Technology engagement is associated with higher perceived physical well-being in stroke patients prescribed smartwatches for atrial fibrillation detection.

Background: Increasing ownership of smartphones among Americans provides an opportunity to use these technologies to manage medical conditions. We examine the influence of baseline smartwatch ownership on changes in self-reported anxiety, patient engagement, and health-related quality of life when prescribed smartwatch for AF detection. Method: We performed a post-hoc secondary analysis of the Pulsewatch study (NCT03761394), a clinical trial in which 120 participants were randomized to receive a smartwatch-smartphone app dyad and ECG patch monitor compared to an ECG patch monitor alone to establish the accuracy of the smartwatch-smartphone app dyad for detection of AF. At baseline, 14 days, and 44 days, participants completed the Generalized Anxiety Disorder-7 survey, the Health Survey SF-12, and the Consumer Health Activation Index. Mixed-effects linear regression models using repeated measures with anxiety, patient activation, physical and mental health status as outcomes were used to examine their association with smartwatch ownership at baseline. Results: Ninety-six participants, primarily White with high income and tertiary education, were randomized to receive a study smartwatch-smartphone dyad. Twenty-four (25%) participants previously owned a smartwatch. Compared to those who did not previously own a smartwatch, smartwatch owners reported significant greater increase in their self-reported physical health (ß = 5.07, P < 0.05), no differences in anxiety (ß = 0.92, P = 0.33), mental health (ß = -2.42, P = 0.16), or patient activation (ß = 1.86, P = 0.54). Conclusions: Participants who own a smartwatch at baseline reported a greater positive change in self-reported physical health, but not in anxiety, patient activation, or self-reported mental health over the study period.

Association of S100A8/A9 with Lipid-Rich Necrotic Core and Treatment with Biologic Therapy in Patients with Psoriasis: Results from an Observational Cohort Study.

Psoriasis is a systemic inflammatory disease with an increased risk of atherosclerotic events and premature cardiovascular disease. S100A7, A8/A9, and A12 are protein complexes that are produced by activated neutrophils, monocytes, and keratinocytes in psoriasis. Lipid-rich necrotic core (LRNC) is a high-risk coronary plaque feature previously found to be associated with cardiovascular risk factors and psoriasis severity. LRNC can decrease with biologic therapy, but how this occurs remains unknown. We investigated the relationship between S100 proteins, LRNC, and biologic therapy in psoriasis. S100A8/A9 associated with LRNC in fully adjusted models (ß = 0.27, P = 0.009; n = 125 patients with psoriasis with available coronary computed tomography angiography scans; LRNC analyses; and serum S100A7, S100A8, S100A9, S100A12, and S100A8/A9 levels). At 1 year, in patients receiving biologic therapy (36 of 73 patients had 1-year coronary computed tomography angiography scans available), a 79% reduction in S100A8/A9 levels (‒172 [‒291.7 to 26.4] vs. ‒29.9 [‒137.9 to 50.5]; P = 0.04) and a 0.6 mm2 reduction in average LRNC area (0.04 [‒0.48 to 0.77] vs. ‒0.56 [‒1.8 to 0.13]; P = 0.02) were noted. These results highlight the potential role of S100A8/A9 in the development of high-risk coronary plaque in psoriasis.

A Human Pleiotropic Multiorgan Condition Caused by Deficient Wnt Secretion.

