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Background: Studies on exercise-induced left ventricular hypertrophy (LVH) in veteran athletes suggest the presence of abnormal diastolic filling and incomplete regression of LVH on cessation of exercise. Hypothesis: Myocardial fibrosis occurs in exercise induced LVH in veteran athletes. Aim: To document non-invasively the presence of fibrosis in veteran athletes Design: Prospective case–control study. Setting: City centre district general hospital. Participants: 45 normotensive elite veteran athletes and 45 normal sedentary subjects. Interventions: Echocardiographic assessment was made of LV mass, LV systolic and LV diastolic function. Plasma carboxyterminal propeptide of collagen type I (PICP), carboxyterminal telopeptide of collagen type I (CITP) and tissue inhibitor of matrix metalloproteinase type I (TIMP-1) were measured as markers of collagen synthesis, degradation and inhibition of degradation, respectively. Results: Veteran athletes had significant elevation in LV dimensions and calculated LV mass index (LVMI). Diastolic and systolic function was normal. Plasma PICP (259 vs 166 μg/l, p<0.001), CITP (5.4 vs 2.9 μg/l, p<0.001) and TIMP-1 (350 vs 253 ng/ml, p = 0.01) were elevated in the cohort of athletes. There was a further elevation of TIMP-1 in athletes with echocardiographic LVH, defined as an LVMI >130 g/m2 (417 vs 266 ng/ml, p = 0.02). Conclusion: There is biochemical evidence of disruption of the collagen equilibrium favouring fibrosis in veteran athletes with LVH. This may suggest that fibrosis occurs as part of the hypertrophic process in veteran athletes.

Percutaneous coronary intervention (PCI) is increasingly used in revascularisation of patients with left main coronary artery disease in place of the standard treatment, coronary artery bypass grafting (CABG). The NOBLE trial aimed to evaluate whether PCI was non-inferior to CABG in the treatment of left main coronary artery disease and reported outcomes after a median follow-up of 3·1 years. We now report updated 5-year outcomes of the trial. The prospective, randomised, open-label, non-inferiority NOBLE trial was done at 36 hospitals in nine northern European countries. Patients with left main coronary artery disease requiring revascularisation were enrolled and randomly assigned (1:1) to receive PCI or CABG. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, repeat revascularisation, and stroke. Non-inferiority of PCI to CABG was defined as the upper limit of the 95% CI of the hazard ratio (HR) not exceeding 1·35 after 275 MACCE had occurred. Secondary endpoints included all-cause mortality, non-procedural myocardial infarction, and repeat revascularisation. Outcomes were analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01496651. Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were enrolled and allocated to PCI (n=598) or CABG (n=603), with 17 subsequently lost to early follow-up. 592 patients in each group were included in this analysis. At a median of 4·9 years of follow-up, the predefined number of events was reached for adequate power to assess the primary endpoint. Kaplan-Meier 5-year estimates of MACCE were 28% (165 events) for PCI and 19% (110 events) for CABG (HR 1·58 [95% CI 1·24–2·01]); the HR exceeded the limit for non-inferiority of PCI compared to CABG. CABG was found to be superior to PCI for the primary composite endpoint (p=0·0002). All-cause mortality was estimated in 9% after PCI versus 9% after CABG (HR 1·08 [95% CI 0·74–1·59]; p=0·68); non-procedural myocardial infarction was estimated in 8% after PCI versus 3% after CABG (HR 2·99 [95% CI 1·66–5·39]; p=0·0002); and repeat revascularisation was estimated in 17% after PCI versus 10% after CABG (HR 1·73 [95% CI 1·25–2·40]; p=0·0009). In revascularisation of left main coronary artery disease, PCI was associated with an inferior clinical outcome at 5 years compared with CABG. Mortality was similar after the two procedures but patients treated with PCI had higher rates of non-procedural myocardial infarction and repeat revascularisation. Biosensors.

Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease. In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1:1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1·35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651. Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 28% for PCI (121 events) and 18% for CABG (80 events), HR 1·51 (95% CI 1·13–2·00), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0·0044). As-treated estimates were 28% versus 18% (1·48, 1·11–1·98, p=0·0069). Comparing PCI with CABG, 5 year estimates were 11% versus 9% (1·08, 0·67–1·74, p=0·84) for all-cause mortality, 6% versus 2% (2·87, 1·40–5·89, p=0·0040) for non-procedural myocardial infarction, 15% versus 10% (1·50, 1·04–2·17, p=0·0304) for any revascularisation, and 5% versus 2% (2·20, 0·91–5·36, p=0·08) for stroke. The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease. Biosensors, Aarhus University Hospital, and participating sites.

