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•A relationship between high baseline DOAC levels and early bleeding events in 1-year follow-up was found.•Early measurement allows to identify patients with high DOAC levels and, hopefully, to adjust treatment to reduce bleeding events.

•A relationship between low baseline DOAC levels and thrombotic events in 1-year follow-up was found.•Early measurement allows the identification of patients with low DOAC levels and treatment adjustment to avoid future thrombotic events.

AbstractThe Tokamak à Configuration variable (TCV) is equipped with two neutral beam injection (NBI) systems delivering up to 1.2 MW each for pulse durations of up to 2 s. The first system (NBI1), designed for an injection energy in the range of 25 to 30 keV has been operational since 2016. The existing concrete neutron shielding of the experimental hall proved insufficient for fully protecting human accessible areas, limiting the number of daily plasma pulses using NBI1. The recently commissioned second system (NBI2) is designed for injection synergies in the range 50 to 60 keV. Both systems are tangentially oriented in opposite directions in order to permit experiments with low or no net torque.Calculations with the TRANSP and ORBIS heating codes show that neutron rates from deuterium-deuterium fusion reactions may be as high as 1014 n/s, up to 10 times higher than with the lower energy beam only. This is due both to the ~five times larger beam-plasma neutron rates from the higher energy beam and to an exceptionally high contribution from beam-beam reactions between the opposing beams. The radiation protection policy at the Swiss Plasma Center is that all staff members be considered as members of the general public, limiting the daily personal dose to 4 µSv. This is also the maximum admissible daily dose in any publicly accessible zone, whether occupied or not.Currently, with only the lower energy beam, this limit can be attained in the control room adjacent to the device hall after only five NBI pulses out of a possible 30 daily pulses. To allow for exploitation of the two beams at full specifications, the source side of the existing barite concrete walls of the 15 × 20 × 8 m large TCV hall will be covered with 20-cm-thick polythene (PE) cladding and a ceiling made of 35-cm-thick PE will be added. The total mass of PE will be 200 tons. The usage of PE at this scale for neutron shielding is unprecedented at any fusion research facility.

Isoprene affects new particle formation rates in environments and experiments also containing monoterpenes. For the most part, isoprene reduces particle formation rates, but the reason is debated. It is proposed that due to its fast reaction with OH, isoprene may compete with larger monoterpenes for oxidants. However, by forming a large amount of peroxy-radicals (RO2), isoprene may also interfere with the formation of the nucleating species compared to a purely monoterpene system. We explore the RO2cross reactions between monoterpene and isoprene oxidation products using the radical Volatility Basis Set (radical-VBS), a simplified reaction mechanism, comparing with observations from the CLOUD experiment at CERN. We find that isoprene interferes with covalently bound C20dimers formed in the pure monoterpene system and consequently reduces the yields of the lowest volatility (Ultra Low Volatility Organic Carbon, ULVOC) VBS products. This in turn reduces nucleation rates, while having less of an effect on subsequent growth rates.

To determine the location of the rectus femoris (RF) motor branch nerve, as well as its coordinates with reference to anatomical and ultrasound landmarks. Thirty chronic stroke patients with stiff knee gait (SKG) and RF hyperactivity were included. The motor nerve branch to the RF muscle was identified medially to the vertical line from anterior superior iliac spine and the midpoint of the superior margin of the patella (line AP) and vertically to the horizontal line from the femoral pulse and its intersection point with the line AP (line F). The point of the motor branch (M) was located with ultrasound, and nerve depth and subcutaneous tissue thickness (ST) were calculated. The coordinates of the motor branch to the RF were 2.82 (0.47) cm medially to the line AP and 4.61 (0.83) cm vertically to the line F. Nerve depth and subcutaneous tissue thickness were 2.71 (0.62) cm and 1.12 (0.75) cm, respectively. The use of specific coordinates may increase clinicians' confidence when performing RF motor nerve block. This could lead to better decision‐making when assessing SKG in chronic stroke patients.

