encouraged to include a specific statement to that effect in their communications to the public. The Executive Committee of the HOVER Taskforce will maintain a list of all human psychophysical research in the relevant fields of research on the same website to provide an overview of methods and outcomes of all clinical work being performed in an attempt to restore vision to the blind. This website will also specify which scientific publications contain the statement of certification. The website will be updated every 2 years and continue to exist as a living document of worldwide efforts to restore vision to the blind.The HOVER consensus document has been written by over 80 of the world's experts in vision restoration and low vision and provides recommendations on the measurement and reporting of patient outcomes in vision restoration trials.

First approval of generic dry powder inhaler drug products in Japan.

The Japanese Ministry of Health, Labour and Welfare (MHLW) published the basic principles of bioequivalence evaluations for generic dry powder inhaler (DPI) drug products in March 2016. The basic principles were formulated to promote the development of effective and safe generic DPI drugs. Based on this document, the Pharmaceuticals and Medical Devices Agency (PMDA) advises generic companies on effective development through consultation meetings. The PMDA generally requires data from in vitro tests, pharmacokinetic studies, and pharmacodynamic or clinical endpoint studies for generic drug development. The MHLW approved the first generic version of the Symbicort Turbuhaler in 30- and 60-dose pack sizes in February 2019. This article presents the concrete data on the first approval of generic DPI drug products based on public information. Graphical abstract.

Givinostat: an emerging treatment for polycythemia vera

ABSTRACT Introduction Polycythemia vera (PV), a Philadelphia chromosome-negative myeloproliferative neoplasm, is characterized by panmyelosis, pancytosis, and a JAK2 mutation. Patients are at increased risk of thrombohemorrhagic events, and progression to myelofibrosis or acute leukemia. Current treatments include aspirin, phlebotomy, and cytoreductive drugs (most commonly hydroxyurea). Givinostat is a potent, class I/II histone deacetylase (HDAC) inhibitor that is in phase I/II clinical trials in PV. Givinostat was well tolerated and yielded promising clinico-hematological responses. A phase III study of givinostat versus hydroxyurea in high-risk PV patients is planned. Areas covered We present an overview of PV, current treatment guidelines, and the putative mechanism(s) of action of givinostat. We discuss the preclinical and clinical studies of givinostat in PV and briefly review approved and investigational competitor compounds. Expert opinion HDAC inhibitors have long been known to be active in PV, but chronic toxicities can be challenging. Givinostat, however, is active and well tolerated, and is entering a pivotal Phase III randomized trial. Givinostat offers the possibility of replacing hydroxyurea as the standard first-line cytoreductive choice for PV patients. This would completely change the current therapeutic paradigm and guidelines for PV management. Although surrogate clinical study endpoints may suffice for regulatory purposes, thrombosis reduction and prevention of disease progression remain most important to patients and clinicians.

Therapy of type 2 diabetes - Recommendations of the European Association for the Study of Diabetes (EASD)

New joint clinical recommendations for the treatment of patients with type 2 diabetes of the european (EASD) and american (ADA) diabetes associations and the european society for cardiology (ESC) implement the evidence from clinical cardiovascular endpoint studies into daily clinical practice. The individual patient profile and it´s cardiovascular risk rather than HbA1c levels alone dominate treatment strategies. In case of high oder very high cardiovascular risk GLP-1-receptor agonists or SGLT-2-inhibitors are the preferred choice, the latter especially in patients with chronic heart failure or increased risk, respectively.

Plasma oxalate levels in primary hyperoxaluria type I show significant intra-individual variation and do not correlate with kidney function.

Primary hyperoxalurias are rare diseases with endogenous overproduction of oxalate, thus leading to hyperoxaluria, hyperoxalemia, urolithiasis, and/or nephrocalcinosis and eventually early kidney failure. Plasma oxalate (POx) is an important diagnostic parameter in clinical studies on primary hyperoxaluria (PH). This is especially the case in kidney failure, where urinary parameters are no longer suitable. We aimed to evaluate whether POx would be an adequate endpoint for clinical studies in PH patients with stable kidney function. In addition, the correlation of POx to serum creatinine (SCr) and calculated glomerular filtration rate (eGFR) was examined. We retrospectively analyzed follow-up of individual POx values over time, as well as POx correlation to SCr, eGFR, and vitamin B6 (VB6), a common therapeutic in PH1. Results from 187 blood samples taken between 2009 and 2017, during routine laboratory evaluations from 41 patients with PH1 who had neither undergone dialysis nor transplantation, were evaluated. Negligibly low correlation coefficients (CCs) between POx vs. SCr (CC = -0.0950), POx vs. eGFR (CC = -0.1237), and POx vs. VB6 (CC = 0.1879) were found, with the exception of CKD stage 3a patients, who showed a positive correlation (CC of - 0.7329, POx vs eGFR).The intra-individual analysis of POx over time showed a high fluctuation of POx values. We conclude that POx has a limited validity as a primary endpoint for clinical studies in PH1 patients with stable kidney function. In addition, it does not correlate to SCr and eGFR in this group of patients.

