Search

Abstract By 2050, 1 in 4 people worldwide will be living with hearing impairment. We propose a digital Speech Hearing Screener (dSHS) using short nonsense word recognition to measure speech-hearing ability. The importance of hearing screening is increasing due to the anticipated increase in individuals with hearing impairment globally. We compare dSHS outcomes with standardized pure-tone averages (PTA) and speech-recognition thresholds (SRT). Fifty participants (aged 55 or older underwent pure-tone and speech-recognition thresholding. One-way ANOVA was used to compare differences between hearing impaired and hearing not-impaired groups, by the dSHS, with a clinical threshold of moderately impaired hearing at 35 dB and severe hearing impairment at 50 dB. dSHS results significantly correlated with PTAs/SRTs. ANOVA results revealed the dSHS was significantly different (F(1,47) = 38.1, p

IntroductionAlzheimer’s disease and related dementias (ADRD) represent a substantial global public health challenge with multifaceted impacts on individuals, families, and healthcare systems. Brief cognitive screening tools such as the Mini-Cog© can help improve recognition of ADRD in clinical practice, but widespread adoption continues to lag. We compared the Digital Clock and Recall (DCR), a next-generation process-driven adaptation of the Mini-Cog, with the original paper-and-pencil version in a well-characterized clinical trial sample.MethodsDCR was administered to 828 participants in the Bio-Hermes-001 clinical trial (age median ± SD = 72 ± 6.7, IQR = 11; 58% female) independently classified as cognitively unimpaired (n = 364) or as having mild cognitive impairment (MCI, n = 274) or dementia likely due to AD (DLAD, n = 190). MCI and DLAD cohorts were combined into a single impaired group for analysis. Two experienced neuropsychologists rated verbal recall accuracy and digitally drawn clocks using the original Mini-Cog scoring rules. Inter-rater reliability of Mini-Cog scores was computed for a subset of the data (n = 508) and concordance between Mini-Cog rule-based and DCR scoring was calculated.ResultsInter-rater reliability of Mini-Cog scoring was good to excellent, but Rater 2’s scores were significantly higher than Rater 1’s due to variation in clock scores (p

BackgroundDual task paradigms are thought to offer a quantitative means to assess cognitive reserve and the brain’s capacity to allocate resources in the face of competing cognitive demands. The most common dual task paradigms examine the interplay between gait or balance control and cognitive function. However, gait and balance tasks can be physically challenging for older adults and may pose a risk of falls. ObjectiveWe introduce a novel, digital dual-task assessment that combines a motor-control task (the “ball balancing” test), which challenges an individual to maintain a virtual ball within a designated zone, with a concurrent cognitive task (the backward digit span task [BDST]). MethodsThe task was administered on a touchscreen tablet, performance was measured using the inertial sensors embedded in the tablet, conducted under both single- and dual-task conditions. The clinical use of the task was evaluated on a sample of 375 older adult participants (n=210 female; aged 73.0, SD 6.5 years). ResultsAll older adults, including those with mild cognitive impairment (MCI) and Alzheimer disease–related dementia (ADRD), and those with poor balance and gait problems due to diabetes, osteoarthritis, peripheral neuropathy, and other causes, were able to complete the task comfortably and safely while seated. As expected, task performance significantly decreased under dual task conditions compared to single task conditions. We show that performance was significantly associated with cognitive impairment; significant differences were found among healthy participants, those with MCI, and those with ADRD. Task results were significantly associated with functional impairment, independent of diagnosis, degree of cognitive impairment (as indicated by the Mini Mental State Examination [MMSE] score), and age. Finally, we found that cognitive status could be classified with >70% accuracy using a range of classifier models trained on 3 different cognitive function outcome variables (consensus clinical judgment, Rey Auditory Verbal Learning Test [RAVLT], and MMSE). ConclusionsOur results suggest that the dual task ball balancing test could be used as a digital cognitive assessment of cognitive reserve. The portability, simplicity, and intuitiveness of the task suggest that it may be suitable for unsupervised home assessment of cognitive function.

