Subtle Patterns of Altered Responsiveness to Delayed Auditory Feedback during Finger Tapping in People Who Stutter.

Differences in sensorimotor integration mechanisms have been observed between people who stutter (PWS) and controls who do not. Delayed auditory feedback (DAF) introduces timing discrepancies between perception and action, disrupting sequence production in verbal and non-verbal domains. While DAF consistently enhances speech fluency in PWS, its impact on non-verbal sensorimotor synchronization abilities remains unexplored. A total of 11 PWS and 13 matched controls completed five tasks: (1) unpaced tapping; (2) synchronization-continuation task (SCT) without auditory feedback; (3) SCT with DAF, with instruction either to align the sound in time with the metronome; or (4) to ignore the sound and align their physical tap to the metronome. Additionally, we measured participants' sensitivity to detecting delayed feedback using a (5) delay discrimination task. Results showed that DAF significantly affected performance in controls as a function of delay duration, despite being irrelevant to the task. Conversely, PWS performance remained stable across delays. When auditory feedback was absent, no differences were found between PWS and controls. Moreover, PWS were less able to detect delays in speech and tapping tasks. These findings show subtle differences in non-verbal sensorimotor performance between PWS and controls, specifically when action-perception loops are disrupted by delays, contributing to models of sensorimotor integration in stuttering.

Elevated levels of citrullinated fibrinogen in patients with cancer.

Neutrophil released peptidyl arginine deiminase 4 (PAD4) converts arginine residues on plasma proteins into citrulline. Here, we developed an assay to quantify citrullinated fibrinogen. We employed a biotin-conjugated phenylglyoxal (biotin-phenylglyoxal (PG)) compound that selectively labels citrulline. Patient samples were derived from a multicenter prospective cohort study that aimed to identify cancer patients at high risk for venous thromboembolism (VTE). Our data show that cancer patients have higher (median 2-fold increased) citrullinated fibrinogen levels when compared to normal human plasma and a cohort of healthy donors. Our results show that citrullination of fibrinogen is a common posttranslational modification in patients with cancer.

Adjuvant Hyperthermic Intraperitoneal Chemotherapy in Patients With Locally Advanced Colon Cancer (COLOPEC): 5-Year Results of a Randomized Multicenter Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Whether adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) might prevent peritoneal metastases after curative surgery for high-risk colon cancer is an ongoing debate. This study aimed to determine 5-year oncologic outcomes of the randomized multicenter COLOPEC trial, which included patients with clinical or pathologic T4N0-2M0 or perforated colon cancer and randomly assigned (1:1) to either adjuvant systemic chemotherapy and HIPEC (n = 100) or adjuvant systemic chemotherapy alone (n = 102). HIPEC was performed using a one-time administration of oxaliplatin (460 mg/m2, 30 minutes, 42°C, concurrent fluorouracil/leucovorin intravenously), either simultaneously (9%) or within 5-8 weeks (91%) after primary tumor resection. Outcomes were analyzed according to the intention-to-treat principle. Long-term data were available of all 202 patients included in the COLOPEC trial, with a median follow-up of 59 months (IQR, 54.5-64.5). No significant difference was found in 5-year overall survival rate between patients assigned to adjuvant HIPEC followed by systemic chemotherapy or only adjuvant systemic chemotherapy (69.6% v 70.9%, log-rank; P = .692). Five-year peritoneal metastases rates were 63.9% and 63.2% (P = .907) and 5-year disease-free survival was 55.7% and 52.3% (log-rank; P = .875), respectively. No differences in quality-of-life outcomes were found. Our findings implicate that adjuvant HIPEC should still be performed in trial setting only.

Contact system and intrinsic pathway activation in patients with advanced pancreatic cancer: a prospective cohort study.

