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Background: The optimal dosing strategy for rifampicin in treating drug-susceptible tuberculosis (TB) is still highly debated. In the phase 3 clinical trial Study 31/ACTG 5349 (NCT02410772), all participants in the control regimen arm received 600 mg rifampicin daily as a flat dose. Here, we evaluated relationships between rifampicin exposure and efficacy and safety outcomes., Methods: We analyzed rifampicin concentration time profiles using population nonlinear mixed-effects models. We compared simulated rifampicin exposure from flat- and weight-banded dosing. We evaluated the effect of rifampicin exposure on stable culture conversion at 6 months; TB-related unfavorable outcomes at 9, 12, and 18 months using Cox proportional hazard models; and all trial-defined safety outcomes using logistic regression., Results: Our model-derived rifampicin exposure ranged from 4.57 mg · h/L to 140.0 mg · h/L with a median of 41.8 mg · h/L. Pharmacokinetic simulations demonstrated that flat-dosed rifampicin provided exposure coverage similar to the weight-banded dose. Exposure-efficacy analysis (n = 680) showed that participants with rifampicin exposure below the median experienced similar hazards of stable culture conversion and TB-related unfavorable outcomes compared with those with exposure above the median. Exposure-safety analysis (n = 722) showed that increased rifampicin exposure was not associated with increased grade 3 or higher adverse events or serious adverse events., Conclusions: Flat-dosing of rifampicin at 600 mg daily may be a reasonable alternative to the incumbent weight-banded dosing strategy for the standard-of-care 6-month regimen. Future research should assess the optimal dosing strategy for rifampicin, at doses higher than the current recommendation., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Immunoglobulin A nephropathy (IgAN) frequently leads to kidney failure. The urinary proteomics-based classifier IgAN237 may predict disease progression at the time of kidney biopsy. We studied whether IgAN237 also predicts progression later in the course of IgAN., Methods: Urine from patients with biopsy-proven IgAN was analyzed using capillary electrophoresis-mass spectrometry at baseline (IgAN237-1, n = 103) and at follow-up (IgAN237-2, n = 89). Patients were categorized as "non-progressors" (IgAN237 ≤0.38) and "progressors" (IgAN237 >0.38). Estimated glomerular filtration rate (eGFR) and urinary albumin-creatinine ratio slopes were calculated., Results: Median age at biopsy was 44 years, interval between biopsy and IgAN237-1 was 65 months and interval between IgAN237-1 and IgAN237-2 was 258 days (interquartile range 71-531). IgAN237-1 and IgAN237-2 values did not differ significantly and were correlated (rho = 0.44, P < .001). Twenty-eight percent and 26% of patients were progressors based on IgAN237-1 and IgAN237-2, respectively. IgAN237 inversely correlated with chronic eGFR slopes (rho = -0.278, P = .02 for score-1; rho = -0.409, P = .002 for score-2) and with ±180 days eGFR slopes (rho = -0.31, P = .009 and rho = -0.439, P = .001, respectively). The ±180 days eGFR slopes were worse for progressors than for non-progressors (median -5.98 versus -1.22 mL/min/1.73 m2 per year for IgAN237-1, P < .001; -3.02 vs 1.08 mL/min/1.73 m2 per year for IgAN237-2, P = .0047). In multiple regression analysis baseline progressor/non-progressor according to IgAN237 was an independent predictor of eGFR180days-slope (P = .001)., Conclusion: The urinary IgAN237 classifier represents a risk stratification tool in IgAN also later in the course of the dynamic disease. It may guide patient management in an individualized manner., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Machine learning (ML)-driven computable phenotypes are among the most challenging to share and reproduce. Despite this difficulty, the urgent public health considerations around Long COVID make it especially important to ensure the rigor and reproducibility of Long COVID phenotyping algorithms such that they can be made available to a broad audience of researchers. As part of the NIH Researching COVID to Enhance Recovery (RECOVER) Initiative, researchers with the National COVID Cohort Collaborative (N3C) devised and trained an ML-based phenotype to identify patients highly probable to have Long COVID. Supported by RECOVER, N3C and NIH's All of Us study partnered to reproduce the output of N3C's trained model in the All of Us data enclave, demonstrating model extensibility in multiple environments. This case study in ML-based phenotype reuse illustrates how open-source software best practices and cross-site collaboration can de-black-box phenotyping algorithms, prevent unnecessary rework, and promote open science in informatics., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Dyspareunia affects approximately half of postpartum women and is attributed to multiple factors. Despite its high prevalence and resultant negative effects, data are lacking regarding the causes and different pain components, the usefulness of recommended treatments, and the prognosis., Aim: To evaluate causes of postpartum dyspareunia, targeted treatment modalities, and their effectiveness., Methods: A retrospective observational study was conducted of women diagnosed with postpartum dyspareunia between September 2008 and January 2017 at a single designated vulvovaginal disorder clinic. The inclusion criterion was complaint of painful intercourse commencing postdelivery. The cohort was divided into 4 groups based on the causes of dyspareunia: muscle hypertonicity, scar tenderness, vestibular tenderness, and atrophy., Outcomes: The following were assessed for each group: patient background demographics, clinical and obstetric data, physical findings, recommended therapy, adherence to the suggested treatment, level of improvement at follow-up visits, and length of time until maximal improvement., Results: A hundred women met the inclusion criterion; the majority (n = 60) presented with >1 causative factor. The most common finding was vestibular tenderness (n = 78, 78%), which was significantly associated with atrophy (adjusted odds ratio [aOR], 15.08; 95% CI, 2.45-93.35), contraceptive usage (aOR, 4.76; 95% CI, 1.07-21.39), and primiparity (aOR, 4.89; 95% CI, 1.01-23.88). Episiotomy was the only risk factor for scar tenderness (aOR, 5.43; 95% CI, 1.20-24.53), while the existence of a spontaneous perineal tear was not. No specific correlation was found with pelvic floor muscle hypertonicity. Targeted treatment resulted in significant improvement in most patients., Clinical Implications: A targeted diagnostic and treatment approach for postpartum dyspareunia is effective and can be beneficial for caregivers treating postpartum women., Strengths and Limitations: A uniform and consistent protocol for patient selection and management is a major strength, which magnifies the clinical implication of our findings. The retrospective nature of the study is the primary limitation., Conclusion: Postpartum dyspareunia is a common problem; however, many women refrain from discussing it with their providers. Therefore, it is important to assess this condition with all women during the postpartum visit as targeted diagnosis and treatment can significantly improve outcomes., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: This article describes the implementation of a privacy-preserving record linkage (PPRL) solution across PCORnet®, the National Patient-Centered Clinical Research Network., Material and Methods: Using a PPRL solution from Datavant, we quantified the degree of patient overlap across the network and report a de-duplicated analysis of the demographic and clinical characteristics of the PCORnet population., Results: There were ∼170M patient records across the responding Network Partners, with ∼138M (81%) of those corresponding to a unique patient. 82.1% of patients were found in a single partner and 14.7% were in 2. The percentage overlap between Partners ranged between 0% and 80% with a median of 0%. Linking patients' electronic health records with claims increased disease prevalence in every clinical characteristic, ranging between 63% and 173%., Discussion: The overlap between Partners was variable and depended on timeframe. However, patient data linkage changed the prevalence profile of the PCORnet patient population., Conclusions: This project was one of the largest linkage efforts of its kind and demonstrates the potential value of record linkage. Linkage between Partners may be most useful in cases where there is geographic proximity between Partners, an expectation that potential linkage Partners will be able to fill gaps in data, or a longer study timeframe., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