Abstract Background Disease-modifying treatments for Alzheimer’s disease highlight the need for early detection of cognitive decline. However, at present, most primary care providers do not perform routine cognitive testing, in part due to a lack of access to practical cognitive assessments, as well as time and resources to administer and interpret the tests. Brief and sensitive digital cognitive assessments, such as the Digital Clock and Recall (DCR™), have the potential to address this need. Here, we examine the advantages of DCR over the Mini-Mental State Examination (MMSE) in detecting mild cognitive impairment (MCI) and mild dementia. Methods We studied 706 participants from the multisite Bio-Hermes study (age mean ± SD = 71.5 ± 6.7; 58.9% female; years of education mean ± SD = 15.4 ± 2.7; primary language English), classified as cognitively unimpaired (CU; n = 360), mild cognitive impairment (MCI; n = 234), or probable mild Alzheimer’s dementia (pAD; n = 111) based on a review of medical history with selected cognitive and imaging tests. We evaluated cognitive classifications (MCI and early dementia) based on the DCR and the MMSE against cohorts based on the results of the Rey Auditory Verbal Learning Test (RAVLT), the Trail Making Test-Part B (TMT-B), and the Functional Activities Questionnaire (FAQ). We also compared the influence of demographic variables such as race (White vs. Non-White), ethnicity (Hispanic vs. Non-Hispanic), and level of education (≥ 15 years vs.

Abstract INTRODUCTION Early detection of Alzheimer's disease and cognitive impairment is critical to improving the healthcare trajectories of aging adults, enabling early intervention and potential prevention of decline. METHODS To evaluate multi‐modal feature sets for assessing memory and cognitive impairment, feature selection and subsequent logistic regressions were used to identify the most salient features in classifying Rey Auditory Verbal Learning Test‐determined memory impairment. RESULTS Multimodal models incorporating graphomotor, memory, and speech and voice features provided the stronger classification performance (area under the curve = 0.83; sensitivity = 0.81, specificity = 0.80). Multimodal models were superior to all other single modality and demographics models. DISCUSSION The current research contributes to the prevailing multimodal profile of those with cognitive impairment, suggesting that it is associated with slower speech with a particular effect on the duration, frequency, and percentage of pauses compared to normal healthy speech.

The prevalence of Alzheimer’s disease (AD) and related dementias (ADRD) is increasing. African Americans are twice as likely to develop dementia than other ethnic populations. Traditional cognitive screening solutions lack the sensitivity to independently identify individuals at risk for cognitive decline. The DCTclock is a 3-min AI-enabled adaptation of the well-established clock drawing test. The DCTclock can estimate dementia risk for both general cognitive impairment and the presence of AD pathology. Here we performed a retrospective analysis to assess the performance of the DCTclock to estimate future conversion to ADRD in African American participants from the Rush Alzheimer’s Disease Research Center Minority Aging Research Study (MARS) and African American Clinical Core (AACORE). We assessed baseline DCTclock scores in 646 participants (baseline median age = 78.0 ± 6.4, median years of education = 14.0 ± 3.2, 78% female) and found significantly lower baseline DCTclock scores in those who received a dementia diagnosis within 3 years. We also found that 16.4% of participants with a baseline DCTclock score less than 60 were significantly more likely to develop dementia in 5 years vs. those with the highest DCTclock scores (75–100). This research demonstrates the DCTclock’s ability to estimate the 5-year risk of developing dementia in an African American population. Early detection of elevated dementia risk using the DCTclock could provide patients, caregivers, and clinicians opportunities to plan and intervene early to improve cognitive health trajectories. Early detection of dementia risk can also enhance participant selection in clinical trials while reducing screening costs.

Digital health technologies have been in use for many years in a wide spectrum of healthcare scenarios. This narrative review outlines the current use and the future strategies and significance of digital health technologies in modern healthcare applications. It covers the current state of the scientific field (delineating major strengths, limitations, and applications) and envisions the future impact of relevant emerging key technologies. Furthermore, we attempt to provide recommendations for innovative approaches that would accelerate and benefit the research, translation and utilization of digital health technologies.

The COVID-19 pandemic highlighted the need to prioritise mature digital health and data governance at both national and supranational levels to guarantee future health security. The Riyadh Declaration on Digital Health was a call to action to create the infrastructure needed to share effective digital health evidence-based practices and high-quality, real-time data locally and globally to provide actionable information to more health systems and countries. The declaration proposed nine key recommendations for data and digital health that need to be adopted by the global health community to address future pandemics and health threats. Here, we expand on each recommendation and provide an evidence-based roadmap for their implementation. This policy document serves as a resource and toolkit that all stakeholders in digital health and disaster preparedness can follow to develop digital infrastructure and protocols in readiness for future health threats through robust digital public health leadership.

