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Background Many patients with atrial fibrillation (AF) remain undiagnosed despite availability of interventions to reduce stroke risk. Predictive models to date are limited by data requirements and theoretical usage. We aimed to develop a model for predicting the 2-year probability of AF diagnosis and implement it as proof-of-concept (POC) in a production electronic health record (EHR). Methods We used a nested case–control design using data from the Indiana Network for Patient Care. The development cohort came from 2016 to 2017 (outcome period) and 2014 to 2015 (baseline). A separate validation cohort used outcome and baseline periods shifted 2 years before respective development cohort times. Machine learning approaches were used to build predictive model. Patients ≥ 18 years, later restricted to age ≥ 40 years, with at least two encounters and no AF during baseline, were included. In the 6-week EHR prospective pilot, the model was silently implemented in the production system at a large safety-net urban hospital. Three new and two previous logistic regression models were evaluated using receiver-operating characteristics. Number, characteristics, and CHA2DS2-VASc scores of patients identified by the model in the pilot are presented. Results After restricting age to ≥ 40 years, 31,474 AF cases (mean age, 71.5 years; female 49%) and 22,078 controls (mean age, 59.5 years; female 61%) comprised the development cohort. A 10-variable model using age, acute heart disease, albumin, body mass index, chronic obstructive pulmonary disease, gender, heart failure, insurance, kidney disease, and shock yielded the best performance (C-statistic, 0.80 [95% CI 0.79–0.80]). The model performed well in the validation cohort (C-statistic, 0.81 [95% CI 0.8–0.81]). In the EHR pilot, 7916/22,272 (35.5%; mean age, 66 years; female 50%) were identified as higher risk for AF; 5582 (70%) had CHA2DS2-VASc score ≥ 2. Conclusions Using variables commonly available in the EHR, we created a predictive model to identify 2-year risk of developing AF in those previously without diagnosed AF. Successful POC implementation of the model in an EHR provided a practical strategy to identify patients who may benefit from interventions to reduce their stroke risk.

Rapid response teams (RRTs) improve mortality by intervening in the hours preceding arrest. Implementation of these teams varies across institutions.Our health-care system has two different RRT models at two hospitals: Hospital A does not utilize a proactive rounder while Hospital B does. We studied the patterns of RRT calls at each hospital focusing on the differences between night and day and during nursing shift transitions.The presence of proactive surveillance appeared to be associated with an increased total number of RRT calls with more than twice as many calls made at the smaller Hospital B than Hospital A. Hospital B had more calls in the daytime compared to the nighttime. Both hospitals showed a surge in the night-to-day shift transition (7-8am) compared to the preceding nighttime. Hospital A additionally showed a surge in calls during the day-to-night shift transition (7-8pm) compared to the preceding daytime.Differences in the diurnal patterns of RRT activation exist between hospitals even within the same system. As a continuously learning system, each hospital should consider tracking these patterns to identify their unique vulnerabilities. More calls are noted between 7-8am compared to the overnight hours. This may represent the reestablishment of the 'afferent' arm of the RRT as the hospital returns to daytime staffing and activity. Factors that influence the impact of proactive rounding on RRT performance may deserve further study.

BACKGROUND Annual computed tomography (CT) scans are a component of the current standard of care for the posttreatment surveillance of survivors of colorectal cancer (CRC) after curative-intent resection. The authors conducted a retrospective study with the primary aim of assessing patient, physician, and organizational characteristics associated with the receipt of CT surveillance among veterans. METHODS The Department of Veterans Affairs Central Cancer Registry was used to identify patients diagnosed with AJCC collaborative stage I to III CRC between 2001 and 2009. Patient sociodemographic and clinical (ie, CRC stage and comorbidity) characteristics, provider specialty, and organizational characteristics were measured. Hierarchical multivariable logistic regression models were used to assess the association between patient, provider, and organizational characteristics on receipt of 1) consistently guideline-concordant care (at least 1 CT every 12 months for both of the first 2 years of CRC surveillance) versus no CT receipt and 2) potential overuse (>1 CT every 12 months during the first 2 years of CRC surveillance) of CRC surveillance using CT. The authors also analyzed the impact of the 2005 American Society of Clinical Oncology update in CRC surveillance guidelines on care received over time. RESULTS For 2263 survivors of stage II/III CRC who were diagnosed after 2005, 19.4% of patients received no surveillance CT, whereas potential overuse occurred in both surveillance years for 14.9% of patients. Guideline-concordant care was associated with younger age, higher stage of disease (stage III vs stage II), and geographic region. In adjusted analyses, younger age and higher stage of disease (stage III vs stage II) were found to be associated with overuse. There was no significant difference in the annual rate of CT scanning noted across time periods (year ≤ 2005 vs year > 2005). CONCLUSIONS Among a minority of veteran survivors of CRC, both underuse and potential overuse of CT surveillance were present. Patient factors, but no provider or organizational characteristics, were found to be significantly associated with patterns of care. The 2005 change in American Society of Clinical Oncology guidelines did not appear to have an impact on rates of surveillance CT. Cancer 2017;123:2338-2351. © 2017 American Cancer Society.

Background Intrauterine devices are effective and safe, long-acting reversible contraceptives, but the risk of uterine perforation occurs with an estimated incidence of 1 to 2 per 1000 insertions. The European Active Surveillance Study for Intrauterine Devices, a European prospective observational study that enrolled 61,448 participants (2006–2012), found that women breastfeeding at the time of device insertion or with the device inserted at ≤36 weeks after delivery had a higher risk of uterine perforation. The Association of Uterine Perforation and Expulsion of Intrauterine Device (APEX-IUD) study was a Food and Drug Administration–mandated study designed to reflect current United States clinical practice. The aims of the APEX-IUD study were to evaluate the risk of intrauterine device–related uterine perforation and device expulsion among women who were breastfeeding or within 12 months after delivery at insertion. Objective We aimed to describe the APEX-IUD study design, methodology, and analytical plan and present population characteristics, size of risk factor groups, and duration of follow-up. Study Design APEX-IUD study was a retrospective cohort study conducted in 4 organizations with access to electronic health records: Kaiser Permanente Northern California, Kaiser Permanente Southern California, Kaiser Permanente Washington, and Regenstrief Institute in Indiana. Variables were identified through structured data (eg, diagnostic, procedural, medication codes) and unstructured data (eg, clinical notes) via natural language processing. Outcomes include uterine perforation and device expulsion; potential risk factors were breastfeeding at insertion, postpartum timing of insertion, device type, and menorrhagia diagnosis in the year before insertion. Covariates include demographic characteristics, clinical characteristics, and procedure-related variables, such as difficult insertion. The first potential date of inclusion for eligible women varies by research site (from January 1, 2001 to January 1, 2010). Follow-up begins at insertion and ends at first occurrence of an outcome of interest, a censoring event (device removal or reinsertion, pregnancy, hysterectomy, sterilization, device expiration, death, disenrollment, last clinical encounter), or end of the study period (June 30, 2018). Comparisons of levels of exposure variables were made using Cox regression models with confounding adjusted by propensity score weighting using overlap weights. Results The study population includes 326,658 women with at least 1 device insertion during the study period (Kaiser Permanente Northern California, 161,442; Kaiser Permanente Southern California, 123,214; Kaiser Permanente Washington, 20,526; Regenstrief Institute, 21,476). The median duration of continuous enrollment was 90 (site medians 74–177) months. The mean age was 32 years, and the population was racially and ethnically diverse across the 4 sites. The mean body mass index was 28.5 kg/m2, and of the women included in the study, 10.0% had menorrhagia ≤12 months before insertion, 5.3% had uterine fibroids, and 10% were recent smokers; furthermore, among these women, 79.4% had levonorgestrel-releasing devices, and 19.5% had copper devices. Across sites, 97,824 women had an intrauterine device insertion at ≤52 weeks after delivery, of which 94,817 women (97%) had breastfeeding status at insertion determined; in addition, 228,834 women had intrauterine device insertion at >52 weeks after delivery or no evidence of a delivery in their health record. Conclusion Combining retrospective data from multiple sites allowed for a large and diverse study population. Collaboration with clinicians in the study design and validation of outcomes ensured that the APEX-IUD study results reflect current United States clinical practice. Results from this study will provide valuable information based on real-world evidence about risk factors for intrauterine devices perforation and expulsion for clinicians.

