A European regulatory pathway for Tidepool loop following clearance in the United States?

The recent clearance by the United States Food and Drug Administration of Tidepool Loop sets an important precedent within the medical device landscape. For the first time, an automated insulin delivery mobile application-based on an algorithm initially designed and developed by users -has been recognised as safe and effective by a regulatory body. The aim of this paper is twofold: firstly, we map out the regulatory pathways and processes that were navigated by Tidepool, the non-profit behind Tidepool Loop, in order to make this landmark moment possible. Secondly, we set out potential approvals processes in the European Union and United Kingdom with a view to examining the challenges to obtaining regulatory clearance for Tidepool Loop in these jurisdictions. In so doing, we highlight the significant differences, not only between the United States and European systems but also between the European Union and Great Britain systems. We conclude by arguing that the complexity encountered when seeking to introduce an innovative solution in different regulatory systems has the potential to act as a disincentive to open source developers from seeking regulatory approvals for such technologies in the future.

An overview of the perspectives used in health economic evaluations.

The term 'perspective' in the context of economic evaluations and costing studies in healthcare refers to the viewpoint that an analyst has adopted to define the types of costs and outcomes to consider in their studies. However, there are currently notable variations in terms of methodological recommendations, definitions, and applications of different perspectives, depending on the objective or intended user of the study. This can make it a complex area for stakeholders when interpreting these studies. Consequently, there is a need for a comprehensive overview regarding the different types of perspectives employed in such analyses, along with the corresponding implications of their use. This is particularly important, in the context of low-and-middle-income countries (LMICs), where practical guidelines may be less well-established and infrastructure for conducting economic evaluations may be more limited. This article addresses this gap by summarising the main types of perspectives commonly found in the literature to a broad audience (namely the patient, payer, health care providers, healthcare sector, health system, and societal perspectives), providing their most established definitions and outlining the corresponding implications of their uses in health economic studies, with examples particularly from LMIC settings. We then discuss important considerations when selecting the perspective and present key arguments to consider when deciding whether the societal perspective should be used. We conclude that there is no one-size-fits-all answer to what perspective should be used and the perspective chosen will be influenced by the context, policymakers'/stakeholders' viewpoints, resource/data availability, and intended use of the analysis. Moving forward, considering the ongoing issues regarding the variation in terminology and practice in this area, we urge that more standardised definitions of the different perspectives and the boundaries between them are further developed to support future studies and guidelines, as well as to improve the interpretation and comparison of health economic evidence.

What are economic costs and when should they be used in health economic studies?

Economic analyses of healthcare interventions are an important consideration in evidence-based policymaking. A key component of such analyses is the costs of interventions, for which most are familiar with using budgets and expenditures. However, economic theory states that the true value of a good/service is the value of the next best alternative forgone as a result of using the resource and therefore observed prices or charges do not necessarily reflect the true economic value of resources. To address this, economic costs are a fundamental concept within (health) economics. Crucially, they are intended to reflect the resources' opportunity costs (the forgone opportunity to use those resources for another purpose) and they are based on the value of the resource's next-best alternative use that has been forgone. This is a broader conceptualization of a resource's value than its financial cost and recognizes that resources can have a value that may not be fully captured by their market price and that by using a resource it makes it unavailable for productive use elsewhere. Importantly, economic costs are preferred over financial costs for any health economic analyses aimed at informing decisions regarding the optimum allocation of the limited/competing resources available for healthcare (such as health economic evaluations), and they are also important when considering the replicability and sustainability of healthcare interventions. However, despite this, economic costs and the reasons why they are used is an area that can be misunderstood by professionals without an economic background. In this paper, we outline to a broader audience the principles behind economic costs and when and why they should be used within health economic analyses. We highlight that the difference between financial and economic costs and what adjustments are needed within cost calculations will be influenced by the context of the study, the perspective, and the objective.

Influence of Fibrinogen Concentrate on Neonatal Clot Structure When Administered Ex Vivo After Cardiopulmonary Bypass.

