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.

Synthesis, In silico and Biological Studies of Thiazolyl-2h-chromen-2-one Derivatives as Potent Antitubercular Agents.

BACKGROUND: A series of new six thiazolyl-2-amine-based Schiff base derivatives (4a-4f) were synthesized by a sequential multistep reaction starting with Salicylaldehyde. METHODS: All the Schiff base derivatives were screened in-vitro for their antibacterial activity against Mycobacterium tuberculosis (H37RV strain) ATCC No-27294. The synthesized compounds were characterized by FTIR, 1H-NMR, 13C-NMR and Mass spectrometry. RESULTS: Among the compounds tested, 4c and 4f derivatives exhibited potent antitubercular activity against M. tuberculosis at MIC 6.25 µg/mL. CONCLUSION: We extended our study to explore the inhibition mechanism by conducting molecular docking analysis by using Schrodinger's molecular modeling software. All the newly synthesized compounds were found to be in-silico AMES test non-toxic and non-carcinogens. The good Qikprop's Absorption, Distribution, Metabolism and Excretion (ADMET) would definitely help the researchers in order to make more potent Anti-TB agents.

The Novel ß-Lactam Enhancer Zidebactam Augments the In Vivo Pharmacodynamic Activity of Cefepime in a Neutropenic Mouse Lung Acinetobacter baumannii Infection Model.

WCK 5222 is a combination of cefepime and the high-affinity PBP2-binding ß-lactam enhancer zidebactam. The cefepime-zidebactam combination is active against multidrug-resistant Gram-negative bacteria, including carbapenemase-expressing Acinetobacter baumannii The mechanism of action of the combination involves concurrent multiple penicillin binding protein inhibition, leading to the enhanced bactericidal action of cefepime. The aim of the present study was to assess the impact of the zidebactam-mediated enhanced in vitro bactericidal action in modulating the percentage of the time that the free drug concentration remains above the MIC (percent fT>MIC) for cefepime required for the in vivo killing of A. baumannii Cefepime and cefepime-zidebactam MICs were comparable and ranged from 2 to 16 mg/liter for the A. baumannii strains (n = 5) employed in the study. Time-kill studies revealed the improved killing of these strains by the cefepime-zidebactam combination compared to that by the constituents alone. Employing a neutropenic mouse lung infection model, exposure-response analyses for all the A. baumannii strains showed that the cefepime fT>MIC required for 1-log10 kill was 38.9%. In the presence of a noneffective dose of zidebactam, the cefepime fT>MIC requirement dropped significantly to 15.5%, but it still rendered a 1-log10 kill effect. Thus, zidebactam mediated the improvement in cefepime's bactericidal effect observed in time-kill studies, manifested in vivo through the lowering of cefepime's pharmacodynamic requirement. This is a first-ever study demonstrating a ß-lactam enhancer role of zidebactam that helps augment the in vivo activity of cefepime by reducing the magnitude of its pharmacodynamically relevant exposures against A. baumannii.

RAF inhibitor LY3009120 sensitizes RAS or BRAF mutant cancer to CDK4/6 inhibition by abemaciclib via superior inhibition of phospho-RB and suppression of cyclin D1.

KRAS, NRAS and BRAF mutations are among the most important oncogenic drivers in many major cancer types, such as melanoma, lung, colorectal and pancreatic cancer. There is currently no effective therapy for the treatment of RAS mutant cancers. LY3009120, a pan-RAF and RAF dimer inhibitor advanced to clinical study has been shown to inhibit both RAS and BRAF mutant cell proliferation in vitro and xenograft tumor growth in vivo. Abemaciclib, a CDK4/6-selective inhibitor, is currently in phase III studies for ER-positive breast cancer and KRAS mutant lung cancer. In this study, we found that combinatory treatment with LY3009120 and abemaciclib synergistically inhibited proliferation of tumor cells in vitro and led to tumor growth regression in xenograft models with a KRAS, NRAS or BRAF mutation at the doses of two drugs that were well tolerated in combination. Further in vitro screen in 328 tumor cell lines revealed that tumor cells with KRAS, NRAS or BRAF mutation, or cyclin D activation are more sensitive, whereas tumor cells with PTEN, PIK3CA, PIK3R1 or retinoblastoma (Rb) mutation are more resistant to this combination treatment. Molecular analysis revealed that abemaciclib alone inhibited Rb phosphorylation partially and caused an increase of cyclin D1. The combinatory treatment cooperatively demonstrated more complete inhibition of Rb phosphorylation, and LY3009120 suppressed the cyclin D1 upregulation mediated by abemaciclib. These results were further verified by CDK4/6 siRNA knockdown. Importantly, the more complete phospho-Rb inhibition and cyclin D1 suppression by LY3009120 and abemaciclib combination led to more significant cell cycle G0/G1 arrest of tumor cells. These preclinical findings suggest that combined inhibition of RAF and d-cyclin-dependent kinases might provide an effective approach to treat patients with tumors harboring mutations in RAS or RAF genes.

