Abstract
Since the publication of the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines for the Management of Arterial Hypertension, several high-quality ...studies, including randomised, sham-controlled trials on catheter-based renal denervation (RDN) were published, confirming both the blood pressure (BP)-lowering efficacy and safety of radiofrequency and ultrasound RDN in a broad range of patients with hypertension, including resistant hypertension. A clinical consensus document by the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on RDN in the management of hypertension was considered necessary to inform clinical practice. This expert group proposes that RDN is an adjunct treatment option in uncontrolled resistant hypertension, confirmed by ambulatory BP measurements, despite best efforts at lifestyle and pharmacological interventions. RDN may also be used in patients who are unable to tolerate antihypertensive medications in the long term. A shared decision-making process is a key feature and preferably includes a patient who is well informed on the benefits and limitations of the procedure. The decision-making process should take (i) the patient’s global cardiovascular (CV) risk and/or (ii) the presence of hypertension-mediated organ damage or CV complications into account. Multidisciplinary hypertension teams involving hypertension experts and interventionalists evaluate the indication and facilitate the RDN procedure. Interventionalists require expertise in renal interventions and specific training in RDN procedures. Centres performing these procedures require the skills and resources to deal with potential complications. Future research is needed to address open questions and investigate the impact of BP-lowering with RDN on clinical outcomes and potential clinical indications beyond hypertension.
Significance Understanding emerging disease origins is important to gauge future human infection risks. This is particularly true for the various forms of the AIDS virus, HIV-1, which were ...transmitted to humans on four independent occasions. Previous studies identified chimpanzees in southern Cameroon as the source of the pandemic M group, as well as the geographically more restricted N group. Here, we show that the remaining two groups also emerged in southern Cameroon but had their origins in western lowland gorillas. Although group P has only been detected in two individuals, group O has spread extensively throughout west central Africa. Thus, both chimpanzees and gorillas harbor viruses that are capable of crossing the species barrier to humans and causing major disease outbreaks.
HIV-1, the cause of AIDS, is composed of four phylogenetic lineages, groups M, N, O, and P, each of which resulted from an independent cross-species transmission event of simian immunodeficiency viruses (SIVs) infecting African apes. Although groups M and N have been traced to geographically distinct chimpanzee communities in southern Cameroon, the reservoirs of groups O and P remain unknown. Here, we screened fecal samples from western lowland ( n = 2,611), eastern lowland ( n = 103), and mountain ( n = 218) gorillas for gorilla SIV (SIVgor) antibodies and nucleic acids. Despite testing wild troops throughout southern Cameroon ( n = 14), northern Gabon ( n = 16), the Democratic Republic of Congo ( n = 2), and Uganda ( n = 1), SIVgor was identified at only four sites in southern Cameroon, with prevalences ranging from 0.8–22%. Amplification of partial and full-length SIVgor sequences revealed extensive genetic diversity, but all SIVgor strains were derived from a single lineage within the chimpanzee SIV (SIVcpz) radiation. Two fully sequenced gorilla viruses from southwestern Cameroon were very closely related to, and likely represent the source population of, HIV-1 group P. Most of the genome of a third SIVgor strain, from central Cameroon, was very closely related to HIV-1 group O, again pointing to gorillas as the immediate source. Functional analyses identified the cytidine deaminase APOBEC3G as a barrier for chimpanzee-to-gorilla, but not gorilla-to-human, virus transmission. These data indicate that HIV-1 group O, which spreads epidemically in west central Africa and is estimated to have infected around 100,000 people, originated by cross-species transmission from western lowland gorillas.
Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients ...with uncontrolled hypertension on antihypertensive medications with drug adherence testing.
In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20–80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing.
Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure −7·0 mm Hg, 95% CI −12·0 to −2·1; p=0·0059, 24 h diastolic blood pressure −4·3 mm Hg, −7·8 to −0·8; p=0.0174, office systolic blood pressure −6·6 mm Hg, −12·4 to −0·9; p=0·0250, and office diastolic blood pressure −4·2 mm Hg, −7·7 to −0·7; p=0·0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference −6·8 mm Hg, 95% CI −12·5 to −1·1; p=0·0205), 24 h systolic blood pressure (difference −7·4 mm Hg, −12·5 to −2·3; p=0·0051), office diastolic blood pressure (difference −3·5 mm Hg, −7·0 to −0·0; p=0·0478), and 24 h diastolic blood pressure (difference −4·1 mm Hg, −7·8 to −0·4; p=0·0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group.
Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common.
Medtronic.
Previous randomised renal denervation studies did not show consistent efficacy in reducing blood pressure. The objective of our study was to evaluate the effect of renal denervation on blood pressure ...in the absence of antihypertensive medications.
SPYRAL HTN-OFF MED was a multicentre, international, single-blind, randomised, sham-controlled, proof-of-concept trial. Patients were enrolled at 21 centres in the USA, Europe, Japan, and Australia. Eligible patients were drug-naive or discontinued their antihypertensive medications. Patients with an office systolic blood pressure (SBP) of 150 mm Hg or greater and less than 180 mm Hg, office diastolic blood pressure (DBP) of 90 mm Hg or greater, and a mean 24-h ambulatory SBP of 140 mm Hg or greater and less than 170 mm Hg at second screening underwent renal angiography and were randomly assigned to renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were blinded to randomisation assignments. The primary endpoint, change in 24-h blood pressure at 3 months, was compared between groups. Drug surveillance was done to ensure patient compliance with absence of antihypertensive medication. The primary analysis was done in the intention-to-treat population. Safety events were assessed at 3 months. This study is registered with ClinicalTrials.gov, number NCT02439749.
Between June 25, 2015, and Jan 30, 2017, 353 patients were screened. 80 patients were randomly assigned to renal denervation (n=38) or sham control (n=42) and followed up for 3 months. Office and 24-h ambulatory blood pressure decreased significantly from baseline to 3 months in the renal denervation group: 24-h SBP −5·5 mm Hg (95% CI −9·1 to −2·0; p=0·0031), 24-h DBP −4·8 mm Hg (−7·0 to −2·6; p<0·0001), office SBP −10·0 mm Hg (−15·1 to −4·9; p=0·0004), and office DBP −5·3 mm Hg (−7·8 to −2·7; p=0·0002). No significant changes were seen in the sham-control group: 24-h SBP −0·5 mm Hg (95% CI −3·9 to 2·9; p=0·7644), 24-h DBP −0·4 mm Hg (−2·2 to 1·4; p=0·6448), office SBP −2·3 mm Hg (−6·1 to 1·6; p=0·2381), and office DBP −0·3 mm Hg (−2·9 to 2·2; p=0·8052). The mean difference between the groups favoured renal denervation for 3-month change in both office and 24-h blood pressure from baseline: 24-h SBP −5·0 mm Hg (95% CI −9·9 to −0·2; p=0·0414), 24-h DBP −4·4 mm Hg (−7·2 to −1·6; p=0·0024), office SBP −7·7 mm Hg (−14·0 to −1·5; p=0·0155), and office DBP −4·9 mm Hg (−8·5 to −1·4; p=0·0077). Baseline-adjusted analyses showed similar findings. There were no major adverse events in either group.
Results from SPYRAL HTN-OFF MED provide biological proof of principle for the blood-pressure-lowering efficacy of renal denervation.
Medtronic.
