Lattice dynamics and vibrational spectra of the orthorhombic, tetragonal and cubic phases of methylammonium lead iodide

The hybrid halide perovskite CH3NH3PbI3 exhibits a complex structural behaviour, with successive transitions between orthorhombic, tetragonal and cubic polymorphs at ca. 165 K and 327 K. Herein we report first-principles lattice dynamics (phonon spectrum) for each phase of CH3NH3PbI3. The equilibrium structures compare well to solutions of temperature-dependent powder neutron diffraction. By following the normal modes we calculate infrared and Raman intensities of the vibrations, and compare them to the measurement of a single crystal where the Raman laser is controlled to avoid degradation of the sample. Despite a clear separation in energy between low frequency modes associated with the inorganic PbI3 network and high-frequency modes of the organic CH3NH3+ cation, significant coupling between them is found, which emphasises the interplay between molecular orientation and the corner-sharing octahedral networks in the structural transformations. Soft modes are found at the boundary of the Brillouin zone of the cubic phase, consistent with displacive instabilities and anharmonicity involving tilting of the PbI6 octahedra around room temperature.Comment: 9 pages, 4 figure

Renal artery sympathetic denervation:observations from the UK experience

Background: Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response—particularly in those prescribed aldosterone antagonists at the time of RDN. Methods: We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres. Results: Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg (SD 26/19; n = 253) and mean daytime ABP was 170/98 mmHg (SD 22/16; n = 186). Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg (fall of 12/7 mmHg). Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p < 0.001 for trend). Use of aldosterone antagonist did not predict response (p < 0.2). Conclusion: In 253 patients treated with RDN, office BP fell by 22/9 mmHg. Ambulatory BP fell by 12/7 mmHg, though little response was seen in the lowermost quartile of starting blood pressure. Fall in BP was not explained by medication changes and aldosterone antagonist use did not affect response

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Disparities in spatially variable gene calling highlight the need for benchmarking spatial transcriptomics methods

Abstract Identifying spatially variable genes (SVGs) is a key step in the analysis of spatially resolved transcriptomics data. SVGs provide biological insights by defining transcriptomic differences within tissues, which was previously unachievable using RNA-sequencing technologies. However, the increasing number of published tools designed to define SVG sets currently lack benchmarking methods to accurately assess performance. This study compares results of 6 purpose-built packages for SVG identification across 9 public and 5 simulated datasets and highlights discrepancies between results. Additional tools for generation of simulated data and development of benchmarking methods are required to improve methods for identifying SVGs

Generating an iPSC line (with isogenic control) from the PBMCs of an ACTA1 (p.Gly148Asp) nemaline myopathy patient

To produce an in vitro model of nemaline myopathy, we reprogrammed the peripheral blood mononuclear cells (PBMCs) of a patient with a heterozygous p.Gly148Asp mutation in exon 3 of the ACTA1 gene to iPSCs. Using CRISPR/Cas9 gene editing we corrected the mutation to generate an isogenic control line. Both the mutant and control show a normal karyotype, express pluripotency markers and could differentiae into the three cell states that represent embryonic germ layers (endoderm, mesoderm and neuroectoderm) and the dermomyotome (precursor of skeletal muscle). When differentiated these cell lines will be used to explore disease mechanisms and evaluate novel therapeutics