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Recent findings suggest that in dual-tasking the elements of the two tasks are associated across tasks and are stored in a conjoint memory episode, meaning that the tasks are not represented as isolated task-sets. In the current study, we tested whether frequent long stimulus onset ansynchronies (SOAs) can foster the representation of two separated task-sets thereby reducing or even hindering participants to generate conjoint memory episodes-compared to an integrated task-set representation induced by frequent short SOAs. Alternatively, it is conceivable that conjoint memory episodes are an inevitable consequence of presenting two tasks within a single trial. In two dual-task experiments, we tested between consecutive trials whether repeating the stimulus-response bindings of both tasks would lead to faster responses than repeating only one of the two tasks' stimulus-response bindings. The dual-task consisted of a visual-manual search task (VST) and an auditory-manual discrimination task (ADT). Overall, the results suggest that, after processing two tasks within a single trial, generating a conjoint memory episode seems to be a default process, regardless of SOA frequency. However, the respective SOA frequency affected the participants' strategy to group the processing of the two tasks or not, thereby modulating the impact of the reactivated memory episode on task performance., (© 2024. The Author(s).)

Background: Acute symptomatic epileptic seizures are frequently seen in neurocritical care. To prevent subsequent unprovoked seizures, long-term treatments with antiseizure medications are often initiated although supporting evidence is lacking. This study aimed at prospectively assessing the risk of unprovoked seizure relapse with respect to the use of antiseizure medications. It was hypothesized that after a first acute symptomatic seizure of structural etiology, the cumulative 12-month risk of unprovoked seizure relapse is ≤ 25%., Methods: Inclusion criteria were age ≥ 18 and acute symptomatic first-ever epileptic seizure; patients with status epilepticus were excluded. Using telephone and mail interviews, participants were followed for 12 months after the acute symptomatic first seizure. Primary endpoint was the occurrence and timing of a first unprovoked seizure relapse. In addition, neuro-intensivists in Germany were interviewed about their antiseizure treatment strategies through an anonymous online survey., Results: Eleven of 122 participants with structural etiology had an unprovoked seizure relapse, resulting in a cumulative 12-month risk of 10.7% (95%CI, 4.7%-16.7%). None of 19 participants with a non-structural etiology had a subsequent unprovoked seizure. Compared to structural etiology alone, combined infectious and structural etiology was independently associated with unprovoked seizure relapse (OR 11.1; 95%CI, 1.8-69.7). Median duration of antiseizure treatment was 3.4 months (IQR 0-9.3). Seven out of 11 participants had their unprovoked seizure relapse while taking antiseizure medication; longer treatment durations were not associated with decreased risk of unprovoked seizure relapse. Following the non-representative online survey, most neuro-intensivists consider 3 months or less of antiseizure medication to be adequate., Conclusions: Even in case of structural etiology, acute symptomatic seizures bear a low risk of subsequent unprovoked seizures. There is still no evidence favoring long-term treatments with antiseizure medications. Hence, individual constellations with an increased risk of unprovoked seizure relapse should be identified, such as central nervous system infections causing structural brain damage. However, in the absence of high-risk features, antiseizure medications should be discontinued early to avoid overtreatment., (© 2023. La Société de Réanimation de Langue Francaise = The French Society of Intensive Care (SRLF).)

The most serious complication in the treatment of hemophilia A (HA) is the development of factor (F)VIII inhibitors or antidrug antibodies (ADA) occurring in 25-35% of patients with severe HA. The immunological mechanisms underlying the development of ADA against FVIII products have not been completely understood yet. Immunological danger signals associated with events such as infection or surgery have been suggested to play a critical role. In previous studies, we demonstrated that plasma-derived (pd)FVIII but not recombinant (r)FVIII can activate human monocyte-derived dendritic cells (DC) in a danger signal-dependent manner, which subsequently mediate the proliferation of autologous CD4+ T cells. In this study, we investigated the ability of plasma components, naturally present in pdFVIII products, to mediate T-cell responses. In fact, we show that addition of plasma to rFVIII plus lipopolysaccharide (LPS)-stimulated DC induces proliferation of autologous CD4+ T cells. Interestingly, although DC pulsed with LPS plus plasma induce T-cell proliferation upon co-culture, the addition of FVIII significantly increases the number of proliferating as well as FVIII-specific CD4+ T cells. Total proliferating CD4+ T cells and FVIII-specific subsets were identified mainly as central memory T cells. Experiments using blocking antibodies and receptor antagonists revealed that the complement proteins C3a and, to a lesser extent, C5a are critically involved in these LPS-mediated T-cell responses. Collectively, our results indicate that complement proteins are potent drivers of T-cell responses to FVIII. Data presented provide a model how event-related substitution of FVIII in HA patients might contribute to inhibitor development.

