Momelotinib versus Continued Ruxolitinib or Best Available Therapy in JAK Inhibitor-Experienced Patients with Myelofibrosis and Anemia: Subgroup Analysis of SIMPLIFY-2.

INTRODUCTION: Some Janus kinase (JAK) inhibitors such as ruxolitinib and fedratinib do not address and may worsen anemia in patients with myelofibrosis. In these cases, the JAK inhibitor may be continued at a reduced dose in an effort to maintain splenic and symptom control, with supportive therapy and/or red blood cell (RBC) transfusions added to manage anemia. This post hoc descriptive analysis of the phase 3 SIMPLIFY-2 trial evaluated the relative benefits of this approach versus switching to the JAK1/JAK2/activin A receptor type 1 inhibitor momelotinib in patients for whom anemia management is a key consideration. METHODS: SIMPLIFY-2 was a randomized (2:1), open-label, phase 3 trial of momelotinib versus best available therapy (BAT; 88.5% continued ruxolitinib) in JAK inhibitor-experienced patients with myelofibrosis (n = 156). Patient subgroups (n = 105 each) were defined by either baseline (1) hemoglobin (Hb) of < 100 g/L or (2) non-transfusion independence (not meeting the criteria of no transfusions and no Hb of < 80 g/L for the previous 12 weeks); outcomes have been summarized descriptively. RESULTS: In both subgroups of interest, week 24 transfusion independence rates were higher with momelotinib versus BAT/ruxolitinib: baseline Hb of < 100 g/L, 22 (33.3%) versus 5 (12.8%); baseline non-transfusion independent, 25 (34.7%) versus 1 (3.0%). Mean Hb levels over time were also generally higher in both subgroups with momelotinib, despite median transfusion rates through week 24 with momelotinib being comparable to or lower than with BAT/ruxolitinib. Spleen and symptom response rates with momelotinib in these subgroups were comparable to the intent-to-treat population, while rates with BAT/ruxolitinib were lower. CONCLUSION: In patients with moderate-to-severe anemia and/or in need of RBC transfusions, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using anemia supportive therapies. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02101268.

Patients with the rare blood cancer myelofibrosis often experience symptoms such as tiredness, an increase in the size of their spleens (an organ involved in filtering the blood), and anemia (too few red blood cells). One type of treatment for myelofibrosis, called a Janus kinase (JAK) inhibitor, can help patients to feel better and reduce the size of their spleens, but some JAK inhibitors do not help with anemia and may make it worse. In those situations, patients may continue to take their JAK inhibitor but also receive another type of treatment, called an anemia supportive therapy, and may also receive red blood cell transfusions. This study compared 2 treatment approaches, continuing the JAK inhibitor ruxolitinib and adding an anemia supportive therapy and/or transfusions versus switching to another treatment called momelotinib, in 2 groups of patients from a clinical trial: (1) patients with levels of hemoglobin (a red blood cell protein) at the start of the trial that indicated that they had anemia, and (2) patients who were already receiving red blood cell transfusions at the start of the trial. In both groups, more patients did not need red blood cell transfusions anymore at week 24 with momelotinib, and their hemoglobin levels on average became higher over time. More patients also had improvements in spleen size and symptoms with momelotinib. Overall, outcomes were improved by switching to momelotinib rather than continuing ruxolitinib and using supportive therapies and/or red blood cell transfusions to treat anemia.

The mitogenomic landscape of Banisteriopsis caapi (Malpighiaceae), the sacred liana used for ayahuasca preparation.

The sacred ayahuasca brew, utilized by indigenous communities in the Amazon and syncretic religious groups in Brazil, primarily consists of a decoction of two plants: (i) the Amazonian liana known as Mariri or Jagube (Banisteriopsis caapi), and (ii) the shrub referred as Chacrona or Rainha (Psychotria viridis). While Chacrona leaves are rich in N,N-Dimethyltryptamine (DMT), a potent psychedelic, the macerated vine of Mariri provides beta-carboline alkaloids acting as monoamine oxidase inhibitors, preventing DMT's degradation. This study sequenced, assembled, and analyzed the complete genome of B. caapi's mitochondrion, yielding a circular structure spanning 503,502 bp. Although the mtDNA encompasses most plant mitochondrial genes, it lacks some ribosomal genes, presents some atypical genes, and contains plastid pseudogenes, suggesting gene transfer between organelles. The presence of a 7-Kb repetitive segment containing copies of the rrnL and trnfM genes suggests mitogenome isomerization, supporting the hypothesis of dynamic mitogenome maintenance in plants. Phylogenetics and phylogenomics across 24 Malpighiales confirms the sample's placement in the "Tucunacá" ethnovariety, aligning with morphological identification. This study spearheads efforts to decode the genome of this esteemed Malpighiaceae.