The extent to which the pathophysiology of autosomal dominant Alzheimer's disease corresponds to the pathophysiology of 'sporadic' late onset Alzheimer's disease is unknown, thus limiting the extrapolation of study findings and clinical trial results in autosomal dominant Alzheimer's disease to late onset Alzheimer's disease. We compared brain MRI and amyloid PET data, as well as CSF concentrations of amyloid-β42, amyloid-β40, tau and tau phosphorylated at position 181, in 292 carriers of pathogenic variants for Alzheimer's disease from the Dominantly Inherited Alzheimer Network, with corresponding data from 559 participants from the Alzheimer's Disease Neuroimaging Initiative. Imaging data and CSF samples were reprocessed as appropriate to guarantee uniform pipelines and assays. Data analyses yielded rates of change before and after symptomatic onset of Alzheimer's disease, allowing the alignment of the ∼30-year age difference between the cohorts on a clinically meaningful anchor point, namely the participant age at symptomatic onset. Biomarker profiles were similar for both autosomal dominant Alzheimer's disease and late onset Alzheimer's disease. Both groups demonstrated accelerated rates of decline in cognitive performance and in regional brain volume loss after symptomatic onset. Although amyloid burden accumulation as determined by PET was greater after symptomatic onset in autosomal dominant Alzheimer's disease than in late onset Alzheimer's disease participants, CSF assays of amyloid-β42, amyloid-β40, tau and p-tau181 were largely overlapping in both groups. Rates of change in cognitive performance and hippocampal volume loss after symptomatic onset were more aggressive for autosomal dominant Alzheimer's disease participants. These findings suggest a similar pathophysiology of autosomal dominant Alzheimer's disease and late onset Alzheimer's disease, supporting a shared pathobiological construct., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: Social determinants of health (SDoH) are nonclinical dispositions that impact patient health risks and clinical outcomes. Leveraging SDoH in clinical decision-making can potentially improve diagnosis, treatment planning, and patient outcomes. Despite increased interest in capturing SDoH in electronic health records (EHRs), such information is typically locked in unstructured clinical notes. Natural language processing (NLP) is the key technology to extract SDoH information from clinical text and expand its utility in patient care and research. This article presents a systematic review of the state-of-the-art NLP approaches and tools that focus on identifying and extracting SDoH data from unstructured clinical text in EHRs., Materials and Methods: A broad literature search was conducted in February 2021 using 3 scholarly databases (ACL Anthology, PubMed, and Scopus) following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 6402 publications were initially identified, and after applying the study inclusion criteria, 82 publications were selected for the final review., Results: Smoking status (n = 27), substance use (n = 21), homelessness (n = 20), and alcohol use (n = 15) are the most frequently studied SDoH categories. Homelessness (n = 7) and other less-studied SDoH (eg, education, financial problems, social isolation and support, family problems) are mostly identified using rule-based approaches. In contrast, machine learning approaches are popular for identifying smoking status (n = 13), substance use (n = 9), and alcohol use (n = 9)., Conclusion: NLP offers significant potential to extract SDoH data from narrative clinical notes, which in turn can aid in the development of screening tools, risk prediction models, and clinical decision support systems., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: Rifapentine exposure is associated with bactericidal activity against Mycobacterium tuberculosis, but high interindividual variation in plasma concentrations is encountered., Objectives: To investigate a genomic association with interindividual variation of rifapentine exposure, SNPs of six human genes involving rifamycin metabolism (AADAC, CES2), drug transport (SLCO1B1, SLCO1B3) and gene regulation (HNF4A, PXR) were evaluated., Methods: We characterized these genes in 173 adult participants in treatment trials of the Tuberculosis Trials Consortium. Participants were stratified by self-identified race (black or non-black), and rifapentine AUC from 0 to 24 h (AUC0-24) was adjusted by analysis of covariance for SNPs, rifapentine dose, sex, food and HIV coinfection. This study was registered at ClinicalTrials.gov under identifier NCT01043575., Results: The effect on rifapentine least squares mean AUC0-24 in black participants overall decreased by -10.2% for AADAC rs1803155 G versus A allele (Wald test: P = 0.03; false discovery rate, 0.10). Black participants with one G allele in AADAC rs1803155 were three times as likely to have below target bactericidal rifapentine exposure than black participants with the A allele (OR, 2.97; 95% CI: 1.16, 7.58). With two G alleles, the OR was greater. In non-black participants, AADAC rs1803155 SNP was not associated with rifapentine exposure. In both black and non-black participants, other evaluated genes were not associated with rifapentine exposure (P > 0.05; false discovery rate > 0.10)., Conclusions: Rifapentine exposure in black participants varied with AADAC rs1803155 genotype and the G allele was more likely to be associated with below bactericidal target rifapentine exposure. Further pharmacogenomic study is needed to characterize the association of the AADAC rs1803155 with inadequate rifapentine exposure in different patient groups., (Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy 2020. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Multiple sclerosis is a chronic autoimmune demyelinating disorder of the CNS. Immune-mediated oligodendrocyte cell loss contributes to multiple sclerosis pathogenesis, such that oligodendrocyte-protective strategies represent a promising therapeutic approach. The integrated stress response, which is an innate cellular protective signalling pathway, reduces the cytotoxic impact of inflammation on oligodendrocytes. This response is initiated by phosphorylation of eIF2α to diminish global protein translation and selectively allow for the synthesis of protective proteins. The integrated stress response is terminated by dephosphorylation of eIF2α. The small molecule Sephin1 inhibits eIF2α dephosphorylation, thereby prolonging the protective response. Herein, we tested the effectiveness of Sephin1 in shielding oligodendrocytes against inflammatory stress. We confirmed that Sephin1 prolonged eIF2α phosphorylation in stressed primary oligodendrocyte cultures. Moreover, by using a mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis, we demonstrated that Sephin1 delayed the onset of clinical symptoms, which correlated with a prolonged integrated stress response, reduced oligodendrocyte and axon loss, as well as diminished T cell presence in the CNS. Sephin1 is reportedly a selective inhibitor of GADD34 (PPP1R15A), which is a stress-induced regulatory subunit of protein phosphatase 1 complex that dephosphorylates eIF2α. Consistent with this possibility, GADD34 mutant mice presented with a similar ameliorated experimental autoimmune encephalomyelitis phenotype as Sephin1-treated mice, and Sephin1 did not provide additional therapeutic benefit to the GADD34 mutant animals. Results presented from the adoptive transfer of encephalitogenic T cells between wild-type and GADD34 mutant mice further indicate that the beneficial effects of Sephin1 are mediated through a direct protective effect on the CNS. Of particular therapeutic relevance, Sephin1 provided additive therapeutic benefit when combined with the first line multiple sclerosis drug, interferon β. Together, our results suggest that a neuroprotective treatment based on the enhancement of the integrated stress response would likely have significant therapeutic value for multiple sclerosis patients.

Background: In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria., Methods: Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000-13. UV radiation levels for 2000-13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute., Results: A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71-2.62]}, younger age [OR per year 0.97 (95% CI 0.96-0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01-1.02); P < 0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO:PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis., Conclusions: The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels.

White matter alterations are present in the majority of patients with Alzheimer's disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer's disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer's disease. In early-onset autosomal-dominantly inherited Alzheimer's disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres-many connecting default mode network regions-between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts' projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer's disease pathology and microglia activity in the brain.

Background: Patient-provider electronic communication has proliferated in recent years, yet there is a dearth of published research either leading to, or including, recommendations that improve clinical care and prevent unintended negative consequences. We critically appraise published guidelines and suggest an agenda for future work in this area., Objective: To understand how existing guidelines align with current practice, evidence, and technology., Methods: We performed a narrative review of provider-targeted guidelines for electronic communication between patients and providers, searching Ovid MEDLINE, Embase, and PubMed databases using relevant terms. We limited the search to articles published in English, and manually searched the citations of relevant articles. For each article, we identified and evaluated the suggested practices., Results: Across 11 identified guidelines, the primary focus was on technical and administrative concerns, rather than on relational communication. Some of the security practices recommended by the guidelines are no longer needed because of shifts in technology. It is unclear the extent to which the recommendations that are still relevant are being followed. Moreover, there is no guideline-cited evidence of the effectiveness of the practices that have been proposed., Conclusion: Our analysis revealed major weaknesses in current guidelines for electronic communication between patients and providers: the guidelines appear to be based on minimal evidence and offer little guidance on how best to use electronic tools to communicate effectively. Further work is needed to systematically evaluate and identify effective practices, create a framework to evaluate quality of communication, and assess the relationship between electronic communication and quality of care.

