A Proposal for the Comprehensive Care of Men on Androgen Deprivation Therapy: Recommendations From the Multidisciplinary Prostate Cancer 360 Working Group.

INTRODUCTION: To promote comprehensive care of patients throughout the androgen deprivation therapy (ADT) prescribing process, the Prostate Cancer 360 (PC360) Working Group developed monitoring and management recommendations intended to mitigate or prevent ADT-associated adverse events. METHODS: The PC360 Working Group included 14 interdisciplinary experts with a dedicated clinical interest in prostate cancer and ADT management. The working group defined challenges associated with ADT adverse event management and then collaboratively developed comprehensive care recommendations intended to be practical for ADT prescribers. RESULTS: The PC360 Working Group developed both overarching recommendations for ADT adverse event management and specific recommendations across 5 domains (cardiometabolic, bone, sexual, psychological, and lifestyle). The working group recommends an interdisciplinary, team-based approach wherein the ADT prescriber retains an oversight role for ADT management while empowering patients and their primary and specialty care providers to manage risk factors. The PC360 recommendations also emphasize the importance of proactive patient education that involves partners or other support providers. Recommended monitoring and assessment tools, risk factor management, and patient counseling points are also included for the 5 identified domains, with an emphasis on lifestyle and behavioral interventions that can improve quality of life and reduce the risk for ADT-associated complications. CONCLUSIONS: Comprehensive care of patients receiving ADT requires early and ongoing coordinated management of a variety of health domains, including cardiometabolic, bone, sexual, psychological health. Patient education and primary care provider involvement should begin prior to ADT initiation and continue throughout treatment to improve patient and partner quality of life.

Establishing clinically meaningful ranges of metal hypersensitivity in orthopaedic patients using COVID-19 vaccine-induced adaptive immune responses from fully vaccinated adults.

Background: This study aimed to assess metal sensitization ranges among orthopaedic patients by comparing adaptive immune responses in all-comer pre- and post-operative orthopaedic adults who were COVID-19 unvaccinated or vaccinated vs patients with a painful aseptic implant by lymphocyte transformation test (LTT) to SARS-CoV-2-Spike-Protein (SP) and implant metal(s), respectively. Methods: Data were retrospectively reviewed from three independent groups: unvaccinated COVID-19 adults (n = 23); fully COVID-19 vaccinated adults (n = 35); unvaccinated, painful aseptic implant patients with history of metal allergy (n = 98). Standard in vitro LTT for SP and implant metal(s) (nickel, cobalt) were performed and rated as negative (stimulation index [SI]<2), mild (SI ≥ 2), positive (SI ≥ 4-15), and high sensitization (SI > 15) adaptive immune responses to tested antigen. Results: Overall, 17/23 (74%) of unvaccinated adults showed negative to mild LTT ranges, and 35/35 (100%) of vaccinated showed mild to positive LTT ranges to SP. Vaccinated individuals showed significantly higher median SI (16.1) to SP than unvaccinated (median SI, 1.7; P < 0.0001). Most vaccinated adults (94%) showed a lymphocyte SI > 4 to SP, establishing LTT SI ≥ 4 with >90% sensitivity for diagnosing effective COVID-19 adaptive immune responses. Significantly fewer painful orthopaedic patients (41%) showed comparable elevated levels of lymphocyte metal sensitivity at SI ≥ 4 compared to vaccinated group (P < 0.0001). Conclusions: Vaccinated adults showed significantly higher lymphocyte SI to SP than unvaccinated indicating that SI ranges ≥4 should be set as unequivocally diagnostic of LTT-positive adaptive immune responses to tested antigen. This analysis supports using higher LTT SI ranges (SI ≥ 4) in diagnosing clinical orthopaedic-related Type IV metal-hypersensitivity responses among orthopaedic patients.

Interprovincial variation in antibiotic use in Canada, 2019: a retrospective cross-sectional study.

