Monte Carlo simulation of an ammonia adsorption refrigeration system based on calcium chloride impregnated nanoporous carbon.

We use Monte Carlo simulations to investigate the effect of incorporating calcium chloride salt into nanoporous carbon on the performance of an ammonia-carbon adsorption refrigeration system. Simulations of ideal carbon slit-pores with pore sizes of 1, 2, and 3 nm, each containing calcium chloride with ion densities of 0.0, 0.25, and 0.5 nm-3, were carried out at temperatures between 0 and 30 °C and ammonia pressures up to 15.0 bar. The results reveal that ideal 1 nm pores are able to achieve a good refrigeration performance using waste heat below 100 °C to drive the process, but adding salt to these pores increases the waste heat temperature required beyond 100 °C. However, ideal 2 nm pores require the addition of 0.25 nm-3 salt to achieve a similar performance, while the 3 nm pores were unable to achieve a satisfactory refrigeration performance. Considering that real nanoporous carbons usually feature a variety of specific adsorption sites and non-ideal geometries that should have a similar impact to adding salt, these results indicate that nanoporous carbons with pores in the range of 1-2 nm are likely to hold the most promise for adsorption refrigeration applications and that the addition of salt may not always be helpful.

Diagnostic Performance of Quantitative Perfusion Cardiac Magnetic Resonance Imaging in Patients with Prior Coronary Artery Disease.

AIMS: The diagnostic performance of quantitative perfusion cardiac magnetic resonance (QP-CMR) imaging has scarcely been evaluated in patients with a history of coronary artery disease (CAD) and new onset chest pain. The present study compared the diagnostic performance of automated QP-CMR for detection of fractional flow reserve (FFR) defined hemodynamically significant CAD with visual assessment of first-pass stress perfusion CMR (v-CMR) and quantitative [15O]H2O positron emission tomography (PET) imaging in a true head-to-head fashion in patients with prior CAD. METHODS AND RESULTS: This PACIFIC-2 substudy included 145 symptomatic chronic coronary symptom patients with prior myocardial infarction (MI) and/or percutaneous coronary intervention (PCI). All patients underwent dual-sequence, single bolus perfusion CMR and [15O]H2O PET perfusion imaging followed by invasive coronary angiography with three-vessel FFR. Hemodynamically significant CAD was defined as an FFR ≤0.80. QP-CMR, v-CMR and PET exhibited a sensitivity of 66%, 67%, and 80%, respectively, whereas specificity was 60%, 62%, and 63%. Sensitivity of QP-CMR was lower than PET (P=0.015), whereas specificity of QP-CMR and PET was comparable. Diagnostic accuracy and area under the curve (AUC) of QP-CMR (64% and 0.66) was comparable to both v-CMR (66% [P=NS] and 0.67 (P=NS]) and PET (74% [P=NS] and 0.78 [P=NS]). CONCLUSIONS: In patients with prior MI and/or PCI, the diagnostic performance of QP-CMR was comparable to visual assessment of first-pass stress perfusion CMR and quantitative [15O]H2O PET for the detection of hemodynamically significant CAD as defined by FFR.

Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOSSMARCB1-, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOSSMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOSSmarcb1-. In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOSSMARCB1- within the TME.

Structural basis for the rescue of hyperexcitable cells by the amyotrophic lateral sclerosis drug Riluzole.

Neuronal hyperexcitability is a key element of many neurodegenerative disorders including the motor neuron disease Amyotrophic Lateral Sclerosis (ALS), where it occurs associated with elevated late sodium current (INaL). INaL results from incomplete inactivation of voltage-gated sodium channels (VGSCs) after their opening and shapes physiological membrane excitability. However, dysfunctional increases can cause hyperexcitability-associated diseases. Here we reveal the atypical binding mechanism which explains how the neuroprotective ALS-treatment drug riluzole stabilises VGSCs in their inactivated state to cause the suppression of INaL that leads to reversed cellular overexcitability. Riluzole accumulates in the membrane and enters VGSCs through openings to their membrane-accessible fenestrations. Riluzole binds within these fenestrations to stabilise the inactivated channel state, allowing for the selective allosteric inhibition of INaL without the physical block of Na+ conduction associated with traditional channel pore binding VGSC drugs. We further demonstrate that riluzole can reproduce these effects on a disease variant of the non-neuronal VGSC isoform Nav1.4, where pathologically increased INaL is caused directly by mutation. Overall, we identify a model for VGSC inhibition that produces effects consistent with the inhibitory action of riluzole observed in models of ALS. Our findings will aid future drug design and supports research directed towards riluzole repurposing.

