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In Indieland, we're seeing more picture books that explore neurodiversity among children and consider the emotional effects of being 'wired differently.' In kid-friendly terms, the books explain, for example, the [...]

The concept of myocardial viability is usually referred to areas of the myocardium, which show contractile dysfunction at rest and in which contractility is expected to improve after revascularization. The traditional paradigm states that an improvement in function after revascularization leads to improved health outcomes and that assessment of myocardial viability in patients with ischaemic left ventricular dysfunction (ILVD) is a prerequisite for clinical decisions regarding treatment. A range of retrospective observational studies supported this ‘viability hypothesis’. However, data from prospective trials have diverged from earlier retrospective studies and challenge this hypothesis. Traditional binary viability assessment may oversimplify ILVD’s complexity and the nuances of revascularization benefits. A conceptual shift from the traditional paradigm centred on the assessment of viability as a dichotomous variable to a more comprehensive approach encompassing a thorough understanding of ILVD’s complex pathophysiology and the salutary effect of revascularization in the prevention of myocardial infarction and ventricular arrhythmias is required.

Steve Thorngate's sensitive and thoughtful treatment of liturgical imagery is praiseworthy ('Should we avoid liturgical language of light and dark?,' December). He gives darkness its due. He made me think [...]

There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort (n= 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD). The panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver) or fibrosis stages >2, >3 or 4 (enhanced liver fibrosis (ELF) test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Multiple biomarkers met these metrics. NIS4 had an AUROC of 0.81 (95% confidence interval: 0.78–0.84) for at-risk NASH. The AUROCs of the ELF test, PROC3 and FibroMeterVCTE for clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) or cirrhosis (stage 4), respectively, were all ≥0.8. ELF and FibroMeter VCTE outperformed FIB-4 for all fibrosis endpoints. These data represent a milestone toward qualification of several biomarker panels for at-risk NASH and also fibrosis severity in individuals with NAFLD.

Background: Ischaemic stroke may occur despite antiplatelet therapy (APT). We aimed to investigate frequency, potential causes and outcomes in patients with ischaemic stroke despite APT.Methods: In this cohort study, we enrolled patients with imaging-confirmed ischaemic stroke from the Swiss Stroke Registry (01/2014-07/2022). We determined the frequency of prior APT, assessed stroke aetiology (modified TOAST classification) and determined the association of prior APT with unfavourable functional outcome (modified Rankin Scale score 3–6) and recurrent ischaemic stroke at 3 months using regression models.Results: Among 53,352 patients, 27,484 (51.5%) had no prior antithrombotic treatment, 17,760 (33.3%) were on APT, 7039 (13.2%) on anticoagulation and 1069 (2.0%) were on APT + anticoagulation. In patients with a history of ischaemic stroke/TIA (n= 11,948; 22.4%), 2401 (20.1%) had no prior antithrombotic therapy, 6594 (55.2%) were on APT, 2489 (20.8%) on anticoagulation and 464 (3.9%) on APT + anticoagulation. Amongst patients with ischaemic stroke despite APT, aetiology was large artery atherosclerosis in 19.8% (n= 3416), cardiac embolism in 23.6% (n= 4059), small vessel disease in 11.7% (n= 2011), other causes in 7.4% (n= 1267), more than one cause in 6.3% (n= 1078) and unknown cause in 31.3% (n= 5388). Prior APT was not independently associated with unfavourable outcome (aOR = 1.06; 95% CI: 0.98–1.14; p= 0.135) or death (aOR = 1.10; 95% CI: 0.99–1.21; p= 0.059) at 3-months but with increased odds of recurrent stroke (6.0% vs 4.3%; aOR 1.26; 95% CI: 1.11–1.44; p< 0.001).Conclusions: One-third of ischaemic strokes occurred despite APT and 20% of patients with a history of ischaemic stroke had no antithrombotic therapy when having stroke recurrence. Aetiology of breakthrough strokes despite APT is heterogeneous and these patients are at increased risk of recurrent stroke.

The evacuated-tube collector (ETC) for solar heat production is one of the most efficient systems to convert Sun energy into usable energy. Unfortunately, some technological barriers are still present in solar-thermal heat systems that limit the use of these technologies to decarbonize processes. An important obstacle is the requirement for heat at stable temperatures, which is not always achievable by solar fields, e.g. variable sky. For that reason, in this work, we studied the phase-change materials embedded in the ETC to keep stable the water temperature for a short period (minutes, hours). In this study, carnauba wax was used as a sustainable phase-change material (PCM), to avoid the use of PCM based on hydrocarbon waxes. The PCM has been packaged using a polyethylene bag inserted into an ETC with heat-pipe technologies and tested. The collector has been tested outdoors under solar irradiation and under shading conditions. The experimental results show that is possible to detect a sensible effect of the PCM on the temperature using 4 kg of carnauba wax while there is an important effect on the temperature stabilization using 9 kg of PCM. Using 9 kg of the PCM, we observed a stability of the outlet water temperature at 65°C for 30 minutes under shading conditions.Collection and storage of solar thermal energy is tested experimentally using a phase-change material (carnuba wax) in an evacuated-tube collector used for solar water heating. Under shading conditions, the energy-storage effect of carnauba wax keeps the water temperature stable for minutes to hours.Graphical Abstract