Background: Previous international studies have shown that over-indebtedness is associated with poor health. However, in Switzerland research addressing over-indebtedness is widely lacking, strongly needed and particularly important because it is evidently a rising but still commonly tabooed, socially "undesired" and highly stigmatized phenomenon that is rarely discussed and largely ignored and unexplored., Methods: A cross-sectional survey was conducted among over-indebted adults seeking advice from one of the four official debt advisory centers in the Canton of Zurich. The survey finally included 219 respondents participating voluntarily and anonymously. This sample was then linked with a comparable subsample of the nationally representative Swiss Health Survey of 2017, namely 1,997 respondents of the same age from the Canton of Zurich. For reasons of comparability identical health questions and measures were taken from the Swiss Health Survey and used in the over-indebtedness survey. The pooled or combined dataset covered a total of 2,216 adult individuals., Results: Remarkably high prevalence rates and relative risks of poor self-rated health, severe musculoskeletal and sleep disorders and moderate to severe depression were observed among over-indebted individuals compared to the general population. More than 50% of the over-indebted individuals had poor general health or moderate to severe depression compared to the general population with 14% and 7%, respectively. And far above one third of the over-indebted but 'only' between 6% and 8% of the general population showed severe musculoskeletal disorders and sleep disorders. Even after adjustment for various control variables and covariates, over-indebtedness increased the odds ratios for poor health outcomes consistently and dramatically, i.e. by a factor of 8 and more (aOR = 8.5-11.6)., Conclusions: Over-indebtedness in Switzerland has particularly negative effects on various aspects of the health of the persons concerned, irrespective of their demographic characteristics and their social and employment status., Competing Interests: The authors have declared that no competing interests exist.

Background and Objectives: In 2020, a wide range of hygiene measures was implemented to mitigate infections caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In consequence, pulmonary infections due to other respiratory pathogens also decreased. Here, we evaluated the number of bacterial and viral meningitis and encephalitis cases during the coronavirus disease 2019 (COVID-19) pandemic., Methods: In a multicentre retrospective analysis of data from January 2016 until December 2020, numbers of patients diagnosed with bacterial meningitis and other types of CNS infections (such as viral meningitis and encephalitis) at 26 German hospitals were studied. Furthermore, the number of common meningitis-preceding ear-nose-throat infections (sinusitis, mastoiditis and otitis media) was evaluated., Results: Compared to the previous years, the total number of patients diagnosed with pneumococcal meningitis was reduced (n = 64 patients/year in 2020 vs. n = 87 to 120 patients/year between 2016 and 2019, all p < 0.05). Additionally, the total number of patients diagnosed with otolaryngological infections was significantly lower (n = 1181 patients/year in 2020 vs. n = 1525 to 1754 patients/year between 2016 and 2019, all p < 0.001). We also observed a decline in viral meningitis and especially enterovirus meningitis (n = 25 patients/year in 2020 vs. n = 97 to 181 patients/year between 2016 and 2019, all p < 0.001)., Discussion: This multicentre retrospective analysis demonstrates a decline in the number of patients treated for viral and pneumococcal meningitis as well as otolaryngological infections in 2020 compared to previous years. Since the latter often precedes pneumococcal meningitis, this may point to the significance of the direct spread of pneumococci from an otolaryngological focus such as mastoiditis to the brain as one important pathophysiological route in the development of pneumococcal meningitis., (© 2022. The Author(s).)

