Mimicking kidney flow shear efficiently induces aggregation of LECT2, a protein involved in renal amyloidosis.

Aggregation of leukocyte cell-derived chemotaxin 2 (LECT2) causes ALECT2, a systemic amyloidosis that affects the kidney and liver. Previous studies established that LECT2 fibrillogenesis is accelerated by the loss of its bound zinc ion and stirring/shaking. These forms of agitation create heterogeneous shear conditions, including air-liquid interfaces that denature proteins, that are not present in the body. Here, we determined the extent to which a more physiological form of mechanical stress-shear generated by fluid flow through a network of narrow channels-drives LECT2 fibrillogenesis. To mimic blood flow through the kidney, where LECT2 and other proteins form amyloid deposits, we developed a microfluidic device consisting of progressively branched channels narrowing from 5 mm to 20 µm in width. Shear was particularly pronounced at the branch points and in the smallest capillaries. Aggregation was induced within 24 h by shear levels that were in the physiological range and well below those required to unfold globular proteins such as LECT2. EM images suggested the resulting fibril ultrastructures were different when generated by laminar flow shear versus shaking/stirring. Importantly, results from the microfluidic device showed the first evidence that the I40V mutation accelerated fibril formation and increased both the size and the density of the aggregates. These findings suggest that kidney-like flow shear, in combination with zinc loss, acts in combination with the I40V mutation to trigger LECT2 amyloidogenesis. These microfluidic devices may be of general use for uncovering mechanisms by which blood flow induces misfolding and amyloidosis of circulating proteins.

Comparison of LASSO and random forest models for predicting the risk of premature coronary artery disease.

PURPOSE: With the change of lifestyle, the occurrence of coronary artery disease presents a younger trend, increasing the medical and economic burden on the family and society. To reduce the burden caused by this disease, this study applied LASSO Logistic Regression and Random Forest to establish a risk prediction model for premature coronary artery disease(PCAD) separately and compared the predictive performance of the two models. METHODS: The data are obtained from 1004 patients with coronary artery disease admitted to a third-class hospital in Liaoning Province from September 2019 to December 2021. The data from 797 patients were ultimately evaluated. The dataset of 797 patients was randomly divided into the training set (569 persons) and the validation set (228 persons) scale by 7:3. The risk prediction model was established and compared by LASSO Logistic and Random Forest. RESULT: The two models in this study showed that hyperuricemia, chronic renal disease, carotid artery atherosclerosis were important predictors of premature coronary artery disease. A result of the AUC between the two models showed statistical difference (Z = 3.47, P < 0.05). CONCLUSIONS: Random Forest has better prediction performance for PCAD and is suitable for clinical practice. It can provide an objective reference for the early screening and diagnosis of premature coronary artery disease, guide clinical decision-making and promote disease prevention.

A novel inductively coupled capacitor wireless sensor system for rapid antibiotic susceptibility testing.

BACKGROUND: The increasing prevalence and severity of antimicrobial resistance (AMR) present a major challenge to our healthcare system. Rapid detection of AMR is essential for lifesaving under emergent conditions such as sepsis. The current gold standard phenotypic antibiotic susceptibility testing (AST) takes more than a day to obtain results. Genotypic ASTs are faster (hours) in detecting the presence of resistance genes but require specific probes/knowledge of each AMR gene and do not provide specific information at the phenotype level. To address this unmet challenge, we developed a new rapid phenotypic AST. RESULT: We designed a new electrochemical biosensor based on the concept of magnetically coupled LC sensors. The engineered LC sensors can be placed in 96-well plates and communicate the reading remotely with a receiver coil for signal analysis. The sensors were validated by monitoring the growth of Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa in the presence and absence of different antibiotics. Drug-resistant strains were used as controls. Bacterial growth was detected within 30 min after inoculation, allowing rapid determination of antibiotic susceptibility at the phenotype level. The sensor also functions in the presence of host proteins when tested with 2% FBS in growth media. CONCLUSIONS: With the compatibility with 96-well plates, this label-free rapid 30-min AST has the potential for low-cost applications with simple integration into the existing workflow in clinical settings.

