Preexisting and treatment-emergent autoimmune cytopenias in patients with CLL treated with targeted drugs.

Autoimmune cytopenias (AICs) affect 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs-ibrutinib, idelalisib, and venetoclax-have a prominent role in the treatment of CLL, but their impact on CLL-associated AICs is largely unknown. In this study, we evaluated the characteristics and outcome of preexisting AICs and described the incidence, quality, and management of treatment-emergent AICs during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab, and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of preexisting AICs was reported in 104 (13%) of 815 patients. Interestingly, 80% of patients whose AICs had not resolved when treatment with a targeted drug was started experienced an improvement or a resolution during therapy. Treatment-emergent AICs occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib therapy, and in 7% during venetoclax therapy, with an estimated incidence rate of 5, 6, and 69 episodes per 1000 patients per year of exposure in the 3 treatment groups, respectively. The vast majority of patients who developed treatment-emergent AICs had unfavorable biological features such as an unmutated IGHV and a del(17p) and/or TP53 mutation. Notably, despite AICs, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib, or venetoclax seems to have a beneficial impact on CLL-associated AICs, inducing an improvement or even a resolution of preexisting AICs in most cases and eliciting treatment-emergent AICs in a negligible portion of patients.

Beyond ibrutinib: novel BTK inhibitors for the treatment of chronic lymphocytic leukemia.

PURPOSE OF THE REVIEW: Ibrutinib was the first Bruton tyrosine kinase inhibitor (BTKi) approved for clinical use, contributing to a dramatic change in the treatment landscape of chronic lymphocytic leukemia (CLL). This review provides an overview of next-generation BTKi that have been recently approved or are being investigated for the treatment of CLL, specifically highlighting differences and similarities compared to ibrutinib. RECENT FINDINGS: Acalabrutinib presented comparable response rates to ibrutinib with lower rates of adverse events and is currently approved for the treatment of CLL. Zanubrutinib displayed excellent response rates with a lower incidence of BTKi-related adverse events, but major rates of neutropenia, and its approval is awaited. With the aim of overcoming drug resistance, noncovalent BTKi have been developed. Of all the explored agents to date, pirtobrutinib has shown promising results with manageable toxicities. SUMMARY: For the treatment of CLL, several effective therapeutic strategies to target BTK are or will soon be available: these drugs present different safety profiles, thus making it possible to tailor the treatment choice according to patient's characteristics. Importantly, noncovalent BTKi will provide a therapeutic chance also for those relapsed/refractory CLL patients who are BTKi-resistant and are considered an unmet clinical need.

Puumala Virus Infection in Family, Switzerland.

We report 3 cases of Puumala virus infection in a family in Switzerland in January 2019. Clinical manifestations of the infection ranged from mild influenza-like illness to fatal disease. This cluster illustrates the wide range of clinical manifestations of Old World hantavirus infections and the challenge of diagnosing travel-related hemorrhagic fevers.

[Palliative and intensive care collaborative approach in the management of therapeutic withdrawals: lessons learned from the COVID-19 experience]. / Approche collaborative des soins palliatifs et des soins intensifs dans la gestion des retraits thérapeutiques - Ce qu'il faut retenir de l'expérience du COVID-19.

During the COVID-19 pandemic, many of the usual aspects of therapeutic withdrawals had to be adapted. Preparing and supporting patients, next of kin and staff to death was particularly challenging. Palliative care was integrated into the process of therapeutic withdrawals in intensive care units during this crisis. Continuing education related to end-of-life issues and defining collaboration with palliative care is essential for intensive care teams.

Durant la pandémie Coronavirus Disease 19, certains aspects habituels des retraits thérapeutiques ont dû être adaptés. L'accompagnement des patients et de leurs proches au décès ainsi que le soutien aux équipes de soins ont amené à résoudre de nouveaux défis. L'intégration des soins palliatifs dans les processus de retraits thérapeutiques aux soins intensifs a pu être mise en œuvre durant cette crise sanitaire. La formation continue aux questions en lien avec la fin de vie et l'établissement de plans de collaboration avec les soins palliatifs est essentielle aux soins intensifs.

The impact of SLCO1B1 rs4149056 on LDL-C target achievement after lipid lowering therapy optimization in men and women with familial hypercholesterolemia.