BACKGROUND: Despite high risk of venous thromboembolism (VTE) in patients with pancreatic cancer, there are little data on contact system activation in these patients. OBJECTIVES: To quantify contact system and intrinsic pathway activation and subsequent VTE risk in patients with pancreatic cancer. METHODS: Patients with advanced pancreatic cancer were compared with controls. Blood was drawn at baseline and patients were followed for 6 months. Complexes of proteases with their natural inhibitors, C1-esterase inhibitor (C1-INH), antithrombin (AT), or alpha-1 antitrypsin (α1at), were measured for complexes containing kallikrein (PKa:C1-INH), factor (F)XIIa (FXIIa:C1-INH), and FXIa (FXIa:C1-INH, FXIa:AT, FXIa:α1at). The association of cancer with complex levels was assessed in a linear regression model, adjusted for age, sex, and body mass index. In a competing risk regression model, we assessed associations between complex levels and VTE. RESULTS: One hundred nine patients with pancreatic cancer and 22 controls were included. The mean age was 66 years (SD, 8.4) in the cancer cohort and 52 years (SD, 10.1) in controls. In the cancer cohort, 18 (16.7%) patients developed VTE during follow-up. In the multivariable regression model, pancreatic cancer was associated with increased complexes of PKa:C1-INH (P < .001), FXIa:C1-INH (P < .001), and FXIa:AT (P < .001). High FXIa:α1at (subdistribution hazard ratio, 1.48 per log increase; 95% CI, 1.02-2.16) and FXIa:AT (subdistribution hazard ratio, 2.78 highest vs lower quartiles; 95% CI, 1.10-7.00) were associated with VTE. CONCLUSION: Complexes of proteases with their natural inhibitors were elevated in patients with cancer. These data suggest that the contact system and intrinsic pathway activation are increased in patients with pancreatic cancer.

Mesenteric occlusive disease of the inferior mesenteric artery is associated with anastomotic leak after left-sided colon and rectal cancer surgery: a retrospective cohort study.

PURPOSE: Anastomotic leak (AL) is a serious complication following colorectal surgery. Atherosclerosis causes inadequate anastomotic perfusion and is suggested to be a risk factor for AL. The aim of this study was to investigate the association of mesenteric occlusive disease on preoperative computed tomography (CT) scan with AL after left-sided colon or rectal cancer surgery. METHODS: This was a retrospective, multicenter cohort study including 1273 patients that underwent left-sided or rectal cancer resection between 2009 and 2018 from three hospitals in the Netherlands. AL patients were 1:1 matched with non-leak patients and preoperative contrast-enhanced CT-scans were retrospectively analyzed for mesenteric atherosclerotic lesions. The main outcome measure was the presence of mesenteric occlusive disease on the preoperative CT-scan. RESULTS: Anastomotic leak developed in 6% of 1273 patients (N = 76). Low anterior resection and stage I-III disease were statistically significant associated with AL (p = 0.01, p = 0.04). No other statistically significant differences in patient characteristics between AL and non-leak patients were found. A clinically significant stenosis (≥ 70-100%) of the inferior mesenteric artery was statistically significant more frequent present in AL patients, compared to non-leak patients (p < 0.01). No statistically significant differences in the presence of mesenteric occlusive disease of the celiac artery and superior mesenteric artery between AL patients and non-leak patients were found. CONCLUSION: Mesenteric occlusive disease of the IMA on preoperative CT-scan is associated with AL after left-sided colon or rectal resection for cancer. Preoperative identification of high-risk patients with a preoperative CT-scan of the mesenteric vasculature might be useful to reduce the risk of AL.

Growth differentiation factor-15 for prediction of bleeding in cancer patients.

