High Events Research Articles

From bremsstrahlung to channeling radiation a promising way for positron generation

For a long time the necessity of having intense positron beams to get a high rate of events with fixed targets as with e+e− collisions, led to conventional positron sources using high energy and high intensity electron beams generating bremsstrahlung photons in thick high Z targets. The inconveniences for such scheme, heat load and large emittance, are underlined. Alternative ways aiming to provide a high number of photons impinging on rather thin conversion targets have been developed: they are using magnetic undulators, laser Compton backscattering and channeling radiation in axially oriented crystals. A brief description of these methods is given. However, the emphasis is put here on the channeling radiation. The advantages of channeling radiation, described by M.Kumakhov and others, were confirmed by many simulations and experiments. We are reporting, hereafter, on two schemes: positron all-crystal converters involving thick crystals where photon radiation and e+e− pair creation are occurring in the crystal and hybrid sources where the two functions are separated. With the hybrid scheme, including a thin crystal-radiator and a thick amorphous-converter, the heat load and the local deposited energy density can be lowered. Simulations and experiments related to these two schemes are reported. Further developments concerning the converter, granular instead of bulk, are providing additional advantages. The promising, already gathered results led to consider these kinds of positron sources for future e-e+ colliders. More physicists, from different laboratories, concerned by the studies on positron sources are now contributing in this field.

Appropriate dose of regorafenib based on body weight of colorectal cancer patients: a retrospective cohort study

PurposePrevious randomized studies have shown a survival benefit of using regorafenib but a high rate of adverse events in unresectable colorectal cancer patients. To reduce these adverse events and improve the tolerability, we examined the appropriate dose of regorafenib based on body weight.MethodsWe used a nationwide claims database in Japan and examined the efficacy and safety of regorafenib for patients with metastatic colorectal cancer between groups divided by body weight (60 kg) and median average dose (120 mg) between 2013 and 2018. We also assessed overall survival (OS) and adverse events between these groups.ResultsWe identified 2530 Japanese patients (heavy weight/high dose: 513, light weight/low dose: 921, heavy weight/low dose: 452, and light weight/high dose: 644). There was no significant difference in the adverse events and OS after inverse probability treatment weighting (IPTW) adjustment between heavy weight/high dose group and light weight/low dose group (hazard ratio, HR=0.97). Among the light-weight patients, higher average dose was associated with shorter OS (IPTW adjusted HR=1.21, 95% CI 1.05 – 1.39, Table 3) while among the heavy-weight patients, there was no significant difference in OS between high and low dose groups (IPTW adjusted HR=1.14, 95% CI 0.95 – 1.37).ConclusionThe findings suggest that a low dose of regorafenib for light-weight patients may be as safe and effective as high doses for heavy-weight patients. Further studies should be conducted to identify an appropriate dose based on each patient's physique and condition.

Geriatric Nutritional Risk Index predicts bleeding event in patients with heart failure.

We aimed to elucidate the association between malnutrition and the occurrence of bleeding events in patients with heart failure. We evaluated the nutritional status of patients with heart failure [n=2044, median (inter-quartile range) age 69.0 (59.0-78.0) years, 1209 (59.1%) males] using the Geriatric Nutritional Risk Index (GNRI). The primary endpoint was a composite of bleeding events such as haemorrhagic stroke or gastrointestinal bleeding. According to the survival classification and regression tree analysis, the accurate cut-off point of GNRI for predicting the primary endpoint was 106.2. We divided the patients into two groups based on GNRI levels: high GNRI group (GNRI≥106.2, n=606, 29.6%) and low GNRI group (GNRI<106.2, n=1438, 70.4%). We compared the patients' characteristics and prognosis between the two groups. The low GNRI group was older [72.0 (63.0-79.0) vs. 63.0 (53.0-73.0) years, P<0.001] and had a lower prevalence of male sex (56.9% vs. 64.5%, P=0.001). There were no differences in the use of antiplatelet agents and anticoagulants between the two groups. Levels of B-type natriuretic peptide were higher [321.1 (123.3-667.4) vs. 111.6 (42.6-235.4) pg/mL, P<0.001] and levels of haemoglobin were lower [12.4 (10.8-13.7) vs. 14.2 (12.9-15.4) g/dL, P<0.001] in the low GNRI group. The Kaplan-Meier analysis demonstrated that bleeding event rates were higher in the low GNRI group (log-rank P<0.001). The multivariable Cox proportional hazard analysis revealed that low GNRI (hazard ratio 1.952, 95% confidence interval 1.002-3.805, P=0.049) was associated with bleeding events. Heart failure patients with poor nutritional status, determined by GNRI under 106.2, experienced high bleeding event rates. Comprehensive management is required to avoid bleeding event in those populations.

Examining Rates of Traumatic Events and Posttraumatic Stress Disorder Symptoms Among Autistic Adults.

Autistic adults experience high rates of traumatic events and posttraumatic stress disorder (PTSD) symptoms. However, less is known about how autistic adults experience (i.e., by directly experiencing, witnessing, and/or learning about) distinct types of traumatic events (e.g., social, nonsocial traumas). Little research has considered whether the four-factor structure of PTSD symptom domains (e.g., avoidance, intrusions, hypervigilance, negative mood/cognition) can be applied for autistic adults. Lastly, understanding how demographic factors (e.g., gender, race/ethnicity) relate to rates of traumatic events and symptoms among autistic adults is critical for understanding disparities relating to PTSD. Therefore, the current study aims to examine self-reported traumatic events and PTSD symptoms, and identify associations with demographic factors, among autistic adults. Participants included 276 autistic adults and a nationally representative sample of 361 nonautistic adults who completed online measures, including the Life Events Checklist for DSM-5, Posttraumatic Stress Disorder Checklist for DSM-5 (PCL-5), Autism-Spectrum Quotient-Short, and Patient Health Questionnaire-4. Analyses focused on evaluating group differences in traumatic events and symptoms and considered associations with demographic factors. Autistic adults reported significantly higher rates of directly experiencing, witnessing, and learning about traumatic events than nonautistic adults, including more interpersonal events (e.g., physical assault, sexual assault) and fewer transportation accidents than nonautistic adults. Autistic adults also reported significantly higher levels of all PTSD symptom clusters than nonautistic adults. A confirmatory factor analysis and follow-up invariance analyses of the PCL-5 revealed that the four-factor Diagnostic and Statistical Manual of Mental Health Disorders, Fifth Edition (DSM-5) PTSD symptom subscale structure was equivalent across groups of autistic and nonautistic adults. Autistic adults experienced more traumatic events and PTSD symptoms overall, particularly more interpersonal traumas and hyperarousal and negative mood/cognition symptoms than nonautistic adults. Future research should examine outcomes of trauma exposure, identify protective factors, and examine efficacy of trauma-focused treatments for autistic individuals, in partnership with autistic adults.

