Chronic Phase Research Articles

Exploring neural tracking of acoustic and linguistic speech representations in individuals with post-stroke aphasia.

Aphasia is a communication disorder that affects processing of language at different levels (e.g., acoustic, phonological, semantic). Recording brain activity via Electroencephalography while people listen to a continuous story allows to analyze brain responses to acoustic and linguistic properties of speech. When the neural activity aligns with these speech properties, it is referred to as neural tracking. Even though measuring neural tracking of speech may present an interesting approach to studying aphasia in an ecologically valid way, it has not yet been investigated in individuals with stroke-induced aphasia. Here, we explored processing of acoustic and linguistic speech representations in individuals with aphasia in the chronic phase after stroke and age-matched healthy controls. We found decreased neural tracking of acoustic speech representations (envelope and envelope onsets) in individuals with aphasia. In addition, word surprisal displayed decreased amplitudes in individuals with aphasia around 195 ms over frontal electrodes, although this effect was not corrected for multiple comparisons. These results show that there is potential to capture language processing impairments in individuals with aphasia by measuring neural tracking of continuous speech. However, more research is needed to validate these results. Nonetheless, this exploratory study shows that neural tracking of naturalistic, continuous speech presents a powerful approach to studying aphasia.

Results of ponatinib as frontline therapy for chronic myeloid leukemia in chronic phase.

Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) with robust activity in Philadelphia chromosome-positive leukemias. Herein, we report the long-term follow-up of the phase 2 trial of ponatinib in chronic myeloid leukemia in chronic phase. Patients received ponatinib 30 to 45 mg/day. The primary end point was the rate of 6-month complete cytogenetic response (CCyR). The study was held in June 2014 because of the risk of cardiovascular toxicity, requiring patients to change TKI. Fifty-one patients were treated with ponatinib (median dose, 45 mg/day). Median age was 48 years (range, 21-75); 30 (59%) had baseline cardiovascular comorbidities. Median treatment duration was 13 months (range, 2-25). Fourteen patients (28%) discontinued ponatinib because of toxicities, 36 (71%) after the Food and Drug Administration warning/study closure, and one for noncompliance. Dasatinib was the most frequently chosen second-line TKI (n=34; 66%). Among 46 patients evaluable at 6 months, 44 (96%) achieved CCyR, 37 (80%) major molecular response, 28 (61%) MR4, and 21 (46%) MR4.5. The cumulative 6-month rates of CCyR, major molecular response, MR4, and MR4.5 were 96%, 78%, 50%, and 36%, respectively. Durable MR4 ≥24 or ≥60 months was observed in 67% and 51% of patients, respectively. The 24-month event-free survival rate was 97%. After a median follow-up of 128 months, the 10-year overall survival rate was 90%. Eight patients (16%) had serious grade 2 to 3 cardiovascular adverse events, leading to permanent discontinuation in five (10%). Ponatinib yielded high cytogenetic and molecular responses in newly diagnosed chronic myeloid leukemia in chronic phase. Its use in the frontline setting is hindered by arterio-/vaso-occlusive and other severe toxicities.

Incidence, Predictors, and Implications of Secondary Aortic Intervention Following Thoracic Endovascular Aortic Repair for Type B Dissection.

Secondary aortic intervention (SAI) following thoracic endovascular aortic repair (TEVAR) is not uncommon. However, a satisfactory management system has not been established for these patients. We aimed to report our single-center experience with SAI after prior TEVAR for type B aortic dissection (TBAD). From January 2010 to May 2017, 860 eligible patients with TBAD underwent TEVAR. One hundred seven (12.4%) patients required SAI, either endovascularly (n=76) or surgically (n=31). The main indications for SAI were entry flow (n=58 [54.2%]), aneurysm expansion of the proximal or remote aorta (n=26 [24.3%]), retrograde type A aortic dissection (n=11 [10.3%]), distal stent-graft-induced new entry tear (n=6 [5.6%]), and stent migration (n=4 [3.7%]). The Kaplan-Meier curves were generated to determine the degree of freedom from SAI and the prognosis. Cox proportional hazards were used to screen for risk factors for SAI and poor prognosis. The overall 30-day mortality rate after SAI was 4.7% (n=5): endovascular (n=2 [2.6%]) vs open surgery (n=3 [9.7%]; p=0.145). The cumulative survival rates with or without SAI were 86.3%±3.6% vs 95.7%±0.8% at 3 years and 82.0%±4.2% vs 92.2%±1.1% at 5 years, respectively (log-rank p<0.001). Although no significant difference in survival was observed, the incidence of SAI was significantly greater in patients who underwent TEVAR during the chronic phase (acute [11.6%] vs subacute [9.6%] vs chronic [27.8]; p<0.001). Multivariate regression analysis revealed that prior TEVAR in the chronic phase (hazard ratio [HR]=1.73, 95% confidence interval [CI]=1.03-2.90; p=0.039), maximum aortic diameter (HR=1.05, 95% CI=1.04-1.07; p<0.001), and arch involvement (HR=1.48, 95% CI=1.01-2.18; p=0.048) were predictors of the incidence of SAI. In addition, the maximum aortic diameter was demonstrated to be the only risk factor for prognosis after adjusting for confounding factors. Thoracic endovascular aortic repair for chronic TBAD patients should be reconsidered. Open surgery is preferable for those with proximal progression, whereas endovascular treatment is more suitable for distal lesions. Close surveillance and timely reintervention after TEVAR, whether via endovascular techniques or open surgery, are necessary to prevent devastating complications. The management of patients with type B aortic dissection (TBAD) after thoracic endovascular aortic repair (TEVAR) is challenging. We summarized our single-center experience regarding secondary aortic intervention after TEVAR for TBAD. We found that TEVAR for chronic TBAD patients should be carefully evaulated, and open surgery is recommended for those with proximal progession, while endovascular treatment is more preferable for distal lesions.

