Ion-pair reorganization regulates reactivity in photoredox catalysts.

Cyclometalated and polypyridyl complexes of d6 metals are promising photoredox catalysts, using light to drive reactions with high kinetic or thermodynamic barriers via the generation of reactive radical intermediates. However, while tuning of their redox potentials, absorption energy, excited-state lifetime and quantum yield are well-known criteria for modifying activity, other factors could be important. Here we show that dynamic ion-pair reorganization controls the reactivity of a photoredox catalyst, [Ir[dF(CF3)ppy]2(dtbpy)]X. Time-resolved dielectric-loss experiments show how counter-ion identity influences excited-state charge distribution, evincing large differences in both the ground- and excited-state dipole moment depending on whether X is a small associating anion (PF6-) that forms a contact-ion pair versus a large one that either dissociates or forms a solvent-separated pair (BArF4-). These differences correlate with the reactivity of the photocatalyst toward both reductive and oxidative electron transfer, amounting to a 4-fold change in selectivity toward oxidation versus reduction. These results suggest that ion pairing could be an underappreciated factor that modulates reactivity in ionic photoredox catalysts.

Genome-wide association analysis of clinical vs. nonclinical origin provides insights into Saccharomyces cerevisiae pathogenesis.

Because domesticated Saccharomyces cerevisiae strains have been used to produce fermented food and beverages for centuries without apparent health implications, S. cerevisiae has always been considered a Generally Recognized As Safe (GRAS) microorganism. However, the number of reported mucosal and systemic S. cerevisiae infections in the human population has increased and fatal infections have occurred even in relatively healthy individuals. In order to gain insight into the pathogenesis of S. cerevisiae and improve our understanding of the emergence of fungal pathogens, we performed a population-based genome-wide environmental association analysis of clinical vs. nonclinical origin in S. cerevisiae. Using tiling array-based, high-density genotypes of 44 clinical and 44 nonclinical S. cerevisiae strains from diverse geographical origins and source substrates, we identified several genetic loci associated with clinical background in S. cerevisiae. Associated polymorphisms within the coding sequences of VRP1, KIC1, SBE22 and PDR5, and the 5' upstream region of YGR146C indicate the importance of pseudohyphal formation, robust cell wall maintenance and cellular detoxification for S. cerevisiae pathogenesis, and constitute good candidates for follow-up verification of virulence and virulence-related factors underlying the pathogenicity of S. cerevisiae.

A retrospective, exploratory, secondary analysis of the association between antipsychotic use and mortality in elderly patients with delirium.

BACKGROUND: Delirium, an acute altered level of cognition, is a frequent complication of medical illness in the elderly. Antipsychotic medications (APs) are often used to treat agitation and psychosis in delirium. The goal of this study is to compare mortality in delirious elderly medical inpatients treated with APs with those who did not receive APs. METHOD: 326 elderly hospitalized patients were identified with delirium at an acute care community hospital. A nested case-control analysis was conducted on this cohort. Cases consisted of all patients who died in hospital within eight weeks of admission. Each case was matched for age and severity of illness to patients (controls) alive on the same day post-admission. Conditional logistic regression was used to assess the impact of exposure to AP on mortality. Covariates used for adjustment were the Charlson comorbidity score and the acute physiology score. Odds ratio (OR) and 95% confidence intervals were calculated from the regression coefficients. RESULTS: 111 patients received an AP. A total of 62 patients died, 16 of whom were exposed to an AP. The OR of association between AP use and death was 1.53 (95% C.I, 0.83-2.80) in univariate and 1.61 (95% C.I, 0.88-2.96) in multivariate analysis. CONCLUSION: In elderly medical inpatients with delirium, administration of APs was not associated with a statistically significant increased risk of mortality. Larger studies are needed to clarify the safety of AP medication in elderly patients with delirium.

Bimolecular electron and energy transfer reactivity of exchange-coupled dinuclear iron(III) complexes.