Clinical Outcomes of Continuation and Maintenance Electroconvulsive Therapy.

Importance: Large-scale evidence for the efficacy of continuation and maintenance electroconvulsive therapy (c/mECT) is lacking. Objective: To provide an exhaustive and naturalistic insight into the real-world outcomes and the cost-effectiveness of c/mECT in a large dataset. Design, Setting, and Participants: This cohort study included all patients in the Danish National Patient Registry who initiated treatment with ECT from 2003 through 2022. The data were analyzed from October 2023 to February 2024. Exposures: ECT. An algorithm to identify c/mECTs in the dataset was developed: (>3 treatments with ≥7 and <90 days between adjacent treatments, occurring within a time frame of 180 days [cECT] or more [mECT] after an acute [aECT] series). Main Outcomes and Measures: The association of c/mECT with subsequent 6- to 12-month risk of hospitalization or suicidal behavior using Cox proportional hazard regression with multiple adjustments and aECT only as a reference, propensity score matching, and self-controlled case series analysis using a Poisson regression model. A cost-effectiveness analysis based on hospitalization and ECT expenses was made. Results: A total of 19 944 individuals were treated with ECT (12 157 women [61%], 7787 men [39%]; median [IQR] age, 55 [41-70] years). Of these, 1533 individuals (7.7%) received c/mECT at any time point (1017 [5.1%] cECT only and 516 [2.6%] mECT). Compared with patients receiving aECT only, c/mECT patients more frequently experienced schizophrenia (odds ratio [OR], 2.14; 95% CI, 1.86-2.46) and schizoaffective disorder (OR, 2.42; 95% CI, 1.90-3.09) and less frequently unipolar depression (OR, 0.56; 95% CI, 0.51-0.62). In all models, c/mECT was associated with a lower rate of hospitalization after finishing aECT (eg, 6-month adjusted hazard ratio, 0.68; 95% CI, 0.60-0.78 [Cox regression]; 6-month incidence rate ratio, 0.51; 95% CI, 0.41-0.62 [Poisson regression]). There was no significant difference in the risk of suicidal behavior. Compared with the periods before the end of aECT, c/mECT was associated with a substantial reduction in total treatment costs. Conclusions and Relevance: In a nationwide and naturalistic setting, c/mECT after aECT was infrequently used but associated with a lower risk of readmission than aECT alone. The totality of the evidence indicates that c/mECT should be considered more often to prevent relapse after successful aECT in patients whose condition does not respond sufficiently to other interventions.

Safety and procedural success of daycase-based endovascular procedures in lower extremity arteries of patients with peripheral artery disease: a systematic review and meta-analysis.