Objectives: The aim is to investigate whether and why over-indebted individuals in German-speaking Switzerland have poorer mental health than the general population., Methods: A cross-sectional study among over-indebted people in the canton of Zurich was conducted in 2019. The study population (n = 219) was compared to the cantonal subsample of the general adult population selected from the nationally representative sample of the Swiss Health Survey 2017 (n = 1,997). Bivariate and multivariate statistical analyses were used to examine associations between over-indebtedness, mastery and health outcomes like mental stress and depression., Results: Over-indebted people have poorer mental health and weaker mastery than the general population. Low mastery is the strongest predictor of poor mental health (beta coefficient = 0.58/-0.62 for mental stress/depression respectively) among the over-indebted, followed by the perception of one's health being affected by over-indebtedness (beta coefficient = -0.19/0.15). The amount of debt, anticipated time until repayment of debt and duration of indebtedness had no predictive effects., Conclusion: Surprisingly, traditional debt parameters cannot explain the poor mental health of the over-indebted, in contrast to a strong sense of mastery, which was identified as a highly protective factor.

Several molecular aberrations affect the prognosis of patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with excess blasts (EB). This study aimed to determine the incidence and clinical impact of molecular genetic aberrations in Thai patients with AML and MDS-EB, detected by the next-generation sequencing (NGS) technique. This prospective, observational study was conducted between 2018 and 2020 on newly diagnosed Thai AML or MDS-EB patients aged above 15 years. NGS was performed using a custom amplicon-based targeted enrichment assay for 42 genes recurrently mutated in myeloid neoplasms. The molecular results were correlated with baseline patient and disease characteristics as well as outcomes. Forty-nine patients were enrolled in this study. The median age was 56 years (interquartile range [IQR], 44-64), with nearly equal proportions of males and females. The median number of mutations was 3 (IQR, 2-4). The most frequent alterations were FLT3 internal tandem duplications (ITD) (28.6%), DNMT3A (24.5%), and WT1 (22.4%) mutations. FLT3-ITD was more frequent in the de novo AML group than in the MDS/secondary AML group, whereas in the MDS/secondary AML group, ASXL1, ETV6, and SRSF2 mutations were more frequent. Patients aged greater than 65 years and patients with mutated TP53 were more likely to have inferior overall survival from multivariate analysis. FLT3-ITD was the most common mutation among newly diagnosed Thai AML patients. TP53 mutation and advanced age were independent adverse factors for survival outcome. The genetic landscapes of AML patients vary between national populations. Thai Clinical Trials Registry identifier: TCTR20190227003., (© 2021. The Author(s).)

In the international randomized phase 3 RATIFY (Randomized AML Trial In FLT3 in patients less than 60 Years old) trial, the multikinase inhibitor midostaurin significantly improved overall and event-free survival in patients 18 to 59 years of age with FLT3-mutated acute myeloid leukemia (AML). However, only 59% of patients in the midostaurin arm achieved protocol-specified complete remission (CR), and almost half of patients achieving CR relapsed. To explore underlying mechanisms of resistance, we studied patterns of clonal evolution in patients with FLT3-internal tandem duplications (ITD)-positive AML who were entered in the RATIFY or German-Austrian Acute Myeloid Leukemia Study Group 16-10 trial and received treatment with midostaurin. To this end, paired samples from 54 patients obtained at time of diagnosis and at time of either relapsed or refractory disease were analyzed using conventional Genescan-based testing for FLT3-ITD and whole exome sequencing. At the time of disease resistance or progression, almost half of the patients (46%) became FLT3-ITD negative but acquired mutations in signaling pathways (eg, MAPK), thereby providing a new proliferative advantage. In cases with FLT3-ITD persistence, the selection of resistant ITD clones was found in 11% as potential drivers of disease. In 32% of cases, no FLT3-ITD mutational change was observed, suggesting either resistance mechanisms bypassing FLT3 inhibition or loss of midostaurin inhibitory activity because of inadequate drug levels. In summary, our study provides novel insights into the clonal evolution and resistance mechanisms of FLT3-ITD-mutated AML under treatment with midostaurin in combination with intensive chemotherapy., (© 2021 by The American Society of Hematology.)