Incidence of Postoperative Pain after Single Visit and Two Visit Root Canal Therapy: A Randomized Controlled Trial.

INTRODUCTION: Root Canal Treatment (RCT) has become a mainstream procedure in dentistry. A successful RCT is presented by absence of clinical signs and symptoms in teeth without any radiographic evidence of periodontal involvement. Completing this procedure in one visit or multiple visits has long been a topic of discussion. AIM: To evaluate the incidence of postoperative pain after root canal therapy performed in single visit and two visits. MATERIAL AND METHODS: An unblinded/ open label randomized controlled trial was carried out in the endodontic department of the Dental Institute, where 78 patients were recruited from the regular pool of patients. A total of 66 maxillary central incisors requiring root canal therapy fulfilled the inclusion and exclusion criteria. Using simple randomization by biased coin randomization method, the selected patients were assigned into two groups: group A (n=33) and group B (n=33). Single visit root canal treatment was performed for group A and two visit root canal treatment for group B. Independent sample t-test was used for statistical analysis. RESULTS: Thirty three patients were allotted to group A where endodontic treatment was completed in single visit while 33 patients were allotted to group B where endodontic treatment was completed in two visits. One patient dropped-out from Group A. Hence in Group A, 32 patients were analysed while in Group B, 33 patients were analysed. After 6 hours, 12 hours and 24 hours of obturation, pain was significantly higher in Group B as compared to Group A. However, there was no significant difference in the pain experienced by the patients 48 hours after treatment in both the groups. CONCLUSION: Incidence of pain after endodontic treatment being performed in one-visit or two-visits is not significantly different.

Evaluation of Emblica officinalis fruit powder as a growth promoter in commercial broiler chickens.

AIM: The present study was conducted to evaluate the dietary addition of Emblica officinalis (Amla) fruit powder as a growth promoter in commercial broiler chickens. MATERIALS AND METHODS: An experiment was conducted on 135 commercial broiler chicks (Ven-Cobb 400 strain) divided into three groups with three replicates of 15 chicks each. Three treatment groups were as follows - T1: Basal diet as per BIS standards; T2: Basal diet supplemented with 0.4% of E. officinalis fruit powder; and T3: Basal diet supplemented with 0.8% of E. officinalis fruit powder. RESULTS: The average body weights at the end of the 6(th) week were significantly higher (p<0.05) in groups T2 and T3 compared to group T1. Feed intake, feed conversion ratio and feed cost per kg live weight production were similar among the treatment groups. The net profit per bird was the highest in group T2 (Rs. 19.22/bird) followed by group T3 (Rs. 17.86/bird) and the lowest in group T1 (Rs. 14.61/bird). CONCLUSION: Based on the results of the present study, it was concluded that dietary addition of E. officinalis (Amla) fruit powder had a positive effect on growth performance and net profit per bird in commercial broiler chickens.

The transverse lumbar perforator flap: An anatomic and clinical study.