Haematopoietic stem cell transplantation after reduced intensity conditioning in children and adolescents with chronic myeloid leukaemia: A prospective multicentre trial of the I-BFM Study Group.

This prospective multicentre trial evaluated the safety and the efficacy of a thiotepa/melphalan-based reduced intensity conditioning (RIC) haematopoietic stem cell transplantation (HSCT) in children and adolescents with chronic myeloid leukaemia (CML) in chronic phase (CP). Thirty-two patients were transplanted from matched siblings or matched unrelated donors. In 22 patients, HSCT was performed due to insufficient molecular response or loss of response to first- or second-generation tyrosine kinase inhibitor (TKI), with pretransplant BCR::ABL1 transcripts ranging between 0.001% and 33%. The protocol included a BCR::ABL1-guided intervention with TKI retreatment in the first year and donor lymphocyte infusions (DLI) in the second-year post-transplant. All patients engrafted. The 1-year transplant-related mortality was 3% (confidence interval [CI]: 0%-6%). After a median follow-up of 6.3 years, 5-year overall survival and event-free survival are 97% (CI: 93%-100%) and 91% (CI: 79%-100%) respectively. The current 5-year leukaemia-free survival with BCR::ABL1 <0.01% is 97% (CI: 88%-100%) and the current TKI- and DLI-free survival is 95% (CI: 85%-100%). The incidence of chronic graft-versus-host disease (GvHD) was 32%, being severe in four patients (13%). At last follow-up, 31 patients are GvHD-free and have stopped immunosuppression. RIC HSCT following pretreatment with TKI is feasible and effective in children and adolescents with CP-CML with an excellent disease-free and TKI-free survival.

Time-dependent activation and repolarization changes following left bundle branch area pacing versus conventional biventricular pacing in patients with dyssynchronous heart failure

Abstract Background Cardiac Resynchronization Therapy (CRT) is the standard treatment for patients with dyssynchronous heart failure. Despite the effectiveness of conventional biventricular pacing (BiVP), 6-16% of patients develop ventricular tachyarrhythmias (VTAs) within a year of implantation. The relationship between BiVP and the development of VTAs is still under debate. During BiVP, the left-sided epicardium-to-endocardium activation creates a non-physiological activation and hence a non-physiological repolarization, which might trigger VTAs. A novel alternative treatment option to BiVP that on the contrary induces a left ventricular endocardium-to-epicardium activation, is left bundle branch area pacing (LBBAP). We hypothesized that LBBAP leads to a more homogenous repolarization than conventional BiVP. Purpose To compare time-dependent activation and repolarization changes in patients with dyssynchronous heart failure receiving LBBAP versus BiVP. Methods Patients eligible for CRT who underwent LBBAP (n=21) or BiVP (n=94) were retrospectively included. Standard 12-lead electrocardiograms obtained prior to implantation [baseline], shortly following implantation (0-2 days, [acute phase]), and after prolonged pacing during follow-up (31-180 days, [chronic phase]) were analyzed. QRS duration and QRS area were calculated through reconstruction of the vectorcardiogram and further analyzed together with corrected QT (QTc) and corrected Tpeak-Tend (Tp-e,c) intervals using a semi-automatic approach in MATLAB. Differences between LBBAP and BiVP patients were determined using the Mann-Whitney U-test. Time-dependent changes within groups were determined using the Wilcoxon signed-rank tests. Significance was defined as a p-value ≤0.05. Results (see figure): Compared to baseline, QRS duration and QRS area decreased significantly during the acute phase (both p &amp;lt; 0.01) and stabilized during chronic pacing for both BiVP and LBBAP patients. Differences in QRS duration or QRS area between LBBAP and BiVP were not significant at any of the time points. In the acute phase, BiVP resulted in a temporary and significant prolongation of both QTc and Tp-e,c compared to baseline (both p &amp;lt; 0.01). However, there was a subsequent shortening observed between the acute and chronic phases for both QTc and Tp-e,c (both p &amp;lt; 0.01). Compared to baseline, LBBAP acutely shortened Tp-e,c (p = 0.02) and tended to shorten QTc. During chronic pacing, LBBAP shortened QTc and Tp-e,c compared to baseline (p = 0.01 and p &amp;lt; 0.01). The decreases in QTc and Tp-e,c were larger in LBBAP than in BiVP patients in the acute and chronic pacing phase (all p &amp;lt;0.01). Conclusion CRT induces activation changes in both BiVP and LBBAP patients to a comparable extent. While BiVP leads to an acute increase in repolarization dispersions, LBBAP reduces markers of repolarization dispersion compared to baseline. The diminished dispersion of repolarization might contribute to an antiarrhythmic effect with LBBAP.

