SARS-CoV-2 Transmission in Alberta, British Columbia, and Ontario, Canada, January 2020-January 2022.

We estimated COVID-19 transmission potential and case burden by variant type in Alberta, British Columbia, and Ontario, Canada, during January 23, 2020-January 27, 2022; we also estimated the effectiveness of public health interventions to reduce transmission. We estimated time-varying reproduction number (Rt) over 7-day sliding windows and nonoverlapping time-windows determined by timing of policy changes. We calculated incidence rate ratios (IRRs) for each variant and compared rates to determine differences in burden among provinces. Rt corresponding with emergence of the Delta variant increased in all 3 provinces; British Columbia had the largest increase, 43.85% (95% credible interval [CrI] 40.71%-46.84%). Across the study period, IRR was highest for Omicron (8.74 [95% CrI 8.71-8.77]) and burden highest in Alberta (IRR 1.80 [95% CrI 1.79-1.81]). Initiating public health interventions was associated with lower Rt and relaxing restrictions and emergence of new variants associated with increases in Rt.

Impact of hyperleptinemia during placental ischemia-induced hypertension in pregnant rats.

The prevalence of preeclampsia and obesity have increased. Although obesity is a major risk factor for preeclampsia, the mechanisms linking these morbidities are poorly understood. Circulating leptin levels increase in proportion to fat mass. Infusion of this adipokine elicits hypertension in nonpregnant rats, but less is known about how hyperleptinemia impacts blood pressure during placental ischemia, an initiating event in the pathophysiology of hypertension in preeclampsia. We tested the hypothesis that hyperleptinemia during reduced uterine perfusion pressure (RUPP) exaggerates placental ischemia-induced hypertension. On gestational day (GD) 14, Sprague-Dawley rats were implanted with osmotic mini-pumps delivering recombinant rat leptin (1 µg/kg/min iv) or vehicle concurrently with the RUPP procedure to induce placental ischemia or Sham. On GD 19, plasma leptin was elevated in Sham + Leptin and RUPP + Leptin. Leptin infusion did not significantly impact mean arterial pressure (MAP) in Sham. MAP was increased in RUPP + Vehicle vs. Sham + Vehicle. In contrast to our hypothesis, placental ischemia-induced hypertension was attenuated by leptin infusion. To examine potential mechanisms for attenuation of RUPP-induced hypertension during hyperleptinemia, endothelial-dependent vasorelaxation to acetylcholine was similar between Sham and RUPP; however, endothelial-independent vasorelaxation to the nitric oxide (NO)-donor, sodium nitroprusside, was increased in Sham and RUPP. These findings suggest that NO/cyclic guanosine monophosphate (cGMP) signaling was increased in the presence of hyperleptinemia. Plasma cGMP was elevated in Sham and RUPP hyperleptinemic groups compared with vehicle groups but plasma and vascular NO metabolites were reduced. These data suggest that hyperleptinemia during placental ischemia attenuates hypertension by compensatory increases in NO/cGMP signaling.NEW & NOTEWORTHY Ours is the first study to examine the impact of hyperleptinemia on the development of placental ischemia-induced hypertension using an experimental animal model.

xCT/SLC7A11 antiporter function inhibits HIV-1 infection.

Human macrophages are protected by intrinsic antiviral defenses that provide moderate protection against HIV-1 infection. Macrophages that do become infected can serve as long-lived reservoirs, to disseminate HIV-1 to CD4+ T cells. Infection of macrophages with HIV-1 and HIV-2 is inhibited by constitutive mobilization of antioxidant response master transcription regulator Nrf2. The downstream mediator of this restriction was not identified. Among the tens of genes controlled directly by Nrf2 in macrophages, we found that xCT/SLC7A11, a 12-transmembrane, cystine-glutamate antiporter promotes antiretroviral activity. We show here that depletion of xCT mRNA increases HIV-1 infection. Reconstitution of xCT knock out cells with wild-type xCT but not a transport-deficient mutant restores anti-HIV-1 activity. Pharmacological inhibitors of xCT amino acid transport also increase infection. The block is independent of known restriction factors and acts against HIV-1 and HIV-2. Like the block triggered through Nrf2, xCT function impedes infection immediately before 2-LTR circle formation.