BACKGROUND: Growth differentiation factor-15 (GDF-15) is a strong predictor for bleeding in patients with atrial fibrillation, but there are no data on cardiovascular outcomes for this biomarker in cancer patients. Bleeding risk assessment is important in cancer patients when considering primary thromboprophylaxis because it is associated with an increased bleeding risk. OBJECTIVES: To evaluate GDF-15 as predictor for bleeding events in cancer patients previously enrolled in the AVERT trial. PATIENTS/METHODS: In this trial, 574 participants were randomized to prophylactic apixaban or placebo and followed for 180 days for venous thromboembolism, major bleeding, clinically relevant nonmajor bleeding, and any bleeding. Plasma concentrations of GDF-15 were measured centrally with the Elecsys GDF-15 commercial assay kit (Roche Diagnostics GmbH). RESULTS: In apixaban recipients, the area under the receiver operator characteristic curve of GDF-15 for major bleeding was 0.73 (95% confidence interval [CI], 0.44-1.00). Compared with the lowest GDF-15 tertile (<1470 ng/L), major bleeding risk was significantly higher in the highest tertile (≥2607 ng/L; hazard ratio [HR] 3.19; 95% CI, 2.41-4.22), also when adjusting for sex, age, antiplatelet use, and gastrointestinal cancer (adjusted HR 2.80; 95% CI, 1.91-4.11). GDF-15 was also significantly associated with clinically relevant nonmajor bleeding (adjusted HR 1.67; 95% CI, 1.08-2.58) and any bleeding (adjusted HR 2.12; 95% CI, 1.38-3.25). CONCLUSIONS: Although hypothesis generating, this is the first study to show that GDF-15 predicts bleeding in cancer patients receiving thromboprophylaxis.

Risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer using edoxaban.

BACKGROUND: In the Hokusai VTE Cancer study, the risk of major bleeding was 2.9% higher in the edoxaban group compared with the dalteparin group, mainly due to more gastrointestinal bleedings in patients with gastrointestinal cancer. The identification of risk factors for gastrointestinal bleeding may help to guide the use of DOACs in these patients. OBJECTIVES: To evaluate risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. PATIENTS/METHODS: In this nested case-control study in patients with gastrointestinal cancer randomized to edoxaban in the Hokusai VTE Cancer study, cases (patients with clinically relevant gastrointestinal bleeding during treatment) were randomly matched to three controls (patients who had no gastrointestinal bleeding). Data for the 4-week period prior to bleeding were retrospectively collected. Odds ratios (ORs) were calculated in a crude conditional logistic regression model and a multivariable model adjusted for age, sex, and cancer type. RESULTS: Twenty-four cases and 64 matched controls were included. In the multivariable analysis, advanced cancer, defined as regionally advanced or metastatic cancer (OR 3.6, 95% CI 1.01-12.6) and low hemoglobin levels (OR 4.8, 95% CI 1.5-16.0) were significantly associated with bleeding. There was no significant difference in patients with resected tumors (OR 0.4, 95% CI 0.1-1.4), or in patients on chemotherapy (OR 1.3, 95% CI 0.5-3.5). CONCLUSION: Advanced cancer and low hemoglobin levels were associated with an increased risk of gastrointestinal bleeding in patients with gastrointestinal cancer receiving edoxaban. We were unable to identify other risk factors, mainly due to limited statistical power.

The effect of non-pharmaceutical interventions on the demand for health care and on mortality: evidence from COVID-19 in Scandinavia.

We study the effectiveness of non-pharmaceutical interventions (NPIs) against COVID-19 on the allocation of scarce resources in the hospital sector in Scandinavia. Denmark and Norway imposed strict NPIs, but Sweden followed an extraordinarily lenient approach. We use an event study to compare COVID-19 hospitalizations, intensive-care (ICU) patients, and deaths in Sweden with Denmark and Norway. The outcome variables initially follow a common trend, but diverge 2-3 weeks after lockdown. Both the timing of the effect and the similarity in the trend between Denmark and Norway are highly consistent with a causal effect of the lockdown. We use our event study to build a counterfactual model that predicts the outcome variables for Denmark and Norway if they had followed Sweden's approach. In the absence of strict NPIs, the peak number of hospitalizations would have been 2.5 (3.5) times as large in Denmark (Norway). Overall, Denmark (Norway) would have had 334 (671) percent more hospital-patient days, 277 (379) percent more ICU-patient days, and 402 (1015) percent more deaths. The benefit of lockdown in terms of healthcare and mortality costs amounts to between 1 and 4 (0.9 and 3.5) percent of GDP in Denmark (Norway).

