Incomplete Recovery Research Articles

Azacitidine combined with venetoclax alleviates AML-MR with TP53 mutation in SDS: a case report and literature review.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic disease, which is prone to transform into myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). TP53 mutation is a driving factor involved in the transformation of SDS into MDS/AML, and in the evolution of MDS to AML. Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the only curable approach, however, challenge remains regarding the balance between efficacy and the high risk from treatment-related toxicity and mortality to achieve temporary disease control before transplantation to gain time and opportunities for transplantation. At present, pre-transplant bridging therapy has emerged as one of the important options with improved efficacy, reduced tumor burden, and less treatment-related toxicity. Here we reported azacitidine combined with venetoclax was used as pre-transplant bridging regimen in a TP53-mutant AML-MR case developed from SDS. He achieved complete remission with incomplete recovery and proceeded to Allo-HSCT. We hope to provide some evidence and insight for in-depth research and clinical treatment by presenting this case.

Prognosis in meningoencephalitis of unknown origin in dogs: Risk factors associated with survival, clinical relapse, and long-term disability.

Meningoencephalitis of unknown origin (MUO) comprises a group of noninfectious inflammatory diseases affecting the central nervous system of dogs. Previous studies have reported individual risk factors for survival but prognostication for MUO remains challenging. Identify clinical prognostic variables in dogs with MUO. A retrospective study of 447 dogs presented to 2 UK referral hospitals and diagnosed with MUO. Medical records of dogs diagnosed with MUO were retrospectively reviewed. Multivariable logistic regression was used for the identification of risk factors for survival and Cox proportional hazards analysis for the identification of risk factors for clinical relapse. Eighty-two percent (366/447) of dogs with presumptive MUO survived to discharge and 63.5% (284/447) were alive at 6 months; 36% of the latter (103/284) had persistent neurological deficits. Breed (pugs; P = .03), epileptic seizures (P < .001), paresis (P < .001), and higher neurodisability scale (NDS) score (P < .001) at presentation were negatively associated with survival to 6 months. Dogs with persistent deficits had higher NDS scores on presentation (P = .001). Median follow-up time was 11 months (interquartile range [IQR], 1-24) and 50.6% (160/316) relapsed during treatment (median time to relapse, 7 months; IQR, 2-15). Incomplete resolution of the clinical signs during the 6 months after diagnosis (P < .001), higher NDS score (P < .001), and longer duration of the clinical signs (P < .001) were associated with relapse. Knowledge of risk factors associated with survival, incomplete recovery and clinical relapse in MUO can help guide monitoring and treatment and improve owner communications regarding prognosis for this debilitating disease.

Activity of venetoclax in patients with relapsed or refractory chronic lymphocytic leukaemia: analysis of the VENICE-1 multicentre, open-label, single-arm, phase 3b trial

Most patients with chronic lymphocytic leukaemia progress after treatment or retreatment with targeted therapy or chemoimmunotherapy and have limited subsequent treatment options. Response levels to the single-agent venetoclax in the relapsed setting is unknown. We aimed to assess venetoclax activity in patients with or without previous B-cell receptor-associated kinase inhibitor (BCRi) treatment. This multicentre, open-label, single-arm, phase 3b trial (VENICE-1) assessed activity and safety of venetoclax monotherapy in adults with relapsed or refractory chronic lymphocytic leukaemia, stratified by previous exposure to a BCRi. Eligible participants were aged 18 years or older with previously treated relapsed or refractory chronic lymphocytic leukaemia. Presence of del(17p) or TP53 aberrations and previous BCRi treatment were permitted. Patients received 5-week ramp-up to 400 mg of oral venetoclax once daily and were treated for up to 108 weeks, with 2 years follow-up after discontinuation, or optional extended access. The primary activity endpoint was complete remission rate (complete remission or complete remission with incomplete marrow recovery) in BCRi-naive patients. Analyses used the intent-to-treat (ie, all enrolled patients, which coincided with those who received at least one dose of venetoclax). This study was registered with ClinicalTrials.gov, NCT02756611, and is complete. Between June 22, 2016, and March 11, 2022, we enrolled 258 patients with relapsed or refractory chronic lymphocytic leukaemia (180 [70%] were male; 252 [98%] were White; 191 were BCRi-naive and 67 were BCRi-pretreated). Median follow-up in the overall cohort was 49·5 months (IQR 47·2-54·1), 49·2 months (47·2-53·2) in the BCRi-naive group, and 49·7 months (47·4-54·3) in the BCRi-pretreated group. Of 191 BCRi-naive patients, 66 (35%; 95% CI 27·8-41·8) had complete remission or complete remission with incomplete marrow recovery. 18 (27%; 95% CI 16·8-39·1) of 67 patients in the BCRi-pretreated group had complete remission or complete remission with incomplete marrow recovery. Grade 3 or worse treatment-emergent adverse events were reported in 203 (79%) and serious adverse events were reported in 136 (53%) of 258 patients in the overall cohort. The most common treatment-emergent adverse event was neutropenia (96 [37%]) and the most common and serious adverse event was pneumonia (21 [8%]). There were 13 (5%) deaths reported due to adverse events; one of these deaths (autoimmune haemolytic anaemia) was possibly related to venetoclax. No new safety signals were identified. These data demonstrate deep and durable responses with venetoclax monotherapy in patients with relapsed or refractory chronic lymphocytic leukaemia, including BCRi-pretreated patients, suggesting that venetoclax monotherapy is an effective strategy for treating BCRi-naive and BCRi-pretreated patients. AbbVie.