Purpose: There is little data on the safety and efficacy of endovascular treatment (EVT) in comparison with intravenous thrombolysis (IVT) in acute ischemic stroke due to isolated posterior cerebral artery occlusion (IPCAO). We aimed to investigate the functional and safety outcomes of stroke patients with acute IPCAO treated with EVT (with or without prior bridging IVT) compared to IVT alone.Methods: We did a multicenter retrospective analysis of data from the Swiss Stroke Registry. The primary endpoint was overall functional outcome at 3 months in patients undergoing EVT alone or as part of bridging, compared with IVT alone (shift analysis). Safety endpoints were mortality and symptomatic intracranial hemorrhage. EVT and IVT patients were matched 1:1 using propensity scores. Differences in outcomes were examined using ordinal and logistic regression models.Findings: Out of 17,968 patients, 268 met the inclusion criteria and 136 were matched by propensity scores. The overall functional outcome at 3 months was comparable between the two groups (EVT vs IVT as reference category: OR = 1.42 for higher mRS, 95% CI = 0.78–2.57, p= 0.254). The proportion of patients independent at 3 months was 63.2% in EVT and 72.1% in IVT (OR = 0.67, 95% CI = 0.32–1.37, p= 0.272). Symptomatic intracranial hemorrhages were overall rare and present only in the IVT group (IVT = 5.9% vs EVT = 0%). Mortality at 3 months was also similar between the two groups (IVT = 0% vs EVT = 1.5%).Conclusion: In this multicenter nested analysis, EVT and IVT in patients with acute ischemic stroke due to IPCAO were associated with similar overall good functional outcome and safety. Randomized studies are warranted.

SWITCH-1 was a phase 2b study assessing the efficacy, safety, and dose-response relationship of elinzanetant, a selective neurokinin-1,3 receptor antagonist, for the treatment of vasomotor symptoms. Elinzanetant resulted in significant and clinically meaningful improvements in vasomotor symptoms, sleep and quality of life and was well tolerated across all doses.

Ongoing advancements of coronary computed tomographic angiography (CTA) continue to challenge the role of invasive coronary angiography (ICA) as the gold standard for the evaluation of coronary artery disease (CAD). To investigate the comparative effectiveness of ICA when compared with CTA as an initial diagnostic imaging strategy the DISCHARGE Trial enrolled 3561 patients with stable chest pain and an intermediate pre-test probability of obstructive CAD. The study showed no difference between CTA and ICA in the incidence of the primary composite outcome of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke during 3.5 years of follow up. As with many trials that advance a field, this trial raises several additional questions of interest that will be discussed. Furthermore, recent studies focused on the discrepancies of CTA vs. ICA indicate that the status of CTA remains unchanged in its ability to rule out disease but at present cannot be considered a substitute for ICA when coronary lesions are documented. Thus, a change in clinical practice patterns likely requires evidence from clinical studies demonstrating equivalence of CT to ICA for guiding medical management. Developments, however, are swift, and CT technology is catching up on its invasive counterpart.

OBJECTIVE--Development of critical limb ischemia (CLI) has been reported as an independent predictor of cardiac mortality in diabetic patients. We aimed to determine whether CLI, managed in a structured setting [...]

The ISCHEMIA trial found no statistical difference in the primary endpoint between initial invasive and conservative management of patients with chronic coronary disease and moderate-to-severe ischaemia on stress testing. However, an invasive strategy increased peri-procedural myocardial infarction (MI) but decreased spontaneous MI with continued separation of curves over time. Thus, in order to assess the long-term effect of invasive management strategy on mortality, the ISCHEMIA-EXTEND observational study was planned including surviving participants from the initial phase of the ISCHEMIA trial with a projected median follow-up of nearly 10 years. Recently, an interim report of 7-year all-cause, cardiovascular (CV), and non-CV mortality rates has been published showing no difference in all-cause mortality between the two strategies, but with a lower risk of CV mortality and higher risk of non-CV mortality with an initial invasive strategy over a median follow-up of 5.7 years. The trade-offs in CV and non-CV mortality observed in ISCHEMIA-EXTEND raise many important questions regarding the heterogeneity of treatment effect, the drivers of mortality, and the relative importance and reliability of CV vs. all-cause mortality. Overall, findings from ISCHEMIA and ISCHEMIA-EXTEND trials might help physicians in shared decision-making as to whether to add invasive management to guideline-directed medical management in selected patients with chronic coronary artery disease and moderate or severe ischaemia.