Recognition memory for human motor learning.

Motor skill retention is typically measured by asking participants to reproduce previously learned movements from memory. The analog of this retention test (recall memory) in human verbal memory is known to underestimate how much learning is actually retained. Here we asked whether information about previously learned movements, which can no longer be reproduced, is also retained. Following visuomotor adaptation, we used tests of recall that involved reproduction of previously learned movements and tests of recognition in which participants were asked whether a candidate limb displacement, produced by a robot arm held by the subject, corresponded to a movement direction that was experienced during active training. The main finding was that 24 h after training, estimates of recognition memory were about twice as accurate as those of recall memory. Thus, there is information about previously learned movements that is not retrieved using recall testing but can be accessed in tests of recognition. We conducted additional tests to assess whether, 24 h after learning, recall for previously learned movements could be improved by presenting passive movements as retrieval cues. These tests were conducted immediately prior to recall testing and involved the passive playback of a small number of movements, which were spread across the workspace and included both adapted and baseline movements, without being marked as such. This technique restored recall memory for movements to levels close to those of recognition memory performance. Thus, somatic information may enable retrieval of otherwise inaccessible motor memories.

Pulmonary embolism at autopsy in cancer patients.

BACKGROUND: Pulmonary embolism (PE) is a potentially fatal disease, but data on the incidence of fatal PE in cancer patients are scant. OBJECTIVE: We sought to estimate the proportion of cancer patients with PE at autopsy. METHODS: For this retrospective cohort study, all autopsy reports of cancer patients were retrieved from PALGA: Dutch Pathology Registry and used for data extraction. The primary outcome was PE at time of autopsy, defined as any clot obstructing a pulmonary artery. The secondary outcome was venous thromboembolism, defined as the composite of thrombotic PE, deep vein thrombosis, splanchnic vein thrombosis, or internal jugular vein thrombosis. RESULTS: A total of 9571 cancer patients were included. In 1191 (12.4%; 95% confidence interval [CI], 11.8-13.1) patients, one or more PE events were observed at autopsy, of whom 1074 (90.2%) had a thrombotic embolism, 168 (14.1%) a tumor embolism, 9 (0.8%) a septic embolism, 7 (0.6%) a fat tissue embolism, and 3 (0.3%) a bone marrow embolism. Among patients with PE for whom the cause of death was specified in the autopsy report, death was considered PE-related in 642 patients (66.7%), which was 6.7% of the total study population. Venous thromboembolism was observed in 1223 (12.8%; 95% CI, 12.1-13.5) patients. CONCLUSION: The proportion of PE in cancer patients at autopsy is substantial. Although the study population is not representative for the total cancer population, it suggests that PE is an important disease complication in cancer patients.

Primary thromboprophylaxis in ambulatory cancer patients with a high Khorana score: a systematic review and meta-analysis.

Guidelines suggest thromboprophylaxis for ambulatory cancer patients starting chemotherapy with an intermediate to high risk of venous thromboembolism (VTE) according to Khorana score. Data on thromboprophylaxis efficacy in different Khorana score risk groups remain ambiguous. We sought to evaluate thromboprophylaxis in patients with an intermediate- to high-risk (≥2 points) Khorana score and an intermediate-risk score (2 points) or high-risk score (≥3 points) separately. MEDLINE, Embase, and CENTRAL were searched for randomized controlled trials (RCTs) comparing thromboprophylaxis with placebo or standard care in ambulatory cancer patients. Outcomes were VTE, major bleeding, and all-cause mortality. Relative risks (RRs) were calculated in a profile-likelihood random-effects model. Six RCTs were identified, involving 4626 cancer patients. Thromboprophylaxis with direct oral anticoagulants (DOACs) or low molecular weight heparin (LMWH) significantly reduced VTE risk in intermediate- to high-risk (RR, 0.51; 95% confidence interval [CI], 0.34-0.67), intermediate-risk (RR, 0.58; 95% CI, 0.36-0.83), and high-risk patients (RR, 0.45; 95% CI, 0.28-0.67); the numbers needed to treat (NNTs) were 25 (intermediate to high risk), 34 (intermediate risk), and 17 (high risk), respectively. There was no significant difference in major bleeding (RR, 1.06; 95% CI, 0.69-1.67) or all-cause mortality (RR, 0.90; 95% CI, 0.82-1.01). The numbers needed to harm (NNHs) for major bleeding in intermediate- to high-risk, intermediate-risk, and high-risk patients were 1000, -500, and 334, respectively. The overall NNH was lower in DOAC studies (100) versus LMWH studies (-500). These findings indicate thromboprophylaxis effectively reduces the risk of VTE in patients with an intermediate- to high-risk Khorana score, although the NNT is twice as high for intermediate-risk patients compared with high-risk patients.

