Efficacy and Safety of a Novel Broad-Spectrum Anti-MRSA Agent Levonadifloxacin Compared with Linezolid for Acute Bacterial Skin and Skin Structure Infections: A Phase 3, Openlabel, Randomized Study.

BACKGROUND: Levonadifloxacin is a novel broad-spectrum anti-MRSA agents belonging to the benzoquinolizine subclass of quinolone. It is developed for oral or intravenous administration for the treatment of infections caused by Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA). OBJECTIVES: To establish the non-inferiority of levonadifloxacin compared with linezolid for the treatment of acute bacterial skin and skin structure infections (ABSSSI) and to compare the safety of the two antimicrobials. SUBJECTS AND METHODS: This was a Phase 3, multicentre, randomized, open-label, active- comparator study with 500 subjects. Oral levonadifloxacin 1000 mg was compared with oral linezolid 600 mg whereas IV levonadifloxacin 800mg was compared with IV linezolid 600 mg, each treatment was administered twice daily for 7-10 days. Non-inferiority was evaluated by comparing oral levonadifloxacin to oral linezolid and IV levonadifloxacin to IV linezolid for overall clinical response at TOC (Test of Cure) Visit. RESULTS: The clinical cure rates observed at the TOC in the mITT (modified Intent to treat) populations for levonadifloxacin was numerically higher compared to linezolid in the IV sub-group [(91.0% verses 87.8%); treatment difference of 3.2% (95%CI, -4.5 to 10.9)] and in the oral sub-group (95.2% versus 93.6%); treatment difference of 1.6 % [95%CI, -4.2 to 7.3]). As the lowerbound of the 95% CI around the treatment difference was greater than -15% for both subgroups, the primary objective of the study was met. Therefore, both IV levonadifloxacin and oral levonadifloxacin were non-inferior to IV linezolid and oral linezolid, respectively. The majority of subjects in the micro-ITT population had a baseline infection caused by S. aureus with approximately 30% of subjects having MRSA. Levonadifloxacin (IV and oral) had a higher clinical cure rate at TOC for MRSA patients compared with linezolid (IV and oral), (95.0% vs. 89.3% respectively). Levonadifloxacin showed evidence of favourable clinical and microbiological efficacy in subjects with concurrent bacteraemia as well as in subjects with diabetes including diabetic foot infections caused by Gram-positive pathogens including MRSA. Pharmacokinetic analysis showed that bioavailability of oral levonadifloxacin was 90% and similar pharmacokinetic profile of levonadifloxacin by both routes provide an option for IV to oral switch for the treatment of subjects. Incidences of treatment-emergent adverse events (TEAEs) were similar between treatment groups and between IV (20.8% vs. 22.4%, for levonadifloxacin and linezolid, respectively) and oral therapy (16.0% vs. 13.5%, respectively), There were no SAEs or deaths related to study drug and the majority of the AEs observed were mild in nature. Overall, the administration of both IV and oral levonadifloxacin was well-tolerated in subjects with ABSSSI. CONCLUSIONS: The results demonstrate that IV and oral levonadifloxacin therapy has excellent clinical activity against MRSA and offers advantage compared to other quinolones which generally lack MRSA coverage. Levonadifloxacin is safe and well tolerated in the treatment of ABSSSI caused by Gram -positive pathogens including MRSA as well as non-inferior to IV and oral linezolid, respectively. Similar pharmacokinetic profile of IV and oral levonadifloxacin provides an option for IV to oral switch for the treatment of subjects. Both oral and IV levonadifloxacin have recently been granted approval in India for the treatment of ABSSSI including diabetic foot infections and concurrent bacteraemia in adults (18 years of age or older). ClinicalTrials.gov Registration: NCT03405064. CTRI No.: CTRI/2017/06/008843.

Mosaic variant in ATP2C1 presenting as relapsing linear acantholytic dermatosis.