BackgroundData on initiation and utilization of direct-acting antiviral therapies for hepatitis C virus infection in the United States are limited. This study evaluated treatment initiation, time to treatment, and real-world effectiveness of direct-acting antiviral therapy in individuals with hepatitis C virus infection treated during the first 2 years of availability of all-oral direct-acting antiviral therapies.MethodsA retrospective cohort analysis was undertaken using electronic medical records and chart review abstraction of hepatitis C virus-infected individuals aged >18 years diagnosed with chronic hepatitis C virus infection between January 1, 2014, and December 31, 2015 from the Indiana University Health database.ResultsEight hundred thirty people initiated direct-acting antiviral therapy during the 2-year observation window. The estimated incidence of treatment initiation was 8.8%±0.34% at the end of year 1 and 15.0%±0.5% at the end of year 2. Median time to initiating therapy was 300 days. Using a Cox regression analysis, positive predictors of treatment initiation included age (hazard ratio, 1.008), prior hepatitis C virus treatment (1.74), cirrhosis (2.64), and history of liver transplant (1.5). History of drug abuse (0.43), high baseline alanine aminotransferase levels (0.79), hepatitis B virus infection (0.41), and self-pay (0.39) were negatively associated with treatment initiation. In the evaluable population (n = 423), 83.9% (95% confidence interval, 80.1-87.3%) of people achieved sustained virologic response.ConclusionIn the early years of the direct-acting antiviral era

Anticossos; Immunoteràpia; Càncer de cap i coll Anticuerpos; Inmunoterapia; Cáncer de cabeza y cuello Antibodies; Immunotherapy; Head and neck cancer Background Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study ( NCT02207530 ) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC. Patients and methods Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS). Results Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9–24.4); 29.4% (95% CI, 15.1–47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5–21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9–3.7) and 7.1 months (95% CI, 4.9–9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5–22.1) and 33.6% (95% CI, 24.8–42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up. Conclusion Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients. This study was supported by AstraZeneca.

Background and objective Electronic health records databases are increasingly used for identifying cohort populations, covariates, or outcomes, but discerning such clinical ‘phenotypes’ accurately is an ongoing challenge. We developed a flexible method using overlapping (Venn diagram) queries. Here we describe this approach to find patients hospitalized with acute congestive heart failure (CHF), a sampling strategy for one-by-one ‘gold standard’ chart review, and calculation of positive predictive value (PPV) and sensitivities, with SEs, across different definitions. Materials and methods We used retrospective queries of hospitalizations (2002–2011) in the Indiana Network for Patient Care with any CHF ICD-9 diagnoses, a primary diagnosis, an echocardiogram performed, a B-natriuretic peptide (BNP) drawn, or BNP >500 pg/mL. We used a hybrid between proportional sampling by Venn zone and over-sampling non-overlapping zones. The acute CHF (presence/absence) outcome was based on expert chart review using a priori criteria. Results Among 79 091 hospitalizations, we reviewed 908. A query for any ICD-9 code for CHF had PPV 42.8% (SE 1.5%) for acute CHF and sensitivity 94.3% (1.3%). Primary diagnosis of 428 and BNP >500 pg/mL had PPV 90.4% (SE 2.4%) and sensitivity 28.8% (1.1%). PPV was

Objectives: To evaluate whether race influences agreement between screening results and documentation of cognitive impairment and delirium. Design: Secondary data analysis. Setting: An urban, public hospital and healthcare system. Participants: Hospitalized older adults aged 65 and older admitted to general inpatient medical services evaluated for cognitive impairment (n = 851) and evaluated for delirium (n = 424). Measurements: Cognitive impairment and delirium were measured in each participant using the Short Portable Mental Status Questionnaire (SPMSQ) and the Confusion Assessment Method (CAM), respectively, as the reference identification method. Clinical documentation of cognitive impairment and delirium was defined according to the presence of International Classification of Diseases, Ninth Revision (ICD-9), codes from within 1 year before hospitalization through discharge for cognitive impairment or from hospital admission through discharge for delirium. Results: Two hundred ninety-four participants (34%) had cognitive impairment based on SPMSQ performance, and 163 (38%) had delirium based on CAM results. One hundred seventy-one (20%) of those with cognitive impairment had an ICD-9 code for cognitive impairment, whereas 92 (22%) of those with delirium had an ICD-9 code for delirium. After considering age, sex, education, socioeconomic status, chronic comorbidity, and severity of acute illness, of those who screened positive on the SPMSQ, African Americans had a higher adjusted odds ratio (AOR) than non-African Americans for clinical documentation of cognitive impairment (AOR = 1.66, 95% confidence interval (CI) = 0.95�2.89), and of those who screened negative on the SPMSQ, African Americans had higher odds of clinical documentation of cognitive impairment (AOR = 2.10, 95% CI = 1.17�3.78) than non-African Americans. There were no differences in clinical documentation rates of delirium between African Americans and non-African Americans. Conclusion: Racial differences in coding for cognitive impairment may exist, resulting in higher documentation of cognitive impairment in African Americans screening positive or negative for cognitive impairment.

The relative efficacy of natural language processing (NLP) of text reports compared to structured data queries for identifying patients from electronic health records (EHRs) with metastatic cancer remains unclear. Such identification is critical for identifying and recruiting potential study candidates for cancer trials, particularly trials of cancer chemotherapy. For such purposes, we performed a direct comparison between NLP and structured data query methods for identifying patients with metastatic melanoma. Using EHR data from two large institutions, we found that NLP of text reports identified close to three times as many patients with metastatic melanoma compared to a structured data query algorithm (1,727 vs. 607 patients). Using an external tumour registry, we also found NLP had much higher sensitivity than structured query for identifying such patients (67% vs. 35%). Our results emphasise the importance of employing NLP criteria when identifying potential cancer study candidates with metastatic disease.

In 2001, approximately 12.6 million individuals aged 65 and older were discharged from American hospitals with an average length of stay of 5.8 days1 and up to 66% of them suffered from cognitive impairment (CI)2–20. CI in hospitalized older adults includes a variety of disorders ranging from mild cognitive deficit, delirium, to full-blown dementia. Dementia is a syndrome of decline in memory plus at least one other cognitive domain, such as language, visuo-spatial, or executive function sufficient to interfere with social or occupational functioning in an alert person21. Delirium is a disturbance of consciousness with reduced ability to focus, sustain, or shift attention that occurs over a short period of time and tends to fluctuate over the course of the day22. Mild cognitive impairment without dementia is defined as the presence of a cognitive deficit in the absence of delirium that does not affect functional performance23. Hospitalized older adults with CI are vulnerable to hospital complications including delirium, physical restraints, urinary catheters, and tethers2,3,24–35. The management of their medical or surgical illnesses requires avoiding certain medications with anticholinergic activities that might worsen cognition36. Furthermore, CI may delay diagnostic and therapeutic procedures, demand more time for informed-consent related issues, and result in difficulty in adherence to medical recommendations37,38. The special needs of hospitalized older adults with delirium and dementia has been shown to increase demands on nursing staff, risk of post-discharge institutionalization, length of stay and health care costs3–10,27,39–48. We wanted to look specifically at CI because it often goes undetected49–51 and can have a great impact on the hospital course of elders. Screening for CI among hospitalized older adults has been considered to have potential benefit in hospital care of older adults52. Screening may lead to early detection by uncovering subtle symptoms not yet apparent to families or other caregivers who know the patient well but do not notice small declines or changes in day-to-day functioning. Early recognition of CI may lead to early treatment and subsequently may delay progression of cognitive decline improve health outcomes. Screening may enhance physician’s prescribing practices and reduce exposure to harmful medications among these vulnerable patients. Finally, delirium is an important prognostic indicator and screening patients could provide invaluable information towards the overall clinical picture. Despite all of this, the current literature does not provide sufficient information to support the use of routine screening on admission2–20,41,52–54. Most of the published studies were conducted among elders who stayed in the hospital for more than 48 hours, missing data on the crucial first 48 hours of the hospital course2–20,41,52–54. These studies did not evaluate the impact of unrecognized CI on the hospital course and the majority of these studies were not conducted in the urban and lower socioeconomic status populations of elders that are the most vulnerable for bad health outcomes2–20,41,52–54. Finally, few studies evaluated the impact of delirium superimposed on cognitive impairment on the hospital course and mortality of elders2–20,41,52–54. With these details in mind we wanted to explore the impact of cognitive impairment recognition among patients aged 65 and older admitted to the medical services of an urban, public hospital in Indianapolis to determine the prevalence and the impact of recognized and unrecognized CI on the hospital course of these elders. Furthermore, we examined the role of delirium superimposed on these hospitalized elders with CI.

