Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.

Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease.

ß-Blockers, heart disease and COPD: current controversies and uncertainties.

Treating people with cardiovascular disease and COPD causes significant clinician anxiety. ß-Blockers save lives in people with heart disease, specifically postinfarction and heart failure. COPD and heart disease frequently coexist and people with both disorders have particularly high cardiovascular mortality. There are concerns about giving ß-blockers to people with concomitant COPD that include reduced basal lung function, diminished effectiveness of emergency ß-agonist treatments, reduced benefit of long-acting ß-agonist treatment and difficulty in discriminating between asthma and COPD. ß-Blockers appear to reduce lung function in both the general population and those with COPD because they are poorly selective for cardiac ß1-adrenoceptors over respiratory ß2-adrenoceptors, and studies have shown that higher ß-agonist doses are required to overcome the ß-blockade. COPD and cardiovascular disease share similar environmental risks and both disease states have high adrenergic and inflammatory activation. ß-Blockers may therefore be particularly helpful in reducing cardiovascular events in this high-risk group. They may reduce the background inflammatory state, and inhibit the tachycardia and hypertension associated with both the endogenous adrenaline and high-dose ß-agonist treatment associated with acute exacerbations of COPD. Some studies have suggested no increased and, at times, reduced mortality in patients with COPD taking ß-blockers for heart disease. However, these are all observational studies and there are no randomised controlled trials. Potential ways to improve this dilemma include the development of highly ß1-selective ß-blockers or the use of non-ß-blocking heart rate reducing agents, such as ivabridine, if these are proven to be beneficial in randomised controlled trials.

Strategies to attenuate micro-vascular obstruction during P-PCI: the randomized reperfusion facilitated by local adjunctive therapy in ST-elevation myocardial infarction trial.

BACKGROUND: Microvascular obstruction (MVO) following primary percutaneous coronary intervention (PPCI) treatment of ST-segment elevation myocardial infarction (STEMI) contributes to infarct expansion, left ventricular (LV) remodelling, and worse clinical outcomes. The REFLO-STEMI trial tested whether intra-coronary (IC) high-dose adenosine or sodium nitroprusside (SNP) reduce infarct size and/or MVO determined by cardiac magnetic resonance (CMR). METHODS AND RESULTS: REFLO-STEMI, a prospective, open-label, multi-centre trial with blinded endpoints, randomized (1:1:1) 247 STEMI patients with single vessel disease presenting within 6 h of symptom onset to IC adenosine (2-3 mg total) or SNP (500 µg total) immediately following thrombectomy and again following stenting, or to standard PPCI. The primary endpoint was infarct size % LV mass (%LVM) on CMR undertaken 24-96 h after PPCI (n = 197). Clinical follow-up was to 6 months. There was no significant difference in infarct size (%LVM, median, interquartile range, IQR) between adenosine (10.1, 4.7-16.2), SNP (10.0, 4.2-15.8), and control (8.3, 1.9-14.0), P = 0.062 and P = 0.160, respectively, vs. CONTROL: MVO (% LVM, median, IQR) was similar across groups (1.0, 0.0-3.7, P = 0.205 and 0.6, 0.0-2.4, P = 0.244 for adenosine and SNP, respectively, vs. control 0.3, 0.0-2.8). On per-protocol analysis, infarct size (%LV mass, 12.0 vs. 8.3, P = 0.031), major adverse cardiac events (hazard ratio, HR, 5.39 [1.18-24.60], P = 0.04) at 30 days and 6 months (HR 6.53 [1.46-29.2], P = 0.01) were increased and ejection fraction reduced (42.5 ± 7.2% vs. 45.7 ± 8.0%, P = 0.027) in adenosine-treated patients compared with control. CONCLUSIONS: High-dose IC adenosine and SNP during PPCI did not reduce infarct size or MVO measured by CMR. Furthermore, adenosine may adversely affect mid-term clinical outcome. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01747174; https://clinicaltrials.gov/ct2/show/NCT01747174.