Mimicking Kidney Flow Shear Efficiently Induces Aggregation of LECT2, a Protein Involved in Renal Amyloidosis.

Aggregation of leukocyte cell-derived chemotaxin 2 (LECT2) causes ALECT2, a systemic amyloidosis that affects the kidney and liver. Homozygosity of the I40V LECT2 mutation is believed to be necessary but not sufficient for the disease. Previous studies established that LECT2 fibrillogenesis is greatly accelerated by loss of its single bound zinc ion and stirring or shaking. These forms of agitation are often used to facilitate protein aggregation, but they create heterogeneous shear conditions, including air-liquid interfaces that denature proteins, that are not present in the body. Here, we determined the extent to which a more physiological form of mechanical stress-shear generated by fluid flow through a network of artery and capillary-sized channels-drives LECT2 fibrillogenesis. To mimic blood flow through the human kidney, where LECT2 and other proteins form amyloid deposits, we developed a microfluidic device consisting of progressively branched channels narrowing from 5 mm to 20 µm in width. Flow shear was particularly pronounced at the branch points and in the smallest capillaries, and this induced LECT2 aggregation much more efficiently than conventional shaking methods. EM images suggested the resulting fibril structures were different in the two conditions. Importantly, results from the microfluidic device showed the first evidence that the I40V mutation accelerated fibril formation and increased both size and density of the aggregates. These findings suggest that kidney-like flow shear, in combination with zinc loss, acts in combination with the I40V mutation to trigger LECT2 amyloidogenesis. These microfluidic devices may be of general use for uncovering the mechanisms by which blood flow induces misfolding and amyloidosis of circulating proteins.

Three-dimensional inversion analysis of transient electromagnetic response signals of water-bearing abnormal bodies in tunnels based on numerical characteristic parameters.

The transient electromagnetic inversion of detection signals mainly depends on fast inversion in the half-space state. However, the interpretation results have a certain degree of uncertainty and blindness, so the accuracy and applicability of the three-dimensional full-space inversion need to be investigated. Two different three-dimensional full-space inversions were carried out. First, the numerical characteristic parameters of the response signals were extracted. Then, the correlations between the numerical characteristic parameters and physical parameters of the water-bearing abnormal bodies were judged, and the judgment criterion of the iterative direction was proposed. Finally, the inversion methods of the iterative algorithm and the BP neural network were utilized based on the virtual example samples. The results illustrate that the proposed numerical characteristic parameters can accurately reflect the response curve of the full-space surrounding rock. The difference in the numerical characteristic parameters was used to determine the update direction and correction value. Both inversion methods have their advantages and disadvantages. A single inversion method cannot realize the three-dimensional inversion of the physical parameters of water-bearing abnormal bodies quickly, effectively and intelligently. Therefore, the benefits of different inversion methods need to be considered to comprehensively select a reasonable inversion method. The results can provide essential ideas for the subsequent interpretation of the three-dimensional spatial response signals of water-bearing abnormal bodies.

Characterisation of transient electromagnetic signals during fixed interference sources in tunnel structure.

The detection effect of the transient electromagnetic method is ambiguous in engineering applications due to the existence of interference sources, so explaining the influence of these fixed interference sources on is crucial. In this paper, the response characterisation of transient electromagnetic signals of fixed interference sources are thoroughly investigated. First, the secondary field generated by these interference sources is analyzed, and a typical fixed interference source is calculated. Then, a sensitivity analysis of the transient electromagnetic response curve is carried out. Finally, the mathematical superposition method for multiple field sources is proposed and verified. The results illustrate that the transient electromagnetic response curve of uniform full-space surrounding rock with a single fixed interference source has an apparent lifting phenomenon in the middle stage and presents an approximate horizontal change rule at the late stage. The transient electromagnetic response curves of multiple field sources separately illustrate the response characterisation of different field sources at different time stages. These research results can provide a valuable reference for the on-site interpretation of detection signals.

Noninvasive Control of Bacterial Biofilms by Wireless Electrostimulation.