Lessons from studies of medication reduction in psychosis: giving participants accurate information about risk in psychiatric research trials.

All research needs ethical regulation, which is institutionalized in research ethics committees. The patient information sheet, approved by a research ethics committee, sets out what patients need to know to make an informed choice about research participation. However, guidance from research ethics committees is much less explicit about risk communication. In this commentary, the balance of risk in the patient information sheets from protocols of 2 randomized controlled trials (RCTs) of medication reduction in psychosis was compared with numbers needed to treat and harm from the literature. The patient information sheet omitted risk of excess death and incomplete recovery following relapse, and overestimated the anticipated benefits. All of these risks were demonstrated in the published results of 1 of the 2 RCTs. Quantifying and tabulating risk might improve patient information sheets.

Venetoclax plus cytarabine and azacitidine in relapsed/refractory AML: An open-label, single-arm, phase 2 study

BackgroundThe outcome of relapsed/refractory (R/R) acute myeloid leukemia (AML) remains extremely poor. Venetoclax (VEN)-based regimens have shown promise in treating R/R AML. ObjectiveThis phase 2 study aimed to systematically evaluate the efficacy and safety of the VAA regimen (VEN plus Cytarabine and Azacitidine) in R/R AML patients. MethodsThirty R/R AML patients were enrolled. The study adopted a stepwise ramp-up of VEN dosing, starting with 100 mg on day 1, escalating to 200 mg on day 2, and reaching 400 mg from day 3 to day 9. Cytarabine (10 mg/m2, q12h) was administered intravenously twice daily from days 1 to 10, and Azacitidine (75 mg/m2) was administered via subcutaneous injection once daily from days 1–7. The primary efficacy endpoint was the composite complete remission rate (CRc), including complete response (CR) and complete response with incomplete blood count recovery (CRi). Secondary endpoints included overall survival (OS), duration of response (DOR), and safety analysis. ResultsThe CRc rate was 63.3% (19/30), with CR in 36.7% of patients and CRi in 26.7%. Notably, 14 (73.7%) of 19 patients achieving CRc showed undetectable measurable residual disease by flow cytometry. With a median follow-up of 10.7 months, the median OS had not been reached, and the median DOR was 18.3 months. The most common grade 3–4 adverse events (AEs) were neutropenia (100%), anemia (96.7%), thrombocytopenia (90.0%), and leukopenia (90.0%). Infections, with pneumonia being the most prevalent (43.3%), were observed, including one fatal case of Pseudomonas aeruginosa septicemia. There were no treatment-related deaths. ConclusionThe VAA regimen is an effective and safe option for patients with R/R AML, demonstrating a high CRc rate and manageable safety profile.

Physical functional recovery in the early period after hospitalization for COVID-19: impact of hypertension and outcome prediction model

