Search

Recent success of established treatment has driven concerns about the ethics of using placebo-controlled trials in psychiatry. Active-controlled (superiority or non-inferiority) trials do not include a placebo-arm and thus avoid the associated ethical concerns but show disadvantages in other respects. The aim of this paper is to review the available literature and critically discuss the evidence regarding the use of placebo-controlled- versus active-controlled trials. A MEDLINE/PubMed and Google Scholar search was performed. Studies included focused on the deliberation on placebo-controlled- versus active-controlled trials. Twenty-six studies were included. The most cited benefits of placebo-controlled trials were greater scientific reliability of the results and no average impact on patients' health. Disadvantages were mainly related to withholding effective treatment and limited generalizability. The most frequent argument in favor of active-controlled trials is the lower chance of receiving ineffective medication during the trial. Downsides include larger sample sizes, higher costs and lower scientific reliability of results. Most authors agree that all trial designs are relevant to psychiatric research depending on study goals. Whatsoever, data does not support forgoing placebo-controlled trials. Expert consensus is warranted to permit drawing conclusions on the debate on the relevance of placebo-controlled trials.

To obtain complete DNA sequences of adenoviral (AdV) D8 genome from patients with conjunctivitis and determine the relation of sequence variation to clinical outcomes.This study is a post hoc analysis of banked conjunctival swab samples from the BAYnovation Study, a previously conducted, randomized controlled clinical trial for AdV conjunctivitis.Ninety-six patients with AdV D8-positive conjunctivitis who received placebo treatment in the BAYnovation Study were included in the study.DNA from conjunctival swabs was purified and subjected to whole-genome viral DNA sequencing. Adenovirus D8 variants were identified and correlated with clinical outcomes, including 2 machine learning methods.Viral DNA sequence and development of subepithelial infiltrates (SEIs) were the main outcome measures.From initial sequencing of 80 AdV D8-positive samples, full adenoviral genome reconstructions were obtained for 71. A total of 630 single-nucleotide variants were identified, including 156 missense mutations. Sequence clustering revealed 3 previously unappreciated viral clades within the AdV D8 type. The likelihood of SEI development differed significantly between clades, ranging from 83% for Clade 1 to 46% for Clade 3. Genome-wide analysis of viral single-nucleotide polymorphisms failed to identify single-gene determinants of outcome. Two machine learning models were independently trained to predict clinical outcome using polymorphic sequences. Both machine learning models correctly predicted development of SEI outcomes in a newly sequenced validation set of 16 cases (Adenovirus D8 has ≥ 3 prevalent molecular substrains, which differ in propensity to result in SEIs. Development of SEIs can be accurately predicted from knowledge of full viral sequence. These results suggest that development of SEIs in AdV D8 conjunctivitis is largely attributable to pathologic viral sequence variants within the D8 type and establishes machine learning paradigms as a powerful technique for understanding viral pathogenicity.

To evaluate the efficacy and safety of a nano-emulsion artificial tear (OM3) containing carboxymethylcellulose (CMC) and glycerin, flaxseed oil and castor oil, and three osmoprotectants (levocarnitine, erythritol, and trehalose) compared with an artificial tear (Refresh Optive Advanced [ROA]) containing the same ingredients with the exception of trehalose and flaxseed oil.In this multicenter, double-masked, randomized, two-arm, parallel-group, 6-visit study (screening, baseline, and days 7, 30, 60, and 90), subjects with dry eye disease underwent an open-label, 7-day run-in with CMC 0.5% (Refresh Plus), before 1:1 randomization to OM3 or ROA for 90 days (both instilled ≥2 daily). Ocular Surface Disease Index (OSDI; primary endpoint change from baseline at day 90), tear film breakup time (TBUT), and ocular staining (combined/corneal/conjunctival) were assessed; change from baseline in these parameters was calculated at each timepoint. Treatment-related adverse events (AEs) were assessed at each visit.Overall, 242 subjects were randomized (OM3, n = 120; ROA, n = 122). At day 90, significant improvements in OSDI, ocular staining and TBUT were evident in both treatment groups. Significant (P 0.05) between-group differences in favor of OM3 were observed for combined ocular staining (all timepoints), corneal staining (day 90), and conjunctival staining (day 30). Treatment-related AEs were higher in the ROA (9.8%) versus OM3 (6.7%) group; blurred vision was among the most commonly reported AE (OM3 0% vs ROA 4.1%).These findings support the application of OM3, a novel preservative-free, nano-emulsion tear formulation with trehalose and flaxseed oil, for the treatment of dry eye disease.