Validity of TIMI Risk Score and HEART Score for Risk Assessment of Patients with Unstable Angina/Non-ST Elevation Myocardial Infarction Presented to an Emergency Department in Jordan.

To examine the validity and predictability of thrombolysis in myocardial infarction (TIMI) risk and HEART scores in patients presenting to the emergency department (ED) with chest pain in Jordan (representative of the Middle East and North Africa Region, MENA). Risk scores were calculated for 237 patients presenting to the ED with chest pain. Patients were followed-up prospectively for the need for percutaneous coronary intervention, major adverse cardiovascular events, and all-cause mortality, looking for correlation and accuracy between the predicted cardiovascular risk from TIMI risk score and HEART score and the clinical outcome. Of the 237 patients, approximately 77% were diagnosed with unstable angina and 23% diagnosed with non-ST elevation myocardial infarction (NSTEMI). about two thirds of the study population were smokers and known to have hypertension and dyslipidaemia. In 50 patients, the primary outcome (need for percutaneous coronary intervention (PCI) and/or major adverse cardiovascular events (MACE) at days 14 and 40, all-cause mortality) was observed. Regarding the predictability of the TIMI score, a larger number of events were observed in the study population than predicted. Patients with TIMI scores of 3 to 5 have about a 5-8% higher event rate than predicted. Both TIMI and HEART risk scores were able to predict an elevated risk of major cardiovascular adverse events (MACE). The overall impression was that the TIMI risk score tended to underestimate risk in the study population.

Outcome and treatment-related adverse events of combined immune checkpoint inhibition with flipped dosing in a real-world cohort of 79 patients with metastasized melanoma

IntroductionCombined immune checkpoint inhibition (ICI) with ipilimumab and nivolumab is a widely used treatment regimen for metastatic melanoma with non-resectable metastases. Nevertheless, the standard dose of ipilimumab 3 mg/kg bw and nivolumab 1 mg/kg bw is associated with a high rate of treatment-related adverse events (trAEs) (59% grade 3–4). In the CheckMate 511 study, it could be shown that flipped dosing with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw resulted in a significant reduction of trAE.MethodsWe have also used this regimen in the clinical setting and report the trAE, progression-free survival, and overall survival for 79 patients with metastatic melanoma who started combined ICI in the flipped dosing between March 2019 and April 2020.Resultsin total, 40 patients started first-line, 50% of whom had an elevated lactate dehydrogenase level at baseline. The disease control rate of these patients was 50%. The 2-year overall survival rate 67%. Moreover, 33% of the patients suffered grade 3 or 4 treatment related adverse events. DiscussionThe results of our study correspond very well to the results of the CheckMate 511 study (2-year OS: 65%, grade 3-4 immune-related side effects: 35%). Combined ICI with ipilimumab 1 mg/kg bw and nivolumab 3 mg/kg bw seems to be an equally effective but better-tolerated therapy regimen for metastasized melanoma patients, also in a real-world cohort.

12-month mortality and hospitalizations in patients with heart failure with preserved ejection fraction and comorbid hypertension and type 2 diabetes mellitus

Background: Heart failure with preserved ejection fraction (HFpEF) carries a high risk of mortality and hospitalization, especially in patients with comorbid hypertension and type 2 diabetes mellitus. Little is known about the prognosis of hypertensivediabetic HFpEF in Vietnam. Objective: To examine the 12-month mortality, hospitalization, and combined outcome of all-cause mortality or heart failure hospitalization in hypertensivediabetic HFpEF patients. Methods and Materials: A 12-month prospective cohort study conducted in University Medical Center, HCMC and Nhan Dan Gia Dinh hospital. Recruiting period started in January 2021 and ended in April 2022. Results: 233 patients were recruited. During 12-month, 6.9% died (n=16), in which 50% were due to cardiovascular cause. Hospital admission was reported in 62.2% of patients (n=145). 23.5% (n =55) were hospitalized at least 3 times. During the first hospitalization, 57.3% were due to cardiovascular reasons, most often heart failure (24.2%) and acute myocardial infarction (9%). Among non-cardiovascular admissions (42.7%), infection was the leading cause (22.1%). Combined outcome was observed in 24.9% (n=58). Conclusions: Hypertensivediabetic HFpEF patients experienced high rates of adverse events during a 12-month period, which were not restricted to cardiovascular causes, but also triggered by non-cardiovascular diseases. Comprehensive management should be taken into consideration to reduce both cardiovascular and noncardiovascular events.