Scientific and Regulatory Considerations for Efficacy Studies of Cytomegalovirus Vaccines.

The considerable public health burden due to cytomegalovirus (CMV) supports current interest in vaccine development. Clinical studies intended to support regulatory action should be designed to demonstrate substantial evidence of effectiveness. However, design and conduct of clinical endpoint studies may be hampered by low incidence of disease, especially for congenital CMV. Discussion and experience from other vaccines directed against congenital disease (including rubella and Zika) may be instructive. This article summarizes current scientific and US regulatory considerations related to design of studies of vaccines intended to prevent congenital CMV and complications of CMV in transplantation, as discussed at the 2018 workshop entitled "Cytomegalovirus Infection: Advancing Strategies for Prevention and Treatment."

He Frustration and Hope for Improved Clinical Study Endpoints for Anterior and Posterior Uveitis

he Frustration and Hope for Improved Clinical Study Endpoints for Anterior and Posterior Uveitis

Development and content validation of two new patient-reported outcome measures for endometriosis: the Endometriosis Symptom Diary (ESD) and Endometriosis Impact Scale (EIS)

BackgroundEndometriosis is a common, chronic, impactful condition in women of reproductive age. In the absence of established sensitive and specific biomarkers, disease severity is determined by patient-reported symptoms and impacts. This article details the development of two new patient-reported outcome (PRO) measures designed to assess efficacy endpoints in clinical studies: The Endometriosis Symptom Diary (ESD) and the Endometriosis Impact Scale (EIS).MethodsThe ESD and EIS were developed according to best practice and scientific standards (including the Food and Drug Administration (FDA) PRO Guidance) and with extensive input from women with surgically-confirmed endometriosis. Research included: a review of published qualitative literature; concept elicitation interviews in the US, Germany and France (n = 45) to explore the experiences of women with endometriosis and to inform ESD and EIS development; and cognitive interviews in the US and Germany (n = 31) to assess relevance and understanding of the ESD and EIS and usability of administration using an electronic handheld device. The FDA and the European Medicines Agency (EMA) as well as PRO and clinical experts were consulted throughout the process.ResultsPelvic pain was identified as the most frequent, severe and bothersome symptom for women with endometriosis. Pain was reported to be greatest during menstruation (dysmenorrhea) and during or after sexual intercourse (dyspareunia). Pain resulted in significant impairments in physical activities, work/study, social/leisure activities, household activities and sexual functioning. All women highlighted the emotional impact of endometriosis. Descriptions of pain and associated impacts were largely consistent across participants from the US and Europe, with the most notable differences being the words used to describe the location of pain (e.g., ‘pelvis’ vs. ‘abdomen’). Testing during cognitive interviews indicated that the ESD and EIS were well understood and consistently interpreted. Furthermore, all participants found the ePRO devices easy to use and no issues regarding visual presentation, selection of responses or navigation were identified.ConclusionsEvidence from extensive qualitative research supports the content validity of the ESD and EIS as patient-reported measures of the disease-defining symptoms of endometriosis and the associated impact on women’s lives. Future research will seek to establish the measurement properties of the measures.

564 Cardiac magnetic resonance myocardial feature tracking for optimized risk assessment after acute myocardial infarction in patients with type 2 diabetes

Abstract Objective Type 2 diabetes mellitus (T2DM) associates with worse cardiovascular outcome following acute myocardial infarction (AMI) as compared to non-diabetic patients. Since the mechanisms behind these observations are not fully understood we aimed to quantify the underlying pathophysiology on ventricular and atrial levels and study their prognostic implications using cardiovascular magnetic resonance (CMR) quantitative feature-tracking (FT) and tissue characterization. Research Design and Methods: A total of 1147 consecutive patients with AMI (n = 265 with diabetes; n = 882 without diabetes) undergoing cardiac magnetic resonance (CMR) imaging in median 3 days after AMI were included in this multicenter study. Left ventricular (LV) function and volumetry included LV ejection fraction (LV-EF), global longitudinal (GLS), radial (GRS) and circumferential strain (GCS) as well as left atrial (LA) strain and strain rate parameters of LA reservoir, conduit and booster pump function. LV damage assessment included infarct size (IS), edema and microvascular obstruction (MO). The clinical study endpoint was the rate of major adverse cardiovascular events (MACE) at 12 months. Results T2DM patients had impaired LA reservoir (19.8 vs. 21.2%, p < 0.01) and conduit strains 7.6 vs. 9.0%, p < 0.01) but no differences in ventricular function or myocardial damage. They were at higher risk of MACE than non-diabetic patients (10.2% vs. 5.8%, p < 0.01) with the majority of MACE occurring in patients with LVEF ≥ 35%. Whilst LVEF was an independent predictor of adverse events in non-diabetic patients (p = 0.04 on multivariable analysis), LV GLS as well as LA strain emerged as independent predictors of poor prognosis in patients with diabetes (p < 0.02 on multivariable analysis). Considering patients with diabetes and LVEF ≥35% (n = 237), GLS and LA reservoir strain below median were significantly associated with higher 12-month event rates. Conclusions In patients with diabetes, LA and LV longitudinal strain permit optimized risk assessment early after reperfused AMI with incremental prognostic value over and above LVEF.

