Combinatorial ASO-mediated therapy with low dose SMN and the protective modifier Chp1 is not sufficient to ameliorate SMA pathology hallmarks.

Spinal muscular atrophy (SMA) is a devastating genetically inherited neuromuscular disorder characterized by the progressive loss of motor neurons in the spinal cord, leading to muscle atrophy and weakness. Although SMA is caused by homozygous mutations in SMN1, the disease severity is mainly determined by the copy number of SMN2, an almost identical gene that produces ~10% correctly spliced SMN transcripts. Recently, three FDA- and EMA-approved therapies that either increase correctly spliced SMN2 transcripts (nusinersen and risdiplam) or replace SMN1 (onasemnogen abeparvovec-xioi) have revolutionized the clinical outcome in SMA patients. However, for severely affected SMA individuals carrying only two SMN2 copies even a presymptomatic therapy might be insufficient to fully counteract disease development. Therefore, SMN-independent compounds supporting SMN-dependent therapies represent a promising therapeutic approach. Recently, we have shown a significant amelioration of SMA disease hallmarks in a severely affected SMA mouse carrying a mutant Chp1 allele when combined with low-dose of SMN antisense oligonucleotide (ASO) treatment. CHP1 is a direct interacting partner of PLS3, a strong protective modifier of SMA. Both proteins ameliorate impaired endocytosis in SMA and significantly restore pathological hallmarks in mice. Here, we aimed to pharmacologically reduce CHP1 levels in an ASO-based combinatorial therapy targeting SMN and Chp1. Chp1 modulation is a major challenge since its genetic reduction to ~50% has shown to ameliorate SMA pathology, while the downregulation below that level causes cerebellar ataxia. Efficacy and tolerability studies determined that a single injection of 30 µg Chp1-ASO4 in the CNS is a safe dosage that significantly reduced CHP1 levels to ~50% at postnatal day (PND)14. Unfortunately, neither electrophysiological predictors such as compound muscle action potential (CMAP) or motor unit number estimation (MUNE) nor histological hallmarks of SMA in neuromuscular junction (NMJ), spinal cord or muscle were ameliorated in SMA mice treated with Chp1-ASO4 compared to CTRL-ASO at PND21. Surprisingly, CHP1 levels were almost at control level 4-weeks post injection, indicating a rather short-term effect of the ASO. Therefore, we re-administrated Chp1-ASO4 by i.c.v. bolus injection at PND28. However, no significant improvement of SMA hallmarks were seen at 2 month-of-age either. In conclusion, in contrast to the protective effect of genetically-induced Chp1 reduction on SMA, combinatorial therapy with Chp1- and SMN-ASOs failed to significantly ameliorate the SMA pathology. Chp1-ASOs compared to SMN-ASO proved to have rather short-term effect and even reinjection had no significant impact on SMA progression, suggesting that further optimization of the ASO may be required to fully explore the combination.

Risk Prediction Score for Pediatric Patients with Suspected Ebola Virus Disease.

Rapid diagnostic tools for children with Ebola virus disease (EVD) are needed to expedite isolation and treatment. To evaluate a predictive diagnostic tool, we examined retrospective data (2014-2015) from the International Medical Corps Ebola Treatment Centers in West Africa. We incorporated statistically derived candidate predictors into a 7-point Pediatric Ebola Risk Score. Evidence of bleeding or having known or no known Ebola contacts was positively associated with an EVD diagnosis, whereas abdominal pain was negatively associated. Model discrimination using area under the curve (AUC) was 0.87, which outperforms the World Health Organization criteria (AUC 0.56). External validation, performed by using data from International Medical Corps Ebola Treatment Centers in the Democratic Republic of the Congo during 2018-2019, showed an AUC of 0.70. External validation showed that discrimination achieved by using World Health Organization criteria was similar; however, the Pediatric Ebola Risk Score is simpler to use.

Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms.

Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-α (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2-nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N-acetyl-ß-D-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain.

The long non-coding RNA Gomafu is acutely regulated in response to neuronal activation and involved in schizophrenia-associated alternative splicing.