Bidirectional DNA replication complexes initiated from the same origin remain colocalized in a factory configuration for part or all their lifetimes. However, there is little evidence that sister replisomes are functionally interdependent, and the consequence of factory replication is unknown. Here, we investigated the functional relationship between sister replisomes in Escherichia coli, which naturally exhibits both factory and solitary configurations in the same replication cycle. Using an inducible transcription factor roadblocking system, we found that blocking one replisome caused a significant decrease in overall progression and velocity of the sister replisome. Remarkably, progression was impaired only if the block occurred while sister replisomes were still in a factory configuration – blocking one fork had no significant effect on the other replisome when sister replisomes were physically separate. Disruption of factory replication also led to increased fork stalling and requirement of fork restart mechanisms. These results suggest that physical association between sister replisomes is important for establishing an efficient and uninterrupted replication program. We discuss the implications of our findings on mechanisms of replication factory structure and function, and cellular strategies of replicating problematic DNA such as highly transcribed segments.

Background: There is a need to identify approaches to reduce medication errors. Interest has converged on ePrescribing systems that incorporate computerised provider order entry and clinical decision support functionality. Objectives: We sought to describe the procurement, implementation and adoption of basic and advanced ePrescribing systems; to estimate their effectiveness and cost-effectiveness; and to develop a toolkit for system integration into hospitals incorporating implications for practice from our research. Design: We undertook a theoretically informed, mixed-methods, context-rich, naturalistic evaluation. Setting: We undertook six longitudinal case studies in four hospitals (sites C, E, J and K) that did not have ePrescribing systems at the start of the programme (three of which went live and one that never went live) and two hospitals (sites A and D) with embedded systems. In the three hospitals that implemented systems, we conducted interviews pre implementation, shortly after roll-out and at 1 year post implementation. In the hospitals that had embedded systems, we conducted two rounds of interviews, 18 months apart. We undertook a three-round eDelphi exercise involving 20 experts to identify 80 clinically important prescribing errors, which were developed into the Investigate Medication Prescribing Accuracy for Critical error Types (IMPACT) tool. We elicited the cost of an ePrescribing system at one (non-study) site and compared this with the calculated ‘headroom’ (the upper limit that the decision-maker should pay) for the systems (sites J, K and S) for which effectiveness estimates were available. We organised four national conferences and five expert round-table discussions to contextualise and disseminate our findings. Intervention: The implementation of ePrescribing systems with either computerised provider order entry or clinical decision support functionality. Main outcome measures: Error rates were calculated using the IMPACT tool, with changes over time represented as ratios of error rates (as a proportion of opportunities for errors) using Poisson regression analyses. Results: We conducted 242 interviews and 32.5 hours of observations and collected 55 documents across six case studies. Implementation was difficult, particularly in relation to integration and interfacing between systems. Much of the clinical decision support functionality in embedded sites remained switched off because of concerns about over alerting. Getting systems operational meant that little attention was devoted to system optimisation or secondary uses of data. The prescriptions of 1244 patients were audited pre computerised provider order entry and 1178 post computerised provider order entry implementation of system A at sites J and K, and system B at site S. A total of 21,138 opportunities for error were identified from 28,526 prescriptions. Across the three sites, for those prescriptions for which opportunities for error were identified, the error rate was found to reduce significantly post computerised provider order entry implementation, from 5.0% to 4.0% (p

Organizational, administrative, and educational challenges in establishing and sustaining biomedical data science infrastructures lead to the inefficient use of Research Patient Data Repositories (RPDRs). The challenges, including but not limited to deployment, sustainability, cost optimization, collaboration, governance, security, rapid response, reliability, stability, scalability, and convenience, restrict each other and may not be naturally alleviated through traditional hardware upgrades or protocol enhancements. This article attempts to borrow data science thinking and practices in the business realm, which we call the data industry viewpoint, to improve RPDRs.