Diagnostic and Therapeutic Management of Upper Extremity Deep Vein Thrombosis.

Upper extremity deep vein thrombosis (UEDVT) accounts for 5% of all deep vein thromboses (DVTs). UEDVT may be complicated by post thrombotic syndrome and pulmonary embolism, and early recognition and prompt start of anticoagulant treatment are key. Primary UEDVT, also known as Paget-von Schrötter syndrome, is associated with repeated or sudden physical activity of the upper arm and venous outflow obstruction due to anatomical variations. Secondary UEDVT is often associated with malignancy or use of intravenous devices, such as central venous catheters or pacemaker leads. Although the diagnosis and treatment of UEDVT have many similarities with DVT of the lower extremities, knowledge of specific aspects regarding UEDVT is important to guide optimal management. In this review, we will discuss the epidemiology, diagnosis, and treatment of UEDVT based on the current literature.

Direct oral anticoagulants for cancer-associated venous thromboembolism: a systematic review and meta-analysis.

Direct oral anticoagulants (DOACs) are an emerging treatment option for patients with cancer and acute venous thromboembolism (VTE), but studies have reported inconsistent results. This systematic review and meta-analysis compared the efficacy and safety of DOACs and low-molecular-weight heparins (LMWHs) in these patients. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and conference proceedings were searched to identify relevant randomized controlled trials. Additional data were obtained from the original authors to homogenize definitions for all study outcomes. The primary efficacy and safety outcomes were recurrent VTE and major bleeding, respectively. Other outcomes included the composite of recurrent VTE and major bleeding, clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality. Summary relative risks (RRs) were calculated in a random effects meta-analysis. In the primary analysis comprising 2607 patients, the risk of recurrent VTE was nonsignificantly lower with DOACs than with LMWHs (RR, 0.68; 95% CI, 0.39-1.17). Conversely, the risks of major bleeding (RR, 1.36; 95% CI, 0.55-3.35) and CRNMB (RR, 1.63; 95% CI, 0.73-3.64) were nonsignificantly higher. The risk of the composite of recurrent VTE or major bleeding was nonsignificantly lower with DOACs than with LMWHs (RR, 0.86; 95% CI, 0.60-1.23). Mortality was comparable in both groups (RR, 0.96; 95% CI, 0.68-1.36). Findings were consistent during the on-treatment period and in those with incidental VTE. In conclusion, DOACs are an effective treatment option for patients with cancer and acute VTE, although caution is needed in patients at high risk of bleeding.

Primary Thromboprophylaxis in Ambulatory Cancer Patients: Where Do We Stand?

Venous thromboembolism (VTE), comprising deep-vein thrombosis and pulmonary embolism, is a frequent complication in ambulatory cancer patients. Despite the high risk, routine thromboprophylaxis is not recommended because of the high number needed to treat and the risk of bleeding. Two recent trials demonstrated that the number needed to treat can be reduced by selecting cancer patients at high risk for VTE with prediction scores, leading the latest guidelines to suggest such an approach in clinical practice. Yet, the interpretation of these trial results and the translation of the guideline recommendations to clinical practice may be less straightforward. In this clinically-oriented review, some of the controversies are addressed by focusing on the burden of VTE in cancer patients, discussing the performance of available risk assessment scores, and summarizing the findings of recent trials. This overview can help oncologists, hematologists, and vascular medicine specialists decide about thromboprophylaxis in ambulatory cancer patients.

