Gut microbiota‐dependent trimethylamine N‐oxide and cardiovascular outcomes in patients with prior myocardial infarction: A nested case control study from the PEGASUS‐TIMI 54 trial

Background Trimethylamine N‐oxide (TMAO) may have prothrombotic properties. We examined the association of TMAO quartiles with major adverse cardiovascular events (MACE) and the effect of TMAO on the efficacy of ticagrelor. Methods and Results PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin ‐ Thrombolysis in Myocardial Infarction 54) randomized patients with prior myocardial infarction to ticagrelor or placebo (median follow‐up 33 months). Baseline plasma concentrations of TMAO were measured in a nested case‐control study of 597 cases with cardiovascular death, myocardial infarction, or stroke (MACE) and 1206 controls matched for age, sex, and estimated glomerular filtration rate [eGFR]. Odds ratios (OR) were used for the association between TMAO quartiles and MACE, adjusting for baseline clinical characteristics (age, sex, eGFR, region, body mass index, hypertension, hypercholesterolemia, diabetes mellitus, smoking, peripheral artery disease, index event, aspirin dosage and treatment arm), and cardiovascular biomarkers (hs‐TnT [high‐sensitivity troponin T], hs‐CRP [high‐sensitivity C‐reactive protein], NT‐proBNP [N‐terminal‐pro‐B‐type natriuretic peptide]). Higher TMAO quartiles were associated with risk of MACE (OR for quartile 4 versus quartile 1, 1.43, 95% CI, 1.06–1.93, P trend=0.015). The association was driven by cardiovascular death (OR 2.25, 95% CI, 1.28–3.96, P trend=0.003) and stroke (OR 2.68, 95% CI, 1.39–5.17, P trend<0.001). After adjustment for clinical factors, the association persisted for cardiovascular death (ORadj 1.89, 95% CI, 1.03–3.45, P trend=0.027) and stroke (ORadj 2.01, 95% CI, 1.01–4.01, P trend=0.022), but was slightly attenuated after adjustment for cardiovascular biomarkers (cardiovascular death: ORadj 1.74, 95% CI, 0.88–3.45, P trend=0.079; and stroke: ORadj 1.82, 95% CI, 0.88–3.78, P trend=0.056). The reduction in MACE with ticagrelor was consistent across TMAO quartiles (P interaction=0.92). Conclusions Among patients with prior myocardial infarction, higher TMAO levels were associated with cardiovascular death and stroke but not with recurrent myocardial infarction. The efficacy of ticagrelor was consistent regardless of TMAO levels. Registration URL: https://www.clini​caltr​ials.gov; Unique identifiers: PEGASUS‐TIMI 54, NCT01225562

Acute viral bronchiolitis in South Africa : diagnostic flow

Bronchiolitis may be diagnosed on the basis of clinical signs and symptoms. In a young child, the diagnosis can be made on the clinical pattern of wheezing and hyperinflation. Clinical symptoms and signs typically start with an upper respiratory prodrome, including rhinorrhoea, low-grade fever, cough and poor feeding, followed 1 - 2 days later by tachypnoea, hyperinflation and wheeze as a consequence of airway inflammation and air trapping. The illness is generally self limiting, but may become more severe and include signs such as grunting, nasal flaring, subcostal chest wall retractions and hypoxaemia. The most reliable clinical feature of bronchiolitis is hyperinflation of the chest, evident by loss of cardiac dullness on percussion, an upper border of the liver pushed down to below the 6th intercostal space, and the presence of a Hoover sign (subcostal recession, which occurs when a flattened diaphragm pulls laterally against the lower chest wall). Measurement of peripheral arterial oxygen saturation is useful to indicate the need for supplemental oxygen. A saturation of <92% at sea level and 90% inland indicates that the child has to be admitted to hospital for supplemental oxygen. Chest radiographs are generally unhelpful and not required in children with a clear clinical diagnosis of bronchiolitis. Blood tests are not needed routinely. Complete blood count tests have not been shown to be useful in diagnosing bronchiolitis or guiding its therapy. Routine measurement of C-reactive protein does not aid in management and nasopharyngeal aspirates are not usually done. Viral testing adds little to routine management. Risk factors in patients with severe bronchiolitis that require hospitalisation and may even cause death, include prematurity, congenital heart disease and congenital lung malformations.http://www.samj.org.zaam2016Paediatrics and Child Healt

Acute viral bronchiolitis in South Africa : viral aetiology and clinical epidemiology

Bronchiolitis is a viral-induced lower respiratory tract infection that occurs predominantly in children <2 years of age, particularly infants. Many viruses have been proven or attributed to cause bronchiolitis, including and most commonly the respiratory syncytial virus (RSV) and rhinovirus. RSV is responsible for more severe disease and complications (including hospitalisation) in bronchiolitis patients. Whereas bronchiolitis is exclusively due to respiratory viral infections, with little evidence of bacterial co-infection, the former could nevertheless predispose to superimposed bacterial infections. Although data support an interaction between RSV and pneumococcal superimposed infections, it should be noted that this specifically refers to children who are hospitalised with RSV-associated pneumonia, and not to children with bronchiolitis or milder outpatient RSV-associated illness. As such, empiric antibiotic treatment against pneumococcus in children with RSV-associated pneumonia is only warranted in cases of hospitalisation and when the clinical syndrome is more in keeping with pneumonia than uncomplicated bronchiolitis. In South Africa, the peak in the RSV season varies only slightly by province, with onset in February, and lasting until June. The important implication of these new seasonality findings is that where prophylaxis is possible, as in the case of RSV, it should be commenced in January of each year.http://www.samj.org.zaam2016Paediatrics and Child Healt