Economic viability of tech-check-tech in an independent community pharmacy.

OBJECTIVES: To determine the economic feasibility of implementing community pharmacy-based tech-check-tech compared with other common community pharmacy practice models. METHODS: A decision tree analysis compared 4 community pharmacy practice models: (1) historical (pharmacist or technician fills prescriptions and pharmacist gives immunizations); (2) historical with tech-check-tech (technician or certified technician fills prescriptions and pharmacist gives vaccinations); (3) modern (historical model plus medication therapy management [MTM] services); and (4) modern with tech-check-tech (modern model but a technician or certified technician handles all fills). A series of summed Markov models with a 1-year time horizon compared strategies on gross profit with the use of cycles of 1 hour of work attributed to either filling prescriptions, giving vaccinations, or conducting MTM. RESULTS: Based on current MTM volume, the splitting of pharmacist time across all services (modern model) was the most profitable strategy, resulting in approximately $1700 more than the next most profitable approach (historical model). Models incorporating tech-check-tech need significant time to be filled by MTM services, vaccinations, or other billable services to make up for the investment made into pharmacists' time. For these models, the likelihood of conducting a comprehensive medication review (CMR) in a given hour needs to exceed 47% for allocating all pharmacist time to nonfilling functions to be more profitable. Performing targeted medication reviews alone (without the chance of a CMR) was not sufficient to make tech-check-tech a profitable strategy. At the current inputs, billable services of exceeding approximately $18 and $20 per hour are needed for tech-check-tech to be the most profitable model with and without MTM services, respectively. CONCLUSION: Tech-check-tech implementation in the community setting has the potential to be profitable if pharmacist time is adequately scheduled with other billable services. Future research in this area should increase the number of pharmacies included and expand analyses to encompass chain-based community pharmacies.

Activation kinetics of skinned cardiac muscle by laser photolysis of nitrophenyl-EGTA.

The kinetics of Ca(2+)-induced contractions of chemically skinned guinea pig trabeculae was studied using laser photolysis of NP-EGTA. The amount of free Ca(2+) released was altered by varying the output from a frequency-doubled ruby laser focused on the trabeculae, while maintaining constant total [NP-EGTA] and [Ca(2+)]. The time courses of the rise in stiffness and tension were biexponential at 23 degrees C, pH 7.1, and 200 mM ionic strength. At full activation (pCa < 5.0), the rates of the rapid phase of the stiffness and tension rise were 56 +/- 7 s(-1) (n = 7) and 48 +/- 6 s(-1) (n = 11) while the amplitudes were 21 +/- 2 and 23 +/- 3%, respectively. These rates had similar dependencies on final [Ca(2+)] achieved by photolysis: 43 and 50 s(-1) per pCa unit, respectively, over a range of [Ca(2+)] producing from 15% to 90% of maximal isometric tension. At all [Ca(2+)], the rise in stiffness initially was faster than that of tension. The maximal rates for the slower components of the rise in stiffness and tension were 4.1 +/- 0.8 and 6.2 +/- 1.0 s(-1). The rate of this slower phase exhibited significantly less Ca(2+) sensitivity, 1 and 4 s(-1) per pCa unit for stiffness and tension, respectively. These data, along with previous studies indicating that the force-generating step in the cross-bridge cycle of cardiac muscle is marginally sensitive to [Ca(2+)], suggest a mechanism of regulation in which Ca(2+) controls the attachment step in the cross-bridge cycle via a rapid equilibrium with the thin filament activation state. Myosin kinetics sets the time course for the rise in stiffness and force generation with the biexponential nature of the mechanical responses to steps in [Ca(2+)] arising from a shift to slower cross-bridge kinetics as the number of strongly bound cross-bridges increases.