BACKGROUND: It is generally believed that multinodular goiter (MNG) is associated with a lower risk of malignancy compared to solitary thyroid nodules (STN). This will be the null hypothesis in this retrospective study and we aim to prove or reject it. METHODS: Medical files and histopathology reports of 600 patients who underwent thyroidectomy over 4-year period were reviewed. Data including patient’ age, gender, presentation, ultrasonography, FNAC, surgical procedures, final histopathologic diagnosis and stage of malignant tumors were collected and analyzed. The primary end point was assessment of risk of thyroid carcinoma in patients with MNG compared to those with STN. Secondary endpoints included demographic differences and prognosis. RESULTS: There were 459 females (76.5%). Mean age was 44.3 ± 14.5 years (range 14–85). After exclusion of 33 patients, 224 (39.5%) had STN and 343 (60.5%) had MNG. The prevalence of thyroid cancer was 41.1% (92/224) in STN compared to 29.2% (100/343) in MNG (Chi-Square = 8.593, p

To compare the intraocular pressure (IOP)-lowering efficacy and safety of netarsudil once daily (QD) and timolol twice daily (BID).Double-masked, randomized, phase 3, noninferiority study.Patients with open-angle glaucoma or ocular hypertension (unmedicated baseline IOP20 to30 mm Hg at 8:00 AM) were randomized to netarsudil ophthalmic solution 0.02% QD (PM) or timolol ophthalmic solution 0.5% BID. The primary endpoint was mean IOP at 8:00 AM, 10:00 AM, and 4:00 PM at week 2, week 6, and month 3 in patients with baseline IOP25 mm Hg (per-protocol population). Safety was recorded over the 6-month treatment period.A total of 186 patients from each treatment arm were included in the primary efficacy analysis. Netarsudil QD met the criteria for noninferiority to timolol BID. Mean treated IOP ranged from 16.3 to 17.9 mm Hg for netarsudil and 16.7 to 17.6 for timolol, with mean reductions from baseline of 3.9 to 4.7 mm Hg and 3.8 to 5.2 mm Hg, respectively. In prespecified secondary analyses, netarsudil demonstrated noninferiority to timolol in patients with baseline IOP27 mm Hg and30 mm Hg. The IOP-lowering effects of netarsudil were sustained over 6 months of treatment. No treatment-related serious adverse event (AE) was reported for either study drug. However, statistically significant reductions in mean heart rate were recorded at all study visits for the timolol group. The most frequent ocular AE among netarsudil-treated patients was conjunctival hyperemia (47.9%), which was predominately mild.Netarsudil QD (PM), a first-in-class IOP-lowering medication, was noninferior to timolol BID and was associated with tolerable ocular AEs.

Purpose To determine host and pathogen factors predictive of outcomes in a large clinical cohort with keratoconjunctivitis. Design Retrospective analyses of the clinical and molecular data from a randomized, controlled, masked trial for auricloscene for keratoconjunctivitis (NVC-422 phase IIB, NovaBay; clinicaltrials.gov identifier, NCT01877694). Participants Five hundred participants from United States, India, Brazil, and Sri Lanka with clinical diagnosis of keratoconjunctivitis and positive rapid test results for adenovirus. Methods Clinical signs and symptoms and bilateral conjunctival swabs were obtained on days 1, 3, 6, 11, and 18. Polymerase chain reaction (PCR) analysis was performed to detect and quantify adenovirus in all samples. Regression models were used to evaluate the association of various variables with keratoconjunctivitis outcomes. Time to resolution of each symptom or sign was assessed by adenoviral species with Cox regression. Main Outcome Measures The difference in composite scores of clinical signs between days 1 and 18, mean visual acuity change between days 1 and 18, and time to resolution of each symptom or sign. Results Of 500 participants, 390 (78%) showed evidence of adenovirus by PCR. Among adenovirus-positive participants, adenovirus D species was most common (63% of total cases), but a total of 4 species and 21 different types of adenovirus were detected. Adenovirus D was associated with more severe signs and symptoms, a higher rate of subepithelial infiltrate development, and a slower decline in viral load compared with all other adenovirus species. The clinical courses of all patients with non–adenovirus D species infection and adenovirus-negative keratoconjunctivitis were similar. Mean change in visual acuity between days 1 and 18 was a gain of 1.9 letters; worse visual outcome was associated with older age. Conclusions A substantial proportion of keratoconjunctivitis is not associated with a detectable adenovirus. The clinical course of those with adenovirus D keratoconjunctivitis is significantly more severe than those with non–adenovirus D species infections or adenovirus-negative keratoconjunctivitis; high viral load at presentation and non-United States origin of participants is associated with poorer clinical outcome.