BACKGROUND AND AIMS: Lumbosacral defects are complex reconstructive problems requiring tension-free vascularised soft tissue reconstruction in patients who often have comorbidities. In an area prone to recurrent tissue breakdown, both free and islanded flaps risk complete failure. Cadaveric studies have demonstrated the consistency of lumbar perforators, yet ipsilateral lumbar perforator flaps have modest reconstructive potential owing to geometric limitations. An axial pattern lumbar perforator flap based on a contralateral lumbar perforator may surmount these problems; however, it has only been described in a small clinical and cadaveric study previously. METHODS: An anatomical study was performed in the consecutive patients undergoing computed tomographic angiography (CTA) of the trunk, assessing the presence and location of lumbar artery perforators. The use of midline or contralateral lumbar artery perforators in the lumbar perforator flap was assessed in the reconstruction of lumbosacral defects. RESULTS: A total of 102 patients with 102 lumbosacral defects have been managed with the use of contralaterally based transverse lumbar perforator flaps over a period of 20 years. In 96 patients, the defects requiring reconstruction followed debridement of a pressure ulcer, with seven cases following debridement of pilonidal sinuses and one following abdominoperineal resection. There were 65 men and 37 women, with a mean follow-up of 1.5 years. Necrosis of the tip of the flap occurred in 3%, with no cases of complete flap loss. Recurrence occurred in two cases (both sacral pressure sores). All recurrences and/or necrosis were managed with flap advancement or skin grafts. All the donor sites were closed directly. CONCLUSION: The contralateral-based transverse lumbar perforator flap is a simple, reliable, versatile and, in some cases, reusable choice in the management of lumbosacral defects. Flap dimensions of 24 × 15 cm can be based on one lumbar perforator.

DNA barcoding using skin exuviates can improve identification and biodiversity studies of snakes.

Snakes represent a taxonomically underdeveloped group of animals in India with a lack of experts and incomplete taxonomic descriptions being the main deterrents to advances in this area. Molecular taxonomic approaches using DNA barcoding could aid in snake identification as well as studies of biodiversity. Here a non-invasive sampling method using DNA barcoding is tested using skin exuviates. Taxonomically authenticated samples were collected and tested for validation and comparisons to unknown snake exuviate samples. This approach was also used to construct the first comprehensive study targeting the snake species from Maharashtra state in India. A total of 92 skin exuviate samples were collected and tested for this study. Of these, 81 samples were successfully DNA barcoded and compared with unknown samples for assignment of taxonomic identity. Good quality DNA was obtained irrespective of age and quality of the exuviate material, and all unknown samples were successfully identified. A total of 23 species of snakes were identified, six of which were in the list of Endangered species (Red Data Book). Intra- and inter-specific distance values were also calculated, and these were sufficient to allow discrimination among species and between species without ambiguity in most cases. Two samples were suspected to represent cryptic species based on deep K2P divergence values (>3%), and one sample could be identified to the genus level only. Eleven samples failed to amplify COI sequences, suggesting the need for alternative PCR primer pairs. This study clearly documents how snake skin exuviates can be used for DNA barcoding, estimates of diversity and population genetic structuring in a noninvasive manner.

Clinicopathological characteristics of ameloblastomas in Western Uttar Pradesh population: An institutional study.

OBJECTIVE: The aim of this study was to compare the clinical, radiologic, and histopathological features of 28 intraosseous ameloblastomas. In addition, we compared the data obtained in this study with that of previous studies. MATERIALS AND METHODS: Data with regard to age, gender, clinical manifestation, radiographic aspect, anatomical distribution, and histopathological subtypes were analyzed in 28 subjects. RESULTS: The patients' age ranged from 7 years to 65 years (mean, 30.4 years). Sixteen (57.14%) of the 28 subjects were males, and 12 (42.85%) were females. A total of 22 cases (78.5%) were located in the mandible, posterior region was more often affected with 17 cases (77.27%) than only 5 cases (22.72%) in the anterior segment. Swelling was the most common symptom and was experienced by 12 (42.85%) patients. Radiographically, 14 cases (50%) were multilocular with a well-demarcated border. Of the remaining 14 cases, 10 were unilocular and 4 were unknown in appearance. The most common histopathological pattern was follicular followed by plexiform or acanthomatous. CONCLUSIONS: The clinical epidemiological profile to patients in the present study is similar to that in other populations, with follicular ameloblastoma being the most common histological subtypes seen.

Evaluation of clinical skills for first-year surgical residents using orientation programme and objective structured clinical evaluation as a tool of assessment.