In today's environment, providers are extremely time-constrained. Assembling relevant contextual data to make decisions on laboratory results can take a significant amount of time from the day. The Regenstrief Institute has created a system which leverages data within Indiana Health Information Exchange's (IHIE's) repository, the Indiana Network for Patient Care (INPC), to provide well-organized and contextual information on returning laboratory results to outpatient providers. The system described here uses data extracted from INPC to add historical test results, medication-dispensing events, visit information, and clinical reminders to traditional laboratory result reports. These "Enhanced Laboratory Reports" (ELRs) are seamlessly delivered to outpatient practices connected through IHIE via the DOCS4DOCS clinical messaging service. All practices, including those without electronic medical record systems, can receive ELRs. In this paper, the design and implementation issues in creating this system are discussed, and generally favorable preliminary results of attitudes by providers towards ELRs are reported.

The effectiveness of parathyroidectomy (PTHX) for the control of secondary hyperparathyroidism was assessed in 46 adult end-stage renal disease (ESRD) patients whose bone mineral content at the midshaft and distal radius was measured using single-photon absorptiometry (SPA) every 6 months before and after the surgery. They were compared to 46 age-, race-, and sex-matched ESRD patient controls who had not undergone surgery but who had had at least five SPA studies at similar intervals. Presurgery midradius bone mass was significantly lower for PTHX patients compared to controls. Comparing changes in bone mass of PTHX patients across surgery to controls in comparable time periods showed that PTHX patients lost significantly less bone mass after surgery. Similar results were obtained when rates of change in bone mass were evaluated. When patient characteristics were examined, the effect of surgery was found to be diminished in elderly patients and in oophorectomized patients. It is concluded that PTHX can have a salutary effect on renal osteodystrophy in the appendicular skeleton, but factors other than bone mass also need to be considered in identifying those patients who will benefit from surgery.

The identification of those at highest risk of osteoporotic fractures is a clinical goal that requires appropriate statistical comparisons of potential predictors of fractures. This article provides a formal approach for comparing individual predictors (e.g., bone mass at one site vs bone mass at another), or sets of predictors (e.g., bone mass vs other risk factors), and contrasts newer methods, such as bootstrapping, to receiver-operating-characteristics (ROC) curves, which have been previously used. The advantages of the bootstrapping approach are illustrated using time-to-fracture data from a published study demonstrating the use of baseline bone mass measurements in the prediction of fractures in 521 subjects with variable lengths of follow-up, extending to 12.5 years. Bone mineral density (BMD) was shown to be significantly better than bone mineral content (BMC) in predicting fractures in free-living subjects, but not in retirement-community subjects. Bone mineral apparent density (BMAD) was also compared with BMC and BMD and shown not to improve fracture prediction in these subjects.

Differences in osteoporotic hip fracture incidence between American whites and blacks and between women and men are considered to result, in part, from differences in bone mineral density and geometry at the femur. The aim of this study was to quantify differences in femoral bone density and geometry between a large sample of healthy American white and black women and men.Healthy American white (n=612) and black (n=164) premenopausal women, aged 23 to 57 years, and healthy American white (n=492) and black (n=169) men, aged 20 to 63 years, had volumetric bone mineral density (vBMD) and geometry variables measured at the femur by computerized tomography (CT), and areal bone mineral density (aBMD) at femoral neck measured by dual X-ray absorptiometry (DXA).American blacks had higher vBMD at the femoral neck and femoral shaft cortex than American whites whereas femoral axis length and femoral neck area were not different. Men had lower vBMD at the femoral neck and femoral cortex than women but had greater femoral axis length and femoral neck area than women. The higher aBMD in American blacks than whites persisted after correction for measured area whereas the higher aBMD in men than women disappeared.At the femoral neck, American whites have lower bone density than American blacks but similar geometry. Women have higher bone density than men in both races but have smaller geometry variables. The differences in bone density may account in part for the differences in hip fracture incidence between American blacks and whites, whereas the differences in femur size may account for the differences in hip fracture rates between men and women.

Low-intensity pulsed ultrasound (LIPUS) and nonsteroidal anti-inflammatory drugs (NSAIDs) were used to treat stress fracture. Bilateral stress fractures were induced in the ulnas of 48 adult rats. Animals were divided into two groups (NSAID and VEH), and treated 5 days per week with celecoxib (5 mg/kg) mixed in a vehicle solution of polyethylene glycol and saline (NSAID) or vehicle alone (VEH). One-to-three hours following drug administration, all animals were treated with unilateral active-LIPUS and contralateral inactive-LIPUS. Equal numbers of ulnas from each drug group were histologically evaluated at 2, 4, and 8 weeks following induction of stress fracture. Neither LIPUS nor NSAID influenced bone resorption, but each had significant and opposite effects on intracortical bone formation rate. These effects indicate that LIPUS may be used to facilitate stress fracture repair whereas NSAID may delay tissue level repair of stress fractures. There was no interaction between LIPUS and NSAID, indicating that the beneficial LIPUS effect was not mediated by the cyclooxygenase-2 pathway. LIPUS accelerated stress fracture healing, whereas the NSAID delayed repair. When used in combination, the beneficial LIPUS effect was not impaired by the detrimental NSAID effect.

Osteoporosis treatment rates within 2 years following an index event (fragility fracture, osteoporotic bone mineral density (BMD) T-score, or osteoporosis ICD-9 codes) were determined from 2005 to 2011. Most patients were not treated. Fracture patients had the lowest treatment rate. Low treatment rates also occurred in patients that were male, black, or had non-commercial insurance. Clinical recognition of osteoporosis (osteoporotic BMD, assignment of an ICD-9 code, or the occurrence of fragility fractures) provides opportunities to treat patients at risk for future fracture. A cohort of 36,965 patients was identified from 2005 to 2011 in the Indiana Health Information Exchange, with index events after age 50 of either non-traumatic fractures, an osteoporosis ICD-9 code, or a BMD T-score ≤ −2.5. Patients with osteoporosis treatment in the preceding year were excluded. Medication records during the ensuing 2 years were extracted to identify osteoporosis treatments, demographics, comorbidities, and co-medications. Predictors of treatment were evaluated in a multivariable logistic regression model. The cohort was 78 % female, 11 % black, 91 % urban-dwelling, and 53 % commercially insured. The index events were as follows: osteoporosis diagnosis (47 % of patients), fragility fracture (44 %), and osteoporotic T-scores (9 %). Within 2 years after the index event, 23.3 % received osteoporosis medications (of which, 82.2 % were oral bisphosphonates). Treatment rates were higher after osteoporosis diagnosis codes (29.3 %) or osteoporotic T-score (53.9 %) than after fracture index events (10.5 %) (p

Background Adherence to oral bisphosphonates is often low, but even adherent patients may remain at elevated fracture risk. The goal of this study was to estimate the proportion of bisphosphonate-adherent women remaining at high risk of fracture. Methods A retrospective cohort of women aged 50 years and older, adherent to oral bisphosphonates for at least two years was identified, and data were extracted from a multi-system health information exchange. Adherence was defined as having a dispensed medication possession ratio ≥ 0.8. The primary outcome was clinical occurrence of: low trauma fracture (months 7–36), persistent T-score ≤ − 2.5 (months 13–36), decrease in bone mineral density (BMD) at any skeletal site ≥ 5%, or the composite of any one of these outcomes. Results Of 7435 adherent women, 3110 had either pre- or post-adherent DXA data. In the full cohort, 7% had an incident osteoporotic fracture. In 601 women having both pre- and post-adherent DXA to evaluate BMD change, 6% had fractures, 22% had a post-treatment T-score ≤ − 2.5, and 16% had BMD decrease by ≥ 5%. The composite outcomes occurred in 35%. Incident fracture was predicted by age, previous fracture, and a variety of co-morbidities, but not by race, glucocorticoid treatment or type of bisphosphonate. Conclusion Despite bisphosphonate adherence, 7% had incident osteoporotic fractures and 35% had either fracture, decreases in BMD, or persistent osteoporotic BMD, representing a substantial proportion of treated patients in clinical practices remaining at risk for future fractures. Further studies are required to determine the best achievable goals for osteoporosis therapy, and which patients would benefit from alternate therapies.