BACKGROUND: Structural birth defects occur in approximately 3% of live births; most such defects lack defined genetic or environmental causes. Despite advances in surgical approaches, pharmacologic prevention remains largely out of reach. METHODS: We queried worldwide databases of 20,248 families that included children with neurodevelopmental disorders and that were enriched for parental consanguinity. Approximately one third of affected children in these families presented with structural birth defects or microcephaly. We performed exome or genome sequencing of samples obtained from the children, their parents, or both to identify genes with biallelic pathogenic or likely pathogenic mutations present in more than one family. After identifying disease-causing variants, we generated two mouse models, each with a pathogenic variant "knocked in," to study mechanisms and test candidate treatments. We administered a small-molecule Wnt agonist to pregnant animals and assessed their offspring. RESULTS: We identified homozygous mutations in WLS, which encodes the Wnt ligand secretion mediator (also known as Wntless or WLS) in 10 affected persons from 5 unrelated families. (The Wnt ligand secretion mediator is essential for the secretion of all Wnt proteins.) Patients had multiorgan defects, including microcephaly and facial dysmorphism as well as foot syndactyly, renal agenesis, alopecia, iris coloboma, and heart defects. The mutations affected WLS protein stability and Wnt signaling. Knock-in mice showed tissue and cell vulnerability consistent with Wnt-signaling intensity and individual and collective functions of Wnts in embryogenesis. Administration of a pharmacologic Wnt agonist partially restored embryonic development. CONCLUSIONS: Genetic variations affecting a central Wnt regulator caused syndromic structural birth defects. Results from mouse models suggest that what we have named Zaki syndrome is a potentially preventable disorder. (Funded by the National Institutes of Health and others.).

Mutations in Spliceosomal Genes PPIL1 and PRP17 Cause Neurodegenerative Pontocerebellar Hypoplasia with Microcephaly.

Autosomal-recessive cerebellar hypoplasia and ataxia constitute a group of heterogeneous brain disorders caused by disruption of several fundamental cellular processes. Here, we identified 10 families showing a neurodegenerative condition involving pontocerebellar hypoplasia with microcephaly (PCHM). Patients harbored biallelic mutations in genes encoding the spliceosome components Peptidyl-Prolyl Isomerase Like-1 (PPIL1) or Pre-RNA Processing-17 (PRP17). Mouse knockouts of either gene were lethal in early embryogenesis, whereas PPIL1 patient mutation knockin mice showed neuron-specific apoptosis. Loss of either protein affected splicing integrity, predominantly affecting short and high GC-content introns and genes involved in brain disorders. PPIL1 and PRP17 form an active isomerase-substrate interaction, but we found that isomerase activity is not critical for function. Thus, we establish disrupted splicing integrity and "major spliceosome-opathies" as a new mechanism underlying PCHM and neurodegeneration and uncover a non-enzymatic function of a spliceosomal proline isomerase.

Association Among Noncalcified Coronary Burden, Fractional Flow Reserve, and Myocardial Injury in Psoriasis.

Background Myocardial infarction and premature death have been observed in patients with psoriasis. Although inflammation-driven accelerated atherosclerosis has been proposed as a mechanism, the relationship between subclinical noncalcified coronary burden (NCB), functional coronary flow impairment, and myocardial injury is unclear. Methods and Results In an ongoing longitudinal cohort study, 202 consecutive patients with psoriasis (168 at 1 year) underwent coronary computed tomography angiography to identify coronary plaque, quantify NCB, and calculate coronary fractional flow reserve by computed tomography. Serum high-sensitivity troponin-T (hs-cTn-T) was measured using a fifth-generation assay. Overall, patients were middle-aged, predominantly male, and low cardiovascular risk. A higher than median NCB associated with a positive hs-cTn-T (fully adjusted model [odds ratio (OR), 1.72; 95% CI, 1.10-2.69, P=0.018]) at baseline. Additionally, patients with a higher than median baseline NCB had higher odds of positive hs-cTn-T at 1 year in fully adjusted analyses (adjusted OR, 2.36; 95% CI, 1.47-3.79, P<0.001). Higher NCB was associated with a higher frequency of fractional flow reserve by computed tomography ≤0.80 (36.11% versus 25.11%, Pearson χ2=6.84, P=0.009, unadjusted OR, 2.09; 95% CI, 1.36-3.22, P<0.001) and higher frequency of a positive hs-cTn-T (54.36% versus 27.54%, Pearson χ2=32.23, P<0.001) in adjusted models (OR, 2.63; 95% CI, 1.56-4.42, P<0.001). Conclusions NCB was associated with hs-cTn-T at baseline as well as at 1 year. Furthermore, patients with high NCB had higher prevalence of fractional flow reserve by computed tomography ≤0.80 and a >2- fold higher odds of positive hs-cTn-T. These findings underscore the importance of early vascular disease in driving myocardial injury, and support conduct of myocardial perfusion studies to better understand these findings.

