INTRODUCTION: Approximately one-third of all AML patients have a mutation in the Fms-like tyrosine kinase 3 (FLT3) gene, which is associated with a poor prognosis in these individuals. The 2017 approval of midostaurin, the first FLT3 inhibitor, spurred extensive development of more potent and selective inhibitors with an improved safety profile. AREAS COVERED: This review analyzes patent inventions for the treatment of AML using FLT3 inhibitors, covering developments from the earliest to the most recent, disclosed in 2024. Our search using the global Espacenet database identified numerous compounds with low nanomolar inhibitory concentrations against FLT3-ITD and FLT3-TKD mutants. These compounds have shown promise in preclinical studies. Co-inhibition strategies and combinatorial therapies to overcome resistance and enhance anti-leukemic efficacy are also discussed. EXPERT OPINION: Recent patents highlight advances in the field of FLT3 inhibitors with a focus on overcoming resistance, improving selectivity and potency. Future strategies may include third-generation inhibitors such as type III allosteric inhibitors, irreversible inhibitors, or PROTACs. Personalized medicine approaches utilizing genetic profiling to tailor therapies are emphasized. Exploration of novel combination regimens with emerging therapies like CAR T-cell therapy, immune checkpoint inhibitors, and small molecules targeting critical AML pathways is ongoing to further enhance anti-leukemic efficacy.

• MeSH
• Leukemia, Myeloid, Acute * drug therapy   genetics   MeSH
• Drug Resistance, Neoplasm * MeSH
• Precision Medicine MeSH
• Protein Kinase Inhibitors * pharmacology   MeSH
• Humans MeSH
• Mutation * MeSH
• Patents as Topic * MeSH
• Prognosis MeSH
• Antineoplastic Agents * pharmacology   MeSH
• Staurosporine analogs & derivatives   pharmacology   MeSH
• fms-Like Tyrosine Kinase 3 * antagonists & inhibitors   genetics   MeSH
• Drug Development MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: Hyperkalaemia is a life-threatening electrolyte disturbance and also a potential cause of cardiac arrest. The objective was to assess the effects of acute pharmacological interventions for the treatment of hyperkalaemia in patients with and without cardiac arrest. METHODS: The review was reported according to PRISMA guidelines and registered on PROSPERO (CRD42023440553). We searched OVID Medline, EMBASE, and CENTRAL on September 9, 2024 for randomized trials, non-randomized trials, observational studies, and experimental animal studies. Two investigators performed abstract screening, full-text review, data extraction, and bias assessment. Outcomes included potassium levels, ECG findings, and clinical outcomes. Certainty of evidence was evaluated using GRADE. RESULTS: A total of 101 studies were included, with two studies including patients with cardiac arrest. In meta-analyses including adult patients without cardiac arrest, treated with insulin in combination with glucose, inhaled salbutamol, intravenous salbutamol dissolved in glucose, or a combination, the average reduction in potassium was between 0.7 and 1.2 mmol/l (very low to low certainty of evidence). The use of bicarbonate had no effect on potassium levels (very low certainty of evidence). In neonatal and paediatric populations, inhaled salbutamol and intravenous salbutamol reduced the average potassium between 0.9 and 1.0 mmol/l (very low to low certainty of evidence). There was no evidence to support a clinical beneficial effect of calcium for treatment of hyperkalemia. CONCLUSIONS: Evidence supports treatment with insulin in combination with glucose, inhaled or intravenous sal-butamol, or the combination. No evidence supporting a clinical effect of calcium or bicarbonate for hyperkalaemia was identified.