BACKGROUND: Bleeding is a serious complication of cardiopulmonary bypass (CPB) in neonates. Blood product transfusions are often needed to adequately restore hemostasis, but are associated with significant risks. Thus, neonates would benefit from other effective, and safe, hemostatic therapies. The use of fibrinogen concentrate (FC; RiaSTAP, CSL Behring, Marburg, Germany) is growing in popularity, but has not been adequately studied in neonates. Here, we characterize structural and degradation effects on the neonatal fibrin network when FC is added ex vivo to plasma obtained after CPB. METHODS: After approval by the institutional review board and parental consent, blood samples were collected from neonates undergoing cardiac surgery and centrifuged to yield platelet poor plasma. Clots were formed ex vivo from plasma obtained at several time points: (1) baseline, (2) immediately post-CPB, and (3) post-transfusion of cryoprecipitate. In addition, we utilized post-CPB plasma to construct the following conditions: (4) post-CPB +0.5 mg/mL FC, and (5) post-CPB +0.9 mg/mL FC. The resultant fibrin networks were imaged using confocal microscopy to analyze overall structure, fiber density, and alignment. Clots were also analyzed using a microfluidic degradation assay. Fibrinogen content was quantified for all plasma samples. RESULTS: The addition of 0.5 or 0.9 mg/mL FC to post-CPB samples significantly enhanced the median fiber density when compared to untreated post-CPB samples (post-CPB = 0.44 [interquartile range {IQR}: 0.36-0.52], post-CPB +0.5 mg/mL FC = 0.69 [0.56-0.77], post-CPB +0.9 mg/mL FC = 0.87 [0.59-0.96]; P = .01 and P = .006, respectively). The addition of 0.9 mg/mL FC to post-CPB samples resulted in a greater fiber density than that observed after the in vivo transfusion of cryoprecipitate (post-transfusion = 0.54 [0.45-0.77], post-CPB +0.9 mg/mL FC = 0.87 [0.59-0.96]; P = .002). Median fiber alignment did not differ significantly between post-CPB samples and samples treated with FC. Degradation rates were not statistically significant from baseline values with either 0.5 or 0.9 mg/mL FC. In addition, we found a significant correlation between the difference in the baseline and post-CPB fibrinogen concentration with patient age ( P = .033) after controlling for weight. CONCLUSIONS: Our results show that clots formed ex vivo with clinically relevant doses of FC (0.9 mg/mL) display similar structural and degradation characteristics compared to the in vivo transfusion of cryoprecipitate. These findings suggest that FC is effective in restoring structural fibrin clot properties after CPB. Future studies after the administration of FC in vivo are needed to validate this hypothesis.

Error traps in Pediatric Patient Blood Management in the Perioperative Period.

Patient blood management is a patient-centered evidence-based approach to improve patient outcomes by harnessing the patient's own hematopoietic system to optimize blood health while promoting patient safety and empowerment. Perioperative patient blood management is a standard of care in adult medicine, yet it is not commonly accepted in pediatrics. Raising awareness may be the first step in improving perioperative care for the anemic and/or bleeding child. This article highlights five preventable perioperative blood conservation error traps for children. The goal is to provide practical clinical guidance to improve preoperative diagnosis and treatment of anemia, facilitate recognition and treatment of massive hemorrhage, reduce unnecessary allogeneic blood transfusions, and decrease associated complications of anemia and blood component transfusions utilizing a patient/family-centered informed consent and shared decision-making approach.

#WeAreNotWaiting DIY artificial pancreas systems and challenges for the law.

Commercial hybrid closed-loop systems are becoming more readily available, yet the number of DIY artificial pancreas system (DIY APS) users continues to rise. These DIY systems have not gone through the usual regulatory approvals processes, and, thus, present a number of legal difficulties for a number of actors, including clinicians, parents who build DIY APS for their children, and users themselves. These issues have so far received insufficient attention. Due to the complex constellation of actors involved in both development of DIY APSs and in its deployment, it is not currently clear who, and to what extent, different parties might (successfully) be held liable if something goes wrong. Despite this uncertainty, unless and until clearer guidance is issued by relevant bodies, or a case appears before the courts which clarifies the situation, existing legal principles apply. In this article, we examine some of these to shed light on how the law would likely be applied if harm were to result from the use of a DIY APS.

Risk Factors for Adverse Events in Children with Pulmonary Hypertension Undergoing Cardiac Catheterization.