•Germ line genetic predisposition to myeloid neoplasms significantly contributes to cytopenias and hypoplastic BM in adulthood.•Pathogenic/likely pathogenic germ line variants are associated with a higher risk of severe cytopenias and advanced myeloid neoplasms.

Self-reported symptom studies rapidly increased understanding of SARS-CoV-2 during the COVID-19 pandemic and enabled monitoring of long-term effects of COVID-19 outside hospital settings. Post-COVID-19 condition presents as heterogeneous profiles, which need characterisation to enable personalised patient care. We aimed to describe post-COVID-19 condition profiles by viral variant and vaccination status.

AbstractBackgroundPanic disorder (PD) is a prevalent and impairing anxiety disorder with previous reports suggesting that the longer the condition remains untreated, the greater the likelihood of nonresponse. However, patients with PD may wait for years before receiving a guideline-recommended pharmacological treatment. The widespread prescription of benzodiazepines (BDZ) for managing anxiety symptoms and disorders might delay the administration of pharmacotherapy according to guidelines (eg, selective serotonin reuptake inhibitors, SSRIs). The present study aimed to determine the mean duration of untreated illness (DUI) in a sample of PD patients, to quantify and compare DUI-SSRI to DUI-BDZ, and to compare findings with those from previous investigations.MethodsThree hundred and fourteen patients with a Diagnostic and Statistical Manual of Mental Disorders, fifth edition diagnosis of PD were recruited from an Italian outpatient psychotherapy unit, and epidemiological and clinical variables were retrieved from medical records. Descriptive statistical analyses were undertaken for sociodemographic and clinical variables, Wilcoxon matched-pair signed rank test was applied to compare the distribution of DUI-SSRI vs DUI-BDZ, and Welch’s ttest was performed to compare findings with those from previous studies.ResultsThe mean DUI-SSRI of the total sample was 64.25 ± 112.74 months, while the mean DUI-BDZ was significantly shorter (35.09 ± 78.62 months; P< 0.0001). A significantly longer DUI-SSRI, compared to findings from previous studies, was also observed.ConclusionsThe present results confirm a substantial delay in implementing adequate pharmacological treatments in patients with PD, and highlight the discrepancy between recommendations from international treatment guidelines and common clinical practice in relation to BDZ prescription.

Aims: Laparoscopic appendectomy (LA) for acute appendicitis (AA) is one of the most performed procedures. The effects of peritoneal lavage (PL) and the reasons to perform it have not been cleared and all meta-analyses didn’t show a statistical advantage to prevent infectious complications. This study aims to investigate surgeons’ perceptions during LA, comparing intraoperative findings with histological results, and exploring how surgeons’ subjectivity influences the decision-making process on PL. Methods: Data were extracted from the two-year data lock from REsiDENT-1 registry, a prospective resident-led multicentre observational trial. This study investigates the relationships between PL and postoperative intraabdominal abscesses (pIAA) introducing a classification for AA to standardize the intraoperative grading. We included pre, intra, and postoperative variables. We applied our classification proposal, used a five-point Likert scale (Ls) to assess subjective LA difficulty and ran a concordance analysis between the assessment of AA and histology. Subsequently, a multivariate logistic regression model was built to find factors influencing PL. Results: 561 patients were enrolled from twenty-one hospitals and 51 residents. 542 procedures were included in the logistic regression analysis and 441 in the concordance analysis, due to missing data. PL was used in 222 LA (39, 6%). We discovered a moderate positive monotonic relationship between surgical evaluation and histology, p&lt; 0.001. Despite this, the reliability of the surgeon’s assessment of appendicitis is progressively lower for gangrenous and perforated forms. The increasing grade of contamination, the increasing grade of subjective difficulty and the intraoperative finding of a gangrenous or perforated appendicitis were independent predictors of PL. Conclusion: This study shows how surgeons’ evaluation of AA severity overestimated more than half of gangrenous or perforated appendices with the perception of a challenging procedure. These perceptions influenced the choice of PL. We proved that the evaluation during LA could be affected by subjectivity with a non-negligible impact on the decision-making process. Graphical abstract:

Understanding the predictability drivers for the North Atlantic Oscillation (NAO) during boreal winter at seasonal time scales remains challenging. This study uses large ensembles with the ECMWF seasonal forecasting system to investigate the relative impact of tropical Indian and Pacific heating on NAO predictability by examining the tropical forcing, teleconnection pathways, and sources of uncertainty. We select three case studies ‐ 1997/98, 2015/16 and 2019/20 ‐ with strong Indian Ocean heating anomalies, but with different El Niño conditions. We show that in 2019/20, with neutral ENSO conditions, Indian Ocean SSTs favor a positive NAO response via stratospheric and tropospheric pathways. In the cases with strong El Niño, we find contrasting results: in 1997/98, the Pacific forcing dominates, producing a negative NAO. In 2015/16, despite the strong El Niño, the Indian Ocean forcing dominates, leading to a positive NAO via intensification of the stratospheric polar vortex (SPV). While the stratospheric pathway exhibits varying responses to Indian Ocean forcing ‐ being weaker in 1997/98 and strongest in 2015/16, the Indian Ocean‐related tropospheric pathway remains robust along the Pacific subtropical jet across years. However, there is destructive interference between teleconnections from Indian and Pacific SST anomalies in both the tropospheric and stratospheric pathways. The competing effects of tropical heating in both basins, uncertainties in the Rossby wave response to tropical heating and SPV variability contribute to uncertainty in seasonal NAO predictions. The flow‐dependent nature of the stratospheric pathway underscores the complexity of seasonal forecast predictability, and the existence of windows of opportunity. The NAO is a phenomenon that manifests as a pressure see‐saw in the North Atlantic, affecting the seasonal climate in many parts of the northern hemisphere. In this study, we demonstrate that the predictability of the phases of the NAO can be affected by the remote and opposing influence of surface temperatures in the tropical Indian and Pacific oceans, which propagate via the troposphere and stratosphere. This interplay, in turn, contributes to the uncertainty of seasonal forecasts of the NAO. Large ensemble seasonal forecasts reveal a predictable link between tropical heating and the NAO via a flow‐dependent stratospheric pathwayThe impact of Indian Ocean heating on the NAO can be stronger than that of El Niño in the presence of an anomalously strong stratospheric pathwayCompetition between basins, flow‐dependent response, and intrinsic variability contribute to the uncertainty in seasonal forecasts of NAO Large ensemble seasonal forecasts reveal a predictable link between tropical heating and the NAO via a flow‐dependent stratospheric pathway The impact of Indian Ocean heating on the NAO can be stronger than that of El Niño in the presence of an anomalously strong stratospheric pathway Competition between basins, flow‐dependent response, and intrinsic variability contribute to the uncertainty in seasonal forecasts of NAO

The SARS-CoV-2 variant of concern, omicron, appears to be less severe than delta. We aim to quantify the differences in symptom prevalence, risk of hospital admission, and symptom duration among the vaccinated population.

In the context of side-channel attacks against cryptographic circuits, t-probing security characterizes the amount of information derivable about sensitive values (e.g., keys) by observing toutput/internal values. Non-interference is a useful mathematical tool used by researchers to assess the probing security of a circuit which employs Boolean masking to protect itself from attacks. However, reasoning about non-interference still requires either difficult ratiocination or complex automatic tools. In this work, we propose a novel point of view to reason about non-interference, by exploiting the Walsh transform of a Boolean function. To this end, we introduce a calculus for mechanically reasoning about the shares of a variable and show that this formalism provides a lean algebraic explanation of known compositional patterns allowing for the discovery of new ones. Eventually, we show how this formalism can be applied to study the probing security of known cryptographic gadgets.