Genomic decoding of Theobroma grandiflorum (cupuassu) at chromosomal scale: evolutionary insights for horticultural innovation.

BACKGROUND: Theobroma grandiflorum (Malvaceae), known as cupuassu, is a tree indigenous to the Amazon basin, valued for its large fruits and seed pulp, contributing notably to the Amazonian bioeconomy. The seed pulp is utilized in desserts and beverages, and its seed butter is used in cosmetics. Here, we present the sequenced telomere-to-telomere genome of cupuassu, disclosing its genomic structure, evolutionary features, and phylogenetic relationships within the Malvaceae family. FINDINGS: The cupuassu genome spans 423 Mb, encodes 31,381 genes distributed in 10 chromosomes, and exhibits approximately 65% gene synteny with the Theobroma cacao genome, reflecting a conserved evolutionary history, albeit punctuated with unique genomic variations. The main changes are pronounced by bursts of long-terminal repeat retrotransposons at postspecies divergence, retrocopied and singleton genes, and gene families displaying distinctive patterns of expansion and contraction. Furthermore, positively selected genes are evident, particularly among retained and dispersed tandem and proximal duplicated genes associated with general fruit and seed traits and defense mechanisms, supporting the hypothesis of potential episodes of subfunctionalization and neofunctionalization following duplication, as well as impact from distinct domestication process. These genomic variations may underpin the differences observed in fruit and seed morphology, ripening, and disease resistance between cupuassu and the other Malvaceae species. CONCLUSIONS: The cupuassu genome offers a foundational resource for both breeding improvement and conservation biology, yielding insights into the evolution and diversity within the genus Theobroma.

Clinical impact of mutated JAK2 allele burden reduction in polycythemia vera and essential thrombocythemia.

The variant allele frequency (VAF) of driver mutations (JAK2, CALR) in myeloproliferative neoplasms is associated with features of advanced disease and complications. Ruxolitinib and interferon were reported to variably reduce the mutant VAF, but the long-term impact of molecular responses (MR) remains debated. We prospectively measured changes in JAK2 and CALR VAF in 77 patients with polycythemia vera and essential thrombocythemia, treated with ruxolitinib for a median of 8 years, and assessed correlation with complete clinical and hematological response (CCHR) and outcomes. At last observation time, JAK2 VAF reduced overall from a median of 68% (range, 20%-99%) to 3.5% (0%-98%). A profound and durable MR (DMR; defined as a VAF stably ≤2%), including complete MR in 8%, was achieved in 20% of the patients, a partial MR (PMR; VAF reduction >50% of the baseline level) in 25%, and 56% had no molecular response (NMR). A CCHR was reached by 69% overall, independently of any degree of MR achieved; conversely, a DMR correlated with longer duration of CCHR and, most importantly, with reduced rate of progression to myelofibrosis and with longer myelofibrosis-free, event-free and progression-free survival. Achievement of PMR also had some favorable impact on outcomes, compared to NMR. A baseline JAK2 VAF <50%, and a VAF reduction of ≥35% after 2 years of treatment, predicted for the achievement of DMR and reduced progression to myelofibrosis. Overall, these findings support the clinical value of achieving profound, durable MR and its consideration as surrogate endpoint in future clinical trials.

Long-term pharmacodynamic and clinical effects of twice- versus once-daily low-dose aspirin in essential thrombocythemia: The ARES trial.