Pulmonary hypertension (PH) can lead to progressive heart failure with high morbidity and mortality. Cardiac catheterization (CC) is the gold standard for diagnosis and response to vasodilatory medications. The invasive nature of CC and associated anesthesia predispose this patient population to adverse events including death. Catheterization records were queried from 1/1/2011 to 10/31/2016. Patients with PH, defined as pulmonary vascular resistance (PVR) greater than 3 WU m2, pulmonary artery pressure above 20 mmHg, and pulmonary wedge pressure less than or equal to 15 mmHg, who underwent hemodynamic CC were included in this retrospective study. Both patients with and without congenital heart disease were included. There were 198 CC in 191 patients. Adverse events (n = 28, 14.1%) included cardiac arrest, increased respiratory support requiring ICU care, PH crisis, bradycardia/hypotension requiring intervention, and arrhythmias. Odds of an adverse event increased by 22% for every 15-min increase in procedure times (OR 1.22, CI 1.01-1.39, p = 0.002) and were significantly increased for procedures longer than 80 min (OR 3.75, CI 1.56-9.00, p = 0.007) (Fig. 1). Patients with an adverse event had higher mean pulmonary artery pressures while breathing oxygen (43 [35-58] versus 34 [27-44] mmHg, p = 0.017) and oxygen with inhaled nitric oxide (37 [32-56] versus 32 [25-40] mmHg, p = 0.026). Females carried more risk than males (OR 3.88, CI 1.44-10.40, p = 0.007). Younger age, medication regimens, prematurity, and genetic disease did not carry an increased risk. Adverse events are common in pediatric patients with PH undergoing CC. The risk of adverse events correlates with greater procedure times and higher mean pulmonary artery pressure. Minimizing procedure time may improve patient outcomes.

Impact of Electronic Medication Reminder Caps on Patient Adherence and Blood Pressure.

Background: Medication adherence is widely recognized as an essential component of chronic disease management, yet only 50% of patients take their medication as prescribed. Newer technologies have the potential to improve medication adherence. Objective: To conduct a pilot study estimating the impact of a pharmacy-dispensed electronic reminder cap (SMARxT cap), which also records cap openings, on medication adherence and blood pressure (BP). Methods: After a 30-day run-in period, 28 individuals were randomized to receive a SMARxT or placebo cap on each BP medication. The primary outcome was adherence measured via (1) the medication possession ratio, (2) number of cap openings, and (3) self-report. The secondary outcome was the average of 2 BP readings at 6 months. Mean changes from baseline to 6 months were compared between the 2 groups. Results: The medication possession ratio increased 2.7% in the SMARxT cap group and decreased 1.1% in the control group (P = .13), and cap openings increased 11.9% in the SMARxT cap group and 9.9% in the control group (P = .83). Self-reported adherence increased 1.1 points in the SMARxT cap group and 0.8 points in the control group (P = .64). Systolic BP decreased 8.2 mm Hg in the SMARxT cap group and 2.8 mm Hg in the placebo cap group (P = .35), and diastolic BP decreased to 6.2 mm Hg in the SMARxT cap group and was unchanged in the placebo cap group (P = .06). Conclusions: Use of SMARxT cap showed nonsignificant improvement in medication adherence and BP lowering. This technology has potential to characterize and improve medication-taking behavior.

Risk Factors for Red Blood Cell Transfusions in Children Undergoing Cardiac Catheterization.

OBJECTIVE: To identify risk factors associated with risk of red blood cell transfusions (RBCTs) following pediatric cardiac catheterizations. STUDY DESIGN: We performed a review of all pediatric cardiac catheterizations from 2012 to 2017. The primary endpoint was RBCT within 72 hours of pediatric cardiac catheterization. Patient and procedural factors were reviewed. Generalized linear modelling was performed to describe interactions among relevant risk factors. RESULTS: In total, 831 RBCTs occurred within 72 hours of 6028 pediatric cardiac catheterizations (13.8%). Univariate analysis revealed that the prevalence of RBCT was highest among infants (37.6% incidence of RBCT) and among those with higher estimated blood loss as a percent of blood volume (P = .03). Among infants, multivariate analysis revealed that weight (OR 0.72; 95% CI 0.63-0.81), complex 2-ventricle (OR 3.14, 95% CI 2.18-4.57), and single ventricle status (OR 5.21, 95% CI 3.42-8.01) were associated with risk of RBCT. Inpatient infants from intensive care (OR 4.74; 95% CI 3.49-6.49) or stepdown units (OR 2.33; 95% CI 1.58-3.46) were at higher risk. Length of procedure (OR 2.57; 95% CI 2.03-3.26) and oxygen saturation (OR 0.98; 95% CI 0.97-0.99; P < .01) were also associated with RBCTs. CONCLUSIONS: Hospitalized infants with single ventricle or complex 2-ventricle anatomy are at highest risk of RBCT. Length of procedure, blood loss, and oxygen saturations are additional risk factors associated with RBCT. Operators should consider these factors when planning pediatric cardiac catheterizations, particularly when exposure to RBCT is undesirable.

