Brantleyvilhelmsen2150

A clinical trial proved the clinical effectiveness of perfusion imaging-guided intravenous thrombolysis with alteplase for patients with acute ischemic stroke (AIS) with the time of onset between 4.5 and 9 hours. This study aimed to assess the lifetime cost-effectiveness of alteplase versus placebo from the perspective of Chinese and United States (US) healthcare payers.

A decision-analytic model was built to estimate lifetime costs and quality-adjusted life-years (QALYs) associated with alteplase or placebo. Model inputs were extracted from published sources. Incremental costs, incremental QALYs, and incremental cost-effectiveness ratio (ICER) were calculated to evaluate the base-case scenario. One-way and probabilistic sensitivity analysis were performed to evaluate uncertainty in the results.

In China, alteplase yielded an additional lifetime QALY of 0.126 with an additional cost of Chinese Yuan (¥) ¥9552 compared with placebo, and the ICER was ¥83 950 (US$12 157)/QALY. In the US, alteplase had a higher QALY (difference 0.193) with a lower cost (difference US$-2024) compared with placebo. In probabilistic sensitivity analyses, alteplase had a 42.54% to 78.3% probability of being cost-effective compared with placebo in China when the willingness-to-pay (WTP) threshold ranged from ¥72 447/QALY to ¥217 341/QALY. In the US, alteplase had a 93.47% to 93.57% probability of being cost-effective under the WTP threshold of US$100 000/QALY to US$150 000/QALY. These findings remained robust under one-way sensitivity analysis.

For patients with AIS with a time of onset between 4.5 and 9 hours, perfusion imaging-guided intravenous alteplase was likely to be cost-effective in China and was cost-effective in the US when compared with placebo.

For patients with AIS with a time of onset between 4.5 and 9 hours, perfusion imaging-guided intravenous alteplase was likely to be cost-effective in China and was cost-effective in the US when compared with placebo.The development of small-molecules targeting different components of SARS-CoV-2 is a key strategy to complement antibody-based treatments and vaccination campaigns in managing the COVID-19 pandemic. Here, we show that two thiol-based chemical probes that act as reducing agents, P2119 and P2165, inhibit infection by human coronaviruses, including SARS-CoV-2, and decrease the binding of spike glycoprotein to its receptor, the angiotensin-converting enzyme 2 (ACE2). Proteomics and reactive cysteine profiling link the antiviral activity to the reduction of key disulfides, specifically by disruption of the Cys379-Cys432 and Cys391-Cys525 pairs distal to the receptor binding motif in the receptor binding domain (RBD) of the spike glycoprotein. Computational analyses provide insight into conformation changes that occur when these disulfides break or form, consistent with an allosteric role, and indicate that P2119/P2165 target a conserved hydrophobic binding pocket in the RBD with the benzyl thiol-reducing moiety pointed directly toward Cys432. These collective findings establish the vulnerability of human coronaviruses to thiol-based chemical probes and lay the groundwork for developing compounds of this class, as a strategy to inhibit the SARS-CoV-2 infection by shifting the spike glycoprotein redox scaffold.

The ATN framework has been developed to categorize biological processes within the Alzheimer disease (AD) continuum. Because AD pathology often coincides with dementia with Lewy bodies (DLB), we aimed to investigate the distribution of ATN profiles in DLB and associate ATN profiles in DLB with prognosis.

We included 202 patients with DLB from the Amsterdam Dementia Cohort (68±7 years; 19% female; Mini-Mental State Examination 24 ± 3; abnormal DAT-SPECT 105/119). Patients were classified into 8 profiles according to the ATN framework, using CSF β-amyloid (Aβ)

(A), CSF p-tau (T), and medial temporal atrophy scores (N). We compared presence of clinical symptoms in ATN profiles and used linear mixed models to analyze decline on cognitive tests (follow-up 3±2 years for n = 139). Mortality risk was assessed using Cox proportional hazards analysis. Analyses were performed on the 8 profiles as well as 3 clustered categories (normal AD biomarkers, non-AD pathologic change, and AD continuum).

Fifty (25%) patien (for example, AD-modifying treatment). Expanding the framework by incorporating markers for α-synucleinopathy would improve the use of the framework to characterize patients with dementia with mixed pathology, which could enhance proper stratification of patients for therapeutic trials.

In our DLB cohort, we found clinically relevant associations between ATN categories and disease manifestation. Patients within the AD continuum had steeper cognitive decline and shorter survival. Implementing the ATN framework within patients with DLB aids in subtyping patients based on underlying biological processes and could provide targets for future treatment strategies (for example, AD-modifying treatment). Menadione Expanding the framework by incorporating markers for α-synucleinopathy would improve the use of the framework to characterize patients with dementia with mixed pathology, which could enhance proper stratification of patients for therapeutic trials.

Pathogenic variants in the neuronal sodium channel α1 subunit gene (

) are the most frequent monogenic cause of epilepsy. Phenotypes comprise a wide clinical spectrum, including severe childhood epilepsy; Dravet syndrome, characterized by drug-resistant seizures, intellectual disability, and high mortality; and the milder genetic epilepsy with febrile seizures plus (GEFS+), characterized by normal cognition. Early recognition of a child's risk for developing Dravet syndrome vs GEFS+ is key for implementing disease-modifying therapies when available before cognitive impairment emerges. Our objective was to develop and validate a prediction model using clinical and genetic biomarkers for early diagnosis of

-related epilepsies.