Patients with essential thrombocythemia (ET) are treated with once-daily low-dose aspirin to prevent thrombosis, but their accelerated platelet turnover shortens the antiplatelet effect. The short-term Aspirin Regimens in EsSential Thrombocythemia trial showed that twice-daily aspirin dosing restores persistent platelet thromboxane (TX) inhibition. However, the long-term pharmacodynamic efficacy, safety and tolerability of twice-daily aspirin remain untested. We performed a multicenter, randomized, open-label, blinded-endpoint, phase-2 trial in which 242 patients with ET were randomized to 100 mg aspirin twice- or once-daily and followed for 20 months. The primary endpoint was the persistence of low serum TXB2, a surrogate biomarker of antithrombotic efficacy. Secondary endpoints were major and clinically relevant non-major bleedings, serious vascular events, symptom burden assessed by validated questionnaires, and in vivo platelet activation. Serum TXB2 was consistently lower in the twice-daily versus once-daily regimen on 10 study visits over 20 months: median 3.9 ng/mL versus 19.2 ng/mL, respectively; p < .001; 80% median reduction; 95% CI, 74%-85%. No major bleeding occurred. Clinically relevant non-major bleedings were non-significantly higher (6.6% vs. 1.7%), and major thromboses lower (0.8% vs. 2.5%) in the twice-daily versus once-daily group. Patients on the twice-daily regimen had significantly lower frequencies of disease-specific symptoms and severe hand and foot microvascular pain. Upper gastrointestinal pain was comparable in the two arms. In vivo platelet activation was significantly reduced by the twice-daily regimen. In patients with ET, twice-daily was persistently superior to once-daily low-dose aspirin in suppressing thromboxane biosynthesis and reducing symptom burden, with no detectable excess of bleeding and gastrointestinal discomfort.

Towards a 'step-up approach' for the treatment of recurrent non-stenotic cholangitis after hepaticojejunostomy: systematic review.

BACKGROUND: Recurrent non-stenotic cholangitis (NSC) is a difficult-to-treat complication after hepaticojejunostomy (HJ) leading to multiple hospital admissions. The optimal treatment strategy is unclear as a systematic review is lacking. METHODS: A systematic review was performed including studies detailing treatment strategies and outcomes for recurrent NSC in patients with a surgical HJ in PubMed, Embase, and Cochrane Library (inception - September 2023). Primary outcome was resolution of NSC as defined by the included studies. RESULTS: Overall, 72 patients with recurrent NSC after HJ were included from seven retrospective studies. The rate of recurrent NSC (specified in five studies) was 4% (46/1143 HJs). Diagnosis of NSC was mostly made after excluding HJ stenosis and assessing bile reflux. Initial treatment consisted of short-course antibiotics for all patients. Second step treatment consisted of prolonged antibiotic therapy (n = 10, 13.8%). Third step treatment consisted of surgery (n = 9, n = 12.5%); mostly lengthening of the biliary loop. Together, the overall reported resolution-rate of recurrent NSC was 66.6% (n = 48). CONCLUSION: A 'step-up approach' may be effective in two-thirds of patients with recurrent NSC after HJ, starting with short-course antibiotics, and eventually adding prolonged antibiotic therapy and, ultimately, surgery aimed at preventing intestinal content and food reflux. Prospective studies are needed.

Safety and efficacy of fedratinib in patients with myelofibrosis previously treated with ruxolitinib: primary analysis of FREEDOM trial.

The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 109/L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population (n = 35), nine (25.7%; 95% confidence interval 12.5-43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 (n = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs.

Heavy-intensity priming exercise extends the V̇O2max plateau and increases peak power output during ramp-incremental exercise.