• MeSH
• Albuterol * administration & dosage   therapeutic use   MeSH
• Administration, Inhalation MeSH
• Potassium blood   MeSH
• Glucose administration & dosage   MeSH
• Bicarbonates administration & dosage   MeSH
• Hyperkalemia * drug therapy   MeSH
• Insulin * administration & dosage   therapeutic use   MeSH
• Humans MeSH
• Heart Arrest drug therapy   therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Review MeSH
• Systematic Review MeSH

Limited evidence exists about preserving neurovascular bundles during radical prostatectomy (RP) for high-risk prostate cancer (HRPCa) patients. Hence, we validated an existing algorithm predicting contralateral extraprostatic extension (cEPE) risk in unilateral high-risk cases. This algorithm aims to assist in determining the suitability of unilateral nerve-sparing RP. Among 264 patients, 48 (18%) had cEPE. The risk of cECE varied: 8%, 17.2%, and 30.8% for the low, intermediate, and high-risk groups, respectively. Despite a higher risk of cECE among individuals classified as low-risk in the development group compared to the validation group, our algorithm's superiority over always/never nerve-sparing RP was reaffirmed by decision curve analysis. Therefore, we conclude that bilateral excision may not always be justified in men with unilateral HRPCa. Instead, decisions can be based on our suggested nomogram.

• MeSH
• Algorithms * MeSH
• Risk Assessment methods   MeSH
• Organ Sparing Treatments * methods   MeSH
• Middle Aged MeSH
• Humans MeSH
• Prostatic Neoplasms * surgery   pathology   MeSH
• Nomograms MeSH
• Prostate surgery   innervation   pathology   MeSH
• Prostatectomy * methods   MeSH
• Robotic Surgical Procedures * methods   MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Validation Study MeSH

Recent reviews have highlighted conflicting findings regarding the validity of finger flexor strength and endurance tests in sport climbers, often due to small sample sizes and low ecological validity of the tests used. To address these gaps, 185 male and 122 female climbers underwent maximal finger flexor strength, intermittent and continuous finger flexor endurance, and the finger hang tests in a sport-specific setting to determine the predictive and concurrent validity of these tests. The finger hang test showed the strongest relationship to climbing ability for both sexes (R ≈ 0.75). However, despite its widespread use as an endurance test, the finger hang was found to be primarily determined by finger strength, explaining 65% and 80% of the variance in males and females, respectively. Finger strength emerged as the dominant factor, explaining the majority of variance in climbing ability (males 68%; females 64%), followed by intermittent endurance (males 28%; females 34%). These findings emphasize finger strength as the primary predictor of climbing ability and highlight the importance of intermittent endurance testing for assessing climbing-specific endurance of the finger flexors. No significant differences were found between male and female climbers in finger flexor strength and endurance when normalized to body mass.

• MeSH
• Adult MeSH
• Physical Endurance * physiology   MeSH
• Mountaineering * physiology   MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Fingers * physiology   MeSH
• Reproducibility of Results MeSH
• Sex Factors MeSH
• Hand Strength physiology   MeSH
• Muscle Strength physiology   MeSH
• Exercise Test methods   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Validation Study MeSH

The GPCR signalling cascade is a key pathway responsible for the signal transduction of a multitude of physical and chemical stimuli, including light, odorants, neurotransmitters and hormones. Understanding the structural and functional properties of the GPCR cascade requires direct observation of signalling processes in high spatial and temporal resolution, with minimal perturbation to endogenous systems. Optical microscopy and spectroscopy techniques are uniquely suited to this purpose because they excel at multiple spatial and temporal scales and can be used in living objects. Here, we review recent developments in microscopy and spectroscopy technologies which enable new insights into GPCR signalling. We focus on advanced techniques with high spatial and temporal resolution, single-molecule methods, labelling strategies and approaches suitable for endogenous systems and large living objects. This review aims to assist researchers in choosing appropriate microscopy and spectroscopy approaches for a variety of applications in the study of cellular signalling. LINKED ARTICLES: This article is part of a themed issue Complexity of GPCR Modulation and Signaling (ERNST). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v182.14/issuetoc.

