Blood pressure effects of canagliflozin and clinical outcomes in type 2 diabetes and chronic kidney disease: Insights from the CREDENCE trial

Background: People with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) experience a high burden of hypertension but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population is uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP lowering therapy is also unknown. Methods: The CREDENCE trial randomized people with T2DM and CKD to canagliflozin or placebo. Post-hoc, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mmHg while receiving ≥3 classes of BP lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4,401 participants of whom 3,361 (76.4%) had baseline systolic BP ≥130 mmHg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50mmHg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP lowering therapy subgroups (all P-interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP lowering agents during the trial (HR 0.68, 95% CI 0.61-0.75). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death due to kidney or cardiovascular disease (HR 0.70, 95% CI 0.59-0.82) was consistent across BP and BP lowering therapy subgroups (all P-interaction ≥0.35), as were effects on other key kidney, cardiovascular and safety outcomes. Conclusions: In people with T2DM and CKD, canagliflozin lowers systolic BP across all BP defined subgroups and reduces the need for additional BP lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP lowering therapy in people with CKD. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique Identifier: NCT02065791

Sex differences in cardiovascular complications and mortality in hospital patients with covid-19: registry based observational study

Objective To assess whether the risk of cardiovascular complications of covid-19 differ between the sexes and to determine whether any sex differences in risk are reduced in individuals with pre-existing cardiovascular disease. Design Registry based observational study. Setting 74 hospitals across 13 countries (eight European) participating in CAPACITY-COVID (Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY), from March 2020 to May 2021 Participants All adults (aged ≥18 years), predominantly European, admitted to hospital with highly suspected covid-19 disease or covid-19 disease confirmed by positive laboratory test results (n=11 167 patients). Main outcome measures Any cardiovascular complication during admission to hospital. Secondary outcomes were in-hospital mortality and individual cardiovascular complications with ≥20 events for each sex. Logistic regression was used to examine sex differences in the risk of cardiovascular outcomes, overall and grouped by pre-existing cardiovascular disease. Results Of 11 167 adults (median age 68 years, 40% female participants) included, 3423 (36% of whom were female participants) had pre-existing cardiovascular disease. In both sexes, the most common cardiovascular complications were supraventricular tachycardias (4% of female participants, 6% of male participants), pulmonary embolism (3% and 5%), and heart failure (decompensated or de novo) (2% in both sexes). After adjusting for age, ethnic group, pre-existing cardiovascular disease, and risk factors for cardiovascular disease, female individuals were less likely than male individuals to have a cardiovascular complication (odds ratio 0.72, 95% confidence interval 0.64 to 0.80) or die (0.65, 0.59 to 0.72). Differences between the sexes were not modified by pre-existing cardiovascular disease; for the primary outcome, the female-to-male ratio of the odds ratio in those without, compared with those with, pre-existing cardiovascular disease was 0.84 (0.67 to 1.07). Conclusions In patients admitted to hospital for covid-19, female participants were less likely than male participants to have a cardiovascular complication. The differences between the sexes could not be attributed to the lower prevalence of pre-existing cardiovascular disease in female individuals. The reasons for this advantage in female individuals requires further research

A real-time controller for sustaining thermally relevant acoustic cavitation during ultrasound therapy.

A novel method for sustaining inertial cavitation during high-intensity focused ultrasound (HIFU) exposure in an agar-based tissue-mimicking material is presented. Inertial cavitation occurs during HIFU therapy when the local rarefaction pressure exceeds the inertial cavitation threshold of the insonated medium, and is characterized by broadband acoustic emissions which can be easily detected non-invasively using a passive cavitation detector (PCD). Under the right conditions, inertial cavitation has been previously shown to greatly enhance the rate of heat deposition by redistributing part of the energy carried at the fundamental HIFU frequency to higher frequencies, which are more readily absorbed by visco-elastic media such as soft tissue. However, in the absence of any cavitation control, inertial cavitation activity at the focus decays rapidly over a few seconds of exposure because of the combined effects of cavitation nuclei depletion, bubble dissolution, bubble-bubble interactions, increased vapor pressure caused by heating, and focal shielding caused by pre-focal bubble activity. The present work describes the design, validation, and testing of a real-time adaptive controller, with integrated passive localization capabilities, for sustaining inertial cavitation within the focal region of a HIFU transducer by modulation of the HIFU amplitude. Use of the controller in agar gel, originally at room temperature, has enabled therapeutically relevant temperatures in excess of 55°C to be maintained continuously in the focal region for more than 20 s using significantly less acoustic energy than is required to achieve the same temperature rise in the absence of cavitation control

A real-time controller for sustaining thermally relevant acoustic cavitation during ultrasound therapy.