Since the publication of the 2018 European Society of Cardiology/European Society of Hypertension (ESC/ESH) Guidelines for the Management of Arterial Hypertension, several high-quality studies, ...including randomised, sham-controlled trials on catheter-based renal denervation (RDN) were published, confirming both the blood pressure (BP)-lowering efficacy and safety of radiofrequency and ultrasound RDN in a broad range of patients with hypertension, including resistant hypertension. A clinical consensus document by the ESC Council on Hypertension and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) on RDN in the management of hypertension was considered necessary to inform clinical practice. This expert group proposes that RDN is an adjunct treatment option in uncontrolled resistant hypertension, confirmed by ambulatory BP measurements, despite best efforts at lifestyle and pharmacological interventions. RDN may also be used in patients who are unable to tolerate antihypertensive medications in the long term. A shared decision-making process is a key feature and preferably includes a patient who is well informed on the benefits and limitations of the procedure. The decision-making process should take (i) the patient's global cardiovascular (CV) risk and/or (ii) the presence of hypertension-mediated organ damage or CV complications into account. Multidisciplinary hypertension teams involving hypertension experts and interventionalists evaluate the indication and facilitate the RDN procedure. Interventionalists require expertise in renal interventions and specific training in RDN procedures. Centres performing these procedures require the skills and resources to deal with potential complications. Future research is needed to address open questions and investigate the impact of BP-lowering with RDN on clinical outcomes and potential clinical indications beyond hypertension.
5-HT receptors expressed throughout the human body are targets for established therapeutics and various drugs in development. Their diversity of structure and function reflects the important role ...5-HT receptors play in physiologic and pathophysiological processes. The present review offers a framework for the official receptor nomenclature and a detailed understanding of each of the 14 5-HT receptor subtypes, their roles in the systems of the body, and, where appropriate, the (potential) utility of therapeutics targeting these receptors. SIGNIFICANCE STATEMENT: This review provides a comprehensive account of the classification and function of 5-hydroxytryptamine receptors, including how they are targeted for therapeutic benefit.
Bacteria associated with coral hosts are diverse and abundant, with recent studies suggesting involvement of these symbionts in host resilience to anthropogenic stress. Despite their putative ...importance, the work dedicated to culturing coral-associated bacteria has received little attention. Combining published and unpublished data, here we report a comprehensive overview of the diversity and function of culturable bacteria isolated from corals originating from tropical, temperate, and cold-water habitats. A total of 3,055 isolates from 52 studies were considered by our metasurvey. Of these, 1,045 had full-length 16S rRNA gene sequences, spanning 138 formally described and 12 putatively novel bacterial genera across the
,
,
, and
phyla. We performed comparative genomic analysis using the available genomes of 74 strains and identified potential signatures of beneficial bacterium-coral symbioses among the strains. Our analysis revealed >400 biosynthetic gene clusters that underlie the biosynthesis of antioxidant, antimicrobial, cytotoxic, and other secondary metabolites. Moreover, we uncovered genomic features-not previously described for coral-bacterium symbioses-potentially involved in host colonization and host-symbiont recognition, antiviral defense mechanisms, and/or integrated metabolic interactions, which we suggest as novel targets for the screening of coral probiotics. Our results highlight the importance of bacterial cultures to elucidate coral holobiont functioning and guide the selection of probiotic candidates to promote coral resilience and improve holistic and customized reef restoration and rehabilitation efforts.
Our paper is the first study to synthesize currently available but decentralized data of cultured microbes associated with corals. We were able to collate 3,055 isolates across a number of published studies and unpublished collections from various laboratories and researchers around the world. This equated to 1,045 individual isolates which had full-length 16S rRNA gene sequences, after filtering of the original 3,055. We also explored which of these had genomes available. Originally, only 36 were available, and as part of this study, we added a further 38-equating to 74 in total. From this, we investigated potential genetic signatures that may facilitate a host-associated lifestyle. Further, such a resource is an important step in the selection of probiotic candidates, which are being investigated for promoting coral resilience and potentially applied as a novel strategy in reef restoration and rehabilitation efforts. In the spirit of open access, we have ensured this collection is available to the wider research community through the web site http://isolates.reefgenomics.org/ with the hope many scientists across the globe will ask for access to these cultures for future studies.