Efficacy and Safety of Chimeric Antigen Receptor T Cells Therapy Combined with Zanubrutinib in the Treatment of Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Background: While complete response rate of CD19 CAR-T in diffuse large B-cell lymphoma (DLBCL) reached 40-60%, about 30%-50% of patients still face relapse, strategies that can enhance the therapeutic effects of CAR-T cells infusion should be actively explored. Bruton's tyrosine kinase (BTK) is an essential component of multiple signaling pathways including B-cell receptor signaling that regulate B cell proliferation, survival, and functions. These receptor signaling has been implicated in the survival of malignant B-cells making it a promising therapeutic target for various B-cell malignancies and inflammatory diseases. Different types of BTKi regulate T cell and B cell function through different signal pathways. Research has proved that CD19 CAR-T Cells in combination with ibrutinib for the treatment of relapsed/refractory aggressive B-cell lymphomas shows a high response rate and low level of adverse events, while zanubrutinib has not been reported. Therefore, our center explored the efficacy and safety of CD19 CAR-T Cells in combination with zanubrutinib for the strategy of relapsed/refractory DLBCL. Patients and Methods: The study included 6 r/r DLBCL patients, 4 patients have previously received 3-line or above treatment, and 2 patients began CAR-T treatment after 1-line chemotherapy. All patients received fludarabine (FLU) and cyclophosphamide (CTX) conditioning chemotherapy (FLU 30mg/m 2. d1-3; CTX 500mg/m 2, d1-3) before CAR-T infusions. T cells were apheresis collected and transduced with a lentiviral CD19 scFv CAR fused with intracellular signaling domains: CD28/CD27/CD3z-iCasp9. CAR-T cells were infused at dose of 2.0x10 6 cells/kg. The quality of apheresis cells, gene transfer and T cell proliferation efficiencies, and effective CAR-T infusion dose were quantitatively scored and documented. All patients began to combine with zanubrutinib after one month of CAR-T cells infusion. Results: After one month of CAR-T cells infusion, total of 50% (3/6) of patients achieved complete response (CR), while 50%(3/6) of patients were evaluated as partial response (PR), with an overall response rate (ORR) of 100%. Within 6 months after combined with zanubrutinib, all patients of PR achieved CR. In the evaluation of safety, 83% (5/6) of patients occurred grade 2 cytokine release syndrome (CRS), and 33.3% (2/6) patient occurred grade 1 immune effector cell-associated neurotoxicity syndrome (ICANS), no case of severe CRS defined as≥grade 3 occurred, 66.7% (4/6) of patients occurred grade 2 hematotoxicity and 33.3% (2/6) of patients occurred grade 4 hematotoxicity. After a median follow-up of 19.5 months, 6 patients maintained CR, with an duration of response (DOR) of 100%, median DFS and OS were not reached. All patients can be detected CAR-T cells sustain in peripheral blood mononuclear cells continuously until last follow-up date(Fig.2). Continued follow-up will confirm whether the CAR-T cells therapy combined with zanubrutinib can obtain long term overall survival in these study. Conclusions: Our study proved that CD19 CAR-T Cells combined with zanubrutinib for the strategy of relapsed/refractory DLBCL and as maintenance treatment showed strong efficacy with acceptable toxicity, the current results already support that zanubrutinib in the treatment of r/r DLBCL is expected to reduce the risk of relapsed, thereby prolonging the disease-free survival of patients, without increasing the incidence of adverse effects. More follow-up and clinical trials are needed to clarify the efficacy of Chimeric Antigen Receptor T Cells Therapy combined with zanubrutinib in the treatment of r/r DLBCL.

The Optimal Threshold for Hemoglobin S Percent Level While Performing Regular Blood Transfusion Therapy to Prevent Severe Vaso-Occlusive Pain Events in Children with Sickle Cell Anemia: A Secondary Data Analysis of Participants in the SIT Trial

Introduction: Children with sickle cell disease (SCD) often experience frequent severe acute vaso-occlusive pain events, unresponsive to FDA-approved therapies (hydroxyurea, L-glutamine, crizanlizumab) to decrease the severe acute vaso-occlusive pain event incidence rate. The ASH guidelines for pain management recommend regular blood transfusion therapy after FDA-approved therapies have failed to decrease the high rate of severe acute vaso-occlusive pain events ( The Journal of Pediatrics, 139(6), 785-789). However, unlike regular blood transfusion therapy for primary and secondary stroke prevention, for which the goal hemoglobin S (Hb S) level is ≤ 30% , no optimal Hb S threshold has been established to attenuate the severe acute vaso-occlusive pain event incidence rate. We tested the hypothesis that among children receiving regular blood transfusion therapy with a goal to keep the mean hemoglobin S level &amp;lt; 30%, participants that achieved a mean Hb S level &amp;lt; 30% would have lower rates of severe acute vaso-occlusive pain events requiring hospitalization than children regularly transfused with mean Hb S level &amp;gt; 30%. Evidence to support our hypothesis would provide the first evidence-based guidelines for the optimal hemoglobin S threshold to decrease the acute vaso-occlusive pain event incidence rate in children with sickle cell anemia (HbSS). Methods: The SIT trial was a single-blind clinical trial( Blood Advances, 4(12), 2656-2701), where participants were children with sickle cell anemia randomly allocated to receive regular blood transfusion therapy (transfusion group) or standard care (observation group). Participants receiving regular blood transfusion therapy from the SIT Trial were included in the secondary analysis. Eligibility criteria include participants between 5 and 15 years of age, with no history of stroke, one or more silent cerebral infarcts on magnetic resonance imaging, and a neurologic examination showing no abnormalities. The transfusion therapy goal was to keep the maximum Hb S level &amp;lt; 30%. For the ancillary study, participants were included only in the transfusion arm of the trial. The primary endpoint of this ancillary study was the incidence rate of hospitalization for vaso-occlusive pain episodes among those receiving only regular blood transfusion therapy. We conducted a zero-inflated negative binomial regression analysis to determine the association between the incidence rate for severe acute vaso-occlusive pain events requiring hospitalization and independent covariates, including age at the time of random allocation, sex, and mean hemoglobin S level (&amp;lt; 30% and &amp;gt; 30%). Results: A total of 90 participants received regular blood transfusion therapy in the SIT trial. Among participants transfused, 53 and 37 individuals had a mean Hb S level of &amp;lt; 30% and &amp;gt; 30%, respectively. The median time on transfusions for the groups with Hb S levels of &amp;lt; 30% and &amp;gt; 30% was 2.9 years for both groups. Among the participants, 10.8% (4/37) who had a mean Hb S &amp;lt; 30% and 20.8% (11/53) of those with a mean Hb S &amp;gt; 30% experienced at least one hospitalization for a severe acute vaso-occlusive pain event. The mean hemoglobin S levels in the &amp;lt; 30% and &amp;gt; 30% groups were 25.4% and 37.5%, respectively. The mean hospital rates for severe acute vaso-occlusive pain events in the two groups &amp;lt; 30% and &amp;gt;30% were 9.4 (95% confidence interval 9.4 - 17.2 person-years) and 29.2 per 100 person-years (95% confidence interval, 21.0 - 39.5 person-years), respectively, P = 0.078. In the multivariable analysis, the incidence rate ratio for severe acute vaso-occlusive pain events showed that there was no statistical difference between those with a mean Hb S level in groups &amp;lt; 30% and &amp;gt; 30%, 0.65; P=0.43. Children with a higher baseline hemoglobin level were more likely to achieve a mean hemoglobin S level &amp;lt; 30%. Conclusion: In children with sickle cell anemia, receiving regular blood transfusion therapy with the goal of keeping the mean hemoglobin S level &amp;lt; 30%, achieving a mean hemoglobin S level &amp;gt; 30% was as effective as a mean hemoglobin S level &amp;lt; 30 % in decreasing the incidence rate of severe acute vaso-occlusive pain events requiring hospitalization. Further studies are warranted to identify reliable measures of the efficacy of regular blood transfusion therapy for the reduction of acute vaso-occlusive pain events.