Background and aims: FH women are less likely to receive intensive statin treatment and to obtain a 50% reduction of LDL-C from baseline compared to men with FH. SLCO1B1 rs4149056 might influence statin therapy compliance and thus LDL-C target achievement. Our aim was to evaluate the impact of SLCO1B1 rs4149056 on LDL-C target achievement after lipid lowering therapy (LLT) optimization in men and women with FH. Methods: This was a retrospective observational study involving 412 FH subjects with a probable or defined clinical diagnosis of FH who had had genetic analysis from June 2016 to September 2022. Biochemical analysis was obtained from all subjects at baseline and at the last follow-up after LLT optimization. Results: After LLT optimization the percentage of FH subjects on high-intensity statins decreased from the M/SLCO1B1- group to the W/SLCO1B1+ group and the same was found in LDL-C target distribution (for both p for trend < 0.01). The prevalence of SASE fear increased from the M/SLCO1B1- group to the W/SLCO1B1+ group and the same was observed in reported myalgia distribution (for both p for trend < 0.01). Logistic regression analysis showed that the W/SCLO1B1-, M/SCLO1B1+ and W/SCLO1B1+ groups were inversely associated with LDL-C target achievement (p for trend < 0.001) and the W/SCLO1B1+ group exhibited the strongest association. Conclusion: A low prevalence of FH women with SLCO1B1 rs4149056 were on high intensity statins and they rarely achieved LDL-C target. The genotype effect of SLCO1B1 rs4149056 could be more pronounced in FH women than men.

Influence of Chitin Nanocrystals on the Crystallinity and Mechanical Properties of Poly(hydroxybutyrate) Biopolymer.

This study focuses on the use of pilot-scale produced polyhydroxy butyrate (PHB) biopolymer and chitin nanocrystals (ChNCs) in two different concentrated (1 and 5 wt.%) nanocomposites. The nanocomposites were compounded using a twin-screw extruder and calendered into sheets. The crystallization was studied using polarized optical microscopy and differential scanning calorimetry, the thermal properties were studied using thermogravimetric analysis, the viscosity was studied using a shear rheometer, the mechanical properties were studied using conventional tensile testing, and the morphology of the prepared material was studied using optical microscopy and scanning electron microscopy. The results showed that the addition of ChNCs significantly affected the crystallization of PHB, resulting in slower crystallization, lower overall crystallinity, and smaller crystal size. Furthermore, the addition of ChNCs resulted in increased viscosity in the final formulations. The calendering process resulted in slightly aligned sheets and the nanocomposites with 5 wt.% ChNCs evaluated along the machine direction showed the highest mechanical properties, the strength increased from 24 to 33 MPa, while the transversal direction with lower initial strength at 14 MPa was improved to 21 MPa.

Decreased CRRT Filter Lifespan in COVID-19 ICU Patients.

(1) Background: Increased thromboembolic events and an increased need for continuous renal replacement therapy (CRRT) have been frequently reported in COVID-19 patients. Our aim was to investigate CRRT filter lifespan in intensive care unit (ICU) COVID-19 patients. (2) Methods: We compared CRRT adjusted circuit lifespan in COVID-19 patients admitted for SARS-CoV-2 infection to a control group of patients admitted for septic shock of pulmonary origin other than COVID-19. Both groups underwent at least one session of CRRT for AKI. (3) Results: Twenty-six patients (13 in each group) were included. We analysed 117 CRRT circuits (80 in the COVID-19 group and 37 in the control group). The adjusted filter lifespan was shorter in the COVID-19 group (17 vs. 39 h, p < 0.001). This trend persisted after adjustment for confounding factors (-14 h, p = 0.037). Before CRRT circuit clotting, the COVID-19 group had a more procoagulant profile despite higher heparin infusion rates. Furthermore, we reported a decreased relation between activated partial thromboplastin time (aPTT) and cumulative heparin dose in COVID-19 patients when compared to historical data of 23,058 patients, suggesting a heparin resistance. (4) Conclusion: COVID-19 patients displayed a shorter CRRT filter lifespan that could be related to a procoagulant profile and heparin resistance.

Autoimmune Complications in Chronic Lymphocytic Leukemia in the Era of Targeted Drugs.