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

Objective: To characterize patients who voluntarily enrolled in an electronic health information exchange (HIE) program designed to share data between Veterans Health Administration (VHA) and non-VHA institutions., Materials and Methods: Patients who agreed to participate in the HIE program were compared to those who did not. Patient characteristics associated with HIE enrollment were examined using a multivariable logistic regression model. Variables selected for inclusion were guided by a health care utilization model adapted to explain HIE enrollment. Data about patients' sociodemographics (age, gender), comorbidity (Charlson index score), utilization (primary and specialty care visits), and access (distance to VHA medical center, insurance, VHA benefits) were obtained from VHA and HIE electronic health records., Results: Among 57 072 patients, 6627 (12%) enrolled in the HIE program during its first year. The likelihood of HIE enrollment increased among patients ages 50-64, of female gender, with higher comorbidity, and with increasing utilization. Living in a rural area and being unmarried were associated with decreased likelihood of enrollment., Discussion and Conclusion: Enrollment in HIE is complex, with several factors involved in a patient's decision to enroll. To broaden HIE participation, populations less likely to enroll should be targeted with tailored recruitment and educational strategies. Moreover, inclusion of special populations, such as patients with higher comorbidity or high utilizers, may help refine the definition of success with respect to HIE implementation., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2016. This work is written by US Government employees and is in the public domain in the United States.)

Structural magnetic resonance imaging data are frequently analysed to reveal morphological changes of the human brain in dementia. Most contemporary imaging biomarkers are scalar values, such as the volume of a structure, and may miss the localized morphological variation of early presymptomatic disease progression. Neuroanatomical shape descriptors, however, can represent complex geometric information of individual anatomical regions and may demonstrate increased sensitivity in association studies. Yet, they remain largely unexplored. In this article, we introduce a novel technique to study shape asymmetries of neuroanatomical structures across subcortical and cortical brain regions. We demonstrate that neurodegeneration of subcortical structures in Alzheimer's disease is not symmetric. The hippocampus shows a significant increase in asymmetry longitudinally and both hippocampus and amygdala show a significantly higher asymmetry cross-sectionally concurrent with disease severity above and beyond an ageing effect. Our results further suggest that the asymmetry in these structures is undirectional and that primarily the anterior hippocampus becomes asymmetric. Based on longitudinal asymmetry measures we subsequently study the progression from mild cognitive impairment to dementia, demonstrating that shape asymmetry in hippocampus, amygdala, caudate and cortex is predictive of disease onset. The same analyses on scalar volume measurements did not produce any significant results, indicating that shape asymmetries, potentially induced by morphometric changes in subnuclei, rather than size asymmetries are associated with disease progression and can yield a powerful imaging biomarker for the early presymptomatic classification and prediction of Alzheimer's disease. Because literature has focused on contralateral volume differences, subcortical disease lateralization may have been overlooked thus far., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The Xpert MTB/RIF (Xpert) assay is a rapid nucleic acid amplification test widely used in settings of high tuberculosis prevalence to detect tuberculosis as well asrpoBmutations associated with rifampin resistance. Data are needed on the diagnostic performance of Xpert in lower-prevalence settings to inform appropriate use for both tuberculosis detection and the need for respiratory isolation., Methods: Xpert was compared to 2 sputum samples, each evaluated with acid-fast bacilli (AFB) smear and mycobacterial culture using liquid and solid culture media, from participants with suspected pulmonary tuberculosis from the United States, Brazil, and South Africa., Results: Of 992 participants enrolled with evaluable results, 22% had culture-confirmed tuberculosis. In 638 (64%) US participants, 1 Xpert result demonstrated sensitivity of 85.2% (96.7% in participants with AFB smear-positive [AFB(+)] sputum, 59.3% with AFB smear-negative [AFB(-)] sputum), specificity of 99.2%, negative predictive value (NPV) of 97.6%, and positive predictive value of 94.9%. Results did not differ between higher- and low-prevalence settings. A second Xpert assay increased overall sensitivity to 91.1% (100% if AFB(+), 71.4% if AFB(-)), with specificity of 98.9%. In US participants, a single negative Xpert result predicted the absence of AFB(+)/culture-positive tuberculosis with an NPV of 99.7%; NPV of 2 Xpert assays was 100%, suggesting a role in removing patients from airborne infection isolation. Xpert detected tuberculosis DNA and mutations associated with rifampin resistance in 5 of 7 participants with rifampin-resistant, culture-positive tuberculosis. Specificity for rifampin resistance was 99.5% and NPV was 98.9%., Conclusions: In the United States, Xpert testing performed comparably to 2 higher-tuberculosis-prevalence settings. These data support the use of Xpert in the initial evaluation of tuberculosis suspects and in algorithms assessing need for respiratory isolation., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Purpose of the Study: To describe key adaptive challenges and leadership behaviors to implement culture change for person-directed care., Design and Methods: The study design was a qualitative, observational study of nursing home staff perceptions of the implementation of culture change in each of 3 nursing homes. We conducted 7 focus groups of licensed and unlicensed nursing staff, medical care providers, and administrators. Questions explored perceptions of facilitators and barriers to culture change. Using a template organizing style of analysis with immersion/crystallization, themes of barriers and facilitators were coded for adaptive challenges and leadership., Results: Six key themes emerged, including relationships, standards and expectations, motivation and vision, workload, respect of personhood, and physical environment. Within each theme, participants identified barriers that were adaptive challenges and facilitators that were examples of adaptive leadership. Commonly identified challenges were how to provide person-directed care in the context of extant rules or policies or how to develop staff motivated to provide person-directed care., Implications: Implementing culture change requires the recognition of adaptive challenges for which there are no technical solutions, but which require reframing of norms and expectations, and the development of novel and flexible solutions. Managers and administrators seeking to implement person-directed care will need to consider the role of adaptive leadership to address these adaptive challenges., (© The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent investigations into appointment scheduling within facilities operated by the US Department of Veterans Affairs (VA) illuminate systemic challenges in meeting its goal of providing timely access to care for all Veterans. In the wake of these investigations, new policies have been enacted to expand access to care at VA facilities as well as non-VA facilities if the VA is unable to provide access within a reasonable timeframe or a Veteran lives more than 40 miles from a VA medical facility. These policies are similar to broader health reform efforts that seek to expand access to care for other vulnerable populations. In this perspective, we discuss the informatics implications of expanded access within the VA and its wider applicability across the US health system. Health systems will require robust health information exchange, to maintain coordination while access to care is expanded. Existing informatics research can guide short-term implementation; furthermore, new research is needed to generate evidence about how best to achieve the long-term aim of expanded access to care., (Published by Oxford University Press on behalf of the American Medical Informatics Association 2015. This work is written by US Government employees and is in the public domain in the US.)

Objectives: The objectives of this study were to compare incidence rates, renal and patient survival between lupus nephritis (LN) and anti-neutrophil cytoplasmic antibody-associated nephritis (AAN) during a 12-year period in two geographically defined populations in Sweden., Methods: In the health care districts surrounding the Skåne University Hospital in Lund [mean population ≥18 years (1997-2008), 188 400] and the University Hospital in Linköping [mean population ≥18 years (1997-2008), 328 900] all patients with biopsy-proven LN and AAN during the period 1997-2008 were included in the study if they (i) were residing within the study areas at the time of onset of nephritis, (ii) had a clinical diagnosis of either SLE or ANCA-associated vasculitis (AAV) and (iii) experienced a first flare of biopsy-proven nephritis during the study period., Results: Eighty-two patients (Lund 44 + Linköping 38) with biopsy-proven AAN were identified and 27 patients with LN (Lund 13 + Linköping 14). The annual incidence rate per million inhabitants aged ≥18 years in both study areas was estimated to be 13.2 (95% CI 10.4-16.1) for AAN and 4.3 (95% CI 2.7-6.0) for LN, P < 0.001. The patients were followed until January 2013. During the follow-up time 38 patients died (AAN 36, LN 2; P = 0.001), and 20 patients went into end-stage renal disease (AAN 19 and LN 1), P = 0.020., Conclusions: In Sweden, AAN was three times more common than LN, and the outcome was considerably worse. SLE is often diagnosed before the onset of nephritis leading to earlier treatment, while AAN is still often diagnosed at a later stage., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

The transport of organophosphates across the cytoplasma membrane is mediated by organophosphate:phosphate antiporter proteins. In this work, we present the application of a recombinant phosphoenolpyruvate:phosphate antiporter for isotopic labeling experiments in E. coli strains. The antiporters UhpT, UhpT-D388C, and PgtP were investigated regarding transport activity and growth on phosphoenolpyruvate as sole carbon source. The expression of the protein variant UhpT-D388C in a shikimic acid producing E. coli strain was used to show the successful isotopic labeling of shikimic acid from extracellular phosphoenolpyruvate. The results demonstrate the possibility of a direct incorporation of exogenously applicated glycolysis intermediates into E. coli cells for 13 C-labeling experiments., (© 2014 Federation of European Microbiological Societies.)