Objective: To evaluate quantitative measures of eye movements as possible biomarkers in prediagnostic and early stages of Huntington disease (HD). Methods: The study sample (n = 215) included individuals both at risk and recently diagnosed with HD. All participants completed a uniform clinical evaluation which included administration of the Unified Huntington’s Disease Rating Scale (UHDRS) by a movement disorder neurologist and molecular testing to determine HD gene status. A high resolution, video-based eye tracking system was employed to quantify measures of eye movement (error rates, latencies, SD of latencies, velocities, and accuracies) during a computerized battery of saccadic and steady fixation tasks. Results: Prediagnostic HD gene carriers and individuals with early HD demonstrated three types of significant abnormalities while performing memory guided and anti-saccade tasks: increased error rate, increased saccade latency, and increased variability of saccade latency. The eye movement abnormalities increased with advancing motor signs of HD. Conclusions: Abnormalities in eye movement measures are a sensitive biomarker in the prediagnostic and early stages of Huntington disease (HD). These measures may be more sensitive to prediagnostic changes in HD than the currently employed neurologic motor assessment.

The Alox15 gene was recently identified as a negative regulator of peak BMD in mice. Polymorphisms in human ALOX12, but not ALOX15, were significantly associated with spine BMD in white men and women, suggesting that ALOX12 may contribute to normal variation in BMD. Introduction: Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporosis is peak BMD, which is a highly heritable trait. Recently, the arachidonate 15-lipoxygenase (Alox15) gene was identified as a negative regulator of peak BMD in mice. Materials and Methods: To assess the contribution of lipoxygenase genes to normal BMD variation in healthy white men and women, we performed population- and family-based association studies of two arachidonate lipoxygenase genes: ALOX15, which is the human homolog of mouse Alox15, and ALOX12, which is functionally similar to Alox15. Single nucleotide polymorphisms (SNPs) distributed across the two genes were genotyped. BMD was measured at the femoral neck and lumbar spine in 411 men 18–61 years of age and 1291 premenopausal women 20–50 years of age. Results: Moderate evidence of association was found between spine BMD and six SNPs in the ALOX12 gene in both men and women (p = 0.0052–0.050). Furthermore, the most common SNP haplotype in ALOX12 showed evidence of significant association with high spine BMD in men (p = 0.0083), whereas the second most common haplotype was associated with high spine BMD in women (p = 0.0081). Conclusions: Polymorphisms in the ALOX12 gene may contribute to normal variation in spine BMD.

Our goal was to review and extend statistical methods for discriminating between normal subjects and those with dementia or cognitive impairment. We compared six different methods to one constructed by expert opinion, in their brevity and predictive power. The methods include logistic regression and neural networks, with standard and least absolute shrinkage and selection operator (LASSO) variable selection, as well as decision trees with and without boosting. These methods were applied to the baseline data of a subgroup of subjects in a dementia study, using their screening interview items to predict their clinical diagnosis of normal or non-normal (cognitively impaired or demented). The derived models were then validated on a different subgroup of subjects in the same study who had the screening and clinical diagnosis two to five years later. Performance of different models was compared based on their sensitivity and specificity in the validation sample. Generally, the six statistical methods performed slightly to moderately better than the expert-opinion model. Neural networks generally performed better than the logistic and decision tree models. LASSO improved the performance of logistic and neural network models, but it eliminated few input variables in the neural network. The single decision tree performed at least as well as the standard logistic model, and with fewer items, making it an attractive pre-screening tool. Using the boosting option for decision trees did not substantially improve the performance. We recommend that for each situation, different methods of classification should be attempted to obtain optimal results for a given purpose.

A significant source of missing data in longitudinal epidemiological studies on elderly individuals is death. Subjects in large scale community-based longitudinal dementia studies are usually evaluated for disease status in study waves, not under continuous surveillance as in traditional cohort studies. Therefore, for the deceased subjects, disease status prior to death cannot be ascertained. Statistical methods assuming deceased subjects to be missing at random may not be realistic in dementia studies and may lead to biased results. We propose a stochastic model approach to simultaneously estimate disease incidence and mortality rates. We set up a Markov chain model consisting of three states, non-diseased, diseased and dead, and estimate the transition hazard parameters using the maximum likelihood approach. Simulation results are presented indicating adequate performance of the proposed approach.

Objective The authors conducted a longitudinal, population-based survey of African Americans in Indianapolis, Indiana, and Yoruba in Ibadan, Nigeria, using the Community Screening Interview for Dementia to assess the predictive value of informant reports of changes in personality on incident dementia and Alzheimer disease. Methods In all, 3,021 subjects had informants' reports of changes in personality and dementia status (2,084 subjects residing in Ibadan and 937 subjects residing in Indianapolis). Results After adjusting for demographic, cognitive, and functional characteristics in two markedly different populations, socioeconomically and culturally, subjects with changes in personality had approximately twice the odds of having dementia as subjects with no change in personality Conclusions The finding that in two markedly different populations, personality change is a significant predictor of future dementia, independent of cognition and functional status, should make clinicians particularly sensitive to these reports when they occur in their elderly patients.

To design a brief cognitive screener with acceptable sensitivity and specificity for identifying subjects with cognitive impairment.Cohort one is assembled from a community-based survey coupled with a second-stage diagnostic evaluation using formal diagnostic criteria for dementia. Cohort two is assembled from referrals to a specialty clinic for dementing disorders that completed the same diagnostic evaluation.Urban neighborhoods in Indianapolis, Indiana and the Indiana Alzheimer Disease Center.Cohort one consists of 344 community-dwelling black persons identified from a random sample of 2212 black persons aged 65 and older residing in Indianapolis; cohort two consists of 651 subject referrals to the Alzheimer Disease Center.Formal diagnostic clinical assessments for dementia including scores on the Mini-mental state examination (MMSE), a six-item screener derived from the MMSE, the Blessed Dementia Rating Scale (BDRS), and the Word List Recall. Based on clinical evaluations, subjects were categorized as no cognitive impairment, cognitive impairment-not demented, or demented.The mean age of the community-based sample was 74.4 years, 59.4% of the sample were women, and the mean years of education was 10.1. The prevalence of dementia in this sample was 4.3% and the prevalence of cognitive impairment was 24.6%. Using a cut-off of three or more errors, the sensitivity and specificity of the six-item screener for a diagnosis of dementia was 88.7 and 88.0, respectively. In the same sample, the corresponding sensitivity and specificity for the MMSE using a cut-off score of 23 was 95.2 and 86.7. The performance of the two scales was comparable across the two populations studied and using either cognitive impairment or dementia as the gold standard. An increasing number of errors on the six-item screener is highly correlated with poorer scores on longer measures of cognitive impairment.The six-item screener is a brief and reliable instrument for identifying subjects with cognitive impairment and its diagnostic properties are comparable to the full MMSE. It can be administered by telephone or face-to-face interview and is easily scored by a simple summation of errors.

Autosomal dominant osteopetrosis type II (ADO2) is typically diagnosed from radiographs, which demonstrate the pathognomonic findings of osteosclerosis and endobone formation. Individuals with ADO2 also have elevated serum levels of tartrate-resistant acid phosphatase (TRAP) and the BB isoenzyme of creatine kinase (CK-BB). In the current study, we tested the utility of these enzymes in making or refuting a diagnosis of ADO2. Furthermore, because ADO2 has incomplete penetrance, we examined whether TRAP and CK-BB were helpful in identifying gene carriers. We studied eight families, measured serum levels of TRAP and CK-BB in 52 affected individuals and 12 obligate gene carriers, and compared their values with age-matched controls. Our results demonstrate that affected patients have significantly elevated levels of both TRAP and CK-BB. In contrast, gene carriers have values that are not different from controls. Furthermore, in our study population, TRAP and CK-BB have a high diagnostic sensitivity and specificity, particularly in children. From this large study of ADO2 patients and carriers, we conclude that: 1) TRAP and CK-BB are significantly elevated in patients with ADO2, 2) obligate carriers cannot be adequately identified by measurement of these analytes, and 3) TRAP and CK-BB are highly sensitive and specific diagnostic tests that can efficiently and effectively screen high-risk individuals who have not had previous radiographic assessment.