Fibrinolysis or primary PCI in ST-segment elevation myocardial infarction.

BACKGROUND: It is not known whether prehospital fibrinolysis, coupled with timely coronary angiography, provides a clinical outcome similar to that with primary percutaneous coronary intervention (PCI) early after acute ST-segment elevation myocardial infarction (STEMI). METHODS: Among 1892 patients with STEMI who presented within 3 hours after symptom onset and who were unable to undergo primary PCI within 1 hour, patients were randomly assigned to undergo either primary PCI or fibrinolytic therapy with bolus tenecteplase (amended to half dose in patients ≥75 years of age), clopidogrel, and enoxaparin before transport to a PCI-capable hospital. Emergency coronary angiography was performed if fibrinolysis failed; otherwise, angiography was performed 6 to 24 hours after randomization. The primary end point was a composite of death, shock, congestive heart failure, or reinfarction up to 30 days. RESULTS: The primary end point occurred in 116 of 939 patients (12.4%) in the fibrinolysis group and in 135 of 943 patients (14.3%) in the primary PCI group (relative risk in the fibrinolysis group, 0.86; 95% confidence interval, 0.68 to 1.09; P=0.21). Emergency angiography was required in 36.3% of patients in the fibrinolysis group, whereas the remainder of patients underwent angiography at a median of 17 hours after randomization. More intracranial hemorrhages occurred in the fibrinolysis group than in the primary PCI group (1.0% vs. 0.2%, P=0.04; after protocol amendment, 0.5% vs. 0.3%, P=0.45). The rates of nonintracranial bleeding were similar in the two groups. CONCLUSIONS: Prehospital fibrinolysis with timely coronary angiography resulted in effective reperfusion in patients with early STEMI who could not undergo primary PCI within 1 hour after the first medical contact. However, fibrinolysis was associated with a slightly increased risk of intracranial bleeding. (Funded by Boehringer Ingelheim; ClinicalTrials.gov number, NCT00623623.).

ST-segment-elevation myocardial infarction patients randomized to a pharmaco-invasive strategy or primary percutaneous coronary intervention: Strategic Reperfusion Early After Myocardial Infarction (STREAM) 1-year mortality follow-up.

BACKGROUND: In the Strategic Reperfusion Early After Myocardial Infarction (STREAM) trial, a pharmaco-invasive (PI) strategy was compared with primary percutaneous coronary intervention (pPCI) in ST-segment-elevation myocardial infarction patients presenting within 3 hours after symptom onset but unable to undergo pPCI within 1 hour. At 30 days, the PI approach was associated with a nominally but nonstatistically significant lower incidence of the composite primary end point of death, shock, congestive heart failure, and reinfarction when compared with pPCI. The aim of the present study was to determine the effect of these strategies on 1-year mortality. METHODS AND RESULTS: Vital status at 1 year was available in 936 of 944 (99.2%) and 941 of 948 (99.3%) patients in the PI and pPCI arm, respectively. At 1 year, all-cause mortality rates (6.7% versus 5.9%) were similar for PI and pPCI-treated patients (P=0.49; risk ratio, 1.13; 95% confidence interval, 0.79-1.62). Cardiac mortality rates were similar as well (4.0% versus 4.1%, P=0.93; risk ratio, 0.98; 95% confidence interval, 0.62-1.54). Overall, only 34 patients died between day 30 and 1 year, 20 in the PI arm and 14 in the pPCI arm, of whom 20 died of noncardiac reasons (13 in the PI and 7 in the pPCI arm). There was no significant difference in 1-year all-cause mortality between the 2 groups among the prespecified key subgroups. CONCLUSIONS: At 1 year, mortality rates in the PI and pPCI arms were similar in ST-segment-elevation myocardial infarction patients presenting within 3 hours after symptom onset and unable to undergo pPCI within 1 hour. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00623623.

Crystalline and liquid structure of zinc chloride trihydrate: a unique ionic liquid.