Bacteria are well-known to form biofilms on biomaterials and implanted medical devices and cause serious infections that are incurable by conventional antibiotics. Consequently, such infections can lead to explantation and, in severe cases, amputation or even death. To address this unmet challenge, we developed a new method for noninvasive treatment of device-associated biofilm infections. We demonstrate that antibiotic tolerant biofilm cells of Pseudomonas aeruginosa and Staphylococcus aureus can be effectively killed by electromagnetically induced direct current generated wirelessly using a remote power source, which was further enhanced through synergy with conventional antibiotics. Electrochemical analyses attributed the cidal effects to DC-generated reactive oxygen species. The treatment conditions were found safe to the epithelial and fibroblast cell lines. On the basis of these findings, a prototype device was engineered and demonstrated for effective killing of biofilm cells using both ex vivo and in vivo models. With the capability to kill bacteria without using a directly connected power source, this platform technology has possible applications in noninvasive treatment of biofilm infections associated with cochlear, orthopedic, and other implanted medical devices.

Sensing the unreachable: challenges and opportunities in biofilm detection.

Bacteria can attach to essentially all materials and form multicellular biofilms with high-level tolerance to antimicrobials. Detrimental biofilms are responsible for a variety of problems ranging from food and water contamination, bio-corrosion, to drug resistant infections. Besides the challenges in control, biofilms are also difficult to detect due to the lack of biofilm-specific biomarkers and methods for non-destructive imaging. In this article, we present a concise review of recent advancements in this field, with a focus on medical device-associated infections. We also discuss the technologies that have potential for non-destructive detection of bacterial biofilms.

Does early improvement predict endpoint response in patients with generalized anxiety disorder (GAD) treated with pregabalin or venlafaxine XR?

Many patients with generalized anxiety disorder (GAD) only respond to pharmacological treatment after a delay of some weeks, and approximately 35% of patients do not respond. Therefore, early identification of potential responders may have important implications for clinical decision-making. In order to identify early improvement criteria that optimally predict eventual response during short-term treatment of GAD with pregabalin or venlafaxine XR, data were pooled from four double-blind, placebo-controlled GAD treatment studies. A range of measures were analyzed using logistic regression models and receiver operator characteristic (ROC) curve analysis, to predict endpoint response. Results showed that early improvement (≥ 20% reduction from baseline score) on the Hamilton Anxiety Scale (HAM-A) was associated with a high probability of achieving an endpoint response at Weeks 1 and 2 among patients treated with pregabalin (~67%), and at Week 2 with venlafaxine XR (60%). A Clinical Global Impression - Improvement (CGI-I) score ≤ 3 at Week 2 was a reliable predictor of achieving endpoint response for pregabalin and venlafaxine XR (odds ratio [OR], 5.33 and 2.47, respectively) with high sensitivity (pregabalin, 0.91; venlafaxine XR, 0.86) and relatively low specificity (pregabalin, 0.33; venlafaxine XR, 0.29), indicating a high true positive rate, but relatively low true negative rate. These findings indicate that improvement by Week 2 on the single item CGI may be a simple and reliable way to predict treatment response with pregabalin or venlafaxine XR in patients with GAD, but a less reliable way to predict non-responders.

Analyzing the impact of 23 mg/day donepezil on language dysfunction in moderate to severe Alzheimer's disease.

