MINSTED tracking of single biomolecules.

Here we show that MINSTED localization, a method whereby the position of a fluorophore is identified with precisely controlled beams of a STED microscope, tracks fluorophores and hence labeled biomolecules with nanometer/millisecond spatiotemporal precision. By updating the position for each detected photon, MINSTED recognizes fluorophore steps of 16 nm within <250 µs using about 13 photons. The power of MINSTED tracking is demonstrated by resolving the stepping of the motor protein kinesin-1 walking on microtubules and switching protofilaments.

Antarctic ice dynamics amplified by Northern Hemisphere sea-level forcing.

Sea-level rise due to ice loss in the Northern Hemisphere in response to insolation and greenhouse gas forcing is thought to have caused grounding-line retreat of marine-based sectors of the Antarctic Ice Sheet (AIS)1-3. Such interhemispheric sea-level forcing may explain the synchronous evolution of global ice sheets over ice-age cycles. Recent studies that indicate that the AIS experienced substantial millennial-scale variability during and after the last deglaciation4-7 (roughly 20,000 to 9,000 years ago) provide further evidence of this sea-level forcing. However, global sea-level change as a result of mass loss from ice sheets is strongly nonuniform, owing to gravitational, deformational and Earth rotational effects8, suggesting that the response of AIS grounding lines to Northern Hemisphere sea-level forcing is more complicated than previously modelled1,2,6. Here, using an ice-sheet model coupled to a global sea-level model, we show that AIS dynamics are amplified by Northern Hemisphere sea-level forcing. As a result of this interhemispheric interaction, a large or rapid Northern Hemisphere sea-level forcing enhances grounding-line advance and associated mass gain of the AIS during glaciation, and grounding-line retreat and mass loss during deglaciation. Relative to models without these interactions, the inclusion of Northern Hemisphere sea-level forcing in our model increases the volume of the AIS during the Last Glacial Maximum (about 26,000 to 20,000 years ago), triggers an earlier retreat of the grounding line and leads to millennial-scale variability throughout the last deglaciation. These findings are consistent with geologic reconstructions of the extent of the AIS during the Last Glacial Maximum and subsequent ice-sheet retreat, and with relative sea-level change in Antarctica3-7,9,10.

Patient-Level Pooled Analysis of Endovascular Ultrasound Renal Denervation or a Sham Procedure 6 Months After Medication Escalation: The RADIANCE Clinical Trial Program.

BACKGROUND: The randomized, sham-controlled RADIANCE-HTN (A Study of the Recor Medical Paradise System in Clinical Hypertension) SOLO, RADIANCE-HTN TRIO, and RADIANCE II (A Study of the Recor Medical Paradise System in Stage II Hypertension) trials independently met their primary end point of a greater reduction in daytime ambulatory systolic blood pressure (SBP) 2 months after ultrasound renal denervation (uRDN) in patients with hypertension. To characterize the longer-term effectiveness and safety of uRDN versus sham at 6 months, after the blinded addition of antihypertensive treatments (AHTs), we pooled individual patient data across these 3 similarly designed trials. METHODS: Patients with mild to moderate hypertension who were not on AHT or with hypertension resistant to a standardized combination triple AHT were randomized to uRDN (n=293) versus sham (n=213); they were to remain off of added AHT throughout 2 months of follow-up unless specified blood pressure (BP) criteria were exceeded. In each trial, if monthly home BP was ≥135/85 mm Hg from 2 to 5 months, standardized AHT was sequentially added to target home BP <135/85 mm Hg under blinding to initial treatment assignment. Six-month outcomes included baseline- and AHT-adjusted change in daytime ambulatory, home, and office SBP; change in AHT; and safety. Linear mixed regression models using all BP measurements and change in AHT from baseline through 6 months were used. RESULTS: Patients (70% men) were 54.1±9.3 years of age with a baseline daytime ambulatory/home/office SBP of 150.5±9.8/151.0±12.4/155.5±14.4 mm Hg, respectively. From 2 to 6 months, BP decreased in both groups with AHT titration, but fewer uRDN patients were prescribed AHT (P=0.004), and fewer additional AHT were prescribed to uRDN patients versus sham patients (P=0.001). Whereas the unadjusted between-group difference in daytime ambulatory SBP was similar at 6 months, the baseline and medication-adjusted between-group difference at 6 months was -3.0 mm Hg (95% CI, -5.7, -0.2; P=0.033), in favor of uRDN+AHT. For home and office SBP, the adjusted between-group differences in favor of uRDN+AHT over 6 months were -5.4 mm Hg (-6.8, -4.0; P<0.001) and -5.2 mm Hg (-7.1, -3.3; P<0.001), respectively. There was no heterogeneity between trials. Safety outcomes were few and did not differ between groups. CONCLUSIONS: This individual patient-data analysis of 506 patients included in the RADIANCE trials demonstrates the maintenance of BP-lowering efficacy of uRDN versus sham at 6 months, with fewer added AHTs. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT02649426 and NCT03614260.