A 26-year-old female with haemolytic–uraemic syndrome (HUS) refractory to daily plasma exchange was successfully treated with rituximab. Subsequent testing confirmed the presence of mutations in genes encoding complement factor I and CD46. On Day 32 she developed pulmonary oedema, and echocardiography demonstrated severe left ventricular systolic dysfunction. There was no evidence of recent myocardial infarction. Cardiac involvement has been reported, not only in thrombotic thrombocytopaenic purpura (TTP) but also with rituximab therapy. However, it is unclear if atypical HUS is also associated with cardiac disease. We recommend echocardiography in all patients with TTP–HUS and in any patients commencing treatment with rituximab.

Infarct size assessed early after acute ST-segment elevation myocardial infarction (STEMI) can overestimate the true extent of infarction, limiting its usefulness as a prognostic biomarker. Myocardial strain derived from displacement encoding with stimulated echoes (DENSE) cardiovascular magnetic resonance (CMR) provides information on myocardial contractility with high precision and accuracy. We hypothesised that the prognostic value of peak circumferential strain is higher than infarct size. In a prospective, single centre study, participants underwent 1·5T CMR 2 days and 6 months after myocardial infarction. The 5-SD technique was used to quantify late gadolinium enhancement (LGE) as proportion of left ventricular mass. Mid-left ventricular DENSE acquisitions were analysed using postprocessing software. During longer-term follow-up, major adverse cardiac events (MACE) were independently assessed by masked cardiologists. Participants provided written informed consent and ethics approval was given (reference 10/S0703/28). This study is registered with ClinicalTrials.gov, number NCT02072850. 300 patients underwent CMR (mean age 58·6 years [SD 13·2], 237 men [79%], 118 anterior myocardial infarction [39%], 30 with diabetes [10%], 284 with normal flow [Thrombolysis in Myocardial Infarction grade 3] after percutaneous coronary intervention [95%]). 259 of these patients had DENSE acquired, of whom 21 (8%) experienced a MACE at 3 years' follow-up. DENSE and baseline LGE had reasonable power for prediction of adverse events (area under the curve [AUC] DENSE 0·712, p=0·001; AUC LGE 0·644, p=0·028). For MACE (receiver operating characteristic analysis), optimal cut-offs for peak circumferential strain using DENSE was −10·51%, and LGE 24·05 g. Cox-regression analysis showed that DENSE (hazard ratio 1·175, 95% CI 0·036–1·334; p=0·012) offered an incremental prognostic benefit over LGE (1·040, 1·010–1·070; p=0·008) to predict MACE. DENSE-derived peak circumferential strain offers an incremental prognostic benefit over infarct size revealed by LGE to predict MACE; a cut-off of −10·51% can identify STEMI patients at higher risk of events. This is the first time, to our knowledge, that CMR-derived strain has been shown to provide prognostic utility in patients with STEMI. This research was supported by project grants from the Chief Scientist Office (SC01), Medical Research Scotland (343 FRG), and the British Heart Foundation (BHF-PG/14/64/31043).

The complete assembly of each human chromosome is essential for understanding human biology and evolution 1 , 2 . Here we use complementary long-read sequencing technologies to complete the linear assembly of human chromosome 8. Our assembly resolves the sequence of five previously long-standing gaps, including a 2.08-Mb centromeric α-satellite array, a 644-kb copy number polymorphism in the β-defensin gene cluster that is important for disease risk, and an 863-kb variable number tandem repeat at chromosome 8q21.2 that can function as a neocentromere. We show that the centromeric α-satellite array is generally methylated except for a 73-kb hypomethylated region of diverse higher-order α-satellites enriched with CENP-A nucleosomes, consistent with the location of the kinetochore. In addition, we confirm the overall organization and methylation pattern of the centromere in a diploid human genome. Using a dual long-read sequencing approach, we complete high-quality draft assemblies of the orthologous centromere from chromosome 8 in chimpanzee, orangutan and macaque to reconstruct its evolutionary history. Comparative and phylogenetic analyses show that the higher-order α-satellite structure evolved in the great ape ancestor with a layered symmetry, in which more ancient higher-order repeats locate peripherally to monomeric α-satellites. We estimate that the mutation rate of centromeric satellite DNA is accelerated by more than 2.2-fold compared to the unique portions of the genome, and this acceleration extends into the flanking sequence. The complete assembly of human chromosome 8 resolves previous gaps and reveals hidden complex forms of genetic variation, enabling functional and evolutionary characterization of primate centromeres.