Introduction: Rapid treatment of acute ischemic stroke (AIS) depends on sufficient staffing which differs between Stroke Centers and Stroke Units in Switzerland. We studied the effect of admission time on performance measures of AIS treatment and related temporal trends over time.Patients and methods: We compared treatment rates, door-to-image-time, door-to-needle-time, and door-to-groin-puncture-time in stroke patients admitted during office hours (Monday–Friday 8:00–17:59) and non-office hours at all certified Stroke Centers and Stroke Units in Switzerland, as well as secular trends thereof between 2014 and 2019, using data from the Swiss Stroke Registry. Secondary outcomes were modified Rankin Scale and mortality at 3 months.Results: Data were eligible for analysis in 31,788 (90.2%) of 35,261 patients. Treatment rates for IVT/EVT were higher during non-office hours compared with office hours in Stroke Centers (40.8 vs 36.5%) and Stroke Units (21.8 vs 18.5%). Door-to-image-time and door-to-needle-time increased significantly during non-office hours. Median (IQR) door-to-groin-puncture-time at Stroke Centers was longer during non-office hours compared to office hours (84 (59–116) vs 95 (66–130) minutes). Admission during non-office hours was independently associated with worse functional outcome (1.11 [95%CI: 1.04–1.18]) and increased mortality (1.13 [95%CI: 1.01–1.27]). From 2014 to 2019, median door-to-groin-puncture-time improved and the treatment rate for wake-up strokes increased.Discussion and Conclusion: Despite differences in staffing, patient admission during non-office hours delayed IVT to a similar, modest degree at Stroke Centers and Stroke Units. A larger delay of EVT was observed during non-office hours, but Stroke Centers sped up delivery of EVT over time. Patients admitted during non-office hours had worse functional outcomes, which was not explained by treatment delays.

Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation.

Background: Combination therapy with alendronate and estrogen for 2 years increases bone mineral density at the spine and hip more than does therapy with either ag3ent alone. Changes in bone mineral density after discontinuation of therapy have not been compared directly. Objective: To determine the rate of bone loss when therapy with alendronate, estrogen, or both agents is discontinued. Design: Double-blind, placebo-controlled discontinuation trial. Setting: 18 U.S. centers. Patients: 244 postmenopausal, hysterectomized women 44 to 77 years of age. Intervention: 2 years of therapy with alendronate, 10 mg/d (n=92); conjugated estrogen, 0.625 mg/d (n=143); alendronate and conjugated estrogen (n=140); or placebo (n=50). At year 3, women were allocated into five groups: Twenty-eight women continued to take placebo and 44 women continued to take combination therapy, but 50 women taking alendronate, 81 taking conjugated estrogen, and 41 taking combination therapy were switched to placebo. Measurements: Bone mineral density and biochemical markers of bone turnover. Results: Women taking alendronate or combination therapy who were switched to placebo for year 3 of the study maintained bone mass. Bone mineral density in these women was 4.1% (CI, 2.6% to 5.7%) and 6.6% (CI, 5.0% to 8.2%) higher, respectively, at the spine (P Conclusions: Accelerated bone loss is seen after withdrawal of estrogen therapy but not after withdrawal of alendronate or combination therapy. The differential effects after withdrawal of therapy should be considered in the management of postmenopausal osteoporosis.

Second trimester ultrasound scan measurements appear to be a more reliable means of identifying women at risk for delivering prematurely than measurements done during a physical examination. Cervical length measurements using both ultrasound and physical examination were taken between 14 and 30 weeks of pregnancy in 96 high-risk women. Women with a cervix shorter than 25 millimeters as measured by ultrasound were 4.8 times more likely to deliver prematurely than were those with a longer cervix. Manual cervical measurements were not significantly different between full-term and pre-term pregnancies.

Optimal management for patients with ST-segment elevation myocardial infarction (STEMI) who arrive at a hospital late remains uncertain since evidence and real-world data are limited. Patients who present late with a STEMI are a heterogeneous population, and the clinical decision regarding percutaneous coronary intervention (PCI) should not be the same for all. One randomized clinical trial, multiple mechanistic studies, and contemporary registries suggest a presumed benefit for a prompt restoration of coronary flow even in late presenting STEMI. Crucial elements in decision-making are the presence of haemodynamic or electrical instability, and ongoing ischaemic signs or symptoms to tip the scales toward PCI. Among clinically stable, late-presenting patients, myocardial viability assessment and functional testing can identify yet another subgroup that may benefit from late PCI