BACKGROUND: Postgraduate specialities require a combination of knowledge and clinical skills. The internship year is less structured. Clinical and practical skills that are picked up during training are not well regulated and the impact is not assessed. In this study, we assessed knowledge and skills using objective structured clinical examination (OSCE). AIM: To evaluate the clinical skills of new first-year surgical residents using orientation programme and OSCE as a tool for assessment. SETTINGS AND DESIGN: Observational study. MATERIALS AND METHODS: Twenty new first-year surgical residents (10 each in 2008 and 2009) participated in a detailed structured orientation programme conducted over a period of 7 days. Clinically important topics and skills expected at this level (e.g., suturing, wound care etc.) were covered. The programme was preceded by an OSCE to test pre-programme knowledge (the "pre-test"). The questions were validated by senior department staff. A post-programme OSCE (the "post-test") helped to evaluate the change in clinical skill level brought about by the orientation programme. STATISTICAL ANALYSIS: Wilcoxson matched-pairs signed-ranks test. RESULTS: Passing performance was achieved by all participants in both pre- and post-tests. Following the orientation programme, significant improvement was seen in tasks testing the psychomotor and cognitive domains. (P = 0.0001 and P = 0.0401, respectively). Overall reliability of the OSCE was found to be 0.7026 (Cronbach's coefficient alpha). CONCLUSIONS: This study highlighted the lacunae in current internship training, especially for skill-based tasks. There is a need for universal inclusion of structured orientation programmes in the training of first-year residents. OSCE is a reliable, valid and effective method for the assessment of clinical skills.

Biodiversity baselines, thresholds and resilience: testing predictions and assumptions using palaeoecological data.

Fossil records are replete with examples of long-term biotic responses to past climate change. One particularly useful set of records are those preserved in lake and marine sediments, recording both climate changes and corresponding biotic responses. Recently there has been increasing focus on the need for conservation of ecological and evolutionary processes in the face of climate change. We review key areas where palaeoecological archives contribute to this conservation goal, namely: (i) determination of rates and nature of biodiversity response to climate change; (ii) climate processes responsible for ecological thresholds; (iii) identification of ecological resilience to climate change; and (iv) management of novel ecosystems. We stress the importance of long-term palaeoecological data in fully understanding contemporary and future biotic responses.

Non-templated hydrothermal growth of anisotropic magnetite nanostructures using hexamine as the directing agent.

Anisotropic growth of magnetite (Fe3O4) nanoparticles is achieved in a hydrothermal growth process using hexamine to play a dual role of oxide forming and directing agent. The samples are characterized by X-ray diffraction, scanning electron microscopy, high resolution transmission electron microscopy, squid magnetometry, ferromagnetic resonance technique, diffuse reflectance spectroscopy and Mössbauer spectroscopy, which collectively establish the formation of Fe3O4 phase. Anisotropic structures such as nanorods and nanotubules are revealed and these are shown to exhibit good humidity sensing properties.

Invasive cervical resorption: a case report.

Invasive cervical resorption (ICR) is a relatively uncommon form of external resorption, which may occur in any tooth in the permanent dentition. Characterized by its cervical location and invasive nature, this resorptive process leads to progressive and usually destructive loss of the tooth structure, the clinical features of which often resemble internal resorption ("pink tooth"). This article describes a case report of ICR and its management. The salient features were a large resorptive defect and localized fibrous in-growth located almost wholly on the cervicolabial aspect of the maxillary incisor crown involving the enamel and dentin.

An intervarietal genetic linkage map of Indian bread wheat (Triticum aestivum L.) and QTL maps for some metric traits.