357. High Rate of Adverse Events in Patients Receiving Oral Antimicrobials Under a COpAT Monitoring Protocol

Abstract Background Oral linezolid (LZD), trimethoprim sulfamethoxazole (SXT), voriconazole (VRC), and itraconazole (ITC) are used often for prolonged durations and are associated with an array of adverse events (AEs). Establishing specific protocols for monitoring such courses of Complex Outpatient Antibiotic Therapy (COpAT) regimens as parenteral alternatives is a priority. Methods Patients receiving LZD, SXT, VRC, ITC between January 1st, 2019 and December 31st, 2022 with monitoring by our Outpatient Parenteral Antimicrobial Therapy (OPAT) program staff were identified for retrospective review of electronic health records. Weekly labs were highly encouraged in the first month of therapy, and at least monthly thereafter. All patients were reviewed during weekly OPAT rounds. An AE grading tool was derived using Common Terminology Criteria for Adverse Events (CTCAE 2017) to capture common AEs associated with study drugs. Primary study endpoint was occurrence of up to three AEs of any severity during antibiotic therapy. Secondary analyses evaluated risk factors and treatment outcomes associated with AE occurrence using chi-square statistic (MedCalc Software Ltd.). Results A total of 133 adverse events were identified in 70 (56.5%) of 124 patients receiving COpAT with LZD, SXT, VRC, ITC. Most common infections were pulmonary, bone/joint, and bacteremia/endocarditis (Figure 1). Median length of therapy ranged 21 days (LZD) to 102 days (ITC). Median time to AE onset ranged 8 days (SXT) to 14 days (VRC). Most AEs (88.3%) were &amp;lt; Grade 2 in severity, but 44 (62.9%) of 70 patients incurred &amp;gt; 2 AEs per treatment course. Although VRC incurred highest proportion of AEs, rates were &amp;gt; 50% for all agents (Figure 2), and gastrointestinal AEs were most common (Figure 3). Occurrence of AE of any severity was significantly associated with modification of drug regimen and change in treatment duration.Figure 1.Infectious Disease Diagnoses Represented Under COpAT. Pulmonary, bone/joint, and endovascular infectious were most commonly represented.Figure 2.Proportion of Study Patients with Adverse Events by Medication. Adverse events were incurred in half or more of all treatment courses represented in this studyFigure 3.Adverse Event Categories by Medication. Gastrointestinal toxicity was most frequently represented, followed by derangements in electrolyte or renal function. Conclusion High rates of multiple low- grade AEs per patient treated were associated with use of oral LZD, SXT, VRC, and ITC for severe infections, and frequently required modifications in regimen or duration of therapy. Evidence based protocols are needed to help guide monitoring and clinical management for patients receiving COpAT with these important agents. Disclosures All Authors: No reported disclosures

Assessing the effectiveness of autism spectrum disorder roadway warning signs: A case study in New Jersey

In 2018, the Centers for Disease Control and Prevention (CDC) found that the prevalence rate for children identified with autism spectrum disorder (ASD) in New Jersey is 1 in 35 children, the second highest rate of ASD diagnosis in the country. Children with autism face numerous obstacles, including learning road safety and interacting with road elements that could raise the risk of their traffic crash involvement. Many agencies across the nation have used disability warning signs as a tool to eliminate such risks. However, the effectiveness of these signs has not been explored yet. This study assesses the effectiveness of specific disability warning signs for autism at multiple locations in New Jersey using video and speed data. To investigate all drivers' responses to the ASD warning signs, the study defined two proxies of following the speed limit and applying brakes to show caution, where the events that did not correspond with the defined proxies were recorded as non-compliance events. Additionally, the Mann-Whitney U test was employed to evaluate the effectiveness during the presence and absence of ASD sign. Study results showed a high rate of non-compliance events for both proxies, and no significant difference in the driving speed was observed during the presence and absence of ASD sign. Additionally, the estimated relative risk/rate ratio revealed that the drivers that did not follow the speed limit were 1.5 times more likely not to apply brakes than the drivers who followed the speed limit, representing careless driving behavior in the area with ASD individuals.