Background: Timely and economic provision of revascularisation procedures is a major healthcare need. We aimed to examine the safety and efficacy of daycase-based lower extremity endovascular revascularisation procedures in patients with peripheral artery disease. Methods: In this systematic review and meta-analysis, we searched MEDLINE and Embase for studies from Jan 01, 2000 through Apr 01, 2024 reporting complications of lower limb endovascular revascularisation procedures with same-day discharge. Eligibility-criteria, complications, and patient characteristics were extracted, methodological quality assessed (adapted Newcastle-Ottawa Scale), and meta-analyses of complications and technical success performed to provide pooled estimates. This study is registered with PROSPERO, CRD42022316466. Findings: Thirty observational studies (17 retrospective, 13 prospective) and 1 RCT reported 2427 minor and 653 major complications after 99,600 daycase procedures (93,344 patients). Eighteen studies reported daycase eligibility-criteria including 'responsible adult companion' (78%), 'proximity to hospital', and 'telephone availability' and excluding unstable and severe co-morbidities, offset coagulation, and severe chronic kidney disease. Pooled incidences of minor (4.7% [95% CI 3.8-5.6%], I 2 = 96%) and major (0.64% [95% CI 0.48-0.79%], I 2  = 46%) complications were low and technical success high (93% [95% CI 91-96%], I 2 = 97%). Most complications were related to the puncture site. Pooled conversion-to-hospitalisation rates and re-admission after discharge were 1.6% (95% CI 1.1-2.2%, I 2 = 82%) and 0.11% (95% CI 0.095-0.23%, I 2 = 97%), respectively. Meta-regression identified that minor complications decreased since 2000. Male sex and coronary artery disease were associated with more frequent, and higher age and closure device use with less minor complications. Diabetes mellitus and chronic kidney disease were associated with less major complications. Six studies reported complication rates both in daycases and inpatients and there was no significant difference (-0.8% [95% CI -1.9 to 0.3%]). Interpretation: After careful evaluation of eligibility, lower limb angioplasty can be performed safely with high technical success in a daycase setting. Most complications arise from the puncture site and not the procedure itself highlighting the importance of optimal access site management. The heterogeneity between studies warrants standardised monitoring of complications and outcomes. Funding: European Partnership on Metrology, co-financed from European Union's Horizon Europe Research and Innovation Programme and UK Research and Innovation, and Medical Research Council.

Investigating synergy between beta-blockers and transarterial chemoembolization in the treatment of hepatocellular carcinoma: preliminary data from a propensity matched analysis.

PURPOSE: Favorable clinical outcomes have been reported with the adjunct use of beta-blockers in cancer treatment, hypothetically secondary to their anti-angiogenic/anti-proliferative effects. Hereby, we investigate whether there is synergy between beta-blockers and TACE in the treatment of HCC. METHODS: 36 HCC patients on beta-blockers (mean dose of 48 mg daily) at the time of first-line treatment with TACE at our institution were retrospectively identified out of a cohort of 221 patients between 2008 and 2019. Using propensity scoring, a matched cohort of 36 patients not exposed to beta-blockers was generated based on age, gender, ethnicity, etiology of liver disease, BCLC, child Pugh score, PS/ECOG, cirrhosis, largest mass treated, type of TACE and treated liver segments. Tumor response was assessed at 1st and 2nd post-TACE imaging timepoints (1.4 and 4.1 months on average respectively). Variables were compared using chi-square test and Student's t-test. Kaplan-Meier transplant-free survival plots were generated using IBM® SPSS® software. Cox regression analysis was used to evaluate survival predictors. A p values < 0.05 was considered significant. RESULTS: Comparing the control and beta-blocker cohorts, there were no differences in baseline characteristics, post-TACE imaging timepoints, tumor response or transplant free survival (p > 0.05). Tumor size was found to be a predictor of survival when the two cohorts were combined (p = 0.03). CONCLUSION: Transplant-free survival and HCC response to first-line TACE treatment were similar in the control and beta-blocker groups. Large tumor sizes were associated with higher mortality in combined analysis of the cohorts.

HLA-E and NKG2A Mediate Resistance to M. bovis BCG Immunotherapy in Non-Muscle-Invasive Bladder Cancer.

Mycobacterium bovis Bacillus Calmette-Guerin (BCG) is the primary treatment for non-muscle-invasive bladder cancer (NMIBC), known to stimulate inflammatory cytokines, notably interferon (IFN)-γ. We observed that prolonged IFN-γ exposure fosters adaptive resistance in recurrent tumors, aiding immune evasion and tumor proliferation. We identify HLA-E and NKG2A, part of a novel NK and T cell checkpoint pathway, as key mediators of resistance in BCG-unresponsive NMIBC. IFN-γ enhances HLA-E and PD-L1 expression in recurrent tumors, with an enrichment of intra-tumoral NKG2A-expressing NK and CD8 T cells. CXCL9+ macrophages and dendritic cells and CXCL12-expressing stromal cells likely recruit CXCR3/CXCR4-expressing NK and T cells and CXCR7+ HLA-EHIGH tumor cells. NK and CD8 T cells remain functional within BCG-unresponsive tumors but are inhibited by HLA-E and PD-L1, providing a framework for combined NKG2A and PD-L1 blockade strategy for bladder-sparing treatment of BCG-unresponsive NMIBC.