A novel method for sustaining inertial cavitation during high-intensity focused ultrasound (HIFU) exposure in an agar-based tissue-mimicking material is presented. Inertial cavitation occurs during HIFU therapy when the local rarefaction pressure exceeds the inertial cavitation threshold of the insonated medium, and is characterized by broadband acoustic emissions which can be easily detected non-invasively using a passive cavitation detector (PCD). Under the right conditions, inertial cavitation has been previously shown to greatly enhance the rate of heat deposition by redistributing part of the energy carried at the fundamental HIFU frequency to higher frequencies, which are more readily absorbed by visco-elastic media such as soft tissue. However, in the absence of any cavitation control, inertial cavitation activity at the focus decays rapidly over a few seconds of exposure because of the combined effects of cavitation nuclei depletion, bubble dissolution, bubble-bubble interactions, increased vapor pressure caused by heating, and focal shielding caused by pre-focal bubble activity. The present work describes the design, validation, and testing of a real-time adaptive controller, with integrated passive localization capabilities, for sustaining inertial cavitation within the focal region of a HIFU transducer by modulation of the HIFU amplitude. Use of the controller in agar gel, originally at room temperature, has enabled therapeutically relevant temperatures in excess of 55°C to be maintained continuously in the focal region for more than 20 s using significantly less acoustic energy than is required to achieve the same temperature rise in the absence of cavitation control

Development and characterization of microsatellite loci in Mormon crickets (Anabrus simplex, Orthoptera, Tettigoniidae)

Anabrus simplex is an economically significant crop pest in the western United States and is a model organism for studying the influence of sex role reversal on sperm allocation and utilization patterns and population genetics. We isolated seven polymorphic microsatellite loci in Anabrus simplex, and within population allele numbers ranged from 10 to 25. High polymorphism is not unusual for Orthopteran insects, although observed heterozygosities ranged from 0.24 to 0.91 and were lower than expected heterozygosities, suggesting null alleles. These microsatellites will greatly facilitate studies of postcopulatory reproductive isolation in nuptial gift-giving insects and historical phylogenetics in the Rocky Mountains.</p

Spatiotemporal quantification of therapeutically relevant cavitation for ablation and drug delivery by ultrasound.

Stable and inertial cavitation have been shown to play a key role in several therapeutic ultrasound applications, ranging from non-invasive ablation to drug delivery. In order to achieve meaningful quantification of therapeutically relevant cavitation, a hypothesis as to the underlying mechanism by which bubbles enhance energy delivery and momentum transfer to their surroundings must first be formulated. Based on this hypothesis, correlations can be sought between time-based or frequency-based metrics of a relevant cavitation 'dose' and the desirable associated bioeffects, enabling the establishment of thresholds for therapeutically relevant processes to occur. However, the problem is complicated further by the fact that a single type of cavitation activity rarely occurs throughout an ultrasound exposure, or throughout the acoustic field of a therapeutic transducer. A recently developed method, known as passive acoustic mapping, makes it possible to obtain real-time maps of inertial and stable cavitation activity and could thus enable improved dosimetry of therapeutically relevant cavitational processes. The use of passive acoustic mapping for spatiotemporal classification and quantification of cavitation will be illustrated in the context of HIFU ablation, drug release from thermosensitive liposomes and drug delivery

The intensity of pre- and post-copulatory mate guarding in relation to spermatophore transfer in the cricket Gryllus bimaculatus

While post-copulatory mate guarding has been well documented in field crickets (Orthoptera: Gryllidae), the occurrence of pre-copulatory mate guarding in this family has been largely overlooked. We examined the relationship between the intensity of two components of mate guarding (body judders and antennal whips) and the time before and after copulation. We found that when male Gryllus bimaculatus encounter a female but do not have a spermatophore ready to transfer, they engage in pre-copulatory mate guarding that is very similar to post-copulatory mate guarding. The intensity of pre-copulatory mate guarding increased up to the point at which the male was ready to transfer his spermatophore. Following copulation, the intensity of mate guarding initially remained high before declining, after which it began to increase again just before the male resumed courtship stridulation. We interpret this pattern of post-copulatory mate guarding as being consistent with both the ejaculate-protection and spermatophore-renewal hypotheses for the function of mate guarding. We found no significant relationship between mate guarding intensity and male body mass