Age-related cognitive impairment (ARCI) has a profound impact on individuals, families, health care systems, and societies at large. Evidence suggests that ARCI is the consequence of underlying brain pathology. Therefore, efforts to minimize the impact of ARCI and thus closing the gap between health span and life span, which has widened in recent years, requires early detection and timely deployment of targeted, personalized interventions. Access to clinical experts is limited and technology screening and assessment methods are thus appealing. However, as traditionally implemented patients were deprived of the benefit of personalized connection with a clinician, which is particularly critical for the prescription and to ensure the adherence to and ultimate success of therapeutic interventions. We present the concept of Intelligent Technology Therapy Assistant (ITA) as a scalable solution that increases the reach of clinical experts while sustaining the personal connection between each patient and their clinician. We illustrate ITA with the “Guttman Neuro Personal Trainer”®, a tele-rehabilitation platform that provides neuropsychological evaluation and care, and the Barcelona Brain Health Initiative (BBHI) multimodal intervention coaching app, a mobile-based platform that provides lifestyle coaching support in domains related to brain health. In addition, we discuss the translation of these models to a large-scale enterprise with Linus Health. To this end, we conclude with a discussion of challenges and opportunities to move the field forward.

Helicase regulation involves modulation of unwinding speed to maintain coordination of DNA replication fork activities and is vital for replisome progression. Currently, mechanisms for helicase regulation that involve interactions with both DNA strands through a steric exclusion and wrapping (SEW) model and conformational shifts between dilated and constricted states have been examined in vitro. To better understand the mechanism and cellular impact of helicase regulation, we used CRISPR-Cas9 genome editing to study four previously identified SEW-deficient mutants of the bacterial replicative helicase DnaB. We discovered that these four SEW mutations stabilize constricted states, with more fully constricted mutants having a generally greater impact on genomic stress, suggesting a dynamic model for helicase regulation that involves both excluded strand interactions and conformational states. These dnaB mutations result in increased chromosome complexities, less stable genomes, and ultimately less viable and fit strains. Specifically, dnaB:mut strains present with increased mutational frequencies without significantly inducing SOS, consistent with leaving single-strand gaps in the genome during replication that are subsequently filled with lower fidelity. This work explores the genomic impacts of helicase dysregulation in vivo, supporting a combined dynamic regulatory mechanism involving a spectrum of DnaB conformational changes and relates current mechanistic understanding to functional helicase behavior at the replication fork.

Introduction: Oncologic patients who develop chemotherapy-associated liver injury (CALI) secondary to chemotherapy treatment tend to have worse outcomes. Biopsy remains the gold standard for the diagnosis of hepatic steatosis. The purpose of this article is to compare 2 alternatives: Proton-Density-Fat-Fraction (PDFF) MRI and MultiMaterial-Decomposition (MMD) DECT. Materials and Methods: 49 consecutive oncologic patients treated with Chemotherapy underwent abdominal DECT and abdominal MRI within 2 weeks of each other. Two radiologists tracked Regions of Interest independently both in the PDFF fat maps and in the MMD DECT fat maps. Non-parametric exact Wilcoxon signed rank test and Cohen’s K were used to compare the 2 sequences and to evaluate the agreement. Results: There was no statistically significant difference in the fat fraction measured as a continuous value between PDFF and DECT between 2 readers. Within the same imaging method (PDFF) the degree of agreement based on the k coefficient between reader 1 and reader 2 is 0.88 (p-value < 0.05). Similarly, for single-source DECT(ssDECT) the degree of agreement based on the k coefficient between reader 1 and reader 2 is 0.97 (p-value < 0.05). Conclusions: The results of this study demonstrate that the hepatic fat fraction of ssDECT with MMD are not significantly different from PDFF. This could be an advantage in an oncological population that undergoes serial CT scans for follow up of chemotherapy response.