Fibrinogen Concentrate as an Alternative to Cryoprecipitate in a Postcardiopulmonary Transfusion Algorithm in Infants Undergoing Cardiac Surgery: A Prospective Randomized Controlled Trial.

BACKGROUND: Infants undergoing cardiac surgery are at risk for bleeding and massive transfusion due to an immature coagulation system, complex surgeries, and cardiopulmonary bypass (CPB) effects. Hemodilution from CPB promotes an acquired hypofibrinogenemia that results in impaired fibrin formation, inadequate clot formation, and increased bleeding. In North America, the current standard of care to supplement fibrinogen is cryoprecipitate. An alternative option is the off-label use of fibrinogen concentrate (FC; RiaSTAP; CSL Behring, Marburg, Germany), a purified fibrinogen. Because perioperative allogenic transfusions are associated with increased morbidity and mortality, we sought to determine whether FC would be an acceptable alternative to cryoprecipitate in a post-CPB transfusion algorithm in infants undergoing open-heart surgery. METHODS: We randomized 60 infants (<12 months) undergoing nonemergent cardiac surgery with CPB at 2 tertiary care children's hospitals to receive either cryoprecipitate or FC in a post-CPB transfusion algorithm. Infants underwent a stratified randomization based on institution and surgical complexity. The primary outcome was the difference in number of intraoperative allogenic blood product transfusions. Secondary outcomes included 24-hour chest tube output (CTO), mechanical ventilation time, adverse events (AEs), intensive care unit (ICU) length of stay (LOS), hospital LOS, postoperative thrombosis, and death within 30 days of surgery. The primary analysis followed the intent-to-treat (ITT) principle and was performed using linear regression adjusted for institution and complexity of surgery. A per-protocol (PP) analysis was also performed. RESULTS: Between June 2016 and January 2018, we enrolled 60 patients with complete data available for 25 patients who received cryoprecipitate and 29 patients who received FC. Patients in the cryoprecipitate group (median age: 4 months [2-6 months]) received 5.5 (4.0-7.0) allogeneic blood units in the ITT analysis and 6.0 units (5.0-7.0 units) in the PP analysis. Patients in the FC group (median age: 4 months [2-5]) received 4 units (3.0-5.0 units) in the ITT analysis and 4.0 units (3.0-5.0 units) in the PP analysis. In the adjusted ITT analysis, the FC group received 1.79 units (95% confidence interval [CI], 0.64-2.93; P = .003) less than the cryoprecipitate group. In the adjusted PP analysis, the FC group received 2.67 units (95% CI, 1.75-3.59; P < .001) less than the cryoprecipitate group. There were no significant differences in secondary outcomes or AEs. CONCLUSIONS: Our findings suggest that FC may be considered as an alternative to cryoprecipitate for the treatment of hypofibrinogenemia in infants with bleeding after CPB. Although we found no significant differences between secondary outcomes or AEs, further studies are needed to assess safety.

What do we need to know? Data sources to support evidence-based decisions using health technology assessment in Ghana.