Autoimmune phenomena are frequently observed in patients with chronic lymphocytic leukemia (CLL) and are mainly attributable to underlying dysfunctions of the immune system. Autoimmune cytopenias (AIC) affect 4-7% of patients with CLL and mainly consist of autoimmune hemolytic anemia and immune thrombocytopenia. Although less common, non-hematological autoimmune manifestations have also been reported. Treatment of CLL associated AIC should be primarily directed against the autoimmune phenomenon, and CLL specific therapy should be reserved to refractory cases or patients with additional signs of disease progression. New targeted drugs (ibrutinib, idelalisib and venetoclax) recently entered the therapeutic armamentarium of CLL, showing excellent results in terms of efficacy and became an alternative option to standard chemo-immunotherapy for the management of CLL associated AIC. However, the possible role of these drugs in inducing or exacerbating autoimmune phenomena still needs to be elucidated. In this article, we review currently available data concerning autoimmune phenomena in patients with CLL, particularly focusing on patients treated with ibrutinib, idelalisib, or venetoclax, and we discuss the possible role of these agents in the management of AIC.

Quantitative determination of casein genetic variants in goat milk: Application in Girgentana dairy goat breed.

The study was conducted to develop a high-performance liquid chromatographic (HPLC) method to quantify casein genetic variants (αs2-, ß-, and κ-casein) in milk of homozygous individuals of Girgentana goat breed. For calibration experiments, pure genetic variants were extracted from individual milk samples of animals with known genotypes. The described HPLC approach was precise, accurate and highly suitable for quantification of goat casein genetic variants of homozygous individuals. The amount of each casein per allele was: αs2-casein A = 2.9 ± 0.8 g/L and F = 1.8 ± 0.4 g/L; ß-casein C = 3.0 ± 0.8 g/L and C1 = 2.0 ± 0.7 g/L and κ-casein A = 1.6 ± 0.3 g/L and B = 1.1 ± 0.2 g/L. A good correlation was found between the quantities of αs2-casein genetic variants A and F, and ß-casein C and C1 with other previously described method. The main important result was obtained for κ-casein because, till now, no data were available on quantification of single genetic variants for this protein.

Development and validation of RP-HPLC method for the quantitative estimation of αs1-genetic variants in goat milk.

A high-performance liquid chromatographic (HPLC) method was developed and validated for separation and quantification of the most common genetic variants of αs1-casein in goat's milk, to evaluate the effect of αs1-casein polymorphisms on casein content. Chromatography was carried out by binary gradient technique on a reversed-phase C8 Zorbax column and the detection was made at a wavelength of 214nm. The procedure was developed using individual raw milk samples of Girgentana goats. For calibration experiments, pure genetic variants were extracted from individual milk samples of animals with known genotypes, considering that commercial standards for goat genetic variants were not available. The data obtained for Girgentana goat breed showed that A, B, F variants were alleles associated with a content of αs1-casein in milk of 3.2±0.4, 5.4±0.5 and 0.7±0.1g/L, respectively, whereas N variant was a 'null' allele associated with the absence of αs1-casein in milk.

Oxidation processes in Sicilian olive oils investigated by a combination of optical and EPR spectroscopy.

UNLABELLED: Extra virgin olive oil (EVOO) is recognized as one of the healthiest foods for its high content of antioxidants, which forestall and slow down radical formation. Free radical-initiated oxidation is considered one of the main causes of rancidity in fats and oils. As a consequence, reliable protocols for the investigation of oil oxidation based on selective, noninvasive, and fast methods are highly desirable. Here we report an experimental approach based on UV-Vis absorbance, steady-state fluorescence, and electron paramagnetic resonance (EPR) spectroscopy for studying oxidation processes induced by temperature for a period up to 35 d on Sicilian EVOO samples. We followed the decrease in ß-carotene content during incubation time and observed changes in polyphenols and tocopherols during the oxidation processes, focusing on the time scale of those changes. Using EPR spectroscopy, the free radical formation in different oil samples is reported, providing a fingerprint for both the antioxidant content and temporal features of the oxidation process at its early stage. PRACTICAL APPLICATION: We monitor ß-carotene and chlorophyll in an auto-oxidation process. A protocol based on spectroscopic measurements is presented and can be used for the quality control process of commercial olive oil.