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vs 7.7%; hazard ratio, 1.45; 95% CI, 1.13-1.85). Conclusions and relevance Among patients with obesity and end-stage kidney disease, bariatric surgery was associated with lower all-cause mortality compared with usual care. Bariatric surgery was also associated with an increase in kidney transplant. Bariatric surgery may warrant further consideration in the treatment of patients with obesity and end-stage kidney disease.Importance Malignant arrhythmic mitral valve prolapse (MVP) phenotype poses a substantial risk of sudden cardiac death (SCD), and an estimated 26 000 individuals in the United States are at risk of SCD per year. Thus, identifying risk-stratification strategies for SCD is imperative. Observations Patients with MVP have a heterogenous clinical spectrum, ranging from a benign course to a devastating complication such as SCD. Some of the high-risk markers of MVP, which are identified electrocardiographically, include inverted or biphasic T waves, QT dispersion, QT prolongation, and premature ventricular contractions originating from the left ventricular outflow tract and papillary muscles. Morphofunctional characteristics of SCD are leaflet thickness of 5 mm or greater, mitral annulus disjunction, paradoxical systolic increase of the mitral annulus diameter, increased tissue Doppler velocity of the mitral annulus, and higher mechanical dispersion on echocardiography and fibrosis identified by late gadolinium enhancement on cardiac magnetic resonance imaging. Conclusions and relevance Findings from this review suggest that SCD can occur earlier in the course of MVP from complex arrhythmias that are triggered by the repeated tugging and traction of the chordopapillary muscle unit and basal mid-myocardium, even before macrofibrosis can be identified in these regions by late gadolinium enhancement on cardiac magnetic resonance imaging. Some of the newer markers identified by speckle-tracking Doppler, such as mechanical dispersion, myocardial work index, and postsystolic shortening, need further validation in a larger population.Study objectives Rhythmic movements during sleep are frequent and often considered as benign in children. Disabling forms are diagnosed as rhythmic movement disorder and may persist in adulthood. Whether rhythmic movements severely impact sleep architecture in patients with rhythmic movement disorder remain unclear. We performed a case-control study to characterize the clinical and polysomnographic patterns of children and adults with a diagnosis of rhythmic movement disorder in comparison to controls, and to assess the associations between the rhythmic movements and the sleep architecture. Methods All consecutive patients (n=50; 27 children, 35 males) with rhythmic movement disorder from a single sleep clinic (from 2006 to 2019) underwent a comprehensive clinical evaluation and a polysomnographic recording in comparison to 75 controls (42 children, 53 males). Results Eighty-two percent of children and adult patients had a complaint of disturbed nighttime sleep. Comorbid neurodevelopmental, affective or sleep disorders were found in 92% of patients. HPPE mouse While rhythmic movement sequences defined by videopolysomnographic criteria were observed in 82.0% of patients (in wakefulness and in all sleep stages), no similar sequences were observed in controls. Patients had altered sleep continuity, with low sleep efficiency, increased wake time after sleep onset, and frequent periodic leg movements and apnea events. The severity of rhythmic movements was associated with disrupted nightime sleep, even after controlling for comorbid motor and respiratory events. Conclusions Rhythmic movement disorder is a rare, highly comorbid and disabling condition both in children and adults with frequent disturbed nighttime sleep that may contribute to the burden of the disease.Background Diffuse Midline Glioma, formerly Diffuse Intrinsic Pontine Glioma (DIPG), is the deadliest pediatric brainstem tumor with median survival of less than one year. Here, we investigated 1) whether direct delivery of adenovirus expressing CD40L (Ad-CD40L) to brainstem tumors would induce immune-mediated tumor clearance and, 2) if so, whether therapy would be associated with a manageable toxicity due to immune-mediated inflammation in the brainstem. Methods Syngeneic gliomas in the brainstems of immune competent mice were treated with Ad-CD40L and survival, toxicity and immune profiles determined. A clinically translatable vector, whose replication would be tightly restricted to tumor cells, rAd-Δ24-CD40L, was tested in human patient-derived Diffuse Midline Gliomas and immunocompetent models. Results Expression of Ad-CD40L restricted to brainstem gliomas by pre-infection induced complete rejection, associated with immune cell infiltration, of which CD4+ T cells were critical for therapy. Direct intra-tumoral injection of Ad-CD40L into established brainstem tumors improved survival and induced some complete cures but with some acute toxicity. RNA-seq analysis showed that Ad-CD40L therapy induced neuroinflammatory immune responses associated with IL-6, IL-1β and TNF-α. Therefore, to generate a vector whose replication, and transgene expression, would be tightly restricted to tumor cells, we constructed rAd-Δ24-CD40L, the backbone of which has already entered clinical trials for Diffuse Midline Glioma. Direct intra-tumoral injection of rAd-Δ24-CD40L, with systemic blockade of IL-6 and IL-1β, generated significant numbers of cures with readily manageable toxicity. Conclusions Virus-mediated delivery of CD40L has the potential to be effective in treating Diffuse Midline Gliomas without obligatory neuroinflammation-associated toxicity.Restriction endonucleases naturally target DNA duplexes. Systematic screening has identified a small minority of these enzymes that can also cleave RNA/DNA heteroduplexes and that may therefore be useful as tools for RNA biochemistry. We have chosen AvaII (G↓GWCC, where W stands for A or T) as a representative of this group of restriction endonucleases for detailed characterization. Here, we report crystal structures of AvaII alone, in specific complex with partially cleaved dsDNA, and in scanning complex with an RNA/DNA hybrid. The specific complex reveals a novel form of semi-specific dsDNA readout by a hexa-coordinated metal cation, most likely Ca2+ or Mg2+. Substitutions of residues anchoring this non-catalytic metal ion severely impair DNA binding and cleavage. The dsDNA in the AvaII complex is in the A-like form. This creates space for 2'-OH groups to be accommodated without intra-nucleic acid steric conflicts. PD-(D/E)XK restriction endonucleases of known structure that bind their dsDNA targets in the A-like form cluster into structurally similar groups.
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