The Role of Neutrophil to Lymphocytes Ratio and It's Common Clinical Outcomes Amount the Patient with Non ST Elevation Acute Coronary Syndrome

Objectives: To evaluate the admission neutrophil-to-lymphocyte ratio (NLR) for risk stratification for in-hospital out-comes and complications in non-ST-elevation acute coronary syndrome (non-ST-ACS) patients.&#x0D; Methodology: Methods: We recruited consecutive patients with non-ST-ACS. The NLR was obtained and stratified as low, inter- mediate, and high-risk based on &lt;3.0, 3.0e6.0, and &gt;6.0, respectively. The new ST-T changes, arrhythmias, contrast-induced nephropathy (CIN), and mortality were recorded.&#x0D; Results: Results: Median NLR was 3 [2.1-5.3] for 346 patients with 19.9% and 30.6% in high- and intermediate-risk group. New ST-T changes were observed in 3.5% (12) out of which 8, 3, and 1 patient in low, intermediate, and high-risk group (p = 0.424), respectively. Arrhythmias were observed in 5.8% (20) with 7, 5, and 8 patients in low, intermediate, and high- risk group (p = 0.067), respectively. CIN was observed in 4.9% (17) with 5, 5, and 7 in low, intermediate, and high-risk group (p = 0.064), respectively. In-hospital mortality was recorded in 1.4% (5) with 2 and 3 patients in high and low-risk group (p = 0.260), respectively.&#x0D; Conclusion: A significant number of non-ST-ACS patients fall in the high-risk category of NLR. Although, the association between NLR and in-hospital mortality and adverse events was not statistically significant but relatively higher rates of events were observed in high risk group.

Prognostic implications of individual and combinations of coronary pressure and flow parameters measured under resting and hyperemic conditions

Abstract Background Coronary pressure- and flow-derived parameters that reflect resting and hyperemic conditions have prognostic value, but their relative prognostic implications has not been established. Purpose To evaluate the individual and combined prognostic relevance of hyperemic pressure, hyperemic flow, resting pressure, and resting flow Methods A total of 1,971 vessels, in which revascularization was deferred after invasive pressure and flow assessment, were included from the international, multicenter registry composed of 16 hospitals across 7 countries. Abnormal resting pressure and flow were defined as a distal coronary pressure/aortic pressure (Pd/Pa) ≤0.92 and high resting flow (1/resting mean transit time [Tmn] &amp;gt;2.4 or resting average peak flow [APV]&amp;gt;22.7 cm/s), and abnormal hyperemic pressure and flow, as fractional flow reserve (FFR) ≤0.80 and low hyperemic flow (1/hyperemic Tmn &amp;lt;2.2 or hyperemic APV &amp;lt;25.0 cm/s), respectively. The clinical endpoint was target vessel failure (TVF), target vessel-myocardial infarction (MI), or cardiac death at 5 years. Results The mean age of patients was 62.8 ± 10.2 years, and the mean % diameter stenosis was 46.8±16.5%. Abnormal pressure and flow were independent predictors of TVF (HR 1.83 [95% CI, 1.25–2.68], P =0.002 for high resting flow; HR 2.89 [2.04–4.10], P &amp;lt;0.001 for low resting Pd/Pa; HR 1.87 [1.16–3.00], P =0.010 for low hyperemic flow; HR 3.13 [2.22–4.41], P &amp;lt;0.001 for low FFR) and cardiac death/MI (HR 1.99 [1.16–3.42], P =0.013 for high resting flow; HR 3.28 [1.99–5.39], P &amp;lt;0.001 for low resting Pd/Pa; HR 2.20 [1.12–4.32], P =0.022 for low hyperemic flow; HR 3.11 [1.91–5.07], P &amp;lt;0.001 for low FFR). In the order of neither, either, and both abnormal resting pressure and flow, the risk of 5-year TVF or cardiac death/MI increased proportionally (P-for-trend &amp;lt;0.001). This was also true for abnormal hyperemic pressure and flow (P-for-trend &amp;lt;0.001). In 1,640 vessels with normal FFR, a higher clinical event rate was observed when the vessels had a high resting flow (HR 2.08 [1.28–3.37], P =0.003 for TVF; HR 2.11 [1.04–4.27], P =0.039 for cardiac death/MI) or low resting Pd/Pa (HR 3.14 [1.90 – 5.19], P &amp;lt;0.001 for TVF; HR 3.49 [1.70–7.18], P &amp;lt;0.001 for cardiac death/MI). Similarly in 1,556 vessels with a normal resting Pd/Pa, a higher event rate was related to a low hyperemic flow (HR 2.13 [1.17–3.84], P =0.014 for TVF; HR 2.73 [1.16–6.33], P =0.021 for cardiac death/MI) or low FFR (HR 3.86 [2.35–6.34], P &amp;lt;0.001 for TVF; HR 3.50 [1.71–7.19], P &amp;lt;0.001 for cardiac death/MI) (Figure). Overall results were similar when the different cut-off values for pressure and flow parameters were applied. Conclusions Abnormal resting and hyperemic pressure and flow were independent prognostic predictors. The abnormal flow had an additive prognostic value for pressure in both resting and hyperemic conditions. Resting and hyperemic parameters showed complementary prognostic implications.

Effect of eplerenone according to duration of heart failure in EMPHASIS-HF: It is never too late to start an MRA in HFrEF