This study assesses the relative prognostic value of increased left ventricular (LV) mass compared with residual ischemic myocardium and angiographic characteristics of the diseased vessel in 76 patients with uncomplicated acute myocardial infarction associated with 1-vessel coronary artery disease (CAD). All patients underwent symptom-limited treadmill exercise testing, resting and dipyridamole echocardiography and coronary angiography before discharge, and were followed-up for 32 [+ or -] 6 months. LV measurements were obtained in diastole according to the Penn convention. Measurements of LV mass were divided by body surface area to obtain LV mass index. A cut-off value of 135 g/[m.sup.2] body surface area for men and 112 g/[m.sup.2] for women was prospectively selected. The individual effects of clinical, stress testing and angiographic variables were evaluated by using the Cox regression model. Echocardiographic LV mass index was increased in 43 patients and normal in 33. There was no intergroup difference with respect to baseline clinical and angiographic variables, ejection fraction and prevalence of stress-induced ischemia. During follow-up there were 23 cardiac events in the 43 patients with increased LV mass index and only 5 in the 33 with normal LV mass index (p (Am J Cardiol 1994;73:1-5)

PURPOSE: To determine the prognostic capability of the dipyridamole echocardiography test (DET) early after an acute myocardial infarction. PATIENTS AND METHODS: On the basis of 11 different echocardiographic laboratories, all with established experience in stress echocardiography and fulfilling quality-control requirements for stress echocardiographic readings, 925 patients were evaluated after a mean of 10 days from an acute myocardial infarction and followed up for a mean of 14 months. RESULTS: During the follow-up, there were 34 deaths and 37 nonfatal myocardial infarctions; 104 patients developed class III or IV angina and 149 had coronary revascularization procedures (bypass or angioplasty). Considering all spontaneous events (angina, reinfarction, and death), the most important univariate predictor was the presence of an inducible wall motion abnormality after dipyridamole administration ([[chi].sub.2] = 45.8). With a Cox analysis, echocardiographic positivity, age, and male gender were found to have an independent and additive value. Considering survival (and, therefore, death as the only event), age was the most meaningful parameter, followed by the wall motion score index during dipyridamole administration ([[chi].sub.2] = 12.1). Among other parameters, the resting wall motion score index was a significant predictor of death. In a multivariate analysis, the prognostic contributions of age (relative risk estimate = 1.08) and wall motion score index during dipyridamole administration (relative risk estimate = 4.1) were independent and additive. In particular, considering death only, the event rate was 2% in patients with negative DET results, 4% in patients with positive high-dose DET results, and 7% in patients with positive low-dose DET results. CONCLUSIONS: DET is feasible and safe early after uncomplicated myocardial infarction and allows effective risk stratification on the basis of the presence, severity, extent, and timing of the induced dyssynergy.

Early functional evaluation of patients after thrombolytic therapy for myocardial infarction should quantify ventricular function, establish vessel patency and myocardial viability, and assess prognosis. Stress echocardiography may have the potential to accomplish this evaluation safely, noninvasively, and conveniently

The usefulness of the intravenous dipyridamole-echocardiography test (12-lead and two-dimensional [2-D] echo monitoring during dipyridamole infusion) in the diagnosis of coronary artery disease recently has been suggested. However, the intravenous [...]

In a randomized trial of the effects on in-hospital mortality of intravenous urokinase plus heparin versus heparin alone, 2,531 patients with acute myocardial infarction in 89 coronary care units were enrolled for >30 months. Patients admitted within 4 hours of the onset of pain were randomized to receive either intravenous urokinase (a bolus dose of 1 million U repeated after 60 minutes) plus heparin (a bolus dose of 10,000 U followed by 1,000 IU/hour for 48 hours) or heparin alone (infused at the same rate). Complete data were obtained in 2,201 patients (1,128 taking urokinase and 1,073 taking heparin). At 16 days, overall hospital mortality was 8% in the urokinase and 8.3% in the heparin group (p = not significant). Among patients with anterior infarction, mortality was 10.3% in the urokinase and 13.9% in the heparin group (p = 0.09; relative risk = 0.73). The incidence of major bleeding (urokinase 0.44%, heparin 0.37%) as well as the overall incidence of stroke (urokinase 0.35%, heparin 0.20%) was similar in the 2 groups. The rates of major in-hospital cardiac complications (reinfarction, postinfarction angina) were also similar. (Am J Cardiol 1991;68:585-592), It has been demonstrated that thrombolytic (clot-dissolving) therapy re-establishes blood flow to the heart after myocardial infarction (heart attack) caused by blood clot-induced obstruction of the coronary arteries. However, controversy exists over which clot-dissolving agent to use. The effect of intravenous urokinase, a thrombolytic agent, on mortality has not been assessed. This study compared mortality between 1,128 patients who were given urokinase plus heparin, an anticoagulant, and 1,073 patients who received heparin alone. The incidence of mortality was calculated 16 days after myocardial infarction. The incidence of nonfatal cardiac events and side effects, such as bleeding complications, were also compared between the two groups. No significant difference was found in the death rate between the urokinase plus heparin and the heparin only groups. Mortality among the patients who received heparin was 8.3 percent, an unexpectedly low rate compared with other major clinical trials (which have reported about 13 percent mortality). Early treatment with heparin alone may lower mortality after a heart attack, as aspirin has been shown to do. However, in the group receiving urokinase, there was a significant reduction in heart failure and pericarditis (inflammation of the pericardium, the fibrous sac that encloses the heart). It is also likely that the urokinase plus heparin group suffered less heart damage and had better heart function than the heparin only group. Patients who suffered anterior wall infarction, usually a more serious condition, had lower mortality when given urokinase. However, mortality was increased among patients who sustained inferior wall infarction. The authors conclude that the added risk of thrombolytic therapy is probably not warranted in patients with small inferior wall infarcts, as this condition does not cause severe heart damage and patients usually recover. (Consumer Summary produced by Reliance Medical Information, Inc.)