Objective: To apply human factors engineering principles to improve alert interface design. We hypothesized that incorporating human factors principles into alerts would improve usability, reduce workload for prescribers, and reduce prescribing errors., Materials and Methods: We performed a scenario-based simulation study using a counterbalanced, crossover design with 20 Veterans Affairs prescribers to compare original versus redesigned alerts. We redesigned drug-allergy, drug-drug interaction, and drug-disease alerts based upon human factors principles. We assessed usability (learnability of redesign, efficiency, satisfaction, and usability errors), perceived workload, and prescribing errors., Results: Although prescribers received no training on the design changes, prescribers were able to resolve redesigned alerts more efficiently (median (IQR): 56 (47) s) compared to the original alerts (85 (71) s; p=0.015). In addition, prescribers rated redesigned alerts significantly higher than original alerts across several dimensions of satisfaction. Redesigned alerts led to a modest but significant reduction in workload (p=0.042) and significantly reduced the number of prescribing errors per prescriber (median (range): 2 (1-5) compared to original alerts: 4 (1-7); p=0.024)., Discussion: Aspects of the redesigned alerts that likely contributed to better prescribing include design modifications that reduced usability-related errors, providing clinical data closer to the point of decision, and displaying alert text in a tabular format. Displaying alert text in a tabular format may help prescribers extract information quickly and thereby increase responsiveness to alerts., Conclusions: This simulation study provides evidence that applying human factors design principles to medication alerts can improve usability and prescribing outcomes., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: In a phase 3, randomized clinical trial (PREVENT TB) of 8053 people with latent tuberculosis infection, 12 once-weekly doses of rifapentine and isoniazid had good efficacy and tolerability. Children received higher rifapentine milligram per kilogram doses than adults. In the present pharmacokinetic study (a component of the PREVENT TB trial), rifapentine exposure was compared between children and adults., Methods: Rifapentine doses in children ranged from 300 to 900 mg, and adults received 900 mg. Children who could not swallow tablets received crushed tablets. Sparse pharmacokinetic sampling was performed with 1 rifapentine concentration at 24 hours after drug administration (C24). Rifapentine area under concentration-time curve (AUC) was estimated from a nonlinear, mixed effects regression model (NLME)., Results: There were 80 children (age: median, 4.5 years; range, 2-11 years) and 77 adults (age: median, 40 years; all ≥18 years) in the study. The geometric mean rifapentine milligram per kilogram dose was greater in children than in adults (children, 23 mg/kg; adults, 11 mg/kg). Rifapentine geometric mean AUC and C24 were 1.3-fold greater in children (all children combined) than in adults. Children who swallowed whole tablets had 1.3-fold higher geometric mean AUC than children who received crushed tablets, and children who swallowed whole tablets had a 1.6-fold higher geometric mean AUC than adults. The higher rifapentine doses in children were well tolerated. To obtain rifapentine exposures comparable in children to adults, dosing algorithms modeled by NLME were developed., Conclusions: A 2-fold greater rifapentine dose for all children resulted in a 1.3-fold higher AUC compared to adults administered a standard dose. Use of higher weight-adjusted rifapentine doses for young children are warranted to achieve systemic exposures that are associated with successful treatment of latent tuberculosis infection in adults., (Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society 2014. This work is written by US Government employees and is in the public domain in the US.)

Objectives: Latent tuberculosis infection and tuberculosis disease are prevalent worldwide. However, antimycobacterial rifamycins have drug interactions with many antiretroviral drugs. We evaluated the effect of rifapentine on the pharmacokinetic properties of raltegravir., Methods: In this open-label, fixed-sequence, three-period study, 21 healthy volunteers were given: raltegravir alone (400 mg every 12 h for 4 days) on days 1-4 of Period 1; rifapentine (900 mg once weekly for 3 weeks) on days 1, 8 and 15 of Period 2 and raltegravir (400 mg every 12 h for 4 days) on days 12-15 of Period 2; and rifapentine (600 mg once daily for 10 scheduled doses) on days 1, 4-8 and 11-14 of Period 3 and raltegravir (400 mg every 12 h for 4 days) on days 11-14 of Period 3. Plasma raltegravir concentrations were measured. ClinicalTrials.gov database: NCT00809718., Results: In 16 subjects who completed the study, coadministration of raltegravir with rifapentine (900 mg once weekly; Period 2) compared with raltegravir alone resulted in the geometric mean of the raltegravir AUC from 0 to 12 h (AUC0-12) being increased by 71%; the peak concentration increased by 89% and the trough concentration decreased by 12%. Coadministration of raltegravir with rifapentine in Period 3 did not change the geometric mean of the raltegravir AUC0-12 or the peak concentration, but it decreased the trough concentration by 41%. Raltegravir coadministered with rifapentine was generally well tolerated., Conclusions: The increased raltegravir exposure observed with once-weekly rifapentine was safe and tolerable. Once-weekly rifapentine can be used with raltegravir to treat latent tuberculosis infection in patients who are infected with HIV.

A myelopoiesis gene signature in circulating leucocytes, exemplified by increased myeloperoxidase (MPO) and proteinase 3 (PR3) mRNA levels, has been reported in patients with active anti-neutrophil cytoplasm antibody-associated vasculitis (AAV), and to a lesser extent during remission. We hypothesized that this signature could predict disease relapse. mRNA levels of PR3, MPO, selected myelopoiesis transcription factors [CCAAT/enhancer binding protein α (CEBP-α), CCAAT/enhancer binding protein β (CEBP-β), SPI1/PU.1-related transcription factor (SPIB), spleen focus forming virus proviral integration oncogene, PU.1 homologue (SPI1)] and microRNAs (miRNAs) from patient and control peripheral blood mononuclear cells (PBMC) and polymorphonuclear cells (PMN) were analysed and associated with clinical data. Patients in stable remission had higher mRNA levels for PR3 (PBMC, PMN) and MPO (PBMC). PR3 and SPIB mRNA correlated positively in controls but negatively in patient PBMC. Statistically significant correlations existed between PR3 mRNA and several miRNAs in controls, but not in patients. PR3/MPO mRNA levels were not associated with previous or future relapses, but correlated with steroid treatment. Prednisolone doses were negatively linked to SPIB and miR-155-5p, miR-339-5p (PBMC) and to miR-221, miR-361 and miR-505 (PMN). PR3 mRNA in PBMC correlated with time since last flare, blood leucocyte count and estimated glomerular filtration rate. Our results show that elevated leucocyte PR3 mRNA levels in AAV patients in remission do not predict relapse. The origin seems multi-factorial, but to an important extent explainable by prednisolone action. Gene signatures in patients with AAV undergoing steroid treatment should therefore be interpreted accordingly., (© 2013 British Society for Immunology.)