The water/ZnCl(2) phase diagram in the vicinity of the 75 mol % water composition is reported, demonstrating the existence of a congruently melting phase. Single crystals of this 3-equiv hydrate were grown, and the crystal structure of [Zn(OH(2))(6)][ZnCl(4)] was determined. Synchrotron X-ray and neutron diffraction and IR and Raman spectroscopy along with reverse Monte Carlo modeling demonstrate that a CsCl-type packing of the molecular ions persists into the liquid state. Consistent with the crystalline and liquid structural data, IR spectroscopy demonstrates that the O-H bonds of coordinated water do not exhibit strong intermolecular hydrogen ion bonding but are significantly weakened because of the water's coordination to Lewis acidic zinc ions. The O-H bond weakening makes this system a very strong hydrogen-bond donor, whereas the ionic packing along with the nonpolar geometry of the molecular ions makes this system a novel nonpolar, hydrogen-bonding, ionic liquid solvent.

Whispering dysphonia (DYT4 dystonia) is caused by a mutation in the TUBB4 gene.

OBJECTIVE: A study was undertaken to identify the gene underlying DYT4 dystonia, a dominantly inherited form of spasmodic dysphonia combined with other focal or generalized dystonia and a characteristic facies and body habitus, in an Australian family. METHODS: Genome-wide linkage analysis was carried out in 14 family members followed by genome sequencing in 2 individuals. The index patient underwent a detailed neurological follow-up examination, including electrophysiological studies and magnetic resonance imaging scanning. Biopsies of the skin and olfactory mucosa were obtained, and expression levels of TUBB4 mRNA were determined by quantitative real-time polymerase chain reaction in 3 different cell types. All exons of TUBB4 were screened for mutations in 394 unrelated dystonia patients. RESULTS: The disease-causing gene was mapped to a 23cM region on chromosome 19p13.3-p13.2 with a maximum multipoint LOD score of 5.338 at markers D9S427 and D9S1034. Genome sequencing revealed a missense variant in the TUBB4 (tubulin beta-4; Arg2Gly) gene as the likely cause of disease. Sequencing of TUBB4 in 394 unrelated dystonia patients revealed another missense variant (Ala271Thr) in a familial case of segmental dystonia with spasmodic dysphonia. mRNA expression studies demonstrated significantly reduced levels of mutant TUBB4 mRNA in different cell types from a heterozygous Arg2Gly mutation carrier compared to controls. INTERPRETATION: A mutation in TUBB4 causes DYT4 dystonia in this Australian family with so-called whispering dysphonia, and other mutations in TUBB4 may contribute to spasmodic dysphonia. Given that TUBB4 is a neuronally expressed tubulin, our results imply abnormal microtubule function as a novel mechanism in the pathophysiology of dystonia.

Hand function is impaired in healthy older adults at risk of Parkinson's disease.

Abnormal substantia nigra morphology in healthy individuals, viewed with transcranial ultrasound, is a significant risk factor for Parkinson's disease. However, little is known about the functional consequences of this abnormality (termed 'hyperechogenicity') on movement. The aim of the current study was to investigate hand function in healthy older adults with (SN+) and without (SN-) substantia nigra hyperechogenicity during object manipulation. We hypothesised that SN+ subjects would exhibit increased grip force and a slower rate of force application compared to SN- subjects. Twenty-six healthy older adults (8 SN+ aged 58 ± 8 years, 18 SN- aged 57 ± 6 years) were asked to grip and lift a light-weight object with the dominant hand. Horizontal grip force, vertical lift force, acceleration, and first dorsal interosseus EMG were recorded during three trials. During the first trial, SN+ subjects exhibited a longer period between grip onset and lift onset (i.e. preload duration; 0.27 ± 0.25 s) than SN- subjects (0.13 ± 0.08 s; P = 0.046). They also exerted a greater downward force prior to lift off (-0.54 ± 0.42 N vs. -0.21 ± 0.12 N; P = 0.005) and used a greater grip force to lift the object (19.5 ± 7.0 N vs. 14.0 ± 4.3 N; P = 0.022) than SN- subjects. No between group differences were observed in subsequent trials. SN+ subjects exhibit impaired planning for manipulation of new objects. SN+ individuals over-estimate the grip force required, despite a longer contact period prior to lifting the object. The pattern of impairment observed in SN+ subjects shares similarities with de novo Parkinson's disease patients.

Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial.

BACKGROUND: Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial. METHODS: In TRA 2°P-TIMI 50--a randomised, placebo-controlled, parallel trial--we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2·5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474). FINDINGS: 17,779 of 26,449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2·5 years (IQR 2·0-2·9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8·1%vs 9·7%, HR 0·80, 95% CI 0·72-0·89; p<0·0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3·4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2·1%, 3-year Kaplan-Meier estimate], HR 1·61, 95% CI 1·31-1·97; p<0·0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0·6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0·4%, 3-year Kaplan-Meier estimate) with placebo (p=0·076). Other serious adverse events were equally distributed between groups. INTERPRETATION: For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding. FUNDING: Merck.

Simple quantitative planimetric measurement of nigrosome-1 for clinical settings.

INTRODUCTION: Loss of MRI hyperintense signal in nigrosome-1 (assessed with susceptibility-weighted imaging) is a biomarker for Parkinson's disease (PD). Current clinical practice involves subjectively rating the appearance of nigrosome-1 which is challenging. The study aimed to test and compare a simple method for quantifying nigrosome-1 with the current subjective rating method. METHODS: Two experienced neuroradiologists measured area of hyperintense signal in nigrosome-1 (quantitative method) and rated nigrosome-1 appearance (as normal, attenuated, or absent; subjective method) in 42 patients encompassing the full spectrum of nigrosome-1 integrity (21 patients aged 55.5 ± 20.9 years with Essential tremor (ET) and a subset of 21 patients aged 69.6 ± 8.6 years with PD). Neuroradiologists were blinded to each other's measurements, clinical notes, and patient group. RESULTS: Both methods yielded a significant difference between the groups (PD vs ET; p < 0.001). Pooled (across sides) area of nigrosome-1 hyperintense signal was significantly smaller in the PD group (median = 2.1 mm2, range = 0-15.8 mm2) than ET group (median = 8.3 mm2, range = 0-15.7 mm2; p < 0.001). Inter-rater reliability was high to very high for both methods (subjective: weighted kappa = 0.640, p < 0.001; quantitative: W = 0.733, p = 0.004). Our primary hypothesis that area of nigrosome-1 hyperintense signal exhibits higher inter-rater reliability than subjective rating of nigrosome-1 appearance was not supported. CONCLUSION: The simple quantitative method, used with subjectively rated nigrosome-1 appearance, may improve confidence in longitudinal clinical reporting, when nigrosome-1 is attenuated. However, further work on the incremental diagnostic value of planimetry and bias, repeatability and reproducibility are needed before it can be recommended in clinical practice.

Understanding the Water-in-Salt to Salt-in-Water Characteristics across the Zinc Chloride : Water Phase Diagram.

Using a series of time- and temperature-resolved synchrotron diffraction experiments, the relationship between multiple polymorphs of ZnCl2 and its respective hydrates is established. The δ-phase is found to be the pure anhydrous phase, while the α, ß, and γ phases result from partial hydration. Diffraction, gravimetric, and calorimetric measurements across the entire ZnCl2·R H2O, 0 > R > ∞ composition range using ultrapure, doubly sublimed ZnCl2 establish the ZnCl2 : H2O phase diagram. The results are consistent with the existence of crystalline hydrates at R = 1.33, 3, and 4.5 and identify a mechanistic pathway for hydration. All water is not removed from hydrated ZnCl2 until the system is heated above its melting point. While hydration/dehydration is reversible in concentrated solutions, dehydration from dilute aqueous solutions can result in loss of HCl, the source of hydroxide impurities commonly found in commercial ZnCl2 preparations. The strong interaction between ZnCl2 and water exerts a significant impact on the solvent water such that the system exhibits a deep eutectic at a composition of about R = 7 (87.5 mol %) and a eutectic temperature below -60 °C.

