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.

Leaf biochemical adjustments in two Mediterranean resprouter species facing enhanced UV levels and reduced water availability before and after aerial biomass removal.

Effects of supplemented UV radiation and diminished water supply on the leaf concentrations of phenols and antioxidants of two Mediterranean resprouter species, Arbutus unedo and Quercus suber, were assessed before and after entire aerial biomass removal. Potted seedlings of both species were grown outdoors for 8 months with enhanced UV-A + UV-B, enhanced UV-A or ambient UV, in combination with two watering conditions (field capacity or watering reduction). After this period, all aerial biomass was removed and new shoots (resprouts) developed for a further 8 months under the two treatments. In general, the investment in leaf phenols was substantially greater in A. unedo than in Q. suber, while Q. suber allocated more resources to non-phenolic antioxidants (ascorbate and glutathione). In response to enhanced UV-B radiation, Q. suber leaves rose their UV-screening capacity mainly via accumulation of kaempferols, accompanied by an increased concentration of rutins, being these effects exacerbated under low-watering conditions. Conversely, A. unedo leaves responded to UV-B radiation reinforcing the antioxidant machinery by increasing the overall amount of flavonols (especially quercetins) in seedlings, and of ascorbate and glutathione, along with catalase activity, in resprouts. Nevertheless, UV effects on the amount/activity of non-phenolic antioxidants of A. unedo resprouts were modulated by water supply. Indeed, the highest concentration of glutathione was found under the combination of enhanced UV-B radiation and reduced watering, suggesting an enlargement of the antioxidant response in A. unedo resprouts. Different biochemical responses to enhanced UV and drier conditions in seedlings and resprouts of these two species might modulate their competitive interactions in the near future.

Altitudinal and seasonal changes of phenolic compounds in Buxus sempervirens leaves and cuticles.

The variation in the leaf content of phenolic compounds has been related to the UV-B changes of the environment in which plants grow. In this context, we aimed to investigate: a) whether the seasonal and altitudinal changes in the content of phenolic compounds of Buxus sempervirens L. leaves and cuticles could be related to the natural fluctuations in UV-B levels and b) the possible use of specific phenolic compounds as biomarkers of ambient UV-B levels. To achieve these goals we sampled, every three months during one year, leaves of B. sempervirens along an altitudinal gradient. At the lowest and the highest altitudes, we also conducted a UV-exclusion experiment to discern whether the observed changes could be attributed to the natural variation in UV-B. Results show that total phenolic content of leaves was lower in June than in the other sampling dates, which suggests a leaf ontogenic rather than a UV-B effect on the leaf content of these compounds. Regarding the elevational gradient, the overall amount of phenolic acids and neolignan of entire leaves increased with altitude while the total amount of flavonoids in leaf cuticles decreased. However, the lack of a significant effect of our UV-exclusion treatment on the content of these compounds suggests that the observed variations along the altitudinal gradient would respond to other factors rather than to UV-B. Concomitantly, we did not find any phenolic compound in leaves or cuticles of B. sempervirens that could be considered as a biomarker of ambient UV-B levels.

Intravenous doripenem at 500 milligrams versus levofloxacin at 250 milligrams, with an option to switch to oral therapy, for treatment of complicated lower urinary tract infection and pyelonephritis.

The prospective, multicenter, double-blind study presented in this report evaluated whether or not intravenous (IV) administration of doripenem, a carbapenem with bactericidal activity against gram-negative and gram-positive uropathogens, is inferior to IV administration of levofloxacin in the treatment of complicated urinary tract infection (cUTI). Patients (n = 753) with complicated lower UTI or pyelonephritis were randomly assigned to receive IV doripenem at 500 mg every 8 h (q8h) or IV levofloxacin at 250 mg q24h. Patients in both treatment arms were eligible to switch to oral levofloxacin after 3 days of IV therapy to complete a 10-day treatment course if they demonstrated significant clinical and microbiological improvements. The microbiological cure rate (primary end point) was determined at the test-of-cure (TOC) visit occurring 5 to 11 days after the last dose of antibiotic. For the microbiologically evaluable patients (n = 545), the microbiological cure rates were 82.1% and 83.4% for doripenem and levofloxacin, respectively (95% confidence interval [CI] for the difference, -8.0 to 5.5%); in the microbiological modified intent-to-treat cohort (n = 648), the cure rates were 79.2% and 78.2%, respectively. Clinical cure rates at the TOC visit were 95.1% in the doripenem arm and 90.2% in the levofloxacin arm (95% CI around the difference in cure rates [doripenem cure rate minus levofloxacin cure rate], 0.2% to 9.6%). Both treatment regimens were generally well tolerated. Doripenem was found not to be inferior to levofloxacin in terms of therapeutics and is now approved for use in the United States and Europe for the treatment of adults with cUTI, including pyelonephritis. As fluoroquinolone resistance increases, doripenem may become a more important option for successful treatment of cUTIs, including treatment of pyelonephritis.