Bread wheat (Triticum aestivum L.) exhibits very narrow genetic diversity and hence there is high relatedness among cultivated varieties. However, a population generated from an intervarietal cross, with the parents differing in a large number of traits, could lead to the generation of QTL maps which will be useful in practice. In this report a genetic linkage map of wheat is constructed using a cross between two Indian bread wheat varieties: Sonalika and Kalyansona. The linkage map consisted of 236 markers and spanned a distance of 3639 cM, with 1211.2 cM for the A genome, 1669.2 cM for the B genome, 192.4 cM for the D genome and 566.2 cM for unassigned groups. Linkage analysis defined 37 linkage groups of which 24 were assigned to 17 chromosomes. The genetic map was used to identify QTLs by composite internal mapping (CIM) for three metric traits, viz. culm length (CL), flag leaf length (FLL) and flag leaf breadth (FLB). Of 25 QTLs identified in this study, 15 have not been reported previously. Multitrait CIM (MCIM) analysis was carried out for traits that were significantly correlated such as FLB-FLL and CL-FLB-FLL. Detection of a large number of QTLs for the three traits analysed suggests that in parent cultivars that are not too diverse, the differences at genetic level detected as polymorphisms may be mostly associated with QTLs for the observed differences.

Clinical evaluation of postoperative sensitivity in composite resin restorations using various liners.

Light-cured resin composites are a viable option for restoring Class I and Class II cavities; however, several researchers have reported postoperative sensitivity in such restorations. In this in vivo study, 80 teeth with Class I and Class II cavities were selected. They were divided into four groups of 20 teeth each, to be restored with composite resin using different treatment protocols. Postoperative sensitivity to cold water at various temperatures was assessed for up to three months. The data was interpreted using Chi Square Test for homogeneity among the groups, and Z values of significance for pair-wise evaluation were determined. It was found that use of self-etching primers as bonding agents underneath the composite resin restorations were associated with significantly decreased incidence of postoperative sensitivity to cold stimuli.

Chlorination of aromatic compounds in micellar media: regioselectivity.

Chlorination of phenol and ortho-chlorophenol was studied in micellar media in order to observe the effect on regioselectivity. Hydrogen peroxide/hydrochloric acid-aqueous system, which is environmentally a safer route was employed for chlorination. Selectivity ratio was found to be dependent on the nature and concentration of the surfactant. Ortho/para selectivity ratio up to 12 was realized for the chlorination of phenol. 2,6-/2,4-dichlorophenol ratio up to 1.01 was realized for the chlorination of ortho-chlorophenol.

Effects of SP500263, a novel selective estrogen receptor modulator, on bone, uterus, and serum cholesterol in the ovariectomized rat.

We describe here the activity of a novel selective estrogen receptor modulator, SP500263. When given to adult ovariectomized (OVX) rats for 28 days at doses of 0.3, 1, or 3 mg/kg/day, we found that SP500263 partially protected against OVX-induced loss of bone mineral content in the distal ends of femurs and in the whole bone. SP500263 also antagonized the OVX-induced increase in body weight. However, unlike 17beta-estradiol, SP500263 at efficacious doses did not prevent the OVX-induced loss in uterine wet weight. A small but significant effect on uterine wet weight was noted with raloxifene dosed at 1 mg/kg. As expected, SP500263 but not raloxifene acted as an estrogen antagonist on the uterus in adult rats when administered for 7 days at 30 mg/kg/day. Finally, SP500263 had no statistically significant effects on total serum cholesterol and serum triglycerides in OVX rats treated for 28 days. Raloxifene had no significant effects on body weight, bone mineral content, and serum cholesterol or triglycerides in the OVX-rat model. In summary, SP500263 is a new orally active SERM that acts in rats as an estrogen agonist on bone without causing uterine stimulatory effects.

Determination of the morphological irregularities in the middle and apical 1/3rd region of the root canal system of permanent maxillary incisors.

A thorough knowledge of the root canal anatomy and an understanding of its variations from the normal are mandatory for the successful root canal therapy. The assessment and exploration of the accessory canal and apical delta is necessary to combat the persistent infection at the periapical area. The purpose of this study is to determine the morphological irregularities in the middle and apical 1/3rd region of the root canal system of maxillary incisors. A total of 100 maxillary incisors were decalcified, processed, sectioned at the middle and apical 1/3rd region and observed under an ordinary microscope. The frequency of accessory canals, apical delta and type of canal configuration were studied. Accessory canals were found in 5% of the teeth. There was absence of apical delta in all the specimens. Total specimens showed single canal extended from the pulp chamber to the apex (Type 1 canal configuration).