Purpose: This paper aims to present the application and critical reflection on the effects of a intervention for children with autism spectrum disorder (ASD): the Soundbeam Imitation Intervention (SII). The intervention is based on the imitation of meaningless body gestures supported by a musical feedback. The rationale underlying SII is that mirror neurons deficit may represent the cause for the incomplete development of social and motor functioning in children with ASD. Following this assumption, it is possible to hypothesise that a systematic activation of this a system through the simultaneous observation-execution of meaningless body gestures may affect functional changes of mirror-related functions. Design/methodology/approach: A sample of 14 children, who were between 5 and 9 years of age, with a diagnosis of ASD were involved in a six weeks’ SII programme. The programme is designed as a three-step progression, where each step includes exercises that focus on an activity: synchronous/one arm imitation, synchronous/two arms imitation and delayed imitation. Exercises are based on repeated movements-melodies associations of increasing difficulty. Motor imitation and social attention were assessed using a synchronous video-modelling task pre and post intervention. Findings: Data highlight significant improvements in imitation accuracy and duration of social sustained attention were achieved. Originality/value: Data reported in this paper provide preliminary and promising evidence that imitation and social attention skills acquired through SII can be generalised to a video-modelling imitation setting. The SII ordinal execution has included meaningless gestures, usually excluded from previous interventions, and this adds further validity to the training.

AbstractWhile official science has given its answer to the question on the origin of the Coronavirus (animal to human transmission), alternative theories on human creation of the virus – purposely or inadvertently – have flourished. Those alternative theories can be easily located among the family of conspiracy theories, as they always assume some secretive activity of some groups acting on their self-interest and against the good of the many. The article assesses the prevalence of these beliefs during the COVID-19 pandemic in Italy, studies its development during the pandemic, and investigates its potential determinants. In particular, it analyses the relationship between beliefs in alternative theories on the origin of the virus and political orientation, by arguing that the association cannot be attributed to (politically) motivated reasoning, as the issue has not been highly politicized in the Italian context. Alternatively, the article suggests that the main factor driving beliefs in alternative accounts on the origins of the virus is institutional trust. Political orientation moderates its effects, depending on specific conditions (e.g. cue taking, position of the supported party either in government or opposition), and eventually reinforcing scepticism towards epistemic authorities for those with low trust in institutions. Data come from the ResPOnsE COVID-19 survey, carried out with daily samples from April to July 2020 (N> 15.000) to monitor the development of the Italian public opinion during the Coronavirus pandemic.

Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after 6 months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (1) RUX dose <20 mg twice daily at baseline, months 3 and 6 (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.07-3.00; P = .03), (2) palpable spleen length reduction from baseline ≤30% at months 3 and 6 (HR, 2.26; 95% CI, 1.40-3.65; P = .0009), (3) red blood cell (RBC) transfusion need at months 3 and/or 6 (HR, 1.66; 95% CI, 0.95-2.88; P = .07), and (4) RBC transfusion need at all time points (ie, baseline and months 3 and 6; HR, 2.32; 95% CI, 1.19-4.54; P = .02). Hence, we developed a prognostic model, named Response to Ruxolitinib After 6 Months (RR6), dissecting 3 risk categories: low (median OS, not reached), intermediate (median OS, 61 months; 95% CI, 43-80), and high (median OS, 33 months; 95% CI, 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.

Ruxolitinib (RUX) is extensively used in myelofibrosis (MF). Despite its early efficacy, most patients lose response over time and, after discontinuation, have a worse overall survival (OS). Currently, response criteria able to predict OS in RUX-treated patients are lacking, leading to uncertainty regarding the switch to second-line treatments. In this study, we investigated predictors of survival collected after 6 months of RUX in 209 MF patients participating in the real-world ambispective observational RUXOREL-MF study (NCT03959371). Multivariable analysis identified the following risk factors: (1) RUX dose <20 mg twice daily at baseline, months 3 and 6 (hazard ratio [HR], 1.79; 95% confidence interval [CI], 1.07-3.00; P= .03), (2) palpable spleen length reduction from baseline ≤30% at months 3 and 6 (HR, 2.26; 95% CI, 1.40-3.65; P= .0009), (3) red blood cell (RBC) transfusion need at months 3 and/or 6 (HR, 1.66; 95% CI, 0.95-2.88; P= .07), and (4) RBC transfusion need at all time points (ie, baseline and months 3 and 6; HR, 2.32; 95% CI, 1.19-4.54; P= .02). Hence, we developed a prognostic model, named Response to Ruxolitinib After 6 Months (RR6), dissecting 3 risk categories: low (median OS, not reached), intermediate (median OS, 61 months; 95% CI, 43-80), and high (median OS, 33 months; 95% CI, 21-50). The RR6 model was validated and confirmed in an external cohort comprised of 40 MF patients. In conclusion, the RR6 prognostic model allows for the early identification of RUX-treated MF patients with impaired survival who might benefit from a prompt treatment shift.

