Association of BKV viremia and nephropathy with adverse alloimmune outcomes in kidney transplant recipients.

BACKGROUND: Immunosuppression reduction for BK polyoma virus (BKV) must be balanced against risk of adverse alloimmune outcomes. We sought to characterize risk of alloimmune events after BKV within context of HLA-DR/DQ molecular mismatch (mMM) risk score. METHODS: This single-center study evaluated 460 kidney transplant patients on tacrolimus-mycophenolate-prednisone from 2010-2021. BKV status was classified at 6-months post-transplant as "BKV" or "no BKV" in landmark analysis. Primary outcome was T-cell mediated rejection (TCMR). Secondary outcomes included all-cause graft failure (ACGF), death-censored graft failure (DCGF), de novo donor specific antibody (dnDSA), and antibody-mediated rejection (ABMR). Predictors of outcomes were assessed in Cox proportional hazards models including BKV status and alloimmune risk defined by recipient age and molecular mismatch (RAMM) groups. RESULTS: At 6-months post-transplant, 72 patients had BKV and 388 had no BKV. TCMR occurred in 86 recipients, including 27.8% with BKV and 17% with no BKV (p = .05). TCMR risk was increased in recipients with BKV (HR 1.90, (95% CI 1.14, 3.17); p = .01) and high vs. low-risk RAMM group risk (HR 2.26 (95% CI 1.02, 4.98); p = .02) in multivariable analyses; but not HLA serological MM in sensitivity analysis. Recipients with BKV experienced increased dnDSA in univariable analysis, and there was no association with ABMR, DCGF, or ACGF. CONCLUSIONS: Recipients with BKV had increased risk of TCMR independent of induction immunosuppression and conventional alloimmune risk measures. Recipients with high-risk RAMM experienced increased TCMR risk. Future studies on optimizing immunosuppression for BKV should explore nuanced risk stratification and may consider novel measures of alloimmune risk.

Expanding Access to High KDPI Kidney Transplant for Recipients Aged 60 y and Older: Cost Utility and Survival.

Background: Modern organ allocation systems are tasked with equitably maximizing the utility of transplanted organs. Increasing the use of deceased donor organs at risk of discard may be a cost-effective strategy to improve overall transplant benefit. We determined the survival implications and cost utility of increasing the use of marginal kidneys in an older adult Canadian population of patients with end-stage kidney disease. Methods: We constructed a cost-utility model with microsimulation from the perspective of the Canadian single-payer health system for incident transplant waitlisted patients aged 60 y and older. A kidney donor profile index score of ≥86 was considered a marginal kidney. Donor- and recipient-level characteristics encompassed in the kidney donor profile index and estimated posttransplant survival scores were used to derive survival posttransplant. Patients were followed up for 10 y from the date of waitlist initiation. Our analysis compared the routine use of marginal kidneys (marginal kidney scenario) with the current practice of limited use (status quo scenario). Results: The 10-y mean cost and quality-adjusted life-years per patient in the marginal kidney scenario were estimated at $379 485.33 (SD: $156 872.49) and 4.77 (SD: 1.87). In the status quo scenario, the mean cost and quality-adjusted life-years per patient were $402 937.68 (SD: $168 508.85) and 4.37 (SD: 1.87); thus, the intervention was considered dominant. At 10 y, 62.8% and 57.0% of the respective cohorts in the marginal kidney and status quo scenarios remained alive. Conclusions: Increasing the use of marginal kidneys in patients with end-stage kidney disease aged 60 y and older may offer cost savings, improved quality of life, and greater patient survival in comparison with usual care.

Safety and efficacy of a reduced frequency viral monitoring strategy for Epstein-Barr virus, cytomegalovirus, and BK polyomavirus post-kidney transplant: A quality assurance initiative.