After demonstration of the antihypertensive efficacy of the combination of the beta-blocker nebivolol and the angiotensin receptor blocker valsartan in an 8-week, randomized, placebo-controlled trial (N = 4161), we now report the effects of this treatment on the renin-angiotensin-aldosterone system in a substudy (n = 805). Plasma renin activity increased with valsartan (54%–73%) and decreased with nebivolol (51%–65%) and the combination treatment (17%–39%). Plasma aldosterone decreased with individual treatments (valsartan, 11%–22%; nebivolol, 20%–26%), with the largest reduction (35%) observed with maximum combination dose (20 mg nebivolol/320 mg valsartan). Baseline ln(plasma renin activity) correlated with the 8-week reductions in 24-hour systolic and diastolic BP following treatments with the combination (all doses combined, P = .003 and P

Here we present characterization of solution and thin film properties of Lissamine rhodamine B sulfonyl didodecyl amine (LRSD), an amphiphilic derivative of rhodamine. LRSD was synthesized by functionalizing Lissamine rhodamine B sulfonyl chloride (LRSC) with didodecylamine via a straightforward sulfonylation reaction. LRSD's long alkane chains make it highly soluble in chloroform, with a marked increase in brightness compared to the starting material. LRSD is shown to form well-defined robust micelles in water, without the addition of a co-surfactant and stable monolayers at the air–water interface. The greater lipophilicity of LRSD also enables doping into non-polar polymeric host matrices such as polystyrene with less aggregation and hence higher fluorescence quantum yield than LRSC or even rhodamine B. The monolayers of LRSD were prepared via Langmuir–Blodgett deposition and showed shifts in the photoluminescence peak from 575 nm to 595 nm, as the surface pressure is varied from 3 mN/m to 11 mN/m.

GNE myopathy is an autosomal recessive adult onset disorder caused by mutations in the GNE gene. GNE encodes the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetyl mannosamine kinase, the key enzyme in the biosynthesis pathway of sialic acid. Additional functions for GNE have been described recently, but the mechanism leading from GNE mutation to this myopathy is unclear. Therefore a gene therapy approach could address all potential defects caused by GNE mutations in muscle. We show that AAV8 viral vectors carrying wild type human GNE cDNA are able to transduce murine muscle cells and human GNE myopathy-derived muscle cells in culture and to express the transgene in these cells. Furthermore, the intravenous administration of this viral vector to healthy mice allows expression of the GNE transgene mRNA and of the coexpressed luciferase protein, for at least 6months in skeletal muscles, with no clinical or pathological signs of focal or general toxicity, neither from the virus particles nor from the wild type human GNE overexpression. Our results support the future use of an AAV8 based vector platform for a safe and efficient therapy of muscle in GNE myopathy.

Introduction Chronic inflammation is the primary pathological element of cancer development. Here we demonstrate a synthetic cyclic peptide ALOS4 capable of suppressing tumour growth following systemic administration and possessing anti-inflammatory properties. ALOS4 was initially isolated by phage display for its ability to bind αvβ3 integrin, possessing no functional activity of RGD peptides and characterised by tumour suppressor activity in preclinical xenograft and syngeneic models of melanoma. Importantly, ALOS4 displayed no signs of toxicity in treated animals even at the highest doses, which significantly exceeded optimal efficacious doses. In this study, we aimed to identify the mechanisms underlying the profound antitumor activity of this safe peptide. Material and methods We utilised a large panel of cell-based repeater assays designed to detect modulators of a variety of signalling pathways including p53-, NF-kB-, hypoxia, heat shock, irradiation and other types of stress responses. We also tested the effects of ALOS4 on tumour cell growth, adhesion, migration, clonogenicity, morphology and other in vitro properties. Results and discussions ALOS4 showed no detectable activity in most of these assays with some exceptions: first, ALOS4 treatment prevented weight lost in cancer bearing mice and second, ALOS4 suppressed the ability of treated cells to induce interferon type I signalling in response to double stranded RNA mimics (Poly I:C). Based on this observation, as well as negative in vitro cell-based assay results, we hypothesised that the antitumor effect of ALOS4 may be mediated by a systemic anti-inflammatory effect rather than by a direct effect on tumour cells. Consistent with this hypothesis, ALOS4 treatment dramatically modulated the abundance and content of the population of immunocytes infiltrating subcutaneously growing melanomas in mice. Conclusion These results suggest that ALOS4 can represent an anticancer agent with a new mechanism of activity that targets the tumor-supporting interferon-driven mechanism of tumor-host interaction and improves the overall condition of the mouse as a whole.