Effect of Alcohol-Mediated Renal Denervation on Blood Pressure in the Presence of Antihypertensive Medications: Primary Results From the TARGET BP I Randomized Clinical Trial.

BACKGROUND: Renal denervation (RDN) has demonstrated clinically relevant reductions in blood pressure (BP) among individuals with uncontrolled hypertension despite lifestyle intervention and medications. The safety and effectiveness of alcohol-mediated RDN have not been formally studied in this indication. METHODS: TARGET BP I is a prospective, international, sham-controlled, randomized, patient- and assessor-blinded trial investigating the safety and efficacy of alcohol-mediated RDN. Patients with office systolic BP (SBP) ≥150 and ≤180 mm Hg, office diastolic BP ≥90 mm Hg, and mean 24-hour ambulatory SBP ≥135 and ≤170 mm Hg despite prescription of 2 to 5 antihypertensive medications were enrolled. The primary end point was the baseline-adjusted change in mean 24-hour ambulatory SBP 3 months after the procedure. Secondary end points included mean between-group differences in office and ambulatory BP at additional time points. RESULTS: Among 301 patients randomized 1:1 to RDN or sham control, RDN was associated with a significant reduction in 24-hour ambulatory SBP at 3 months (mean±SD, -10.0±14.2 mm Hg versus -6.8±12.1 mm Hg; treatment difference, -3.2 mm Hg [95% CI, -6.3 to 0.0]; P=0.0487). Subgroup analysis of the primary end point revealed no significant interaction across predefined subgroups. At 3 months, the mean change in office SBP was -12.7±18.3 and -9.7±17.3 mm Hg (difference, -3.0 [95% CI, -7.0 to 1.0]; P=0.173) for RDN and sham, respectively. No significant differences in ambulatory or office diastolic BP were observed. Adverse safety events through 6 months were uncommon, with one instance of accessory renal artery dissection in the RDN group (0.7%). No significant between-group differences in medication changes or patient adherence were identified. CONCLUSIONS: Alcohol-mediated RDN was associated with a modest but statistically significant reduction in 24-hour ambulatory SBP compared with sham control. No significant differences between groups in office BP or 6-month major adverse events were observed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02910414.

Systematic identification of factors involved in the silencing of germline genes in mouse embryonic stem cells.

In mammals, many germline genes are epigenetically repressed to prevent their illegitimate expression in somatic cells. To advance our understanding of the mechanisms restricting the expression of germline genes, we analyzed their chromatin signature and performed a CRISPR-Cas9 knock-out screen for genes involved in germline gene repression using a Dazl-GFP reporter system in mouse embryonic stem cells (mESCs). We show that the repression of germline genes mainly depends on the polycomb complex PRC1.6 and DNA methylation, which function additively in mESCs. Furthermore, we validated novel genes involved in the repression of germline genes and characterized three of them: Usp7, Shfm1 (also known as Sem1) and Erh. Inactivation of Usp7, Shfm1 or Erh led to the upregulation of germline genes, as well as retrotransposons for Shfm1, in mESCs. Mechanistically, USP7 interacts with PRC1.6 components, promotes PRC1.6 stability and presence at germline genes, and facilitates DNA methylation deposition at germline gene promoters for long term repression. Our study provides a global view of the mechanisms and novel factors required for silencing germline genes in embryonic stem cells.

CXCR4 PET/MRI for follow-up of gastric mucosa-associated lymphoid tissue lymphoma after first-line Helicobacter pylori eradication.