Relapsing linear acantholytic dermatosis (RLAD) is a rare disease that manifests as recurring episodes of crusted and vesicular lesions distributed in a Blaschkoid pattern with histology resembling Hailey-Hailey disease. RLAD, in the presence of generalized disease, has been shown to be a type 2 mosaic form of Hailey-Hailey disease. RLAD, without systemic disease, has been hypothesized to be type 1 mosaic Hailey-Hailey disease, but this assertion has lacked genetic conformation. To determine the genetic abnormalities causing RLAD, we performed exome sequencing of affected tissue and blood in one patient. Exome sequencing of a punch biopsy revealed a c.238A>T, p.(Lys80*) variant in ATP2C1 found in 26% of the reads from lesional skin but absent in germline DNA. This somatic variant causes a truncated protein that would likely result in loss of function. Our findings indicate that, in this patient, RLAD is a clinical presentation of type 1 segmental Hailey-Hailey disease. What's already known about this topic? Relapsing linear acantholytic dermatosis (RLAD) is postulated to be a mosaic form of Hailey-Hailey disease. This hypothesis has remained unproven for type 1 disease and the putative gene and driving genetic variants have remained unknown. What does this study add? Exome sequencing, performed on lesional skin and matched blood, found RLAD lesions to be mosaic for variants causing a premature stop codon in ATP2C1. Our findings support the hypothesis that RLAD is a type 1 segmental form of Hailey-Hailey disease caused by postzygotic variants in ATP2C1.

Langmuir probe electronics upgrade on the tokamak à configuration variable.

A detailed description of the Langmuir probe electronics upgrade for TCV (Tokamak à Configuration Variable) is presented. The number of amplifiers and corresponding electronics has been increased from 48 to 120 in order to simultaneously connect all of the 114 Langmuir probes currently mounted in the TCV divertor and main-wall tiles. Another set of 108 amplifiers is ready to be installed in order to connect 80 new probes, built in the frame of the TCV divertor upgrade. Technical details of the amplifier circuitry are discussed as well as improvements over the first generation of amplifiers developed at SPC (formerly CRPP) in 1993/1994 and over the second generation developed in 2012/2013. While the new amplifiers have been operated successfully for over a year, it was found that their silicon power transistors can be damaged during some off-normal plasma events. Possible solutions are discussed.

Application of 1-methylcyclopropene on mango fruit (Cv. Kesar): potential for shelf life enhancement and retention of quality.

The present investigation was carried out to study the effect of gaseous application of 1-methylcyclopropene (1-MCP) on quality and shelf life of mango fruits of Cv. Kesar. The freshly harvested matured mango fruits were washed, cleaned and treated with fungicide at 500 ppm concentration for 10 min. The fruits were then subjected to 1-MCP treatment at different concentrations (500, 1000, 1500, 2000 ppb) and exposed for 18 and 24 h at 20 °C temperature in an air tight chamber along with control sample. The results indicated that the ripening in the early stages of mango was delayed by 1-MCP and shelf life of the fruits was increased with increase in the concentration of 1-MCP, also the physico-chemical changes such as percent physiological loss in weight of fruit, total soluble solids and colour was slowly increased and ascorbic acid content was effectively reduced. 1-MCP treatment of 2000 ppb for 24 h exposure time gave the best results for percent physiological loss in weight of fruit from 6.1 to 13% and ascorbic acid content from 80.28 to 22.34 mg/100 g, total soluble solids increased from 7.3 to 16.23 °Brix and the colour was improved from 50.9 to 68.6 h with shelf life of 20 days.

Efficacy and timing of adjunctive therapy in the anti-VEGF treatment regimen for macular oedema in retinal vein occlusion: 12-month real-world result.

PurposeVarious combination treatment regimens have been tried to improve the short-term efficacy of intravitreal monotherapy for the treatment of macular oedema (MO) secondary to retinal vein occlusion (RVO). Our study introduces the RandOL protocol (Ranibizumab and Ozurdex with Laser photocoagulation) of initial anti-VEGF therapy, controlling recurrent non-ischaemic MO with an intravitreal steroid and applying laser therapy to non-perfused retina. We describe our 12-month follow-up experience on timing for adjunctive therapy and real-world effectiveness and safety data.MethodsA retrospective analysis was carried out on 66 consecutive treatment-naive RVO patients with MO who received our RandOL treatment regimen. Baseline visual acuity (VA) and central retinal thickness (CRT) were compared with 12-month result.ResultsAt 12 months, 77% had significant VA improvement, 52% had ≥3-line improvement, and 15% were worse. Significant improvements in CRT were observed in 97% (baseline median CRT=531 µm (IQR 435-622) reduced to 245 µm (IQR 221-351, P<0.001) at 12 months); 76% achieved a dry fovea at 1 year. Mean number of total injections required was 5.5 (range 2-11) and 6% required ≥9 injections in 1 year. Although 70% received additional Ozurdex, 82% received ≥1 sessions of laser therapy. The BRVO subgroup achieved better VA and CRT improvement at 1 year, but small numbers limit definitive statistical conclusions.ConclusionsOur real-world results using a combination treatment protocol for RVO-related MO achieved similar desirable anatomical and visual outcomes as with a single-agent therapy with less intravitreal re-treatment rates at first year. Randomised controlled studies are needed to evaluate the role of laser and the ideal timing of combination therapy.