Acute viral bronchiolitis in South Africa : strategies for management and prevention

Management of acute viral bronchiolitis is largely supportive. There is currently no proven effective therapy other than oxygen for hypoxic children. The evidence indicates that there is no routine benefit from inhaled, rapid short-acting bronchodilators, adrenaline or ipratropium bromide for children with acute viral bronchiolitis. Likewise, there is no demonstrated benefit from routine use of inhaled or oral corticosteroids, inhaled hypertonic saline nebulisation, montelukast or antibiotics. The last should be reserved for children with severe disease, when bacterial co-infection is suspected. Prevention of respiratory syncytial virus (RSV) disease remains a challenge. A specific RSV monoclonal antibody, palivizumab, administered as an intramuscular injection, is available for children at risk of severe bronchiolitis, including premature infants, young children with chronic lung disease, immunodeficiency, or haemodynamically significant congenital heart disease. Prophylaxis should be commenced at the start of the RSV season and given monthly during the season. The development of an RSV vaccine may offer a more effective alternative to prevent disease, for which the results of clinical trials are awaited. Education of parents or caregivers and healthcare workers about diagnostic and management strategies should include the following: bronchiolitis is caused by a virus; it is seasonal; it may start as an upper respiratory tract infection with low-grade fever; symptoms are cough and wheeze, often with fast breathing; antibiotics are generally not needed; and the condition is usually self limiting, although symptoms may occur for up to 4 weeks in some children.http://www.samj.org.zaam2016Paediatrics and Child Healt

Mirror Symmetry and Other Miracles in Superstring Theory

The dominance of string theory in the research landscape of quantum gravity physics (despite any direct experimental evidence) can, I think, be justified in a variety of ways. Here I focus on an argument from mathematical fertility, broadly similar to Hilary Putnam's 'no miracles argument' that, I argue, many string theorists in fact espouse. String theory leads to many surprising, useful, and well-confirmed mathematical 'predictions' - here I focus on mirror symmetry. These predictions are made on the basis of general physical principles entering into string theory. The success of the mathematical predictions are then seen as evidence for framework that generated them. I attempt to defend this argument, but there are nonetheless some serious objections to be faced. These objections can only be evaded at a high (philosophical) price.Comment: For submission to a Foundations of Physics special issue on "Forty Years Of String Theory: Reflecting On the Foundations" (edited by G. `t Hooft, E. Verlinde, D. Dieks and S. de Haro)

The bronchiolitis season is upon us – recommendations for the management and prevention of acute viral bronchiolitis

Despite being so common, bronchiolitis remains poorly diagnosed and managed. This article is intended as an update on issues pertaining to this condition.http://www.samj.org.zaam201

Reduction in Subtypes and Sizes of Myocardial Infarction With Ticagrelor in PEGASUS-TIMI 54

Background: Ticagrelor reduced cardiovascular death, myocardial infarction (MI), or stroke in patients with prior MI in PEGASUSTIMI 54 (Prevention of Cardiovascular Events [eg, Death From Heart or Vascular Disease, Heart Attack, or Stroke] in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin). MI can occur in diverse settings and with varying severity; therefore, understanding the types and sizes of MI events prevented is of clinical importance. Methods and Results: MIs were adjudicated by a blinded clinical events committee and categorized by subtype and fold elevation of peak cardiac troponin over the upper limit of normal. A total of 1042 MIs occurred in 898 of the 21 162 randomized patients over a median follow-up of 33 months. The majority of the MIs (76%) were spontaneous (Type 1), with demand MI (Type 2) and stent thrombosis (Type 4b) accounting for 13% and 9%, respectively; sudden death (Type 3), percutaneous coronary intervention–related (Type 4a) and coronary artery bypass graft–related (Type 5) each accounted for <1%. Half of MIs (520, 50%) had a peak troponin ≥10x upper limit of normal and 21% of MIs (220) had a peak troponin ≥1009 upper limit of normal. A total of 21% (224) were ST-segment–elevation MI STEMI. Overall ticagrelor reduced MI (4.47% versus 5.25%, hazard ratio 0.83, 95% confidence interval 0.72–0.95, P=0.0055). The benefit was consistent among the subtypes, including a 31% reduction in MIs with a peak troponin ≥1009 upper limit of normal (hazard ratio 0.69, 95% confidence interval 0.53–0.92, P=0.0096) and a 40% reduction in ST-segment elevation MI (hazard ratio 0.60, 95% confidence interval 0.46–0.78, P=0.0002). Conclusions: In stable outpatients with prior MI, the majority of recurrent MIs are spontaneous and associated with a high biomarker elevation. Ticagrelor reduces the MI consistently among subtypes and sizes including large MIs and ST-segment elevation MI

Genetic drivers of kidney defects in the digeorge syndrome

BACKGROUND The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. METHODS We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. RESULTS We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P = 4.5×1014). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-Altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. CONCLUSIONS We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver