Recent advances in the treatment of uremic pruritus.

PURPOSE OF REVIEW: This article provides a focused update on uremic pruritus, highlighting the latest evidence concerning the epidemiology, pathophysiology, and treatment options for this common and bothersome condition. RECENT FINDINGS: Half of dialysis patients and a quarter of those with nondialysis chronic kidney disease experience bothersome itch that reduces quality of life and is increasingly recognized to be associated with poor outcomes including mortality. The KALM-1 trial, which reported effective symptomatic relief with difelikefalin, has bolstered support for the role of an imbalance of µ and κ-opioid receptor activity in pruritogenesis. The role of a chronic inflammatory state, increased cytokine levels and altered immune signaling in pruritogenic nerve activation continues to be elucidated with basic science, which paves the wave for future novel therapeutics. In the meantime, gabapentin appears to be the most evidence-based widely available uremic pruritus treatment, as long as care is taken with dosing and monitoring of side-effects. SUMMARY: Uremic pruritus remains a top research priority. Patients with uremic pruritus may be able to look forward to a new decade of understanding, knowledge, and novel treatment options for this burdensome condition. As difelikefalin and other potential agents come to market, cost-effectiveness assessments of these interventions will help determine if the widespread use of them is feasible amongst renal programs.

Impact of payment model on the behaviour of specialist physicians: A systematic review.

Physician payment models are perceived to be an important strategy for improving health, access, quality, and the value of health care. Evidence is predominantly from primary care, and little is known regarding whether specialists respond similarly. We conducted a systematic review to synthesize evidence on the impact of specialist physician payment models across the domains of health care quality; clinical outcomes; utilization, access, and costs; and patient and physician satisfaction. We searched Medline, Embase, and six other databases from their inception through October 2018. Eligible articles addressed specialist physicians, payment models, outcomes of interest, and used an experimental or quasi-experimental design. Of 11,648 studies reviewed for eligibility, 11 articles reporting on seven payment reforms were included. Fee-for-service (FFS) was associated with increased desired utilization and fewer adverse outcomes (in the case of hemodialysis patients) and better access to care (in the case of emergency department services). Replacing FFS with capitation and salary models led to fewer elective surgical procedures (cataracts and tubal ligations) and, with an episode-based model, appeared to increase the use of less costly resources. Four of the seven reforms met their goals but many had unintended consequences. Payment model appears to affect utilization of specialty care, although the association with other outcomes is unclear due to mixed results or lack of evidence. Studies of salary and salary-based reforms point to specialists responding to some incentives differently than theory would predict. Additional research is warranted to improve the evidence driving specialist payment policy.

Association between change in physician remuneration and use of peritoneal dialysis: a population-based cohort analysis.

BACKGROUND: Health care payers are interested in policy-level interventions to increase peritoneal dialysis use in end-stage renal disease. We examined whether increases in physician remuneration for peritoneal dialysis were associated with greater peritoneal dialysis use. METHODS: We studied a cohort of patients in Alberta who started long-term dialysis with at least 90 days of preceding nephrologist care between Jan. 1, 2001, and Dec. 31, 2014. We compared peritoneal dialysis use 90 days after dialysis initiation in patients cared for by fee-for-service nephrologists and those cared for by salaried nephrologists before and after weekly peritoneal dialysis remuneration increased from $0 to $32 (fee change 1, Apr. 1, 2002), $49 to $71 (fee change 2, Apr. 1, 2007), and $71 to $135 (fee change 3, Apr. 1, 2009). Remuneration for peritoneal dialysis remained less than hemodialysis until fee change 3. We performed a patient-level differences-in-differences logistic regression, adjusted for demographic characteristics and comorbidities, as well as an unadjusted interrupted time-series analysis of monthly outcome data. RESULTS: Our cohort included 4262 patients. There was no statistical evidence of a difference in the adjusted differences-indifferences estimator following fee change 1 (0.89, 95% confidence interval [CI] 0.44-1.81), 2 (1.15, 95% CI 0.73-1.83), or 3 (1.52, 95% CI 0.96-2.40). There was no significant difference in the immediate change or the trend over time in peritoneal dialysis use between fee-for-service and salaried groups following any of the fee changes in the interrupted time-series analysis. INTERPRETATION: We identified no statistical evidence of an increase in peritoneal dialysis use following increased fee-for-service remuneration for peritoneal dialysis. It remains unclear what role, if any, physician payment plays in selection of dialysis modality.

Multimodal MRI of grey matter, white matter, and functional connectivity in cognitively healthy mutation carriers at risk for frontotemporal dementia and Alzheimer's disease.

BACKGROUND: Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are associated with divergent differences in grey matter volume, white matter diffusion, and functional connectivity. However, it is unknown at what disease stage these differences emerge. Here, we investigate whether divergent differences in grey matter volume, white matter diffusion, and functional connectivity are already apparent between cognitively healthy carriers of pathogenic FTD mutations, and cognitively healthy carriers at increased AD risk. METHODS: We acquired multimodal magnetic resonance imaging (MRI) brain scans in cognitively healthy subjects with (n=39) and without (n=36) microtubule-associated protein Tau (MAPT) or progranulin (GRN) mutations, and with (n=37) and without (n=38) apolipoprotein E ε4 (APOE4) allele. We evaluated grey matter volume using voxel-based morphometry, white matter diffusion using tract-based spatial statistics (TBSS), and region-to-network functional connectivity using dual regression in the default mode network and salience network. We tested for differences between the respective carriers and controls, as well as for divergence of those differences. For the divergence contrast, we additionally performed region-of-interest TBSS analyses in known areas of white matter diffusion differences between FTD and AD (i.e., uncinate fasciculus, forceps minor, and anterior thalamic radiation). RESULTS: MAPT/GRN carriers did not differ from controls in any modality. APOE4 carriers had lower fractional anisotropy than controls in the callosal splenium and right inferior fronto-occipital fasciculus, but did not show grey matter volume or functional connectivity differences. We found no divergent differences between both carrier-control contrasts in any modality, even in region-of-interest analyses. CONCLUSIONS: Concluding, we could not find differences suggestive of divergent pathways of underlying FTD and AD pathology in asymptomatic risk mutation carriers. Future studies should focus on asymptomatic mutation carriers that are closer to symptom onset to capture the first specific signs that may differentiate between FTD and AD.

Cost analysis of medical assistance in dying in Canada.

BACKGROUND: The legalization of medical assistance in dying will affect health care spending in Canada. Our aim was to determine the potential costs and savings associated with the implementation of medical assistance in dying. METHODS: Using published data from the Netherlands and Belgium, where medically assisted death is legal, we estimated that medical assistance in dying will account for 1%-4% of all deaths; 80% of patients will have cancer; 50% of patients will be aged 60-80 years; 55% will be men; 60% of patients will have their lives shortened by 1 month; and 40% of patients will have their lives shortened by 1 week. We combined current mortality data for the Canadian population with recent end-of-life cost data to calculate a predicted range of savings associated with the implementation of medical assistance in dying. We also estimated the direct costs associated with offering medically assisted death, including physician consultations and drug costs. RESULTS: Medical assistance in dying could reduce annual health care spending across Canada by between $34.7 million and $138.8 million, exceeding the $1.5-$14.8 million in direct costs associated with its implementation. In sensitivity analyses, we noted that even if the potential savings are overestimated and costs underestimated, the implementation of mdedical assistance in dying will likely remain at least cost neutral. INTERPRETATION: Providing medical assistance in dying in Canada should not result in any excess financial burden to the health care system, and could result in substantial savings. Additional data on patients who choose medical assistance in dying in Canada should be collected to enable more precise estimates of the impact of medically assisted death on health care spending and to enable further economic evaluation.

ICA-based artifact removal diminishes scan site differences in multi-center resting-state fMRI.

Resting-state fMRI (R-fMRI) has shown considerable promise in providing potential biomarkers for diagnosis, prognosis and drug response across a range of diseases. Incorporating R-fMRI into multi-center studies is becoming increasingly popular, imposing technical challenges on data acquisition and analysis, as fMRI data is particularly sensitive to structured noise resulting from hardware, software, and environmental differences. Here, we investigated whether a novel clean up tool for structured noise was capable of reducing center-related R-fMRI differences between healthy subjects. We analyzed three Tesla R-fMRI data from 72 subjects, half of whom were scanned with eyes closed in a Philips Achieva system in The Netherlands, and half of whom were scanned with eyes open in a Siemens Trio system in the UK. After pre-statistical processing and individual Independent Component Analysis (ICA), FMRIB's ICA-based X-noiseifier (FIX) was used to remove noise components from the data. GICA and dual regression were run and non-parametric statistics were used to compare spatial maps between groups before and after applying FIX. Large significant differences were found in all resting-state networks between study sites before using FIX, most of which were reduced to non-significant after applying FIX. The between-center difference in the medial/primary visual network, presumably reflecting a between-center difference in protocol, remained statistically significant. FIX helps facilitate multi-center R-fMRI research by diminishing structured noise from R-fMRI data. In doing so, it improves combination of existing data from different centers in new settings and comparison of rare diseases and risk genes for which adequate sample size remains a challenge.

Inequities in ambulatory care and the relationship between socioeconomic status and respiratory hospitalizations: a population-based study of a canadian city.

PURPOSE: Individuals of lower socioeconomic status have higher rates of hospitalization due to ambulatory care-sensitive conditions, particularly chronic obstructive pulmonary disease and asthma. We examined whether differences in patient demographics, ambulatory care use, or physician characteristics could explain this disparity in avoidable hospitalizations. METHODS: Using administrative data from the city of Winnipeg, Manitoba, Canada, we identified all adults aged 18 to 70 years with chronic obstructive pulmonary disease or asthma, grouped together as obstructive airway disease. We divided patients into census-derived income quintiles using average household income. We performed a series of multivariate logistic regression analyses to determine how the association of socioeconomic status with the risk of obstructive airway disease-related hospitalizations changed after controlling for blocks of covariates related to patient demographics (socioeconomic status, age, sex, and comorbidity), ambulatory care use (continuity influenza vaccination and specialist referral), and characteristics of the patient's usual physician (eg, payment mechanism, sex, years in practice). RESULTS: We included 34,741 patients with obstructive airway disease, 729 (2.1%) of whom were hospitalized with a related diagnosis during a 2-year period. Patients having a lower income were more likely to be hospitalized than peers having the highest income, and this effect of socioeconomic status remained virtually unchanged after controlling for every other variable studied. In a fully adjusted model, patients in the lowest income quintile had approximately 3 times the odds of hospitalization relative to counterparts in the highest income quintile (odds ratio = 2.93; 95% confidence limits: 2.19, 3.93). CONCLUSIONS: In the setting of universal health care, the income-based disparity in hospitalizations for respiratory ambulatory care-sensitive conditions cannot be explained by factors directly related to the use of ambulatory services that can be measured using administrative data. Our findings suggest that we look beyond the health care system at the broader social determinants of health to reduce the number of avoidable hospitalizations among the poor.

Apolipoprotein E genotype, gender and age modulate connectivity of the hippocampus in healthy adults.

Important risk factors for Alzheimer's disease (AD) are ageing and the Apolipoprotein E (APOE) ε4 allele, with female APOE ε4 carriers having the greatest risk. In this study we investigated effects of AD risk factors on connectivity of the hippocampus, a structure that shows early AD related pathology. Resting-state functional magnetic resonance imaging and diffusion tensor imaging data from 86 cognitively healthy subjects aged 30 to 78years were analysed. Female APOE ε4 carriers showed overall significantly reduced functional connectivity between the hippocampus and precuneus/posterior cingulate cortex (PCC) and a significant age-related decrease in connectivity of these regions. In females and APOE ε4 carriers we found significantly reduced white matter integrity of the tract connecting the hippocampus and PCC with a significant positive correlation of white matter integrity and resting-state connectivity. Increased vulnerability of the connection between the hippocampus and PCC might be one reason for increased AD risk in female APOE ε4 carriers. Interventions targeting hippocampal connectivity might be especially effective in this at risk population.

The forgotten APOE allele: a review of the evidence and suggested mechanisms for the protective effect of APOE ɛ2.

Ongoing efforts to improve survival, and enhance quality of life have led biomedical research to focus on disease and the mechanisms that increase risk for disease. The other side of that coin may be as important, i.e. examining the protective factors that allow some individuals to enjoy long, healthy lives. One of the best examples of a gene that positively influences cognitive health is the apolipoprotein (APOE) ɛ2 allele. The APOE ɛ4 allele is a well-established risk factor for Alzheimer's disease (AD) and has thus dominated the APOE literature, with the putative protective role of ɛ2 receiving little attention. This review describes the effects of APOE ɛ2 on the structure and function of the brain. With a focus on neurodegeneration, we discuss evidence for APOE ɛ2's protective effects, explore some key mechanisms through which this protection may be conferred, and address a few inconsistencies in the literature. Understanding the mechanisms that underlie the association between APOE ɛ2, cognition and longevity may provide new targets for research on promoting life-long health.

Task-driven ICA feature generation for accurate and interpretable prediction using fMRI.

Functional Magnetic Resonance Imaging (fMRI) shows significant potential as a tool for predicting clinically important information such as future disease progression or drug effect from brain activity. Multivariate techniques have been developed that combine fMRI signals from across the brain to produce more robust predictive capabilities than can be obtained from single regions. However, the high dimensionality of fMRI data makes overfitting a significant problem. Reliable methods are needed for transforming fMRI data to a set of signals reflecting the underlying spatially extended patterns of neural dynamics. This paper demonstrates a task-specific Independent Component Analysis (ICA) procedure which identifies signals associated with coherent functional brain networks, and shows that these signals can be used for accurate and interpretable prediction. The task-specific ICA parcellations outperformed other feature generation methods in two separate datasets including parcellations based on resting-state data and anatomy. The pattern of response of the task-specific ICA parcellations to particular feature selection strategies indicates that they identify important functional networks associated with the discriminative task. We show ICA parcellations to be robust and informative with respect to non-neural artefacts affecting the fMRI series. Together, these results suggest that task-specific ICA parcellation is a powerful technique for producing predictive and informative signals from fMRI time series. The results presented in this paper also contribute evidence for the general functional validity of the parcellations produced by ICA approaches.

The effects of APOE-ε4 on the BOLD response.

In the last decade, functional magnetic resonance imaging (fMRI) has emerged as a tool to study changes in brain function associated with a genetic risk for Alzheimer's disease (AD), with a particular focus on the effects of the APOE-ε4 allele. This review compiles the existing literature concerning the effects of APOE genotype on the blood oxygen level dependent (BOLD) response, measured during task-based functional magnetic resonance imaging. While most studies report a significant difference in brain activity between carriers and noncarriers of the ε4 allele, there are inconsistencies in the direction and location of change. These inconsistencies were addressed by examining the effect of task, family history of Alzheimer's disease, and age on the relationship between APOE genotype and the BOLD response, but no clear pattern emerged. The review discusses the interpretation of BOLD differences between ε4 carriers and noncarriers, provides suggestions for future studies, and highlights important limitations of this type of research.

The effects of APOE on brain activity do not simply reflect the risk of Alzheimer's disease.

Possession of the APOE-ε4 allele is the best established genetic risk factor for sporadic Alzheimer's disease (AD), while the ε2 allele may confer protection against the disease. Previous functional magnetic resonance imaging (fMRI) studies have shown an effect of APOE genotype on brain function, typically by comparing only ε4 carriers with noncarriers. Here we included a wide range of genotype groups to determine how closely the effects of APOE on brain function are related to differences in relative risk for AD. We used functional magnetic resonance imaging (fMRI) to compare the pattern of activation during an episodic encoding task and during a counting Stroop task in 76 adults, aged 32 to 55, with different APOE genotypes (23 ε2/ε3, 20 ε3/ε3, 26 ε3/ε4, and 7 ε4/ε4). Strikingly, participants with an increased risk (ε4 carriers) and with a decreased risk (ε2 carriers) for AD both showed increased activation, relative to ε3 homozygotes, during both tasks. The increased activation was due to decreased deactivation or paradoxical activation of nontask-related regions of the brain, which suggests an intrinsic effect of APOE on the differentiation of functional cortical networks. These results question the often assumed link between APOE, the blood oxygenation level dependent (BOLD) response, and AD risk.

The effects of APOE on the functional architecture of the resting brain.

There is a well-established association between APOE genotype and the risk of developing Alzheimer's disease (AD). Relative to individuals with the common ε3/ε3 genotype, carriers of the ε4 allele are at increased risk of developing AD, while carriers of the ε2 allele appear to be protected against the disease. However, we recently reported that in a sample of cognitively healthy adults, both ε4 and ε2 carriers showed nearly identical changes in the pattern of fMRI activity during memory and non-memory tasks, relative to ε3 homozygotes. These findings suggest that the effects of APOE on brain function are not tightly linked to the effects of this gene on AD risk. Here we test the hypothesis that APOE has an intrinsic effect on the brain's functional networks. Resting-state fMRI was used to compare the pattern of functional connectivity of a variety of resting-state networks between 77 cognitively healthy participants aged 32 to 55 with different APOE genotypes (23 ε2/ε3, 20 ε3/ε3, 26 ε3/ε4, and 8 ε4/ε4). Differences between genotype groups were found in two hippocampal networks, the auditory network, the left frontal-parietal network, and the lateral visual network. While there was considerable variety in the brain regions affected and the direction of change across networks, the main finding was that changes in functional connectivity were similar in ε4 and ε2 carriers, relative to ε3 homozygotes. APOE appears to have an intrinsic effect on the differentiation of functional networks in the brain. This effect is apparent in cognitively healthy adults and does not manifest in a manner reflective of the link between APOE and AD risk. Rather, the effects of APOE on brain function may relate to the role of this gene in neurodevelopment.