Agreement and classification performance of malnutrition tools in patients with chronic heart failure

Background: Malnutrition is common in chronic heart failure (CHF) patients and is associated with adverse outcome, but few data exist. Objectives: To report the prevalence of malnutrition and classification performance of 6 malnutrition tools in CHF patients. Methods: Controlling nutritional status index (CONUT); geriatric nutritional risk index (GNRI); prognostic nutritional index (PNI); malnutrition universal screening tool (MUST); mini nutritional assessment-short form (MNA-SF); and subjective global assessment (SGA) were used to evaluate malnutrition. Since there is no “gold-standard” for malnutrition evaluation, for each of the malnutrition tools, we used the results of the other 5 tools to produce a standard combined index. Subjects were ‘malnourished’ if so identified by ≥3/5 tools. Results: We studied 467 consecutive ambulatory CHF patients (67% male, median age 76 (IQR: 69–82) years, median NTproBNP 1156 (IQR: 469–2463) ng/L). The prevalence of any degree and at least moderate malnutrition ranged between 6–60% and 3–9% respectively, with CONUT classifying the highest proportion of subjects as malnourished. Malnourished patients tended to be older, have worse symptoms, higher NT-proBNP and more co-morbidities. CONUT had the highest sensitivity (80%), MNA-SF and SGA had the highest specificity (99%) and MNA-SF had the lowest misclassification rate (2%) in identifying at least moderate malnutrition as defined by the combined index. Conclusion: Malnutrition is common in CHF patients. The prevalence of malnutrition varies depending on the tool used. Amongst the 6 malnutrition tool studied, MNA-SF has the best classification performance in identifying significant malnutrition as defined by the combined index

Split selectable markers.

Selectable markers are widely used in transgenesis and genome editing for selecting engineered cells with a desired genotype but the variety of markers is limited. Here we present split selectable markers that each allow for selection of multiple unlinked transgenes in the context of lentivirus-mediated transgenesis as well as CRISPR-Cas-mediated knock-ins. Split marker gene segments fused to protein splicing elements called inteins can be separately co-segregated with different transgenic vectors, and rejoin via protein trans-splicing to reconstitute a full-length marker protein in host cells receiving all intended vectors. Using a lentiviral system, we create and validate 2-split Hygromycin, Puromycin, Neomycin and Blasticidin resistance genes as well as mScarlet fluorescent proteins. By combining split points, we create 3- and 6-split Hygromycin resistance genes, demonstrating that higher-degree split markers can be generated by a chaining design. We adapt the split marker system for selecting biallelically engineered cells after CRISPR gene editing. Future engineering of split markers may allow selection of a higher number of genetic modifications in target cells

CRISPR artificial splicing factors.

Alternative splicing allows expression of mRNA isoforms from a single gene, expanding the diversity of the proteome. Its prevalence in normal biological and disease processes warrant precise tools for modulation. Here we report the engineering of CRISPR Artificial Splicing Factors (CASFx) based on RNA-targeting CRISPR-Cas systems. We show that simultaneous exon inclusion and exclusion can be induced at distinct targets by differential positioning of CASFx. We also create inducible CASFx (iCASFx) using the FKBP-FRB chemical-inducible dimerization domain, allowing small molecule control of alternative splicing. Finally, we demonstrate the activation of SMN2 exon 7 splicing in spinal muscular atrophy (SMA) patient fibroblasts, suggesting a potential application of the CASFx system

C11orf95-RELA reprograms 3D epigenome in supratentorial ependymoma.

Supratentorial ependymoma (ST-EPN) is a type of malignant brain tumor mainly seen in children. Since 2014, it has been known that an intrachromosomal fusion C11orf95-RELA is an oncogenic driver in ST-EPN [Parker et al. Nature 506:451-455 (2014); Pietsch et al. Acta Neuropathol 127:609-611 (2014)] but the molecular mechanisms of oncogenesis are unclear. Here we show that the C11orf95 component of the fusion protein dictates DNA binding activity while the RELA component is required for driving the expression of ependymoma-associated genes. Epigenomic characterizations using ChIP-seq and HiChIP approaches reveal that C11orf95-RELA modulates chromatin states and mediates chromatin interactions, leading to transcriptional reprogramming in ependymoma cells. Our findings provide important characterization of the molecular underpinning of C11orf95-RELA fusion and shed light on potential therapeutic targets for C11orf95-RELA subtype ependymoma

What proportion of patients with chronic heart failure are eligible for sacubitril-valsartan?