Endpoint selection for noninferiority percutaneous coronary intervention trials: a methodological description.

Background:The objective of this review is to provide a practical update on endpoint selection for noninferiority (NI) studies in percutaneous coronary intervention studies.Methods:A PubMed search was conducted for predefined terms to explore the use of NI designs and intrapatient comparisons to determine their current importance. Sample size calculations for the most frequently used endpoints with NI hypotheses were done to increase statistical awareness.Results:Reported NI trials, with the most frequently chosen clinical endpoint of major adverse cardiac events (MACE), had NI margins ranging from 1.66% to 5.00%, resulting in patient populations of 400–1500 per treatment group. Clinical study endpoints comprising of MACE complemented with rates of bleeding complications and stent thrombosis (ST) are suggested to conduct a statistically and clinically meaningful NI trial. Study designs with surrogate endpoints amenable to intrapatient randomizations, are a very attractive option to reduce the number of necessary patients by about half. Comparative clinical endpoint studies with MACE and ST/bleeding rates to study a shortened dual antiplatelet therapy (DAPT) in coronary stent trials are feasible, whereas ST as the sole primary endpoint is not useful.Conclusions:Expanded composite clinical endpoints (MACE complemented by ST and bleeding rates and intrapatient randomization for selected surrogate endpoints) may be suitable tools to meet future needs in device approval, recertification and reimbursement.

A Randomized Open Label Parallel Group Clinical Study to Evaluate the Efficacy and Safety of Clevira in Fever of Viral Origin

Objective: To evaluate the efficacy and safety of Clevira, an ayurvedic formulation in fever of viral origin. Methods: This was a prospective, randomised, multicentre, open label, parallel group interventional clinical end point study. Patients attending general outpatient department, were screened for viral fever including Dengue by using the haematological, Biochemical and microbiological anti body assay for Dengue and NS1 (Non-structural protein) antigen testing. Forty eight patients who satisfied the selection criteria were enrolled in the study. Participants were randomized into 4 groups with 12 patients in each group. Patients were given standard treatment. In addition, Tab. Clevira of Apex laboratories Pvt. Ltd., was administered to test groups. Results: There is highly significant improvement (P<0.001) in the subjects Temperature, fever score, arthralgia score, Myalgia score, Headache and loss of appetite, suggesting a good Analgesic and anti pyretic activity of Clevira. There is a significant improvement in platelet count in the Clevira treated group (P<0.01) when compared to the control group, proving its efficacy in treating thrombocytopenia. The improvement (P<0.01) in the WBC count in the Clevira treated group depicts the anti viral property of Clevira. The overall quality of life was better in Clevira treated group compared to the control group. There were no serious adverse events reported. Conclusion: Clevira is safe and efficacious in reversing thrombocytopenia and thus normalizing the platelet counts and relieving the clinical signs and symptoms (fever, myalgia, arthralgia, headache) of Viral fever associated with thrombocytopenia and other cases of viral fever without thrombocytopenia. Clevira is having good anti-viral, antipyretic, analgesic and immunomodulatory property. Hence, Clevira should be used as an add on drug in patients with viral fever with or without thrombocytopenia for a rapid recovery without any adverse effects.

Assessment of age-related decline of neurovascular coupling responses by functional near-infrared spectroscopy (fNIRS) in humans.

Preclinical studies provide strong evidence that age-related impairment of neurovascular coupling (NVC) plays a causal role in the pathogenesis of vascular cognitive impairment (VCI). NVC is a critical homeostatic mechanism in the brain, responsible for adjustment of local cerebral blood flow to the energetic needs of the active neuronal tissue. Recent progress in geroscience has led to the identification of critical cellular and molecular mechanisms involved in neurovascular aging, identifying these pathways as targets for intervention. In order to translate the preclinical findings to humans, there is a need to assess NVC in geriatric patients as an endpoint in clinical studies. Functional near-infrared spectroscopy (fNIRS) is a non-invasive neuroimaging technique that enables the investigation of local changes in cerebral blood flow, quantifying task-related changes in oxygenated and deoxygenated hemoglobin concentrations. In the present overview, the basic principles of fNIRS are introduced and the application of this technique to assess NVC in older adults with implications for the design of studies on the mechanistic underpinnings of VCI is discussed.

ISOPT Clinical Hot Topic Panel Discussion on Uveitis and Inflammation.

For this "hot topic" session in uveitis we selected first and foremost an issue that puts our clinical work and research in "holding pattern." The issue is our method of evaluating the severity of uveitis. We posed the following questions to our esteemed panelists: 1.The relative significance of cells vs. flare in following uveitis patients 2.Cells/flare measurements 3.A glance into the future and the relevance of endpoints in clinical studies and their methodologies While there are different opinions in managing and monitoring uveitis patients, there seems to be an agreement on the high need of improving objective mode/s of reliably measuring both cells and flare and better understand their significance.