Posttreatment evaluation of gastric mucosa-associated lymphoid tissue (MALT) lymphoma currently relies on esophagogastroduodenoscopy with histological assessment of biopsies. Overexpression of the G protein-coupled C-X-C chemokine receptor type 4 (CXCR4) has been previously observed in MALT lymphoma. The aim of this prospective study was to evaluate positron emission tomography (PET) with the novel CXCR4 tracer [68Ga]Pentixafor as a potential alternative to follow up biopsies for assessment of residual disease (noncomplete remission [CR]) after first-line Helicobacter pylori eradication. Forty-six post-H pylori eradication [68Ga]Pentixafor-PET/magnetic resonance imaging (MRI) examinations of 26 gastric MALT lymphoma patients, and 20 [68Ga]Pentixafor-PET/MRI examinations of 20 control group patients without lymphoma, were analyzed. In the MALT lymphoma group, time-matched gastric biopsies were used as reference standard and showed CR in 6 cases. Pooled examination-based accuracy, sensitivity, specificity, and positive and negative predictive values of [68Ga]Pentixafor-PET for detection of residual gastric MALT lymphoma at follow-up were 97.0%, 95.0%, 100.0%, 100.0%, and 92.9%, respectively. Maximum and mean PET standardized uptake values showed moderate correlation with immunohistochemistry-based CXCR4+ cell counts, with correlation coefficients of r = 0.51 and r = 0.52 (P = .008 and P = .006). In summary, CXCR4 imaging with [68Ga]Pentixafor-PET may represent a promising test for assessment of residual gastric MALT lymphomas after H pylori eradication.

Multiparametric prenatal imaging characterization of fetal brain edema in Chiari II malformation might help to select candidates for fetal surgery.

OBJECTIVE: To identify brain edema in fetuses with Chiari II malformation using a multiparametric approach including structural T2-weighted, diffusion tensor imaging (DTI) metrics, and MRI-based radiomics. METHODS: A single-center retrospective review of MRI scans obtained in fetuses with Chiari II was performed. Brain edema cases were radiologically identified using the following MR criteria: brain parenchymal T2 prolongation, blurring of lamination, and effacement of external CSF spaces. Fractional anisotropy (FA) values were calculated from regions of interest (ROI), including hemispheric parenchyma, internal capsule, and corticospinal tract, and compared group-wise. After 1:1 age matching and manual single-slice 2D segmentation of the fetal brain parenchyma using ITK-Snap, radiomics features were extracted using pyradiomics. Areas under the curve (AUCs) of the features regarding discriminating subgroups were calculated. RESULTS: Ninety-one fetuses with Chiari II underwent a total of 101 MRI scans at a median gestational age of 24.4 weeks and were included. Fifty scans were visually classified as Chiari II with brain edema group and showed significantly reduced external CSF spaces compared to the nonedema group (9.8 vs. 18.3 mm, p < 0.001). FA values of all used ROIs were elevated in the edema group (p < 0.001 for all ROIs). The 10 most important radiomics features showed an AUC of 0.81 (95%CI: 0.71, 0.91) for discriminating between Chiari II fetuses with and without edema. CONCLUSIONS: Brain edema in fetuses with Chiari II is common and radiologically detectable on T2-weighted fetal MRI sequences, and DTI-based FA values and radiomics features provide further evidence of microstructure differences between subgroups with and without edema. CLINICAL RELEVANCE STATEMENT: A more severe phenotype of fetuses with Chiari II malformation is characterized by prenatal brain edema and more postnatal clinical morbidity and disability. Fetal brain edema is a promising prenatal MR imaging biomarker candidate for optimizing the risk-benefit evaluation of selection for fetal surgery. KEY POINTS: Brain edema of fetuses prenatally diagnosed with Chiari II malformation is a common, so far unknown, association. DTI metrics and radiomics confirm microstructural differences between the brains of Chiari II fetuses with and without edema. Fetal brain edema may explain worse motor outcomes in this Chiari II subgroup, who may substantially benefit from fetal surgery.

Ultra-low-dose vs. standard-of-care-dose CT of the chest in patients with post-COVID-19 conditions-a prospective intra-patient multi-reader study.