The aim – to study the influence of hypertension (HT) on the dynamics of natural recovery of physical functional status in the early period after hospitalization for COVID-19 and to develop a model for predicting recovery results at 1 month after discharge.Materials and methods. 221 hospitalized patients with COVID-19 (age 53.4±13.6 years, 53 % women) were included in the study, 176 of whom underwent the 6-minute walk test (6MWT) using an extended protocol within 1-2 days before discharge. A repeat visit to assess the dynamics of natural recovery was performed at 1 month after discharge.Results and discussion. Pre-discharge 6-minute walk distance was 378±57 m in patients with HT and 418±75 m without it, p=0.001, during the second visit – 440±52 versus 478±68, p=0.002; the achieved percentage of the individually predicted distance was 67.4±10.5 vs. 69.5±13.6 % and 81.6±9.9 vs. 81.9±15.7 %, respectively, p&gt;0.05 for both visits. The increase in heart rate during the test at visit 1 was 18.5±8.3 versus 30.1±19.3 bpm, p&lt;0.001, the percentage of chronotropic reserve utilizatoin was 21.3±9.6 % versus 29.2±11.4 %, p&lt;0.001. During the second visit, residual manifestations of this trend were observed, with an increase in HR by 24.0±9.5 vs. 30.8±12.1, p=0.003 and the use of chronotropic reserve of 28.1±10.1 % vs. 33.4±12.4 %, respectively, p=0.029. The developed multivariate linear regression model explained 59 % of the variability in the achieved percentage of the individually predicted 6-minute walk distance at 1 month after discharge. The use of machine learning allowed to create an artificial neural network based regression model that used age, height, use of remdesivir in treatment, and SBP and DBP values at the time of discharge as predictors, and explained 90 % of observed variability.Conclusions. Hospitalized patients with COVID-19 were characterized by a decrease in the general physical functional status as assessed by 6MWT at the time of discharge and incomplete recovery after 1 month. Presence of hypertension was associated with more pronounced disturbances of the autonomic regulation of heart rate, but did not affect the reached percentage of the distance walked. The proposed artificial neural network based regression model allows for a high accuracy prediction of the 6MWT results at 1 month after discharge, which can be used in the selection of candidates for cardiopulmonary rehabilitation programs.

Efficacy and safety of mitoxantrone, etoposide, and cytarabine for treatment of relapsed or refractory acute myeloid leukemia

Background/rationaleMost patients with acute myeloid leukemia (AML) develop relapsed or refractory (R/R) disease after receiving initial induction chemotherapy. Salvage chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative therapy for R/R AML. Mitoxantrone, etoposide, and cytarabine (MEC) is the current standard of care salvage regimen for R/R AML at Cleveland Clinic. The primary objective was to determine the overall remission rate (ORR: defined as patients achieving complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)) in R/R AML patients who received MEC. MethodsAdult patients with R/R AML treated with MEC between July 1, 2014 and September 30, 2022 were included. ORR and its association with baseline characteristics were determined. Secondary outcomes included overall survival (OS), event-free survival (EFS), relapse-free survival (RFS), and safety. ResultsSixty patients were evaluated. The ORR was 51.7% (33.3% CR and 18.3% CRi). The median time from receipt of MEC to CR/CRi was 7.7 weeks. Patients with bone marrow blasts ≤20% and peripheral blood blasts ≤30% at MEC initiation were more than twice as likely to achieve CR/CRi compared to those with a higher blast burden. The median OS was 6.3 months. Twenty-four (40.0%) patients proceeded to alloHSCT. Twenty-one (35.0%) patients were transferred to the intensive care unit (ICU) during their admission. ConclusionsMEC is an effective salvage regimen for patients with R/R AML, especially among those with low disease burden at initiation. Febrile neutropenia, infections, and severe oral mucositis were common with MEC administration.

Differentiated mesenchymal stem cells-derived exosomes immobilized in decellularized sciatic nerve hydrogels for peripheral nerve repair

Peripheral nerve injury (PNI) and the limitations of current treatments often result in incomplete sensory and motor function recovery, which significantly impact the patient's quality of life. While exosomes (Exo) derived from stem cells and Schwann cells have shown promise on promoting PNI repair following systemic administration or intraneural injection, achieving effective local and sustained Exo delivery holds promise to treat local PNI and remains challenging. In this study, we developed Exo-loaded decellularized porcine nerve hydrogels (DNH) for PNI repair. We successfully isolated Exo from differentiated human adipose-derived mesenchymal stem cells (hADMSC) with a Schwann cell-like phenotype (denoted as dExo). These dExo were further combined with polyethylenimine (PEI), and DNH to create polyplex hydrogels (dExo-loaded pDNH). At a PEI content of 0.1%, pDNH showed cytocompatibility for hADMSCs and supported neurite outgrowth of dorsal root ganglions. The sustained release of dExos from dExo-loaded pDNH persisted for at least 21 days both in vitro and in vivo. When applied around injured nerves in a mouse sciatic nerve crush injury model, the dExo-loaded pDNH group significantly improved sensory and motor function recovery and enhanced remyelination compared to dExo and pDNH only groups, highlighting the synergistic regenerative effects. Interestingly, we observed a negative correlation between the number of colony-stimulating factor-1 receptor (CSF-1R) positive cells and the extent of PNI regeneration at the 21-day post-surgery stage. Subsequent in vitro experiments demonstrated the potential involvement of the CSF-1/CSF-1R axis in Schwann cells and macrophage interaction, with dExo effectively downregulating CSF-1/CSF-1R signaling.