This study measured bone mineral content (BMC), bone mineral density (BMD), and bone area at the spine and hip to learn whether bone loss takes place premenopausally. Participants were 130 non-Hispanic white women 31 to 50 years of age who were in good general health and had taken no drugs that affect bone metabolism. Measurements were made by dual-energy x-ray absorptiometry at the L2-4 segment of the lumbar spine, in the femoral neck, and in the total hip. The studies were repeated at least twice over 1 to 9 years. Both BMC and bone area increased significantly over time in the spine, as did BMD. If, however, BMC was normalized by bone volume, there was no age-related change in volumetric density. Measurements of the total hip showed no significant change with age. BMD in the femoral neck declined at a rate of about 0.0036 g/cm2 per year. BMC was lost as well, so the drop in BMD was not an artifact of bone expansion. Changes in BMD correlated positively with weight change and estradiol levels and negatively with gonadotropin levels. Somewhat less bone loss was noted in subjects who gained more weight during the study. Higher levels of LH and FSH were documented in women who lost more than 1% of BMD per year. Estrogen levels were highest in women who manifested no bone loss. Declining BMD was more a result of a loss of BMC in women with high FSH levels, but due more to an expansion in bone area in those with relatively low FSH levels. The positive association between body weight change and BMD was not entirely mediated by higher estrogen. Premenopausal women more than 30 years of age in this study lost BMD at the femoral neck at an average annual rate of 0.4%. Bone loss was less in women who gained more weight but greater in those with reduced estrogen levels even in the absence of symptoms. Early bone loss might be preventable if premenopausal women with suboptimal sex hormone levels are detected at an early stage.

Background Limited data exist on the impact of dementia in developing nations, including its association with mortality. Objective The purpose of this paper is to assess the relationship between dementia and five-year mortality on a community dwelling elderly Yoruba population in the developing country of Nigeria and to compare those results with those from an elderly African–American community in Indianapolis. Methods A two-phase design was used to ascertain dementia status in two sites. In the first phase, the Community Screening Instrument for Dementia (CSI-D) was administered. In the second phase, subjects were sampled for the clinical assessment according to their CSI-D performance category. Proportional hazards regression was used to assess the relationship between mortality and cognitive status at both sites after adjusting for demographics and chronic disease conditions. Results For the entire screened population, poor and intermediate performance on the CSI-D is associated with increased mortality at both sites; however the effect of CSI-D performance did not significantly differ between the two sites. For the clinically assessed sample, dementia was significantly associated with increased mortality at both sites (Ibadan RR = 2.83, Indianapolis RR = 2.05), but the effect was not significantly different across the two sites. Conclusion Dementia resulted in an increased risk of mortality for Yoruba of a magnitude similar to African–Americans suggesting that the impact of dementia on mortality risk may be similar for developing and developed countries. Copyright © 2002 John Wiley & Sons, Ltd.

Femoral structure contributes to bone strength at the proximal femur and predicts hip fracture risk independently of bone mass. Quantitative components of femoral structure are highly heritable traits. To identify genetic loci underlying variation in these structural phenotypes, we conducted an autosomal genome screen in 309 white sister pairs. Seven structural variables were measured from femoral radiographs and used in multipoint sib-pair linkage analyses. Three chromosomal regions were identified with significant evidence of linkage (log10 of the odds ratio [LOD] > 3.6) to at least one femoral structure phenotype. The maximum LOD score of 4.3 was obtained for femur neck axis length on chromosome 5q. Evidence of linkage to chromosome 4q was found with both femur neck axis length (LOD = 3.9) and midfemur width (LOD = 3.5). Significant evidence of linkage also was found to chromosome 17q, with a LOD score of 3.6 for femur head width. Two additional chromosomal regions 3q and 19p gave suggestive (LOD > 2.2) evidence of linkage with at least two of the structure phenotypes. Chromosome 3 showed evidence of linkage with pelvic axis length (LOD = 3.1), midfemur width (LOD = 2.8), and femur head width (LOD = 2.3), spanning a broad (60 cm) region of chromosome 3q. Linkage to chromosome 19 was supported by two phenotypes, femur neck axis length (LOD = 2.8) and femur head width (LOD = 2.8). This study is the first genome screen for loci underlying variation in femoral structure and represents an important step toward identifying genes contributing to the risk of osteoporotic hip fracture in the general population.

A major determinant of the risk for osteoporosis is peak bone mineral density (BMD), which is largely determined by genetic factors. We recently reported linkage of peak BMD in a large sample of healthy sister pairs to chromosome 11q12–13. To identify additional loci underlying normal variations in peak BMD, we conducted an autosomal genome screen in 429 Caucasian sister pairs. Multipoint LOD scores were computed for BMD at four skeletal sites. Chromosomal regions with LOD scores above 1.85 were further pursued in an expanded sample of 595 sister pairs (464 Caucasians and 131 African-Americans). The highest LOD score attained in the expanded sample was 3.86 at chromosome 1q21–23 with lumbar spine BMD. Chromosome 5q33–35 gave a LOD score of 2.23 with femoral neck BMD. At chromosome 6p11–12, the 464 Caucasian pairs achieved a LOD score of 2.13 with lumbar spine BMD. Markers within the 11q12–13 region continued to support linkage to femoral neck BMD, although the peak LOD score was decreased to 2.16 in the sample of 595 sibling pairs. Our study is the largest genome screen to date for genes underlying variations in peak BMD and represents an important step toward identifying genes contributing to osteoporosis in the general population.

Two-phase sampling designs have been used in the field of psychiatry to estimate prevalence and incidence of a rare disease such as dementia and Alzheimer's disease. In a longitudinal study on dementia, since the repeated two-phase sampling is conducted several years after the baseline wave, some subjects may die before the follow-up wave, thus their disease status prior to death is missing. There are reasons to suggest that the missing due to death is non-ignorable. Estimation of disease incidence from longitudinal dementia study has to appropriately adjust for data missing by death as well as the sampling design used at each study wave. In this paper we adopt a selection model approach to model the missing data by death and use a likelihood approach to derive incidence estimates. A modified EM algorithm is used to deal with data from sampling selection. The non-parametric jack-knife variance estimator is used to derive variance estimates for the model parameters and the incidence estimates. The proposed approaches are applied to data from the Indianapolis-Ibadan Dementia Study.

Longitudinal studies of dementia are often undertaken to estimate the incidence of dementia and to identify incident cases for the study of risk factors measured on the entire cohort at baseline. The power of these analyses is determined primarily by the number of demented cases identified. Increasing the number of waves of evaluation of the cohort in a given time period increases the yield of demented cases but it also increases the cost of the study. This paper provides a method for estimating dementia incidence in the presence of mortality and loss to follow-up. It also assesses the trade-off between the cost (as measured by the number of re-evaluations) and the yield of incident dementia cases so that longitudinal studies of dementia can be designed optimally in the future.

A major determinant of the risk for osteoporosis in later life is bone mineral density (BMD) attained during early adulthood. BMD is a complex trait that presumably is influenced by multiple genes. Insulin-like growth factor I (IGF-I) is an attractive candidate gene for osteoporosis susceptibility, because IGF-I has marked effects on bone cells and has been implicated in the pathogenesis of osteoporosis. The IGF-I gene contains a microsatellite repeat polymorphism approximately 1 kb upstream from the IGF-I gene transcription start site, and previous investigators have found a higher prevalence of the 192/192 genotype of this polymorphism among men with idiopathic osteoporosis compared to controls. In this study we used this IGF-I polymorphism to test for an association between this polymorphism and BMD in our large population of premenopausal women (1 sister randomly chosen from 292 Caucasian and 71 African-American families). We also used this polymorphism to detect linkage to BMD elsewhere in the IGF-I gene or in a nearby gene using sibling pair linkage analysis in healthy premenopausal sister pairs (542 sibling pairs: 418 Caucasian and 124 African-American). Neither test provided any evidence of linkage or association between the IGF-I gene locus and spine or femoral neck BMD in Caucasians or AfricanAmericans. (J Clin Endocrinol Metab 84: 4467‐ 4471, 1999)

Oxidative stress has been implicated both in the aging process and in the pathological changes associated with Alzheimer's disease. Antioxidants, which have been shown to reduce oxidative stress in vitro, may represent a set of potentially modifiable protective factors for poor memory, which is a major component of the dementing disorders. The authors investigated the association between serum antioxidant (vitamins E, C, A, carotenoids, selenium) levels and poor memory performance in an elderly, multiethnic sample of the United States. The sample consisted of 4,809 non-Hispanic White, non-Hispanic Black, and Mexican-American elderly who visited the Mobile Examination Center during the Third National Health and Nutrition Examination Survey, a national cross-sectional survey conducted from 1988 to 1994. Memory is assessed using delayed recall (six points from a story and three words) with poor memory being defined as a combined score less than 4. Decreasing serum levels of vitamin E per unit of cholesterol were consistently associated with increasing levels of poor memory after adjustment for age, education, income, vascular risk factors, and other trace elements and minerals. Serum levels of vitamins A and C, beta-carotene, and selenium were not associated with poor memory performance in this study.