Refining clinical trial composite outcomes: an application to the Assessment of the Safety and Efficacy of a New Thrombolytic-3 (ASSENT-3) trial.

BACKGROUND: Traditional time-to-event analysis assigns equal weight to the first event in the composite end point. This is counterintuitive to many stakeholders. METHODS: We constructed weights for components of a composite efficacy end point and a net clinical outcome by including metrics of safety and efficacy and compared the weighted with the traditional approach. Through an externally validated, clinician-investigator Delphi panel, the relative severity of individual components of a composite end point (30-day death, recurrent myocardial infarction, cardiogenic shock, and congestive heart failure) was determined. The net clinical outcome was assessed through the incorporation of risk thresholds for safety events (intracranial hemorrhage and major systemic bleeding). These weights were then applied to a modified analysis of the ASSENT-3 trial. RESULTS: The weights for the efficacy composite were as follows: death, 1.0; shock, 0.5; congestive heart failure, 0.3; and recurrent myocardial infarction, 0.2. The traditional time-to-first-event approach demonstrated a comparable advantage for both enoxaparin (enox) and abciximab (abx) over unfractionated heparin (P = .05), whereas the weighted efficacy analysis suggested an advantage for enox and similar outcomes between unfractionated heparin and abx (P = .2). The apparent advantage of enox was attenuated when the net clinical outcome was examined; the apparent efficacy of abx combination therapy was also diminished by an elevated major systemic bleeding rate (P < .001). CONCLUSION: This novel approach adds an alternative dimension to treatment evaluation by more efficiently incorporating the differential value of all events in each patient. Further development and application of this approach to future trial design and analysis are warranted.

Pedunculopontine nucleus deep brain stimulation produces sustained improvement in primary progressive freezing of gait.

OBJECTIVE: To assess the efficacy of bilateral pedunculopontine nucleus (PPN) deep brain stimulation (DBS) as a treatment for primary progressive freezing of gait (PPFG). METHODS: A patient with PPFG underwent bilateral PPN-DBS and was followed clinically for over 14 months. RESULTS: The PPFG patient exhibited a robust improvement in gait and posture following PPN-DBS. When PPN stimulation was deactivated, postural stability and gait skills declined to pre-DBS levels, and fluoro-2-deoxy-d-glucose positron emission tomography revealed hypoactive cerebellar and brainstem regions, which significantly normalised when PPN stimulation was reactivated. CONCLUSIONS: This case demonstrates that the advantages of PPN-DBS may not be limited to addressing freezing of gait (FOG) in idiopathic Parkinson's disease. The PPN may also be an effective DBS target to address other forms of central gait failure.

Whispering dysphonia in an Australian family (DYT4): a clinical and genetic reappraisal.

The designation, DYT4, was assigned to an Australian family with whispering dysphonia. The role of known causes of dystonia has not been comprehensively investigated in this family, nor has the possible relationship with Wilson disease (WND) in 2 siblings. Eighteen family members were neurologically examined, and DNA samples were obtained. Linkage analysis was performed to DYT1, DYT6, DYT7, DYT11, DYT13, DYT15, and ATP7B with microsatellite markers and the THAP1 (DYT6), PRKRA (DYT16), and ATP7B (WND) genes were sequenced. Reevaluation of the family identified 9 living affected family members, 6 of whom are newly affected. Phenotypic expression was variable, ranging from isolated spasmodic dysphonia (often with mild craniocervical dystonia) to severe generalized dystonia. Two newly described features included an extrusional tongue dystonia and a unique "hobby horse gait." Genetic analyses excluded all tested loci. Haplotype analysis of the ATP7B region resulted in three different combinations of the two parental alleles in the 8 investigated siblings of the 2 deceased WND patients, indicating that the fourth combination (of two mutated alleles) had occurred only in the deceased WND patients. On these two alleles, we identified a missense (c.2297C>G; p.T766R) and a splice-site mutation (IVS5+1G>T). The c.2297C>G mutation was detected in 3 affected and 4 unaffected family members, whereas the IVS5+1G>T mutation was detected in 1 affected and unaffected family member. Five DYT4 patients carried neither mutation. DYT4 is a familial form of dystonia unrelated to known dystonia genes and loci. ATP7B mutations do not segregate with the dystonia phenotype, indicating two independent genetic diseases in this family.