Schizophrenia (SZ) is a complex disease characterized by impaired neuronal functioning. Although defective alternative splicing has been linked to SZ, the molecular mechanisms responsible are unknown. Additionally, there is limited understanding of the early transcriptomic responses to neuronal activation. Here, we profile these transcriptomic responses and show that long non-coding RNAs (lncRNAs) are dynamically regulated by neuronal activation, including acute downregulation of the lncRNA Gomafu, previously implicated in brain and retinal development. Moreover, we demonstrate that Gomafu binds directly to the splicing factors QKI and SRSF1 (serine/arginine-rich splicing factor 1) and dysregulation of Gomafu leads to alternative splicing patterns that resemble those observed in SZ for the archetypal SZ-associated genes DISC1 and ERBB4. Finally, we show that Gomafu is downregulated in post-mortem cortical gray matter from the superior temporal gyrus in SZ. These results functionally link activity-regulated lncRNAs and alternative splicing in neuronal function and suggest that their dysregulation may contribute to neurological disorders.

Derivation and Internal Validation of a Mortality Prognostication Machine Learning Model in Ebola Virus Disease Based on Iterative Point-of-Care Biomarkers.

Background: Although multiple prognostic models exist for Ebola virus disease mortality, few incorporate biomarkers, and none has used longitudinal point-of-care serum testing throughout Ebola treatment center care. Methods: This retrospective study evaluated adult patients with Ebola virus disease during the 10th outbreak in the Democratic Republic of Congo. Ebola virus cycle threshold (Ct; based on reverse transcriptase polymerase chain reaction) and point-of-care serum biomarker values were collected throughout Ebola treatment center care. Four iterative machine learning models were created for prognosis of mortality. The base model used age and admission Ct as predictors. Ct and biomarkers from treatment days 1 and 2, days 3 and 4, and days 5 and 6 associated with mortality were iteratively added to the model to yield mortality risk estimates. Receiver operating characteristic curves for each iteration provided period-specific areas under curve with 95% CIs. Results: Of 310 cases positive for Ebola virus disease, mortality occurred in 46.5%. Biomarkers predictive of mortality were elevated creatinine kinase, aspartate aminotransferase, blood urea nitrogen (BUN), alanine aminotransferase, and potassium; low albumin during days 1 and 2; elevated C-reactive protein, BUN, and potassium during days 3 and 4; and elevated C-reactive protein and BUN during days 5 and 6. The area under curve substantially improved with each iteration: base model, 0.74 (95% CI, .69-.80); days 1 and 2, 0.84 (95% CI, .73-.94); days 3 and 4, 0.94 (95% CI, .88-1.0); and days 5 and 6, 0.96 (95% CI, .90-1.0). Conclusions: This is the first study to utilize iterative point-of-care biomarkers to derive dynamic prognostic mortality models. This novel approach demonstrates that utilizing biomarkers drastically improved prognostication up to 6 days into patient care.

Physicochemical Parameters of Raw Pet Food and Dehydrated Pet Treats Developed from Beef Processing Co-Products.

Pet humanization and premiumization of pet foods have led to significant changes in the co-product market, as pet food companies are looking for more profitable protein sources for their products. Co-products such as beef liver (BL) and beef heart (BH) can be combined to generate restructured pet foods rich in vitamins and nutrients. Sodium alginate and encapsulated calcium lactate (ALGIN) can improve the acceptability of meat pieces by transforming them into a singular shape. The objective of this experiment was to assess the physiochemical parameters of co-products for utilization in raw pet foods and restructured pet treats generated from BL and BH by using ALGIN as a structure-forming agent. Results demonstrated increased cooking loss as ALGIN inclusion decreased, but cooking loss decreased as BL proportions increased (p = 0.0056). Expressible moisture of raw pet food decreased as ALGIN inclusion increased, but more moisture was released from treats when BL proportions increased (p < 0.0001). Increasing ALGIN and BH led to increased water activity of cooked treats (p < 0.0001). Thus, we suggest that BL and BH combinations with ALGIN inclusion produces a viable platform for higher inclusions of co-products in pet treats. Additionally, these ingredients improved the finished product quality characteristics of raw pet foods.