PURPOSE: To investigate whether a heavy-intensity priming exercise precisely prescribed within the heavy-intensity domain would lead to a greater peak-power output (POpeak) and a longer maximal oxygen uptake (V̇O2max) plateau. METHODS: Twelve recreationally active adults participated in this study. Two visits were required: (i) a step-ramp-step test (RI control), and (ii) a RI-test preceded by a priming exercise within the heavy-intensity domain (RI primed). A piece-wise equation was used to quantify the V̇O2 plateau duration (V̇O2plateau-time). The mean response time (MRT) was computed during the RI control condition. The delta (Δ) V̇O2-slope (S; mL·min-1·W-1) and V̇O2-Y-intercept (Y; mL·min-1) within the moderate-intensity domain between conditions (RI primed minus RI control) was also assessed using a novel graphical analysis. RESULTS: V̇O2plateau-time (P = 0.001; d = 1.27) and POpeak (P = 0.003; d = 1.08) were all greater in the RI Primed. MRT (P < 0.001; d = 2.45) was shorter in the RI primed compared to the RI control. A larger ΔV̇O2plateau-time was correlated with a larger ΔMRT between conditions (r = -0.79; P = 0.002). CONCLUSIONS: This study demonstrated that heavy-intensity priming exercise lengthened the V̇O2plateau-time and increased POpeak. The overall faster RI-V̇O2 responses seem to be responsible for the longer V̇O2plateau-time. Specifically, a shorter MRT, but not changes in RI-V̇O2-slopes, was associated to a longer V̇O2plateau-time following priming exercise.

ß-Alanine Plus Sodium Bicarbonate Co-Supplementation Does Not Decrease Neuromuscular Fatigue in Swimming.

This study aimed to investigate the effects of chronic ß-alanine (ßA) plus acute sodium bicarbonate (SB) co-supplementation on neuromuscular fatigue during high-intensity intermittent efforts in swimming. Eleven regional and national competitive-level young swimmers performed a neuromuscular fatigue assessment before and immediately after two 20 × 25-m front crawl maximal efforts every 90 s, performed at pre- and post-4-week co-supplementation. Neuromuscular fatigue was evaluated by percutaneous electrical stimuli through the twitch interpolation technique on the triceps brachii and quadriceps femoris. Performance was defined by the mean time of the 20 efforts and blood samples to lactate concentrations were collected every four efforts. Participants supplemented 3.2-6.4 g·day-1 of chronic ßA or placebo (PL) during four weeks, and acute 0.3 g·kg-1 of SB or PL 60 min before the second assessment (allowing ßA+SB and PL+PL groups). No statistical changes were found in neuromuscular fatigue of triceps brachii. In the quadriceps femoris, a main effect of time was found in potentiated twitch delta values in pooled groups, showing a statistical increase of 19.01% after four weeks (Δ = 13.05 [0.35-25.75] N; p = 0.044), without time × group interactions. No statistical difference was found in the swimming performance. Blood lactate increased by 25.06% only in the ßA+SB group (Δ = 6.40 [4.62-8.18] mM; p Bonf < 0.001) after the supplementation period. In conclusion, 4-week ßA and SB co-supplementation were not able to reduce neuromuscular fatigue levels and improve performance in highintensity intermittent efforts, but statistically increased blood lactate levels.

Enhancing Tribological Performance of Self-Lubricating Composite via Hybrid 3D Printing and In Situ Spraying.

In this work, a self-lubricating composite was manufactured using a novel hybrid 3D printing/in situ spraying process that involved the printing of an acrylonitrile butadiene styrene (ABS) matrix using fused deposition modeling (FDM), along with the in situ spraying of alumina (Al2O3) and hexagonal boron nitride (hBN) reinforcements during 3D printing. The results revealed that the addition of the reinforcement induced an extensive formation of micropores throughout the ABS structure. Under tensile-loading conditions, the mechanical strength and cohesive interlayer bonding of the composites were diminished due to the presence of these micropores. However, under tribological conditions, the presence of the Al2O3 and hBN reinforcement improved the frictional resistance of ABS in extreme loading conditions. This improvement in frictional resistance was attributed to the ability of the Al2O3 reinforcement to support the external tribo-load and the shearing-like ability of hBN reinforcement during sliding. Collectively, this work provides novel insights into the possibility of designing tribologically robust ABS components through the addition of in situ-sprayed ceramic and solid-lubricant reinforcements.

Annotation and Comparative Genomics of Prokaryotic Transposable Elements.