Report of 12-months efficacy and safety of intravitreal fluocinolone acetonide implant for the treatment of chronic diabetic macular oedema: a real-world result in the United Kingdom.

PurposeTo report the 12-months visual and anatomical outcomes of chronic diabetic macular oedema (DMO) treated with ILUVIEN in a real-world clinical practice in a single tertiary referral centre.MethodRetrospective data collection and analysis of consecutive 28 eyes of 23 diabetic patients received ILUVIEN implant for refractory DMO. Standard assessment included visual acuity (VA), central retinal thickness (CRT), slit-lamp biomicroscopy, and Goldmann tonometry for intraocular pressure (IOP) at 1, 6, and 12 months.ResultsBaseline mean VA was 47 (SD 18) letters improved to 55 (SD 17) letters (P=0.004) at 12 months. VA was improved in 16 eyes (57%), stabilised in 9 eyes (32%), and decreased in 3 eyes (11%). Seven eyes (25%) gained ≥15 letters, and 10 eyes (36%) gained >10 letters from baseline. The percentage of eyes achieved driving vision (≥70 Early Treatment Diabetic Retinopathy Study letters) was doubled from baseline 18 to 36% at 6 months and 32% at 12 months. Mean CRT decreased by 198 µm from baseline 494 µm (SD 191) to 296 µm (SD 121) at 12 months (P<0.001). Two eyes received additional anti-vascular endothelial growth factor injections after 10 months. COMPLICATIONS: Raised IOP in three eyes (11%) controlled with IOP-lowering drops, vitreous haemorrhage in one eye and one endophthalmitis (1 year vision improved to 6/24).ConclusionOur real-world results show that the visual and the anatomical improvements achieved by a single ILUVIEN implant injection were maintained up to 12 months with minimal adjunctive therapy. IOP monitoring remains essential in ILUVIEN patients, although our study shows a relatively low risk of IOP elevation post ILUVIEN injection, even in existing controlled ocular hypertension. Our results demonstrate that ILUVIEN is an effective long-term option in treating chronic refractory DMO.

Surveillance of acute respiratory infections in Mumbai during 2011-12.

PURPOSE: Acute respiratory infections (ARIs) are a leading cause of morbidity and mortality in individuals aged less than 5 years. ARI often leads to hospitalisation, and it has been indicated that causative viral and bacterial infections go undetermined and results in the occurrence of resistant strains. The objective of the study was to assess the prevalence of various viral and bacterial infections in patients with ARIs. MATERIALS AND METHODS: Two hundred samples were collected from July 2011 to July 2012 with patients suffering from ARI. Viral and bacterial infections were determined by real time reverse transcriptase polymerase chain reaction. RESULTS: Influenza-like illness (ILI) consisted of 109 patients and ARI consisted of 91 patients. Pandemic influenza A H1N1 was the major viral infection with 21 (19.2%) patients in ILI as compared with 16 (17.4%) patients in ARI. Respiratory syncytial virus (RSV) was found to be 1 (0.9%) in ILI and ARI. Viral co-infections were 16 (14.4%) in ILI and 4 (4.37%) in ARI where pandemic influenza A H1N1 and influenza type B were major contributors. In bacterial infections, Streptococcus pneumoniae with 11 (10.9%) cases were predominant in both the groups. Bacterial co-infection accounted for only 1 (1.09%) case in both the groups but the most significant finding was the viral-bacterial co-infection in which Haemophilus influenzae was the major co-infecting bacteria with the influenza viruses with 4 (4.36%) cases as compared with Streptotoccus pneumoniae. CONCLUSION: This data indicate the need to undertake continued surveillance that will help to better define the circulation of respiratory viruses along with the bacterial infections.

Technology for the manufacture of Diabetic Rosogolla.