The Myanmar Snakebite Project is an Australian government (Department of Foreign Affairs and Trade) supported foreign aid project in collaboration with the Myanmar government with the aim of improving outcomes for snakebite patients in Myanmar. As part of the project a case record database was established to document prospective cases of snakebite presenting to Mandalay General Hospital, in Upper Myanmar. The study period was 12 months (1-2-2016 to 31-1-2017). Snake identity was based on a mixture of identified dead snakes brought with patients, doctor's clinical opinion and patient identification. 965 patients were enrolled during the 12 month period, of whom 948 were included for analysis. The male: female ratio was 1.58:1. Most cases involved bites to the lower limbs (82.5%) and adults involved in farm work, confirming snakebite as an occupational disease in this community. Motorised transport was by far the most common form of transport to health care and most patients sought care from the health system (87.7%), not traditional healers (11.5%) as their first point of contact. The officially promoted application of a pressure pad, bandage and immobilisation as first aid for snakebite was almost never used, while most patients used some form of tourniquet (92.0%). 85.4% of cases where a snake ID was listed were bitten by Russell's vipers. Russell's viper bites were responsible for all fatalities (9.8% of cases) and all cases of Acute Kidney Injury (AKI). For all cases, clinical features included local swelling (76.5%), local pain (62.6%), AKI (59.8%), incoagulable blood (57.9%), regional lymphadenopathy (39.8%), nausea/vomiting (40.4%), thrombocytopenia (53.6%), abdominal pain (28.8%), shock (11.8%), secondary infection (8.6%), panhypopituitarism (2.1%). AKI required renal replacement therapy (RRT) in 23.9% of cases, all ascribed to Russell's viper bite. Green pit viper bites were the next most common cause of bites (7.6%) and were associated with incoagulable blood (29%) and occasionally shock (5%) and local necrosis (3%), and in one case AKI not requiring RRT. In contrast to Russell's viper bites, green pit viper bite was most likely to occur in the home (49%). Some green pit viper patients were treated with Russell's viper antivenom (15%), presumably because they had incoagulable blood, although this antivenom is not effective against green pit viper envenoming. For the entire patient group, antivenom was given in 80.5% of cases. The most common indications were presence of coagulopathy/non-clotting blood (59.8%), local swelling (47.4%), oliguria/anuria (19.8%), heavy proteinuria (19.4%). A febrile reaction to antivenom was reported in 47.9% of cases, while anaphylaxis, occurred in 7.9% of cases. Keywords: Snakebite, Antivenom, Russell's viper, AKI, Coagulopathy, Prospective observational study, Myanmar

Introduction The opioid epidemic in North America has, in part, been attributed to an increase in opiate use for non-cancer pain and the prescription of more potent molecules. In contrast, the United Kingdom appears unaffected by this crisis, possibly because of differences in primary care prescribing, or health system policies. Objective To determine if there are differences in opiate prescribing for new users in primary care in the United Kingdom, United States, and Canada. Approach Electronic health record data from Quebec, Canada (MOXXI), the United States (Partners Health Care, Boston MA), and the United Kingdom (CPRD random sample of 600,000) were used to identify new users of opiates (no prior prescription in 2 years), at least 18 years old between 2006-2016. Cancer patients were excluded after harmonizing equivalent READ and ICD9/10 codes. Generic drug names in each jurisdiction were mapped to the WHO ATC classification, and characterized using morphine milligram equivalents (MME). Results Overall 655,877 new users were identified, of whom 78% of 58,286 (U.S.), 88% of 6,251 (Canada), and 96% of 600,000 (UK) were non-cancer patients. Mean age of new users was 49 (SD 16) in the US, 57 (SD 16) in Canada, and 52 (SD 19) in the UK. 57.6% (UK) to 67.3% (US) of new users were women. In the UK, 86.5% of patients were started on codeine (MME:0.15), compared to 43.9% in Canada and 8.5% in the U.S. In the U.S 65.0\% were started on oxycodone (MME:1.5), and 10.9% on hydrocodone (MME:1). In Canada, tramadol (18.2%; MME: 0.1) followed by oxycodone (13.2%) were the next most commonly prescribed drugs. Conclusion/Implications Substantial differences in opioid prescribing practices for non-cancer pain were observed between the UK and Canadian and United States sites. The predilection to start patients on more potent opiates in North America may be a contributing cause to the opiate epidemic.

Background The ageing population worldwide is increasingly acquiring multiple chronic diseases. The complex management of chronic diseases could be improved with electronic health records (EHRs) tailored to chronic disease care, but most EHRs in use today do not adequately support longitudinal data management. A key aspect of chronic disease management is that it takes place over long periods, but the way that most EHRs display longitudinal data makes it difficult to trend changes over time and slows providers as they review each patient's unique course. Methods We present five clinical scenarios illustrating longitudinal data needs in complex chronic disease management. These scenarios may function as example cases for software development. Outputs For each scenario, we describe and illustrate improvements in temporal data views. Two potential solutions are visualisation for numerical data and disease-oriented text summaries for non-numerical data. Conclusions We believe that development and widespread implementation of improved temporal data views in EHRs will improve the efficiency and quality of chronic disease management in primary care.

