Factors determining phage stability/activity: challenges in practical phage application

Introduction: Phages consist of nucleic acids and proteins that may lose their activity under different physico-chemical conditions. The production process of phage formulations may decrease phage infectivity. Ingredients present in the preparation may influence phage particles, although preparation and storage conditions may also cause variations in phage titer. Significant factors are the manner of phage application, the patient’s immune system status, the type of medication being taken, and diet.

Areas covered: We discuss factors determining phage activity and stability, which is relevant for the preparation and application of phage formulations with the highest therapeutic efficacy. Our article should be helpful for more insightful implementation of clinical trials, which could pave the way for successful phage therapy.

Expert opinion: The number of naturally occurring phages is practically unlimited and phages vary in their susceptibility to external factors. Modern methods offer engineering techniques which should lead to enhanced precision in phage delivery and anti-bacterial activity. Recent data suggesting that phages may also be used in treating nonbacterial infections as well as anti-inflammatory and immunomodulatory agents add further weight to such studies. It may be anticipated that different phage activities could have varying susceptibility to factors determining their actions.     

Forced Oxidative Degradation Pathways of the Imidazole Moiety of Daclatasvir

Daclatasvir hydrochloride (DCV) is the active pharmaceutical ingredient of Daklinza, a marketed product for the treatment of hepatitis C viral infection. The intrinsic stability of daclatasvir was evaluated via a forced degradation study. DCV was found to be stable in the solid state. In solution, its carbamate moiety is susceptible to basic hydrolysis, whereas its imidazole is liable to base-mediated autoxidation to form degradants 1 and 3, 7-8, respectively. The imidazole moiety can also be oxidized to form degradants 6-7 in the presence of hydrogen peroxide or azobisisobutyronitrile. The chloro-adduct degradant 9 was also observed in hydrogen peroxide solution. Furthermore, the imidazole moiety is sensitive to photodegradation in solution. Degradants 2-8 were observed in a solution of DCV exposed to high intensity light/UV light; the formation of degradants 2 and 5-8 was postulated through 4 degradation pathways. The degradants 3 and 4 were deemed to be secondary degradants of 7 and 5, respectively.     

Burnett Order Stress and Spatially-Dependent Boundary Conditions for the Lattice Boltzmann Method

Stress boundary conditions for the lattice Boltzmann equation that are consistent to Burnett order are proposed and imposed using a moment-based method. The accuracy of the method with complicated spatially-dependent boundary conditions for stress and velocity is investigated using the regularized lid-driven cavity flow. The complete set of boundary conditions, which involve gradients evaluated at the boundaries, are implemented locally. A recently-derived collision operator with modified equilibria and velocity-dependent collision rates to reduce the defect in Galilean invariance is also investigated. Numerical results are in excellent agreement with existing benchmark data and exhibit second-order convergence. The lattice Boltzmann stress field is studied and shown to depart significantly from the Newtonian viscous stress when the ratio of Mach to Reynolds numbers is not negligibly small.     

Oligo-monocytic CMML and other pre-CMML states: Clinical impact,prognostication and management

Chronic myelomonocytic leukemia (CMML) is defined by myelodysplasia, pathologic accumulation of monocytes and a substantial risk to transform to secondary acute myeloid leukemia (sAML). In recent years, minimal diagnostic criteria for classical CMML and CMML-variants were proposed. Moreover, potential pre-stages of CMML and interface conditions have been postulated. Oligomonocytic CMML is a condition where the absolute peripheral blood monocyte count does not reach a diagnostic level but all other criteria for CMML are fulfilled. Among potential pre-stages of CMML, clonal and non-clonal conditions have been described, including idiopathic monocytosis (IMUS) and clonal monocytosis of unknown significance (CMUS). Patients with myelodysplastic syndromes (MDS), clonal cytopenia of unknown significance (CCUS), clonal hematopoiesis of indeterminate potential (CHIP) and idiopathic cytopenia of undetermined significance (ICUS) may also progress to CMML. The current article provides an overview of pre-CMML conditions and oligomonocytic CMML, with special reference to diagnostic criteria, differential diagnoses, clinical outcomes and management.     

Community involvement in the development and implementation of chronic condition programmes across the continuum of care in high- and upper-middle income countries: A systematic review

BackgroundCommunity involvement is an important component of health programme development and implementation, including those focused on chronic condition treatment and management. Yet, few studies explore the manifestations of community involvement in chronic care programmes. Our review aims to examine the evidence on how communities are involved in planning and implementing chronic condition programmes in high and upper-middle income countries.MethodsEligible studies included those that involved the community in the planning, implementation, monitoring and evaluation of health services, policy or health interventions. We searched Medline, Embase, Global Health, Scopus, and LILACs from 2000 to 2016, independently screened articles for inclusion, conducted data extraction, and assessed studies for risk of bias.Results27,232 records were identified and after screening, 32 met inclusion criteria. We conducted a narrative synthesis to report on the forms and processes of community involvement used across mental health programmes and contrast this with the paucity of evidence on comparable programmes addressing other chronic conditions. Challenges reported included user factors, organisational factors, and social challenges such as stigma.ConclusionOur review adds to the evidence supporting community involvement in chronic condition management and the processes that contribute to successful and sustainable involvement. We report on a model, derived from inductive analysis, that considers social and cultural components, organisational factors and stakeholder relationships as underpinning the development of community interventions across the care continuum.     

Disparate exposure to physically demanding working conditions in France

BackgroundOur study was aimed at examining disparate exposure to physically demanding working conditions in France, a key objective being to identify the types of employees/jobs requiring high-priority preventive actions.MethodsWe analyzed the data from the 2017 French nationwide cross-sectional survey (SUMER) on occupational hazards to which French employees in various sectors were subjected. The prevalence of several types of physically demanding working conditions (lifting of heavy loads, awkward body postures, vibrations, noise, and extreme temperatures) was explored. Potential associations of individual and job characteristics with these factors of hardship at work were studied by multivariate logistic regression.ResultsIn total, 48% of employees were exposed to at least one physically demanding working condition and 24.8% were exposed to multiple constraints. While managers and intellectual professionals were exposed relatively infrequently to physical constraints, blue-collar workers experienced the highest frequency of exposure. On the one hand, the role of company size depended on the factor of hardship at work considered; on the other hand, employees in large-scale companies were generally less exposed. As expected, employees in the construction industry were the most exposed to physical constraints; that said, our results also show that some activities in the services sector (e.g., personal care, administrative and support services) were quite significantly affected by a wide array of physically demanding working conditions.ConclusionNotwithstanding the establishment in France of Plans de Santé au travail (preventive workplace health and safety plans), occupational risks were found to be high, and above all, they were unevenly distributed among the various socio-professional categories, and strongly contributed to social inequalities in health. Our results identify the types of publics to be designated as high-priority targets for preventive measures aimed at reducing the adverse impacts of physically demanding working conditions and the incidence of associated musculoskeletal disorders.     

Ketamine in the Treatment of Major Depressive Disorder

Major depressive disorder (MDD) is a prevalent and highly debilitating psychiatric condition that affects many young adults worldwide. This brief review summarizes the current available data about the use of ketamine as a treatment for MDD. We describe pharmacological mechanisms, dose considerations, drug interactions, side effects, and the relevancy of ketamine in the treatment of MDD.