INTRODUCTION: Progressive language impairment is among the primary components of cognitive decline in Alzheimer's disease (AD). Because expressive and receptive language help to maintain emotional connections to caregivers and support the management of AD patients' functional needs, language plays a critical role in patients' emotional and physical health. Using data from a large prospective clinical trial comparing two doses of donepezil in patients with moderate to severe AD, we performed a post hoc analysis to determine whether a higher dose of donepezil was associated with greater benefits in language function. METHODS: In the original randomized, double-blind clinical trial, 1,467 patients with moderate to severe AD (baseline Mini-Mental State Examination (MMSE) score 0 to 20) were randomized 2:1 to receive donepezil 23 mg/day or to continue on donepezil 10 mg/day for 24 weeks. In this post hoc analysis, the Severe Impairment Battery-Language scale (SIB-L) and a new 21-item SIB-derived language scale (SIB[lang]) were used to explore differences in language function between the treatment groups. Correlations between SIB-L and SIB[lang] scores and scores on the severe version of the Alzheimer's Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL-sev), the Clinician's Interview-Based Impression of Severity-plus caregiver input/Clinician's Interview-Based Impression of Change-plus caregiver input (CIBIS-plus/CIBIC-plus) and the MMSE were also investigated. RESULTS: At week 24, treatment with donepezil 23 mg/day was associated with an improvement in language in the full intention-to-treat population, whereas language function declined in the group treated with donepezil 10 mg/day (SIB-L treatment difference 0.8, P = 0.0013; SIB[lang] treatment difference 0.8, P = 0.0009). Similar results were observed in a cohort of patients with more severe baseline disease (MMSE score 0 to 16). At baseline and week 24, correlations between the SIB-derived language scales and the ADCS-ADL-sev and CIBIC-plus were moderate, but the correlations were stronger between the language scales and the MMSE scores. CONCLUSIONS: Patients with moderate to severe AD receiving donepezil 23 mg/day showed greater language benefits than those receiving donepezil 10 mg/day as measured by SIB-derived language assessments. Increasing the dose of donepezil to 23 mg/day may provide language benefits in patients with moderate to severe AD, for whom preservation of language abilities is especially critical.ClinicalTrials.gov identifier: NCT00478205.

An MRI substudy of a donepezil clinical trial in mild cognitive impairment.

A magnetic resonance imaging (MRI) study was conducted as part of an intervention study in subjects with amnestic mild cognitive impairment (aMCI) to assess donepezil's treatment effect on brain atrophy. Adults with aMCI were randomly assigned to double-blind treatment with 10 mg/day donepezil hydrochloride or placebo for 48 weeks. Brain MRI scans were acquired at baseline and endpoint. The primary outcome measure was annualized percentage change (APC) in hippocampal volume; the main secondary outcome measure was APC in whole brain volumes. An analysis of variance (ANOVA) model including terms for treatment, site, and age was used to compare the treatment groups. APCs for hippocampal volumes were not significantly different between treatment groups. There were significant differences favoring the donepezil group for total (p = 0.001), ventricular region (p = 0.0002), and cortical region (p = 0.003) whole brain volumes. Although the primary MRI outcome measure was negative, the main secondary MRI outcome measure showed a positive result. These findings suggest a treatment effect of donepezil on brain atrophy in aMCI.

Effect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease.

OBJECTIVE: To determine whether donepezil treatment (10 mg/day over 24 weeks) is associated with delayed emergence of apathy in patients with mild to moderate Alzheimer's disease (AD) and to explore relationships between donepezil's effects on apathy and other Neuropsychiatric Inventory (NPI)-measured behavioural symptoms. METHODS: Two randomised, double-blind, parallel-group, placebo-controlled studies that met prespecified criteria and were sufficiently similar to allow data pooling were derived from all donepezil AD clinical trials. Patients scoring from 10 to 26 on baseline Mini-Mental Status Examination were included. A clinical milestone for apathy and other NPI items was defined as the first emergence of a composite score (frequency × severity) ≥ 3. Differences in time to event (i.e. milestone) between donepezil- and placebo-treated groups were assessed using the Kaplan-Meier method and log-rank test. Shift tables were constructed to evaluate clinical milestone status for apathy and other NPI items at baseline and endpoint, and were analysed using the Cochran-Mantel-Haenszel (CMH) test, stratified by baseline status. RESULTS: Of all NPI items, apathy had the highest proportion of subjects scoring ≥ 3 at baseline. Donepezil was superior to placebo on both apathy milestone analyses (time-to-event log-rank test and shift table CMH test, p = 0.01). Aberrant motor behaviour demonstrated similar benefit. CONCLUSIONS: Donepezil treatment appears to have resulted in a significant reduction over 6 months of the emergence of apathy in patients with AD. These data suggest that a prospective clinical trial in patients with early AD that includes apathy as a primary outcome measure may be warranted.

Effect of donepezil on cognition in severe Alzheimer's disease: a pooled data analysis.