Graft factors as determinants of postoperative delirium after liver transplantation.

Post-operative delirium (POD) is a frequent complication after surgery, occurring in 15-20% of patients. POD is associated with a higher complications rate and mortality. Literature on POD after liver transplantation (LT) is limited, with the few available studies reporting an incidence of 10-47%. The aim of this study was analyzing pattern, risk factors and clinical impact of POD after LT. Data on donor and recipient characteristics, postoperative course and POD of consecutive adult LT recipients from March 2016 to May 2018 were prospectively collected and retrospectively analyzed. Risk factors for POD were analyzed using univariable logistic regression and Lasso regression. Kaplan-Meier method was used for survival analysis. 309 patients underwent LT during study period; 3 were excluded due to perioperative death. Incidence of POD was 13.4% (n = 41). The median day of onset was 5th (IQR [4-7]) with a median duration of 4 days (IQR [3-7]). Several risk factors, related to the severity of liver disease and graft characteristics, were identified. Graft macrovesicular steatosis was the only factor independently associated with POD at multivariable analysis (OR 1.27, CI 1.09-1.51, p = 0.003). POD was associated with a higher rate of severe postoperative complications and longer intensive care unit and hospital stay, but did not significantly impact on patient and graft survival. Incidence of POD after LT is comparable to that observed after general surgery and graft factors are strongly associated with its onset. These results help identifying a subset of patients to be considered for preventive interventions.

Fecal microbiota transplantation in refractory ulcerative colitis - a case report.

Studies comparing gut microbiota profiles of inflammatory bowel disease (IBD) patients have shown several changes in microbiota composition, with marked reduction of local biodiversity relative to that of healthy controls. Modulation of the bacterial community is a promising strategy to reduce the proportion of harmful microorganisms and increase the proportion of beneficial bacteria; this is expected to prevent or treat IBD. The exact mechanism of fecal microbiota transplantation (FMT) remains unknown; however, replacing the host microbiota can reestablish gut microbial composition and function in IBD patients. The present report describes an ulcerative colitis patient who underwent FMT. A 17-year-old male with moderate to severe clinical activity, which was refractory to mesalazine, azathioprine, and infliximab, underwent FMT as alternative therapy. The patient exhibited clinical improvement after the procedure; however, the symptoms returned. A second FMT was performed 8 months after the first procedure, but the patient did not improve. In conclusion, despite the FMT failure observed in this patient, the procedure is a promising therapeutic option for IBD patients, and more in-depth studies of this method are needed.

Convulsions induced by methylmalonic acid are associated with glutamic acid decarboxylase inhibition in rats: a role for GABA in the seizures presented by methylmalonic acidemic patients?

Methylmalonic acid (MMA) is an endogenous convulsing compound that accumulates in methylmalonic acidemia, an inborn error of the metabolism characterized by severe neurological dysfunction, including seizures. The mechanisms by which MMA causes seizures involves the activation of the N-methyl-D-aspartate (NMDA) receptors, but whether GABAergic mechanisms are involved in the convulsions induced by MMA is not known. Therefore, in the current study we investigated the involvement of GABAergic mechanisms in the convulsions induced by MMA. Adult rats were injected (i.c.v.) with muscimol (46 pmol/1 microl), baclofen (0.03, 0.1 and 0.3 micromol/1 microl), MK-801 (6 nmol/1 microl), pyridoxine (2 micromol/4 microl) or physiological saline (0.15 micromol/1 microl). After 30 min, MMA (0.3, 0.1 and 3 micromol/1 microl) or NaCl (6 micromol/1 microl, i.c.v.) was injected. The animals were immediately transferred to an open field and observed for the appearance of convulsions. After behavioral evaluation, glutamic acid decarboxylase (GAD) activity was determined in cerebral cortex homogenates by measuring the 14CO2 released from l-[14C]-glutamic acid. Convulsions were confirmed by electroencephalographic recording in a subset of animals. MMA caused the appearance of clonic convulsions in a dose-dependent manner and decreased GAD activity in the cerebral cortex ex vivo. GAD activity negatively correlated with duration of MMA-induced convulsions (r=-0.873, P<0.01), in an individual basis. Muscimol, baclofen, MK-801 and pyridoxine prevented MMA-induced convulsions, but only MK-801 and pyridoxine prevented MMA-induced GAD inhibition. These data suggest GABAergic mechanisms are involved in the convulsive action of MMA, and that GAD inhibition by MMA depends on the activation of NMDA receptors. While in this study we present novel data about the role of the GABAergic system in MMA-induced convulsions, the central role of NMDA receptors in the neurochemical actions of MMA is further reinforced since they seem to trigger GABAergic failure.