Clinical outcomes of patients with acute myeloid leukemia and cardiovascular disease

Incidence of both acute myeloid leukemia (AML) and cardiovascular disease (CVD) increases with age. We evaluated whether pre-existing CVD impacts clinical outcomes in AML. We retrospectively evaluated 291 consecutive adult AML patients treated at our institution, 2014–2020. Pretreatment comorbidities were identified by chart review. Outcomes included complete remission (CR) and CR with incomplete count recovery (CRi) rates, disease-free survival (DFS), overall survival (OS) and incidence of cardiovascular adverse events. CVD was present in 34% of patients at AML diagnosis. CVD patients had worse performance status (p=0.03) and more commonly had secondary AML (p=0.03) and received hypomethylating (HMA) agent-based therapy (72% vs 38%, p< 0.001). CVD (0.45 vs 0.71, p<0.001) and diabetes mellitus (HR= 0.24, 95% CI: 0.08 – 0.8, p= 0.01) were associated with lower probability of achieving CR/CRi. Accounting for age, performance status (PS), complex karyotype, secondary disease and treatment, CVD patients had shorter OS (HR=1.5, 95% CI: 1.1–2.2, p=0.002), with 1- and 3-year OS 44% vs 67% and 25% vs 40%, respectively, but there was no difference in cumulative incidence of relapse between patients with vs without CVD. Thus, CVD is an independent risk factor for lower response rate and shorter survival in AML patients.

Long-Term Outcomes of Immunosuppressive Therapy for Aplastic Anemia: A Single-Center Experience

Background. Bone marrow transplantation-ineligible aplastic anemia (AA) is most effectively treated with combined immunosuppressive therapy (IST). It yields remissions in most patients. However, it has such disadvantages as frequent relapses, incomplete hematologic recovery, and clonal evolution risk. Besides, АА is not always treated according to standard regimens. For different reasons, some AA patients receive delayed therapy or IST mono-treatment predominantly with cyclosporine A (CsA).&#x0D; Aim. To assess long-term IST outcomes in AA patients followed-up at the Russian Research Institute of Hematology and Transfusiology for 5 years after therapy onset.&#x0D; Materials &amp; Methods. The study enrolled 30 AA patients who received IST for more than 5 years (continuous follow-up of 5.5–33 years) with monitoring of the main hemogram parameters and PNH clone size. Patients were aged 19–73 years (median 29 years). There were 8 women and 12 men. Based on international criteria, severe AA (SAA) was initially diagnosed in 18 patients, and non-severe АА (NAA) was diagnosed in 12 patients. Combined IST was administered to 22 patients (18 SAA patients and 4 NAA patients), the remaining 8 patients received ATG (n = 1) and CsA (n = 7).&#x0D; Results. A response to IST was achieved in 28 (93.3 %) out of 30 patients, 16 (53.3 %) of them showed complete remission. This paper documents the characteristics of hematologic recovery depending on the compliance with standard therapy regimens, as well as on the disease variant, development of late complications and clonal evolution, characteristics of pregnancy and childbirth in 4 female patients in remission. PNH clone increased in more than a half (10 out of 16) patients whose clone was initially &gt; 2.6 %. Long-term clonal evolution to myeloid neoplasia (13 years after IST onset) was registered in 2 (6.7 %) patients with complete AA remission. Aseptic (avascular) osteonecrosis as complication was reported in 6 (20 %) followed-up patients.&#x0D; Conclusion. The results of the study highlight the importance of and the need for early start and adherence to standard combined IST regimens aimed at optimum therapeutic effect in both SAA and NAA patients, as well as for long-term follow-up of patients after completing IST.

Radiolabel Uncovers Nonintuitive Metabolites of BIIB104: Novel Release of [14C]Cyanide from 2-Cyanothiophene and Subsequent Formation of [14C]Thiocyanate.