Adults with a history of recreational cannabis use have altered speech production.

Stereotypical depictions of speech in cannabis users often suggest slow, laboured output, yet objective evidence supporting this assumption is extremely limited. We know that depressants or hallucinogenic drugs such as cannabis can cause acute changes in communication and speech rate, but the long-lasting effects of cannabis use on speech are not well described. The aim of this study was to investigate speech in individuals with a history of recreational cannabis use compared to non-drug-using healthy controls. Speech samples were collected from a carefully described cohort of 31 adults with a history of cannabis use (but not use of illicit stimulant drugs) and 40 non-drug-using controls. Subjects completed simple and complex speech tasks including a monologue, a sustained vowel, saying the days of the week, and reading a phonetically balanced passage. Audio samples were analysed objectively using acoustic analysis for measures of timing, vocal control, and quality. Subtle differences in speech timing, vocal effort, and voice quality may exist between cannabis and control groups, however data remain equivocal. After controlling for lifetime alcohol and tobacco use and applying a false discovery rate, only spectral tilt (vocal effort and intensity) differed between groups and appeared to change in line with duration of abstinence from cannabis use. Differences between groups may reflect longer term changes to the underlying neural control of speech. Our digital analysis of speech shows there may be a signal differentiating individuals with a history of recreational cannabis use from healthy controls, in line with similar findings from gait and hand function studies.

Triple antiplatelet therapy for preventing vascular events: a systematic review and meta-analysis.

BACKGROUND: Dual antiplatelet therapy is usually superior to mono therapy in preventing recurrent vascular events (VEs). This systematic review assesses the safety and efficacy of triple antiplatelet therapy in comparison with dual therapy in reducing recurrent vascular events. METHODS: Completed randomized controlled trials investigating the effect of triple versus dual antiplatelet therapy in patients with ischaemic heart disease (IHD), cerebrovascular disease or peripheral vascular disease were identified using electronic bibliographic searches. Data were extracted on composite VEs, myocardial infarction (MI), stroke, death and bleeding and analysed with Cochrane Review Manager software. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using random effects models. RESULTS: Twenty-five completed randomized trials (17,383 patients with IHD) were included which involving the use of intravenous (iv) GP IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban), aspirin, clopidogrel and/or cilostazol. In comparison with aspirin-based therapy, triple therapy using an intravenous GP IIb/IIIa inhibitor significantly reduced composite VEs and MI in patients with non-ST elevation acute coronary syndromes (NSTE-ACS) (VE: OR 0.69, 95% CI 0.55-0.86; MI: OR 0.70, 95% CI 0.56-0.88) and ST elevation myocardial infarction (STEMI) (VE: OR 0.39, 95% CI 0.30-0.51; MI: OR 0.26, 95% CI 0.17-0.38). A significant reduction in death was also noted in STEMI patients treated with GP IIb/IIIa based triple therapy (OR 0.69, 95% CI 0.49-0.99). Increased minor bleeding was noted in STEMI and elective percutaneous coronary intervention (PCI) patients treated with GP IIb/IIIa based triple therapy. Stroke events were too infrequent for us to be able to identify meaningful trends and no data were available for patients recruited into trials on the basis of stroke or peripheral vascular disease. CONCLUSIONS: Triple antiplatelet therapy based on iv GPIIb/IIIa inhibitors was more effective than aspirin-based dual therapy in reducing VEs in patients with acute coronary syndromes (STEMI and NSTEMI). Minor bleeding was increased among STEMI and elective PCI patients treated with a GP IIb/IIIa based triple therapy. In patients undergoing elective PCI, triple therapy had no beneficial effect and was associated with an 80% increase in transfusions and an eightfold increase in thrombocytopenia. Insufficient data exist for patients with prior ischaemic stroke and peripheral vascular disease and further research is needed in these groups of patients.