Clinical implications of incidental venous thromboembolism in cancer patients.

INTRODUCTION: In cancer patients, current guidance suggests similar treatment for incidental and symptomatic venous thromboembolism (VTE), mainly based on retrospective data. We aimed to evaluate anticoagulant therapy in cancer patients with incidental and symptomatic VTE. METHODS: The Hokusai VTE Cancer Study was a randomised controlled trial comparing edoxaban with dalteparin for cancer-associated VTE. The primary outcome was the composite of first recurrent VTE or major bleeding. Secondary outcomes included major bleeding, recurrent VTE and mortality. Outcomes in patients with incidental and symptomatic VTE were evaluated during the 12-month study period. RESULTS: 331 patients with incidental VTE and 679 patients with symptomatic VTE were enrolled, of whom the index event was confirmed by an independent radiologist. Median durations of anticoagulant treatment were 195 and 189 days, respectively. In patients with incidental VTE, the primary outcome occurred in 12.7% of patients, major bleeding in 6.6% of patients and recurrent VTE in 7.9% of patients. Out of the 26 VTE recurrences in patients with incidental VTE, five (31%) were incidental, seven (44%) were symptomatic and four (25%) were deaths for which pulmonary embolism could not be ruled out. In patients with symptomatic VTE, the primary outcome occurred in 13.8% of patients, major bleeding in 4.9% of patients and recurrent VTE in 10.9% of patients. All-cause mortality was similar in both groups. CONCLUSION: Clinical adverse outcomes are substantial in both cancer patients with incidental and symptomatic VTE, supporting current guideline recommendations that suggest treating incidental VTE in the same manner as symptomatic VTE.

Motivation and social-cognitive abilities in older adults: Convergent evidence from self-report measures and cardiovascular reactivity.

Recently, some authors have suggested that age-related impairments in social-cognitive abilities-emotion recognition (ER) and theory of mind (ToM)-may be explained in terms of reduced motivation and effort mobilization in older adults. We examined performance on ER and ToM tasks, as well as corresponding control tasks, experimentally manipulating self-involvement. Sixty-one older adults and 57 young adults were randomly assigned to either a High or Low self-involvement condition. In the first condition, self-involvement was raised by telling participants were told that good task performance was associated with a number of positive, personally relevant social outcomes. Motivation was measured with both subjective (self-report questionnaire) and objective (systolic blood pressure reactivity-SBP-R) indices. Results showed that the self-involvement manipulation did not increase self-reported motivation, SBP-R, or task performance. Further correlation analyses focusing on individual differences in motivation did not reveal any association with performance, in either young or older adults. Notably, we found age-related decline in both ER and ToM, despite older adults having higher motivation than young adults. Overall, the present results were not consistent with previous claims that motivation affects older adults' social-cognitive performance, opening the route to potential alternative explanations.

A miniaturized push-pull-perfusion probe for few-second sampling of neurotransmitters in the mouse brain.

Measuring biomolecule concentrations in the brain of living animals, in real time, is a challenging task, especially when detailed information at high temporal resolution is also required. Traditionally, microdialysis probes are used that generally have sampling areas in the order of about 1 mm2, and provide information on concentrations with a temporal resolution of at least several minutes. In this paper, we present a novel miniaturized push-pull perfusion sampling probe that uses an array of small 3 µm-wide sampling channels to sample neurotransmitters at a typical recovery rate of 61%, with a reduced risk of clogging. The added feature to segment the dialysate inside the probe into small water-in-decane droplets enables the detection of concentrations with a temporal resolution of a few seconds. Here we used the probe for in vivo recordings of neurotransmitter glutamate released upon electrical stimulation in the brain of a mouse to demonstrate the feasibility of the probe for real-time neurochemical brain analysis.