Background: Rifapentine administered 5 days per week has potent activity in mouse models of antituberculosis chemotherapy, but efficacy and safety data are limited in humans. We compared the antimicrobial activity and safety of rifapentine vs rifampin during the first 8 weeks of pulmonary tuberculosis treatment., Methods: In total, 531 adults with sputum smear-positive pulmonary tuberculosis were randomized to rifapentine 10 mg/kg/dose or rifampin 10 mg/kg/dose, administered 5 days per week for 8 weeks (intensive phase), with isoniazid, pyrazinamide, and ethambutol. Coprimary outcomes were negative sputum culture on liquid and on solid media at completion of intensive phase., Results: Negative cultures on solid media occurred in 145 of 174 participants (83.3%) in the rifampin group and 171 of 198 participants (86.4%) in the rifapentine group (difference, 3.0%; 95% confidence interval [CI]: -4.3, 10.5); negative cultures in liquid media occurred in 110 of 169 (65.1%) in the rifampin group and 133 of 196 (67.9%) in the rifapentine group (difference, 2.8%; 95% CI: -6.9, 12.4). Among 529 participants who received study therapy, 40 of 254 participants (15.7%) in the rifampin group and 40 of 275 participants (14.5%) in the rifapentine group prematurely discontinued treatment (P=.79)., Conclusions: The rifapentine regimen was safe but not significantly more active than a standard rifampin regimen, by the surrogate endpoint of culture status at completion of intensive phase. Assessment of higher exposures to rifapentine for tuberculosis treatment is warranted., Clinical Trials Registration: NCT00694629.

The objective of this study was to investigate how a measure of educational and occupational attainment, a component of cognitive reserve, modifies the relationship between biomarkers of pathology and cognition in Alzheimer's disease. The biomarkers evaluated quantified neurodegeneration via atrophy on magnetic resonance images, neuronal injury via cerebral spinal fluid t-tau, brain amyloid-β load via cerebral spinal fluid amyloid-β1-42 and vascular disease via white matter hyperintensities on T2/proton density magnetic resonance images. We included 109 cognitively normal subjects, 192 amnestic patients with mild cognitive impairment and 98 patients with Alzheimer's disease, from the Alzheimer's Disease Neuroimaging Initiative study, who had undergone baseline lumbar puncture and magnetic resonance imaging. We combined patients with mild cognitive impairment and Alzheimer's disease in a group labelled 'cognitively impaired' subjects. Structural Abnormality Index scores, which reflect the degree of Alzheimer's disease-like anatomic features on magnetic resonance images, were computed for each subject. We assessed Alzheimer's Disease Assessment Scale (cognitive behaviour section) and mini-mental state examination scores as measures of general cognition and Auditory-Verbal Learning Test delayed recall, Boston naming and Trails B scores as measures of specific domains in both groups of subjects. The number of errors on the American National Adult Reading Test was used as a measure of environmental enrichment provided by educational and occupational attainment, a component of cognitive reserve. We found that in cognitively normal subjects, none of the biomarkers correlated with the measures of cognition, whereas American National Adult Reading Test scores were significantly correlated with Boston naming and mini-mental state examination results. In cognitively impaired subjects, the American National Adult Reading Test and all biomarkers of neuronal pathology and amyloid load were independently correlated with all cognitive measures. Exceptions to this general conclusion were absence of correlation between cerebral spinal fluid amyloid-β1-42 and Boston naming and Trails B. In contrast, white matter hyperintensities were only correlated with Boston naming and Trails B results in the cognitively impaired. When all subjects were included in a flexible ordinal regression model that allowed for non-linear effects and interactions, we found that the American National Adult Reading Test had an independent additive association such that better performance was associated with better cognitive performance across the biomarker distribution. Our main conclusions included: (i) that in cognitively normal subjects, the variability in cognitive performance is explained partly by the American National Adult Reading Test and not by biomarkers of Alzheimer's disease pathology; (ii) in cognitively impaired subjects, the American National Adult Reading Test, biomarkers of neuronal pathology (structural magnetic resonance imaging and cerebral spinal fluid t-tau) and amyloid load (cerebral spinal fluid amyloid-β1-42) all independently explain variability in general cognitive performance; and (iii) that the association between cognition and the American National Adult Reading Test was found to be additive rather than to interact with biomarkers of Alzheimer's disease pathology.

Background: Infectious diarrhea is an important problem among travelers and deployed US military overseas causing substantial morbidity due to acute illness and may result in burdensome postinfectious sequelae., Methods: The nonsystemic antibiotic rifaximin was evaluated for prevention of travelers' diarrhea (TD) in a US military and civilian adult beneficiary population in a randomized, double-blind, placebo-controlled clinical trial. In all, 100 volunteers deployed to Incirlik Air Base, Turkey, received rifaximin 1,100 mg once daily or placebo for 2 weeks, and participants were followed daily for 2 weeks., Results: In an intention to treat analysis (n = 95), TD (based on subjects meeting case definition or early treatment) developed in 6.3% (3 of 48) of the rifaximin group compared with 19.2% (9 of 47) in the placebo group (Fisher's exact test p = 0.07). Rifaximin provided 67% (95% confidence interval, -13% to 91%, p = 0.07) protection against TD. Rifaximin 1,100 mg once daily was well tolerated with no observed differences in adverse events, whether solicited or unsolicited among the two treatment groups., Conclusions: Rifaximin may represent an option among military personnel on deployment for prevention of TD with supportive future studies that consider deployment length, settings, and operational situations where widespread use of chemoprophylaxis may increase force health protection without undue risk during critical deployments., (Published 2010. This article is a US Government work and is in the public domain in the USA.)

Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer's disease cause atrophy within two major networks, an anterior 'Salience Network' (atrophied in behavioural variant frontotemporal dementia) and a posterior 'Default Mode Network' (atrophied in Alzheimer's disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer's disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer's disease) and the Default Mode Network (disrupted in Alzheimer's disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer's disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer's disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic connectivity enhancement within the reciprocal network. In behavioural variant frontotemporal dementia, clinical severity correlated with loss of right frontoinsular Salience Network connectivity and with biparietal Default Mode Network connectivity enhancement. Based on these results, we explored whether a combined index of Salience Network and Default Mode Network connectivity might discriminate between the three groups. Linear discriminant analysis achieved 92% clinical classification accuracy, including 100% separation of behavioural variant frontotemporal dementia and Alzheimer's disease. Patients whose clinical diagnoses were supported by molecular imaging, genetics, or pathology showed 100% separation using this method, including four diagnostically equivocal 'test' patients not used to train the algorithm. Overall, the findings suggest that behavioural variant frontotemporal dementia and Alzheimer's disease lead to divergent network connectivity patterns, consistent with known reciprocal network interactions and the strength and deficit profiles of the two disorders. Further developed, intrinsic connectivity network signatures may provide simple, inexpensive, and non-invasive biomarkers for dementia differential diagnosis and disease monitoring.

Although beta-amyloid (Abeta) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via 'Pittsburgh Compound-B' (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Abeta and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P < 0.0001), as well as between aHV and EM (P < 0.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Abeta deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Abeta deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Abeta-induced hippocampus atrophy.

The purpose of this study was to use serial imaging to gain insight into the sequence of pathologic events in Alzheimer's disease, and the clinical features associated with this sequence. We measured change in amyloid deposition over time using serial (11)C Pittsburgh compound B (PIB) positron emission tomography and progression of neurodegeneration using serial structural magnetic resonance imaging. We studied 21 healthy cognitively normal subjects, 32 with amnestic mild cognitive impairment and 8 with Alzheimer's disease. Subjects were drawn from two sources--ongoing longitudinal registries at Mayo Clinic, and the Alzheimer's disease Neuroimaging Initiative (ADNI). All subjects underwent clinical assessments, MRI and PIB studies at two time points, approximately one year apart. PIB retention was quantified in global cortical to cerebellar ratio units and brain atrophy in units of cm(3) by measuring ventricular expansion. The annual change in global PIB retention did not differ by clinical group (P = 0.90), and although small (median 0.042 ratio units/year overall) was greater than zero among all subjects (P < 0.001). Ventricular expansion rates differed by clinical group (P < 0.001) and increased in the following order: cognitively normal (1.3 cm(3)/year) < amnestic mild cognitive impairment (2.5 cm(3)/year) < Alzheimer's disease (7.7 cm(3)/year). Among all subjects there was no correlation between PIB change and concurrent change on CDR-SB (r = -0.01, P = 0.97) but some evidence of a weak correlation with MMSE (r =-0.22, P = 0.09). In contrast, greater rates of ventricular expansion were clearly correlated with worsening concurrent change on CDR-SB (r = 0.42, P < 0.01) and MMSE (r =-0.52, P < 0.01). Our data are consistent with a model of typical late onset Alzheimer's disease that has two main features: (i) dissociation between the rate of amyloid deposition and the rate of neurodegeneration late in life, with amyloid deposition proceeding at a constant slow rate while neurodegeneration accelerates and (ii) clinical symptoms are coupled to neurodegeneration not amyloid deposition. Significant plaque deposition occurs prior to clinical decline. The presence of brain amyloidosis alone is not sufficient to produce cognitive decline, rather, the neurodegenerative component of Alzheimer's disease pathology is the direct substrate of cognitive impairment and the rate of cognitive decline is driven by the rate of neurodegeneration. Neurodegeneration (atrophy on MRI) both precedes and parallels cognitive decline. This model implies a complimentary role for MRI and PIB imaging in Alzheimer's disease, with each reflecting one of the major pathologies, amyloid dysmetabolism and neurodegeneration.