MEDIUM- AND LONG-TERM OUTCOMES OF SURGICAL RECONSTRUCTION IN ACUTE CHARCOT NEUROARTHROPATHY

IntroductionCharcot neuroarthropathy (CN) of foot and ankle presents significant challenges to the orthopaedic foot and ankle surgeon. Current treatment focuses on conservative management during the acute CN phase with offloading followed by deformity correction during the chronic phase. However, the deformity can progress in some feet despite optimal offloading resulting ulceration, infection, and limb loss. Our aim was to assess outcomes of primary surgical management with early reconstruction.MethodsBetween December 2011 and December 2019, 25 patients underwent operative intervention at our specialist diabetic foot unit for CN with progressive deformity and or instability despite advanced offloading. All had peripheral neuropathy, and the majority due to diabetes. Twenty-six feet were operated on in total - 14 during Eichenholtz stage 1 and 12 during stage 2. Fourteen of these were performed as single stage procedures, whereas 12 as two-stage reconstructions. These included isolated hindfoot reconstructions in seven, midfoot in four and combined in 14 feet. Mean age at the time of operation was 54. Preoperative ulceration was evident in 14 patients.ResultsMean follow up was 45 months (Range 12–98). There was 100% limb salvage. One-year ambulation outcomes demonstrate FWB in bespoke footwear for 17 patients and in an ankle foot orthosis (AFO), Charcot restraint orthopaedic walker (CROW) or bivalve cast for seven. All preoperative ulceration had healed. Union was achieved in 18/21 hindfoot reconstructions and 7/18 midfoot reconstructions. There were nine episodes of return to theatre, of which five were within the first 12 months. There was one episode of new ulceration.ConclusionSurgical management of acute CN (Eichenholtz one and two) of the foot provides functional limb salvage. In particular, hindfoot reconstruction shows good rates of bony union. It should be considered in ‘foot at risk’ presentations of acute CN foot.

#2546 CKD-PC risk model for CKD progression: validation and association with outcomes in the FIDELITY population

Abstract Background and Aims The Chronic Kidney Disease Prognosis Consortium (CKD-PC) recently developed risk models to predict the 3-year risk of a ≥40% decrease in estimated glomerular filtration rate (eGFR) or to predict kidney failure in the general population. Unlike the kidney failure risk equation, the CKD-PC model is valid for all levels of eGFR (above and below 60 mL/min/1.73 m2) and includes chronic kidney disease (CKD) progression risk factors besides age, sex, eGFR and albuminuria; namely: systolic blood pressure, antihypertensive medication use, history of heart failure, coronary heart disease, atrial fibrillation, smoking status, body mass index, glycated hemoglobin, insulin use, and oral diabetes medication use [1]. We evaluated whether the CKD-PC model, developed using electronic health record data, is valid for use in a contemporary clinical population using the FIDELITY pooled dataset from international randomized clinical trials of finerenone [2]. Additionally, to inform clinical practice, we evaluated the efficacy of finerenone using categories of 3-year CKD progression risk as predicted by the model. Method FIDELITY was an individual, patient-level, prespecified, pooled efficacy and safety analysis of the phase III FIDELIO-DKD and FIGARO-DKD trials of patients with CKD and type 2 diabetes (T2D), randomized 1:1 to finerenone or placebo. The 3-year CKD progression risk of these patients was predicted and the validity of the CKD-PC model was evaluated using area under the curve (AUC) score (with higher scores indicating better risk prediction), Brier score (lower scores indicating better prediction), and by calibration plots of observed versus predicted risk by deciles of 3-year CKD progression risk. To evaluate the efficacy of finerenone, 3-year risk was categorized in quartiles and the effect of finerenone versus placebo on a kidney composite outcome, defined as kidney failure, a sustained ≥40% decrease in eGFR from baseline over ≥4 weeks, or renal death, was assessed. Results The FIDELITY population comprised 13,026 individuals with a mean eGFR of 58 mL/min/1.73 m2 and urine albumin-to-creatinine ratio of 515 mg/g. The median follow-up was 3 years and there were 1849 total kidney outcome events. Of 12,968 patients analyzed, the median 3-year risk of kidney failure was 15% (Q1–Q3: 9–24%). Overall, the model demonstrated good discrimination to predict a ≥40% kidney composite outcome for patients with CKD and T2D in FIDELITY: AUC score 0.726 (95% confidence interval [CI] 0.712–0.739) and Brier score 0.100 (95% CI 0.097–0.103). The predicted 3-year risk was generally slightly higher than the observed risk (Fig. 1). Finerenone was effective in preventing CKD progression across the risk quartiles (p-interaction = 0.094) with a trend towards greater efficacy in the higher risk quartiles (3-year risk of CKD progression ≥10%) (Fig. 2). All risk groups showed benefit with finerenone compared to placebo regarding eGFR decline in the chronic phase. Conclusion The CKD-PC risk model for CKD progression performed well in a large global clinical trial population of patients with CKD and T2D. Finerenone was effective across the range of baseline risk of CKD progression.