To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N=904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1-5, 6-9, 10-12 and 13-17) to allow investigation of responses at different stages of cognitive impairment. Relationships to global and functional measures were explored. The difference between donepezil- and placebo-treated patients in least squares (LS) mean change in SIB total scores from baseline to week 24 was 6.22 (p < 0.0001, Cohen's d, 0.53). Treatment-placebo differences were statistically significant for each baseline severity stratum, being greatest for the MMSE 6-9 stratum (LS mean difference, 7.60; p < 0.0001, Cohen's d, 0.66). Treatment-placebo differences in LS mean change in SIB domain scores significantly favored donepezil for seven of nine domains (range, p = 0.0056 to p < 0.0001; Cohen's d, 0.17-0.48). Change in total SIB score correlated significantly with change in measures of activities of daily living and global status. These results indicate that donepezil provides cognitive benefits in patients with severe AD, including those most markedly impaired. The treatment effect size and correlation between improvements in SIB scores and functional and global outcome measures suggest the drug-placebo differences are clinically meaningful.

Cognition and function in Alzheimer's disease: identifying the transitions from moderate to severe disease.

BACKGROUND/AIMS: Cognitive and functional decline define the transition from moderate to severe Alzheimer's disease (AD); however, specific relationships between deteriorating cognition and functional abilities are less well characterized. Such relationships are important in care planning and understanding patient needs. Objectives of this post hoc analysis of data from a multicenter randomized double-blind placebo-controlled study were to describe changes in Severe Impairment Battery (SIB) scores over 6 months in patients with moderate to severe AD (MSAD), including an assessment of donepezil treatment on SIB scores, and to potentially identify a cognitive transition point associated with predicted functional disability. METHODS: The study comprised 290 patients with MSAD (standardized Mini-Mental State Examination score, 5-17) treated with donepezil 5-10 mg/day or matching placebo. Measurements were SIB, Functional Rating Scale, and Disability Assessment for Dementia. RESULTS: The largest decline in ability to perform basic activities of daily living (bADLs) occurred in placebo-treated patients with a baseline SIB score of approximately 70. Changes were reduced in the donepezil-treated group. CONCLUSIONS: This post hoc exploratory analysis suggests that a transition point between moderate and severe AD exists at a SIB score of approximately 70 and is associated with predictably declining bADLs.

Effectiveness of donepezil in reducing clinical worsening in patients with mild-to-moderate alzheimer's disease.

BACKGROUND: Therapeutic endpoints based on reduced clinical worsening represent clinically relevant and realistic goals for patients suffering from progressive neurodegenerative disorders such as Alzheimer's disease (AD). METHODS: Data from 906 patients (388 receiving placebo; 518 receiving donepezil) with mild-to-moderate AD [Mini-Mental State Examination (MMSE) score 10-27] were pooled from 3 randomized, double-blind placebo-controlled studies. Clinical worsening was defined as decline in (1) cognition (MMSE), (2) cognition and global ratings (Clinician's Interview-Based Impression of Change plus Caregiver Input/Gottfries-Bråne-Steen scale) or (3) cognition, global ratings and function (various functional measures). RESULTS: At week 24, lower percentages of donepezil-treated patients than placebo patients met the criteria for clinical worsening, regardless of the definition. The odds of declining were significantly reduced for donepezil-treated versus placebo patients (p < 0.0001; all definitions). Among patients meeting criteria for clinical worsening, mean declines in MMSE scores were greater for placebo than donepezil-treated patients. CONCLUSION: In this population, donepezil treatment was associated with reduced odds of clinical worsening of AD symptoms. Moreover, patients worsening on donepezil were likely to experience less cognitive decline than expected if left untreated. This suggests that AD patients showing clinical worsening on donepezil may still derive benefits compared with placebo/untreated patients.

Donepezil treatment in severe Alzheimer's disease: a pooled analysis of three clinical trials.