BACKGROUND: There is variability in recommended viral monitoring protocols after kidney transplant. In response to increased demand for laboratory testing during the COVID-19 pandemic, the Transplant Manitoba Adult Kidney Program updated its monitoring protocols for cytomegalovirus (CMV), Epstein-Barr virus (EBV), and BK polyomavirus (BKV) to a reduced frequency. METHODS: This single-center nested case-control study evaluated 252 adult kidney transplant recipients transplanted from 2015 to 2021, with the updated protocols effective on March 19th 2020. Cases included recipients transplanted after the protocol update who developed CMV, EBV, and BKV DNAemia and were matched to controls with DNAemia transplanted prior to the protocol update. The primary outcome was the difference in maximum DNA load titers between cases and matched controls. Secondary outcomes included time to initial DNAemia detection and DNAemia clearance. Safety outcomes of tissue-invasive viral disease were described. RESULTS: There were 216 recipients transplanted preupdate and 36 recipients postupdate. There was no difference between cases and controls in maximum or first DNA load titers for EBV, CMV, or BKV. Cases experienced earlier EBV DNAemia detection (26 (IQR 8, 32) vs. 434 (IQR 96, 1184) days, p = .005). Median follow-up was significantly longer for recipients transplanted preupdate (4.3 vs. 1.3 years, p < .0001). After adjusting for follow-up time, there was no difference in DNAemia clearance or tissue-invasive viral disease. CONCLUSION: Our findings suggest that reduced frequency viral monitoring protocols may be safe and cost-effective. This quality assurance initiative should be extended to detect longer-term and tissue-invasive disease outcomes.

A rational approach to guide cost-effective de novo donor-specific antibody surveillance with tacrolimus immunosuppression.

De novo donor-specific antibody (dnDSA) after renal transplantation has been shown to correlate with antibody-mediated rejection and allograft loss. However, the lack of proven interventions and the time and cost associated with annual screening for dnDSA are difficult to justify for all recipients. We studied a well-characterized consecutive cohort (n = 949) with over 15 years of prospective dnDSA surveillance to identify risk factors that would help institute a resource-responsible surveillance strategy. Younger recipient age and HLA-DR/DQ molecular mismatch were independent predictors of dnDSA development. Combining both risk factors into recipient age molecular mismatch categories, we found that 52% of recipients could be categorized as low-risk for dnDSA development (median subclinical dnDSA-free survival at 5 and 10 years, 98% and 97%, respectively). After adjustment, multivariate correlates of dnDSA development included tacrolimus versus cyclosporin maintenance immunosuppression (hazard ratio [HR], 0.37; 95% CI, 0.2-0.6; P < .0001) and recipient age molecular mismatch category: intermediate versus low (HR, 2.48; 95% CI, 1.5-4.2; P = .0007), high versus intermediate (HR, 2.56; 95% CI, 1.6-4.2; P = .0002), and high versus low (HR, 6.36; 95% CI, 3.7-10.8; P < .00001). When combined, recipient age and HLA-DR/DQ molecular mismatch provide a novel data-driven approach to reduce testing by >50% while selecting those most likely to benefit from dnDSA surveillance.

Inequities in organ and tissue donation and transplantation for sexual orientation and gender identity diverse people: A scoping review.

Sexual orientation and gender identity (SOGI)-diverse populations experience discrimination in organ and tissue donation and transplantation (OTDT) systems globally. We assembled a multidisciplinary group of clinical experts as well as SOGI-diverse patient and public partners and conducted a scoping review including citations on the experiences of SOGI-diverse persons in OTDT systems globally to identify and explore the inequities that exist with regards to living and deceased OTDT. Using scoping review methods, we conducted a systematic literature search of relevant electronic databases from 1970 to 2021 including a grey literature search. We identified and screened 2402 references and included 87 unique publications. Two researchers independently coded data in included publications in duplicate. We conducted a best-fit framework synthesis paired with an inductive thematic analysis to identify synthesized benefits, harms, inequities, justification of inequities, recommendations to mitigate inequities, laws and regulations, as well as knowledge and implementation gaps regarding SOGI-diverse identities in OTDT systems. We identified numerous harms and inequities for SOGI-diverse populations in OTDT systems. There were no published benefits of SOGI-diverse identities in OTDT systems. We summarized recommendations for the promotion of equity for SOGI-diverse populations and identified gaps that can serve as targets for action moving forward.

Waitlisted and Transplant Patient Perspectives on Expanding Access to Deceased-Donor Kidney Transplant: A Qualitative Study.

Background: A concerning number of kidneys (eg, expanded donor criteria, extended criteria, or marginal kidneys) are discarded yearly while patients experience significant morbidity and mortality on the transplant waitlist. Novel solutions are needed to solve the shortage of kidneys available for transplant. Patient perceptions regarding the use of these less than ideal kidneys remain unexplored. Objective: To explore the perspectives of patients who have previously received a less than ideal kidney in the past and patients awaiting transplant who could potentially benefit from one. Design: Qualitative description study. Setting: 2 provinces in Canada participated (Saskatchewan and Manitoba). Patients: Patients with end-stage kidney disease who were awaiting kidney transplant and were either (a) aged 65 years and older, or (b) 55 years and older with other medical conditions (eg, diabetes). Methods: Criterion sampling was used to identify participants. Semi-structured, one-on-one interviews were conducted virtually, which explored perceived quality of life, perceptions of less than ideal kidneys, risk tolerance for accepting one, and educational needs to make such a choice. The interviews were transcribed verbatim and thematic analysis was used to analyze the data. Results: 15 interviews were conducted with usable data (n = 10 pretransplant; n = 5 posttransplant). Participants were a mean of 65.5 ± 8.8 years old. Four interrelated themes became prominent including (1) patient awareness and understanding of their situation or context, (2) a desire for information, (3) a desire for freedom from dialysis, and (4) trust. Subthemes of transparency, clarity, standardization, and autonomy were deemed important for participant education. The majority of pretransplant participants (n = 8/10) indicated that between 3 and 5 years off of dialysis would make the risk of accepting a less than ideal kidney feel worthwhile. Limitation: The study setting was limited to 2 Canadian provinces, which limits the generalizability. Furthermore, the participants were homogenous in demographics such as ethnicity. Conclusion: These findings indicate that patients are comfortable to accept a less than ideal kidney for transplant in situations where their autonomy is respected, they are provided clear, standardized, and transparent information, and when they trust their physician. These results will be used to inform the development of a new national registry for expanding access to deceased-donor kidney transplant. Trial Registration: Not registered.

Contexte: De nombreux reins sont rejetés chaque année (donneurs à critères élargis, critères étendus ou reins marginaux), alors que les patients qui attendent une greffe présentent une morbidité importante et un taux de mortalité élevé. De nouvelles solutions sont nécessaires pour contrer la pénurie de reins disponibles pour une transplantation. Les perceptions des patients quant à l'utilization de ces reins moins idéaux restent inexplorées. Objectif: Explorer les perceptions des patients ayant reçu un rein moins idéal dans le passé et des patients en attente d'une greffe qui pourraient potentiellement bénéficier d'un tel don. Conception: Étude qualitative et descriptive. Cadre: Deux provinces canadiennes (Saskatchewan et Manitoba). Participants: Des patients atteints d'insuffisance rénale terminale en attente d'une transplantation (a) âgés de 65 ans et plus ou (b) âgés de 55 ans et plus et présentant d'autres problèmes de santé (ex. diabète). Méthodologie: L'échantillonnage avec critères a été utilisé pour identifier les participants. Des entretiens individuels semi-structurés menés virtuellement ont exploré la qualité de vie perçue, la perception quant aux reins moins idéaux, la tolérance à l'égard des risques inhérents à l'acceptation d'un tel rein, et les besoins d'information pour faire ce choix. Les entrevues ont été transcrites intégralement et l'analyze des données a été réalisée par analyze thématique. Résultats: Quinze entrevues avec données utilisables ont été menées (n = 10 avant la greffe; n = 5 après la greffe). Les participants avaient en moyenne 65.5 ± 8.8 ans. Quatre thèmes interreliés ont été dégagés : (1) la sensibilisation et la compréhension des patients quant à leur situation ou au contexte; (2) le besoin d'information; (3) le besoin d'un congé de dialyze; et (4) la confiance envers le médecin. La transparence, la clarté, la normalization et l'autonomie ont été jugées comme des sous-thèmes importants de l'éducation des participants. Pour la majorité des participants en attente d'une greffe (n = 8/10), l'idée d'un congé de 3 à 5 ans de dialyze rendrait acceptables les risques associés à l'acceptation d'un rein moins idéal. Limites: Étude tenue dans deux provinces canadiennes, ce qui limite la généralisabilité des résultats. Homogénéité des participants sur le plan démographique, notamment en ce qui concerne l'origine ethnique. Conclusion: Les résultats indiquent que les patients seraient à l'aise d'accepter un rein moins idéal pour une greffe, pourvu que leur autonomie soit respectée, qu'ils reçoivent des informations claires, standardisées et transparentes, et qu'ils aient confiance en leur médecin. Ces résultats serviront à éclairer l'élaboration d'un nouveau registre national afin d'élargir l'accès à la transplantation de rein provenant de donneurs décédés. Enregistrement de l'essai: Non enregistré.

