Randomized comparison of primary stenting and provisional balloon angioplasty guided by flow velocity measurement.

BACKGROUND: Coronary stenting improves outcomes compared with balloon angioplasty, but it is costly and may have other disadvantages. Limiting stent use to patients with a suboptimal result after angioplasty (provisional angioplasty) may be as effective and less expensive. METHODS AND RESULTS: To analyze the cost-effectiveness of provisional angioplasty, patients scheduled for single-vessel angioplasty were first randomized to receive primary stenting (97 patients) or balloon angioplasty guided by Doppler flow velocity and angiography (523 patients). Patients in the latter group were further randomized after optimization to either additional stenting or termination of the procedure to further investigate what is "optimal." An optimal result was defined as a flow reserve >2.5 and a diameter stenosis <36%. Bailout stenting was needed in 129 patients (25%) who were randomized to balloon angioplasty, and an optimal result was obtained in 184 of the 523 patients (35%). There was no significant difference in event-free survival at 1 year between primary stenting (86.6%) and provisional angioplasty (85.6%). Costs after 1 year were significantly higher for provisional angioplasty (EUR 6573 versus EUR 5885; P:=0.014). Results after the second randomization showed that stenting was also more effective after optimal balloon angioplasty (1-year event free survival, 93.5% versus 84.1%; P:=0. 066). CONCLUSIONS: After 1 year of follow-up, provisional angioplasty was more expensive and without clinical benefit. The beneficial value of stenting is not limited to patients with a suboptimal result after balloon angioplasty

Genome-wide association and HLA fine-mapping studies identify risk loci and genetic pathways underlying allergic rhinitis

Allergic rhinitis is the most common clinical presentation of allergy, affecting 400 million people worldwide, with increasing incidence in westernized countries1,2. To elucidate the genetic architecture and understand the underlying disease mechanisms, we carried out a meta-analysis of allergic rhinitis in 59,762 cases and 152,358 controls of European ancestry and identified a total of 41 risk loci for allergic rhinitis, including 20 loci not previously associated with allergic rhinitis, which were confirmed in a replication phase of 60,720 cases and 618,527 controls. Functional annotation implicated genes involved in various immune pathways, and fine mapping of the HLA region suggested amino acid variants important for antigen binding. We further performed genome-wide association study (GWAS) analyses of allergic sensitization against inhalant allergens and nonallergic rhinitis, which suggested shared genetic mechanisms across rhinitis-related traits. Future studies of the identified loci and genes might identify novel targets for treatment and prevention of allergic rhinitis

Lobar Dementia due to Extreme Widening of Virchow-Robin Spaces in One Hemisphere

Widened perivascular spaces known as Virchow-Robin spaces (VRS) are often seen on MRI and are usually incidental findings. It is unclear if enlarged VRS can be associated with neurological deficits. In this report, we describe a case of lobar dementia associated with unusual VRS widening in one cerebral hemisphere. A 77-year-old woman, seen at a memory clinic, presented with progressive cognitive decline, left hemianopsia, and mild pyramidal signs on the left side. On MRI, unusually wide VRS were visible, predominantly in the right centrum semiovale and the right temporo-occipital white matter. The clinical syndrome was consistent with the extent and location of the abnormally dilated VRS. The high MR signal in white matter bridges between the VRS suggested parenchymal damage, possibly representing gliotic white matter. No evidence for another etiology was found on cerebral MRI and rCBF SPECT. As a conclusion, enlarged VRS in one cerebral hemisphere may be associated with cognitive change and neurological deficits

Multi-ancestry genome-wide association study of 21,000 cases and 95,000 controls identifies new risk loci for atopic dermatitis

Genetic association studies have identified 21 loci associated with atopic dermatitis risk predominantly in populations of European ancestry. To identify further susceptibility loci for this common, complex skin disease, we performed a meta-analysis of >15 million genetic variants in 21,399 cases and 95,464 controls from populations of European, African, Japanese and Latino ancestry, followed by replication in 32,059 cases and 228,628 controls from 18 studies. We identified ten new risk loci, bringing the total number of known atopic dermatitis risk loci to 31 (with new secondary signals at four of these loci). Notably, the new loci include candidate genes with roles in the regulation of innate host defenses and T cell function, underscoring the important contribution of (auto)immune mechanisms to atopic dermatitis pathogenesis

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Initial clinical experience with [177Lu]Lu-PNT2002 radioligand therapy in metastatic castration-resistant prostate cancer: dosimetry, safety, and efficacy from the lead-in cohort of the SPLASH trial

IntroductionSPLASH (NCT04647526) is a multicenter phase III trial evaluating the efficacy and safety of [177Lu]Lu-PNT2002 radioligand therapy in metastatic castration-resistant prostate cancer (mCRPC). This study leveraged a lead-in phase to assess tissue dosimetry and evaluate preliminary safety and efficacy, prior to expansion into a randomized phase. Here we report those results.MethodsEnrolled participants had mCRPC that progressed on one prior androgen receptor pathway inhibitor (ARPI), were prostate-specific membrane antigen (PSMA) PET–positive as determined by a central reader, were chemotherapy-naïve for mCRPC, and had adequate bone marrow and end-organ reserve. Participants received up to 4 cycles of [177Lu]Lu-PNT2002 at 6.8 GBq (± 10%) intravenously per cycle every 8 weeks. Dosimetry (planar + SPECT/CT [n=7]; planar only [n=20]), safety, prostate-specific antigen (PSA) response, objective response rate (ORR), and radiographic progression-free survival (rPFS) per blinded independent central review were assessed.ResultsOf 34 individuals screened, 32 underwent PSMA-PET/CT; 27 met all eligibility criteria. Median (range) age was 72 (57-86) years; all participants were enrolled in North America; 40.7% initiated prior ARPI treatment without distant metastases (M0) and 25.9% while hormone sensitive. Nineteen of 27 (70.4%) participants completed all 4 planned cycles. Organs receiving the largest mean (median, range) specific absorbed doses were lacrimal glands at 1.2 (0.9, 0.4-6.7) Gy/GBq (planar only [n=27]), followed by kidneys at 0.73 (0.63, 0.22-1.8) Gy/GBq (planar + SPECT/CT [n=7]; planar only [n=20]). Mean (median, range) tumor specific absorbed dose was 4.3 (2.1, 0.3-33.4) Gy/GBq (approximately 29 Gy/cycle) based on planar + SPECT/CT of 21 lesions in seven participants. [177Lu]Lu-PNT2002 was associated with no treatment-related deaths, few treatment-related grade ≥3 treatment-emergent adverse events (TEAEs), and no discontinuations for unacceptable toxicity. Treatment-related TEAEs occurring in ≥10% of participants included dry mouth (22.2%; all grade 1), fatigue (18.5%; grades 1-2), nausea (18.5%; grades 1-2), and anemia (14.8%; grades 1-3). Median (95% CI) rPFS was 11.5 (9.2-19.1) months, a PSA decline of ≥50% occurred in 42.3% (11/26) of participants, and confirmed ORR for evaluable disease was 50% (5/10).Conclusion[177Lu]Lu-PNT2002, administered at 6.8 GBq/cycle for 4 cycles, demonstrated a favorable dosimetry and safety profile, as well as promising preliminary efficacy.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT04647526

European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation

Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p