Citations

Background Headache disorders comprise the three most prevalent medical disorders globally and contribute almost 20% to the total burden of neurologic illness. Although the experience of a recurrent headache disorder tends to be highly individualized, patient preferences tend to be a low priority in guidelines for the management of patients with headache. Methods In September 2017, the first Global Patient Advocacy Summit was convened, bringing together patients, patient advocates, patient advocacy organizations, healthcare professionals, pharmaceutical manufacturers, scientists, and regulatory agencies to advance issues of importance to patients affected by headache worldwide. Results Presentations and discussion covered multiple issues, such as improving access to appropriate medical care; incorporating the insights of independent patient advocates and advocacy organizations; leveraging the insights, experience and influence of leading health and neurological organizations; and raising awareness of the role of regulatory agencies in disease advocacy. Attendees agreed that it is important to understand and promote the global, regional, and local interests of people with headache disorders, as well as challenge the pervasive stigma associated with headache. They also agreed that those with severe, recurrent, or disabling headache disorders should have reliable access to competent medical care; healthcare professionals should have access to adequate training in Headache Medicine; global benchmarks should be established for accurate diagnosis and the use of evidence-based treatments in patients with headache; and that information is needed about consultation, diagnosis, and treatment of headache, particularly in regard to patient preferences. Conclusion Based on the group’s consensus around these issues, a series of statements was developed, and they are collectively presented herein as the Vancouver Declaration on Global Headache Patient Advocacy 2018.

ABSTRACT Background: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. Objective: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. Methods: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT ‐associated variants and the entire coding sequence of MAPT were analyzed. Age‐, sex‐, and ethnicity‐adjusted analyses were performed to examine the association between MAPT , PD, and rapid eye movement sleep behavior disorder. Results: MAPT‐ H2 variants were associated with PD (odds ratios: 0.62‐0.65; P = 0.010‐0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12‐2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48‐0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. Conclusions: Our results confirm the protective effect of the MAPT ‐H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society

Objective Synovitis is a prevalent feature in patients with knee osteoarthritis ( OA ) and meniscal tear and is associated with pain and cartilage damage. Patient‐reported swelling is also prevalent in this population. The aim of this study was to investigate the cross‐sectional association between patient‐reported swelling and effusion‐synovitis detected by magnetic resonance imaging ( MRI ) in patients with OA and meniscal tear. Methods We used baseline data from a multicenter, randomized controlled trial, Meniscal Tear in Osteoarthritis Research ( METEOR ). MRI ‐identified effusion‐synovitis, a proxy for effusion and synovitis on noncontrast MRI s, was graded as none/small versus medium/large. Using MRI ‐identified effusion‐synovitis as the gold standard, we assessed the sensitivity, specificity, and positive predictive value of patient self‐reported swelling in the previous week (none, intermittent, constant) to detect effusion and synovitis. Results We analyzed data from 276 patients. Twenty‐five percent of patients reported no swelling, 40% had intermittent swelling, and 36% had constant swelling. Fifty‐two percent had MRI ‐identified medium/large–grade effusion‐synovitis. As compared with MRI ‐identified effusion‐synovitis, any patient‐reported swelling (versus none) had a sensitivity of 84% (95% confidence interval [95% CI ] 77–89), a specificity of 34% (95% CI 26–43), and a positive predictive value of 57% (95% CI 54–61). A history of constant swelling (versus none or intermittent) showed a sensitivity of 46% (95% CI 37–54), a specificity of 75% (95% CI 67–82), and a positive predictive value of 66% (95% CI 58–74). Conclusion We found that the sensitivity and specificity of patient‐reported swelling were modest when compared with effusion‐synovitis detected by MRI . These data urge caution against using patient‐reported swelling as a proxy of inflammation manifesting as effusion‐synovitis.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

Abstract Background Bacteremia caused by extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-E) is associated with inadequate empirical therapy and substantial mortality in neutropenic patients. Strategies are needed to identify neutropenic patients at high risk of these infections. Methods From April 2014 to September 2016, we collected perianal swabs, both at admission and weekly thereafter, from patients undergoing hematopoietic stem cell transplantation (HSCT). Patients received prophylactic levofloxacin while neutropenic. Swabs were plated onto selective agar, colonies were identified and underwent antimicrobial susceptibility testing, and phenotypic ESBL testing and polymerase chain reaction for β-lactamase genes were performed on ceftriaxone-resistant Enterobacteriaceae. We then determined the prevalence of pre-transplant ESBL-E colonization and risk of ESBL-E bacteremia. Colonizing and bloodstream isolates from patients with ESBL-E bacteremia underwent multilocus sequence typing and pulsed-field gel electrophoresis. Results We analyzed 312 patients, including 212 allogeneic and 100 autologous HSCT recipients. Ten percent (31/312) of patients had pre-transplant ESBL-E colonization. Susceptibility rates of colonizing ESBL-E were: levofloxacin, 25%; cefepime, 9%; piperacillin-tazobactam, 84%; and meropenem, 97%. Of 31 patients colonized with ESBL-E pre-transplant, 10 (32%) developed ESBL-E bacteremia during their transplant admission, compared to 1 (0.4%) of 281 patients not colonized with ESBL-E (P &lt; .001). All bloodstream ESBL-E were levofloxacin-resistant and colonizing and bloodstream isolates from individual patients had identical genotypic profiles. Conclusions HSCT recipients who are colonized with levofloxacin-resistant ESBL-E pre-transplant and receive levofloxacin prophylaxis have high rates of bacteremia from their colonizing strain during neutropenia. Assessing for ESBL-E colonization in neutropenic patients could lead to optimization of empirical antibacterial therapy.

Significance Much of the inherited susceptibility to pancreatic cancer remains unexplained. Germline variants that cause protein misfolding and impaired secretion of pancreatic enzymes such as CPA1 (encoding carboxypeptidase A1) can cause pancreatic acinar cell endoplasmic reticulum (ER) stress. We investigated the hypothesis that pancreatic cancer could arise from germline variants in genes encoding pancreatic secretory enzymes that induce pancreatic acinar cell stress. We find ∼1% of 1,579 patients with pancreatic cancer vs. 1 of 2,012 controls have germline variants in the genes encoding CPA1 and CPB1 (carboxypeptidase B1) that impair secretion of its protein product and induce ER stress. These findings implicate pancreatic acinar cell stress as a mechanism of pancreatic cancer susceptibility.

Analysis of biomedical signals can yield invaluable information for prognosis, diagnosis, therapy evaluation, risk assessment, and disease prevention which is often recorded as short time series data that challenges existing complexity classification algorithms such as Shannon entropy (SE) and other techniques. The purpose of this study was to improve previously developed multiscale entropy (MSE) technique by incorporating nearest-neighbor moving-average kernel, which can be used for analysis of nonlinear and non-stationary short time series physiological data. The approach was tested for robustness with respect to noise analysis using simulated sinusoidal and ECG waveforms. Feasibility of MSE to discriminate between normal sinus rhythm (NSR) and atrial fibrillation (AF) was tested on a single-lead ECG. In addition, the MSE algorithm was applied to identify pivot points of rotors that were induced in ex vivo isolated rabbit hearts. The improved MSE technique robustly estimated the complexity of the signal compared to that of SE with various noises, discriminated NSR and AF on single-lead ECG, and precisely identified the pivot points of ex vivo rotors by providing better contrast between the rotor core and the peripheral region. The improved MSE technique can provide efficient complexity analysis of variety of nonlinear and nonstationary short-time biomedical signals.