BIIB104 (formerly PF-04958242), N-((3S,4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide, is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator investigated for the treatment of cognitive impairment associated with schizophrenia. Preliminary in vitro metabolism studies with non-radiolabeled BIIB104 in rat, dog, and human liver microsomes (RLM, DLM, and HLM) showed O-dealkylation in all three species, tetrahydrofuran hydroxylation dominating in DLM and HLM, and thiophene hydroxylation prevalent in RLM. However, a subsequent rat mass balance study with [nitrile-14C]BIIB104 showed incomplete recovery of administered radioactivity (∼80%) from urine and feces over 7 days following an oral dose, and an exceptionally long plasma total radioactivity half-life. Radiochromatographic metabolite profiling and identification, including chemical derivation, revealed that [14C]cyanide was a major metabolite of [nitrile-14C]BIIB104 in RLM, but a minor and trace metabolite in DLM and HLM, respectively. Correspondingly in bile duct-cannulated rats, [14C]thiocyanate accounted for ∼53% of total radioactivity excreted over 48 hours postdose and it, as an endogenous substance, explained the exceptionally long plasma radioactivity half-life. The release of [14C]cyanide from the 2-cyanothiophene moiety is postulated to follow an epoxidation-initiated thiophene-opening based on the detection of non-radiolabeled counterpart metabolites in RLM. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate. Additionally, the potential cyanide metabolite of nitrile-containing drug molecules may be detected in liver microsomes with liquid chromatography-mass spectrometry following a chemical derivatization. SIGNIFICANCE STATEMENT: Using [nitrile-14C]BIIB104, non-intuitive metabolites of BIIB104 were discovered involving a novel cyanide release from the 2-cyanothiophene motif via a postulated epoxidation-initiated thiophene-opening. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate.

Prognostic impact of peripheral blood WT1 mRNA dynamics in patients with acute myeloid leukemia treated with venetoclax combination therapy

BackgroundWilms' tumor gene 1 (WT1) mRNA quantification is a useful marker of measurable residual disease in acute myeloid leukemia (AML). However, whether monitoring the WT1 mRNA levels may predict the outcome of venetoclax (VEN) combination therapy in AML is not reported. This study aims to elucidate whether WT1 mRNA dynamics could predict long-term prognosis.Methods33 patients with untreated or relapsed/refractory AML evaluated for peripheral blood WT1 dynamics in VEN combination therapy were analyzed.ResultsThe median age was 73 years (range 39–87). Azacitidine was combined with VEN in 91% of patients. Overall, the median overall survival (OS) was 334 days (95% CI 210–482), and the complete remission (CR) plus CR with incomplete hematologic recovery rate was 59%. A 1-log reduction of WT1 mRNA values by the end of cycle 2 of treatment was associated with significantly better OS and event-free survival (EFS) (median OS 482 days vs. 237 days, p = 0.049; median EFS 270 days vs. 125 days, p = 0.02). The negativity of post-treatment WT1 mRNA value during the treatment was associated with significantly better OS and EFS (median OS 482 days vs. 256 days, p = 0.02; median EFS not reached vs. 150 days, p = 0.005). Multivariate analysis confirmed the significance of these two parameters as strong EFS predictors (HR 0.26, p = 0.024 and HR 0.15, p = 0.013, respectively). The increase in WT1 mRNA values was correlated with relapse.ConclusionThis study demonstrates that WT1 mRNA dynamics can be a useful marker for assessing long-term prognosis of VEN combination therapy for AML.

Chronic hypoxia impairs skeletal muscle repair via HIF-2α stabilization.