• MeSH
• Humans MeSH
• Microscopy * methods   MeSH
• Receptors, G-Protein-Coupled * chemistry   metabolism   MeSH
• Signal Transduction MeSH
• Spectrum Analysis * methods   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Familial hypercholesterolemia (FH) is a relatively rare genetic disease associated with high serum cholesterol levels but also with abnormalities in blood coagulation. Novel pharmacotherapeutic approaches in FH including proprotein convertase subtilisin/kexin type 9 antibodies (PCSK9Ab) are very efficient in decreasing cholesterol levels but their impact on coagulation in FH is not yet established. Therefore, we hypothesized that these novel antidyslipidemic drugs can positively impact blood coagulation due to their more potent effect on cholesterol. A total of 15 healthy volunteers and all 15 available patients with severe FH treated at the University Hospital Hradec Králové were enrolled, coagulation was assessed by mechanic coagulometer, and the impact of four clinically used direct anticoagulants was analyzed ex vivo. FH patients were treated effectively as their total cholesterol was 4.11 ± 1.57 mM and LDL cholesterol was 2.44 ± 1.46 mM, which were even lower values than detected in our generally healthy controls. Twelve from the 15 FH patients were finally analyzed as 3 were treated with anticoagulants. Coagulation in FH patients was prolonged more extensively by dabigatran and rivaroxaban, when compared to healthy controls. Treatment with PCSK9Ab or lipid apheresis did not seem to have a significant effect on coagulation. The latter procedure however significantly decreased serum levels of one vitamin K form, MK4. Shorter coagulation time was associated with higher levels of LDL, non-HDL, and total cholesterol. Current treatment of FH seems to improve the effects of direct anticoagulants beyond known effects on LDL cholesterol levels.

• MeSH
• Anticholesteremic Agents therapeutic use   MeSH
• Anticoagulants * therapeutic use   pharmacology   MeSH
• Cholesterol blood   MeSH
• Dabigatran therapeutic use   pharmacology   MeSH
• Adult MeSH
• Blood Coagulation * drug effects   MeSH
• Hyperlipoproteinemia Type II * blood   drug therapy   MeSH
• Hypolipidemic Agents * therapeutic use   pharmacology   MeSH
• Cholesterol, LDL blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• PCSK9 Inhibitors MeSH
• Proprotein Convertase 9 MeSH
• Rivaroxaban therapeutic use   pharmacology   MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Carotid plaque composition plays a key role in plaque stability and patient risk stratification. Of unstable plaque features, intraplaque hemorrhage (IPH) is considered the main risk factor for stroke development. AIMS: We aimed to assess an association between the presence of IPH and other plaque characteristics detectable by computed tomography (CT) or magnetic resonance imaging (MRI) and stroke. MATERIAL AND METHODS: Of all consecutive patients from the ANTIQUE study, 132 (91 males; aged 70.0 [8.6] years) with 59 symptomatic and 157 asymptomatic stable carotid plaques were included in the retrospective analysis of prospectively collected data. Plaques in the vascular territory of ischemic stroke within 90 days were classified as symptomatic and were diagnosed by CT and MRI after symptoms occurred. Plaques without progression and clinical infarction were classified as asymptomatic stable. Univariate and multivariate logistic regression analyses were performed to identify risk factors. RESULTS: The presence, age, location, and volume of IPH were not related to stroke risk (P >0.05). Patients with symptomatic plaque were more likely to consume alcohol (P = 0.005), had more severe stenosis (CT median: 80% vs. 72%; P = 0.005; MRI median: 79% vs. 72%; P = 0.01), lower American Heart Association grade (P = 0.03), and more frequent lipid plaque (89.8% vs. 76.4%; P = 0.04) compared to patients with asymptomatic stable plaques. Stenosis severity (odds ratio [OR], 1.037; 95% CI, 1.015-1.059) and additionally alcohol consumption (OR, 3.571; 95% CI, 1.694-7.527) were found to be the only significant predictors of a recent stroke. CONCLUSIONS: In this cohort, no IPH or other plaque characteristics were associated with stroke risk. The degree of stenosis and alcohol consumption were the only factors associated with ipsilateral stroke. Larger prospective studies considering plaque characteristics are needed.