GNE Myopathy (formerly designated HIBM/DMRV) is a rare neuromuscular recessive disorder caused by missense mutations in GNE, the key enzyme of sialic acid biosynthesis. In order to unravel potential novel functions for GNE, we have analyzed interactions of GNE with other proteins by diverse methods. In these studies we have used bimolecular fluorescence complementation (BiFC) in living cells. By this method, we have validated in vivo interactions between GNE–GNE, between actinin and actinin, and between GNE and actinin in HEK293 cells transfected with the relevant expression vectors. To elucidate the interaction domains in GNE, we have applied the BiFC methodology with each of the 2 main domains of GNE, epimerase and kinase, in living cells, as well as with the mutations frequently found in GNE Myopathy patients, such as the Middle Eastern founder mutation M712T (designated M743T according to the novel recommended nomenclature). This method will be very valuable to elucidate the interaction domains (epimerase and kinase) between the GNE monomers and between GNE and actinins, as well as the potential of mutations to disrupt such interactions. These studies could contribute new understandings on the mechanism of GNE in health and disease.

GNE Myopathy is a unique neuromuscular disorder characterized by adult onset and slowly progressive distal and proximal muscle and a typical histology including rimmed vacuoles and filamentous inclusions. The disease is caused by recessive mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene (GNE), encoding the key enzyme in the biosynthetic pathway of sialic acid. (In an attempt to develop a possible treatment for GNE Myopathy patients.) We have established a platform for gene therapy trials based on adeno associated virus (AAV 8) vectors harboring the wild type human GNE gene driven by an MCK promoter. These viral constructs proved to be safe when injected systemically (tail vein) in healthy C57Bl6 mice. No mice presented any physical or behavioral change. All tissues analyzed for histology 35 days post infection showed no pathological findings. Real Time PCR analysis of the expression of human GNE showed it is expressed in all tissues analyzed, including skeletal muscles of the upper and lower limbs. This was confirmed by the expression of a control virus, where GNE was replaced by the luciferase gene, which showed luciferase expression disseminated in all organs. To assess the efficacy of the system, this AAV8/MCKGNE viral vectors are being assayed in the GNE Myopathy mouse model generated by Malicdan et al. (2007) We believe that the assessment of the effects of GNE viral delivery will be of great value by setting the stage for potential human trials.

GNE Myopathy (formerly designated HIBM/DMRV) is a rare neuromuscular recessive disorder caused by missense mutations in GNE, the key enzyme of sialic acid biosynthesis. We have previously shown that GNE interacts with alpha-actinin1 and alpha-actinin2 in vitro, either at different interaction sites on the GNE protein, or alternatively by changing the conformational state of GNE. In the current studies we have analyzed these interactions by the bimolecular fluorescence complementation (BiFC) analysis as a probe of protein interactions in living cells and now demonstrate these interactions also in vivo. In addition, to elucidate the interaction domains in GNE, we have dissected the GNE molecule, first in its 2 main domains, epimerase and kinase. We have generated those TAG proteins in the insect cells/baculovirus system and performed pull down and immunoprecipitation assays, also in the presence of both alpha-actinins. Furthermore, interactions of these “half domain” proteins were also analyzed in living cells by the BiFC methodology. The potential of frequent mutations in GNE myopathy, such as the Middle Eastern founder mutation M712T, to disrupt such interactions will be shown. These studies could contribute new understandings on the mechanism of GNE in health and disease.

GNE Myopathy (formerly designated HIBM/DMRV) is a rare neuromuscular recessive disorder caused by missense mutations in GNE, the key enzyme of sialic acid biosynthesis. To date, over 60 different mutations in GNE have been reported to cause the disease worldwide, but a single homozygous missense mutation M712T, is common in the Middle East. The mechanisms leading from GNE mutations to the disease are not yet understood. In an attempt to elucidate the pathophysiological pathway of the disease, we have searched for proteins potentially interacting with GNE. We have previously determined that GNE interacts with α -actinin1, one of the 4 α -actinins isoforms, a family of proteins binding the actin filaments. We studied the interactions of recombinant human GNE protein with other members of the actinin family, in particular α -actinin2 which is located at the Z-disk of the muscle fiber. Using a Surface Plasmon Resonance (SPR)-Biosensor based assay, we found that GNE, in its wild type and M712T mutated forms, also binds α -actinin 2. Furthermore, GNE binds α -actinin1 and α -actinin 2 differently, either at different interaction sites on the GNE protein, or alternatively, by changing the conformational state of GNE. GNE exists in different oligomeric forms, dimers, tetramers and hexamers, which are in a dynamic interplay in the cell. To evaluate the potential effect of common mutations found in GNE myopathy patients, on the oligomeric state of GNE protein, we have investigated GNE–GNE interactions and affinity, and found the highest affinity between wtGNE and wtGNE, the lowest between mutGNE–mutGNE, and intermediate affinity between wt and mutated GNE proteins. These differences could have a direct effect on both the oligomeric state of GNE and on the dynamic interplay between the oligomeric forms of the protein. These studies could contribute new understandings on the mechanism of GNE in health and disease.