Opioids and the Risk of Motor Vehicle Collision: A Systematic Review.

Background: Opioid analgesics are among the most commonly prescribed medications, but questions remain regarding their impact on the day-to-day functioning of patients including driving. We set out to perform a systematic review on the risk of motor vehicle collision (MVC) associated with prescription opioid exposure. Method: We searched Medline, PubMed, EMBASE, Scopus, and TRID from January 1990 to August 31, 2021 for primary studies assessing prescribed opioid use and MVCs. Results: We identified 14 observational studies that met inclusion criteria. Among those, 8 studies found an increased risk of MVC among those participants who had a concomitant opioid prescription at the time of the MVC and 3 found no significant increase of culpability of fatal MVC. The 3 studies that evaluated the presence of a dose-response relationship between the dose of opioids taken and the effects on MVC risk reported the existence of a dose-response relationship. Due to the heterogeneity of the different studies, a quantitative meta-analysis to sum evidence was deemed unfeasible. Our review supports increasing evidence on the association between motor vehicle collisions and prescribed opioids. This research would guide policies regarding driving legislation worldwide. Conclusion: Our review indicates that opioid prescriptions are likely associated with an increased risk of MVCs. Further studies are warranted to strengthen this finding, and investigate additional factors such as individual opioid medications, opioid doses and dose adjustments, and opioid tolerance for their effect on MVC risk.

Effectiveness of T cell-mediated rejection therapy: A systematic review and meta-analysis.

The effectiveness of T cell-mediated rejection (TCMR) therapy for achieving histological remission remains undefined in patients on modern immunosuppression. We systematically identified, critically appraised, and summarized the incidence and histological outcomes after TCMR treatment in patients on tacrolimus (Tac) and mycophenolic acid (MPA). English-language publications were searched in MEDLINE (Ovid), Embase (Ovid), Cochrane Central (Ovid), CINAHL (EBSCO), and Clinicaltrials.gov (NLM) up to January 2021. Study quality was assessed with the National Institutes of Health Study Quality Tool. We pooled results using an inverse variance, random-effects model and report the binomial proportions with associated 95% confidence intervals (95% CI). Statistical heterogeneity was explored using the I2  statistic. From 2875 screened citations, we included 12 studies (1255 participants). Fifty-eight percent were good/high quality while the rest were moderate quality. Thirty-nine percent of patients (95% CI 0.26-0.53, I2 77%) had persistent ≥Banff Borderline TCMR 2-9 months after anti-rejection therapy. Pulse steroids and augmented maintenance immunosuppression were mainstays of therapy, but considerable practice heterogeneity was present. A high proportion of biopsy-proven rejection exists after treatment emphasizing the importance of histology to characterize remission. Anti-rejection therapy is foundational to transplant management but well-designed clinical trials in patients on Tac/MPA immunosuppression are lacking to define the optimal therapeutic approach.

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.

Does aridity affect spatial ecology? Scaling of home range size in small carnivorous marsupials.

The aim of our study was to determine how body mass affects home range size in carnivorous marsupials (dasyurids) and whether those species living in desert environments require relatively larger areas than their mesic counterparts. The movement patterns of two sympatric species of desert dasyurids (body mass 16 and 105 g) were investigated via radio-telemetry in southwestern Queensland and compared with published records for other Australian dasyurids. Both species monitored occupied stable home ranges. For all dasyurids, home range size scaled with body mass with a coefficient of > 1.2, almost twice that for metabolic rate. Generally, males occupied larger home ranges than females, even after accounting for the size dimorphism common in dasyurids. Of the three environmental variables tested, primary productivity and habitat, a categorical variable based on the 500 mm rainfall isopleth, further improved model performance demonstrating that arid species generally occupy larger home ranges. Similar patterns were still present in the dataset after correcting for phylogeny. Consequently, the trend towards relatively larger home ranges with decreasing habitat productivity can be attributed to environmental factors and was not a result of taxonomic affiliation. We therefore conclude that alternative avenues to reduce energy requirements on an individual and population level (i.e. torpor, basking and population density) do not fully compensate for the low resource availability of deserts demanding an increase in home range size.

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.