Abstract Background In the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure trial (EMPHASIS-HF), the mineralocorticoid receptor antagonist (MRA) eplerenone reduced both the risk of death and heart failure (HF) hospitalization in patients with HF and reduced ejection fraction (HFrEF) and mild symptoms. However, many patients are still not prescribed an MRA and physicians may be reluctant to add another treatment in patients with longstanding HF who appear to be "stable" on their current therapy. Purpose As little is known about how the effect of MRA therapy varies by the duration of HF, we examined the efficacy of eplerenone according to time from HF diagnosis among patients in EMPHASIS-HF. The primary trial outcome was the composite of a first hospitalization for HF or cardiovascular death. Methods Three patient groups of similar size were created according to the duration of HF: &amp;lt;1 year, ≥1 to &amp;lt;5 years, and ≥5 years. Outcomes were analysed using Cox regression and the Kaplan-Meier estimate. Treatment effects were examined according to HF duration category and also using the duration of HF as a continuous variable. Results The number of patients in each group was: 975 (&amp;lt;1 year), 769 (1 - &amp;lt;5 years), and 988 (≥5 years), respectively. Patients with longer duration of HF were older and more frequently had an ischaemic aetiology of HF. Additionally, a longer duration of HF was associated with lower eGFR levels, wider QRS duration, and a higher proportion of atrial fibrillation at baseline. The rate of the primary outcome (per 100 person-year) increased with HF duration: 9.8 (95% CI: 8.4-11.4) for &amp;lt;1 year, 13.5 (11.6-15.7) for 1 - &amp;lt;5 years, and 17.6 (15.6-19.8) for ≥5 years. Similar trends were seen in all other outcomes (Figure 1). The hazard ratios for the effect of eplerenone compared to placebo on the primary outcome were 0.57 (95% CI: 0.42-0.79) for &amp;lt;1 year, 0.81 (0.60-1.10) for 1- &amp;lt;5 years, and 0.61 (0.48-0.78) for ≥5 years; P for interaction = 0.24. The benefits of eplerenone were also consistent across the duration of HF examined as a continuous variable (Figure 2). For the primary outcome, The number needed to treat (NNT) over the duration of the trial, for the primary outcome, was 14 for &amp;lt;1 year, 13 for 1 - &amp;lt;5 years and only 10 for ≥5 years duration. Conclusions Patients with a longer duration of HF had worse clinical status and a higher rate of events, but the benefit of eplerenone was consistent in people with longer-standing HF and HF of shorter duration. These data suggest that it is never too late to start an MRA in patients with HFrEF. Figure 1. Outcomes according to heart failure duration category Abbreviations: CV cardiovascular; HF heart failure Figure 2. Treatment effects according to the duration of heart failure Abbreviations: CV cardiovascular; HF heart failureFigure 1Figure 2

Acute limb ischemia registry, the forgotten emergency

Abstract Background Although acute limb ischemia (ALI) is a leading cause of death and lower limb amputation, knowledge about its epidemiology, presentation, and treatment is limited. Aim The purpose of this study is to describe patient characteristics, diagnostic approaches taken, modes of presentation, and clinical developments in patients with ALI. Methods We prospectively included all ALI outpatients between 2016 and 2022. Patients who had ischemia due to trauma, iatrogenic causes, or those who developed it while in the hospital were excluded. We provide descriptive analysis for our registry, and performed a uni and multivariable regression model in order to identify clinical factors associated with the composite primary endpoint of intrahospital death and limb amputation. Results We included 89 consecutive patients with ALI. Table 1 describes the baseline characteristics. The median time from clinical presentation to first medical contact was 24 hours (IQR 4-72 hours). Time between clinical consultation and diagnosis was 1 hours (1.1–7 hours), and time between diagnosis and revascularization was 12 hours (4–36 hours). Although patients with a threatened limb sought treatment sooner than those without (12 hours vs 72 hours, p = 0.001), they had a higher rate of events. Peripheral thromboembolism was the main cause of ALI and the only etiology associated with death or amputation. Patients considered candidates for reperfusion therapy comprised 92% of the cohort, while 3 patients were considered candidates for direct amputation and 2 patients were considered candidates for anticoagulation due to the comorbidities they presented. Thirteen patients (21%) died or suffered limb amputations (three suprapatellar, two infrapatellar, and one in the forefoot). One third of the patients suffered a complication during hospitalization. Acute renal failure was the most frequent complication (27%). In a univariable regression analysis, age, embolic origin, higher levels of lactacidemia, and threatened limb were associated with the composite event of death and limb amputation, whereas in a multivariable regression model, serum lactic acid and have the vitality of the member threatened were independently associated with an increased odds of death or amputation (Tabla 2). Conclusions Acute limb ischemia is associated with an increased risk of intrahospital death and limb amputation. Serum lactacidemia and limb threatened at presentation were independently associated with an increased risk of clinical events. Risk of events is associated with the limb clinical condition and not with the delay in revascularization. Even those patients who do not die or are amputated have high morbidity and need for prolonged hospitalization. Increased awareness of the disease are critical for improving survival and limb preservation.

Right heart function in isolated severe tricuspid regurgitation. a new stratification approach by Speckle tracking echocardiography

Abstract Background Optimal management of severe tricuspid regurgitation (TR) remains controversial. While right ventricular (RV) systolic function is an established prognostic marker of outcomes, the potential role of right atrial (RA) function is unknown. Purpose to evaluate the clinical utility of combining RV and RA strain by Speckle-tracking echocardiography to assess RV and RA function for prediction of cardiovascular outcomes. Methods Consecutive patients with at least severe TR (severe, massive or torrential TR) evaluated in the Heart Valve Clinic were prospectively included following a comprehensive clinical protocol. Consecutive control subjects and patients with permanent atrial fibrillation were included for comparison. An independent cohort of patients was included for external validation. RA and RV mechanics analysis was performed using a novel, automated 2D strain analytical software. A combined endpoint of hospital admission due to heart failure (HF) or all-cause mortality was defined. Results 176 patients with at least severe TR, 20 AF patients and 20 control subjects were included in this study. Patients with TR showed lower RA reservoir strain (RASr) and RV-free wall longitudinal strain (RV-FWLS) compared to controls and to AF patients (p&amp;lt;0,001). After a median follow-up of 2,2 years (IQR: 12-41 months), 38% reached the combined endpoint. Reservoir RA strain (RASr) and RV-FWLS were predictors of outcomes independently of TR severity and RV dimensions in a multivariate Cox analysis (table, model 1). RA strain showed incremental value to RV strain. Conventional parameters of RV function were not predictive of events. RV-FWLS&amp;gt;-20% and RASr &amp;lt;10% identified patients with a higher event rate (p&amp;lt;0,001). The combination of abnormal values of RA and RV strain (STREI stratification) stratified 4 different groups of risk independently of TR severity, RV dimensions and clinical status (adj HR per stratum 1,89 (1,4-2,34), p&amp;lt;0,001) (table-model 2 and figure). Pre-defined cut-off values achieved similar prognostic performance in the validation cohort (n=50). Conclusion Clinical outcomes demonstrate that strain parameters are superior to conventional indices of RV function in patients with at least severe TR. The combination of RA and RV strain stratify better patients’ risk, reflecting a broader effect of TR on right heart chambers.STREI STRATIFICATION.Cox regression analysis