Hippocampal volume change over time, measured with MRI, has huge potential as a marker for Alzheimer's disease. The objectives of this study were: (i) to test if constant and accelerated hippocampal loss can be detected in Alzheimer's disease, mild cognitive impairment and normal ageing over short periods, e.g. 6-12 months, with MRI in the large multicentre setting of the Alzheimer's Disease Neuroimaging Initiative (ADNI); (ii) to determine the extent to which the polymorphism of the apolipoprotein E (ApoE) gene modulates hippocampal change; and (iii) to determine if rates of hippocampal loss correlate with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, such as the beta-amyloid (Abeta(1-42)) and tau proteins (tau). The MRI multicentre study included 112 cognitive normal elderly individuals, 226 mild cognitive impairment and 96 Alzheimer's disease patients who all had at least three successive MRI scans, involving 47 different imaging centres. The mild cognitive impairment and Alzheimer's disease groups showed hippocampal volume loss over 6 months and accelerated loss over 1 year. Moreover, increased rates of hippocampal loss were associated with presence of the ApoE allele epsilon4 gene in Alzheimer's disease and lower CSF Abeta(1-42) in mild cognitive impairment, irrespective of ApoE genotype, whereas relations with tau were only trends. The power to measure hippocampal change was improved by exploiting correlations statistically between successive MRI observations. The demonstration of considerable hippocampal loss in mild cognitive impairment and Alzheimer's disease patients over only 6 months and accelerated loss over 12 months illustrates the power of MRI to track morphological brain changes over time in a large multisite setting. Furthermore, the relations between faster hippocampal loss in the presence of ApoE allele epsilon4 and decreased CSF Abeta(1-42) supports the concept that increased hippocampal loss is an indicator of Alzheimer's disease pathology and a potential marker for the efficacy of therapeutic interventions in Alzheimer's disease.

Objectives: Only half of consultants' medical recommendations are implemented. We created a tool that lets referring providers review and implement electronic recommendations made by consultants, with the hypothesis that facilitation with our tool could improve implementation., Measurements: The tool was piloted among geriatrics consultants and hospitalists. Pre-post evaluation was done with control (before pilot; N=20) and intervention (after pilot; N=20) patients. Consultants wrote notes containing recommendations for all study patients, and entered electronic recommendations only for intervention patients. We analyzed all recommendations and surveyed hospitalists., Results: A total of 249 recommendations were made for intervention patients versus 192 for controls (p<0.05). Of all recommendations about intervention patients, 78% were implemented, compared to 59% for controls (p=0.01). Of the intervention recommendations, 77% were entered electronically using our tool; of these, 86% were implemented. All 24 survey respondents indicated that the system improved quality, saved time, and should be expanded., Conclusion: Consultant recommendations were implemented 30% more often when there was electronic facilitation of recommendations.

Background: Case reports have suggested that cardiomyopathy may be a complication of recessive dystrophic epidermolysis bullosa (RDEB)., Objective: To determine the risk of congestive heart failure (CHF) or cardiomyopathy in each major EB subtype., Methods: These data represent systematic case findings and data collection performed throughout the continental United States from 1986 through 2002, by the National Epidermolysis Bullosa Registry. Study design is cross-sectional (n = 3280) with a nested randomly sampled longitudinal subcohort (n = 450). Frequencies of CHF and cardiomyopathy were determined by patient self-reporting, medical histories and review of medical records. In those who died, death certificates were reviewed and histories obtained from surviving family. Cumulative risks were stratified by cause and EB subtype., Results: Cardiomyopathy was reported as early as within the first year of life. In patients having no other known risk factors for CHF or cardiomyopathy, the highest risk of cardiomyopathy was seen among patients with Hallopeau-Siemens RDEB (RDEB-HS), with a cumulative risk of 4.51% on or after age 20 years. The cumulative risk of cardiomyopathy was only 1.14% and 0.40% in non-Herlitz junctional EB (JEB) and non-Hallopeau-Siemens RDEB, respectively, and was not observed in any other EB subtype. When patients with coexistent chronic renal failure were included, the cumulative risk for RDEB-HS rose to 18.86% by age 35 years. About 30% of our patients affected with RDEB-HS died of CHF or cardiomyopathy, even those with no other known risk factors., Conclusions: CHF and cardiomyopathy are uncommon complications in both major RDEB subtypes and non-Herlitz JEB, and may be fatal.

As part of a biomarker discovery effort in peripheral blood, we acquired an immunological profile of cell-surface markers from healthy control and untreated subjects with relapsing-remitting MS (RRMS). Fresh blood from each subject was screened ex vivo using a panel of 50 fluorescently labelled monoclonal antibodies distributed amongst 56 pools of four antibodies each. From these 56 pools, we derived an immunological profile consisting of 1018 'features' for each subject in our analysis using a systematic gating strategy. These profiles were interrogated in an analysis with a screening phase (23 patients) and an extension phase (15 patients) to identify cell populations in peripheral blood whose frequency is altered in untreated RRMS subjects. A population of CD8(low)CD4(-) cells was identified as being reduced in frequency in untreated RRMS subjects (P = 0.0002), and this observation was confirmed in an independent sample of subjects from the Comprehensive Longitudinal Investigation of MS at the Brigham & Women's Hospital (P = 0.002). This reduction in the frequency of CD8(low)CD4(-) cells is also observed in 38 untreated subjects with a clinically isolated demyelination syndrome (CIS) (P = 0.0006). We also show that these differences may be due to a reduction in the CD8(low)CD56(+)CD3(-)CD4(-) subset of CD8(low) cells, which have a natural killer cell profile. Similarities between untreated CIS and RRMS subjects extend to broader immunological profiles: consensus clustering of our data suggests that there are three distinct populations of untreated RRMS subjects and that these distinct phenotypic categories are already present in our sample of untreated CIS subjects. Thus, our large-scale immunophenotyping approach has yielded robust evidence for a reduction of CD8(low)CD4(-) cells in both CIS and RRMS in the absence of treatment as well as suggestive evidence for the existence of immunologically distinct subsets of subjects with a demyelinating disease.

Emotional blunting and abnormal processing of rewards and punishments represent early features of frontotemporal lobar degeneration (FTLD). Better understanding of the physiological underpinnings of these emotional changes can be facilitated by the use of classical psychology approaches. Fear conditioning (FC) is an extensively used paradigm for studying emotional processing that has rarely been applied to the study of dementia. We studied FC in controls (n = 25), Alzheimer's disease (n = 25) and FTLD (n = 25). A neutral stimulus (coloured square on a computer screen) was repeatedly paired with a 1 s burst of 100 db white noise. Change in skin conductance response to the neutral stimulus was used to measure conditioning. Physiological-anatomical correlations were examined using voxel-based morphometry (VBM). Both patient groups showed impaired acquisition of conditioned responses. However, the basis for this deficit appeared to differ between groups. In Alzheimer's disease, impaired FC occurred despite normal electrodermal responses to the aversive stimulus. In contrast, FTLD patients showed reduced skin conductance responses to the aversive stimulus, which contributed significantly to their FC deficit. VBM identified correlations with physiological reactivity in the amygdala, anterior cingulate cortex, orbitofrontal cortex and insula. These data indicate that Alzheimer's disease and FTLD both show abnormalities in emotional learning, but they suggest that in FTLD this is associated with a deficit in basic electrodermal response to aversive stimuli, consistent with the emotional blunting described with this disorder. Deficits in responses to aversive stimuli could contribute to both the behavioural and cognitive features of FTLD and Alzheimer's disease. Further study of FC in humans and animal models of dementia could provide a valuable window into these symptoms.