An epidemiological study often uses a two-phase design to estimate the prevalence rate of a mental disease. In a two-phase design study, the first phase assesses a large sample with an inexpensive screening test, and then the second phase selects a subsample for a more expensive diagnostic evaluation. Furthermore, disease status may not be ascertained for all subjects who are selected for disease verification because some subjects are unable to be clinically assessed, while others may refuse. Since not all screened subjects are selected for diagnostic assessments, there is potential for verification bias. In this paper, we propose the maximum likelihood (ML) and bootstrap methods to correct for verification bias for estimating and comparing the prevalence rates under the missing-at-random (MAR) assumption for the verification mechanism. We also propose a method to test this MAR assumption. Finally, we apply our methods to a large-scale prevalence study of dementia disorders.

Information on the clinical utility of neuropsychological tests in non-North-American samples is limited. We examined the diagnostic efficacy of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery in Jamaican men and women age 65 and older. A total of 72 elders were diagnosed as normal and 12 were demented based on history, physical, and neurological examination. Independent of this medical examination, participants were tested with the CERAD battery. Normal controls scored significantly better than dementia patients on all tests in the CERAD battery. A discriminant function found that a combination of Word List Learning Sum Recall and Boston Naming Test correctly classified a total of 81% of the cases (83% of the dements and 81% of the normal controls). This study is the first to demonstrate the clinical utility of the CERAD neuropsychological battery in the differential diagnosis of memory disorders of the aged in a non-North-American sample. (JINS, 1999, 5, 255–259.)

The determination of the safety of a patient with dementia who continues to drive is a difficult task for the physician who cares for geriatric patients. This study used the Traffic Sign Recognition Test (TSRT) discrimination between dementia patients who continue to drive and normal elderly volunteers. Thirty-seven subjects with dementia who continue to drive and 47 normal elderly volunteers were recruited to participate in the study. Each group was tested with the TSRT similar to that used for licensing in the state of Indiana. The difference in total number of signs correctly identified between the two groups was determined using the Wilcoxon Rank Sum Test. The difference between groups of each individual sign recognition was determined using a Chi Square test. The affected group was also tested with a neuropsychological battery (NB) designed to measure skills thought to be needed for driving. Drivers with dementia correctly identified 5.95 (± 2.17) of the 10 traffic signs used in licensing as compared to the normal elderly volunteers who correctly identified 8.77 (± 1.58) total signs (p < 0.0001). The “Slow Moving Vehicle” sign provided the largest difference between the two groups; demented drivers correctly identified the sign 39 percent of the time, compared with 89 percent in the normal volunteers (X2= 15.333, df= 1, p < 0.005). Only 76 percent of the demented drivers correctly identified a “Stop” sign compared with 98 percent of the normal elderly drivers. The percentage of correctly identified signs on the TSRT also correlated with several tests in the NB. Drivers with dementia who continue to drive perform worse on traffic sign recognition than normal elderly drivers. While our current screening tool did not assess the driving safety of either group, it suggests that demented patients who still drive may not recognize common traffic signs and may thus pose a risk to society.

Bone mass and structure at the proximal femur are important predictors of hip fracture. The aims of this study were to compare in a large sample of elderly men and women the precision of measurements of bone mass and structure at multiple sites at the proximal femur, to examine their interrelationships, to establish their relationships with age and body size, and to examine criteria for defining geometric and architectural variables in bone structure. Women (n = 336) and men (n = 141) over the age of 60 years were studied cross-sectionally. Bone mineral density (BMD) and content (BMC) at the proximal femur were measured in duplicate by dual-energy X-ray absorptiometry (DXA). Shaft and total upper femur (hip) sites in addition to femoral neck, Ward's triangle and trochanter were measured. Structural variables, measured from radiographs and from DXA images, including cortical thickness at calcar femorale, lateral cotex and midfemur, width of the femur and medulla, Singh grade, hip and femoral axis length, femoral head and neck width and the center of mass of the femoral neck. BMD and BMC had high reproducibility and there were significant differences in reproducibility across sites. Among sites, total upper femur and shaft had the highest reproducibility. Duplicate measurements substantially improved reliability of the measurement and are recommended when the value is close to a diagnostic level or when it will be used to establish rates of change. Reproducibility of structural variables was also high except for the lateral cortex, center of mass and Singh grade. Variance due to measurement error did not change with either age or gender. Women were significantly different from men, after controlling for differences in body size, in all variables except Singh grade and medulla width. BMD and BMC were negatively related to age and positively to body size. Structural variables examined in relation to age and body size fell into two categories. The first comprised variables that were not age-related but were body-size-related suggesting that they could be classified as geometric variables. The second comprised variables that were both body-size-related and age-related, suggesting that they could be classified as architectural variables. Using these criteria, calcar and lateral cortex were architectural variables, whereas shaft width, hip and femoral axis length, femoral head and neck width, and center of mass were geometric in both men and women. In women, shaft cortex width and medulla width were age-related, whereas in men they were not. Singh grade showed no consistent pattern with age or body size in women and men.

We studied the effects of apolipoprotein E (APOE) genotype and gender on clinical response to tacrine in patients with mild to moderate Alzheimer's disease (AD). We analyzed data from a previously reported 30-week, double-blind, placebo-controlled trial of tacrine, in which APOE genotypes were determined from previously collected plasma samples. Patients were assigned to placebo or tacrine with daily dosages of 80, 120, or 160 mg/day. The outcome measures were Alzheimer's Disease Assessment Scale-Cognitive Component, Clinician Interview Based Impression, Mini-Mental State Examination, and the Caregiver-rated Clinical Global Impression of Change. An intent-to-treat (ITT) analysis of patients with available genotypes (n = 528) did not reveal response differences by genotype, although the effect size was twice as large in the epsilon2-3 as the epsilon4 group (-2.62 versus -1.25). The association of treatment effect with APOE genotype varied significantly according to gender (p0.002 for ITT; p0.05 for evaluables). The treatment effect was larger in the epsilon2-3 compared with epsilon4 women (ITT, 4.24 points, p = 0.03; evaluable, 7.20 points, p = 0.01). In contrast, treatment effect size was not different between epsilon2-3 and epsilon4 of men with AD. APOE genotype and gender may predict response to tacrine in patients with AD.

In this retrospective analysis of 443 Alzheimer disease (AD) patients from a 30-week tacrine trial, change in Alzheimer's Disease Assessment Scale score from baseline to final value was significantly associated with a total serum cholesterol/APOE genotype interaction. Disease progression in the no-APOE epsilon4 allele/high-cholesterol subgroup was greater than in the normal-cholesterol subgroups with or without epsilon4. Cholesterol levels and APOE genotype may interact to affect AD progression. The results are consistent with preclinical data on cholesterol's effects in AD.

Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 176 RXXR 179 /S 180 proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene–environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.

X-Linked hypophosphatemia (XLH) is characterized by renal phosphate wasting, with inappropriately low or normal serum 1,25-dihydroxyvitamin D concentrations causing rickets and osteomalacia. Mutations in PHEX result in increased fibroblast growth factor 23 (FGF23) expression, elevating circulating FGF23 concentrations. Treating XLH with phosphate and calcitriol may further increase FGF23 concentrations, based on in vitro and in vivo models.The aim of the study was to investigate whether current standard XLH therapies increase circulating FGF23 concentrations.We conducted a prospective observational study of XLH subjects during routine clinical management at two tertiary referral centers.The study included 10 XLH patients (seven children, three adults; age, 2-30 yr) initiating therapy and five XLH patients (age, 18-41 yr) electing not to undergo therapy.Oral calcitriol and phosphate were administered.We measured circulating intact FGF23 concentrations.Baseline circulating FGF23 concentrations were elevated in 14 of 15 subjects, increasing after treatment in most subjects. Follow-up was 14.4 +/- 11.7 months (treatment cohort) and 25 +/- 32 months (nontreatment cohort). FGF23 concentrations increased 132.7 +/- 202.4% from pretreatment to peak during therapy but did not change significantly over time in the nontreatment cohort. FGF23 concentrations were related to phosphate doses (P = 0.04) and nonsignificantly to calcitriol doses (P = 0.06).Treating XLH with phosphate and calcitriol was associated with concurrent increases in circulating FGF23 concentrations, which may diminish therapeutic effect or contribute to complications of therapy. Because it is unknown whether the degree of FGF23 elevation correlates with disease severity in XLH, further study is needed to determine whether adjusting therapy to minimize effects on FGF23 concentration is warranted.