BACKGROUND: Evidence-based decision-making for prioritising health is assisted by health technology assessment (HTA) to integrate data on effectiveness, costs and equity to support transparent decisions. Ghana is moving towards universal health coverage, facilitated mainly by the National Health Insurance Scheme (NHIS) established in 2003. The Government of Ghana is committed to institutionalising HTA for priority-setting. We aimed to identify and describe the sources of accessible data to support HTA in Ghana. METHODS: We identified and described data sources encompassing six main domains using an existing framework. The domains were epidemiology, clinical efficacy, costs, health service use and consumption, quality of life, and equity. We used existing knowledge, views of stakeholders, and searches of the literature and internet. RESULTS: The data sources for each of the six domains vary in extent and quality. Ghana has several large data sources to support HTA (e.g. Demographic Health Surveys) that have rigorous quality assurance processes. Few accessible data sources were available for costs and resource utilisation. The NHIS is a potentially rich source of data on resource use and costs but there are some limits on access. There are some data on equity but data on quality of life are limited. CONCLUSIONS: A small number of quality data sources are available in Ghana but there are some gaps with respect to HTA based on greater use of local and contextualised information. Although more data are becoming available for monitoring, challenges remain in terms of their usefulness for HTA, and some information may not be available in disaggregated form to enable specific analyses. We support recent initiatives for the routine collection of comprehensive and reliable data that is easily accessible for HTA users. A commitment to HTA will require concerted efforts to leverage existing data sources, for example, from the NHIS, and develop and maintain new data (e.g. local health utility estimates). It will be critical that an overarching strategic and mandatory approach to the collection and use of health information is developed for Ghana in parallel to, and informed by, the development of HTA approaches to support resource allocation decisions. The key to HTA is to use the best available data while being open about its limitations and the impact on uncertainty.

Criteria Used for Priority-Setting for Public Health Resource Allocation in Low- and Middle-Income Countries: A Systematic Review.

OBJECTIVES: This systematic review aimed to identify criteria being used for priority setting for resource allocation decisions in low- and middle-income countries (LMICs). Furthermore, the included studies were analyzed from a policy perspective to understand priority setting processes in these countries. METHODS: Searches were carried out in PubMed, Embase, Econlit, and Cochrane databases, supplemented with pre-identified Web sites and bibliographic searches of relevant papers. Quality appraisal of included studies was undertaken. The review protocol is registered in International Prospective Register of Systematic Reviews PROSPERO CRD42017068371. RESULTS: Of 16,412 records screened by title and abstract, 112 papers were identified for full text screening and 44 studies were included in the final analysis. At an overall level, cost-effectiveness 52 percent (n = 22) and health benefits 45 percent (n = 19) were the most cited criteria used for priority setting for public health resource allocation. Inter-region (LMICs) and between various approaches (like health technology assessment, multi-criteria decision analysis (MCDA), accountability for reasonableness (AFR) variations among criteria were also noted. Our review found that MCDA approach was more frequently used in upper middle-income countries and AFR in lower-income countries for priority setting in health. Policy makers were the most frequently consulted stakeholders in all regions. CONCLUSIONS AND RECOMMENDATIONS: Priority-setting criteria for health resource allocation decisions in LMICs largely comprised of cost-effectiveness and health benefits criteria at overall level. Other criteria like legal and regulatory framework conducive for implementation, fairness/ethics, and political considerations were infrequently reported and should be considered.

Budgeting for a billion: applying health technology assessment (HTA) for universal health coverage in India.

BACKGROUND: India recently launched the largest universal health coverage scheme in the world to address the gaps in providing healthcare to its population. Health technology assessment (HTA) has been recognised as a tool for setting priorities as the government seeks to increase public health expenditure. This study aims to understand the current situation for healthcare decision-making in India and deliberate on the opportunities for introducing HTA in the country. METHODS: A paper-based questionnaire, adapted from a survey developed by the International Decision Support Initiative (iDSI), was administered on the second day of the Topic Selection Workshop that was conducted as part of the HTA Awareness Raising Workshop held in New Delhi on 25-27 July, 2016. Participants were invited to respond to questions covering the need, demand and supply for HTA in their context as well as the role of their organisation vis-à-vis HTA. The response rate for the survey was about 68% with 41 participants having completed the survey. RESULTS: Three quarters of the respondents (71%) stated that the government allocated healthcare resources on the basis of expert opinion. Most respondents indicated reimbursement of individual health technologies and designing a basic health benefit package (93% each) were important health policy areas while medical devices and screening programmes were cited as important technologies (98% and 92%, respectively). More than half of the respondents noted that relevant local data was either not available or was limited. Finally, technical capacity was seen as a strength and a constraint facing organisations. CONCLUSION: The findings from this study shed light on the current situation, the opportunities, including potential topics, and challenges in conducting HTA in India. There are limitations to the study and further studies may need to be conducted to inform the role that HTA will play in the design or implementation of universal health coverage in India.