Purpose: Many older adults have inadequate health-related literacy, which is associated with poor health outcomes. Thus, it is important to identify determinants of health literacy. We investigated relationships between health literacy and general cognitive and sensory abilities, as well as education, health, and demographic variables, in a community sample of middle-aged and older adults., Design and Methods: Participants were 314 community-dwelling adults (67% female, 48% African American) diagnosed with chronic heart failure recruited for a pharmacist-based intervention study to improve adherence to chronic heart failure medications. We adminstered demographic, health, education, cognitive (e.g., processing speed, working memory), and sensory measures, and the Short Test of Functional Health Literacy in Adults (STOFHLA), as part of the baseline condition of this study., Results: STOFHLA scores were lower for participants who were older, less educated, male, African American, had more comorbidities, or scored lower on all cognitive ability measures. Hierarchical linear regression analyses showed that education and cognitive ability were independently associated with the STOFHLA measure and explained age differences in health literacy., Implications: The association of cognitive abilities and literacy has important implications for health literacy models and for interventions to reduce the impact of low health literacy on health outcomes. For example, medication instructions should be designed to reduce comprehension demands on general cognitive abilities as well as literacy skills.

Background: Because of drug-drug interactions mediated by hepatic cytochrome P450, tuberculosis treatment guidelines recommend an increase in rifabutin from 300 mg to 450 or 600 mg when combined with efavirenz-based antiretroviral therapy. To assess this recommendation, rifabutin and efavirenz pharmacokinetic parameters were investigated., Methods: Plasma concentrations of rifabutin were determined as a baseline control in 15 patients with tuberculosis and human immunodeficiency virus (HIV) infection who were treated with rifabutin 300 mg and isoniazid 15 mg/kg (up to 900 mg) twice weekly. Rifabutin, isoniazid, and efavirenz concentrations were determined after a median of 21 days (interquartile range, 20-34 days) of daily efavirenz-based antiretroviral therapy with twice-weekly rifabutin 600 mg and isoniazid 15 mg/kg., Results: The mean rifabutin area under the concentration-time curve (AUC(0-24)) increased 20% from the baseline value (geometric mean, 5.0 vs. 4.2 microg.h/mL; ratio of geometric means, 1.2 [90% confidence interval, 1.0-1.4]). Also, the mean efavirenz AUC(0-24) in the 15 patients taking concomitant rifabutin 600 mg twice-weekly was 10% higher than that in 35 historical subjects with HIV infection who were not taking rifabutin. Efavirenz-based antiretroviral therapy was effective; HIV load decreased 2.6 log copies/mL, and the median CD4+ T cell count increased from 141 to 240 cells/mm3 after a median of 21 days of efavirenz-based antiretroviral therapy. No statistically significant differences in isoniazid pharmacokinetic parameters were found., Conclusions: The rifabutin dose increase from 300 mg to 600 mg was adequate to compensate for the efavirenz drug interaction in most patients, and no drug interaction with isoniazid was detected. Efavirenz therapy administered at a standard 600-mg dose achieved adequate plasma concentrations in patients receiving intermittent rifabutin and isoniazid therapy, was generally well tolerated, and demonstrated potent antiretroviral activity.

Purpose: We investigated whether patient-centered instructions for chronic heart failure medications increase comprehension and memory for medication information in older adults diagnosed with chronic heart failure., Design and Methods: Patient-centered instructions for familiar and unfamiliar medications were compared with instructions for the same medications from a chain pharmacy (standard pharmacy instructions). Thirty-two adults (age, M = 63.8) read and answered questions about each instruction, recalled medication information (free recall), and then answered questions from memory (cued recall)., Results: Patient-centered instructions were better recalled and understood more quickly than the standard instructions. Instructions for the familiar medications also were better recalled. Patient-centered instructions were understood more accurately for the unfamiliar medications, but standard instructions were understood more accurately for the familiar medications. However, the recall measures showed that the advantage of the standard format for familiar medications was short lived., Implications: The findings suggest that the patient-centered format may improve printed medication instructions available in many pharmacies, which should help older adults to better understand how to take their medications.

Background: The occurrence of acquired rifamycin resistance despite use of directly observed therapy for tuberculosis is associated with advanced human immunodeficiency virus (HIV) disease and highly intermittent administration of antituberculosis drugs. Beyond these associations, the pathogenesis of acquired rifamycin resistance is unknown., Methods: We performed a pharmacokinetic substudy of patients in a trial of treatment with twice-weekly rifabutin and isoniazid., Results: A total of 102 (60%) of 169 patients in the treatment trial participated in the pharmacokinetic substudy, including 7 of 8 patients in whom tuberculosis treatment failure or relapse occurred in association with acquired rifamycin-resistant mycobacteria (hereafter, "ARR failure or relapse"). The median rifabutin area under the concentration-time curve (AUC(0-24)) was lower for patients with than for patients without ARR failure or relapse (3.3 vs. 5.2 microg*h/mL; P = .06, by the Mann-Whitney exact test). In a multivariate analysis adjusted for CD4+ T cell count, the mean rifabutin AUC(0-24) was significantly lower for patients with ARR failure or relapse than for other patients (3.0 microg*h/mL [95% confidence interval {CI}, 1.9-4.5] vs. 5.2 microg*h/mL [95% CI, 4.6-5.8]; P = .02, by analysis of covariance). The median isoniazid AUC(0-12) was not significantly associated with ARR failure or relapse (20.6 vs. 28.0 microg*h/mL; P = .24, by the Mann-Whitney exact test). However, in a multivariate logistic regression model that adjusted for the rifabutin AUC(0-24), a lower isoniazid AUC(0-12) was associated with ARR failure or relapse (OR, 10.5; 95% CI, 1.1-100; P = .04)., Conclusions: Lower plasma concentrations of rifabutin and, perhaps, isoniazid were associated with ARR failure or relapse in patients with tuberculosis and HIV infection treated with twice-weekly therapy.

Background: The presence in a family of a child or children with epidermolysis bullosa (EB) may have profound psychological implications for other family members., Objectives: To assess the impact of the presence of EB in one or more children on the personal relationships between their parents., Methods: Standardized questionnaires were used., Results: In general, the presence of a child severely affected with EB had profound effects on many aspects of marriage. This included a lack of interest in participating in activities as couples [junctional EB (JEB), 45%; recessive dystrophic EB (RDEB), 25%], a lack of energy to invest in such pursuits (JEB, 82%; RDEB, 50%), limitations in opportunities for sharing nonintimate physical activities (reported by most parents having children with some type of generalized EB), and negatively altered parental sex life (JEB, 55%; RDEB, 39%). This is consistent with the fact that 10%, 64%, 25% and 36% of parents of an affected child with EB simplex (EBS), JEB, dominant dystrophic EB (DDEB) and RDEB, respectively, characterized their relationships as couples as revolving almost exclusively around the day-to-day care of their affected children. The severity of disease in an affected child clearly influenced parental decisions about having more children: 24% and 64% of parents of children with JEB and RDEB, respectively, chose not to have additional children, compared with 26% and 54% of parents with children having EBS or DDEB. This choice was most often pursued via tubal ligation; less often, alternative means of surgical sterilization were chosen. Divorce was common among parents of children with EB (range: 17% in EBS to 31% in JEB) and, with the exception of parents of children with EBS, was usually directly attributed by one or both parents to the profound impact that this disease had exerted on their marriage., Conclusions: Physicians caring for children with EB need to give more consideration to the many psychological factors that may contribute to their patients' well being. They may need to assist these children's parents in seeking support and counselling to prevent destruction of the family unit.