AbstractBackgroundLittle is known about the post-acute effects of repetitive transcranial magnetic stimulation (rTMS) in patients with major depression. The present study focused on the 6-month follow-up of a sample of patients with major depression, after the completion of an acute 4 weeks rTMS trial, with the aim of evaluating response (in terms of sustained and late response) and relapse rates.MethodsFollowing the completion of an acute trial of rTMS (T0-T4), 31 drug-resistant depressed patients (bipolar or unipolar) entered a naturalistic follow-up period of 6 months, with three timepoints (T5, T6, and T7) during which they were assessed with the Hamilton Depression Rating Scale and the Young Mania Rating Scale.ResultsResults showed that in the 6 months following an acute transcranial magnetic stimulation (TMS) trial, a higher rate of late responders was observed among previously acute TMS nonresponders (63.64%, 7 out of 11) compared to the rate of relapse among those who had acutely responded to TMS (10%, 2 out of 20). In addition, an overall high rate of maintained response (90%) was observed.ConclusionPresent findings seem to support the possibility of obtaining a clinical response also after the end of an acute TMS trial in patients with major depression. The concomitant low rate of relapse observed at the end of follow-up along with a high rate of maintained response provides further support to the post-acute efficacy of TMS. Nonetheless, further controlled studies, with larger samples and longer follow-up observation, are needed to confirm the reported results.

Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents.

IMPORTANCE: Overall, immunotherapy has been shown to improve outcomes and reduce relapses in individuals with N-methyl-d-aspartate receptor (NMDAR) antibody encephalitis (NMDARE); however, the superiority of specific treatments and combinations remains unclear. OBJECTIVE: To map the use and safety of immunotherapies in individuals with NMDARE, identify early predictors of poor functional outcome and relapse, evaluate changes in immunotherapy use and disease outcome over the 14 years since first reports of NMDARE, and assess the Anti-NMDAR Encephalitis One-Year Functional Status (NEOS) score. DATA SOURCES: Systematic search in PubMed from inception to January 1, 2019. STUDY SELECTION: Published articles including patients with NMDARE with positive NMDAR antibodies and available individual immunotherapy data. DATA EXTRACTION AND SYNTHESIS: Individual patient data on immunotherapies, clinical characteristics at presentation, disease course, and final functional outcome (modified Rankin Scale [mRS] score) were entered into multivariable logistic regression models. MAIN OUTCOMES AND MEASURES: The planned study outcomes were functional outcome at 12 months from disease onset (good, mRS score of 0 to 2; poor, mRS score greater than 2) and monophasic course (absence of relapse at 24 months or later from onset). RESULTS: Data from 1550 patients from 652 articles were evaluated. Of these, 1105 of 1508 (73.3%) were female and 707 of 1526 (46.3%) were 18 years or younger at disease onset. Factors at first event that were significantly associated with good functional outcome included adolescent age and first-line treatment with therapeutic apheresis, corticosteroids plus intravenous immunoglobulin (IVIG), or corticosteroids plus IVIG plus therapeutic apheresis. Factors significantly associated with poor functional outcome were age younger than 2 years or age of 65 years or older at onset, intensive care unit admission, extreme delta brush pattern on electroencephalography, lack of immunotherapy within the first 30 days of onset, and maintenance IVIG use for 6 months or more. Factors significantly associated with nonrelapsing disease were rituximab use or maintenance IVIG use for 6 months or more. Adolescent age at onset was significantly associated with relapsing disease. Rituximab use increased from 13.5% (52 of 384; 2007 to 2013) to 28.3% (311 of 1100; 2013 to 2019) (P &lt; .001), concurrent with a falling relapse rate over the same period (22% [12 of 55] in 2008 and earlier; 10.9% [35 of 322] in 2017 and later; P = .006). Modified NEOS score (including 4 of 5 original NEOS items) was associated with probability of poor functional status at 1 year (20.1% [40 of 199] for a score of 0 to 1 points; 43.8% [77 of 176] for a score of 3 to 4 points; P = .05). CONCLUSIONS AND RELEVANCE: Factors influencing functional outcomes and relapse are different and need to be considered independently in development of evidence-based optimal management guidelines of patients with NMDARE.