Chronic hypoxia and skeletal muscle atrophy commonly coexist in patients with COPD and CHF, yet the underlying physio-pathological mechanisms remain elusive. Muscle regeneration, driven by muscle stem cells (MuSCs), holds therapeutic potential for mitigating muscle atrophy. This study endeavours to investigate the influence of chronic hypoxia on muscle regeneration, unravel key molecular mechanisms, and explore potential therapeutic interventions. Experimental mice were exposed to prolonged normobaric hypoxic air (15% pO2, 1atm, 2weeks) to establish a chronic hypoxia model. The impact of chronic hypoxia on body composition, muscle mass, muscle strength, and the expression levels of hypoxia-inducible factors HIF-1α and HIF-2α in MuSC was examined. The influence of chronic hypoxia on muscle regeneration, MuSC proliferation, and the recovery of muscle mass and strength following cardiotoxin-induced injury were assessed. The muscle regeneration capacities under chronic hypoxia were compared between wildtype mice, MuSC-specific HIF-2α knockout mice, and mice treated with HIF-2α inhibitor PT2385, and angiotensin converting enzyme (ACE) inhibitor lisinopril. Transcriptomic analysis was performed to identify hypoxia- and HIF-2α-dependent molecular mechanisms. Statistical significance was determined using analysis of variance (ANOVA) and Mann-Whitney U tests. Chronic hypoxia led to limb muscle atrophy (EDL: 17.7%, P<0.001; Soleus: 11.5% reduction in weight, P<0.001) and weakness (10.0% reduction in peak-isometric torque, P<0.001), along with impaired muscle regeneration characterized by diminished myofibre cross-sectional areas, increased fibrosis (P<0.001), and incomplete strength recovery (92.3% of pre-injury levels, P<0.05). HIF-2α stabilization in MuSC under chronic hypoxia hindered MuSC proliferation (26.1% reduction of MuSC at 10 dpi, P<0.01). HIF-2α ablation in MuSC mitigated the adverse effects of chronic hypoxia on muscle regeneration and MuSC proliferation (30.9% increase in MuSC numbers at 10 dpi, P<0.01), while HIF-1α ablation did not have the same effect. HIF-2α stabilization under chronic hypoxia led to elevated local ACE, a novel direct target of HIF-2α. Notably, pharmacological interventions with PT2385 or lisinopril enhanced muscle regeneration under chronic hypoxia (PT2385: 81.3% increase, P<0.001; lisinopril: 34.6% increase in MuSC numbers at 10 dpi, P<0.05), suggesting their therapeutic potential for alleviating chronic hypoxia-associated muscle atrophy. Chronic hypoxia detrimentally affects skeletal muscle regeneration by stabilizing HIF-2α in MuSC and thereby diminishing MuSC proliferation. HIF-2α increases local ACE levels in skeletal muscle, contributing to hypoxia-induced regenerative deficits. Administration of HIF-2α or ACE inhibitors may prove beneficial to ameliorate chronic hypoxia-associated muscle atrophy and weakness by improving muscle regeneration under chronic hypoxia.

Dexterity in the Acute Phase of Stroke: Impairments and Neural Substrates

Background Stroke can impair manual dexterity, leading to loss of independence following incomplete recovery. Enhancing our understanding of dexterity impairment may improve neurorehabilitation. Objectives The study aimed to measure dexterity components in acute stroke patients with and without hand motor deficits, compare them to those of healthy controls (HC), and to explore the neural substrates involved in specific components of dexterity. Methods We used the Dextrain Manipulandum to quantify fine finger force control, finger selection accuracy, coactivation, and reaction time (RT). Dexterity was evaluated twice (2 days apart) in 74 patients and 14 HC. Voxel-Lesion-Symptom-Mapping (VLSM) was used to analyze the relationship between tissue damage and dexterity. Results. Due to severe paresis or fatigue, 24 patients could not perform these tasks. In 50 patients (included 4.6 ± 3.3 days post-stroke), finger force control improved (P < .001), as it did in HC (P = .03) who performed better than patients on both evaluations. Accuracy of finger selection did not improve significantly in any group, but the HC performed better on both evaluations. Unexpectedly, coactivation was better in patients than in HC at D3 (P = .03). There were no between-group differences in RT. VLSM showed that damage to the superior temporal gyrus (STG) impaired finger force control while damage to the posterior limb of the internal capsule (PLIC) impaired finger selectivity. Conclusions Acute stroke affecting the STG or PLIC impaired selective components of dexterity. Patients with mild to moderate impairment showed better finger force control and accuracy selection within 48 hours, suggesting the feasibility of detecting early dexterity improvements.

Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML.

Crenolanib is a second-generation tyrosine kinase inhibitor with activity against FLT3-ITD- and TKD-mutant AML. We conducted a trial of crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML. Eligible patients were 18 years and older. Induction chemotherapy consisted of cytarabine (100 mg/m2) continuous infusion on days 1-7 and anthracycline (daunorubicin 60-90 mg/m2 or idarubicin 12 mg/m2, once daily) on days 1-3 followed by consolidation with high-dose cytarabine (1-3 g/m2 twice daily on days 1, 3, 5) and/or allogeneic transplant. Crenolanib (100 mg thrice a day) was given from day 9 until 72 hours before the next cycle, after consolidation, and for 12 months after consolidation or transplant. Forty-four patients (median age, 57; range, 19-75 years) were enrolled. Thirty-six had FLT3-ITD, and 11 had FLT3-TKD mutations. European LeukemiaNet 2017 disease risk was favorable in 34%, intermediate in 30%, and adverse in 36%. The overall response rate was 86% (complete remission [CR], 77%; CR with incomplete count recovery [CRi], 9%): 90% in patients 60 years and younger and 80% in older patients. Measurable residual disease-negative CR/CRi rates were 89% and 45%, respectively. With a 45-month follow-up, median overall survival has not been reached and the median event-free survival was 44.7 months. Among younger patients, the estimated 3-year survival was 71.4% with 15% cumulative incidence of relapse. Treatment-related serious adverse events included febrile neutropenia, diarrhea, and nausea. The median time to platelets ≥100,000/µL and absolute neutrophil count ≥1,000/µL during induction was 29 and 32 days, respectively. No new FLT3-mutant clones were detected at relapse in patients completing consolidation. Crenolanib plus intensive chemotherapy in adults with newly diagnosed FLT3-mutant AML results in high rate of deep responses and long-term survival with acceptable toxicity. A randomized trial of crenolanib versus midostaurin plus chemotherapy in younger patients is ongoing.