Diabetic Rosogolla was manufactured by using low-fat cow milk. Six different combinations viz. type of chhana and two different concentrations (40° and 50° Brix) of cooking medium. All of the experimental samples and control were analyzed for physico-chemical, textural, and sensory properties. A 40° Brix concentration of cooking medium was preferred to give a highly acceptable Diabetic Rosogolla. The average composition of Diabetic Rosogolla is moisture-52.20%, fat-4.46%, protein-12.78%, sorbitol-29.66%, and ash-0.89%. Similarly, the rheological properties were hardness-7.85 N, cohesiveness-0.54, springiness-6.06 mm, gumminess-3.8 N, chewiness-26.07 Nmm, fracture force-4.1 N, adhesiveness-0.0272 Nmm, and stiffness-2.17 N/mm. This protocol can be adopted at commercial level and be used to serve the customers who desire fewer calories but cannot resist having the sweets after their meal.

Is it necessary to use three mandatory loading doses when commencing therapy for neovascular age-related macular degeneration using bevacizumab? (BeMOc Trial).

PURPOSE: To determine whether a Pro Re Nata (PRN) regimen with three initial mandatory loading doses results in better functional and anatomical outcome compared with a PRN regimen without initial loading when using intravitreal bevacizumab in patients with minimal classic or occult choroidal neovascularisation secondary to age-related macular degeneration. METHODS: Patients were randomised (1 : 1) to Loading (LD group) or No Loading (NLD group) and treated with open label intravitreal bevacizumab. In the LD group, patients received two mandatory doses after the baseline dose before entering the PRN phase and in the NLD group, patients did not receive mandatory doses after the baseline dose. Six-weekly evaluations were performed up to week 54 and retreatment was done based on OCT criteria. Visual stability and reduction in central retinal thickness were compared between groups. RESULTS: 49 patients were in the NLD group and 50 patients were in the LD group. At the 12-month end point, 84% of the patients in the LD group achieved visual stability (<15 letter loss) compared with 67% of the patients in the NLD group (P<0.05). The mean reduction in central macular thickness was 105.35 µm in the LD group and 81.45 µm in the NLD group (P>0.05). There was no significant difference in scores of VFQ-25 questionnaire testing between the two groups and no serious ocular or systemic side effects were observed. CONCLUSION: The results supported our hypothesis that a loading dose leads to slightly better visual stability in terms of proportions of patients experiencing moderate visual loss, but did not support the hypothesised difference in anatomical outcome.

Plasma radiation dynamics with the upgraded Absolute Extreme Ultraviolet tomographical system in the Tokamak à Configuration Variable.

We introduce an upgraded version of a tomographical system which is built up from Absolute Extreme Ultraviolet-type (AXUV) detectors and has been installed on the Tokamak à Configuration Variable (TCV). The system is suitable for the investigation of fast radiative processes usually observed in magnetically confined high-temperature plasmas. The upgrade consists in the detector protection by movable shutters, some modifications to correct original design errors and the improvement in the data evaluation techniques. The short-term sensitivity degradation of the detectors, which is caused by the plasma radiation itself, has been monitored and found to be severe. The results provided by the system are consistent with the measurements obtained with the usual plasma radiation diagnostics installed on TCV. Additionally, the coupling between core plasma radiation and plasma-wall interaction is revealed. This was impossible with other available diagnostics on TCV.

A molecular insight into the role of inflammation in the behavior and pathogenesis of odontogenic cysts.

BACKGROUND: Although, odontogenickeratocyst (OKC) and dentigerous cyst (DC) are considered asdevelopmental cysts inflammation has been seen in its connective tissue wall. Inflammation is seen to alter the epithelial lining of both OKC and DC butwhether it plays in altering the behavior of these cysts is not fully understood. AIM: The present study is conducted with the help of molecular marker proliferating cellular nuclear antigen (PCNA) to assess the proliferative activity of OKC and DC and to further evaluate and correlate the effect of inflammation on the proliferative activity and hence on biological behavior of these cysts. MATERIALS AND METHODS: Immunohistochemicalstaining was performed using anti-PCNA antibody in 10 cases each of classical OKC, inflamed OKC, classical DC, and inflamed DC. The resulting data was tabulated on Microsoft excel and subjected to statistical analysis using two-way analysis of variance test, t test and post-hoc test followed by Bonferroni test with the application of statistical package for social sciences (SPSS) (SPSS, Chicago, IL, USA) and Epi-Info 6.04 d, Atlanta, Georgia (USA). RESULTS: Total mean PCNA expression is statistically higher in inflamed OKC than classical OKC and inflamed DC also showed significantly higher PCNA expression than classical DC (P < 0.001). Correlation between inflammation and PCNA expression was not statistically significant (P ≥ 0.05). CONCLUSION: Inflammation is responsible for change in behavior of neoplastic epithelium of OKC, whereas in dentigerous it is responsible for changes in epithelial lining and hence should be treated meticulously.