Validation of the developed ASGARD risk score for safe monitoring of asymptomatic patients with non-severe aortic valve stenosis

Abstract Background The recommended standard monitoring of patients with non-severe aortic valve stenosis (AS) involves echocardiography surveillance at 1-2 year intervals. Since many of these costly routine echocardiograms yield no clinical consequences during a prolonged watchful waiting period, we propose to replace them with a risk stratification approach. Purpose The primary aim was to validate the ability of ASGARD risk score to a) identify low-risk AS patients who do not need new echocardiography for safe monitoring, and b) estimate optimal follow-up intervals. Methods We have developed the ASGARD risk score using data from 1196/1739 (69%) asymptomatic AS-patients with mild-to-moderate AS who were enrolled in the randomized, multicentre Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial. The primary outcome was a composite of AS-related outcomes, aortic valve replacement, or hospitalization with heart failure during a clinically relevant 2-year follow-up. From multivariable Cox proportional hazards regression analyses, we chose the best prognostic model with the lowest Akaike information criterion (AIC) values and p-values &amp;lt;0.05. The risk score included five predictors: age, sex, systolic blood pressure, N-terminal pro-brain natriuretic peptide (NT-proBNP), and last year's measurement of transaortic maximal velocity (Vmax). Kaplan-Meier plot visualized event rates stratified by quartiles of risk score. We validated the ASGARD risk score in an internal validation cohort of 543 patients (31% hold-out from SEAS-population) and an external validation cohort of 69 asymptomatic out-clinic patients with Vmax ≤4 m/s from six hospitals from capital city. Results Patients from the external validation cohort significantly differed from those in the development cohort in terms of higher age (mean [SD], 71.7 [8.5] vs. 67.4 [9.8] years, p&amp;lt;0.001), less prevalent left ventricular hypertrophy (13.0% vs. 37.5%, p&amp;lt;0.001), and higher event-rates (12.5 [95% CI, 7.6-20.8] vs. 4.5 [3.7-5.4] events per 100 patient-years of follow-up, p&amp;lt;0.001). The ASGARD risk score showed consistent predictive performance across the validation cohorts (external validation: area under the curve: 0.82 [95% CI, 0.73-0.91]; calibration-in-the-large, p=0.24; calibration slope, p=0.15; Brier score, 0.18). The score performed just as well or better than a new Vmax measurement (Figure 1A-1B). In the three upper ASGARD score quartiles, 95% of patients had less than 5% risk of AVR or heart failure until 7.5, 16.5, and 22.5 months, respectively (Figure 1C). Conclusion Without a new echocardiogram, the ASGARD risk score identifies patients at low risk for AS-related events among asymptomatic patients with non-severe AS. The ASGARD risk score also estimates the safe watchful-waiting period of 6, 15, 21, and 24 months for the four ASGARD risk score quartiles in decreasing order.Figure 1

Performance of the High-STEACS Early Rule-Out Pathway for High Sensitivity Cardiac Troponin T at 30-days in a US population

Abstract Background The High-STEACS Early Rule-Out Pathway for High Sensitivity Cardiac Troponin T (hs-cTnT) is an algorithm designed to rule-out myocardial infarction (MI) in ED patients with symptoms concerning for acute coronary syndrome (ACS). High-STEACS was validated in the United Kingdom but has yet to be evaluated in the US. Purpose The objective of this secondary analysis of the STOP-CP (High Sensitivity Cardiac Troponin T to Optimize Chest Pain Risk Stratification) United States (US) multicenter study is to determine the performance of the High-STEACS hs-cTnT Pathway in a multisite US cohort. Methods Patients (≥ 21 years old) presenting to the (ED) with symptoms suggestive of ACS were enrolled (1/25/2017-9/6/2018) at 8 US medical centers. Participants with 0- and 1-hour hs-cTnT measures were stratified into outpatient and admission dispositions using the established High-STEACS hs-cTnT cut-points. Cardiac death or MI and major adverse cardiovascular events (MACE; a composite of cardiac death, MI, and coronary revascularization) at 30-days were adjudicated. Negative and positive predictive values (NPV and PPV) and negative and positive likelihood ratios (-LR and +LR) for the High-STEACS pathway were calculated for each outcome with 95% confidence intervals. Results Overall, 1430 patients were studied. 54.2% (775/1430) were male with a mean age of 57.6 ± 12.8 years. At 30-days, 12.8% (183/1430) of patients experienced cardiac death or MI and 14.2% (203/1430) had MACE. High-STEACS classified 59.9% (857/1430) to the outpatient disposition and 40.1% (573/1430) to admission. Among patients stratified to the outpatient group, 1.9% (16/857) experienced cardiac death or MI and 3.4% (29/857) had MACE at 30-days. The NPV and -LR for High-STEACS were 98.1% (95%CI 97.0-98.9) and 0.13 (95%CI 0.08-0.21) for 30-day cardiac death or MI and 96.6% (95%CI 95.2-97.7) and 0.21 (95%CI 0.15-0.30) for 30-day MACE. For patients stratified to admission, 29.1% (167/573) had 30-day cardiac death or MI and 30.4% (174/573) had MACE. This yielded a PPV and +LR for 30-day cardiac death or MI of 29.1% (95%CI 25.5-33.1) and 2.8 (95%CI 2.6-3.1) and 30.4% (95%CI 26.6-34.3) and 2.6 (95%CI 2.4-2.9) for 30-day MACE. Conclusions The High-STEACS hs-cTnT Pathway stratified nearly 60% of patients to an outpatient disposition, but these patients had high rates of 30-day cardiac events. These findings suggest that providers should be cautious before using this pathway among US patients with possible ACS.