The data generated in nearly 30 years of bacterial genome sequencing has revealed the abundance of transposable elements (TE) and their importance in genome and transcript remodeling through the mediation of DNA insertions and deletions, structural rearrangements, and regulation of gene expression. Furthermore, what we have learned from studying transposition mechanisms and their regulation in bacterial TE is fundamental to our current understanding of TE in other organisms because much of what has been observed in bacteria is conserved in all domains of life. However, unlike eukaryotic TE, prokaryotic TE sequester and transmit important classes of genes that impact host fitness, such as resistance to antibiotics and heavy metals and virulence factors affecting animals and plants, among other acquired traits. This provides dynamism and plasticity to bacteria, which would otherwise be propagated clonally. The insertion sequences (IS), the simplest form of prokaryotic TE, are autonomous and compact mobile genetic elements. These can be organized into compound transposons, in which two similar IS can flank any DNA segment and render it transposable. Other more complex structures, called unit transposons, can be grouped into four major families (Tn3, Tn7, Tn402, Tn554) with specific genetic characteristics. This chapter will revisit the prominent structural features of these elements, focusing on a genomic annotation framework and comparative analysis. Relevant aspects of TE will also be presented, stressing their key position in genome impact and evolution, especially in the emergence of antimicrobial resistance and other adaptive traits.

Functional diversity and metabolic response in benthic communities along an ocean acidification gradient.

Altered ocean chemistry caused by ocean acidification (OA) is expected to have negative repercussions at different levels of the ecological hierarchy, starting from the individual and scaling up to the community and ultimately to the ecosystem level. Understanding the effects of OA on benthic organisms is of primary importance given their relevant ecological role in maintaining marine ecosystem functioning. The use of functional traits represents an effective technique to investigate how species adapt to altered environmental conditions and can be used to predict changes in the resilience of communities faced with stresses associated with climate change. Artificial supports were deployed for 1-y along a natural pH gradient in the shallow hydrothermal systems of the Bottaro crater near Panarea (Aeolian Archipelago, southern Tyrrhenian Sea), to explore changes in functional traits and metabolic rates of benthic communities and the repercussions in terms of functional diversity. Changes in community composition due to OA were accompanied by modifications in functional diversity. Altered conditions led to higher oxygen consumption in the acidified site and the selection of species with the functional traits needed to withstand OA. Calcification rate and reproduction were found to be the traits most affected by pH variations. A reduction in a community's functional evenness could potentially reduce its resilience to further environmental or anthropogenic stressors. These findings highlight the ability of the ecosystem to respond to climate change and provide insights into the modifications that can be expected given the predicted future pCO2 scenarios. Understanding the impact of climate change on functional diversity and thus on community functioning and stability is crucial if we are to predict changes in ecosystem vulnerability, especially in a context where OA occurs in combination with other environmental changes and anthropogenic stressors.

Texture analysis of 18F-FDG PET/CT and CECT: Prediction of refractoriness of Hodgkin lymphoma with mediastinal bulk involvement.

To recognize patients at high risk of refractory disease, the identification of novel prognostic parameters improving stratification of newly diagnosed Hodgkin Lymphoma (HL) is still needed. This study investigates the potential value of metabolic and texture features, extracted from baseline 18F-FDG Positron Emission Tomography/Computed Tomography (PET) and Contrast-Enhanced Computed Tomography scan (CECT), together with clinical data, in predicting first-line therapy refractoriness (R) of classical HL (cHL) with mediastinal bulk involvement. We reviewed 69 cHL patients who underwent staging PET and CECT. Lesion segmentation and texture parameter extraction were performed using the freeware software LIFEx 6.3. The prognostic significance of clinical and imaging features was evaluated in relation to the development of refractory disease. Receiver operating characteristic curve, Cox proportional hazard regression and Kaplan-Meier analyses were performed to examine the potential independent predictors and to evaluate their prognostic value. Among clinical characteristics, only stage according to the German Hodgkin Group (GHSG) classification system significantly differed between R and not-R. Among CECT variables, only parameters derived from second order matrices (gray-level co-occurrence matrix (GLCM) and gray-level run length matrix (GLRLM) demonstrated significant prognostic power. Among PET variables, SUVmean, several variables derived from first (histograms, shape), and second order analyses (GLCM, GLRLM, NGLDM) exhibited significant predictive power. Such variables obtained accuracies greater than 70% at receiver operating characteristic analysis and their PFS curves resulted statistically significant in predicting refractoriness. At multivariate analysis, only HISTO_EntropyPET extracted from PET (HISTO_EntropyPET ) and GHSG stage resulted as significant independent predictors. Their combination identified 4 patient groups with significantly different PFS curves, with worst prognosis in patients with higher HISTO_EntropyPET values, regardless of the stage. Imaging radiomics may provide a reference for prognostic evaluation of patients with mediastinal bulky cHL. The best prognostic value in the prediction of R versus not-R disease was reached by combining HISTO_EntropyPET with GHSG stage.