OBJECTIVES: To conduct an intrapatient comparison of ultra-low-dose computed tomography (ULDCT) and standard-of-care-dose CT (SDCT) of the chest in terms of the diagnostic accuracy of ULDCT and intrareader agreement in patients with post-COVID conditions. METHODS: We prospectively included 153 consecutive patients with post-COVID-19 conditions. All participants received an SDCT and an additional ULDCT scan of the chest. SDCTs were performed with standard imaging parameters and ULDCTs at a fixed tube voltage of 100 kVp (with tin filtration), 50 ref. mAs (dose modulation active), and iterative reconstruction algorithm level 5 of 5. All CT scans were separately evaluated by four radiologists for the presence of lung changes and their consistency with post-COVID lung abnormalities. Radiation dose parameters and the sensitivity, specificity, and accuracy of ULDCT were calculated. RESULTS: Of the 153 included patients (mean age 47.4 ± 15.3 years; 48.4% women), 45 (29.4%) showed post-COVID lung abnormalities. In those 45 patients, the most frequently detected CT patterns were ground-glass opacities (100.0%), reticulations (43.5%), and parenchymal bands (37.0%). The accuracy, sensitivity, and specificity of ULDCT compared to SDCT for the detection of post-COVID lung abnormalities were 92.6, 87.2, and 94.9%, respectively. The median total dose length product (DLP) of ULDCTs was less than one-tenth of the radiation dose of our SDCTs (12.6 mGy*cm [9.9; 15.5] vs. 132.1 mGy*cm [103.9; 160.2]; p < 0.001). CONCLUSION: ULDCT of the chest offers high accuracy in the detection of post-COVID lung abnormalities compared to an SDCT scan at less than one-tenth the radiation dose, corresponding to only twice the dose of a standard chest radiograph in two views. CLINICAL RELEVANCE STATEMENT: Ultra-low-dose CT of the chest may provide a favorable, radiation-saving alternative to standard-dose CT in the long-term follow-up of the large patient cohort of post-COVID-19 patients.

Perceptions of radiologists on structured reporting for cancer imaging-a survey by the European Society of Oncologic Imaging (ESOI).

OBJECTIVES: To assess radiologists' current use of, and opinions on, structured reporting (SR) in oncologic imaging, and to provide recommendations for a structured report template. MATERIALS AND METHODS: An online survey with 28 questions was sent to European Society of Oncologic Imaging (ESOI) members. The questionnaire had four main parts: (1) participant information, e.g., country, workplace, experience, and current SR use; (2) SR design, e.g., numbers of sections and fields, and template use; (3) clinical impact of SR, e.g., on report quality and length, workload, and communication with clinicians; and (4) preferences for an oncology-focused structured CT report. Data analysis comprised descriptive statistics, chi-square tests, and Spearman correlation coefficients. RESULTS: A total of 200 radiologists from 51 countries completed the survey: 57.0% currently utilized SR (57%), with a lower proportion within than outside of Europe (51.0 vs. 72.7%; p = 0.006). Among SR users, the majority observed markedly increased report quality (62.3%) and easier comparison to previous exams (53.5%), a slightly lower error rate (50.9%), and fewer calls/emails by clinicians (78.9%) due to SR. The perceived impact of SR on communication with clinicians (i.e., frequency of calls/emails) differed with radiologists' experience (p < 0.001), and experience also showed low but significant correlations with communication with clinicians (r = - 0.27, p = 0.003), report quality (r = 0.19, p = 0.043), and error rate (r = - 0.22, p = 0.016). Template use also affected the perceived impact of SR on report quality (p = 0.036). CONCLUSION: Radiologists regard SR in oncologic imaging favorably, with perceived positive effects on report quality, error rate, comparison of serial exams, and communication with clinicians. CLINICAL RELEVANCE STATEMENT: Radiologists believe that structured reporting in oncologic imaging improves report quality, decreases the error rate, and enables better communication with clinicians. Implementation of structured reporting in Europe is currently below the international level and needs society endorsement. KEY POINTS: • The majority of oncologic imaging specialists (57% overall; 51% in Europe) use structured reporting in clinical practice. • The vast majority of oncologic imaging specialists use templates (92.1%), which are typically cancer-specific (76.2%). • Structured reporting is perceived to markedly improve report quality, communication with clinicians, and comparison to prior scans.

Management of MCI in the Outpatient Setting.