The Strategic Reperfusion Early After Myocardial Infarction (STREAM) study.

BACKGROUND: Primary percutaneous coronary intervention (PCI) has emerged as the preferred therapy for acute ST-elevation myocardial infarction (STEMI) provided it is performed in a timely fashion at an expert 24/7 facility. Fibrinolysis is a well-accepted alternative, especially in patients presenting early after symptom onset. The STREAM study will provide novel information on whether prompt fibrinolysis at first medical contact, followed by timely catheterization or rescue coronary intervention in STEMI patients presenting within 3 hours of symptom onset, represents an appropriate alternative strategy to primary PCI. METHODS: Acute STEMI patients presenting early after symptom onset are eligible if PCI is not feasible within 60 minutes of first medical contact. This is an open-label, prospective, randomized, parallel, comparative, international multicenter trial. Patients are randomized to fibrinolysis combined with enoxaparin, clopidogrel, and aspirin, and cardiac catheterization within 6 to 24 hours or rescue coronary intervention if reperfusion fails within 90 minutes of fibrinolysis versus PCI performed according to local guidelines. Composite efficacy end points at 30 days include death, shock, heart failure, and reinfarction. Safety end points include ischemic stroke, intracranial hemorrhage, and major nonintracranial bleeding. Follow-up is extended to 1 year and includes all-cause mortality. DISCUSSION: Continuing delays in achieving timely PCI remain a difficult issue. Many patients fail to achieve the desired reperfusion times of 90 to 120 minutes after first medical contact. The STREAM results will provide useful additional data on which to base informed therapeutic decisions.

Unexplained international differences in clinical outcomes after acute myocardial infarction and fibrinolytic therapy: lessons from the Hirulog and Early Reperfusion or Occlusion (HERO)-2 trial.

BACKGROUND: Despite advances in therapy, global mortality due to acute myocardial infarction remains high. The international Hirulog and Early Reperfusion or Occlusion (HERO-2) trial of 17,073 patients with ST-segment elevation myocardial infarction provided the opportunity to explore international differences in outcomes. METHODS: Patient characteristics, treatment, and outcomes were compared across 5 diverse regions: Western countries, Latin America, Eastern Europe, Russia, and Asia. In addition, a representative sample of 1,743 screened patients was compared with enrolled patients. RESULTS: Larger percentages of eligible patients were randomized in Eastern Europe, Russia, and Asia than Western countries. These regions enrolled more patients with anterior myocardial infarction, Killip class III or IV, and late presentation (>4 hours). More patients aged >75 years were enrolled from Western countries. Overall risk levels were similar. Eastern Europe and Russia had lower rates than Western countries of coronary revascularization (2% vs 18%) and longer hospital stays (median 18 vs 7 days). Thirty-day mortality was lower in Western countries; 6.7% versus 10.2% to 13.2% elsewhere, whereas reinfarction was more frequent (3.2% vs 1.5% to 3.0%; each, P < .001). Regional mortality differences persisted after adjustment for baseline risk factors, treatments, or national health and economic statistics (each P < .001). CONCLUSIONS: The variation in mortality and other clinical outcomes across geographic regions was not adequately explained by risk factors, patterns of care, or national health statistics. Nevertheless, large international trials are a better way to assess potential new treatments across many countries than the alternative of separate smaller trials in each region.

Diagnostic accuracy of the appearance of Nigrosome-1 on magnetic resonance imaging in Parkinson's disease: A systematic review and meta-analysis.