#337 Renal 3D photoacoustic imaging and contrast-enhanced ultrasound to assess oxygenation and perfusion and to predict fibrosis after ischemia-reperfusion

Abstract Background and Aims Renal 3D photo-acoustic imaging (3D-PAI) and contrast-enhanced ultrasound (CEUS) are promising tools in mice models to assess repeatedly and non-invasively renal ischemia-reperfusion (RIR) consequences and damages, or their improvement by nephroprotective strategies like mild therapeutic hypothermia (mTH), at the early phase of reperfusion as well as in the chronic late phase. Method C57Bl6 mice underwent 15 minutes of unilateral renal vascular clamping, with body temperature at 37°C (RIR-37°C, n=7) or mTH at 34°C (RIR-34°C, n=7), or a sham procedure (Sham, n=5). Renal volume and oxygen saturation (sO2-3D; corresponding to the percentage of oxyhemoglobin over the total hemoglobin content) were measured with 3D-PAI (3D reconstruction of the whole kidney through multi-plane acquisition with an automatized mobile support), and renal perfusion parameters (rBV, mTT, rBF) with CEUS (“destruction-replenishment” model of intravenous microbubbles), performed with VEVO3100 echograph (Fujifilm Visualsonic) 1 week before RIR (basal), 20 minutes after reperfusion, and 1 month after. Renal fibrosis was quantified at 1 month with Masson's trichrome coloration on histological samples. Data were compared with Mann-Whitney test or Wilcoxon test (paired data) as appropriate. Correlation was tested by Spearman test. All animal procedures were approved by the Ethics Committee. Results Sham showed no significant changes during follow-up. RIR-37°C led to renal hypotrophy (volume on 3D-PAI) and fibrosis at 1 month, compared to RIR-34°C (median volume 76 IQR [71-119] vs 143 IQR[108-180] mm3; p=0.03), and those parameters were correlated (R=−0.49; p=0.03). In RIR-37°C, sO2-3D tended to lower at 20 minutes compared to basal values (median sO2-3D 37 IQR [37-44] vs 49 IQR [36-57]%; p=0.08), but not in RIR-34°C (p &amp;gt; 0.99), and these early variations of sO2-3D were correlated with fibrosis at 1 month (R=−0.48; p=0.04). Renal perfusion was altered in RIR-37°C at 20 minutes compared to basal values (median rBV 73 IQR [46-105] vs 100 IQR [89-126] a.u.; p=0.047), and remained altered at 1 month (median rBV 71 IQR [57-83] a.u.; p=0.03), but not in RIR-34°C (p=0.47 at both 20 minutes and 1 month). Renal perfusion early alterations at 20 minutes were correlated with late alterations at 1 month (R=0.63; p=0.005), and tended to correlate with fibrosis (R=−0.41; p=0.08). Conclusion Renal 3D-PAI (on the whole 3D-reconstructed kidney) and CEUS can detect early alterations of renal perfusion and oxygen saturation after RIR, and predict chronic disturbances of perfusion and the onset of fibrosis, as well as the protection conferred by mTH. 3D-PAI can also be used to evaluate non-invasively renal volume as a surrogate of renal fibrosis after RIR.

Immunogenicity of 2 therapeutic mosaic HIV-1 vaccine strategies in individuals with HIV-1 on antiretroviral therapy