Bimolecular quenching between photosensitizers and exchange-coupled transition metal complexes has been studied in an effort to experimentally establish a link between Heisenberg spin exchange and chemical reactivity. The acceptors are members of the oxo/hydroxo-biscarboxylato class of dinuclear Fe(III) compounds, where protonation of the oxo bridge provides a means for modulating the magnitude of spin exchange within the cluster. Photoexcitation of solutions containing Ru(II) polypyridyl sensitizers and the Fe(III) complexes results in quenching of emission from the (3)MLCT excited state of the Ru(II) chromophores; nanosecond time-resolved absorption measurements demonstrate that quenching occurs, in part, by electron transfer. Decoupling electron transfer driving force (DeltaG(0)(ET)) from changes in the magnitude of spin exchange was achieved by varying the bridging carboxylate to afford a series of complexes of the form [Fe(2)O(H)(O(2)CR)(2)(Tp)(2)](n)(+) (n = 0, 1, 2). Electrochemical measurements reveal a greater than 500 mV shift in cluster reduction potential across the series (i.e., R = CH(3) to CF(3)), whereas variable-temperature magnetic susceptibility measurements demonstrate a corresponding invariance in spin exchange between the metal centers (J(oxo) = -119 +/- 4 cm(-1) and J(hydroxo) = -18 +/- 2 cm(-1) for H = -2JS(1).S(2)). Structural analyses suggest that reorganization energies (lambda) associated with electron transfer should be identical for all molecules within a given series (i.e., oxo or hydroxo bridged); likewise Deltalambda between the series is expected to be small. A comparison of quenching rates for the two extended series firmly establishes that neither reorganization energy nor electron transfer driving force considerations can account for differences in reactivity between oxo-bridged (large spin exchange) and hydroxo-bridged (small spin exchange) quenchers. Upon consideration of energy transfer contributions, it is determined that reactivity differences between the oxo- and hydroxo-bridged quenchers must lie in the relative rates of Dexter energy transfer and/or electron transfer, with the origin of the latter linked to something other than DeltaG(0)(ET) or lambda. Finally, the extent to which spin exchange within the dinuclear Fe(III) quenchers can be identified as the key variable influencing these reactivity patterns is discussed.

Rapamycin and less immunosuppressive analogs are toxic to Candida albicans and Cryptococcus neoformans via FKBP12-dependent inhibition of TOR.

Candida albicans and Cryptococcus neoformans cause both superficial and disseminated infections in humans. Current antifungal therapies for deep-seated infections are limited to amphotericin B, flucytosine, and azoles. A limitation is that commonly used azoles are fungistatic in vitro and in vivo. Our studies address the mechanisms of antifungal activity of the immunosuppressive drug rapamycin (sirolimus) and its analogs with decreased immunosuppressive activity. C. albicans rbp1/rbp1 mutant strains lacking a homolog of the FK506-rapamycin target protein FKBP12 were found to be viable and resistant to rapamycin and its analogs. Rapamycin and analogs promoted FKBP12 binding to the wild-type Tor1 kinase but not to a rapamycin-resistant Tor1 mutant kinase (S1972R). FKBP12 and TOR mutations conferred resistance to rapamycin and its analogs in C. albicans, C. neoformans, and Saccharomyces cerevisiae. Our findings demonstrate the antifungal activity of rapamycin and rapamycin analogs is mediated via conserved complexes with FKBP12 and Tor kinase homologs in divergent yeasts. Taken together with our observations that rapamycin and its analogs are fungicidal and that spontaneous drug resistance occurs at a low rate, these mechanistic findings support continued investigation of rapamycin analogs as novel antifungal agents.

Development of Saccharomyces cerevisiae as a model pathogen. A system for the genetic identification of gene products required for survival in the mammalian host environment.

Saccharomyces cerevisiae, a close relative of the pathogenic Candida species, is an emerging opportunistic pathogen. An isogenic series of S. cerevisiae strains, derived from a human clinical isolate, were used to examine the role of evolutionarily conserved pathways in fungal survival in a mouse host. As is the case for the corresponding Candida albicans and Cryptococcus neoformans mutants, S. cerevisiae purine and pyrimidine auxotrophs were severely deficient in survival, consistent with there being evolutionary conservation of survival traits. Resistance to the antifungal drug 5-fluorocytosine was not deleterious and appeared to be slightly advantageous in vivo. Of mutants in three amino acid biosynthetic pathways, only leu2 mutants were severely deficient in vivo. Unlike the glyoxylate cycle, respiration was very important for survival; however, the mitochondrial genome made a respiration-independent contribution to survival. Mutants deficient in pseudohyphal formation were tested in vivo; flo11Delta mutants were phenotypically neutral while flo8Delta, tec1Delta, and flo8Delta tec1Delta mutants were slightly deficient. Because of its ease of genetic manipulation and the immense S. cerevisiae database, which includes the best annotated eukaryotic genome sequence, S. cerevisiae is a superb model system for the identification of gene products important for fungal survival in the mammalian host environment.