Background Although evidence suggests electronic health records (EHRs) can improve quality and efficiency, provider adoption rates in the US ambulatory setting are relatively low. Prior studies have identified factors correlated with EHR use, but less is known about characteristics of physicians on the verge of adoption. Objective To compare characteristics of physicians who are imminent adopters of EHRs with EHR users and non-users. Design and participants A survey was mailed (June - November 2005) to a stratified random sample of all medical practices in Massachusetts. One physician from each practice (n=1884) was randomly selected to participate. Overall, 1345 physicians (71.4%) responded to the survey, with 1082 eligible for analysis due to exclusion criteria. 'Imminent adopters' were those planning to adopt EHRs within 12 months. Measurements We assessed physician and practice characteristics, availability of technology, barriers to adoption or expansion of health information technology (HIT), computer proficiency, and financial considerations. Results Compared to non-users, imminent adopters were younger, more experienced with technology, and more often in practices engaged in quality improvement. More imminent adopters owned or partly owned their practices (57.4%) than users (33.5%; pConclusions Imminent adopters of EHRs differed from users and non-users. Financial considerations appear to play a major role in adoption decisions. Knowledge of these differences may assist policymakers and healthcare leaders as they work to increase EHR adoption rates.

Objective The Massachusetts e-Health Collaborative (MAeHC) is implementing electronic health records (EHRs) in physicians' offices throughout three diverse communities. This study's objective was to assess the degree to which these practices are representative of physicians' practices statewide. Design We surveyed all MAeHC physicians (n=464) and compared their responses to those of a contemporaneously surveyed statewide random sample (n=1884). Measurements The survey questionnaire assessed practice characteristics related to EHR adoption, prevailing office culture related to quality and safety, attitudes toward health information technology (HIT) and perceptions of medical practice. Results A total of 355 MAeHC physicians (77%) and 1345 physicians from the statewide sample (71%) completed the survey. MAeHC practices resembled practices throughout Massachusetts in terms of practice size, physician age and gender, prevailing financial incentives for quality performance and HIT adoption and available resources for practice expansion. MAeHC practices were more likely to be located in rural areas (9.5% vs 4.4%, P=0.004). Physicians in both samples responded similarly to six of seven self-assessments of the office practice environment for quality and safety. Internet connections were more prevalent among MAeHC practices than across the state (96% vs 83%, PConclusion MAeHC is implementing EHRs and health information exchange among communities with physicians and practices that appear generally representative of Massachusetts. The lessons learned from this pilot project should be applicable statewide and to other states with large numbers of physicians in small office practices.

This paper, presented as a panel at the American Medical Informatics Association (AMIA) Fall Symposium 2006, explores a number of secondary uses of primary care clinical data derived from point-of care systems, and the issues arising from those uses. The authors (from the USA and the UK) describe, compare and contrast some secondary uses: pay-for-performance, public disclosure, clinical audit, health resource planning, and clinical system usage; in various environments: national health system, network of small family practice offices, and university teaching centres. In the UK, such data are now being used in pay-for-performance for GPs, and approximately 35% of their salary has been put at risk, which has resulted in close scrutiny. In the USA, pay-for-performance is at an earlier stage but is increasingly prevalent and continues to be hotly debated. Some of the issues that arise from these uses of clinical data _data quality including accuracy, comparability, perverse incentives, effect of secondary uses on care provision, and security and confidentiality among others _were discussed. Finally, options and opportunities for improving secondary uses of data in the light of the issues covered earlier were considered.