To assess the role of high-dose up to 0.84 mg/kg during 10 minutes) dipyridamole echocardiographic testing in the evaluation of coronary artery bYPass graft patency early after surgery, 18 consecutive patients with angina underwent dipyridamole echocardiography and coronary angiography before and 7 to 10 days after bypass surgery. Coronary angiography showed 2- or 3-vessel disease in 7 and 11 patients, respectively. A total of 53 bypass grafts were performed. Before bypass surgery 14 patients had a positive and 4 a negative test result. No complication occurred during the test early after surgery. Of the 14 patients with positive dipyridamole echocardlegraphic results before surgery, 10 had negative and 4 had positive results after surgery. All 4 patients had negative results before and after surgery. in the 4 patients with positive results after dipyridamole echocardlographic testing before and after bypass surgery, dipyridamole time increased from 5.8 +/- 5 to 9.3 +/- 0.9 minutes (p = 0.3) after the procedure and wall motion score index at peak dipyridamole changed from 1.55 +/- 0.2 to 1.28 +/- 0.3 (p = 0.05). Forty-nine of S3 grafts were patent as seen on angiography. Dipyridamole echocardlographic results were positive in 4 of 5 patients who had at least 1 obstructed graft or native vessel obstructed distal to bypass graft insertion. The remaining patient had diagnostic electrocardiogardiographic changes during dipyridamole infusion without wall motion abnormalities. Dipyridamole echocardiographic results were negative in all 13 patients who had complete revascularization. In the 4 patients with positive test results, the procedure correctly identified the localization of the diseased bypass graft. These data suggest that (1) dipyridamole echocardiography can be easily and safely performed after coronary artery bypass graft surgery, (2) there is an excellent correlation between the functional improvement assessed by dipyridamele echocardiography testing and anatomic results of coronary artery bypass surgery, and (3) it reliably detects and identifies diseased bypass grafts. (Am J Cardiol 1991;67:133-136), When the arteries supplying the heart muscle with blood (coronary arteries) become blocked, resulting in a diminution in the cardiac blood supply, several strategies are available for restoring the patency of the vessels. Coronary artery bypass grafting (CABG) is a commonly used technique in which a healthy blood vessel is taken from elsewhere in the body and used to bypass the occluded coronary artery. It is useful to know in the immediate postoperative period whether or not the graft is successful. Standard means of assessing coronary blood flow, such as exercise echocardiography, are dangerous to perform on CABG patients. An alternative to exercise is administration of the drug dipyridamole, which has a pharmacological action on the cardiovascular system quite similar to that of exercise, but without many of the dangers attendant upon vigorous physical exertion. To assess the utility of high-dose dipyridamole echocardiography in the evaluation of coronary blood flow, 18 patients with angina pectoris (chest pain resulting from diminished blood flow to the heart) were evaluated using this technique both prior to and 7 to 10 days after CABG surgery. Presurgery evaluation showed that all patients had either two- or three-vessel disease, and a total of 53 bypass grafts were performed. Angiography (a very accurate, but invasive radiological technique for viewing coronary blood flow) results correlated very highly with the findings of the noninvasive dipyridamole tests. This indicates that dipyridamole echocardiography is a safe, easy technique for use following CABG (and potentially other types of cardiovascular) surgery and has a high degree of accuracy and specificity. (Consumer Summary produced by Reliance Medical Information, Inc.)