Monitoring of measurable residual disease (MRD) provides prognostic information in patients with Nucleophosmin1-mutated (NPM1mut) acute myeloid leukemia (AML) and represents a powerful tool to evaluate treatment effects within clinical trials. We determined NPM1mut transcript levels (TLs) by quantitative reverse-transcription polymerase chain reaction and evaluated the prognostic impact of NPM1mut MRD and the effect of gemtuzumab ozogamicin (GO) on NPM1mut TLs and the cumulative incidence of relapse (CIR) in patients with NPM1mut AML enrolled in the randomized phase 3 AMLSG 09-09 trial. A total of 3733 bone marrow (BM) samples and 3793 peripheral blood (PB) samples from 469 patients were analyzed. NPM1mut TL log10 reduction ≥ 3 and achievement of MRD negativity in BM and PB were significantly associated with a lower CIR rate, after 2 treatment cycles and at end of treatment (EOT). In multivariate analyses, MRD positivity was consistently revealed to be a poor prognostic factor in BM and PB. With regard to treatment effect, the median NPM1mut TLs were significantly lower in the GO-Arm across all treatment cycles, resulting in a significantly greater proportion of patients achieving MRD negativity at EOT (56% vs 41%; P = .01). The better reduction in NPM1mut TLs after 2 treatment cycles in MRD positive patients by the addition of GO led to a significantly lower CIR rate (4-year CIR, 29.3% vs 45.7%, P = .009). In conclusion, the addition of GO to intensive chemotherapy in NPM1mut AML resulted in a significantly better reduction in NPM1mut TLs across all treatment cycles, leading to a significantly lower relapse rate., (© 2020 by The American Society of Hematology.)

Core-binding factor (CBF) acute myeloid leukemia (AML) encompasses AML with inv(16)(p13.1q22) and AML with t(8;21)(q22;q22.1). Despite sharing a common pathogenic mechanism involving rearrangements of the CBF transcriptional complex, there is growing evidence for considerable genotypic heterogeneity. We comprehensively characterized the mutational landscape of 350 adult CBF-AML [inv(16): n = 160, t(8;21): n = 190] performing targeted sequencing of 230 myeloid cancer-associated genes. Apart from common mutations in signaling genes, mainly NRAS, KIT, and FLT3, both CBF-AML entities demonstrated a remarkably diverse pattern with respect to the underlying cooperating molecular events, in particular in genes encoding for epigenetic modifiers and the cohesin complex. In addition, recurrent mutations in novel collaborating candidate genes such as SRCAP (5% overall) and DNM2 (6% of t(8;21) AML) were identified. Moreover, aberrations altering transcription and differentiation occurred at earlier leukemic stages and preceded mutations impairing proliferation. Lasso-penalized models revealed an inferior prognosis for t(8;21) AML, trisomy 8, as well as FLT3 and KIT exon 17 mutations, whereas NRAS and WT1 mutations conferred superior prognosis. Interestingly, clonal heterogeneity was associated with a favorable prognosis. When entering mutations by functional groups in the model, mutations in genes of the methylation group (ie, DNMT3A, TET2) had a strong negative prognostic impact., (© 2020 by The American Society of Hematology.)

In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern. Despite nondetectable CNS leukemia in many cases, prophylactic CNS-directed conventional intrathecal chemotherapy is required for relapse-free survival, indicating subclinical CNS manifestation in most patients. However, CNS-directed therapy is associated with long-term sequelae, including neurocognitive deficits and secondary neoplasms. Therefore, molecular mechanisms and pathways mediating leukemia-cell entry into the CNS need to be understood to identify targets for prophylactic and therapeutic interventions and develop alternative CNS-directed treatment strategies. In this study, we analyzed leukemia-cell entry into the CNS using a primograft ALL mouse model. We found that primary ALL cells transplanted onto nonobese diabetic/severe combined immunodeficiency mice faithfully recapitulated clinical and pathological features of meningeal infiltration seen in patients with ALL. ALL cells that had entered the CNS and were infiltrating the meninges were characterized by high expression of vascular endothelial growth factor A ( VEGF ). Although cellular viability, growth, proliferation, and survival of ALL cells were found to be independent of VEGF, transendothelial migration through CNS microvascular endothelial cells was regulated by VEGF. The importance of VEGF produced by ALL cells in mediating leukemia-cell entry into the CNS and leptomeningeal infiltration was further demonstrated by specific reduction of CNS leukemia on in vivo VEGF capture by the anti-VEGF antibody bevacizumab. Thus, we identified a mechanism of ALL-cell entry into the CNS, which by targeting VEGF signaling may serve as a novel strategy to control CNS leukemia in patients, replacing conventional CNS-toxic treatment., (© 2017 by The American Society of Hematology.)