In many countries, primary care informatics has developed to the point that it is recognised as an important enabler of quality improvement; this has not occurred to date in the United States. With this conference, we aimed to build an international consensus as to whether primary care has unique characteristics that require an informatics subspecialty; and, if so, to establish the role of an international audience of 53 health informaticians, mostly working in primary care. There was consensus among the participants that primary care has many unique characteristics that justify the existence of an informatics subspecialty: primary care informatics (PCI). The conference identified principles and practical examples of: (1) the effective deployment of information technology to underpin the provision of records, communication and access to information; (2) the need to harness the extensive knowledge base about the practice of PCI; and (3) the contribution of the primary care informatics in improving patient care, and to enable its recognition in the national strategy. The conference was organised by the primary care informatics working groups of AMIA, EFMI, IMIA and Wonca and took place at Medinfo 2004 in San Francisco. It consisted of two plenary lectures, two small-group work sessions and a panel discussion to summarise the day. It was attended by experimental work and theory that underpins the science of PCI. These principles and examples of their practical application were largely derived from the extensive knowledge base which has been built up in countries that have developed PCI over the last one to two decades.

Background Patient demand for email contact with physician practices is high. If physicians met this demand, improvements in communication, quality of care and patient satisfaction could result. However, physicians have typically been hesitant to communicate electronically with patients, largely due to concerns relating to workload, security and lack of compensation. Goal To assess physician attitudes towards electronic communication with patients six months after the implementation of an application called Patient Gateway. Patient Gateway allows patients to access an extract of their medical record and facilitates online communication with medical practices. Methods A paper-based survey was administered to the 43 primary care physicians in one integrated delivery system, with a 56% (24/43) response rate. Results Overall, physicians felt that Patient Gateway’s impact on their practices was positive, especially in the areas of refill and referral request management and appointment scheduling. However, physicians are still hesitant to increase general electronic communication with patients; none opted to use Patient Gateway’s general messaging function with patients, and those who had previously used outside systems to exchange emails with some patients continued to communicate with only a small proportion of their patient panel in this way. However, 38% of physicians already communicate with their own physicians via email, and another 19% would like to do so. Conclusions Physicians’ fears about being overwhelmed with messages were not realised. While physicians were generally enthusiastic about the application, none used it directly to communicate with patients. Over three-quarters of respondents indicated that they would be more enthusiastic about electronic communication with patients if this time were compensated.

In this study we developed, characterized and validated in vitro a functional superparagmagnetic iron-oxide based magnetic resonance contrast agent by conjugating a commercially available iron oxide nanoparticle, Molday ION Rhodamine-B Carboxyl (MIRB), with a deimmunized mouse monoclonal antibody (muJ591) targeting prostate-specific membrane antigen (PSMA). This functional contrast agent is intended for the specific and non-invasive detection of prostate cancer cells that are PSMA positive, a marker implicated in prostate tumor progression and metastasis. The two-step carbodiimide reaction used to conjugate the antibody to the nanoparticle was efficient and we obtained an elemental iron content of 1958 ± 611 per antibody. Immunofluorescence microscopy and flow cytometry showed that the conjugated muJ591:MIRB complex specifically binds to PSMA-positive (LNCaP) cells. The muJ591:MIRB complex reduced cell adhesion and cell proliferation on LNCaP cells and caused apoptosis as tested by Annexin V assay, suggesting anti-tumorigenic characteristics. Measurements of the T2 relaxation time of the muJ591:MIRB complex using a 400 MHz Innova NMR and a multi-echo spin-echo sequence on a 3T MRI (Achieva, Philips) showed a significant T2 relaxation time reduction for the muJ591:MIRB complex, with a reduced T2 relaxation time as a function of the iron concentration. PSMA-positive cells treated with muJ591:MIRB showed a significantly shorter T2 relaxation time as obtained using a 3T MRI scanner. The reduction in T2 relaxation time for muJ591:MIRB, combined with its specificity against PSMA+LNCaP cells, suggest its potential as a biologically-specific MR contrast agent.

Using a modified Delphi exercise, Aziz Sheikh and colleagues identify research priorities for patient safety research in primary care contexts. Please see later in the article for the Editors' Summary.

Spontaneous DNA breaks instigate genomic changes that fuel cancer and evolution, yet direct quantification of double-strand breaks (DSBs) has been limited. Predominant sources of spontaneous DSBs remain elusive. We report synthetic technology for quantifying DSBs using fluorescent-protein fusions of double-strand DNA end-binding protein, Gam of bacteriophage Mu. In Escherichia coli GamGFP forms foci at chromosomal DSBs and pinpoints their subgenomic locations. Spontaneous DSBs occur mostly one per cell, and correspond with generations, supporting replicative models for spontaneous breakage, and providing the first true breakage rates. In mammalian cells GamGFP—labels laser-induced DSBs antagonized by end-binding protein Ku; co-localizes incompletely with DSB marker 53BP1 suggesting superior DSB-specificity; blocks resection; and demonstrates DNA breakage via APOBEC3A cytosine deaminase. We demonstrate directly that some spontaneous DSBs occur outside of S phase. The data illuminate spontaneous DNA breakage in E. coli and human cells and illustrate the versatility of fluorescent-Gam for interrogation of DSBs in living cells.