Colorectal Cancer Screening Rates at Federally Qualified Health Centers From 2014 to 2022: Incomplete Recovery From COVID-19 and Worsening Disparities.

Federally Qualified Health Centers (FQHC) provide preventive health services such as colorectal cancer (CRC) screening to low-income and underinsured individuals. Overall CRC screening participation in the United States declined during the COVID-19 pandemic and recovered by 2021; however, trends in underresourced settings are unknown. Using Uniform Data System data from 2014 to 2022, we assessed trends in FQHC CRC screening rates nationally, in California, and in Los Angeles County and determined clinic-level factors associated with recent screening rate changes. For each FQHC, we calculated the screening rate change from 2019 to 2020, 2020 to 2021, and 2020 to 2022. We used mixed-effects linear regression to determine clinic-level characteristics associated with each screening rate change. Across all FQHC (n = 1,281), 7,016,181 patients were eligible for CRC screening in 2022. Across the United States and in California, median screening rates increased from 2014 to 2019, severely declined in 2020, and failed to return to prepandemic levels by 2022. Both nationally and in California, CRC screening declined most dramatically from 2019 to 2020 in FQHC serving majority Hispanic/Latino patients or a high proportion of patients experiencing homelessness. From 2020 to 2022, screening rates did not recover completely in US FQHC, with disproportionate recovery among FQHC serving majority non-Hispanic Black patients. CRC screening rates at FQHC did not return to prepandemic levels by 2022, and recovery varied by FQHC patient characteristics. Tailored interventions addressing low and decreasing CRC screening rates in FQHC are urgently needed to mitigate worsening CRC disparities.

Event rates and incidence of post-COVID-19 condition in hospitalised SARS-CoV-2 positive children and young people and controls across different pandemic waves: exposure-stratified prospective cohort study in Moscow (StopCOVID)

BackgroundLong-term health outcomes in children and young people (CYP) after COVID-19 infection are not well understood and studies with control groups exposed to other infections are lacking. This study aimed to investigate the incidence of post-COVID-19 condition (PCC) and incomplete recovery in CYP after hospital discharge and compare outcomes between different SARS-CoV-2 variants and non-SARS-CoV-2 infections.MethodsA prospective exposure-stratified cohort study of individuals under 18 years old in Moscow, Russia. Exposed cohorts were paediatric patients admitted with laboratory-confirmed COVID-19 infection between April 2 and December 11, 2020 (Wuhan variant cohort) and between January 12 and February 19, 2022 (Omicron variant cohort). CYP admitted with respiratory and intestinal infections, but negative lateral flow rapid diagnostic test and PCR-test results for SARS-CoV-2, between January 12 and February 19, 2022, served as unexposed reference cohort. Comparison between the ‘exposed cohorts’ and ‘reference cohort’ was conducted using 1:1 matching by age and sex. Follow-up data were collected via telephone interviews with parents, utilising the long COVID paediatric protocol and survey developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The WHO case definition was used to categorise PCC.ResultsOf 2595 CYP with confirmed COVID-19, 1707 (65.7%) participated in follow-up interviews, with 1183/1707 (69%) included in the final ‘matched’ analysis. The median follow-up time post-discharge was 6.7 months. The incidence of PCC was significantly higher in the Wuhan variant cohort (89.7 cases per 1000 person-months, 95% CI 64.3–120.3) compared to post-infection sequalae in the reference cohort (12.2 cases per 1000 person-months, 95% CI 4.9–21.9), whereas the difference with the Omicron variant cohort and reference cohort was not significant. The Wuhan cohort had higher incidence rates of dermatological, fatigue, gastrointestinal, sensory, and sleep manifestations, as well as behavioural and emotional problems than the reference cohort. The only significant difference between Omicron variant cohort and reference cohort was decreased school attendance. When comparing the Wuhan and Omicron variant cohorts, higher incidence of PCC and event rates of fatigue, decreased physical activity, and deterioration of relationships was observed. The rate of incomplete recovery was also significantly higher in the Wuhan variant cohort than in both the reference and the Omicron variant cohorts.ConclusionsWuhan variant exhibited a propensity for inducing a broad spectrum of physical symptoms and emotional behavioural changes, suggesting a pronounced impact on long-term health outcomes. Conversely, the Omicron variant resulted in fewer post-infection effects no different from common seasonal viral illnesses. This may mean that the Omicron variant and subsequent variants might not lead to the same level of long-term health consequences as earlier variants.