The RAZOR (Randomized Open versus Robotic Cystectomy) trial revealed noninferior 2-year progression-free survival for robotic radical cystectomy. This update was performed with extended followup for ...3 years to determine potential differences between the approaches. We also report 3-year overall survival and sought to identify factors predicting recurrence, and progression-free and overall survival.
We analyzed the per protocol population of 302 patients from the RAZOR study. Cumulative recurrence was estimated using nonbladder cancer death as the competing risk event and the Gray test was applied to assess significance in differences. Progression-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the log rank test. Predictors of outcomes were determined by Cox proportional hazard analysis.
Estimated progression-free survival at 36 months was 68.4% (95% CI 60.1-75.3) and 65.4% (95% CI 56.8-72.7) in the robotic and open groups, respectively (p=0.600). At 36 months overall survival was 73.9% (95% CI 65.5-80.5) and 68.5% (95% CI 59.8-75.7) in the robotic and open groups, respectively (p=0.334). There was no significant difference in the cumulative incidence rates of recurrence (p=0.802). Patient age greater than 70 years, poor performance status and major complications were significant predictors of 36-month progression-free survival. Stage and positive margins were significant predictors of recurrence, and progression-free and overall survival. Surgical approach was not a significant predictor of any outcome.
This analysis showed no difference in recurrence, 3-year progression-free survival or 3-year overall survival for robotic vs open radical cystectomy. It provides important prospective data on the oncologic efficacy of robotic radical cystectomy and high level data for patient counseling.
Cranial morphology in lepidosaurs is highly disparate and characterised by the frequent loss or reduction of bony elements. In varanids and geckos, the loss of the postorbital bar is associated with ...changes in skull shape, but the mechanical principles underlying this variation remain poorly understood. Here, we sought to determine how the overall cranial architecture and the presence of the postorbital bar relate to the loading and deformation of the cranial bones during biting in lepidosaurs. Using computer-based simulation techniques, we compared cranial biomechanics in the varanid
and the teiid
, two large, active foragers. The overall strain magnitude and distribution across the cranium were similar in the two species, despite lower strain gradients in
In
, the postorbital bar is important for resistance of the cranium to feeding loads. The postorbital ligament, which in varanids partially replaces the postorbital bar, does not affect bone strain. Our results suggest that the reduction of the postorbital bar impaired neither biting performance nor the structural resistance of the cranium to feeding loads in
Differences in bone strain between the two species might reflect demands imposed by feeding and non-feeding functions on cranial shape. Beyond variation in cranial bone strain related to species-specific morphological differences, our results reveal that similar mechanical behaviour is shared by lizards with distinct cranial shapes. Contrary to the situation in mammals, the morphology of the circumorbital region, calvaria and palate appears to be important for withstanding high feeding loads in these lizards.
Identification of regulators of Toxoplasma gondii bradyzoite development and cyst formation is the most direct way to address the importance of parasite development in long-term persistence and ...reactivation of this parasite. Here we show that a T. gondii gene (named Regulator of Cystogenesis 1; ROCY1) is sufficient for T. gondii bradyzoite formation in vitro and in vivo. ROCY1 encodes an RNA binding protein that has a preference for 3' regulatory regions of hundreds of T. gondii transcripts, and its RNA-binding domains are required to mediate bradyzoite development. Female mice infected with ΔROCY1 parasites have reduced (>90%) cyst burden. While viable parasites can be cultivated from brain tissue for up to 6 months post-infection, chronic brain-resident ΔROCY1 parasites have reduced oral infectivity compared to wild type. Despite clear defects in bradyzoite formation and oral infectivity, ΔROCY1 parasites were able to reactivate with similar timing and magnitude as wild type parasites for up to 5 months post-infection. Therefore while ROCY1 is a critical regulator of the bradyzoite developmental pathway, it is not required for parasite reactivation, raising new questions about the persisting life stage responsible for causing recrudescent disease.
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