• MeSH
• Plaque, Atherosclerotic * diagnostic imaging   complications   MeSH
• Stroke * etiology   diagnostic imaging   MeSH
• Middle Aged MeSH
• Humans MeSH
• Magnetic Resonance Imaging MeSH
• Tomography, X-Ray Computed MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Carotid Stenosis * diagnostic imaging   complications   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

The role of aeromonads as contributors to gastrointestinal pathology remains controversial. The aim of this study was to analyse the clinical characteristics and risk factors for the acquisition of an enteric infection by Aeromonas spp. in patients with digestive or nephrological diseases. The method user for the study comprised a retrospective review of the clinical history of all patients in whom Aeromonas spp. was isolated in faeces. The study period included in samples arriving at the microbiology service of the Marqués de Valdecilla University Hospital, from 2016 to 2022. The results showed that there was an increase in the more virulent Aeromonas species in the patients studied. The most common chronic diseases were cancer, inflammatory bowel disease and alcoholic cirrhosis, as well as biliary involvement in acute cases. In conclusión, Aeromonas is a genus to consider in patients with diarrhoea and hepatonephrological involvement.

• MeSH
• Aeromonas * isolation & purification   pathogenicity   classification   genetics   MeSH
• Adult MeSH
• Feces microbiology   MeSH
• Gram-Negative Bacterial Infections * microbiology   epidemiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Diarrhea microbiology   MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare paraneoplastic syndrome associated with various adenocarcinomas, most commonly gastric adenocarcinoma. This condition can progressively worsen pulmonary arterial hypertension, leading to acute or subacute pulmonary heart failure and respiratory insufficiency. This paper examines the pathogenesis, clinical presentation, diagnosis, treatment, and prognosis of PTTM. Given PTTM's poor prognosis, we emphasize treatment strategies. PTTM in adenocarcinoma patients can mimic other pulmonary diseases, causing diagnostic delays. Current PTTM treatment strategies primarily focus on managing the underlying malignancy and addressing thrombotic complications. Anti-angiogenic therapy with bevacizumab and the platelet-derived growth factor receptor antagonist imatinib have shown promise in multiple cases. Further research is needed to develop more effective and targeted therapies for this challenging condition. The precise mechanisms underlying this association remain to be fully elucidated.

• Publication type
• Journal Article MeSH
• Review MeSH

Introduction: The e-STROKE study is a prospective, multicenter observational study designed to assess the impact of various CT parameters (including e-ASPECT, CT perfusion (CTP), collateral flow status, and the size and location of the ischemic lesion) on the clinical outcomes of patients with ischemic stroke, as evaluated by the modified Rankins Scale (mRS) three months post-stroke. This study also aims to investigate whether the use of multimodal CT imaging increases the number of patients eligible for recanalization therapy. The analysis will integrate data from the RES-Q registry and radiological data from the e-STROKE system provided by Brainomix Ltd. Aims: The primary aim is to determine the predictive value of CT parameters (e-ASPECTS, CTP, collateral vessel status, and ischemic lesion volume and location) on three-month functional outcomes, as defined by the mRS, in patients with non-lacunar stroke following recanalization treatment (IVT and/or MT). The secondary aim is to evaluate whether multimodal CT examination leads to an increase in the number of patients eligible for recanalization therapy. Additionally, this study seeks to assess the specificity and sensitivity of multimodal CT in distinguishing stroke mimics from actual strokes. Methods: This multicenter observational study involves patients with suspected acute ischemic stroke and a premorbid mRS ≤ 4, who are treated with endovascular thrombectomy (EVT), intravenous thrombolysis (IVT), or managed conservatively in stroke centers within the Czech Stroke Research Network (STROCZECH), which is part of the Czech Clinical Research Infrastructure Network (CZECRIN). Data collection includes demographic, clinical, and imaging data variables such as age, sex, ethnicity, risk factors, treatment times (OTT, DNT, and OGT), TICI scores, post-treatment hemorrhage (ECAS II), mRS outcome, stroke etiology, e-ASPECTS, acute ischemic volume (AIV), thrombus length on NCCT, CTA collateral score and collateral vessel density, location of large vessel occlusion, ischemic core, hypoperfusion volume, mismatch ratio and volume, final infarct volume, hemorrhage volume, and MRI in case of negative follow-up NCCT. Conclusions: We anticipate collecting robust clinical and radiological data from approximately 2000 patients across 22 centers over a 12-month period. The results are expected to enhance the precision of diagnostic and prognostic radiological markers in managing acute stroke.

• Publication type
• Journal Article MeSH