Holoprosencephaly (HPE) is the failure of the embryonic forebrain to develop into 2 hemispheres promoting midline cerebral and facial defects. The wide phenotypic variability and causal heterogeneity make genetic counseling difficult. Heterozygous variants with incomplete penetrance and variable expressivity in the SHH, SIX3, ZIC2, and TGIF1genes explain ∼25% of the known causes of nonchromosomal HPE. We studied these 4 genes and clinically described 27 Latin American families presenting with nonchromosomal HPE. Three new SHHvariants and a third known SIX3likely pathogenic variant found by Sanger sequencing explained 15% of our cases. Genotype-phenotype correlation in these 4 families and published families with identical or similar driver gene, mutated domain, conservation of residue in other species, and the type of variant explain the pathogenicity but not the phenotypic variability. Nine patients, including 2 with SHHpathogenic variants, presented benign variants of the SHH, SIX3, ZIC2, and TGIF1genes with potential alteration of splicing, a causal proposition in need of further studies. Finding more families with the same SIX3variant may allow further identification of genetic or environmental modifiers explaining its variable phenotypic expression.

Patients with established cardiovascular (CV) disease may suffer further CV events, despite receiving optimal medical treatment. Although platelet inhibition plays a central role in the prevention of new events, the use of anticoagulant therapies to reduce events in atheromatous disease has, until recently, been overlooked. The recent Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease (COMPASS) trial showed that rivaroxaban 2.5 mg twice daily given with low-dose aspirin reduces the incidence of the composite endpoint of stroke, heart attack, and death in patients with stable coronary artery disease. Although there are some limitations to the study, COMPASS offers promising conclusions and may change secondary prevention in patients with stable CV disease. This article reviews the results of the COMPASS study and how these results may affect patient management in everyday clinical practice.

A methodology for direct and simultaneous determination of four phenolic antioxidants—butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate (PG), and tert-butylhydroquinone (TBHQ)—in biodiesel samples using differential pulse voltammetry associated with partial least squares (PLS) regression is presented. Measurements were taken directly in a biodiesel:ethanol 1:1 (v/v) medium using a platinum ultramicroelectrode as the working electrode. The voltammetric signals of the compounds overlapped significantly, and to facilitate the simultaneous determination of the analytes, a PLS chemometric tool was applied and approaches fitting one compound at a time (PLS-1) and multiple compounds (PLS-2) both allowed the quantification of the individual concentrations, overcoming the strongly overlapped voltammograms. Results show that the PLS-2 model provides more accurate predictions than PLS-1. For the PLS-2 model, root mean square errors of prediction of 3 × 10, 16, 24, and 3 × 10 mg L–1have been obtained between nominal and predicted concentrations for BHA, BHT, PG, and TBHQ, respectively. Recovery percentages were between 83 and 104%.

Supplemental Digital Content is available in the text.

The management of Chiari I malformation (CMI) is controversial because treatment methods vary and treatment decisions rest on incomplete understanding of its complex symptom patterns, etiologies, and natural history. Validity of studies that attempt to compare treatment of CMI has been limited because of variable terminology and methods used to describe study subjects. The goal of this project was to standardize terminology and methods by developing a comprehensive set of Common Data Elements (CDEs), data definitions, case report forms (CRFs), and outcome measure recommendations for use in CMI clinical research, as part of the CDE project at the National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health. A working group, comprising over 30 experts, developed and identified CDEs, template CRFs, data dictionaries, and guidelines to aid investigators starting and conducting CMI clinical research studies. The recommendations were compiled, internally reviewed, and posted online for external public comment. In October 2016, version 1.0 of the CMI CDE recommendations became available on the NINDS CDE website. The recommendations span these domains: Core Demographics/Epidemiology; Presentation/Symptoms; Co-Morbidities/Genetics; Imaging; Treatment; and Outcome. Widespread use of CDEs could facilitate CMI clinical research trial design, data sharing, retrospective analyses, and consistent data sharing between CMI investigators around the world. Updating of CDEs will be necessary to keep them relevant and applicable to evolving research goals for understanding CMI and its treatment.

This case report intends to provide the facial characteristics of Escobar syndrome and to describe the orthodontic treatment of a 12-year-old female patient diagnosed with it. Escobar syndrome, a variant of the multiple pterygium syndrome, is a rare disorder with many systemic, facial, and oral manifestations.The patient presented with mixed dentition, severe dolichofacial pattern, increased lower facial height, convex profile, severe anterior open bite, maxillary hypoplasia, and mandibular retrognatism. The multidisciplinary approach included soft cleft palate repair, orthodontic treatment, orthognathic surgery, restorative cosmetic dentistry, speech therapy, and physiotherapy. Despite the limitations imposed by the syndrome, this report illustrates how the multidisciplinary treatment approach aided in the correction of occlusal function and facial esthetics and improvement in the quality of life of the patient with Escobar syndrome.