Chronic inflammation, cardiometabolic diseases and effects of treatment: Psoriasis as a human model.

Chronic inflammation in humans is associated with accelerated development of cardiometabolic diseases such as myocardial infarction, stroke, and diabetes. Strong evidence from animal models and human interventional trials including CANTOS (The Canakinumab Anti-inflammatory Thrombosis Outcome Study) suggests that targeting residual systemic inflammation in humans may impart a benefit in reducing cardiometabolic diseases. Diseases associated with heightened immune-activation and systemic inflammation including psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and human immunodeficiency virus infection are associated with upwards of two to seven-fold risk of future adverse cardiac events even when adjusted for traditional risk factors. Over the past decade, psoriasis has been utilized as a human model to study inflammatory-induced cardiometabolic dysfunction and to better understand residual risk due to inflammation. The high prevalence and early onset of cardiovascular disease in psoriasis enhances the likelihood of discovering novel pathways in vascular disease progression when followed over time. Furthermore, the United States Food and Drug Administration approved treatments for psoriasis include cytokine inhibitors (anti-tumor necrosis factor, anti-interleukin 17, anti-interleukin 12/23) which while treating the skin disease provide a unique opportunity to characterize how treating the inflammatory pathways may impact atherosclerosis. Herein, we provide a review of chronic inflammation, cardiometabolic disease associations, and treatment effects with a focus on psoriasis as a human model of study.

Mutations in LNPK, Encoding the Endoplasmic Reticulum Junction Stabilizer Lunapark, Cause a Recessive Neurodevelopmental Syndrome.

The dynamic shape of the endoplasmic reticulum (ER) is a reflection of its wide variety of critical cell biological functions. Consequently, perturbation of ER-shaping proteins can cause a range of human phenotypes. Here, we describe three affected children (from two consanguineous families) who carry homozygous loss-of-function mutations in LNPK (previously known as KIAA1715); this gene encodes lunapark, which is proposed to serve as a curvature-stabilizing protein within tubular three-way junctions of the ER. All individuals presented with severe psychomotor delay, intellectual disability, hypotonia, epilepsy, and corpus callosum hypoplasia, and two of three showed mild cerebellar hypoplasia and atrophy. Consistent with a proposed role in neurodevelopmental disease, LNPK was expressed during brain development in humans and mice and was present in neurite-like processes in differentiating human neural progenitor cells. Affected cells showed the absence of full-length lunapark, aberrant ER structures, and increased luminal mass density. Together, our results implicate the ER junction stabilizer lunapark in establishing the corpus callosum.

Synthesis of nano-bowls with a Janus template.

Colloidal particles with two or more different surface properties (Janus particles) are of interest in catalysis, biological imaging, and drug delivery. Eccentric nanoparticles are a type of Janus particle consisting of a shell that envelops the majority of a core particle, leaving a portion of the core surface exposed. Previous work to synthesize eccentric nanoparticles from silica and polystyrene have only used microemulsion techniques. In contrast we report the sol-gel synthesis of eccentric Janus nanoparticles composed of a silica shell around a carboxylate-modified polystyrene core (Janus templates). In addition, we have synthesized nano-bowl-like structures after the removal of the polystyrene core by organic solvent. These Janus templates and nanobowls can be used as a versatile platform for site-specific functionalization or controlled theranostic delivery.

Designing hollow nano gold golf balls.

Hollow/porous nanoparticles, including nanocarriers, nanoshells, and mesoporous materials have applications in catalysis, photonics, biosensing, and delivery of theranostic agents. Using a hierarchical template synthesis scheme, we have synthesized a nanocarrier mimicking a golf ball, consisting of (i) solid silica core with a pitted gold surface and (ii) a hollow/porous gold shell without silica. The template consisted of 100 nm polystyrene beads attached to a larger silica core. Selective gold plating of the core followed by removal of the polystyrene beads produced a golf ball-like nanostructure with 100 nm pits. Dissolution of the silica core produced a hollow/porous golf ball-like nanostructure.