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Despite the use of various integrated pest management strategies to control the honey bee mite, Varroa destructor, varroosis remains the most important threat to honey bee colony health in many countries. In Canada, ineffective varroa control is linked to high winter colony losses and new treatment options, such as a summer treatment, are greatly needed. In this study, a total of 135 colonies located in 6 apiaries were submitted to one of these 3 varroa treatment strategies: (i) an Apivar® fall treatment followed by an oxalic acid (OA) treatment by dripping method; (ii) same as in (i) with a summer treatment consisting of formic acid (Formic Pro™); and (iii) same as in (i) with a summer treatment consisting of slow-release OA/glycerin pads (total of 27 g of OA/colony). Treatment efficacy and their effects on colony performance, mortality, varroa population, and the abundance of 6 viruses (acute bee paralysis virus [ABPV], black queen cell virus [BQCV], deformed wing virus variant A [DWV-A], deformed wing virus variant B [DWV-B], Israeli acute paralysis virus [IAPV], and Kashmir bee virus [KBV]) were assessed. We show that a strategy with a Formic Pro summer treatment tended to reduce the varroa infestation rate to below the economic fall threshold of 15 daily varroa drop, which reduced colony mortality significantly but did not reduce the prevalence or viral load of the 6 tested viruses at the colony level. A strategy with glycerin/OA pads reduced hive weight gain and the varroa infestation rate, but not below the fall threshold. A high prevalence of DWV-B was measured in all groups, which could be related to colony mortality., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America.)

Introduction: Multiple stakeholders have recently called for greater research on the barriers to citizenship and community belonging faced by people with mental health challenges. Citizenship has been defined as a person's access to the rights, roles, responsibilities, resources and relationships that help people feel a sense of belonging. Factors that may impact citizenship include financial precarity; intersecting forms of marginalization and oppression (e.g., racism); and the mental health care people receive. Research has yet to examine experiences of citizenship among youth with mental health challenges. To address this gap, this study will examine how youth experience citizenship; predictors of citizenship; how citizenship shapes recovery; and the degree to which youth are receiving citizenship-oriented care., Methods: The research objectives will be evaluated using a multiphase mixed methods research design. Quantitative data will be collected cross-sectionally using validated self-report questionnaires. Qualitative data will be collected using a hermeneutic phenomenological method using semi-structured interviews and focus groups., Analyses: Multiple stepwise regression analyses will be used to determine predictors of citizenship and if of citizenship predict recovery. Pearson correlations will be computed to determine the relationship between participants' perceived desire for, and receipt of citizenship-oriented care. Phenomenological analysis will be used to analyze qualitative data. Findings will then be mixed using a weaving method in the final paper discussion section., Conclusion: Findings from this study may support the development of citizenship-oriented healthcare in Canada., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jordan, Burke, Bailey, Kreidstein, Iftikhar, Plamondon, Young, Davidson, Rowe, Bellamy, Abdel-Baki and Iyer.)

Introduction and Aims: Alcohol pricing is an effective prevention policy. This paper compares the 10 Canadian provinces on three research-based alcohol pricing policies-minimum pricing, pricing by alcohol content and maintaining prices relative to inflation., Design and Methods: The selection of these three policies was based on systematic reviews and seminal research papers. Provincial data for 2012 were obtained from Statistics Canada and relevant provincial ministries, subsequently sent to provincial authorities for verification, and then scored by team members., Results: All provinces, except for Alberta, have minimum prices for at least one beverage type sold in off-premise outlets. All provinces, except for British Columbia and Quebec, have separate (and higher) minimum pricing for on-premise establishments. Regarding pricing on alcohol content, western and central provinces typically scored higher than provinces in Eastern Canada. Generally, minimum prices were lower than the recommended $1.50 per standard drink for off-premise outlets and $3.00 per standard drink in on-premise venues. Seven of 10 provinces scored 60% or higher compared to the ideal on indexing prices to inflation. Prices for a representative basket of alcohol products in Ontario and Quebec have lagged significantly behind inflation since 2006., Discussion and Conclusions: While examples of evidence-based alcohol pricing policies can be found in every jurisdiction in Canada, significant inter-provincial variation leaves substantial unrealised potential for further reducing alcohol-related harm and costs. This comparative assessment of alcohol price policies provides clear indications of how individual provinces could adjust their pricing policies and practices to improve public health and safety. [Giesbrecht N, Wettlaufer A, Thomas G, Stockwell T, Thompson K, April N, Asbridge M, Cukier S, Mann R, McAllister J, Murie A, Pauley C, Plamondon L, Vallance K. Pricing of alcohol in Canada: A comparison of provincial policies and harm-reduction opportunities. Drug Alcohol Rev 2016;35:289-297]., (© 2015 Australasian Professional Society on Alcohol and other Drugs.)