Attenuated total reflection design for in situ FT-IR spectroelectrochemical studies.

A versatile spectroelectrochemical apparatus is introduced to study the changes in IR spectra of organic and inorganic compounds upon oxidation or reduction. The design is based on an attenuated total reflection device, which permits the study of a wide spectral range of 16,700 (600 nm)-250 cm(-1), with a small opaque region of 2250-1900 cm(-1). In addition, an IR data collection protocol is introduced to deal with electrochemically nonreversible background signals. This method is tested with ferrocene in acetonitrile; concentrations as low as 1 mM produce results that agree with those in the literature.

Delirium in older medical inpatients and subsequent cognitive and functional status: a prospective study.

BACKGROUND: Delirium in older hospital inpatients appears to be associated with various adverse outcomes. The limitations of previous research on this association have included small sample sizes, short follow-up periods and lack of consideration of important confounders or modifiers, such as severity of illness, comorbidity and dementia. The objective of this study was to determine the prognostic significance of delirium, with or without dementia, for cognitive and functional status during the 12 months after hospital admission, independent of premorbid function, comorbidity, severity of illness and other potentially confounding variables. METHODS: Patients 65 years of age and older who were admitted from the emergency department to the medical services were screened for delirium during their first week in hospital. Two cohorts were enrolled: patients with prevalent or incident delirium and patients without delirium, but similar in age and cognitive impairment. The patients were followed up at 2, 6 and 12 months after hospital admission. Analyses were conducted for 4 patient groups: 56 with delirium, 53 with dementia, 164 with both conditions and 42 with neither. Baseline measures included delirium (Confusion Assessment Method), dementia (Informant Questionnaire on Cognitive Decline in the Elderly), physical function (Barthel Index [BI] and premorbid instrumental activities of daily living, IADL), the Mini-Mental State Examination (MMSE), comorbidity, and physiologic and clinical severity of illness. Outcome variables measured at follow-up were the MMSe, Barthel Index, IADL and admission to a long-term care facility. RESULTS: After adjustment for covariates, the mean differences in MMSE scores at follow-up between patients with and without delirium were -4.99 (95% confidence interval [CI] -7.17 to -2.81) for patients with dementia and -3.36 (95% CI -6.15 to -0.58) for those without dementia. At 12 months, the adjusted mean differences in the BI were -16.45 (95% CI -27.42 to -5.50) and -13.89 (95% CI -28.39 to 0.61) for patients with and without dementia respectively. Patients with both delirium and dementia were more likely to be admitted to long-term care than those with neither condition (adjusted odds ratio 3.18, 95% CI 1.19 to 8.49). Dementia but not delirium predicted worse IADL scores at follow-up. Unadjusted analyses yielded similar results. INTERPRETATION: For older patients with and without dementia, delirium is an independent predictor of sustained poor cognitive and functional status during the year after a medical admission to hospital.

Agitation in demented patients in an acute care hospital: prevalence, disruptiveness, and staff burden.

UNLABELLED: BACKGROUND/LITERATURE REVIEW: The prevalence of agitated behaviors in different populations with dementia is between 24% and 98%. Although agitated behaviors are potentially disruptive, little research attention has been focused on the effects of these behaviors upon nursing staff. The objectives of this study of demented patients in long-term-care beds at an acute care community hospital were to determine the frequency and disruptiveness of agitated behaviors; to investigate the associations of patient characteristics and interventions with the level of agitation; and to explore the burden of these agitated behaviors on nursing staff. METHOD: The study sample comprised 56 demented patients in the long-term-care unit during the study period. Twenty-seven staff who cared for these patients during three shifts over a 2-week period were interviewed to rate the frequency and disruptiveness of agitated behaviors using the Cohen-Mansfield Agitation Inventory, and the burden of care using a modified version of the Zarit Burden Interview. Data on patient characteristics and interventions extracted from the hospital chart included scores on the Barthel Index and Mini-Mental State Examination, the use of psychotropic medication, and the use of physical restraints. RESULTS: Ninety-five percent of the patients with dementia were reported to have at least one agitated behavior; 75% had at least one moderately disruptive behavior. A small group of six patients (11%) had 17 or more disruptive behaviors. The frequency of most behaviors did not vary significantly by shift. Length of stay on long-term care, Barthel Index score, and the use of psychotropic medications were significantly associated with the number of agitated behaviors. The number of behaviors, their mean frequency, and their mean disruptiveness were all significantly correlated with staff burden. DISCUSSION: The prevalence of agitated behaviors in patients with dementia in long-term-care beds at an acute care hospital is similar to that reported in long-term-care facilities. These behaviors are associated with staff burden.