Antibodies and complement are key drivers of thrombosis.

Venous thromboembolism (VTE) is a common, deadly disease with an increasing incidence despite preventive efforts. Clinical observations have associated elevated antibody concentrations or antibody-based therapies with thrombotic events. However, how antibodies contribute to thrombosis is unknown. Here, we show that reduced blood flow enabled immunoglobulin M (IgM) to bind to FcµR and the polymeric immunoglobulin receptor (pIgR), initiating endothelial activation and platelet recruitment. Subsequently, the procoagulant surface of activated platelets accommodated antigen- and FcγR-independent IgG deposition. This leads to classical complement activation, setting in motion a prothrombotic vicious circle. Key elements of this mechanism were present in humans in the setting of venous stasis as well as in the dysregulated immunothrombosis of COVID-19. This antibody-driven thrombosis can be prevented by pharmacologically targeting complement. Hence, our results uncover antibodies as previously unrecognized central regulators of thrombosis. These findings carry relevance for therapeutic application of antibodies and open innovative avenues to target thrombosis without compromising hemostasis.

Swallowing during provision of helmet ventilation: Review and provisional multidisciplinary guidance.

Use of noninvasive ventilation provided by a helmet increased globally during and after the COVID-19 pandemic. This approach may reduce need for intubation and its associated clinical complications in critically ill patients. Use of helmet interface minimizes virus aerosolization while enabling verbal communication, oral feeding and coughing/expectoration of secretions during its administration. Although improved oral hydration is a recognized benefit of helmet NIV, relatively little is known about the safety and efficiency of swallowing during helmet NIV. Risk of aspiration is a key consideration given the fragile pulmonary status of critically ill patients requiring respiratory support, and therefore the decision to initiate oral intake is best made based on multidisciplinary input. We reviewed the current published evidence on NIV and its effects on upper airway physiology and swallowing function. We then presented a case example demonstrating preservation of swallowing performance with helmet NIV. Last, we offer provisional multidisciplinary guidance for clinical practice, and provide directions for future research.

Long term safety and outcomes after atrial shunting for heart failure with preserved or mildly reduced ejection fraction: 5-year and 3-year follow-up in the REDUCE LAP-HF I and II trials.

BACKGROUND: There is a little evidence regarding long-term safety and efficacy for atrial shunt devices in heart failure (HF). METHODS: The REDUCE LAP-HF I (n = 44) and II (n = 621) trials (RCT-I and -II) were multicenter, randomized, sham-controlled trials of patients with HF and ejection fraction >40%. Outcome data were analyzed from RCT-I, a mechanistic trial with 5-year follow-up, and RCT-II, a pivotal trial identifying a responder group (n = 313) defined by exercise PVR <1.74 WU and no cardiac rhythm management device with 3-year follow-up. RESULTS: At 5 years in RCT I, there were no differences in cardiovascular (CV) mortality, HF events, embolic stroke, or new-onset atrial fibrillation between groups. After 3 years in RCT II, there was no difference in the primary outcome (hierarchical composite of CV mortality, stroke, HF events, and KCCQ) between shunt and sham in the overall trial. Compared to sham, those with responder characteristics in RCT-II had a better outcome with shunt (win ratio 1.6 [95% CI 1.2-2.2], P = .006; 44% reduction in HF events [shunt 9 vs. control 16 per 100 patient-years], P = .005; and greater improvement in KCCQ overall summary score [+17.9 ± 20.0 vs. +7.6 ± 20.4], P < .001), while nonresponders had significantly more HF events. Shunt treatment at 3 years was associated with a higher rate of ischemic stroke (3.2% vs. 0%, 95% CI 2%-6.1%, P = .032) and lower incidence of worsening kidney dysfunction (10.7% vs. 19.3%, P = .041). CONCLUSIONS: With up to 5 years of follow up, adverse events were low in patients receiving atrial shunts. In the responder group, atrial shunt treatment was associated with a significantly lower HF event rate and improved KCCQ compared to sham through 3 years of follow-up. GOV REGISTRATION: NCT02600234, NCT03088033.

The Australian Genomics Mitochondrial Flagship: A National Program Delivering Mitochondrial Diagnoses.