AIMS: The PARADIGM-HF trial showed that sacubitril-valsartan, an ARB-neprilysin inhibitor, is more effective than enalapril for some patients with heart failure (HF). It is uncertain what proportion of patients with HF would be eligible for sacubitril-valsartan in clinical practice. METHODS AND RESULTS: Between 2001 and 2014, 6131 patients consecutively referred to a community HF clinic with suspected HF were assessed. The criteria required to enter the randomized phase of PARADIGM-HF, including symptoms, NT-proBNP, and current treatment with or without target doses of ACE inhibitors or ARBs, were applied to identify the proportion of patients eligible for sacubitril-valsartan. Recognizing the diversity of clinical opinion and guideline recommendations concerning this issue, entry criteria were applied singly and in combination. Of 1396 patients with reduced left ventricular ejection fraction (≤40%, HFrEF) and contemporary measurement of NT-proBNP, 379 were on target doses of an ACE inhibitor or ARB at their initial visit and, of these, 172 (45%) fulfilled the key entry criteria for the PARADIGM-HF trial. Lack of symptoms (32%) and NT-proBNP <600 ng/L (49%) were common reasons for failure to fulfil criteria. A further 122 patients became eligible during follow-up (n = 294, 21%). However, if background medication and doses were ignored, then 701 (50%) were eligible initially and a further 137 became eligible during follow-up. CONCLUSIONS: Of patients with HFrEF referred to a clinic such as ours, only 21% fulfilled the PARADIGM-HF randomization criteria, on which the ESC Guidelines are based; this proportion rises to 60% if background medication is ignored

Non-Isolated Neural Tube Defects with Comorbid Malformations Are Responsive to Population-Level Folic Acid Supplementation in Northern China

Objective: Comorbid congenital malformation of multiple organs may indicate a shared genetic/teratogenic causality. Folic acid supplementation reduces the population-level prevalence of isolated neural tube defects (NTDs), but whether complex cases involving independent malformations are also responsive is unknown. We aimed to describe the epidemiology of NTDs with comorbid malformations in a Chinese population and assess the impact of folic acid supplementation. Study Design: Data from five counties in Northern China were obtained between 2002 and 2021 through a population-based birth defects surveillance system. All live births, stillbirths, and terminations because of NTDs at any gestational age were recorded. NTDs were classified as spina bifida, anencephaly, or encephalocele. Isolated NTDs included spina bifida cases with presumed secondary malformations (hydrocephalus, hip dislocation, talipes). Non-isolated NTDs were those with independent concomitant malformations. Results: A total of 296,306 births and 2031 cases of NTDs were recorded from 2002–2021. A total of 4.8% of NTDs (97/2031) had comorbid defects, which primarily affected the abdominal wall (25/97), musculoskeletal system (24/97), central nervous system (22/97), and face (15/97). The relative risk of cleft lip and/or palate, limb reduction defects, hip dislocation, gastroschisis, omphalocele, hydrocephalus, and urogenital system defects was significantly greater in infants with NTDs than in the general population. Population-level folic acid supplementation significantly reduced the prevalence of both isolated and non-isolated NTDs. Conclusion: Epidemiologically, non-isolated NTDs follow similar trends as isolated cases and are responsive to primary prevention by folic acid supplementation. Various clinically-important congenital malformations are over-represented in individuals with NTDs, suggesting a common etiology

Effect of frailty on treatment, hospitalisation and death in patients with chronic heart failure

Background: Frailty is common in patients with chronic heart failure (CHF) and is associated with poor outcomes. The natural history of frail patients with CHF is unknown. Methods: Frailty was assessed using the clinical frailty scale (CFS) in 467 consecutive patients with CHF (67% male, median age 76 years, median NT-proBNP 1156 ng/L) attending a routine follow-up visit. Those with CFS > 4 were classified as frail. We investigated the relation between frailty and treatments, hospitalisation and death in patients with CHF. Results: 206 patients (44%) were frail. Of 291 patients with HF with reduced ejection fraction (HeFREF), those who were frail (N = 117; 40%) were less likely to receive optimal treatment, with many not receiving a renin–angiotensin–aldosterone system inhibitor (frail: 25% vs. non-frail: 4%), a beta-blocker (16% vs. 8%) or a mineralocorticoid receptor antagonist (50% vs 41%). By 1 year, there were 56 deaths and 322 hospitalisations, of which 25 (45%) and 198 (61%), respectively, were due to non-cardiovascular (non-CV) causes. Most deaths (N = 46, 82%) and hospitalisations (N = 215, 67%) occurred in frail patients. Amongst frail patients, 43% of deaths and 64% of hospitalisations were for non-CV causes; 58% of cardiovascular (CV) deaths were due to advancing HF. Among non-frail patients, 50% of deaths and 57% of hospitalisations were for non-CV causes; all CV deaths were due to advancing HF. Conclusion: Frailty in patients with HeFREF is associated with sub-optimal medical treatment. Frail patients are more likely to die or be admitted to hospital, but whether frail or not, many events are non-CV