Risk models in myelofibrosis-the past, present, and future.

Risk models in myelofibrosis (MYSEC-PM) or primary myelofibrosis (IPSS, DIPSS, DIPSS+, MIPSS70, MIPSS70+, MIPSSv2, GIPSS).

Toltrazuril + fenbendazole for cattle: Pharmacokinetics and efficacy against Eimeria spp. and gastrointestinal nematodes.

The present work evaluated the pharmacokinetics and efficacy of the association of 15cmg/kg toltrazuril +5cmg/kg fenbendazole against Eimeria spp. and gastrointestinal nematodes (GINs) in calves of different regions of Brazil (Center-West, Southeast, and South). A total of seven experiments were carried out, five of which determined formulation efficacy against Eimeria spp., considering the following aspects: therapeutic, preventive, metaphylactic, and residual efficacy. Therapeutic efficacy experiments for GINs were carried out by parasitological necropsy. The toltrazuril + fenbendazole association demonstrated ≥95% efficacy against Eimeria spp. for 21 days post-treatment (DPT). When used preventively and metaphylatically, the same association demonstrated ≥97% efficacy against E. zuernii, E. ellipsoidalis, E. cylindrica, E. bovis, E. wyomingensis and E. auburnensis. Toltrazuril + fenbendazole administered seven days before challenge was 100% effective against all these Eimeria species. Results of therapeutic, preventive, metaphylactic and residual efficacies can be related to the pharmacokinetic results, especially considering toltrazuril sulfone, which was detected in animal plasma for a longer period than the parent compound. Toltrazuril + fenbendazole achieved 100% anthelminthic efficacy against the GINs Haemonchus placei (L4), Cooperia pectinata and Oesophagostomum radiatum; 99.94% against adult H. placei; and 99.98% against C. puntacta. The association of toltrazuril + fenbendazole, associated with other measures, is an important and suitable tool for the control and treatment of Eimeria spp. and GINs in young cattle.

A Ramp versus Step Transition to Constant Work Rate Exercise Decreases Steady-State Oxygen Uptake.

PURPOSE: This study aimed to investigate whether a ramp-to-constant WR (rCWR) transition compared with a square-wave-to-constant WR (CWR) transition within the heavy-intensity domain can reduce metabolic instability and decrease the oxygen cost of exercise. METHODS: Fourteen individuals performed (i) a ramp-incremental test to task failure, (ii) a 21-min CWR within the heavy-intensity domain, and (iii) an rCWR to the same WR. Oxygen uptake (V̇O 2 ), lactate concentration ([La - ]), and muscle oxygen saturation (SmO 2 ) were measured. V̇O 2 and V̇O 2 gain (V̇O 2 -G) during the first 10-min steady-state V̇O 2 were analyzed. [La - ] before, at, and after steady-state V̇O 2 and SmO 2 during the entire 21-min steady-state exercise were also examined. RESULTS: V̇O 2 and V̇O 2 -G during rCWR (2.49 ± 0.58 L·min -1 and 10.7 ± 0.2 mL·min -1 ·W -1 , respectively) were lower ( P < 0.001) than CWR (2.57 ± 0.60 L·min -1 and 11.3 ± 0.2 mL·min -1 ·W -1 , respectively). [La - ] before and at steady-state V̇O 2 during the rCWR condition (1.94 ± 0.60 and 3.52 ± 1.19 mM, respectively) was lower than the CWR condition (3.05 ± 0.82 and 4.15 ± 1.25 mM, respectively) ( P < 0.001). [La - ] dynamics after steady-state V̇O 2 were unstable for the rCWR ( P = 0.011). SmO 2 was unstable within the CWR condition from minutes 4 to 13 ( P < 0.05). CONCLUSIONS: The metabolic disruption caused by the initial minutes of square-wave exercise transitions is a primary contributor to metabolic instability, leading to an increased V̇O 2 -G compared with the rCWR condition approach. The reduced early reliance on anaerobic energy sources during the rCWR condition may be responsible for the lower V̇O 2 -G.