PURPOSE: Families living with mitochondrial diseases (MD) often endure prolonged diagnostic journeys and invasive testing, yet many remain without a molecular diagnosis. The Australian Genomics Mitochondrial flagship, comprising clinicians, diagnostic, and research scientists, conducted a prospective national study to identify the diagnostic utility of singleton genomic sequencing using blood samples. METHODS: 140 children and adults living with suspected MD were recruited using modified Nijmegen criteria (MNC) and randomized to either exome + mtDNA sequencing (ES+mtDNAseq) or genome sequencing (GS). RESULTS: Diagnostic yield was 55% (n=77) with variants in nuclear (n=37) and mtDNA (n=18) MD genes, as well as phenocopy genes (n=22). A nuclear gene etiology was identified in 77% of diagnoses, irrespective of disease onset. Diagnostic rates were higher in pediatric-onset (71%) than adult-onset (31%) cases, and comparable in children with non-European (78%) versus European (67%) ancestry. For children, higher MNC scores correlated with increased diagnostic yield and fewer diagnoses in phenocopy genes. Additionally, three adult patients had a mtDNA deletion discovered in skeletal muscle that was not initially identified in blood. CONCLUSION: Genomic sequencing from blood can simplify the diagnostic pathway for individuals living with suspected MD, especially those with childhood onset diseases and high MNC scores.

Review of Hydroxypropyl Methylcellulose in Artificial Tears for the Treatment of Dry Eye Disease.

Dry eye disease (DED) is a highly prevalent condition, resulting in reduced quality of life, lower participation in social life and impaired work efficiency. Hydroxypropyl methylcellulose (HPMC) is a cellulose-based viscosity-enhancing agent and is one of the most popular therapeutic ingredients in artificial tears. This review aims to evaluate the literature on the efficacy and safety of HPMC used in the treatment of DED. Literature searches were conducted in PubMed and Cochrane CENTRAL. A total of 28 clinical trials from 26 publications are included in this review, including 21 clinical intervention studies evaluating the effect of HPMC treatment over time and seven single instillation studies evaluating the short-term physical and symptomatic effects of HPMC after drop-instillation. The duration of clinical intervention studies ranged from 2 weeks to 5.5 months. DED severity ranged from mild to severe. Drop frequency ranged from two to up to 16 drops per day. HPMC concentration in artificial tears ranged from 0.2% to 0.5%. No major complications or adverse events were reported. Artificial tears containing HPMC were effective at improving symptoms and some signs of DED. However, combination drops with HPMC plus other therapeutic ingredients seem more effective than HPMC alone. HPMC appears to be equally effective or inferior to hyaluronic acid (HA). There is no evidence of superiority or inferiority to either carboxymethylcellulose (CMC) or polyethylene glycol 400/propylene glycol (PEG/PG). No single study explained the choice of drop frequency or HPMC concentration. More well-designed studies are needed to determine an evidence-based standard for HPMC treatment, including drop frequency, concentration and molecular weight for different DED severity and subgroups.

Tailored-Biomaterials Based Potential Strategies for Cardiovascular Disease.

Cardiovascular disease is a significant health concern worldwide, and varied effective treatment and prevention methods have been developed. Among these, tailored biomaterials-based strategies such as stents, scaffolds, patches, and drug delivery systems have emerged as a promising avenue. These devices are designed to match the mechanical and biological mechanisms of the cardiovascular system, ensuring optimal performance and compatibility. By effectively treating or preventing cardiovascular diseases, these devices have the potential to improve patient health outcomes significantly. They can restore blood flow by addressing blocked arteries and regenerate damaged cardiac tissue by delivering bioactive agents or cells directly to the affected area in a targeted, sustained, and controllable manner. Therefore, the objective of this article is to summarize the available evidence on these tailored biomaterial-based tunable cardiovascular devices. This knowledge can help to transform cardiovascular medicine for the treatment or prevention of cardiovascular disease and restore cardiac function to improve patients' quality of life.

Melittin can permeabilize membranes via large transient pores.