Simple liquid chromatography-tandem mass spectrometry method for determination of novel anti-methicillin-resistant Staphylococcus aureus fluoroquinolone WCK 771 in human serum.

A simple, rapid, specific, precise, accurate and sensitive method for determination of WCK 771 in human serum has been developed. The method uses high performance liquid chromatography with tandem mass spectrometric detection. Sample preparation involves protein precipitation method by addition of acetonitrile. Gatifloxacin was used as internal standard. The response was found to be linear from 0.312 to 40 microg/ml of serum with correlation coefficient greater than 0.99. Limit of detection and lower limit of quantification for WCK 771 was found to be 0.078 microg/ml and 0.312 microg/ml, respectively. The intra-day precision and accuracy from analysis of quality control (QC) samples at four concentrations was in the range of 2.36-2.58% and from 96.71 to 103.2%, respectively. The inter-day precision and accuracy from analysis of quality control samples at four concentrations was in the range of 3.14-6.82% and from 96.84 to 105.76%, respectively. WCK 771 was found to be stable for 24 h at auto-injector environment. WCK 771 was also found to be stable for 2h in serum at 25+/-3 degrees C and for 3 months at -20 degrees C. Mean absolute recovery at four different concentrations was 86.92% with standard deviation of 1.79. Throughput of the method is approximately one sample every 4 min. The method was also reproduced with monkey serum. The method was employed for estimation of drug serum levels during pre-clinical and clinical trials.

Disappearing saccular intracranial aneurysms: do they really disappear?

SUMMARY: Evolution and natural history of cerebral aneurysms is a dynamic process. Spontaneous regression in size or complete disappearance of an aneurysm is a known phenomenon, more commonly noted in giant intracranial aneurysms. However, reappearance or regrowth of such aneurysms is rare with few anecdotal reports. We report a series of four cases including one giant aneurysm, which either disappeared or regressed on sequential angiograms. Regrowth or reappearance of two of these previously disappeared or regressed aneurysms was noted and endovascularly treated while the other two cases are being followed up. The decision to follow up was crucial considering the nature of the aneurysms to change in morphology under the influence of various hemodynamic factors.

Orbital Cysticercosis: Comparing Multi-Slice CT and Steady State MR to Identify Scolex.

Orbital cysticercosis with both ocular and extraocular involvement is common in endemic areas. The presence of scolex is considered diagnostic of cysticercosis. We sought to compare multi-slice CT and 3D steady state MR in the identification of scolex in orbital cysticercosis. Three patients with orbital cysticercosis (two extra-ocular, one ocular) were studied using multi-slice CT with thin coronal and sagittal reformations and 3D steady state MR (CISS 3D - Constructive Interference in Steady State) sequence.

Does salvage and tranexamic acid reduce the need for blood transfusion in revision hip surgery?

We carried out a retrospective case-control study in 80 patients who underwent a revision total hip replacement. Group A (40 patients) received tranexamic acid and intra-operative cell salvage. Group B (40 patients) was a matched control group and did not receive this management. Each group was divided into four subgroups: revision of both components, revision of both components with bone grafting, revision of the acetabular component with or without bone graft, and revision of the femoral component with or without bone graft. In group A the total number of units transfused was 52, compared with 139 in group B, representing a reduction in blood usage of 62.5%. The mean amount of blood transfused from cell salvage in each group was 858 ml (113 to 2100), 477 ml (0 to 2680), 228 ml (75 to 315) and 464 ml (120 to 1125), respectively. There was a significant difference in the amount of blood returned between the groups (p < 0.0001). In group A, 22 patients needed transfusion and in group B, 37 (p < 0.0001). A cost analysis calculation showed a total revenue saving of pounds sterling 70 000 and a potential saving throughout our facility of pounds sterling 318 288 per year. Our results show that a significant reduction in blood transfusion can be made using combined cell salvage and tranexamic acid in revision surgery of the hip.