OBJECTIVE: Individual clinical trials have demonstrated benefits of donepezil in patients with severe Alzheimer's disease (AD). Data were pooled from three randomized, placebo-controlled trials of donepezil for severe AD to further evaluate treatment effects and overall tolerability/safety. METHODS: Total scores and sub-scores were analyzed for measures of cognition, global function, function, and behavior. Additional analyses were performed to investigate (1) relationships between cognitive, functional, and behavioral changes, and (2) patterns of combined domain response. RESULTS: Using pooled total scores, significant treatment differences at endpoint in favor of donepezil were observed for cognition, global function (both p < 0.0001), and function (p = 0.03), with an effect size (Cohen's d) of 0.51, 0.26, and 0.17, respectively. There was no significant treatment difference for behavior. However, donepezil-treated patients with stabilized/improved cognition tended to show significant improvements in function and behavior over placebo-treated patients. Patients treated with donepezil were 2-3 times more likely to achieve a combined domain response than placebo-treated patients (p < 0.0001). Adverse events were as expected for cholinergic therapy, and mortality rates were similar between the treatment groups. CONCLUSIONS: These findings suggest measurable donepezil-mediated symptomatic benefits in cognition, global function, and daily living activities in patients with severe AD. The treatment effects support the importance of cholinesterase inhibition as a clinically relevant therapeutic option across the spectrum of AD.

A brief instrument to assess treatment response in the patient with advanced Alzheimer disease.

The availability of effective treatments for severe Alzheimer disease (AD) has accentuated the need for brief, simple tools to evaluate treatment response in busy clinical settings for patients with advanced dementia. To develop such a tool, data on 875 patients from 4 double-blind-randomized studies of donepezil in severe AD [Mini-Mental State Examination (MMSE) 0 to 12 inclusive] were pooled and analyzed to identify Severe Impairment Battery (SIB) items, which are sensitive to change over time. Eight of the 51 SIB items were chosen based on effect sizes and relative ease of administration. The resulting SIB-8 was then applied to a validation data set (not used to generate the short form) to characterize its usefulness. The items, Month, Months of Year, Write Name, Sentence, Fluency, Confrontational Naming-Spoon, Using Spoon-Photograph, and Digit Span, were sensitive to change with treatment (P<0.0001) and easy to administer. Baseline SIB-8 scores were correlated with baseline MMSE and full-scale SIB scores, and provided a good distribution of scores in patients at the lower end of the MMSE. The SIB-8 is a brief (< or =3 min) assessment for patients with severe AD that is sensitive to change and able to detect treatment response.

Effectiveness and safety of donepezil in Hispanic patients with Alzheimer's disease: a 12-week open-label study.

BACKGROUND: Hispanics represent 10% of the U.S. population and are the fastest growing group. Studies show a higher prevalence and incidence of Alzheimer's disease (AD) in Hispanics than in the non-Hispanic white population, with an earlier age of onset. Among the currently estimated 200,000 Hispanics with AD, a significant number remain undiagnosed and untreated, and Hispanic participation in AD clinical trials has been historically low. This study evaluated the efficacy and safety of donepezil hydrochloride (donepezil) in Hispanics with mild-to-moderate AD. METHODS: In this multicenter, open-label, 12-week study conducted in the United States, subjects were Hispanic men or women aged > or =50 years with a diagnosis of mild-to-moderate AD (DSMV-IV and NINCDS/ADRDA criteria), with Mini-Mental State Examination (MMSE) scores of 10-26 (inclusive) at screening. Subjects were treated with donepezil 5 mg/day for 6 weeks followed by 10 mg/day for 6 weeks. Clinical evaluation was performed at baseline, week 6 and week 12. Cognitive improvement was measured using the MMSE, Fuld Object Memory Evaluation (FOME) and Symbol Digit Modality Test (SDMT). Behavioral symptoms and associated caregiver distress were assessed with the Neuropsychiatric Inventory (NPI). RESULTS: One-hundred-six patients with mild-to-moderate AD (mean age 68.6 years) were enrolled (intent to treat, n=97); most chose to have assessments conducted in Spanish. With 12 weeks of treatment, subjects showed statistically significant improvement from baseline on MMSE (P<0.0001), FOME retrieval (P=0.0042), FOME repeated retrieval (P=0.0020) and SDMT correct scores (P<0.0001). The NPI subdomain "apathy/indifference" showed statistically significant improvement (P=0.0010).The NPI Caregiver Distress scale (NPI-D) total score was statistically significantly improved (P=0.0500), suggesting a positive impact on relieving caregivers' burden associated with patient behavior. Most patients tolerated the treatment well, with only 2 discontinuing because of adverse events. The most common (>5%) adverse events were insomnia (9.5%), dizziness (7.6%), diarrhea (5.7%) and nausea (5.7%). CONCLUSION: The cognitive improvement and safety results from this study were consistent with those reported for donepezil in the general population. Increased awareness of AD in the Hispanic population will help more Hispanics with AD to benefit from early diagnosis and effective treatment.