Transesophageal echocardiographic evaluation of the morphologic and hemodynamic cardiac changes during ventricular fibrillation.

To analyze cardiac motion during ventricular fibrillation (VF), we used transesophageal echocardiography to study nine male subjects, aged 44 +/- 7 years, affected by heart disease who have poor left ventricular function, during implantation of an Implantable Cardioverter Defibrillator, when VF is induced several times to determine the defibrillation threshold. Wall and valvular motion, transmitral and transaortic blood flow, and blood echoreflectivity were evaluated in all patients. Moreover, in basal conditions, during VF, 1 and 5 minutes after restoration of basal rhythm, we calculated the left ventricular end-diastolic volume (EDLVV) and area (EDLVA), the left ventricular end-systolic volume and area, the ejection fraction, and the fractional area change with a four-chamber echocardiographic view. At the onset of VF, the myocardium and valves exhibited a chaotic motion. About 10 seconds later the oscillatory movement of the heart walls became more ample and regular; the mitral valve showed a cyclic closure and opening with a forward flow, and the aortic valve exhibited similar behavior, although at a lower intensity. A spontaneous echo contrast appeared inside the atrial and ventricular cavities, gradually becoming an incrt homogeneous mass that was completely flushed away with the restoration of the basal rhythm. When VF started, EDLVV (286 +/- 98 ml) and EDLVA (50 +/- 16.5 cm2) decreased abruptly (EDLVV = 182 +/- 65 ml, p < 0.02; EDLVA = 38 +/- 9.2 cm2,p < 0.05); so did ejection fraction (31.8% +/- 15% versus 11% +/- 5%; p < 0.003) and fractional area change (25.8% +/- 6.5% versus 7% +/- 3.4%; p < 0.001). When the basal rhythm was restored, the heart extended again and EDLVV, EDLVA, ejection fraction, and fractional area change after 1 and 5 minutes were similar to those calculated before induction of VF. This behavior was observed during both the first and last induced VF. Thus during VF, great variations of heart morphology and dynamics, as well as blood echoreflectivity, occur; the heart seems to make attempts to organize its dynamics during the arrhythmia. Repeated episodes of VF and defibrillation with low energies do not seem to worsen left ventricular dynamics even in impaired hearts.

Left ventricular remodeling after aortic valve replacement with the Toronto-SPV prosthesis.

The remarkable hemodynamic features of the aortic Toronto SPV prosthesis have been reported. To assess the efficacy of these characteristics to produce a favorable left ventricular remodeling and to test the limits of the dobutamine stress test to check these results, 25 consecutive patients, who had undergone aortic valve replacement with Toronto SPV, were monitored with dobutamine and exercise stress tests for 1 year. Among the prosthetic and left ventricular morphological and functional parameters evaluated, dobutamine infusion produced an overestimation of prosthetic and left ventricular outflow tract gradients, effective orifice area, and prosthetic resistance compared with the more physiological exercise test (P<.01). These misleading results were probably due to the inotropic and unloading effects of dobutamine in still hypertrophied hearts. Indexed myocardial mass and wall thickness decreased significantly during the follow-up period (P<.01), whereas left ventricular diastolic diameter and ejection fraction showed no significant variations. These data show that the positive left ventricular remodeling is due only to the regression of the hypertrophy and not to the reduction of left ventricular diameters. Based on results from this study, the dobutamine stress test should be avoided to evaluate patients with aortic valve prostheses and still present left ventricular hypertrophy. The Toronto SPV produces a favorable left ventricular remodeling during the first year of follow-up, and is likely to improve.