Mosaic HIV-1 vaccines have been shown to elicit robust humoral and cellular immune responses in people living with HIV-1 (PLWH), that had started antiretroviral therapy (ART) during acute infection. We evaluated the safety and immunogenicity of 2 mosaic vaccine regimens in virologically suppressed individuals that had initiated ART during the chronic phase of infection, exemplifying the majority of PLWH. In this double-blind, placebo-controlled phase 1 trial (IPCAVD013/HTX1002) 25 ART-suppressed PLWH were randomized to receive Ad26.Mos4.HIV/MVA-Mosaic (Ad26/MVA) (n = 10) or Ad26.Mos4.HIV/Ad26.Mos4.HIV plus adjuvanted gp140 protein (Ad26/Ad26+gp140) (n = 9) or placebo (n = 6). Primary endpoints included safety and tolerability and secondary endpoints included HIV-specific binding and neutralizing antibody titers and HIV-specific T cell responses. Both vaccine regimens were well tolerated with pain/tenderness at the injection site and fatigue, myalgia/chills and headache as the most commonly reported solicited local and grade 3 systemic adverse events, respectively. In the Ad26/Ad26+gp140 group, Env-specific IFN-γ T cell responses showed a median 12-fold increase while responses to Gag and Pol increased 1.8 and 2.4-fold, respectively. The breadth of T cell responses to individual peptide subpools increased from 11.0 pre-vaccination to 26.0 in the Ad26/Ad26+gp140 group and from 10.0 to 14.5 in the Ad26/MVA group. Ad26/Ad26+gp140 vaccination increased binding antibody titers against vaccine-matched clade C Env 5.5-fold as well as augmented neutralizing antibody titers against Clade C pseudovirus by 7.2-fold. Both vaccine regimens were immunogenic, while the addition of the protein boost resulted in additional T cell and augmented binding and neutralizing antibody titers. These data suggest that the Ad26/Ad26+gp140 regimen should be tested further.

Evaluation of acute thrombus regression effect of edoxaban for deep vein thrombosis in patients with cancer: a single-center prospective observational study.

Although there are reports on the recurrence prevention in the chronic phase using direct oral anticoagulants (DOACs) for deep vein thrombosis (DVT) in patients with cancer, acute thrombus regression effect using DOACs has not been assessed. This study aimed to assess the thrombus regression effect of initial treatment using edoxaban for acute lower-extremity DVT in patients with active cancer. In this observational study, among the inpatients with cancer and lower-extremity DVT who underwent initial treatment with edoxaban at our hospital from November 2019 to December 2021, 34 consenting patients were recruited in this study. The quantitative ultrasound thrombus (QUT) score of thrombus volume was calculated at baseline (before administration) and 7-14 days after the start of edoxaban administration, using lower-extremity venous ultrasound to evaluate changes in thrombus volume. The primary and secondary endpoints were the acute thrombus regression effect of edoxaban and the impact of patients' clinical frailty on the thrombus regression effect, respectively. Anticoagulant therapy with edoxaban significantly reduced QUT score (p < 0.001). In addition, regardless of the Clinical Frailty Scale scores, QUT score decreased significantly. Initial treatment with edoxaban was effective for lower-extremity DVT in patients with cancer. In addition, the effect was the same independent of the degree of frailty.

Longitudinal neuropsychological performance of post-stroke adults with and without rehabilitation

This study compared the neuropsychological performance of two post-stroke groups, one undergoing rehabilitation and the other not receiving any intervention, on the acute and chronic stroke phases, and explored sociodemographic and neurological variables associated with changes in performance over time. Sixty-three adults underwent neuropsychological assessment with the Cognitive Screening Instrument (TRIACOG) less than thirty days after having a stroke and were reassessed three to six months after stroke. Thirty-eight participants did not undertake rehabilitation and twenty-five did physiotherapy and/or speech therapy between the two time points. The frequency of cognitive deficits (between groups) and the range of cognitive assessment scores over time (between and within groups) were analyzed. There was a significant decrease in the frequency of neuropsychological deficits and improvement on neuropsychological assessment scores over time only in the group undergoing rehabilitation. Severity of the neurological condition, years of education and being in rehabilitation explained the longitudinal changes in several cognitive domains measured by TRIACOG. Engaging in rehabilitation within three to six months post-stroke is crucial for enhancing the recovery of neuropsychological deficits. Cognitive screening instruments like TRIACOG can be used by health professionals to identify stroke-related neuropsychological changes and plan interventions.

Correlation between quantitative HBsAg and quantitative HBV DNA in chronic hepatitis B patients: a systematic review and meta-analysis

BackgroundHBV DNA assays have several limitations including being expensive and not widely available. Detection of HBsAg in serum has been the hallmark of HBV infection. However, previous studies regarding the association between HBsAg and HBV DNA revealed contradictory results. This study aims to reassess the correlation between HBsAg and HBV DNA in chronic hepatitis B patients.MethodsObservational studies with näive chronic hepatitis B patients were included, while studies with other coinfections were excluded. The studies were identified by searching through Google Scholar, PubMed, ScienceDirect, and Springer Link for English and Bahasa articles from 2011 to 2021. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) was followed. Study quality was assessed using the Joanna Briggs Institute (JBI) critical appraisal.ResultsA total of 17 studies with 4134 participants met the criteria. The overall analysis revealed a moderate correlation between quantitative HBsAg and quantitative HBV DNA in the total sample of chronic hepatitis B patients (r = 0.57, 95% CI 0.40–0.75, P < 0.00001). In HBeAg + group, a moderate correlation was indicated while in HBeAg − revealed a weak association (r = 0.55, 95% CI 0.39–0.70, P < 0.00001 vs r = 0.29, 95% CI 0.20–0.38, P < 0.00001). The strongest correlation was discovered in HBeAg + chronic HBV infection phase (r = 0.59, 95% CI 0.35–0.82, P < 0.00001).ConclusionSerum HBsAg titer supports as a predictor of serum HBV DNA levels in clinical practice with moderate strength of correlation.Trial registrationThis review had been registered in PROSPERO (ID: CRD42023421246).