Antisocial behavioral syndromes and return to drug use following residential relapse prevention/health education treatment.

This study compared residential addiction treatment clients meeting full DSM-III-R criteria for antisocial personality disorder (ASPD) with those reporting syndromal levels of antisocial behavior only in adulthood (AABS) on time to and severity of first posttreatment drug use. Antisocial syndrome and selected other mental disorders were assessed using the Diagnostic Interview Schedule, Revised for DSM-III-R, and validity of self-reported posttreatment drug behavior was measured against results of hair analysis. Among subjects followed within 180 days after treatment exit, individuals with ASPD were at modestly increased risk of a first lapse episode compared to those with AABS. However, the two groups did not differ in severity of lapse. Participants with ASPD demonstrated poorer agreement between self-reported posttreatment drug behavior and hair data. These results add to the evidence suggesting that the DSM requirement for childhood onset in ASPD may be clinically important among substance abusers in identifying a severely antisocial and chronically addicted group at elevated risk for early posttreatment recidivism. Our findings support the importance of careful classification of antisocial syndromes among substance abusers and the identification of characteristics of these syndromes that underlie clients' risks for posttreatment return to drug use to provide optimally individualized treatment planning.

Monitoring clinical research: report of one hospital's experience.

Monitoring of research by research ethics boards has been recommended by various organizations that fund clinical studies and by other groups. However, little evidence has been reported on the processes, costs and outcomes of these activities, information that would be helpful to guide the boards in their current work and future policies. We report here 3 years of monitoring experience by the research ethics board of a 313-bed university-affiliated community hospital. Activities newly implemented at the beginning of the study period included the use of recruitment logs, audits of completed consent forms and interviews with research subjects. Over the study period, we monitored 33 protocols, through 188 consent form audits and interviews with 17 research subjects. In addition, 26 of 34 research investigators and collaborators responded to a survey about the monitoring. In general, the investigators were supportive of monitoring activities, but most were not willing to contribute financially. The types of monitoring we conducted are feasible and may be suitable (or could be adapted) for use in other institutions.

Feasibility and effectiveness of treatments for post-stroke depression in elderly inpatients: systematic review.

To determine the feasibility and effectiveness of antidepressive treatments for post-stroke depression in elderly medical inpatients, MEDLINE was searched for potentially relevant articles published from January 1987 to August 1997 using the keywords "depression or depressive disorder" (exploded) and "aged." Thirteen reports met the following inclusion criteria: (1) published in English or French; (2) minimum age criterion of 55 and over or mean age 65 and over; (3) post-stroke subjects admitted to a medical, geriatric, or rehabilitation service; (4) used accepted criteria for depression; (5) examined treatment(s) for depression; and (6) reported outcomes as a depression diagnosis and/or symptom level. Data were abstracted independently from each article by two reviewers. The limited evidence suggests contraindications to treatment of 83% of a group to receive a heterocyclic antidepressant compared with 11% of a group to receive a selective serotonin reuptake inhibitor (SSRI); rates of discontinuation and study completion are similar for heterocyclics, SSRIs and psychostimulants. All of the treatments appear to be at least modestly effective in the short term.

Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients.

BACKGROUND: Use of anticholinergic (ACH) medications is a biologically plausible and potentially modifiable risk factor of delirium, but research findings are conflicting regarding its association with delirium. OBJECTIVES: To evaluate the longitudinal association between use of ACH medications and severity of delirium symptoms and to determine whether this association is modified by the presence of dementia. PATIENTS AND METHODS: A total of 278 medical inpatients 65 years and older with diagnosed incident or prevalent delirium were followed up with repeated assessments using the Delirium Index for up to 3 weeks. Exposure to ACH and other medications was measured daily. The association between change in medication exposure in the 24 hours preceding a Delirium Index assessment was assessed using a mixed linear regression model. RESULTS: During follow-up (mean +/- SD, 12.3 +/- 7.0 days), 47 medications with potential ACH effect were used in the population (mean, 1.4 medications per patient per day). Increase in delirium severity was significantly associated with several measures of ACH medication exposure on the previous day, adjusting for dementia, baseline delirium severity, length of follow-up, and number of non-ACH medications taken. Dementia did not modify the association between ACH medication use and delirium severity. CONCLUSION: Exposure to ACH medications is independently and specifically associated with a subsequent increase in delirium symptom severity in elderly medical inpatients with diagnosed delirium.