Warm water immersion in patients with chronic heart failure: a pilot study: Shah immerse: HF

BackgroundPatients with chronic conditions, such as heart failure, swim regularly and most rehabilitation exercises are conducted in warm hydrotherapy pools. However, little is known about the acute effects of warm water immersion (WWI) on cardiac haemodynamics in patients with chronic heart failure (CHF).MethodsSeventeen patients with CHF (NYHA I and II; mean age 67 years, 88% male, mean left ventricular ejection fraction 33%) and 10 age-matched normal subjects were immersed up to the neck in a hydrotherapy pool (33–35 °C). Cardiac haemodynamics were measured non-invasively, and echocardiography was performed at baseline, during WWI, 3 min after kicking in the supine position and after emerging.ResultsIn patients with CHF, compared to baseline, WWI immediately increased stroke volume (SV, mean ± standard deviation; from 65 ± 21 to 82 ± 22 mL, p less than 0.001), cardiac output (CO, from 4.4 ± 1.4 to 5.7 ± 1.6 L/min, p less than 0.001) and cardiac index (CI, from 2.3 ± 0.6 to 2.9 ± 0.70 L/min/m², p less than 0.001) with decreased systemic vascular resistance (from 1881 ± 582 to 1258 ± 332 dynes/s/cm5, p less than 0.001) and systolic blood pressure (132 ± 21 to 115 ± 23 mmHg, p less than 0.001). The haemodynamic changes persisted for 15 min of WWI. In normal subjects, compared to baseline, WWI increased SV (from 68 ± 11 to 80 ± 18 mL, p less than 0.001), CO (from 5.1 ± 1.9 to 5.7 ± 1.8 L/min, p less than 0.001) and CI (from 2.7 ± 0.9 to 2.9 ± 1.0 L/min/m², p less than 0.001).In patients with CHF, compared to baseline, WWI caused an increase in left atrial volume (from 57 ± 44 to 72 ± 46 mL, p = 0.04), without any changes in left ventricular size or function or amino terminal pro B-type natriuretic peptide.ConclusionsIn patients with CHF, WWI causes an acute increase in cardiac output and a fall in systemic vascular resistance

Exploring the relation between changes in NT-proBNP and renal function in patients with suspected heart failure using structural equation modelling

Background: The relation between changes in NT-proBNP and renal function has commonly been studied using multiple regressions, which may ignore the complexity of relations between related variables. Methods and results: Data were collected from patients referred with suspected heart failure (HF) to a community service. Structural equation modelling (SEM) was used to assess the association between changes in NT-proBNP at 1 year, and other pre-specified variables including age, sex, BMI, eGFR, loop diuretics and ACE inhibitor. Of 1006 patients with a follow-up NT-proBNP at 1 year, 882 (88%) had HF. The baseline median age was 72 (IQR: 63–78) years, 732 (73%) were men, 668 (66%) had left ventricular systolic dysfunction and 769 (76%) had NT-proBNP > 400 pg/ml. For all patients at 1 year, 243 (24%) patients had at least a 50% reduction in NT-proBNP, and 199 (20%) had at least a 50% increase, only 40 (3%) had < 3% change. Change in NT-proBNP was strongly associated with baseline NT-proBNP (the standardized coefficient (r) = 0.73, p < 0.001). The change in NT-proBNP was not associated with changes in eGFR, and was indirectly related with age, BMI, eGFR and loop diuretics (p < 0.01 for all). Conclusions: Baseline NT-proBNP was the main determinant of change in NT-proBNP at one year

Nuclear pore protein NUP210 depletion suppresses metastasis through heterochromatin-mediated disruption of tumor cell mechanical response.

Mechanical signals from the extracellular microenvironment have been implicated in tumor and metastatic progression. Here, we identify nucleoporin NUP210 as a metastasis susceptibility gene for human estrogen receptor positive (ER+) breast cancer and a cellular mechanosensor. Nup210 depletion suppresses lung metastasis in mouse models of breast cancer. Mechanistically, NUP210 interacts with LINC complex protein SUN2 which connects the nucleus to the cytoskeleton. In addition, the NUP210/SUN2 complex interacts with chromatin via the short isoform of BRD4 and histone H3.1/H3.2 at the nuclear periphery. In Nup210 knockout cells, mechanosensitive genes accumulate H3K27me3 heterochromatin modification, mediated by the polycomb repressive complex 2 and differentially reposition within the nucleus. Transcriptional repression in Nup210 knockout cells results in defective mechanotransduction and focal adhesion necessary for their metastatic capacity. Our study provides an important role of nuclear pore protein in cellular mechanosensation and metastasis