Utilizing a fully synthetic route to tetracycline analogues, the C-9 side-chain of the fluorocyclines was optimized for both antibacterial activity and oral efficacy. Compounds were identified that overcome both efflux (tet(K), tet(A)) and ribosomal protection (tet(M)) tetracycline-resistance mechanisms and are active against Gram-positive and Gram-negative organisms. A murine systemic infection model was used as an oral efficacy screen to rapidly identify compounds with oral bioavailability. Two compounds were identified that exhibit both oral bioavailability in rat and clinically relevant bacterial susceptibility profiles against major respiratory pathogens. One compound demonstrated oral efficacy in rodent lung infection models that was comparable to marketed antibacterial agents.

This and the accompanying report (DOI: 10.1021/jm201467r ) describe the design, synthesis, and evaluation of a new generation of tetracycline antibacterial agents, 7-fluoro-9-substituted-6-demethyl-6-deoxytetracyclines ("fluorocyclines"), accessible through a recently developed total synthesis approach. These fluorocyclines possess potent antibacterial activities against multidrug resistant (MDR) Gram-positive and Gram-negative pathogens. One of the fluorocyclines, 7-fluoro-9-pyrrolidinoacetamido-6-demethyl-6-deoxytetracycline (17j, also known as TP-434, 50th Interscience Conference on Antimicrobial Agents and Chemotherapy Conference , Boston, MA , September 12-15, 2010 , poster F1 - 2157 ), is currently undergoing phase 2 clinical trials in patients with complicated intra-abdominal infections (cIAI).

Employing a highly efficient total synthesis approach, we synthesized and evaluated for antibacterial activity diverse and novel pentacycline analogs with systematic variations at C7, C8, C9, and C10. Certain substitution groups, as well as substitution patterns at various positions, were found to be preferred for increased antibacterial activity. A number of pentacycline analogs displayed potent activity in vitro and in vivo, especially against Gram-positive organisms. Several analogs have also shown promising oral bioavailability in rats and cynomolgus monkey.

A novel series of fully synthetic 8-azatetracyclines was prepared and evaluated for antibacterial activity. Compounds were identified that overcome both efflux (tet(K)) and ribosomal protection (tet(M)) tetracycline resistance mechanisms and are active against Gram-positive and Gram-negative organisms. Two compounds were identified that exhibit comparable efficacy to marketed tetracyclines in in vivo models of bacterial infection.

The work described herein considers the impact of stereoelectronic effects and allylic 1,3-strain in controlling the cyclofunctionalization reaction when a hydroxyl group is at the allylic position. The stereoelectronic arguments are supported by independent iodocyclization reactions performed using two secondary alcohols. The transition-state pathways involved in these reactions are established through a comparison of relative reaction rates. A bi-directional approach is used to demonstrate the potential of the iodocyclization reaction to differentiate a terminus in molecules with a pseudo C(2) axis of symmetry, showing that two-directional synthesis can be used to differentiate between alternative transition-state pathways.

We have developed an assay to continuously monitor the branched amino acid preferring peptidase (BrAAP) activity of the proteasome. This assay is based on the hydrolysis of the fluorogenic peptide, Abz-Gly-Pro-Ala-Leu-Ala-Nba (Abz is 2-aminobenzoyl and Nba is 4-nitrobenzylamide) which is cleaved exclusively at the Leu-Ala bond by the 20S proteasome with a kc/Km value of 13 000 M-1 s-1. Hydrolysis of this peptide is accompanied by an increase in fluorescence intensity (lambda ex = 340 nm, lambda em = 415 nm) due to release of the internally quenched 2-aminobenzoyl fluorescence that accompanies diffusion apart of the hydrolysis products, Abz-Gly-Pro-Ala-Leu and Ala-Nba. Using this assay, we examined inhibition of the BrAAP activity of the proteasome by a series of tripeptide aldehydes, Z-Leu-Leu-Xaa-H. When Xaa = Phe, (p-Cl)Phe, and Trp we observe biphasic or partial inhibition of the BrAAP activity. In contrast, when Xaa = Nva and Leu, simple inhibition kinetics are observed and allow us to calculate Ki values of 120 nM and 12 nM, respectively. The inhibitors that exhibit simple inhibition kinetics for BrAAP activity are also approximately equipotent for inhibition of the chymotrypsin-like (ChT-L) and peptidyl-glutamyl peptide hydrolyzing (PGPH) activities, dissociation constants varying by less than 25-fold, whereas the inhibitors that exhibit biphasic inhibition kinetics for BrAAP activity are >300-fold more potent for inhibiting ChT-L activity than for PGPH activity. Inactivation of the BrAAP activity of the proteasome by clasto-lactacystin beta-lactone is also biphasic. beta-Lactone inactivates approximately 60% of the BrAAP activity rapidly, with kinetics indistinguishable from its inactivation of the chymotrypsin-like activity. The remaining 40% of the BrAAP activity is inactivated by beta-lactone at a 50-fold slower rate, with kinetics indistinguishable from its inactivation of the PGPH activity. These results suggest a mechanism in which hydrolysis of Abz-Gly-Pro-Ala-Leu-Ala-Nba (i.e., BrAAP activity) occurs at two different active sites in the 20S proteasome, and that these two active sites are the same ones that catalyze the previously described ChT-L and PGPH activities.