One thousand patients with essential thrombocythemia: the Florence-CRIMM experience.

We describe 1000 patients with essential thrombocythemia seen at the Center Research and Innovation of Myeloproliferative Neoplasms (CRIMM), Florence, Italy, between 1980 and 2023: median age 59 years (18-95), females 65%, JAK2/CALR/MPL-mutated 66%/19%/4%, triple-negative (TN) 11%. Extreme thrombocytosis (ExT, platelets ≥1000 × 109/L) in 16%, leukocytosis (leukocytes >11 × 109/L) in 16%, and at least one cardiovascular risk factor in 52% of cases. JAK2-mutated patients were older (median 62 years) and CALR-mutated and TN (53 years for both) younger (p < 0.001). Female gender clustered with TN (76%) and JAK2 (67%) vs CALR (46%) mutations (p < 0.001). ExT clustered with CALR (type-2 more than type-1), TN and MPL, and leukocytosis with JAK2 mutation (p < 0.001). In multivariable analysis, risk factors for arterial thrombosis-free survival were age ≥60 years (HR 2.0; p < 0.001) and JAK2 mutation (HR 1.3; p = 0.02) with borderline significance for male gender (p = 0.08) and cardiovascular risk factors (p = 0.08); for venous thrombosis-free survival, JAK2 mutation (HR 1.9; p = 0.03) with borderline significance for venous thrombosis history (p = 0.07); for overall survival, older age (p < 0.001), male gender (HR 1.9; p < 0.001), absolute neutrophil count (ANC) ≥ 8 × 109/L (HR 1.8; p = 0.01), absolute lymphocyte count (ALC) < 1.7 × 109/L (HR 1.2; p = 0.03); for myelofibrosis-free survival, CALR mutation (HR 2.7; p < 0.001, particularly for CALR type 1/1-like, HR 3.3) and MPL mutation (HR 3.9; p = 0.001); for leukemia-free survival, older age (p = 0.03). Cytoreductive therapy appeared to mitigate both venous (HR 0.3; p = 0.01) and arterial thrombosis (HR 4; p = 0.04); there was a trend for aspirin in preventing arterial thrombosis recurrence. The current study provides real-world observations in essential thrombocythemia, representing a valid source document for interpreting current literature and planning future studies.

Recurrent cholangitis in patients with a non-stenotic hepaticojejunostomy: incidence and risk factors.

BACKGROUND: Cholangitis is a well-known complication after hepaticojejunostomy (HJ), which is mainly caused by a stenotic anastomosis. However, the rate of cholangitis in patients with a non-stenotic (i.e. patent) HJ is unknown. We aimed to evaluate the incidence and risk factors of recurrent cholangitis in patients with a non-stenotic HJ. METHODS: This single-center retrospective cohort study included all consecutive patients who had undergone hepatobiliary or pancreatic (HPB) surgery requiring HJ (2015-2022). Primary outcome was recurrent non-stenotic cholangitis, risk factors for recurrent non-stenotic cholangitis were identified using logistic regression. RESULTS: Overall, 835 patients with a HJ were included of whom 31/698 (4.4%) patients developed recurrent cholangitis with a non-stenotic HJ during a median follow-up of 34 months (IQR 22-50) and 98/796 (12.3%) patients developed a symptomatic HJ stenosis. These 31 patients experienced 205 cholangitis episodes, median 7.0 (IQR 3.8-8.8) per patient, and 71/205 (34.6%) cholangitis episodes required hospitalization. Male sex (aOR 3.17 (95% CI: 1.34-7.49)) and benign disease (aOR 2.97, 95% CI 1.40-6.33) were identified as risk factors for recurrent cholangitis in non-stenotic HJ in both univariate and multivariable analysis. CONCLUSION: This study shows that 4% of patients developed recurrent cholangitis without an underlying HJ stenosis.