BACKGROUND: Geographic trends in antibiotic prescribing show regional variation in antibiotic overuse and antimicrobial resistance, posing a threat to global health care systems. This study's objective was to examine interprovincial variation in outpatient antibiotic dispensing in Canada in 2019. METHODS: We conducted a cross-sectional study of antibiotic prescriptions dispensed in Canadian provinces in 2019, leveraging the IQVIA Geographic Prescription Monitor database. We report annual rates of overall antibiotic dispensing, broad-spectrum antibiotic dispensing and age-specific antibiotic dispensing as prescriptions per 1000 population in each province and nationally. RESULTS: A total of 23 406 640 antibiotic prescriptions were dispensed nationally in 2019, at a rate of 627.3 prescriptions per 1000 population. Overall antibiotic dispensing rates in Newfoundland and Labrador (920.5 prescriptions per 1000 population) and Saskatchewan (713.7 prescriptions per 1000 population) significantly exceeded the national rate, whereas the rate in British Columbia (543.3 prescriptions per 1000 population) was significantly below the national rate. We observed additional variation when provincial rates of antibiotic dispensing were stratified by drug class and age group. INTERPRETATION: We identified interprovincial variation in antibiotic use in Canadian provinces in 2019. These findings highlight the need for provincial targets for antibiotic use to reduce overuse and antimicrobial resistance.

Measuring the impacts of the Using Antibiotics Wisely campaign on Canadian community utilization of oral antibiotics for respiratory tract infections: a time-series analysis from 2015 to 2019.

BACKGROUND: On 1 November 2018, Choosing Wisely Canada launched their Using Antibiotics Wisely primary care campaign, which aimed to reduce unnecessary antibiotic prescriptions for respiratory tract infections (RTIs) through educational tools for patients and providers. OBJECTIVES: We explored the impact of this campaign on antibiotic utilization in Canada. METHODS: We conducted a population-based study in Canada between January 2015 and December 2019. We used interventional autoregressive integrated moving average models to study the impact of the Using Antibiotics Wisely campaign on the prescribing rate (prescriptions per 1000 population) of RTI-indicated antibiotics. We analysed prescription rates overall and stratified by age group, drug class and province, in each month over the study period. RESULTS: There was a 1.5% reduction in the annual prescribing rate of RTI-indicated antibiotics over the study period, which was generally consistent across age groups and provinces. Following the 2018 Using Antibiotics Wisely clinician toolkit release, we observed no significant change in RTI-indicated antibiotic prescribing rates nationally (P = 0.13). This was consistent by age group (children, P = 0.91; adults, P = 0.58; and older adults, P = 0.67) and drug class (narrow-spectrum penicillins, P = 0.88; macrolides, P = 0.85; broad-spectrum penicillins, P = 0.60; cephalosporins, P = 0.45; tetracyclines, P = 0.55; and fluoroquinolones, P = 0.98). In our secondary analysis of prescription rates in provinces that self-identified as prioritizing Using Antibiotics Wisely, we observed no significant change following the launch of the campaign. CONCLUSIONS: The introduction of the Using Antibiotics Wisely campaign in Canada has not caused a significant change in short-term antibiotic prescribing patterns. Community antibiotic stewardship campaigns that include components beyond education may be more impactful.

Potential Cost Implications of Mandatory Non-Medical Switching Policies for Biologics for Rheumatic Conditions and Inflammatory Bowel Disease in Canada.

In 2018, TNFα inhibitors were the highest cost drug class for Canadian public drug programs. In 2019, two Canadian provinces announced mandatory nonmedical switching policies in an attempt to reduce their costs by increasing biosimilar uptake. The national impact of similar policies across Canada is unknown. We conducted a cross-sectional analysis of monthly publicly funded prescription claims for infliximab, etanercept, and adalimumab between June 2015 and December 2019. We reported the market share of biosimilars for infliximab and etanercept in 2019 for each province and estimated the cost savings that public payers could have realized in 2019 if mandatory switching policies had been implemented across Canada, including a sensitivity analysis, which assumed that governments receive a 25% rebate on all biologics. Provincial drug programs spent CAD $991.84 million on infliximab, etanercept, and adalimumab in 2019, and, when biosimilars were available, they constituted only 15.5% of national utilization of these drugs. In British Columbia, the implementation of a mandatory switching policy for patients with rheumatic conditions increased the biosimilar market share of infliximab and etanercept by 299% (from 19.7% to 78.5%). If applied nationwide to all three biologics for all indications, we estimate such policies could lead to annual savings of between CAD $179.71 million and CAD $425.64 million nationally. The overall market share of biosimilars remains low in all provinces where mandatory switching policies have not been introduced. The cost implications of successfully increasing biosimilar uptake would be substantial, particularly as more biosimilars reach the Canadian market.