Density instabilities in the lithosphere can founder gravitationally via viscous dripping and decoupling from overlying crust. The lithospheric dripping concept has been invoked across the globe, but the diversity of crustal effects, observable evidence, and tectonic settings involved in dripping remain underexplored. Here, we synthesize numerical and analogue modeling studies and geologic data from the literature, including all proposed lithospheric dripping events to‐date. We argue that two distinct styles of dripping can occur depending on crustal strength (relative to that of the mantle lithosphere). Near‐surface contraction and subsidence of strong crusts contrasts with near‐surface extension and uplift of weak crusts. We discuss these events in terms of tectonic setting, timing, size, and the main types of data associated with each event. We also find that lithospheric dripping is associated with a distinct suite of geological observations including sedimentological, structural, volcanic, and geophysical data, which can be used to distinguish strong crusts from weak crusts. We find 27 events for which lithospheric dripping is a key hypothesis, including 9 with clear evidence for strong‐crust dripping and 3 with clear evidence of weak‐crust dripping. We review emerging research methods have the potential to detect the signals of dripping in the geologic and geophysical record, and we suggest additional techniques in light of our strong‐crust versus weak‐crust framework. The diverse tectonic settings and inferred consequences of these lithospheric drips, if confirmed, would demand a shift in our understanding of continental geology to emphasize the role of vertical removal of continental lithosphere. Plain Language Summary If part of the lithosphere (Earth's crust and the rigid upper part of the mantle) increases in density, it may become heavier than the underlying mantle and sink, or founder. Foundering results in the removal of blobs of lithosphere from overlying crust, a process called dripping. Dripping may have occurred in several locations across the globe, but the effects it is capable of producing are not well understood. We synthesize numerical models of dripping with studies of real‐world locations and compile available evidence to better understand the dripping process. We suggest that key observable effects are driven by the strength of the crust relative to the foundering lithosphere. In particular, when the crust is weak and able to flow in response to a lithospheric drip, complex patterns of deformation and sedimentation can result. For the 27 events that have been discussed to date, 9 have clear evidence for strong‐crust behavior, and 3 for a weak‐crust behavior. This framework will help researchers understand what lithospheric dripping looks like in geological and geophysical data, and we discuss avenues for further research on this topic. Key Points Lithospheric dripping has been proposed for 27 locations throughout the globe and may be responsible for a wide range of observable effects A synthesis of modeling studies suggests two distinct types of dripping depending on crustal strength relative to mantle lithosphere Existing data support the strong‐crust versus weak‐crust drip framework and suggest future research opportunities

Cellular immunometabolism among people living with HIV (PLWH) on antiretroviral therapy (ART) remains under investigated. We assessed the relationships between mitochondrial oxidative phosphorylation (OXPHOS) in peripheral blood mononuclear cells (PBMCs) and blood parameters associated with HIV immune dysregulation. PLWH ≥40 years old and on stable ART ≥3 months were enrolled (N = 149). OXPHOS complex I (CI, NADH dehydrogenase) and complex IV (CIV, cytochrome c oxidase) protein levels in PBMCs were quantified using immunoassays. Monocyte subsets and markers of T-cell activation, senescence, and exhaustion were measured on PBMC by flow cytometry. Plasma inflammatory mediators were quantified using a multiplex assay. HIV-uninfected group (N = 44) of similar age, gender, and ethnicity had available OXPHOS levels. PLWH had a median age of 51 years. Majority were male (88.6%), Caucasian (57.7%), and with undetectable plasma HIV RNA <50 copies/mL (84.6%). Median CI level was lower in PLWH compared with the HIV-seronegative group (65.5 vs 155.0 optical density/μg protein x 103, p <0.0001). There was no significant difference in median CIV levels. Lower OXPHOS levels correlated with lower CD4% and CD4/CD8 ratio. On multivariable linear regression adjusted for age, current use of zidovudine/didanosine, and HIV RNA (detectable versus undetectable), lower OXPHOS levels were significantly associated with higher MPO, SAA, SAP, and sVCAM, and higher frequencies of intermediate (CD14++CD16+) monocytes and TIGIT+TIM3+ CD4 T-cell (p<0.01). CI PBMC protein levels were decreased in PLWH on ART. Decreased OXPHOS correlated with disease severity and inflammation. Further studies on the relationship between immunometabolism and immune dysregulation in HIV are warranted.

Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells. CRISPR/Cas and base editing is achieved in a mouse model expressing human sickle cell disease phenotypes for potential foetal haemoglobin reactivation and conversion from sickle to non-sickle alleles. Bone-marrow-homing lipid nanoparticles were also able to achieve Cre-recombinase-mediated genetic deletion in bone-marrow-engrafted leukaemic stem cells and leukaemia cells. We show evidence that diverse cell types in the bone marrow niche can be edited using bone-marrow-homing lipid nanoparticles. The ability to genetically modify haematopoietic stem cells would allow the durable treatment of a diverse range of genetic disorders but gene delivery to the bone marrow has not been achieved. Here lipid nanoparticles that target and deliver mRNA to 14 unique cells within the bone marrow are presented.