Recombinant Factor VIIa Is Associated With Increased Thrombotic Complications in Pediatric Cardiac Surgery Patients.

BACKGROUND: Recombinant factor VIIa (rFVIIa) is routinely used as an off-label hemostatic agent in children undergoing cardiac surgery. Despite evidence that rFVIIa use is associated with an increased incidence of thrombotic complications in adult cardiac surgery, the safety of rFVIIa as a rescue hemostatic agent in the pediatric cardiac surgical population is less definitively delineated. In this retrospective study, we used propensity score matching to compare the incidence of thrombotic complications between children treated with rFVIIa and their matched controls. METHODS: We retrospectively reviewed medical records and pharmacy data from all neonates and children who underwent congenital cardiac surgery between May 1, 2011, and October 31, 2013, at Boston Children's Hospital, and identified those who received rFVIIa during the perioperative period. Using existing knowledge, we chose 10 factors associated with bleeding after cardiac surgery to be used in our propensity score: age, sex, body weight, neonates, prematurity, previous sternotomy, cardiopulmonary bypass time, deep hypothermic circulatory arrest time, aortic cross-clamp time, and the operative surgeon. We then used propensity-matched analysis to match children treated with rFVIIa with 2 controls. The primary outcome was thrombotic complications. Secondary outcomes included reexploration for bleeding, length of cardiac intensive care unit stay, length of hospital stay, and 30-day mortality. RESULTS: One hundred forty-nine patients received perioperative rFVIIa during the study period. Propensity matching yielded 143 rFVIIa patients matched to 2 control patients each (n = 286). Three control patients were found to have received rFVIIa during the perioperative course and were removed from the analysis, for a total of 283 control patients. The administration of rFVIIa was associated with an increased incidence of thrombotic complications (20% vs 8%; odds ratio [OR]: 3.9 [95% confidence interval {CI}: 2.6-5.9], P < .001). Administration of rFVIIa was associated with a prolonged median length of cardiac intensive care unit stay (8 days [interquartile range {IQR}: 4-24] vs 5 days [IQR: 2-10], P < .001) and prolonged length of hospital stay (20 [IQR: 9-44] vs 11 days [IQR: 7-23], P < .001). No difference in reexploration for bleeding (rFVII = 14% vs controls = 9%; OR: 1.7 [95% CI, 0.92-3.1], P = .12) or 30-day mortality was observed (8% vs 6%; OR 1.3 [95% CI, 0.60-2.89], P = .51). CONCLUSIONS: This retrospective analysis confirmed that perioperative administration of rFVIIa is associated with an increased incidence of postoperative thrombotic complications in neonates and children undergoing cardiac surgery, without increase in 30-day mortality. In conclusion, rFVIIa should be used with extreme caution in pediatric patients undergoing cardiac surgery.

Longitudinal diffusion tensor imaging in frontotemporal dementia.

OBJECTIVE: Novel biomarkers for monitoring progression in neurodegenerative conditions are needed. Measurement of microstructural changes in white matter (WM) using diffusion tensor imaging (DTI) may be a useful outcome measure. Here we report trajectories of WM change using serial DTI in a cohort with behavioral variant frontotemporal dementia (bvFTD). METHODS: Twenty-three patients with bvFTD (12 having genetic mutations), and 18 age-matched control participants were assessed using DTI and neuropsychological batteries at baseline and ~1.3 years later. Baseline and follow-up DTI scans were registered using a groupwise approach. Annualized rates of change for DTI metrics, neuropsychological measures, and whole brain volume were calculated. DTI metric performances were compared, and sample sizes for potential clinical trials were calculated. RESULTS: In the bvFTD group as a whole, rates of change in fractional anisotropy (FA) and mean diffusivity (MD) within the right paracallosal cingulum were greatest (FA: -6.8%/yr, p < 0.001; MD: 2.9%/yr, p = 0.01). MAPT carriers had the greatest change within left uncinate fasciculus (FA: -7.9%/yr, p < 0.001; MD: 10.9%/yr, p < 0.001); sporadic bvFTD and C9ORF72 carriers had the greatest change within right paracallosal cingulum (sporadic bvFTD, FA: -6.7%/yr, p < 0.001; MD: 3.8%/yr, p = 0.001; C9ORF72, FA: -6.8%/yr, p = 0.004). Sample size estimates using FA change were substantially lower than neuropsychological or whole brain measures of change. INTERPRETATION: Serial DTI scans may be useful for measuring disease progression in bvFTD, with particular trajectories of WM damage emerging. Sample size calculations suggest that longitudinal DTI may be a useful biomarker in future clinical trials.