Spatiotemporal Variations and Postseismic Relaxation Process Around Mt. Fuji, Japan, During and After the 2011 Tohoku‐Oki Earthquake

AbstractTo monitor the volcanoes at a high spatiotemporal resolution, we introduce the singular value decomposition‐based Wiener filter and the three‐component waveforms in ambient noise velocity monitoring. The continuous ambient noise data from 63 stations around Mt. Fuji and Mt. Hakone, Japan, during the January‐September 2011 were analyzed to estimate the seismic velocity variations at a 1‐day temporal resolution, allowing us to distinguish the velocity drops caused by the 2011 Mw 9.0 Tohoku‐oki and the Mw 6.0 East Shizuoka earthquake. The velocity drop during the Tohoku‐oki earthquake was large in volcanic areas and was larger around Mt. Hakone than Mt. Fuji. This difference is possibly due to the existence of fluid‐ and gas‐rich zones at shallower depths and a higher crack density around Mt. Hakone. In addition, the velocity drop at Mt. Fuji during the Tohoku‐oki and the East Shizuoka earthquake was the same level, despite larger static stress changes beneath Mt. Fuji during the East Shizuoka earthquake. We interpret this inconsistency between the velocity drops and static stress changes to arise from incomplete recovery of the generated cracks during the Tohoku‐oki earthquake when the East Shizuoka earthquake occurred. This study also investigates the spatial variations in recovery speed and recovery amount, finding slow recovery speeds in the volcanic areas and fault areas, possibly due to larger crack densities in the crust. Furthermore, we observe the lowest velocity recovery amount in the volcanic areas, which is likely attributed to the maintained increase in pore pressure due to the volcanic gas bubbles.

Real-world evidence of obinutuzumab and venetoclax in previously treated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma

Venetoclax-obinutuzumab (Ven-O) is frequently administered off-label in relapsed/refractory (r/r) CLL/SLL where venetoclax-rituximab is the approved regimen. We conducted this retrospective, real-world study to evaluate Ven-O in r/r CLL/SLL. Between 7/2019 and 6/2022, 40 patients with r/r CLL/SLL on Ven-O were included. The median age was 72, 28.2% had TP53 mutation and/or 17p deletion, median number of prior therapies was 1 (range, 1–6), and 55% had prior BTK inhibitor exposure. The overall response rate was 90% (complete response [CR] or CR with incomplete marrow recovery in 27.5% and partial response in 62.5%) of patients, and the 2-year progression-free survival was 81.2% (95% CI, 69.5–94.8). Therapy was well tolerated. No laboratory or clinical TLS occurred with venetoclax (Howard criteria). One (3%) patient experienced laboratory TLS with obinutuzumab initiation. In summary, this retrospective cohort study demonstrated that Ven-O achieves frequent, durable responses and can be safely administered in r/r CLL/SLL.

Gilteritinib in combination with venetoclax, low-dose cytarabine and actinomycin D for relapsed or refractory FLT3-mutated acute myeloid leukaemia.

We have conducted a retrospective, single-centre analysis of 20 patients with relapsed or refractory FLT3-mutated acute myeloid leukaemia (FLT3m AML) who received a salvage quadruplet regimen consisting of gilteritinib, venetoclax, low-dose cytarabine and actinomycin D (G-ACTIVE). G-ACTIVE resulted in a 95% (19/20) overall response rate and 75% (15/20) complete remission and complete remission with an incomplete platelet recovery (CR + CRp) rate. Out of 13 transplant-eligible patients, 11 (86%) proceeded to an allogeneic stem cell transplantation. The median overall survival and relapse-free survival after G-ACTIVE were 32 and 12.9 months respectively. The Day 60 mortality rate was 15%.