Familial tumoral calcinosis is characterized by ectopic calcifications and hyperphosphatemia. The disease is caused by inactivating mutations in fibroblast growth factor 23 (FGF23), Klotho (KL), and uridine diphosphate-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3). In vitro studies indicate that GALNT3 O-glycosylates a phosphaturic hormone, FGF23, and prevents its proteolytic processing, thereby allowing secretion of intact FGF23. In this study we generated mice lacking the Galnt3 gene, which developed hyperphosphatemia without apparent calcifications. In response to hyperphosphatemia, Galnt3-deficient mice had markedly increased Fgf23 expression in bone. However, compared with wild-type and heterozygous littermates, homozygous mice had only about half of circulating intact Fgf23 levels and higher levels of C-terminal Fgf23 fragments in bone. Galnt3-deficient mice also exhibited an inappropriately normal 1,25-dihydroxyvitamin D level and decreased alkaline phosphatase activity. Furthermore, renal expression of sodium-phosphate cotransporters and Kl were elevated in Galnt3-deficient mice. Interestingly, there were sex-specific phenotypes; only Galnt3-deficient males showed growth retardation, infertility, and significantly increased bone mineral density. In summary, ablation of Galnt3 impaired secretion of intact Fgf23, leading to decreased circulating Fgf23 and hyperphosphatemia, despite increased Fgf23 expression. Our findings indicate that Galnt3-deficient mice have a biochemical phenotype of tumoral calcinosis and provide in vivo evidence that Galnt3 plays an essential role in proper secretion of Fgf23 in mice.

Longitudinal studies of neurocognitive function in prediagnosis Huntington disease (pre-HD) have been few, and duration of follow-up has been brief. In the current study, 155 individuals at-risk for HD completed a battery of cognitive and motor tasks at two study visits approximately 10 years apart. Participants were classified as: 1) at-risk, without the CAG expansion (normal controls, NC; n = 112), or 2) CAG expanded (CAG+; n = 43). To examine the rate of decline at different stages of the pre-HD period, participants in the CAG+ group were further characterized as converters (i.e., individuals who developed manifest HD over the course of the study; n = 21) or nonconverters (n = 22), and their performances were compared. The CAG+ group exhibited faster rates of neurocognitive decline over the course of the study, relative to the NC group. In addition, more rapid decline was associated with closer proximity to estimated age of disease onset in the CAG+ group. Faster rates of motor and psychomotor decline were observed in the CAG+ converter group, relative to the nonconverters. These findings suggest that neurocognitive decline in pre-HD, particularly in motor and psychomotor domains, begins insidiously and accelerates as individuals approach disease onset.

Osteoporosis is a complex disease with both genetic and environmental risk factors. A major determinant of osteoporotic fractures is peak BMD obtained during young adulthood. We previously reported linkage of chromosome 1q (LOD = 4.3) with variation in spinal areal BMD in healthy premenopausal white women. In this study, we used a two-stage genotyping approach to identify genes in the linked region that contributed to the variation of femoral neck and lumbar spine areal BMD. In the first stage, 654 SNPs across the linked region were genotyped in a sample of 1309 premenopausal white women. The most significant evidence of association for lumbar spine (p = 1.3 x 10(-6)) was found with rs1127091 in the GATAD2B gene. In the second stage, 52 SNPs around this candidate gene were genotyped in an expanded sample of 1692 white women. Significant evidence of association with spinal BMD (p10(-5)), and to a lesser extent with femoral neck BMD, was observed with eight SNPs within a single 230-kb linkage disequilibrium (LD) block. The most significant SNP (p = 3.4 x 10(-7)) accounted for2.5% of the variation in spinal BMD in these women. The 230-kb LD block contains 11 genes, but because of the extensive LD, the specific gene(s) contributing to the variation in BMD could not be determined. In conclusion, the significant association between spinal BMD and SNPs in the 230-kb LD block in chromosome 1q indicates that genetic factor(s) in this block plays an important role in peak spinal BMD in healthy premenopausal white women.

Mutations in the chloride channel 7 gene (CLCN7) cause osteopetrosis, and polymorphisms of CLCN7 in the non-disease allele are associated with penetrance of the autosomal dominant osteopetrosis (ADO) phenotype. Studies have also shown an association between CLCN7 polymorphisms and bone mineral density (BMD) in women. However, there is no study to date that has examined whether CLCN7 polymorphisms underlie normal variation of peak BMD in healthy premenopausal white women and in white men.Six single nucleotide polymorphisms (SNPs) and one variable number tandem repeat (VNTR) polymorphism in the CLCN7 gene were genotyped. Association was tested between CLCN7 gene polymorphisms and both lumbar spine and femoral neck BMD. Healthy premenopausal white sisters (age 33.1+/-7.2, n=1692) and healthy white brothers (age 33.6+/-10.9, n=715) were studied.No significant association between CLCN7 gene polymorphisms and BMD at the lumbar spine or femoral neck was found in white women or white men.Genetic variation in the CLCN7 gene is not a major contributor to the variability in peak BMD at the femoral neck and lumber spine in healthy premenopausal white women and in white men.

We have addressed the relative importance of peak bone mass and subsequent rate of loss in determining postmenopausal women's bone mass in old age, by examining longitudinal measurements of radial mid-shaft bone mass on various samples of healthy white postmenopausal women. Using both the variance estimate of age-specific rates of bone loss and the population variance in bone mass, we determined that rates of loss could contribute importantly to future bone mass. However, since we found a small negative correlation between initial bone mass and rate of loss, it was necessary to estimate the effect of bone loss as the complement of the contribution of initial bone mass. We found that the influence of bone loss (relative to initial bone mass) increases as the women age, such that by about age 70, the contribution of initial bone mass and rate of loss approached equality. However, estimated rates of bone loss were not very stable over time, so it was difficult to identify long-term ‘fast-losers’. We conclude that the rate of postmenopausal bone loss is an important contributor to osteoporosis at old age, but it is difficult to identify long-term fast-losers, thereby reducing the clinical value of assessments of rates of change in bone mass early in the postmenopause.

Background Hepatitis C and chronic kidney disease (CKD) are both highly prevalent diseases in the United States. Data showed that hepatitis C may be causally linked to some glomerular diseases, and patients who are positive for hepatitis C have increased risk of albuminuria. Study Design To determine whether hepatitis C infection is associated with increased likelihood of CKD, we performed retrospective cross-sectional and longitudinal analyses of a large clinical database. Setting & Participants Data for a study population of 13,139 African American and white patients tested for hepatitis C between 1994 and 2004 were extracted from a computerized database from a clinical population of an urban hospital and affiliated clinics. Predictor Hepatitis C by means of enzyme-linked immunosorbent assay. Outcome In cross-sectional analysis, CKD was defined as a minimum estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m 2 by using the 4-variable isotope dilution mass spectrometry–traceable Modification of Diet in Renal Disease Study equation or proteinuria. In longitudinal analysis, CKD was defined as eGFR less than 60 mL/min/1.73 m 2 . Measurements Potential confounders investigated included sex, age, race, human immunodeficiency virus (HIV) status, chronic hypertension, diabetes, and other laboratory test result abnormalities. Results 3,938 patients (30.0%) were positive for hepatitis C and 2,549 (19.4%) had CKD. Of those with CKD, 1,999 (78.4%) had an eGFR less than 60 mL/min/1.73 m 2 , 186 (7.3%) had proteinuria, and 364 (14.3%) had both. In cross-sectional analysis, after controlling for diabetes, hypertension, age, aspartate aminotransferase level, and HIV status, patients who tested positive for hepatitis C had a decreased risk of CKD (odds ratio, 0.69; 95% confidence interval, 0.62 to 0.77). A total of 7,038 subjects without CKD were followed up for a median of 3.5 years. Of these, 2,243 (31.8%) were hepatitis C positive at the onset of follow-up. In longitudinal analysis, after adjustment for age, baseline eGFR, diabetes, hypertension, aspartate aminotransferase level, and HIV status, the hazard ratio for the development of CKD compared with those who were hepatitis C negative was 0.896 (95% confidence interval, 0.790 to 1.015). Limitations Retrospective design, clinical database with missing values, different hepatitis C assays used during the study period, limited data for proteinuria. Conclusions Our results do not support the hypothesis that infection with hepatitis C virus per se is associated with increased risk of having or developing CKD.