Membrane active peptides are known to porate lipid bilayers, but their exact permeabilization mechanism and the structure of the nanoaggregates they form in membranes have often been difficult to determine experimentally. For many sequences at lower peptide concentrations, transient leakage is observed in experiments, suggesting the existence of transient pores. For two well-know peptides, alamethicin and melittin, we show here that molecular mechanics simulations i) can directly distinguish equilibrium poration and non-equilibrium transient leakage processes, and ii) can be used to observe the detailed pore structures and mechanism of permeabilization in both cases. Our results are in very high agreement with numerous experimental evidence for these two peptides. This suggests that molecular simulations can capture key membrane poration phenomena directly and in the future may develop to be a useful tool that can assist experimental peptide design.

Population Screening for Hereditary Haemochromatosis-Should It Be Carried Out, and If So, How?

The Human Genome Project, completed in 2003, heralded a new era in precision medicine. Somewhat tempering the excitement of the elucidation of the human genome is the emerging recognition that there are fewer single gene disorders than first anticipated, with most diseases predicted to be polygenic or at least gene-environment modified. Hereditary haemochromatosis (HH) is an inherited iron overload disorder, for which the vast majority of affected individuals (>90%) have homozygosity for a single pathogenic variant in the HFE gene, resulting in p.Cys282Tyr. Further, there is significant benefit to an individual in identifying the genetic risk of HH, since the condition evolves over decades, and the opportunity to intervene and prevent disease is both simple and highly effective through regular venesection. Add to that the immediate benefit to society of an increased pool of ready blood donors (blood obtained from HH venesections can generally be used for donation), and the case for population screening to identify those genetically at risk for HH becomes more cogent. Concerns about genetic discrimination, creating a cohort of "worried well", antipathy to acting on medical advice to undertake preventive venesection or simply not understanding the genetic risk of the condition adequately have all been allayed by a number of investigations. So why then has HH population genetic screening not been routinely implemented anywhere in the world? The answer is complex, but in this article we explore the pros and cons of screening for HH and the different views regarding whether it should be phenotypic (screening for iron overload by serum ferritin and/or transferrin saturation) or genotypic (testing for HFE p.Cys282Tyr). We argue that now is the time to give this poster child for population genetic screening the due consideration required to benefit the millions of individuals at risk of HFE-related iron overload.

New and Emerging Drug and Gene Therapies for Friedreich Ataxia.

The life shortening nature of Friedreich Ataxia (FRDA) demands the search for therapies that can delay, stop or reverse its relentless trajectory. This review provides a contemporary position of drug and gene therapies for FRDA currently in phase 1 clinical trials and beyond. Despite significant scientific advances in the specificity of both compounds and targets developed and investigated, challenges remain for the advancement of treatments in a limited recruitment population. Currently therapies focus on reducing oxidative stress and improving mitochondrial function, modulating frataxin controlled metabolic pathways and gene replacement and editing. Approval of omaveloxolone, the first treatment for individuals with FRDA aged 16 years and over, has created much excitement for both those living with FRDA and those that care for them. The process of approval of omaveloxolone by the US Food and Drug Administration highlighted the importance of sensitive outcome measures and the significant role of data from natural history studies.

Self and time in individuals with schizophrenia: A motor component?

Phenomenology suggests a disruption in the experience of time in individuals with schizophrenia, related to disorders of the sense of self. Patients themselves relate a fragmentation of their temporal experience and of their sense of self. Temporal expectations help relate the present moment to the future and we have previously shown that temporal expectations are fragile in patients, and relate to disorders of the self. Here, we investigate whether patients' performance is still impaired when the motor response to the expected event can be prepared in advance. In two different experiments participants (41 patients vs. 43 neurotypicals in total) responded to a visual target occurring at a variable interval (or "foreperiod") after an initial warning signal. Moreover, in Experiment 1 we measured the sense of self with the EASE scale. We observed the usual benefit of the passage of time: the longer the waiting period, the better the preparation, and the faster the responses. However, this effect also comprises sequential (surprise) effects, when a target occurs earlier than on the preceding trial. We evaluated the effect of the passage of time, by isolating trials that followed a trial with the same foreperiod. The benefit of long, versus short, foreperiods was still observed in controls but disappeared in patients. The results suggest that the benefit of the passage of time is diminished in patients and relates to self disorders, even when the task allows for motor preparation. The results suggest that a non-verbal impairment sub-tends disorders of the sense of self.