Serious infection is a recognized complication of intravenous drug abuse and a major cause of morbidity and mortality among intravenous drug users. Trends in rates of serious infection and the associated costs related to opioid abuse/dependence have not been previously investigated in the context of the US opioid use epidemic. Our study, using a nationally representative sample of US inpatient hospitalizations, showed that hospitalizations related to opioid abuse/dependence both with and without associated serious infection significantly increased from 2002 to 2012, respectively, from 301,707 to 520,275 and from 3,421 to 6,535. Additionally, inpatient charges for both types of hospitalizations almost quadrupled over the same time period, reaching almost $15 billion for hospitalizations related to opioid abuse/dependence and more than $700 million for those related to associated infection in 2012. Medicaid was the most common primary payer for both types of hospitalizations. Our results characterize the financial burden on the health care system related to opioid abuse/dependence and one of the more serious downstream complications of this epidemic: serious infection. These findings have important implications for the hospitals and government agencies that disproportionately shoulder these costs and for clinicians, researchers, and policy makers interested in estimating the potential impact of targeted public health interventions on a national level., (Project HOPE—The People-to-People Health Foundation, Inc.)

It is known that acoustic heart sounds carry significant information about the mechanical activity of the heart. In this paper, we present a novel type of cardiac monitoring based on heart sound analysis. Specifically, we study two morphological features and their associations with physiological changes from the baseline state. The framework is demonstrated on recordings during laparoscopic surgeries of 15 patients. Insufflation, which is performed during laparoscopic surgery, provides a controlled, externally induced cardiac stress, enabling an analysis of each patient with respect to their own baseline. We demonstrate that the proposed features change during cardiac stress, and the change is more significant for patients with cardiac problems. Furthermore, we show that other well-known ECG morphology features are less sensitive in this specific cardiac stress experiment.

The multiaxial nature of DSM-III has stimulated interest in the personality disorders. There are also indications that it has produced an increase in their diagnosis. However, there is clinical and psychometric evidence that a personality evaluation undertaken while a patient is in a dysphoric mental state may distort or misrepresent traits, the so-called trait-state problem in personality assessment. The present study appears to be the first to investigate this phenomenon with a clinical interview rather than with personality tests. It examined the effect of anxiety, depression, and level of global impairment on the diagnosis of personality disorder and the assessment of the criteria for the individual Axis II disorders. Eighty-four patients, most of whom had current Axis I diagnoses, were evaluated by seven experienced clinicians with a new semistructured interview, the Personality Disorder Examination. The sample evidenced a trend toward acknowledging fewer maladaptive personality traits at follow-up than at entry. There was no evidence, however, that anxiety or depression had affected either the diagnosis of a personality disorder or the criteria associated with most of the individual personality disorders.

The synthesis of the isomeric series 6-chloro-7-sulfamoyl- and 7-chloro-6-sulfamoyl-1(2H)-phthalazinones (1 and 2) and 6-chloro-7-sulfamoyl- and 7-chloro-6-sulfamoyl-3,4-dihydo-1(2H)-phthalazinones (3 and 4), combining structural features characteristic to furosemide and hydralazine, is described, the mechanism of the formation of 1 and 2 is discussed, and their structure-activities relationships are studied. Preliminary screening in the rat shows that series 1 and 3 exhibit diuretic and saluretic activity similar to that of chlorothiazide with, however, Na+/K+ ratios more favorable than chlorothiazide and furosemide. The compounds of series 2 and 4 are practically inactive. All four series show initial antihypertensive activity lower than that of hydralazine. However, compounds 1a, 1c, and 4a show a higher activity at 8 and/or 24 h after administration and thus may offer a unique combination of a "loop" diuresis with direct long-acting peripheral vasodilating effects.