We measured FGF23 concentrations in subjects with ADHR. FGF23 and serum phosphate correlated positively in controls and negatively in subjects with ADHR. Elevated FGF23 concentrations were associated with lower phosphate values. The variable phenotype in ADHR may be caused by fluctuations in FGF23. Introduction: Autosomal dominant hypophosphatemic rickets (ADHR) is a rare disorder of phosphaturia, hypophosphatemia, inappropriately low/normal calcitriol, and rickets/osteomalacia. ADHR is caused by mutations in a circulating peptide, fibroblast growth factor 23 (FGF23). We present the first report of FGF23 concentrations in subjects with ADHR. The aim was to test the hypotheses that subjects with ADHR have elevated FGF23 concentrations and that FGF23 concentrations are associated with disease severity. Materials and Methods: This was an observational study at a tertiary referral center. Subjects were from three kindreds with FGF23 mutations causing ADHR (n = 42). Controls were participants from these families without mutations (n = 55). Fasting blood and urine samples were obtained. Biochemistries were determined, and FGF23 concentrations were measured using two ELISAs. Results: Three cases are presented illustrating activity of disease and FGF23 concentrations. One case shows persistent hypophosphatemia and elevation of FGF23 concentrations, whereas another shows remission of hypophosphatemia corresponding to a decrease in previously elevated FGF23 concentrations. Overall cross-sectional group differences were nonsignificant for serum phosphate and FGF23 concentrations. C-terminal FGF23 concentration in controls was 61.0 ± 28.6 (SD) RU/ml (median, 52.5 RU/ml), and in subjects with mutations was 148.8 ± 374.5 RU/ml (median, 63.1 RU/ml). Mean intact FGF23 concentration in controls was 44.7 ± 14.9 pg/ml (median, 40.4 pg/ml), and in subjects with mutations was 83.2 ± 233.0 pg/ml (median, 39.0 pg/ml). C-terminal FGF23 concentrations were at least +2 SD in 10/42(24%), and intact FGF23 concentrations were at least +2 SD in 3/34(9%). Phosphate correlated positively with C-terminal and intact FGF23 in both controls and in subjects with mutations with phosphate >2.5 mg/dl but correlated significantly negatively with C-terminal and intact FGF23 in ADHR subjects with phosphate ≤2.5 mg/dl. Conclusions: Elevated FGF23 concentrations are associated with hypophosphatemia in ADHR, and remission of the phenotype is associated with lower FGF23 concentrations. FGF23 has an opposite relationship with phosphate in ADHR compared with controls. We conclude that ADHR symptoms and disease severity likely fluctuate with FGF23 concentrations.

Autosomal dominant osteopetrosis (ADO) is a sclerosing bone disorder caused by heterozygous mutations in the chloride channel 7 (ClCN7) gene. The clinical manifestations of this disease have not been well characterized since the discovery of the genetic basis of ADO.The primary objectives were to improve our understanding of ADO clinical characteristics and to study the natural history of the disease in the largest series of patients reported to date.This study was primarily a retrospective cross-sectional analysis of individuals with a ClCN7 mutation that was conducted over a 4-yr period at a tertiary referral center and through family reunions. Longitudinal data on a subset of subjects were also studied.We studied 311 subjects from 11 ADO families, including 62 individuals with ADO (patients with the classic clinical phenotype based on radiographs and/or biochemistry), 32 unaffected gene carriers (subjects with the gene mutation but no radiographic and/or biochemical phenotype), and 217 controls who did not harbor a ClCN7 gene mutation. Clinical data were collected through patient interviews and examinations, medical records, and/or self-reported responses on a questionnaire that was completed by all subjects.The prevalence of fracture, osteomyelitis, visual loss, and bone marrow failure was determined. Differences in clinical manifestations were analyzed according to affected vs. carrier status, age, and underlying genotype.Ninety-two percent of ADO subjects had at least one sequela of the disease. Gene carriers did not have an increased risk of disease manifestations, although they were found to have significant increases in bone mineral density (P0.05). Compared with controls, subjects with ADO had a significantly increased prevalence of fracture (84 vs. 36%; P0.0001) and osteomyelitis (16 vs. 0.9%; P0.0001). Severe fractures (defined asor =10 fractures of any type and/or greater than one hip/femur fracture) were identified only in ADO subjects, and osteomyelitis typically occurred in the maxilla or mandible in older adults. Visual loss, which typically had its onset in childhood, and bone marrow failure occurred in 19 and 3% of ADO subjects, respectively. Adults were more likely to manifest an ADO clinical characteristic, but no definitive genotype-phenotype relationship could be concluded. Longitudinal data suggest that the ADO clinical phenotype worsens over time.ADO caused by mutations in the CLCN7 gene is a frequently symptomatic disease manifested by a high rate of fracture, osteomyelitis, visual loss, and occasional bone marrow failure. The sequelae of ADO, which can be identified as early as infancy, appear to worsen over time. Fracture is the most prevalent consequence of ADO, although other more severe manifestations of disease can occur and should not be confused with recessive forms of osteopetrosis, particularly when identified in early childhood.

To improve contact isolation rates among patients admitted to the hospital with a known history of infection with Methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-resistant Enterococci (VRE).A before and after interventional study implementing computerized reminders for contact isolation between February 25, 2005 and February 28, 2006. We measured rates of appropriate contact isolation, and time to isolation for the 4 month pre-intervention period, and the 12 month intervention period. We conducted a survey of ordering physicians at the midpoint of the intervention period.Implementing a computerized reminder increased the rate of patients appropriately isolated from 33% to fully 89% (P0.0001). The median time to writing contact isolation orders decreased from 16.6 to 0.0 h (P0.0001). Physicians accepted the order 80% of the time on the first or second presentation. Ninety-five percent of physicians felt the reminder had no impact on workflow, or saved them time.A human reviewed computerized reminder can achieve high rates of compliance with infection control recommendations for contact isolation, and dramatically reduce the time to orders being written upon admission.

ContextMost older adults with dementia will be cared for by primary care physicians, but the primary care practice environment presents important challenges to providing quality care.ObjectiveTo test the effectiveness of a collaborative care model to improve the quality of care for patients with Alzheimer disease.Design, Setting, and PatientsControlled clinical trial of 153 older adults with Alzheimer disease and their caregivers who were randomized by physician to receive collaborative care management (n = 84) or augmented usual care (n = 69) at primary care practices within 2 US university-affiliated health care systems from January 2002 through August 2004. Eligible patients (identified via screening or medical record) met diagnostic criteria for Alzheimer disease and had a self-identified caregiver.InterventionIntervention patients received 1 year of care management by an interdisciplinary team led by an advanced practice nurse working with the patient's family caregiver and integrated within primary care. The team used standard protocols to initiate treatment and identify, monitor, and treat behavioral and psychological symptoms of dementia, stressing nonpharmacological management.Main Outcome MeasuresNeuropsychiatric Inventory (NPI) administered at baseline and at 6, 12, and 18 months. Secondary outcomes included the Cornell Scale for Depression in Dementia (CSDD), cognition, activities of daily living, resource use, and caregiver's depression severity.ResultsInitiated by caregivers' reports, 89% of intervention patients triggered at least 1 protocol for behavioral and psychological symptoms of dementia with a mean of 4 per patient from a total of 8 possible protocols. Intervention patients were more likely to receive cholinesterase inhibitors (79.8% vs 55.1%; P = .002) and antidepressants (45.2% vs 27.5%; P = .03). Intervention patients had significantly fewer behavioral and psychological symptoms of dementia as measured by the total NPI score at 12 months (mean difference, −5.6; P = .01) and at 18 months (mean difference, −5.4; P = .01). Intervention caregivers also reported significant improvements in distress as measured by the caregiver NPI at 12 months; at 18 months, caregivers showed improvement in depression as measured by the Patient Health Questionnaire-9. No group differences were found on the CSDD, cognition, activities of daily living, or on rates of hospitalization, nursing home placement, or death.ConclusionsCollaborative care for the treatment of Alzheimer disease resulted in significant improvement in the quality of care and in behavioral and psychological symptoms of dementia among primary care patients and their caregivers. These improvements were achieved without significantly increasing the use of antipsychotics or sedative-hypnotics.Trial Registrationclinicaltrials.gov Identifier: NCT00246896