PURPOSE OF REVIEW: We review current literature related to the clinical assessment of Mild Cognitive Impairment (MCI). We compile recommendations related to the evaluation of MCI and examine literature regarding the use of clinical biomarkers in this assessment, the role of non-pharmacologic therapy in the prevention of cognitive decline, and recent approval of anti-amyloid therapy in the treatment of MCI. RECENT FINDINGS: The role of imaging and plasma biomarkers in the clinical assessment of MCI has expanded. There is data that non-pharmacologic therapy may have a role in the prevention of neurocognitive decline. Anti-amyloid therapies have recently been approved for clinical use. Clinical assessment of MCI remains multifactorial and includes screening and treating for underlying psychiatric and medical co-morbidities. The use of biomarkers in clinical settings is expanding with the rise of anti-amyloid therapies. These new diagnostics and therapeutics require nuanced discussion of risks and benefits. Psychiatrist's skillset is uniquely suited for these complex evaluations.

Larger corpus callosum volume is favorable for theory of mind development in healthy children.

While previous research has demonstrated a link between the corpus callosum (CC) and theory of mind (ToM) abilities in individuals with corpus callosum agenesis (ACC), the relationship between CC volume and ToM remains unclear in healthy children. The present study examined whether CC volume influences children's performance on ToM tasks that assess their understanding of pretense, emotion recognition, and false beliefs. Forty children aged 6-12 years underwent structural magnetic resonance imaging (MRI) and a cognitive test battery. We found that larger mid-anterior and central subsections of the CC significantly correlated with better ToM abilities. We could also demonstrate age- and sex-related effects, as the CC-ToM relationship differed between younger (6-8 years) and older (9-12 years) children, and between female and male participants. Importantly, the older children drove the association between the CC mid-anterior and central subsection volumes and ToM abilities. This study is the first to demonstrate that CC size is associated with ToM abilities in healthy children, underlining the idea that the CC plays a vital role in their socio-cognitive development. CC subsection volumes may thus not only serve as a measure of heterogeneity in neurodevelopmental populations known to exhibit socio-cognitive deficits, but also in typically developing children.

A molecular epidemiological investigation of contagious caprine pleuropneumonia in goats and captive Arabian sand gazelle (Gazella marica) in Oman.

BACKGROUND: Contagious caprine pleuropneumonia (CCPP) is a fatal WOAH-listed, respiratory disease in small ruminants with goats as primary hosts that is caused by Mycoplasma capricolum subspecies capripneumoniae (Mccp). Twelve CCPP outbreaks were investigated in 11 goat herds and a herd of captive Arabian sand gazelle (Gazella marica) in four Omani governorates by clinical pathological and molecular analysis to compare disease manifestation and Mccp genetic profiles in goats and wild ungulates. RESULTS: The CCPP forms in diseased and necropsied goats varied from peracute (5.8%), acute (79.2%) and chronic (4.5%) while all of the five necropsied gazelles showed the acute form based on the clinical picture, gross and histopathological evaluation. Colonies of Mccp were recovered from cultured pleural fluid, but not from lung tissue samples of one gazelle and nine goats and all the isolates were confirmed by Mccp-specific real time PCR. Whole genome-single nucleotide polymorphism (SNP) analysis was performed on the ten isolates sequenced in this study and twenty sequences retrieved from the Genbank database. The Mccp strains from Oman clustered all in phylogroup A together with strains from East Africa and one strain from Qatar. A low variability of around 125 SNPs was seen in the investigated Omani isolates from both goats and gazelles indicating mutual transmission of the pathogen between wildlife and goats. CONCLUSION: Recent outbreaks of CCPP in Northern Oman are caused by Mccp strains of the East African Phylogroup A which can infect goats and captive gazelles likewise. Therefore, wild and captive ungulates should be considered as reservoirs and included in CCPP surveillance measures.

Computed Tomography-Based Body Composition is Related to Perioperative Morbidity in Older Lung Transplant Recipients.

BACKGROUND: In older patients, a limited physical reserve is considered a contraindication for lung transplantation (LTx). Herein, we aimed to establish a computed tomography (CT)-based quantification of physical reserve in older patients scheduled for transplantation. METHODS: This retrospective study included patients older than 60 years who received LTx. Semiautomatic measurements of the mediastinal fat area and the dorsal muscle group area in pretransplantation CT scans were performed, and normalized data were correlated with clinical parameters. RESULTS: Patients (n = 108) were assigned into three groups (Musclehighfatlow [n = 25], Musclelowfathigh [n = 24], and other combinations [n = 59]). The Musclelowfathigh group had a significantly increased risk of wound infections (p = 0.002) and tracheostomy (p = 0.001) compared with Musclehighfatlow patients. The median length of intensive care unit stay (25 vs. 3.5 days; p = 0.002) and the median length of hospital stay (44 vs. 22.5 days; p = 0.013) post-LTx were significantly prolonged in the Musclelowfathigh group. Significantly more patients in this group had a prolonged ventilation time (11 vs. 0; p < 0.001). CONCLUSION: Body composition parameters determined in pretransplant chest CT scans in older LTx candidates might aid in identifying high-risk patients with a worse perioperative outcome after LTx.

Gender roles produce divergent economic expectations.

Expectations about economic variables vary systematically across genders. In the domain of inflation, women have persistently higher expectations than men. We argue that traditional gender roles are a significant factor in generating this gender expectations gap as they expose women and men to different economic signals in their daily lives. Using unique data on the participation of men and women in household grocery chores, their resulting exposure to price signals, and their inflation expectations, we document a tight link between the gender expectations gap and the distribution of grocery shopping duties. Because grocery prices are highly volatile, and consumers focus disproportionally on positive price changes, frequent exposure to grocery prices increases perceptions of current inflation and expectations of future inflation. The gender expectations gap is largest in households whose female heads are solely responsible for grocery shopping, whereas no gap arises in households that split grocery chores equally between men and women. Our results indicate that gender differences in inflation expectations arise due to social conditioning rather than through differences in innate abilities, skills, or preferences.

Hypertension management in patients with cardiovascular comorbidities.

Arterial hypertension is a leading cause of death globally. Due to ageing, the rising incidence of obesity, and socioeconomic and environmental changes, its incidence increases worldwide. Hypertension commonly coexists with Type 2 diabetes, obesity, dyslipidaemia, sedentary lifestyle, and smoking leading to risk amplification. Blood pressure lowering by lifestyle modifications and antihypertensive drugs reduce cardiovascular (CV) morbidity and mortality. Guidelines recommend dual- and triple-combination therapies using renin-angiotensin system blockers, calcium channel blockers, and/or a diuretic. Comorbidities often complicate management. New drugs such as angiotensin receptor-neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists improve CV and renal outcomes. Catheter-based renal denervation could offer an alternative treatment option in comorbid hypertension associated with increased sympathetic nerve activity. This review summarises the latest clinical evidence for managing hypertension with CV comorbidities.

The value of contrast-enhanced ultrasound in percutaneous biopsy of retroperitoneal masses.

PURPOSE: To evaluate the diagnostic yield of contrast-enhanced ultrasound (CEUS)-guided biopsy of retroperitoneal masses (RMs). MATERIALS AND METHODS: Between 2006 and 2023, 87 patients presented at our US center for biopsy of an RM. In all biopsies, CEUS was performed prior to the intervention. The technical success rate of biopsy, the presence of diagnostic tissue in solid tumor biopsy samples, the accuracy of the biopsy and the occurrence of post-interventional complications were evaluated. RESULTS: A US-guided biopsy could be conducted in 84/87 cases (96.6%). In 3/87 cases (3.4%), US-guided biopsy was impossible because the planned needle path was obstructed by vital structures. Of 84 lesions, 80 (95.2%) were solid lesions, and 4 (4.8%) were lesions containing fluid. In all solid tumors, 80/80 (100%), diagnostic vital tissue was successfully obtained. CEUS-guided biopsy showed a sensitivity of 93.2%, a specificity of 100%, a positive predictive value of 100%, a negative predictive value of 72.2%, and a diagnostic accuracy of 94.2% for the differentiation between malignant and benign RMs. In one of the 84 cases (1.2%), there was a complication of postinterventional abdominal pain. CONCLUSION: Percutaneous CEUS-guided biopsy is a safe procedure with a high diagnostic yield and a low complication rate.

Clinical Trial Design Principles and Outcomes Definitions for Device-Based Therapies for Hypertension: A Consensus Document From the Hypertension Academic Research Consortium.