Evaluating risk-based allocation strategies for PCSK9 inhibitors: results from a simulation study in a contemporary ASCVD cohort

Abstract Background/Aim Targeting PCSK9 inhibitors (PCSK9i) to patients with high LDL-cholesterol (LDL-C) as well as a high cardiovascular event rate yields the highest therapeutic effect and is thus reasonable from a health economic perspective. The current European dyslipidaemia guideline determines PCSK9i eligibility solely by LDL-C, whereas guidelines from the US/the UK additionally use a set of clinical risk factors. Such selection criteria require evaluation. Methods We determined the cardiovascular event rate and calculated the cost/preventable cardiovascular event for PCSK9i initiation in the target populations according to three scenarios: (i) European Society of Cardiology (ESC) 2019 dyslipidaemia guideline (PCSK9i recommended for all patients with residual LDL-C &amp;gt;55 mg/dl), (ii) American Heart Association/American College of Cardiology (AHA/ACC) 2018 cholesterol guideline (use of PCSK9i restricted to patients with residual LDL-C &amp;gt;70 mg/dl and clinical risk factors) and (iii) UK National Institute for Health and Care (NICE) recommendation (use of PCSK9i restricted to patients with residual LDL-C &amp;gt;155 mg/dl or &amp;gt;135 mg/dl with clinical risk factors). A Monte Carlo simulation taking into account statin intolerance was used to simulate uptitration of lipid lowering medications according to the different scenarios. Analyses were based on patients with atherosclerotic cardiovascular disease (ASCVD) from a contemporary all-comers cohort recruited at a large tertiary care center in Germany. Major adverse cardiovascular events (MACE, defined as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) were recorded over a median follow-up of 4.2 years. Results We included 1922 patients with ASCVD (mean age 69.3 years, median baseline LDL-C 86.0 mg/dl, 75.0% male). Eligibility for PCSK9i was simulated to be 39.6% (ESC 2019), 6.2% (AHA/ACC 2018) and 1.4% (NICE). The 3 year cardiovascular event rates in the corresponding PCSK9i target populations were 11.4%, 13.8% and 13.8% respectively. Event rate differences were driven by a higher rate of non-fatal myocardial infarction in the risk-based target populations (5.2%, 8.2%, 7.2%). Annual cost/preventable event differed by up to a factor 3 (689,000 €, 515,000 € and 215,000 €), driven mainly by pre-PCSK9i LDL-C levels in the different target populations (68.8 mg/dl, 76.0 mg/dl and 182.7 mg/dl). (Table 1) Conclusion The AHA/ACC and NICE guidelines, based on both residual LDL-C and clinical risk factors, reduced the eligibility for PCSK9i as well as the cost/preventable cardiovascular event compared to the ESC guideline. However, the clinical criteria used for risk classification yielded limited discrimination for the identification of subpopulations at highest cardiovascular risk. Development of accurate risk prediction tools and their integration into risk-based allocation strategies, both requisites for a cost-effective use of PCSK9i, remain a challenge.Table 1

Continuous measurement of percutaneous oxygen saturation during 6-minute walk test is useful for stratification of the prognostic risk in patients with heart failure

Abstract Background The 6-minute walk test (6MWT) is an established test to assess the functional exercise performance and the 6-minute walk distance is strongly correlated with the functional capacity and the prognosis in patients with heart failure (HF). Also, the hypoxia during 6MWT is reported to be associated with severity of pulmonary diseases. However, no study has reported the clinical implication of sequential changes in percutaneous oxygen saturation (SpO2) during 6MWT was not investigated in HF patients. Purpose To prospectively clarify the association between sequential changes in SpO2 during 6MWT and prognosis in patients with HF. Methods In this prospective observational study, 50 patients admitted to our hospital with acute heart failure were enrolled. The 6MWT was performed at the time before discharge, after hemodynamic stability was confirmed. The average of SpO2 was calculated from data obtained at rest (3 minutes just before the test) and during 6MWT by employing the wearable pulse-oximeter which are designed to record and store the SpO2 value every seconds. Alternations in SpO2 (Δ SpO2) were analyzed by subtracting the average during 6MWT from that at rest. Patients were followed 1 year for composite outcome of heart failure-hospitalization and death). Results The mean age of participants was 78.8 years, and 23 (46%) were female. The mean EF was 46.1% and the number of the patients with EF≧50, 50&amp;gt;EF&amp;gt;40, 40≧EF were 22, 6, and 22, respectively. Mean NT-proBNP was 4374.5pg/ml. The mean walk distance was 250 ± 112m and the mean Δ SpO2 was 2.88 ± 4.3%. All cases were classified by walk distance and Δ SpO2; long- (&amp;gt;220m) vs. short-distance group (≦220m) and low- (&amp;lt;3.5%) vs. high-ΔSpO2 group (≧3.5%). There were no significant differences in cardiac parameters and respiratory function between long- and short-distance group as well as between low- and high-ΔSpO2 group. Kaplan-Meier analysis revealed that cardiac event rate was higher in the short-distance group than in the long-distance group (HR = 2.89, CI = 1.24-6.71, p = 0.014), and higher in the high-Δ SpO2 group than in the low-ΔSpO2 group (HR = 3.49, CI = 1.55-7.83, p = 0.002) (Figure 1A and 1B). When these classifications were combined, the patients with short-distance and low-ΔSpO2 showed remarkably high event rate of 91% (Figure 2). Conclusions This study showed that, compared to walk distance, ΔSpO2 was more predictive of prognosis of heart failure patients, and that the combination of ΔSpO2 and walk distance may identify the highest risk group. The elucidation of the usefulness of continuous SpO2monitoring during 6MWT as the marker for severity of heart failure and treatment effect warrants further investigation.Figure1Figure 2