Isopeptidase T (IPaseT) can hydrolyze isopeptide bonds of polyubiquitin (polyUb) chains, simple C-terminal derivatives of Ub, and certain peptides. We recently reported that IPaseT is regulated by ubiquitin (Ub); while submicromolar Ub activates, higher concentrations inhibit this enzyme [Stein et al. (1995) Biochemistry 34, 12616]. To explain these observations, we proposed a model for IPaseT involving two binding sites for Ub. According to the model, the two sites are adjacent to one another and are the extended active site that binds two Ub moieties of a polyUb chain. The "activation site" binds the Ub that donates Lys to the isopeptide bond. The "inhibition site" is adjacent and binds the Ub that donates the C-terminal Gly to the isopeptide bond. We now report that the interaction of IPaseT with the C-terminal aldehyde of Ub (Ub-H) is also modulated by Ub. In the absence of Ub, Ub-H inhibits IPaseT with a Ki of 2.3 nM, while at 0.6 microM Ub, where the "activation site" is occupied, Ki is less than 0.1 nM. At high Ub concentrations, where both the "activation" and "inhibition" sites are occupied, IPaseT cannot bind Ub-H. We also determined the kinetics of inhibition of IPaseT by Ub-H. In the absence of Ub, a two-step mechanism is followed. In the first step, Ub-H slowly combines with IPaseT to form a relatively weak complex (K1 = 260 nM) that slowly isomerizes to the final, stable complex that accumulates in the steady-state (k2 = 2 x 10(-3) s-1; k-2 = 0.02 x 10(-3) s-1). In contrast, Ub-activated IPaseT is inhibited by Ub-H through a three-step process. In the first step, Ub-H rapidly combines with IPaseT to form a complex (K1 = 10 nM) that slowly isomerizes to a second, more stable complex (k2 = 18 x 10(-3) s-1; k-2 = 1.5 x 10(-3) s-1). In the third step, the second complex converts to the final complex (k3 = 1.5 x 10(-3) s-1; k-3 < 0.2 x 10(-3) s-1). To unify the results of this study with our previous results on catalysis, we propose that binding of Ub either to catalytic transition states or to tetrahedral inhibition intermediates liberates more free energy than binding of Ub to the reactant state of IPaseT and that IPaseT can utilize this binding energy to stabilize both of these tetrahedral species. The overall effect is a Ub-induced increase in catalytic efficiency or inhibitory potency.

Many authors have reported middle ear pressure variations during inhalation of high concentrations of nitrous oxide. An on-going study on subjects anaesthetized with nitrous oxide and oxygen supplemented with halogens or narcotics and excluding operations on the ear enables us to register three typical curves of middle ear pressure according to the patency of the Eustachian tube. We recorded significant negative middle ear pressures during the recovery period when there was important obstruction of the Eustachian tube. The presence of a tympanic "neomembrane" due to an old perforation associated with important obstruction of the Eustachian tube could lead to a tympanic perforation that may be unnoticed by the anaesthetist if it is not specifically investigated. In our series, we report one case of tympanic perforation and one case of haemotympanum as examples of such consequences.

Retirement is first defined as a transitory period from a working situation to a situation of definite cessation of work. In order to understand this transitory process, the author looks into the importance of work as a determinant of life conditions and as a structuring influence in life conducts. The change brought about by retirement involves many upheavals on a social level (relationship, loss of income, economical dependency) as well as on a personal level (return to a home life, modification of relationships within the couple and the family life). The importance of these upheavals is such and their effects so acute that retirement is defined as a crisis situation.

The authors describe the socio-economic conditions of the retired in 1980 (poverty, poor health, lack of adequate services, etc.) and explain how these conditions are related to capitalist social organization. Their analysis leads them to set down the principal goal of the community workers in regard to the elderly population as follows : contribute to the organization and to the development of conditions favorable to the mobilization of the retired and elderly workers who, as a group, have the greatest potential for changing their conditions. To attain this long-term objective, the pre-retirement clientele possess the most favorable potential, and this is why the retirement preparation intervention is defined in an educationel orientation of psycho-social prevention. Seconding to the authors, the apprenticeships showed permit the elderly to assume both personal and collective control - thereby making it possible to transform the existing conditions.