Analogously to chromosome cohesion in eukaryotes, newly replicated DNA in E. coli is held together by inter-sister linkages before partitioning into daughter nucleoids. In both cases, initial joining is apparently mediated by DNA catenation, in which replication-induced positive supercoils diffuse behind the fork, causing newly replicated duplexes to twist around each other. Type-II topoisomerase-catalyzed sister separation is delayed by the well-characterized cohesin complex in eukaryotes, but cohesion control in E. coli is not currently understood. We report that the abundant fork tracking protein SeqA is a strong positive regulator of cohesion, and is responsible for markedly prolonged cohesion observed at "snap" loci. Epistasis analysis suggests that SeqA stabilizes cohesion by antagonizing Topo IV-mediated sister resolution, and possibly also by a direct bridging mechanism. We show that variable cohesion observed along the E. coli chromosome is caused by differential SeqA binding, with oriC and snap loci binding disproportionally more SeqA. We propose that SeqA binding results in loose inter-duplex junctions that are resistant to Topo IV cleavage. Lastly, reducing cohesion by genetic manipulation of Topo IV or SeqA resulted in dramatically slowed sister locus separation and poor nucleoid partitioning, indicating that cohesion has a prominent role in chromosome segregation.

Thymineless death (TLD) is a classic and enigmatic phenomenon, documented in bacterial, yeast, and human cells, whereby cells lose viability rapidly when deprived of thymine. Despite its being the essential mode of action of important chemotherapeutic agents, and despite having been studied extensively for decades, the basic mechanisms of TLD have remained elusive. In Escherichia coli, several proteins involved in homologous recombination (HR) are required for TLD, however, surprisingly, RecA, the central HR protein and activator of the SOS DNA-damage response was reported not to be. We demonstrate that RecA and the SOS response are required for a substantial fraction of TLD. We show that some of the Rec proteins implicated previously promote TLD via facilitating activation of the SOS response and that, of the roughly 40 proteins upregulated by SOS, SulA, an SOS-inducible inhibitor of cell division, accounts for most or all of how SOS causes TLD. The data imply that much of TLD results from an irreversible cell-cycle checkpoint due to blocked cell division. FISH analyses of the DNA in cells undergoing TLD reveal blocked replication and apparent DNA loss with the region near the replication origin underrepresented initially and the region near the terminus lost later. Models implicating formation of single-strand DNA at blocked replication forks, a SulA-blocked cell cycle, and RecQ/RecJ-catalyzed DNA degradation and HR are discussed. The data predict the importance of DNA damage-response and HR networks to TLD and chemotherapy resistance in humans.

I omitted a document from my edition of the charters of William the Conqueror on the grounds of arguments which had suggested that it was a charter of William Rufus. The signa are not all consistent with the document’s date of 1084, but the charter, which is included in a pancarte destroyed in 1944, should be regarded as a charter of William I to which additions were made soon after his death. The document has some significance for the politics of 1088 and for relations between the Conqueror’s sons.

Grâce à un retour sur les théories biologiques, épistémologiques et cybernétiques des années 1950-1970, cet article tente de retracer le projet d’augmentation de l’esprit qui préoccupait alors les pionniers de l’intelligence artificielle : la question de l’intelligence artificielle n’était pas posée comme celle de l’imitation ou de la simulation mécanique de l’intellect, mais comme celle de la technicité constitutive de la pensée. Selon cette perspective, l’enjeu ne consiste pas à produire des machines intelligentes, mais à inventer de nouveaux couplages entre cerveaux humains et machines informatiques, susceptibles d’ouvrir de nouvelles possibilités d’invention. À travers une relecture des théories de Medawar, Popper, Bateson, Ashby, Licklider, Englebart, il s’agit ici d’esquisser une histoire artificielle de l’intelligence humaine, toujours extériorisée dans des supports prothétiques et exosomatiques.