We performed a retrospective multicenter cohort study comprising data from patients with

-positive Dravet syndrome and patients with GEFS+ consecutively referred for genetic testing (March 2001-June 2020) including age at seizure onset and a newly developed

genetic score. A trjective estimation at disease onset whether a child will develop Dravet syndrome vs GEFS+, assisting clinicians with prognostic counseling and decisions on early institution of precision therapies (http//scn1a-prediction-model.broadinstitute.org/).

This study provides Class II evidence that a combined

genetic score and seizure onset model distinguishes Dravet syndrome from other GEFS+ phenotypes.

This study provides Class II evidence that a combined SCN1A genetic score and seizure onset model distinguishes Dravet syndrome from other GEFS+ phenotypes.

Long-term treatment with the combination of cilostazol with aspirin or clopidogrel showed a lower risk of stroke recurrence compared to aspirin or clopidogrel alone after high-risk noncardioembolic ischemic stroke in a randomized trial. We aimed to determine whether the effect of the dual medication compared to monotherapy on risk of recurrent ischemic stroke differs according to timing of starting medication after stroke onset.

In a subanalysis of the randomized controlled trial, patients between 8 and 180 days after stroke onset were randomly assigned to receive aspirin or clopidogrel alone or a combination of cilostazol with aspirin or clopidogrel. They were divided into 3 groups according to the timing of starting trial treatment between 8 and 14 days after stroke onset (8-14 days group), between 15 and 28 days after stroke onset (15-28 days group), and between 29 and 180 days after stroke onset (29-180 days group). The primary efficacy outcome was the first recurrence of ischemic stroke. Safety outco cilostazol starting 15-180 days after stroke onset, compared to therapy started 8-14 days after onset, was more effective for secondary stroke prevention than monotherapy without increasing hemorrhage risk.

ClinicalTrials.gov NCT01995370; UMIN Clinical Trials Registry 000012180.

This study provides Class II evidence that for patients with acute noncardioembolic stroke taking either aspirin or clopidogrel, the addition of cilostazol 15-180 days after stroke onset decreases the risk of recurrent ischemic stroke.

This study provides Class II evidence that for patients with acute noncardioembolic stroke taking either aspirin or clopidogrel, the addition of cilostazol 15-180 days after stroke onset decreases the risk of recurrent ischemic stroke.

To examine if a proactive recovery intervention for newly graduated registered nurses (RNs) could prevent the development of sleep problems, burn-out, fatigue or somatic symptoms.

The study was a randomised control trial with parallel design. Newly graduated RNs with less than 12 months' work experience were eligible to participate. 461 RNs from 8 hospitals in Sweden were invited, of which 207 signed up. These were randomised to either intervention or control groups. After adjustments, 99 RNs were included in the intervention group (mean age 27.5 years, 84.7% women) and 108 in the control group (mean age 27.0 years, 90.7% women). 82 RNs in the intervention group attended a group-administered recovery programme, involving three group sessions with 2 weeks between each session, focusing on proactive strategies for sleep and recovery in relation to work stress and shift work. Effects on sleep, burn-out, fatigue and somatic symptoms were measured by questionnaires at baseline, postintervention and at 6 months follow-up.

Preventive effect was seen on somatic symptoms for the intervention group. Also, the intervention group showed less burn-out and fatigue symptoms at postintervention. However, these latter effects did not persist at follow-up. Participants used many of the strategies from the programme.

A proactive, group-administered recovery programme could be helpful in strengthening recovery and preventing negative health consequences for newly graduated RNs.

NCT04246736.

NCT04246736.

Although recent studies have identified important risk factors associated with incident carpal tunnel syndrome (CTS), risk factors associated with its severity have not been well explored.

To examine the associations between personal, workplace psychosocial and biomechanical factors and incident work disability among workers with CTS.

Between 2001 and 2010 five research groups conducted coordinated prospective studies of CTS and related work disability among US workers from various industries. Workers with prevalent or incident CTS (N=372) were followed for up to 6.4 years. Incident work disability was measured as (1) change in work pace or work quality, (2) lost time or (3) job change following the development of CTS. Psychosocial factors were assessed by questionnaire. Biomechanical exposures were assessed by observation and measurements and included force, repetition, duty cycle and posture. HRs were estimated using Cox models.

Disability incidence rates per 100 person-years were 33.2 for changes in work pace or quality, 16.3 for lost time and 20.0 for job change. There was a near doubling of risk for job change among those in the upper tertile of the Hand Activity Level Scale (HR 2.17; 95% CI 1.17 to 4.01), total repetition rate (HR 1.75; 95% CI 1.02 to 3.02), % time spent in all hand exertions (HR 2.20; 95% CI 1.21 to 4.01) and a sixfold increase for high job strain. Sensitivity analyses indicated attenuation due to inclusion of the prevalent CTS cases.

Personal, biomechanical and psychosocial job factors predicted CTS-related disability. Results suggest that prevention of severe disability requires a reduction of both biomechanical and organisational work stressors.

Personal, biomechanical and psychosocial job factors predicted CTS-related disability. Results suggest that prevention of severe disability requires a reduction of both biomechanical and organisational work stressors.