Patient knowledge about risk factors, achievement of target values and guideline adherent secondary prevention therapies 12 months after acute myocardial infarction.

The prospective GULLIVE-R study aimed to evaluate adherence to guideline recommended secondary prevention, physicians' and patients' estimation of cardiac risk, and patients' knowledge about target values of risk factors after acute myocardial infarction (AMI). We performed a prospective study enrolling patients 9-12 months after AMI. Guideline recommended secondary prevention therapies and physicians as well as patients' estimation about their risk, and patients' knowledge about target values were prospectively collected. Between 07/2019 and 06/2021 a total of 2509 outpatients were enrolled in 150 German centers 10 months after AMI. The mean age was 66 years, 26.4% were women, 45.3% had STEMI, 54.7% had NSTEMI, 93.6% had revascularization (84.0% PCI, 7.4% CABG, 1.8% both). Guideline recommended secondary drug therapies were prescribed in over 80% of patients, while only about 50% received all five recommended drugs (aspirin, P2Y12 inhibitors, statins, beta-blockers, RAAS inhibitors) and regular exercise was performed by only one third. About 90% of patients felt well informed about secondary prevention, but the correct target value for blood pressure was known in only 37.9% and for LDL-C in only 8.2%. Both, physicians and patients underestimated the objective risk for future AMIs as determined by the TIMI risk score for secondary prevention. There is still room for improvement in patient education and implementation of guideline recommended non-pharmacological and pharmacological secondary prevention therapies in patients in the chronic phase after AMI.

A Novel Transmembrane CXCR4 Variant That Expands the WHIM Genotype-Phenotype Paradigm

Warts, Hypogammglobulinemia, Infections, Myelokathexis (WHIM) syndrome is a rare immunodeficiency disease that results from impaired leukocyte trafficking (myelokathexis) predominately caused by gain-of-function variants in C-X-C chemokine receptor type 4 (CXCR4). Clinical manifestations of WHIM syndrome can differ in familial forms or in people harboring identical CXCR4 variants. All known pathogenic CXCR4 variants associated with WHIM syndrome (CXCR4WHIM) to date are localized in the intracellular C-terminus of CXCR4. We identified 4 unrelated patients with variable WHIM-like clinical presentations harboring a novel heterozygous CXCR4 variant (c.250G>C; p.D84H) localized at a highly conserved position in the transmembrane domain of the receptor outside the C-terminus. Functional characterization of the CXCR4D84Hvariant (CXCR4D84H) using patient-derived peripheral blood mononuclear cells and in vitro cellular assaysshow decreased CXCR4 internalization and increased chemotaxis in response to CXCL12, similar to known CXCR4WHIM, but also revealed unique features of CXCR4D84H signaling to cAMP, Ca2+ mobilization and AKT/ERK pathways. These findings are consistent with molecular dynamics simulations that show disruption of the Na+ binding pocket by D84H, resulting in collapse of the hydrophobic gate above and destabilization of the inactive state of CXCR4. Mavorixafor, a CXCR4 antagonist being evaluated in clinical trials for chronic neutropenia and WHIM syndrome, normalized CXCL12-mediated chemotaxis of CXCR4D84H patient lymphocytes ex vivo and improved WBC and subset counts in 1 patient with CXCR4D84H enrolled in the chronic neutropenia phase 1b clinical trial (NCT04154488). The present study expands the current understanding of CXCR4 function and genotype-phenotype correlations in WHIM syndrome and in people with WHIM-like phenotypes.

Success rates of intensive aphasia therapy: real-world data from 448 patients between 2003 and 2020.

Aphasia is a devastating consequence after stroke, affecting millions of patients each year. Studies have shown that intensive speech and language therapy (SLT) is effective in the chronic phase of aphasia. Leveraging a large single-center cohort of persons with aphasia (PWA) including patients also in the subacute phase, we assessed treatment effects of intensive aphasia therapy in a real-world setting. Data were collected at the Aachen aphasia ward in Germany between 2003 and 2020. Immediate treatment responses across different language domains were assessed with the Aachen Aphasia Test (AAT) using single-case psychometrics, conducted before and after 6-7 weeks of intensive SLT (10 h per week, median (IQR) dosage = 68 (61-76)). We adjusted for spontaneous recovery in subacute patients. Differential treatment effects between subgroups of chronicity and predictors of therapy response were investigated. A total of 448 PWA were included (29% female, median (IQR) age = 54 (46-62) years, median (IQR) time post-onset = 11 (6-20) months) with 12% in the early subacute, 15% in the late subacute and 74% in the chronic phase of aphasia. The immediate responder rate was 59%. Significant improvements in all AAT subtests und subscales were observed hinting at broad effectiveness across language domains. The degree of therapy-induced improvement did not differ between the chronicity groups. Time post-onset, dosage of therapy and aphasia severity at the beginning of treatment were predictors of immediate treatment response. Intensive therapy protocols for aphasia after stroke are yielding substantial responder rates in a routine clinical setting including a wide range of patients.