Carbon and nitrogen cycles in European ecosystems respond differently to global warming.

The global climate is predicted to become significantly warmer over the next century. This will affect ecosystem processes and the functioning of semi natural and natural ecosystems in many parts of the world. However, as various ecosystem processes may be affected to a different extent, balances between different ecosystem processes as well as between different ecosystems may shift and lead to major unpredicted changes. In this study four European shrubland ecosystems along a north-south temperature gradient were experimentally warmed by a novel nighttime warming technique. Biogeochemical cycling of both carbon and nitrogen was affected at the colder sites with increased carbon uptake for plant growth as well as increased carbon loss through soil respiration. Carbon uptake by plant growth was more sensitive to warming than expected from the temperature response across the sites while carbon loss through soil respiration reacted to warming in agreement with the overall Q10 and response functions to temperature across the sites. Opposite to carbon, the nitrogen mineralization was relatively insensitive to the temperature increase and was mainly affected by changes in soil moisture. The results suggest that C and N cycles respond asymmetrically to warming, which may lead to progressive nitrogen limitation and thereby acclimation in plant production. This further suggests that in many temperate zones nitrogen deposition has to be accounted for, not only with respect to the impact on water quality through increased nitrogen leaching where N deposition is high, but also in predictions of carbon sequestration in terrestrial ecosystems under future climatic conditions. Finally the results indicate that on the short term the above-ground processes are more sensitive to temperature changes than the below ground processes.

A biomechanical study of the long bones in platyrrhines.

The long bones of 72 individuals of extant platyrrhines, belonging to 17 species (11 genera) were studied by regressions of length, diameters and curvature. Cross-sectional shapes at midshaft and axial and bending strength indicators were also calculated. Results show that forelimb bones scale faster than hindlimb bones, for both length and diameters. Curvature scales faster in the femur than in other bones. Strength indicators showed a high variability in the relative importance of axial and bending loadings. Results are consistent with field observations of locomotor behaviour, mainly as regards quadrupedalism versus suspensory locomotion.

Achieving occupational role: accommodations for students with disability.

The purpose of this paper is to describe background and strategies utilized by occupational therapy educators in conjunction with Disabled Students Services personnel and students with disabilities to effect academic accommodations that will enhance their chances for success in academia and subsequently in the practice of occupational therapy.

Photosynthesis and photoprotection in Quercus ilex resprouts after fire.

Plants that resprout after fires often have higher rates of photosynthesis than before a fire. To elucidate the mechanism of this response, we studied gas exchange and chlorophyll fluorescence in Quercus ilex L. plants growing on control (unburned) sites and on sites that had been burned the preceding summer. In early July, photosynthetic rates and stomatal conductance were similar in plants on unburned and burned plots, and in young and old foliage within unburned plots. At this time, photochemical efficiency of photosystem II (PSII), nonphotochemical quenching of chlorophyll fluorescence (NPQ), and the de-epoxidation of violaxanthin to zeaxanthin were also similar among leaves of different ages and treatments. In late July, photosynthetic rates and stomatal conductances were much greater in resprouts on the burned areas than in unburned plants. From early to late July, unburned plants showed an increase in NPQ and the de-epoxidation of violaxanthin to zeaxanthin, indicating increased photoprotection as a result of enhanced nonradiative dissipation of excess light energy. Plants on the burned plots did not show these changes. Leaves of all ages and treatments showed no substantial reduction in potential quantum yield of PSII (F(v)/F(m)) at midday or predawn, indicating that there was little or no photoinhibition. Leaf nitrogen and soluble protein contents varied with leaf age during July, but did not vary between treatments. We conclude that the primary effect of burning is an increase in water availability to resprouting plants that eliminates the need for photoprotection, at least in the short term. The decrease in photosynthetic rates of unburned leaves in late July was the result of reduced stomatal conductance. We suggest that lowered stomatal conductance is the primary limiting factor in Q. ilex leaves, governing the regulation of carboxylation activity and energy dissipation processes.

The effects of habilitative hospital admission on self-care, self-esteem, and frequency of physical care.

The effects of a habilitative hospital admission for the multidisciplinary teaching of activities of daily living were investigated with 3 children with spina bifida and 1 child with juvenile arthritis. Specific evaluation tools included analysis of individualized goals, the Klein-Bell Activity of Daily Living Scale (Klein & Bell, 1979), the Physical Child Care Record (Johnson & Dietz, 1985), and the Piers-Harris Children's Self-Concept Scale (Piers & Harris, 1967). The children were evaluated on hospital admission, at discharge, and 3 months after discharge. The results show that hospital admission can be an effective means of increasing independence and decreasing frequency of physical care by parents. Some changes in self-esteem occurred in both directions; however, these changes may be attributed to variables other than hospitalization or changes in self-care status.