Self-reported cognitive and everyday functioning in persons with psychosis: the Patient Perception of Functioning Scale.

UNLABELLED: This study examined the reliability and validity of a brief, face-valid self-report measure designed to assess subjective judgments of functioning. The Patient Perception of Functioning Scale (PPFS) is a 6-item scale with ratings for both community functioning and cognition. METHOD: Sixty-eight subjects with psychotic disorders were recruited to complete the PPFS on 2 occasions and to complete a battery of neurocognitive tests. Objective ratings of overall illness severity (Clinical Global Impression), illness severity (Global Assessment of Functioning), and functioning (Social and Occupational Functioning Assessment Scale and Role Functioning Scale) were also obtained. RESULTS: The internal consistency and test-retest correlation coefficients revealed that the PPFS possesses good reliability characteristics. The PPFS did not show relationships to demographic, historical, or illness-related variables such as diagnosis or length of illness. The PPFS did show significant associations with several dimensions of community functioning. However, no significant associations were found with neurocognitive measures or clinical status. CONCLUSIONS: In populations with psychotic disorders, self-reported ratings of community function and cognition may converge less with objective cognitive measures than with objective ratings of everyday functioning. Several factors inherent to self-report methodology may have contributed to the poor convergent validity results. Theoretical underpinnings and operationalization of the underlying constructs of some neuropsychological instruments may not closely match how patients conceptualize those constructs.

Assessing therapeutic efficacy in a progressive disease: a study of donepezil in Alzheimer's disease.

OBJECTIVE: To determine the value of continued donepezil treatment in patients with Alzheimer's disease for whom clinical benefit was initially judged to be uncertain. METHODS: The study consisted of three phases: (i) a 12- to 24-week, pre-randomisation, open-label donepezil-treatment phase; (ii) a 12-week, randomised, double-blind, placebo-controlled phase; and (iii) a 12-week, single-blind (i.e. patient-blind) donepezil-treatment phase. Patients with mild to moderate Alzheimer's disease received open-label treatment with donepezil (5 mg/day for 4 weeks, then 10 mg/day for the remainder of the phase) for 12-24 weeks. Patients who exhibited a decline or no change from baseline on the Mini-Mental State Examination (MMSE) and whose physician was not sufficiently certain of clinical benefit to warrant continued treatment were randomised into the double-blind phase in which patients received 12 weeks of treatment with donepezil (10 mg/day) or placebo. At the end of the double-blind phase, donepezil-treated patients continued to receive donepezil, while placebo-treated patients were rechallenged with donepezil, in a 12-week single-blind phase. Patients were assessed at the start of the double-blind phase and at weeks 6 and 12 of this phase, and at the end of the single-blind phase. RESULTS: Six hundred and nineteen patients completed the open-label phase; 69% showed clear clinical benefit and 31% showed uncertain benefit. 202 patients were randomised to continued donepezil treatment (n = 99) or placebo (n = 103). Differences in favour of continued donepezil versus placebo were observed in cognition and behaviour. In addition, there was a non-significant trend favouring donepezil in activities of daily living (ADL) [week 12 observed case mean treatment differences: MMSE, 1.13 (p = 0.02); Alzheimer's Disease Assessment Scale - cognitive subscale, 0.57 (p = 0.5); the Neuropsychiatric Inventory, -3.16 (p = 0.02); Disability Assessment for Dementia scale, 3.67 (p = 0.1)]. CONCLUSION: Most patients showed clear clinical benefit during initial donepezil treatment. Among patients for whom clinical benefit was uncertain, improvement in cognition and behaviour were observed for those who continued donepezil treatment compared with the group switched to placebo. Initial decline or stabilisation does not necessarily indicate a lack of efficacy in Alzheimer's disease, and the decision to discontinue treatment should be based on an evaluation of all domains (cognition, behaviour and ADL) and performed at several timepoints.