CARDIAC REHABILITATION AND PSYCHOLOGICAL TREATMENT: CONTRASTS IN ANXIETY, DEPRESSION AND ILLNESS PERCEPTION LEVELS

Abstract Background Investigating the relationship between psychological factors and cardiovascular diseases (CVD) has long been a focal point of previous research. Researchers have primarily focused on identifying possible predictive factors for CVD’s development and examining patients’ responses during acute or chronic phases, but less is known about the role of cardiac rehabilitation and the types of psychological treatments on patients’ psychological status. Aims The aim of this study is to compare anxiety, depression, and illness perception levels of patients affected by different cardiovascular diseases at the beginning (t0), at the end (t1), and three months after a cardiac rehabilitation program (t2) in which patients were involved in three different types of psychological treatments: psychoeducational intervention group, progressive muscle relaxation training integrated with Jacobson‘s technique and imaginative stabilization techniques, individual counseling. Methods In this study were involved patients with recent episodes of Acute Coronary Syndrome (ACS), heart failure (HF) or cardiac surgery undergoing cardiac rehabilitation between January 2023 and August 2023 at ASST Bergamo Est. To assess anxiety, depression and illness perception levels of participants we used self–report questionnaires that included the Hospital Anxiety and Depression Scale (HADS) and the Brief Illness Perception Questionnaire (Brief–IPQ). Patients could be assigned to different psychological treatments based on their clinical condition. Results The study involved 181 participants, namely N=36 ACS cases (19.9%), N=25 CHF (13.8%), and N=120 cardiac surgery (66.3%). As shown in Table 1, males were 71.3% (N=129) and the average age was 65.96 years old (SD=11.904). One hundred–sixty einght patients participated in psychoeducational intervention group, 120 in relaxation training, and 35 in individual counseling. Statistically significant differences in anxiety, depression, and illness perception levels were observed at the program‘s initiation (t0) and upon completion (t1 and t2) in relation to the psychological treatments: individual counseling had a better impact on levels of anxiety and depression and on the development of a more adequate perception of illness. Conclusions The type of psychological treatment during cardiac rehabilitation appears to give different results in terms of psychological status, self–care and disease management of patients.

Treatment outcome of the tyrosine kinase inhibitor (bosutinib) in previously treated chronic myeloid leukemia patients (sample of Iraqi patients)

Abstract BACKGROUND: Chronic myeloid leukemia (CML) is a type of myeloproliferative neoplasm characterized by the excessive accumulation of malignant myeloid cells in the bone marrow and peripheral blood. This condition is primarily triggered by a specific chromosomal translocation known as t(9;22) (q34.13;q11.23), which leads to the formation of the BCR-ABL fusion gene. The treatment landscape for CML has undergone significant changes with the approval of tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL1 kinase activity. One such inhibitor is bosutinib, which has been available for several years to treat patients with chronic, accelerated, and blast-phase CML who have shown resistance or intolerance to previous therapies. OBJECTIVES: The aim of this study was to assess efficacy and safety of Bosutinib as a 2nd line therapy in CML patients, in addition to effect of adherence to treatment on patients response. PATIENTS AND METHODS: Eighty-five patients with CML were enrolled in a prospective cohort study from October 2021 to October 2022 at Hematology Center in Medical City Complex – Baghdad. All patients failed to at least one TKI, and all of them started escalated dose of bosutinib. The patients were followed-up by assessing molecular and cytogenetic response at 3 and 6 months and monitored carefully for adverse events (AEs) which were graded by common terminology IX criteria for AEs version 5. Adherence to bosutinib was also monitored by a specific adherence scale to optimize the response rate to treatment. RESULTS: The mean age of patients was 47.3 ± 14.9 (range: 18–77), with male:female ratio 1.4:1. Status of CML patients showed that 89.4% were in the chronic phase, 5.8% in accelerated phase, and 4.7% in blast phase. Regarding the number of previous TKIs before bosutinib, 72.9% of patients failed to prior one TKI (imatinib). At 6 months (72.3%), patients achieve optimal response according to European Leukemia Net criteria 2013. Gastrointestinal symptoms and dermatological manifestations were the most common nonhematological AEs of bosutinib. According to 9-item Morisky Medication Adherence Scale, 42% of patients were adherent to medication which showed a significant association with a higher number of optimal response (P = 0.0001). CONCLUSION: Bosutinib is effective with a high and promising response as a subsequent line treatment in CML patients, and it is generally safe and associated with mild-to-moderate tolerable and manageable AEs. Adherence to the drug plays a significant role in optimal response to bosutinib.