Influence of transesophageal echocardiography on intraoperative decision making for toronto stentless prosthetic valve implantation.

BACKGROUND AND AIM OF THE STUDY: Intraoperative transesophageal echocardiography (TEE) is commonly used during aortic valve surgery. In aortic valve replacement (AVR), this permits measurement of the aortic annulus, study of the anatomy of aortic valve components, and prediction of prosthesis valve size. After cardiopulmonary bypass (CPB), echocardiography is valuable in checking prosthesis function. In this study, we evaluated the impact of intraoperative TEE on the decision-making process of aortic Toronto stentless prosthetic valve (TSPV) implantation. METHODS: Fifty-two consecutive patients undergoing elective AVR were collected prospectively. Multiplane TEE was performed before CPB to determine diameters of the aortic valve annulus and sinotubular junction. This was to evaluate the feasibility of TSPV implantation in the aortic position and to predict prosthesis size. Further TEE evaluation was carried out after CPB to assess prosthetic valve function. RESULTS: TEE allowed measurement of the aortic annulus and sinotubular junction, and enabled correct prediction of prosthesis size. Ultrasonic evaluation also revealed contraindications to TSPV implantation in five patients. In one case, color-Doppler examination led to immediate successful surgical correction of prosthetic incompetence. CONCLUSION: Intraoperative multiplane TEE examination is useful in the decision-making process in AVR with the TSPV by selecting patients suitable for the stentless valve, predicting prosthesis size, and checking prosthesis function.

[Grave complications of local anesthesia for cataract extraction: reports of 8 cases]. / Complications graves de l'anesthésie locale dans la chirurgie de la cataracte: a propos de 8 cas.

Cataract extraction performed under local anesthesia is not so safe. During a 2 years period, 8 patients have presented a complication: 3 patients are presented with diplopia, 4 patients are presented with eyeball perforation and 1 patient developed a central complication. All those complications are caused by the superior peribulbar injections of anesthetics. A survey of the different etiologies of the superior rectus muscle blow and of eyeball perforation is given.

[Cat-scratch disease]. / La maladie par griffade de chat.

Cat-scratch disease is a subacute, regional lymphadenitis syndrome that occurs mainly in children. The causative agent is Bartonella henselae. After an incubation period ranging usually between 1 and 2 weeks, red papules develop at the site of cutaneous inoculation and persist until the development of lymphadenopathy with some malaise. Cases with complications have been observed including Parinaud oculoglandular syndrome, encephalopathy, a variety of exanthems and granumatous hepatitis. Diagnosis is based on serologic tests and, when necessary, antimicrobial treatment can be considered. Incision and drainage should not be done.

Prevalence of atrial fibrillation and its associated factors in Spain: An analysis of 6 population-based studies. DARIOS Study. / Prevalencia de fibrilación auricular y factores asociados en España, análisis de seis estudios de base poblacional. Estudio DARIOS.

BACKGROUND AND OBJECTIVES: Atrial fibrillation (AF) is the most common type of arrhythmia. The purpose of this study was to determine the prevalence of atrial fibrillation and its relationship with cardiovascular risk factors in Spain. METHODOLOGY: Cross-sectional study based on a grouped analysis of 17,291 randomized individuals recruited in 6 population studies. RESULTS: The prevalence of atrial fibrillation was 1.5% (95% CI:1.3-1.7%). Men had a greater prevalence of the disease than women (1.9 vs. 1.1%, respectively). The prevalence of atrial fibrillation progressively increased with age: 0.05% for patients younger than 45 years, 0.5% for those between 45-59 years of age, 2.3% for those between 60-74 years of age and 6.3% for those older than 75 years. The percentage of individuals who were underwent anticoagulant treatment was 74.3%. The risk factors significantly associated with arrhythmia were an age older than 60 years (odds ratio [OR]: 7.6; 95% CI: 5.1-11.2), the male sex (OR:1.8; 95% CI: 1.4-2.4), arterial hypertension (OR:1.6; 95% CI: 1.2-2.1), obesity (OR:1.5; 95% CI:1.2-2.1) and a history of coronary artery disease (OR:1.9; 95% CI: 1.3-3.0). CONCLUSION: Atrial fibrillation is a common disease in elderly individuals, while its prevalence is low in individuals younger than 60 years. Most individuals with atrial fibrillation were on anticoagulant treatment. The risk factors for this type of arrhythmia are age, the male sex, hypertension, obesity and a history of coronary artery disease.