The clinical implications of hypertension in addition to a high prevalence of both uncontrolled blood pressure and medication nonadherence promote interest in developing device-based approaches to hypertension treatment. The expansion of device-based therapies and ongoing clinical trials underscores the need for consistency in trial design, conduct, and definitions of clinical study elements to permit trial comparability and data poolability. Standardizing methods of blood pressure assessment, effectiveness measures beyond blood pressure alone, and safety outcomes are paramount. The Hypertension Academic Research Consortium (HARC) document represents an integration of evolving evidence and consensus opinion among leading experts in cardiovascular medicine and hypertension research with regulatory perspectives on clinical trial design and methodology. The HARC document integrates the collective information among device-based therapies for hypertension to better address existing challenges and identify unmet needs for technologies proposed to treat the world's leading cause of death and disability. Consistent with the Academic Research Consortium charter, this document proposes pragmatic consensus clinical design principles and outcomes definitions for studies aimed at evaluating device-based hypertension therapies.

De novo genome assembly resolving repetitive structures enables genomic analysis of 35 European Mycoplasmopsis bovis strains.

Mycoplasmopsis (M.) bovis, the agent of mastitis, pneumonia, and arthritis in cattle, harbors a small genome of approximately 1 Mbp. Combining data from Illumina and Nanopore technologies, we sequenced and assembled the genomes of 35 European strains and isolate DL422_88 from Cuba. While the high proportion of repetitive structures in M. bovis genomes represent a particular challenge, implementation of our own pipeline Mycovista (available on GitHub www.github.com/sandraTriebel/mycovista ) in a hybrid approach enabled contiguous assembly of the genomes and, consequently, improved annotation rates considerably. To put our European strain panel in a global context, we analyzed the new genome sequences together with 175 genome assemblies from public databases. Construction of a phylogenetic tree based on core genes of these 219 strains revealed a clustering pattern according to geographical origin, with European isolates positioned on clades 4 and 5. Genomic data allowing assignment of strains to tissue specificity or certain disease manifestations could not be identified. Seven strains isolated from cattle with systemic circular condition (SCC), still a largely unknown manifestation of M. bovis disease, were located on both clades 4 and 5. Pairwise association analysis revealed 108 genomic elements associated with a particular clade of the phylogenetic tree. Further analyzing these hits, 25 genes are functionally annotated and could be linked to a M. bovis protein, e.g. various proteases and nucleases, as well as ten variable surface lipoproteins (Vsps) and other surface proteins. These clade-specific genes could serve as useful markers in epidemiological and clinical surveys.

Dual endothelin antagonist aprocitentan for resistant hypertension (PRECISION): a multicentre, blinded, randomised, parallel-group, phase 3 trial.

BACKGROUND: Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin antagonist aprocitentan in patients with resistant hypertension. METHODS: PRECISION was a multicentre, blinded, randomised, parallel-group, phase 3 study, which was done in hospitals or research centres in Europe, North America, Asia, and Australia. Patients were eligible for randomisation if their sitting systolic blood pressure was 140 mm Hg or higher despite taking standardised background therapy consisting of three antihypertensive drugs, including a diuretic. The study consisted of three sequential parts: part 1 was the 4-week double-blind, randomised, and placebo-controlled part, in which patients received aprocitentan 12·5 mg, aprocitentan 25 mg, or placebo in a 1:1:1 ratio; part 2 was a 32-week single (patient)-blind part, in which all patients received aprocitentan 25 mg; and part 3 was a 12-week double-blind, randomised, and placebo-controlled withdrawal part, in which patients were re-randomised to aprocitentan 25 mg or placebo in a 1:1 ratio. The primary and key secondary endpoints were changes in unattended office systolic blood pressure from baseline to week 4 and from withdrawal baseline to week 40, respectively. Secondary endpoints included 24-h ambulatory blood pressure changes. The study is registered on ClinicalTrials.gov, NCT03541174. FINDINGS: The PRECISION study was done from June 18, 2018, to April 25, 2022. 1965 individuals were screened and 730 were randomly assigned. Of these 730 patients, 704 (96%) completed part 1 of the study; of these, 613 (87%) completed part 2 and, of these, 577 (94%) completed part 3 of the study. The least square mean (SE) change in office systolic blood pressure at 4 weeks was -15·3 (SE 0·9) mm Hg for aprocitentan 12·5 mg, -15·2 (0·9) mm Hg for aprocitentan 25 mg, and -11·5 (0·9) mm Hg for placebo, for a difference versus placebo of -3·8 (1·3) mm Hg (97·5% CI -6·8 to -0·8, p=0·0042) and -3·7 (1·3) mm Hg (-6·7 to -0·8; p=0·0046), respectively. The respective difference for 24 h ambulatory systolic blood pressure was -4·2 mm Hg (95% CI -6·2 to -2·1) and -5·9 mm Hg (-7·9 to -3·8). After 4 weeks of withdrawal, office systolic blood pressure significantly increased with placebo versus aprocitentan (5·8 mm Hg, 95% CI 3·7 to 7·9, p<0·0001). The most frequent adverse event was mild-to-moderate oedema or fluid retention, occurring in 9%, 18%, and 2% for patients receiving aprocitentan 12·5 mg, 25 mg, and placebo, during the 4-week double-blind part, respectively. This event led to discontinuation in seven patients treated with aprocitentan. During the trial, a total of 11 treatment-emergent deaths occurred, none of which were regarded by the investigators to be related to study treatment. INTERPRETATION: In patients with resistant hypertension, aprocitentan was well tolerated and superior to placebo in lowering blood pressure at week 4 with a sustained effect at week 40. FUNDING: Idorsia Pharmaceuticals and Janssen Biotech.

Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): a randomised, sham-controlled trial.

BACKGROUND: Renal denervation has been shown to lower blood pressure in the presence of antihypertensive medications; however, long-term safety and efficacy data from randomised trials of renal denervation are lacking. In this pre-specified analysis of the SPYRAL HTN-ON MED study, we compared changes in blood pressure, antihypertensive drug use, and safety up to 36 months in renal denervation versus a sham control group. METHODS: This randomised, single-blind, sham-controlled trial enrolled patients from 25 clinical centres in the USA, Germany, Japan, the UK, Australia, Austria, and Greece, with uncontrolled hypertension and office systolic blood pressure between 150 mm Hg and 180 mm Hg and diastolic blood pressure of 90 mm Hg or higher. Eligible patients had to have 24-h ambulatory systolic blood pressure between 140 mm Hg and less than 170 mm Hg, while taking one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned (1:1) to radiofrequency renal denervation or a sham control procedure. Patients and physicians were unmasked after 12-month follow-up and sham control patients could cross over after 12-month follow-up completion. The primary endpoint was the treatment difference in mean 24-h systolic blood pressure at 6 months between the renal denervation group and the sham control group. Statistical analyses were done on the intention-to-treat population. Long-term efficacy was assessed using ambulatory and office blood pressure measurements up to 36 months. Drug surveillance was used to assess medication use. Safety events were assessed up to 36 months. This trial is registered with ClinicalTrials.gov, NCT02439775; prospectively, an additional 260 patients are currently being randomly assigned as part of the SPYRAL HTN-ON MED Expansion trial. FINDINGS: Between July 22, 2015, and June 14, 2017, among 467 enrolled patients, 80 patients fulfilled the qualifying criteria and were randomly assigned to undergo renal denervation (n=38) or a sham control procedure (n=42). Mean ambulatory systolic and diastolic blood pressure were significantly reduced from baseline in the renal denervation group, and were significantly lower than the sham control group at 24 and 36 months, despite a similar treatment intensity of antihypertensive drugs. The medication burden at 36 months was 2·13 medications (SD 1·15) in the renal denervation group and 2·55 medications (2·19) in the sham control group (p=0·26). 24 (77%) of 31 patients in the renal denervation group and 25 (93%) of 27 patients in the sham control group adhered to medication at 36 months. At 36 months, the ambulatory systolic blood pressure reduction was -18·7 mm Hg (SD 12·4) for the renal denervation group (n=30) and -8·6 mm Hg (14·6) for the sham control group (n=32; adjusted treatment difference -10·0 mm Hg, 95% CI -16·6 to -3·3; p=0·0039). Treatment differences between the renal denervation group and sham control group at 36 months were -5·9 mm Hg (95% CI -10·1 to -1·8; p=0·0055) for mean ambulatory diastolic blood pressure, -11·0 mm Hg (-19·8 to -2·1; p=0·016) for morning systolic blood pressure, and -11·8 mm Hg (-19·0 to -4·7; p=0·0017) for night-time systolic blood pressure. There were no short-term or long-term safety issues associated with renal denervation. INTERPRETATION: Radiofrequency renal denervation compared with sham control produced a clinically meaningful and lasting blood pressure reduction up to 36 months of follow-up, independent of concomitant antihypertensive medications and without major safety events. Renal denervation could provide an adjunctive treatment modality in the management of patients with hypertension. FUNDING: Medtronic.