Auditory spatial processing in Alzheimer's disease.

The location and motion of sounds in space are important cues for encoding the auditory world. Spatial processing is a core component of auditory scene analysis, a cognitively demanding function that is vulnerable in Alzheimer's disease. Here we designed a novel neuropsychological battery based on a virtual space paradigm to assess auditory spatial processing in patient cohorts with clinically typical Alzheimer's disease (n = 20) and its major variant syndrome, posterior cortical atrophy (n = 12) in relation to healthy older controls (n = 26). We assessed three dimensions of auditory spatial function: externalized versus non-externalized sound discrimination, moving versus stationary sound discrimination and stationary auditory spatial position discrimination, together with non-spatial auditory and visual spatial control tasks. Neuroanatomical correlates of auditory spatial processing were assessed using voxel-based morphometry. Relative to healthy older controls, both patient groups exhibited impairments in detection of auditory motion, and stationary sound position discrimination. The posterior cortical atrophy group showed greater impairment for auditory motion processing and the processing of a non-spatial control complex auditory property (timbre) than the typical Alzheimer's disease group. Voxel-based morphometry in the patient cohort revealed grey matter correlates of auditory motion detection and spatial position discrimination in right inferior parietal cortex and precuneus, respectively. These findings delineate auditory spatial processing deficits in typical and posterior Alzheimer's disease phenotypes that are related to posterior cortical regions involved in both syndromic variants and modulated by the syndromic profile of brain degeneration. Auditory spatial deficits contribute to impaired spatial awareness in Alzheimer's disease and may constitute a novel perceptual model for probing brain network disintegration across the Alzheimer's disease syndromic spectrum.

Pain and temperature processing in dementia: a clinical and neuroanatomical analysis.

Symptoms suggesting altered processing of pain and temperature have been described in dementia diseases and may contribute importantly to clinical phenotypes, particularly in the frontotemporal lobar degeneration spectrum, but the basis for these symptoms has not been characterized in detail. Here we analysed pain and temperature symptoms using a semi-structured caregiver questionnaire recording altered behavioural responsiveness to pain or temperature for a cohort of patients with frontotemporal lobar degeneration (n = 58, 25 female, aged 52-84 years, representing the major clinical syndromes and representative pathogenic mutations in the C9orf72 and MAPT genes) and a comparison cohort of patients with amnestic Alzheimer's disease (n = 20, eight female, aged 53-74 years). Neuroanatomical associations were assessed using blinded visual rating and voxel-based morphometry of patients' brain magnetic resonance images. Certain syndromic signatures were identified: pain and temperature symptoms were particularly prevalent in behavioural variant frontotemporal dementia (71% of cases) and semantic dementia (65% of cases) and in association with C9orf72 mutations (6/6 cases), but also developed in Alzheimer's disease (45% of cases) and progressive non-fluent aphasia (25% of cases). While altered temperature responsiveness was more common than altered pain responsiveness across syndromes, blunted responsiveness to pain and temperature was particularly associated with behavioural variant frontotemporal dementia (40% of symptomatic cases) and heightened responsiveness with semantic dementia (73% of symptomatic cases) and Alzheimer's disease (78% of symptomatic cases). In the voxel-based morphometry analysis of the frontotemporal lobar degeneration cohort, pain and temperature symptoms were associated with grey matter loss in a right-lateralized network including insula (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest) and anterior temporal cortex (P < 0.001 uncorrected over whole brain) previously implicated in processing homeostatic signals. Pain and temperature symptoms accompanying C9orf72 mutations were specifically associated with posterior thalamic atrophy (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest). Together the findings suggest candidate cognitive and neuroanatomical bases for these salient but under-appreciated phenotypic features of the dementias, with wider implications for the homeostatic pathophysiology and clinical management of neurodegenerative diseases.