Background: In the ATLANTIC (Administration of Ticagrelor in the catheterization laboratory or in the Ambulance for New ST elevation myocardial Infarction to open the Coronary artery) trial the early use of aspirin, anticoagulation, and ticagrelor coupled with very short medical contact-to-balloon times represent good indicators of optimal treatment of ST-elevation myocardial infarction and an ideal setting to explore which factors may influence coronary reperfusion beyond a well-established pre-hospital system.Methods: This study sought to evaluate predictors of complete ST-segment resolution after percutaneous coronary intervention in ST-elevation myocardial infarction patients enrolled in the ATLANTIC trial. ST-segment analysis was performed on electrocardiograms recorded at the time of inclusion (pre-hospital electrocardiogram), and one hour after percutaneous coronary intervention (post-percutaneous coronary intervention electrocardiogram) by an independent core laboratory. Complete ST-segment resolution was defined as ≥70% ST-segment resolution.Results: Complete ST-segment resolution occurred post-percutaneous coronary intervention in 54.9% (n=800/1456) of patients and predicted lower 30-day composite major adverse cardiovascular and cerebrovascular events (odds ratio 0.35, 95% confidence interval 0.19–0.65; p<0.01), definite stent thrombosis (odds ratio 0.18, 95% confidence interval 0.02–0.88; p=0.03), and total mortality (odds ratio 0.43, 95% confidence interval 0.19–0.97; p=0.04). In multivariate analysis, independent negative predictors of complete ST-segment resolution were the time from symptoms to pre-hospital electrocardiogram (odds ratio 0.91, 95% confidence interval 0.85–0.98; p<0.01) and diabetes mellitus (odds ratio 0.6, 95% confidence interval 0.44–0.83; p<0.01); pre-hospital ticagrelor treatment showed a favorable trend for complete ST-segment resolution (odds ratio 1.22, 95% confidence interval 0.99–1.51; p=0.06).Conclusions: This study confirmed that post-percutaneous coronary intervention complete ST-segment resolution is a valid surrogate marker for cardiovascular clinical outcomes. In the current era of ST-elevation myocardial infarction reperfusion, patients’ delay and diabetes mellitus are independent predictors of poor reperfusion and need specific attention in the future.

Recent studies demonstrated that allograft inflammatory factor-1 (AIF-1) and RNASET2 act as chemoattractants for macrophages and modulate the inflammatory processes in both vertebrates and invertebrates. The expression of these proteins significantly increases after bacterial infection; however, the mechanisms by which they regulate the innate immune response are still poorly defined. Here, we evaluate the effect of bacterial lipopolysaccharide injection on the expression pattern of these genes and the interrelation between them during innate immune response in the medicinal leech, an invertebrate model with a simple anatomy and a marked similarity with vertebrates in inflammatory processes. Collectively, prokaryotic-eukaryotic co-cultures and in vivo infection assays suggest that RNASET2 and AIF-1 play a crucial role in orchestrating a functional cross-talk between granulocytes and macrophages in leeches, resulting in the activation of an effective response against pathogen infection. RNASET2, firstly released by granulocytes, likely plays an early antibacterial role. Subsequently, AIF-1+RNASET2-recruited macrophages further recruit other macrophages to potentiate the antibacterial inflammatory response. These experimental data are in keeping with the notion of RNA­SET2 acting as an alarmin-like molecule whose role is to locally transmit a “danger” signal (such as a bacterial infection) to the innate immune system in order to trigger an appropriate host response.

Background: Most nonsteroidal anti-inflammatory drugs (NSAIDs) are nonselective cyclooxygenase (COX-1 and COX-2) inhibitors and are associated with a variety of upper gastrointestinal (GI) tract symptoms. The roles of COX-1 and COX-2 in the pathogenesis of these symptoms are unclear. To test whether COX-2 inhibition with rofecoxib would have greater GI tolerability than nonselective COX-1 and COX-2 inhibition, we compared the incidences of (1) treatment discontinuations for GI adverse events (AEs) and (2) prespecified dyspeptic-type GI AEs among patients with osteoarthritis treated with rofecoxib vs NSAIDs. Methods: A prespecified, combined analysis of investigator-reported GI AEs in all 8 double-blind, randomized, phase 2b/3 osteoarthritis trials of rofecoxib was conducted. Patients included men and women with osteoarthritis (N=5435); there was no upper age limit for entry. Treatments tested included rofecoxib, 12.5, 25, or 50 mg (combined), vs ibuprofen, diclofenac, or nabumetone (combined). Primary outcomes were the time (by survival analysis) to (1) treatment discontinuation due to GI AEs and (2) first reported dyspeptic-type GI AE. Between-treatment comparisons were made by log-rank test. Results: The number of treatment discontinuations caused by GI AEs during 12 months was significantly lower (P = .02) with rofecoxib vs NSAIDs (8.2 vs 12.0 per 100 patient-years; relative risk, 0.70; 95% confidence interval, 0.52-0.94). The incidence of prespecified dyspeptic-type GI AEs during the first 6 months was significantly lower (P = .02) with rofecoxib vs NSAIDs (69.3 vs 85.2 per 100 patient-years; relative risk, 0.85; 95% confidence interval, 0.74-0.97). However, the difference between treatments in dyspeptic-type GI AEs was attenuated after 6 months. Conclusion: Rofecoxib was associated with a lower incidence of treatment discontinuations due to GI AEs over 12 months and a lower incidence of dyspeptic-type GI AEs over 6 months than treatment with nonselective COX inhibitors, or NSAIDs. Arch Intern Med. 2000;160:2998-3003