Time- and Region-Specific Selection of Reference Genes in the Rat Brain in the Lithium-Pilocarpine Model of Acquired Temporal Lobe Epilepsy.

Reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR) is a commonly used tool for gene expression analysis. The selection of stably expressed reference genes is required for accurate normalization. The aim of this study was to identify the optimal reference genes for RT-qPCR normalization in various brain regions of rats at different stages of the lithium-pilocarpine model of acquired epilepsy. We tested the expression stability of nine housekeeping genes commonly used as reference genes in brain research: Actb, Gapdh, B2m, Rpl13a, Sdha, Ppia, Hprt1, Pgk1, and Ywhaz. Based on four standard algorithms (geNorm, NormFinder, BestKeeper, and comparative delta-Ct), we found that after pilocarpine-induced status epilepticus, the stability of the tested reference genes varied significantly between brain regions and depended on time after epileptogenesis induction (3 and 7 days in the latent phase, and 2 months in the chronic phase of the model). Pgk1 and Ywhaz were the most stable, while Actb, Sdha, and B2m demonstrated the lowest stability in the analyzed brain areas. We revealed time- and region-specific changes in the mRNA expression of the housekeeping genes B2m, Actb, Sdha, Rpl13a, Gapdh, Hprt1, and Sdha. These changes were more pronounced in the hippocampal region during the latent phase of the model and are thought to be related to epileptogenesis. Thus, RT-qPCR analysis of mRNA expression in acquired epilepsy models requires careful selection of reference genes depending on the brain region and time of analysis. For the time course study of epileptogenesis in the rat lithium-pilocarpine model, we recommend the use of the Pgk1 and Ywhaz genes.

Outcome of 3q26.2/MECOM rearrangements in chronic myeloid leukemia.

To evaluate the outcomes of patients with 3q26.2/MECOM-rearranged chronic myeloid leukemia (CML). We reviewed consecutive adult patients with 3q26.2/MECOM-rearranged CML between January 1, 1998 and February 16, 2023. Rearrangements of 3q26.2/MECOM were confirmed by conventional cytogenetics, and fluorescence in situ hybridization starting in 2015. We identified 55 patients with MECOM-rearranged CML, including 23 in chronic phase (CP) or accelerated phase (AP) and 32 in blast phase (BP). Nine patients (16%) achieved a major cytogenetic response (MCyR) or deeper. At a median follow-up of 89months, median survival was 14months. The 5-year survival rate was 19% overall, 23% in CML-CP/AP, and 15% in CML-BP. In the 6-month landmark analysis, the 5-year survival rate was 41% for allogeneic stem cell transplantation (allo-SCT) recipients versus 17% for non-recipients (P = 0.050). Multivariate analysis showed that the percentage of marrow blasts and achievement of MCyR or deeper could predict survival. Outcomes of 3q26.2/MECOM-rearranged CML are poor despite the availability of multiple BCR::ABL1 tyrosine kinase inhibitors (TKIs). Third-generation TKIs in combination with novel agents and possible allo-SCT could be considered given the poor outcomes and resistance to second-generation TKIs.

Clinical profile and management of a Spanish single-center retrospective cohort of patients with post-chikungunya associated complications

BackgroundThis study aims to describe post-chikungunya complications chronically developed cases in returning travelers from some epidemic/endemic regions, and the variables that are associated with the progression of acute or subacute cases to the chronic phase. MethodsThis single-center retrospective cohort study included chikungunya fever cases treated at La Paz-Carlos III University Hospital in Madrid, Spain, April 2014 to September 2016, when the chikungunya outbreak in Latin America started through the time of its greatest impact. ResultsThe analysis included 119 cases. Of these, 67.2 % were male, with a median age of 41.0 years [IQR 16.0 to 76.0] years. Only 25.6 % of the patients attended a pre-travel advice consultation. Most patients reported arthralgias, which significantly impacted their daily quality of life (86 %). The mean duration of joint symptoms was 129.4 days, with a median of 90 days [IQR 0 to 715]. Factors found to be associated with chronic arthralgia include female sex, country of infection, age at diagnosis, previous diseases, symptoms during the acute phase, pain in previously injured tendons/joints, acute phase severity, and various laboratory markers such as hemoglobin, hematocrit, total serum bilirubin, and creatinine. Progression to chronic arthralgia significantly increased the need for changes in daily activity. Furthermore, 42.6 % of patients with chronic arthralgia reported recurrence of symptoms once they felt they had disappeared. Targeted treatment regimens led to significant improvements in these patients. ConclusionsThe results of this study underscore the need for: (1) comprehensive pre-travel advice; (2) effective management of patients in specialized units, alongside early diagnosis and treatment, to prevent trivialization of these viral infections; and (3) the development of interdisciplinary recommendations to assist physicians in treating patients and enhancing outcomes.