Background: There is increasing interest in the possible role of new fluoroquinolone antibiotics for treatment of tuberculosis, but widespread use of fluoroquinolones for treatment of other bacterial infections may select for resistant strains of Mycobacterium tuberculosis., Methods: We evaluated fluoroquinolone susceptibility using the proportion method (critical ciprofloxacin concentration for susceptibility testing, 2.0 mu g/mL) in isolates obtained from patients enrolled in Tuberculosis Trial Consortium clinical trials during the period of 1995-2001 and in a referral sample of isolates sent to the Centers for Disease Control and Prevention (Atlanta, GA) during the period of 1996-2000 for additional testing, often because of drug resistance., Results: Of the 1373 isolates from the clinical trials, 1324 (96%) were susceptible to isoniazid and rifampin; 2 (0.15%) of these isolates were also resistant to ciprofloxacin. Of the 1852 isolates from the referral sample, 603 (32.6%) were resistant to isoniazid and rifampin (i.e., multidrug resistant), 849 (45.7%) were resistant to >or=1 first-line drug but were not resistant to both isoniazid and rifampin, and 400 (21.6%) were susceptible to all first-line agents. Ciprofloxacin resistance was found in 33 (1.8%) of the referral-sample isolates. Most ciprofloxacin-resistant isolates (25 [75.8%]) were resistant to isoniazid and rifampin., Conclusions: Despite widespread use of fluoroquinolones for treatment of common bacterial infections, resistance among clinical isolates of M. tuberculosis in the United States and Canada remains rare, occurring primarily among multidrug-resistant strains.

A standardized questionnaire was used to assess mobility, activity and pain in 140 randomly chosen children, who were representative of all major types and subtypes of inherited epidermolysis bullosa (EB). Pain status in these children was compared with 374 randomly selected adults with EB. The level of independence for each of six activities of daily living (ADL) (toileting; feeding; bathing; dressing; grooming; walking) was assessed in these EB children using conventional criteria for scoring. Whereas more than 90% of all EB simplex (EBS) and dominant dystrophic EB (DDEB) children were totally independent for each function (excluding walking), the frequency of similarly totally independent patients with junctional EB (JEB) and recessive dystrophic EB (RDEB) ranged from only 39% to 73%. No DDEB children and only 2% of EBS patients were totally dependent in their individual ADL, in comparison to 8-27% of JEB and 2-27% of RDEB children. Totally independent walking was reported in only 31%, 31%, 67%, and 24% of EBS, JEB, DDEB, and RDEB children, respectively. A daily level of EB-related pain was assessed in children by their parents using a linear scale of 0 (no pain) to 10 (unbearable pain). Whereas 14-19% of all children with EBS, JEB, and DDEB were graded with pain levels of more than 5, 32% of all RDEB children reportedly suffered this much pain. Increased frequencies of pain with scores more than 5 were most often noted in those patients having more clinically extensive or severe EB subtypes. These included JEB-Herlitz (20% vs. 14% in JEB-non-Herlitz) and RDEB-Hallopeau-Siemens (47% vs. 20% in all other RDEB subtypes). Only 5% of all RDEB children reportedly were pain-free, compared to 12-14% of those with EBS, JEB, and DDEB. Collectively, these data provide the first report of the specific impact different forms of EB have on daily living and coping with this genodermatosis.

Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by behavioural disorders that suggest abnormalities of emotional processing. Patients with the temporal variant of FTD (tvFTD) are particularly at risk for developing deficits in emotional processing secondary to atrophy in the amygdala, anterior temporal cortex (ATC) and orbital frontal cortex (OFC), structures that are components of the brain's emotional processing systems. In addition, previous studies have suggested that predominantly right, as opposed to left temporal atrophy is more likely to be associated with behavioural and emotional impairments in tvFTD. However, emotional processing has never been assessed directly in this group. We examined one aspect of emotional processing, namely the comprehension of facial expressions of emotion (emotional comprehension) in nine individuals with tvFTD, and correlated performance on this measure with atrophy (as measured from T(1)-weighted MRI scans by region of interest analysis) in the amygdala, ATC and OFC. Compared with age-matched controls, the tvFTD group was impaired in emotional comprehension, with more severe impairment for emotions with negative valence, including sadness, anger and fear, than for happiness. Emotional comprehension was correlated with atrophy in the right amygdala and the right OFC, and not with atrophy in other structures. When individual profiles of amygdala atrophy were examined across patients and compared with control values, right amygdala atrophy was always accompanied by left amygdala atrophy, whereas patients with volume loss in the left amygdala could have normal or decreased right amygdala volumes. Thus, emotional comprehension appeared to be most impaired when bilateral amygdala atrophy was present, and was not associated with the degree of left amygdala atrophy. Our data indicate that tvFTD is associated with impairments in emotional processing that may underlie some behavioural problems in this disorder, and that the emergence of such deficits depends on the specific pattern of anatomical injury. These results have implications both for the clinical presentation in tvFTD patients and for the study of the neuroanatomical basis of emotion.

Purpose: This study compared the response time, response rate, and cost of two types of survey administration techniques: e-mail/web-based versus conventional postal mail. The main aim of the survey was to collect descriptive information on the existence of Acute Care for Elders units and their characteristics by surveying geriatric division chiefs., Design and Methods: Two randomized cohorts of geriatric division chiefs were formed to receive a survey either by electronic mail (n = 57) or by conventional postal mail (n = 57). If there was no response to the initial mailing, two follow-up mailings were sent to both groups using the original modality; a third follow-up was performed using the alternative modality. For each group, response rate and response time were calculated. The average total cost was computed and compared across two groups., Results: The aggregate response rate was 58% (n = 31) for the e-mail group versus 77% (n = 44) for the postal mail group. The overall average response time was shorter in the e-mail group, 18 days compared with 33 days for the conventional postal mailing group. The cost comparison showed that average cost was $7.70 for the e-mail group, compared to $10.50 per response for the conventional mail group., Implications: It appears that although the web-based technology is gaining popularity and leads to lower cost per response, the conventional postal method of surveying continues to deliver a better response rate among the geriatric medicine division chiefs. The web-based approach holds promise given its lower costs and acceptable response rate combined with the shorter response time.

Inappropriate use of antimicrobial agents results in unnecessary exposure to medication, persistent or progressive infection, emergence of resistance, and increased costs. We implemented a program to control use of restricted agents while improving care. This study compared 2 major mechanisms for improving use of antimicrobial agents: (1) recommendations made by the Antimicrobial Management Team (AMT), which included a clinical pharmacist backed up by a physician from the Division of Infectious Diseases (ID), and (2) recommendations made by ID fellows. Outcome measures included appropriateness of recommendations, cure rate, number of treatment failures, and cost of care, which were assessed for 180 patients. The AMT outperformed the ID fellows in all outcomes examined by the study (including appropriateness [87% vs. 47%; P<.001], cure rate [64% vs. 42%; P=.007], and treatment failures [15% vs. 28%; P=.03]), although the differences in economic outcomes between cases managed by the AMT and those managed by the ID fellows were not statistically significant. In an academic setting with a restricted formulary, the AMT demonstrated better antimicrobial prescribing than ID fellows.

Objective: Many hospitals are investing in computer-based provider order-entry (POE) systems, and providers' evaluations have proved important for the success of the systems. The authors assessed how physicians and nurses viewed the effects of one modified commercial POE system on time spent patients, resource utilization, errors with orders, and overall quality of care., Design: Survey., Measurements: Opinions of 271 POE users on medicine wards of an urban teaching hospital: 96 medical house officers, 49 attending physicians, 19 clinical fellows with heavy inpatient loads, and 107 nurses., Results: Responses were received from 85 percent of the sample. Most physicians and nurses agreed that orders were executed faster under POE. About 30 percent of house officers and attendings or fellows, compared with 56 percent of nurses, reported improvement in overall quality of care with POE. Forty-four percent of house officers and 34 percent of attendings/fellows reported that their time with patients decreased, whereas 56 percent of nurses indicated that their time with patients increased (P < 0.001). Sixty percent of house officers and 41 percent of attendings/fellows indicated that order errors increased, whereas 69 percent of nurses indicated a decrease or no change in errors. Although most nurses reported no change in the frequency of ordering tests and medications with POE, 61 percent of house officers reported an increased frequency., Conclusion: Physicians and nurses had markedly different views about effects of a POE system on patient care, highlighting the need to consider both perspectives when assessing the impact of POE. With this POE system, most nurses saw beneficial effects, whereas many physicians saw negative effects.