Rapid emergency department intervention for older people reduces risk of functional decline: results of a multicenter randomized trial.

OBJECTIVES: To determine the effectiveness of a two-stage (screening and nursing assessment) intervention for older patients in the emergency department (ED) who are at increased risk of functional decline and other adverse outcomes. DESIGN: Controlled trial, randomized by day of ED visit, with follow-up at 1 and 4 months. SETTING: Four university-affiliated hospitals in Montreal. PARTICIPANTS: Patients age 65 and older expected to be released from the ED to the community with a score of 2 or more on the Identification of Seniors At Risk (ISAR) screening tool and their primary family caregivers. One hundred seventy-eight were randomized to the intervention, 210 to usual care. INTERVENTION: The intervention consisted of disclosure of results of the ISAR screen, a brief standardized nursing assessment in the ED, notification of the primary care physician and home care providers, and other referrals as needed. The control group received usual care, without disclosure of the screening result. MEASUREMENTS: Patient outcomes assessed at 4 months after enrollment included functional decline (increased dependence on the Older American Resources and Services activities of daily living scale or death) and depressive symptoms (as assessed by the short Geriatric Depression Scale). Caregiver outcomes, also assessed at baseline and 4 months, included the physical and mental summary scales of the Medical Outcomes Study Short Form-36. Patient and caregiver satisfaction with care were assessed 1 month after enrollment. RESULTS: The intervention increased the rate of referral to the primary care physician and to home care services. The intervention was associated with a significantly reduced rate of functional decline at 4 months, in both unadjusted (odds ratio (OR) = 0.60, 95% confidence interval (CI) = 0.36-0.99) and adjusted (OR = 0.53, 95% CI = 0.31-0.91) analyses. There was no intervention effect on patient depressive symptoms, caregiver outcomes, or satisfaction with care. CONCLUSION: A two-stage ED intervention, consisting of screening with the ISAR tool followed by a brief, standardized nursing assessment and referral to primary and home care services, significantly reduced the rate of subsequent functional decline.

Environmental risk factors for delirium in hospitalized older people.

OBJECTIVES: To evaluate the relationship of environmental risk factors in hospitals to changes over time in delirium symptom severity scores. DESIGN: Observational prospective clinical study with repeated measurements, several times during the first week of hospitalization and then weekly during hospitalization. SETTING: University-affiliated general community hospital. PARTICIPANTS: Four hundred forty-four patients age 65 and older admitted to the medical wards: 326 with delirium and 118 without delirium. Patients with prior cognitive impairment were oversampled. MEASUREMENTS: The severity of delirium symptoms was measured with the Delirium Index, a scale developed and validated by our group, based on the Confusion Assessment Method. Potential environmental risk factors assessed included isolation, hospital unit, room changes, levels of sensory stimulation, aids to orientation, and presence of medical (e.g., intravenous) or physical restraints. RESULTS: Controlling for initial severity of delirium and patient characteristics, variables significantly related to an increase in delirium severity scores included hospital unit (intensive care or long-term care unit), number of room changes, absence of a clock or watch, absence of reading glasses, presence of a family member, and presence of medical or physical restraints. CONCLUSION: The associations of intensive care and medical and physical restraints with severity of delirium symptoms may be due to uncontrolled confounding by indication. However, the other factors identified suggest potentially modifiable risk factors for symptoms of delirium in hospitalized older people.

Prevalence and detection of delirium in elderly emergency department patients.

BACKGROUND: Delirium is a complex medical disorder associated with high morbidity and mortality among elderly patients. The goals of our study were to determine the prevalence of delirium in emergency department (ED) patients aged 65 years and over and to determine the sensitivity and specificity of a conventional clinical assessment by an ED physician for the detection of delirium in the same population. METHODS: All elderly patients presenting to the ED in a primary acute care, university-affiliated hospital who were triaged to the observation room on a stretcher because of the severity of their illness were screened for delirium by a research psychiatrist using the Mini-Mental State Examination and the Confusion Assessment Method. The diagnosis of "delirium" or an equivalent term by the ED physician was determined by 2 methods: completion of a mental status checklist by the ED physician and chart review. The prevalence of delirium and the sensitivity and specificity of the ED physician's clinical assessment were calculated with their 95% confidence intervals. The demographic and clinical characteristics of patients with detected delirium and those with undetected delirium were compared. RESULTS: A sample of 447 patients was screened. The prevalence of delirium was 9.6% (95% confidence interval 6.9%-12.4%). The sensitivity of the detection of delirium by the ED physician was 35.3% and the specificity, 98.5%. Most patients with delirium had neurologic or pulmonary diseases, and most patients with detected delirium had neurologic diseases. INTERPRETATION: Despite the relatively high prevalence of delirium in elderly ED patients, the sensitivity of a conventional clinical assessment for this condition is low. There is a need to improve the detection of delirium by ED physicians.