INTRODUCTION: There is currently no definitive diagnostic test for Parkinson's disease (PD) and the current diagnostic procedure primarily relies on clinical manifestations. A hypointense appearance of nigrosome-1 (or absence of the "swallow tail" sign) on magnetic resonance imaging (MRI) has been proposed as a biomarker for PD. This meta-analysis examined the diagnostic accuracy of the appearance of nigrosome-1 on Magnetic Resonance Imaging (MRI) in differentiating idiopathic PD patients from healthy adults. METHODS: Databases (MEDLINE, Embase, Scopus) were searched from 2012 (first publication of nigrosome-1 MRI scans) up until September 2019. Two researchers independently screened all titles and abstracts to identify studies that met the inclusion criteria and extracted relevant articles in a uniform manner. Two authors independently extracted data and assessed the risk of bias using a customized QUADAS-2 tool. Pooled sensitivity and specificity were calculated using a hierarchical summary receiver operating characteristic approach, as were positive and negative likelihood ratios. RESULTS: Nineteen studies containing a total of 1508 participants (903 idiopathic PD patients and 605 healthy controls) were included. The overall sensitivity and specificity were 0.94 (95%CI, 0.93-0.96) and 0.90 (95%CI, 0.88-0.92), respectively. The likelihood ratios for positive and negative test results were 9.72 (95%CI, 5.58-16.04) and 0.08 (95%CI, 0.05-0.12). The pooled area under the receiver operating characteristics curve (AUC) in the diagnosis of idiopathic PD was 0.98. CONCLUSIONS: Visual assessment of the nigrosome-1 appearance, at 3 or 7T, yields excellent diagnostic accuracy for differentiating idiopathic PD from healthy adults.

Mutations in THAP1 (DYT6) and generalised dystonia with prominent spasmodic dysphonia: a genetic screening study.

BACKGROUND: DYT6 is a primary, early-onset torsion dystonia; however, unlike in DYT1 dystonia, the symptoms of DYT6 dystonia frequently involve the craniocervical region. Recently, two mutations in THAP1, the gene that encodes THAP (thanatos-associated protein) domain-containing apoptosis-associated protein 1 (THAP1), have been identified as a cause of DYT6 dystonia. METHODS: We screened THAP1 by sequence analysis and quantitative real-time polymerase chain reaction (PCR) in 160 white patients of European ancestry who had dystonia with an early age at onset (n=64), generalised dystonia (n=35), a positive family history of dystonia (n=56), or facial or laryngeal dystonia. Another 160 patients with dystonia were screened for reported and novel variants in THAP1. 280 neurologically healthy controls were screened for the newly identified and previously reported changes in THAP1 and these and an additional 75 controls were screened for a rare non-coding mutation. FINDINGS: We identified two mutations in THAP1 (388_389delTC and 474delA), respectively, in two (1%) German patients from the 160 patients with dystonia. Both mutation carriers had laryngeal dystonia that started in childhood and both went on to develop generalised dystonia. Thus, two of three patients with early-onset generalised dystonia with orobulbar involvement had mutations in THAP1. One of the identified patients with DYT6 dystonia had two family members with subtle motor signs who also carried the same mutation. A rare substitution in the 5'untranslated region (-236_235GA-->TT) was found in 20 of 320 patients and in seven of 355 controls (p=0.0054). INTERPRETATION: Although mutations in THAP1 might have only a minor role in patients with different, but mainly focal, forms of dystonia, they do seem to be associated with early-onset generalised dystonia with spasmodic dysphonia. This combination of symptoms might be a characteristic feature of DYT6 dystonia and could be useful in the differential diagnosis of DYT1, DYT4, DYT12, and DYT17 dystonia. In addition to the identified mutations, a rare non-coding substitution in THAP1 might increase the risk of dystonia. FUNDING: Deutsche Forschungsgemeinschaft; Volkswagen Foundation; Dystonia Medical Research Foundation; University of Lübeck.