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). It is not known whether a specific inhibitor of COX-2 will provide efficacy in osteoarthritis (OA) comparable with NSAIDs. Therefore, we compared the efficacy and safety of the rofecoxib, which specifically inhibits COX-2, with those of the NSAID ibuprofen in patients with OA. Objective: To compare the clinical efficacy and tolerability of rofecoxib (12.5 and 25 mg once daily) with ibuprofen (800 mg 3 times daily). Methods: A randomized, double-blind trial of 809 adults with OA was conducted. Patients with OA in whom the knee or hip was the primary source of pain were randomized to 1 of 4 treatment groups on demonstration of disease activity: placebo; rofecoxib, 12.5 or 25 mg once daily; or ibuprofen, 800 mg 3 times daily. Clinical efficacy and safety were monitored during a 6-week treatment period. Results: Both doses of rofecoxib demonstrated efficacy clinically comparable with ibuprofen as assessed by 3 primary end points (pain walking on a flat surface [Western Ontario and McMaster Universities Osteoarthritis Index], patient global assessment of response to therapy, and investigator global assessment of disease status) according to predefined comparability criteria. Both rofecoxib doses and the ibuprofen dose provided significantly (P [is less than] .001) greater efficacy than placebo on all primary end points. Results from secondary end points were consistent with those of the primary end points. All treatments were well tolerated; the overall incidence rates of clinical adverse experiences were not significantly different (P [is greater than] .05) among the treatment groups. Conclusion: Rofecoxib was well tolerated and provided clinical efficacy comparable with a high dose of the NSAID ibuprofen. Arch Intern Med. 2000;160:1781-1787

The goal of treatment in stable coronary artery disease is to improve prognosis and quality of life of the patients. International Guidelines support revascularization procedures for symptomatic patients unresponsive to optimal medical treatment. Previous studies demonstrated, in fact, the therapeutic efficacy of coronary angioplasty in reducing angina and improving the functional capacity of these patients. The ORBITA study, recently published, challenged these assertions by demonstrating the lack of benefit of angioplasty over placebo in terms of effort tolerance in a population of patients with single-vessel coronary artery disease. What lesson could we learn from the ORBITA study?

Background: Delirium is a frequent in-hospital complication in elderly patients, and is associated with poor clinical outcome. Its clinical impact, however, has not yet been fully addressed in the setting of the cardiac intensive care unit (CICU). The present study is a prospective, two-centre registry aimed at assessing the incidence, prevalence and significance of delirium in elderly patients with acute cardiac diseases.Methods: Between January 2014 and March 2015, all consecutive patients aged 65 years or older admitted to the CICU of our institutions were enrolled and followed for 6 months. Delirium was defined according to the confusion assessment method.Results: During the study period, 726 patients were screened for delirium. The mean age was 79.1±7.8 years. A total of 111 individuals (15.3%) were diagnosed with delirium; of them, 46 (41.4%) showed prevalent delirium (PD), while 65 (58.6%) developed incident delirium (ID). Patients 85 years or older showed a delirium rate of 52.3%. Hospital stay was longer in delirious versus non-delirious patients. Patients with delirium showed higher in-hospital, 30-day and 6-month mortality compared to non-delirious patients, irrespective of the onset time (overall, ID or PD). Six-month re-hospitalisation was significantly higher in overall delirium and the PD group, as compared to non-delirious patients. Kaplan–Meier analysis showed a significant reduction of 6-month survival in patients with delirium compared to those without, irrespective of delirium onset time (i.e. ID or PD). A positive confusion assessment method was an independent predictor of short and long-term mortality.Conclusions: Delirium is a common complication in elderly CICU patients, and is associated with a longer and more complicated hospital stay and increased short and long-term mortality. Our findings suggest the usefulness of a protocol for the early identification of delirium in the CICU. Clinicaltrials.gov: NCT02004665

Neurological complications of infective endocarditis are frequent, especially ischaemic strokes. As intravenous thrombolysis in infective endocarditis-related ischaemic stroke has a controversial benefit/risk ratio, alternative treatment regimens have to be considered. We present the case of a young patient with septic embolism of the middle cerebral artery who was successfully treated with mechanical thrombectomy, and give a short review of the existing literature.