Descriptions of the first zoeas of ten xanthid crabs (Crustacea: Decapoda: Xanthoidea) from the Gulf of Aqaba, Red Sea.

Ovigerous females of 10 species of xanthid crabs (Xanthidae MacLeay, 1838), from five subfamilies, namely, Pseudoliomera speciosa (Dana, 1852) (Actaeinae), Chlorodiella cytherea (Dana, 1852), Chl. laevissima (Dana, 1852), Chl. nigra (Forskål, 1775), Cyclodius granulosus (De Man, 1888) (Chlorodiellinae), Danielea noelensis (Ward, 1942) (Euxanthinae), Liomera rugata (H. Milne Edwards, 1834), Lio. tristis (Dana, 1852) (Liomerinae), Lachnopodus subacutus (Stimpson, 1858) and Leptodius sanguineus (H. Milne Edwards, 1834) (Xanthinae), were collected from the Gulf of Aqaba, and the zoea I obtained from them have been described herein. Six species, viz. Chl. cytherea, Chl. laevissima, Cyc. granulosus, Lio. rugata, Lio. tristis and Lep. sanguineus, are described for the first time, and Lac. subacutus and D. noelensis are re-described. Spinulations of dorsal and rostral spines of cephalothorax, length of rostral spine of cephalothorax to protopod of antenna, setations of antennule, ratio of antennal exopod to protopod and setations of exopod of antenna are important characters that distinguish xanthid larvae from their congeners and other closely related species at subfamilial levels.

Morphology of the complete larval stages of Portunus segnis (Forskål, 1775) (Crustacea: Brachyura: Portunidae) from the Gulf of Aqaba, Saudi Arabia.

Portunus pelagicus (Linnaeus, 1758) sensu lato has been recognized as a species complex comprising four species. Of these four species, the larval stages of all except Portunus segnis (Forskål, 1775), have been described. The larvae of P. segnis, hatched from an ovigerous female, caught in the Gulf of Aqaba, were cultured in the laboratory up to the megalopa stage. All the larval stages are described herein for the first time. The number of aesthetascs of the antennules of all the zoeal stages of P. segnis differs from those of the larvae of the other species of the P. pelagicus species complex. In the telson forks of zoea I-IV of P. segnis, there is a pair of ventral spines and two pairs of dorsal spines, whereas in the other P. pelagicus species complex larvae, there is a pair each of ventral and dorsal spines. Another unique feature, in the megalopa of P. segnis, are two endopod hooks in pleonites I-V. Different zoeal and megalopal stages of P. segnis can be distinguished clearly from the other P. pelagicus species complex larvae based on the number of setae and patterns of different appendages.

Suppression of Hepatic CYP3A4 Expression and Activity by 3-Methylcholanthrene in Humanized PXR-CAR-CYP3A4/3A7 Mice.

Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants that activate the aryl hydrocarbon receptor, thereby triggering a range of biologic responses, exemplified by the induction of CYP1A1 PAHs can also regulate the expression of members of the CYP3A subfamily, with reports of mainly suppressive effects on mouse hepatic Cyp3a11 expression, but paradoxically both inductive and suppressive effects on human hepatic CYP3A4 expression. Understanding the regulation of CYP3A4 expression by PAHs is important because of the widespread exposure of humans to these chemicals and the central role of the CYP3A4 enzyme in the metabolism of clinically important drugs and endogenous substances. The present study used 3-methylcholanthrene (MC) as a model PAH to characterize the in vivo regulation of CYP3A4 expression and activity in humanized pregnane X receptor-constitutive androstane receptor-CYP3A4/3A7 mice. Adult mice were treated by intraperitoneal injection with MC (80 mg/kg), or corn oil vehicle, and euthanized 24 or 72 hours later. As a positive control response, pronounced induction of hepatic Cyp1a1 by MC was confirmed at both time points in males and females at the mRNA, protein, and catalytic activity levels. Basal hepatic CYP3A4 expression and activity were significantly higher in female versus male mice. MC treatment suppressed hepatic CYP3A4 in female mice at 72 hours postdosing at the mRNA, protein, and catalytic activity levels. A similar response was observed in male mice, although the suppression of CYP3A4 protein levels did not achieve statistical significance. This mouse model will facilitate further studies of the mechanisms and consequences of CYP3A4 suppression by PAHs.

Antibacterial Activities of Wasabi against Escherichia coli O157:H7 and Staphylococcus aureus.

Escherichia coli O157:H7 and Staphylococcus aureus are two of the major pathogens frequently involved in foodborne outbreaks. Control of these pathogens in foods is essential to food safety. It is of great interest in the use of natural antimicrobial compounds present in edible plants to control foodborne pathogens as consumers prefer more natural "green" foods. Allyl isothiocyanate (AITC) is an antimicrobial compound naturally present in wasabi (Japanese horseradish) and several other edible plants. Although the antibacterial effects of pure AITC and wasabi extract (essential oil) against several bacteria have been reported, the antibacterial property of natural wasabi has not been well studied. This study investigated the antibacterial activities of wasabi as well as AITC against E. coli O157:H7 and S. aureus. Chemical analysis showed that AITC is the major isothiocyanate in wasabi. The AITC concentration in the wasabi powder used in this study was 5.91 ± 0.59 mg/g. The minimum inhibitory concentration (MIC) of wasabi against E. coli O157:H7 or S. aureus was 1% (or 10 mg/ml). Wasabi at 4% displayed higher bactericidal activity against S. aureus than against E. coli O157:H7. The MIC of AITC against either pathogen was between 10 and 100 µg/ml. AITC at 500 µg/ml was bactericidal against both pathogens while AITC at 1000 µg/ml eliminated E. coli O157:H7 much faster than S. aureus. The results from this study showed that wasabi has strong antibacterial property and has high potential to effectively control E. coli O157:H7 and S. aureus in foods. The antibacterial property along with its natural green color, unique flavor, and advantage to safeguard foods at the point of ingestion makes wasabi a promising natural edible antibacterial plant. The results from this study may be of significant interest to the food industry as they develop new and safe foods. These results may also stimulate more research to evaluate the antibacterial effect of wasabi against other foodborne pathogens and to explore other edible plants for their antimicrobial properties. To our knowledge, this is the first report on the antibacterial activity of wasabi in its natural form of consumption against E. coli O157:H7 and S. aureus.

Temporomandibular joint loads in subjects with and without disc displacement.

The likelihood of development of degenerative joint disease (DJD) of the temporomandibular joint (TMJ) is related to the integrity of the TMJ disc. Predilection for mechanical failure of the TMJ disc may reflect inter-individual differences in TMJ loads. Nine females and eight males in each of normal TMJ disc position and bilateral disc displacement diagnostic groups consented to participate in our study. Disc position was determined by bilateral magnetic resonance images of the joints. Three-dimensional (3D) anatomical geometry of each subject was used in a validated computer-assisted numerical model to calculate ipsilateral and contralateral TMJ loads for a range of biting positions (incisor, canine, molar) and angles (1-13). Each TMJ load was a resultant vector at the anterosuperi or-most mediolateral midpoint the condyle and characterized in terms of magnitude and 3D orientation. Analysis of variance (ANOVA) was used to test for effects of biting position and angle on TMJ loads. Mean TMJ loads in subjects with disc displacement were 9.5-69% higher than in subjects with normal disc position. During canine biting, TMJ loads in subjects with disc displacement were 43% (ipsilateral condyle, p=0.029) and 49% (contralateral condyle, p=0.015) higher on average than in subjects with normal disc position. Biting angle effects showed that laterally directed forces on the dentition produced ipsilateral joint loads, which on average were 69% higher (p=0.002) compared to individuals with normal TMJ disc position. The data reported here describe large differences in TMJ loads between individuals with disc displacement and normal disc position. The results support future investigations of inter-individual differences in joint mechanics as a variable in the development of DJD of the TMJ.