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

The Pd(II)-catalyzed reaction of N-allyl-2-aminophenols in the presence of PhI(OCOR)2as the oxidant resulted in an alkoxyacyloxylation process, with the formation of functionalized dihydro-1,4-benzoxazines. The reaction performed in the absence of palladium catalyst switched to an intramolecular Diels–Alder reaction (IMDA) pathway, which was the result of an oxidative dearomatization of the 2-aminophenol, nucleophilic addition, and Diels–Alder reaction cascade, highlighting the role of the oxidant as both a nucleophilic donor and an oxidizing agent.

The incidence and prognosis of clonal hematopoiesis in patients with isolated neutropenia among patients with idiopathic cytopenia of undetermined significance (ICUS), known as ICUS-N or chronic idiopathic neutropenia (CIN) patients, is poorly defined. The current study sought to investigate the frequency and clinical significance of mutations of genes implicated in myeloid malignancies using next-generation sequencing in patients with CIN (n = 185) with a long follow-up. We found that 21 (11.35%) of 185 patients carried a total of 25 somatic mutations in 6 genes with a median variant allele frequency of 12.75%. The most frequently mutated genes were DNMT3A and TET2 involving >80% of patients, followed by IDH1/2, SRSF2, and ZRSR2. The frequency of transformation to a myeloid malignancy was low in the total group of patients (5 of 185 patients [2.70%]). However, from the transformed patients, 4 belonged to the clonal group (4 of 21 [19.05%]) and 1 to the nonclonal group (1 of 164 [0.61%]), indicating that the presence of mutation(s) confers a relative risk for transformation of 31.24 (P = .0017). The variant allele frequency of the mutant clones in the transformed patients was >10% in all cases, and the genes most frequently associated with malignant transformation were SRSF2 and IDH1. No significant differences were identified between the clonal and nonclonal groups in the severity of neutropenia. Patients with clonal disease were older compared with nonclonal patients. These data contribute to the better understanding of the heterogeneous entities underlying ICUS and highlight the importance of mutation analysis for the diagnosis and prognosis of patients with unexplained neutropenias.

The incidence and prognosis of clonal hematopoiesis in patients with isolated neutropenia among patients with idiopathic cytopenia of undetermined significance (ICUS), known as ICUS-N or chronic idiopathic neutropenia (CIN) patients, is poorly defined. The current study sought to investigate the frequency and clinical significance of mutations of genes implicated in myeloid malignancies using next-generation sequencing in patients with CIN (n = 185) with a long follow-up. We found that 21 (11.35%) of 185 patients carried a total of 25 somatic mutations in 6 genes with a median variant allele frequency of 12.75%. The most frequently mutated genes were DNMT3Aand TET2involving >80% of patients, followed by IDH1/2, SRSF2, and ZRSR2.The frequency of transformation to a myeloid malignancy was low in the total group of patients (5 of 185 patients [2.70%]). However, from the transformed patients, 4 belonged to the clonal group (4 of 21 [19.05%]) and 1 to the nonclonal group (1 of 164 [0.61%]), indicating that the presence of mutation(s) confers a relative risk for transformation of 31.24 (P= .0017). The variant allele frequency of the mutant clones in the transformed patients was >10% in all cases, and the genes most frequently associated with malignant transformation were SRSF2and IDH1.No significant differences were identified between the clonal and nonclonal groups in the severity of neutropenia. Patients with clonal disease were older compared with nonclonal patients. These data contribute to the better understanding of the heterogeneous entities underlying ICUS and highlight the importance of mutation analysis for the diagnosis and prognosis of patients with unexplained neutropenias.