Blue-fluorescent antibodies.

The forte of catalytic antibodies has resided in the control of the ground-state reaction coordinate. A principle and method are now described in which antibodies can direct the outcome of photophysical and photochemical events that take place on excited-state potential energy surfaces. The key component is a chemically reactive optical sensor that provides a direct report of the dynamic interplay between protein and ligand at the active site. To illustrate the concept, we used a trans-stilbene hapten to elicit a panel of monoclonal antibodies that displayed a range of fluorescent spectral behavior when bound to a trans-stilbene substrate. Several antibodies yielded a blue fluorescence indicative of an excited-state complex or "exciplex" between trans-stilbene and the antibody. The antibodies controlled the isomerization coordinate of trans-stilbene and dynamically coupled this manifold with an active-site residue. A step was taken toward the use of antibody-based photochemical sensors for diagnostic and clinical applications.

Prediction of hospital utilization among elderly patients during the 6 months after an emergency department visit.

STUDY OBJECTIVE: A simple screening tool, Identification of Seniors at Risk (ISAR), developed for administration in the emergency department for patients 65 years and older, predicts adverse health outcomes during the 6 months after the ED visit. In this study, we investigated whether the ISAR tool can also predict acute care hospital utilization in the same population. METHODS: Patients 65 years and older who visited the EDs of 4 acute care Montreal hospitals during the weekday shift over a 3-month period were enrolled. At the initial (index) ED visit, 27 self-report screening questions (including the 6 ISAR items) were administered. The number of acute care hospital days during the 6 months after the index visit were abstracted from the provincial hospital discharge database. High utilization was defined as the top decile of the distribution of acute care hospital days. RESULTS: Among 1,620 patients with linked data, a score of 2+ on the ISAR tool predicted high hospital utilization with a sensitivity of 73% and a specificity of 51%; the area under the receiver operating characteristic curve was 0.68. The ISAR tool also performed well in subgroups defined by disposition (admitted versus discharged) and by age (65 to 74 years versus 75 years and older). CONCLUSION: The ISAR tool, a 6-item self-report questionnaire, can be used in the ED to identify elderly patients who will experience high acute care hospital utilization as well as adverse health outcomes.

Tracking cognitive decline in Alzheimer's disease using the mini-mental state examination: a meta-analysis.

OBJECTIVES: To estimate the annual rate of change scores (ARC) on the Mini-Mental State Examination (MMSE) in Alzheimer's disease (AD) and to identify study or population characteristics that may affect the ARC estimation. METHODS: MEDLINE was searched for articles published from January 1981 to November 1997 using the following keywords: AD and longitudinal study or prognosis or cognitive decline. The bibliographies of review articles and relevant papers were searched for additional references. All retrieved articles were screened to meet the following inclusion criteria: (a) original study; (b) addressed cognitive decline or prognosis or course of AD; (c) published in English; (d) study population included AD patients with ascertainable sample size; (e) used either clinical or pathological diagnostic criteria; (f) longitudinal study design; and (g) used the MMSE as one of the outcome measures. Data were systematically abstracted from the included studies, and a random effects regression model was employed to synthesize relevant data across studies and to evaluate the effects of study methodology on ARC estimation and its effect size. RESULTS: Of the 439 studies screened, 43 met all the inclusion criteria. After 6 studies with inadequate or overlapping data were excluded, 37 studies involving 3,492 AD patients followed over an average of 2 years were included in the meta-analysis. The pooled estimate of ARC was 3.3 (95% confidence interval [CI]: 2.9-3.7). The observed variability in ARC across studies could not be explained with the covariates we studied, whereas part of the variability in the effect size of ARC could be explained by the minimum MMSE score at entry and number of assessments. CONCLUSIONS: A pooled average estimate of ARC in AD patients was 3.3 points (95% CI: 2.9-3.7) on the MMSE. Significant heterogeneity of ARC estimates existed across the studies and cannot be explained by the study or population characteristics investigated. Effect size of ARC was related to the initial MMSE score of the study population and the number of assessments.