Ambivalent tales of HIV disclosure in San Francisco.

In light of rising levels of unprotected anal intercourse (UAI) among men who have sex with men (MSM) in San Francisco, we sought to understand disclosure practices, the calculus of risk and attitudes about HIV seroconversion. In 2000, 150 MSM participated in interviews pivoting around a detailed narrative of a recent incident of UAI. In order to understand the relationship between individual and community norms, we analyzed the narratives as accounts situated within the respondents' experience of the HIV epidemic and the gay community in San Francisco. In justifying their risky sexual practices, MSM cited a community-wide shift toward non-disclosure and barebacking since the advent of highly active anti-retroviral therapy (HAART). Fearing rejection by HIV-positive partners who refuse to use condoms, HIV-negative men saw little advantage in disclosing to casual partners whom they perceived as overwhelmingly HIV-positive. By contrast, HIV-positive men appeared eager to disclose their positive status to release themselves from responsibility for transmission and facilitate "bareback" or unprotected sex. Disavowal of individual responsibility for safer sex in deference to community norms may contribute to the recent spiraling of risk behavior and HIV incidence. Implications for prevention policy are discussed.

A single methamphetamine administration rapidly decreases vesicular dopamine uptake.

Recent studies demonstrated that vesicular dopamine (DA) uptake can be rapidly altered in synaptic vesicles purified from the striata of stimulant-treated rats. Specifically, a single administration of the plasmalemmal DA transporter inhibitor, cocaine, or the DA D(2) agonist, quinpirole, increases vesicular DA uptake in vesicles purified from the striata of treated rats. These effects of cocaine are prevented by pretreatment with a D(2), but not D(1), DA receptor antagonist. The purpose of the present study was to characterize the effect of a mechanistically different psychostimulant, methamphetamine (METH), on vesicular DA uptake. Results demonstrated that a single administration of this DA-releasing agent rapidly and reversibly decreased vesicular DA uptake. The METH-related decrease in vesicular DA uptake was attenuated by pretreatment with the D(2) antagonist, eticlopride, but not the D(1) antagonist, SCH23390 (R-[+]-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine). Core body temperature did not contribute to the effects of METH on vesicular DA uptake. Neither quinpirole nor cocaine increased vesicular DA uptake when rats were concurrently treated with METH. These studies provide further evidence that psychostimulants rapidly and differentially modify vesicular DA uptake. In addition, these studies demonstrate a complex role for D(2) DA receptors in altering vesicular DA transport.

Phencyclidine increases vesicular dopamine uptake.

Phencyclidine (PCP) rapidly (within 1 h) increased vesicular dopamine uptake and binding of the vesicular monoamine transporter-2 (VMAT-2) ligand, dihydrotetrabenazine. Uptake returned to basal values 3 h in the striatum after a high-dose administration of this drug (15 mg/kg i.p.). In contrast, a similar pretreatment with another non-competitive NMDA receptor antagonist, dizocilpine;([5R,10S]-[+]-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine; MK-801; 1 mg/kg, i.p.), was without effect on vesicular dopamine uptake. Pretreatment with the dopamine D2 receptor antagonist, eticlopride, blocked the increase in vesicular dopamine uptake caused by PCP administration. These data demonstrate a heretofore unreported mechanism that may contribute to the ability of PCP to influence dopamine neuronal function and exert its pharmacological effects.