Involvement of the glutamatergic system in the nociception induced intrathecally for a TRPA1 agonist in rats.

The transient receptor potential ankyrin 1 (TRPA1) is expressed in peripheral and spinal terminals of sensory neurons, jointly to the vanilloid receptor (TRPV1). A relevant peripheral role of TRPA1 receptor has been implicated in a variety of processes, including the detection of noxious cold, and diverse painful stimulus, but the functional role of TRPA1 receptor in nociceptive transmission at spinal cord in vivo is poorly known. Therefore, the aim of this study was to evaluate whether the glutamatergic system is involved in the transmission of nociceptive stimulus induced for a TRPA1 agonist in the rat spinal cord. We observed that cinnamaldehyde, a TRPA1 agonist, on spinal cord synaptosomes leads to an increase in [Ca(2+)](i) and a rapid release of glutamate, but was not able to change the specific [(3)H]-glutamate binding. In addition, spinally administered cinnamaldehyde produced heat hyperalgesia and mechanical allodynia in rats. This behavior was reduced by the co-injection (i.t.) of camphor (TRPA1 antagonist) or MK-801 (N-methyl-D-aspartate (NMDA) receptor antagonist) to cinnamaldehyde. Besides, the pretreatment with resiniferatoxin (RTX), a potent TRPV1 agonist, abolished the cinnamaldehyde-induced heat hyperalgesia. Here, we showed that intrathecal RTX results in a decrease in TRPA1 and TRPV1 immunoreactivity in dorsal root ganglion. Collectively, our results demonstrate the pertinent participation of spinal TRPA1 in the possible enhancement of glutamatergic transmission of nociceptive signals leading to increase of the hypersensitivity, here observed as heat hyperalgesia. Then the modulation of spinal TRPA1 might be a valuable target in painful conditions associated with central pain hypersensitivity.

Prognostic correlates of combined coronary flow reserve assessment on left anterior descending and right coronary artery in patients with negative stress echocardiography by wall motion criteria.

AIMS: To assess the prognostic correlates of Doppler echocardiographically derived coronary flow reserve (CFR) on two coronaries in patients with negative stress echo. Vasodilator stress echocardiography allows dual imaging of regional wall motion and CFR both on left anterior descending (LAD) and right coronary artery (RCA). METHODS: The study group comprised 460 patients with known or suspected coronary artery disease and negative stress echo by wall motion criteria. All underwent dipyridamole (up to 0.84 mg/kg over 6 minutes) stress echo with CFR evaluation of either LAD or RCA by Doppler, and were followed up for a median of 32 months. A CFR value of < or =2.0 was taken as abnormal. RESULTS: CFR was abnormal in 174 patients (38%) (57 in LAD only, 48 in RCA only, and 69 in both LAD and RCA) and normal in 286 patients (62%). During follow-up, there were 77 cardiac events: 5 deaths, 44 acute coronary syndromes (6 STEMI, and 38 NSTEMI) and 28 late (>6 months from stress echo) revascularisations. CFR of < or =2.0 on LAD was the strongest multivariable predictor of either definite (death, acute coronary syndrome) and major (death, acute coronary syndrome, late revascularisation) events, followed by diabetes mellitus. Anti-ischaemic therapy at the time of testing and resting wall motion abnormality were also independently associated with major events. Preserved CFR in both LAD and RCA was associated with better (p<0.0001) definite and major event-free survival compared to abnormal CFR in one or both coronary vessels. CONCLUSION: CFR evaluation of either LAD or RCA allows the identification of distinct prognostic patterns. In particular, preserved CFR in both coronary vessels is highly predictive of a very favourable outcome, while reduced CFR in either coronary vessel, and especially on LAD, is a strong predictor of future cardiac events.