Fístulas arteriovenosas traumáticas: incidencia en población civil / Traumatic arteriovenous fistula: ocurrence in the civil population

Se presentan 12 casos, de un total de 164 traumatismos vasculares, en 118 pacientes con una fístula arteriovenosa traumática (FAVT) (7,3%), entre enero de 1980 y diciembre 1987. Nueve correspondieron a heridas por bala y tres a yatrogenia, todas ubicadas en las extremidades. La totalidad se manifestaron en forma tardía, presentaban soplo y la mitad insuficiencia cardiaca. Tras angiografías fueron sometidas a reparación quirúgica, con resultados excelentes en 11 casos; uno fue inabordable por lo que se efectuaron ligaduras distales y proximales, con reaparición posteriormente de la sintomatología en forma más atenuada

Health care systems models and occupational therapy.

Health care system models featuring four alternative future scenarios are discussed relative to occupational therapy. Five prevailing theoretical models of occupational therapy practice and three practice systems are described as they interact for service provision. Occupational therapy as an open system is presented as possessing the potential to successfully embrace and negotiate changes a in the health care system as projected for the future.

Going to the source.

A small but growing body of occupational therapy literature identifies the value of qualitative research methodology, which is useful with relatively unstudied or complex phenomena. This paper describes the use of qualitative research to obtain insight into the world of adults with significantly limiting cerebral palsy, as seen from their own perspective. The first author conducted extended, guided interviews with five adults who live independently with attendant care. The resulting data, synthesized into recurring themes, suggested guidelines for occupational therapy practice. In this paper, the study methodology is described in depth, and directions for further qualitative and quantitative research are presented.

Activity analysis: agreement among factors in a sensory processing model.

A laboratory model designed to study tasks, activities, and occupation components is described. The feasibility of the model for gathering evidence about inherent factors perceived by participants in five discrete situations that involved spinning, drawing, manual rolling, buttoning, and chewing was tested. Results provide limited but specific evidence to support the concept that tasks, activities, and occupation components possess inherent factors that may be used in assessment and intervention to affect the interrelationships among external actions, external objects, and internal mental operations. Such evidence strengthens the credibility of emerging occupational theory for the practice of occupational therapy.

Nationally speaking. The challenge for research in a practice profession.

We have suggested that certain research challenges now face the profession. In summary, these challenges may be seen as part of the dual mission of research in a practice profession. Research must contribute to the development of a body of knowledge: some research is academic and theoretical in nature and other research helps to sustain and improve clinical practice. In either case, theory in a practice profession differs significantly from that in more traditional sciences. It is, in fact, more sophisticated and complex than the theory utilized by nonpractice professions, because it must provide the means to state intended outcomes and identify the methods required to achieve the prescribed results (5). This is known as "prescriptive theory" and represents the ultimate research challenge to the practice profession. Prescriptive theory cannot rest on studying what is and what has been; it must anticipate what might be--indeed, what must be--if patients are to achieve their greatest potential as functional members of society.

Changing balance: environment and individual.

The role of occupational therapy as a process for changing balance from dysfunction to function is discussed in this paper. The individual as the first level environment to be considered for balance in the occupational therapy process is emphasized. The role of purposeful activity as a change determinant and as a valued treatment modality is recognized as a practice factor that needs verification through research in conjunction with systematic study of the occupational therapy process.

Documentation of occupational therapy services: a process model.

This paper describes a process model of occupational therapy and the Occupational Therapy Sequential Client Care Record (OTSCCR). The OTSCCR incorporates the model and provides comprehensive documentation of occupational therapy services from referral through outcome of intervention.

Learning style preferences of occupational therapy students.

Fifty-five undergraduate and 22 graduate students in occupational therapy were surveyed by using the Canfield-Lafferty Learning Styles Inventory. The results of the study indicate that their learning style preferences favor the learning conditions that permit knowing and liking the instructor personally, setting one's own objectives, and working alone and independently. The highest content and mode preferences for learning were working with people and engaging in direct experience, respectively. The lowest content and mode preferences were for working with numbers and for reading. Achievement expectations for grades were A and B. The findings are discussed.

Occupational therapy sequential client care recording system: a comparative study.

The client care record is a key document for determining standards of care in occupational therapy. The purpose of this study was to determine the effectiveness of a client care recording system for occupational therapy that combined the theoretical framework of the Developmental Analysis, Evaluation and Intervention Schedule, and the scientific method of the Problem Oriented Medical Record. The research form of the client care record was compared to a traditional client care record in current use in an occupational therapy clinic. An interdisciplinary panel of health professionals rated both the original and proposed form of the record on the variables of completeness, organization, understandability, and usefulness. The findings show statistically significant differences between the client care record based on the combined Developmental Analysis, Evaluation and Intervention Schedule and the Problem Oriented Medical Record and the currently used record system.