Citations

Kinesin-5 motors organize mitotic spindles by sliding apart microtubules. They are homotetramers with dimeric motor and tail domains at both ends of a bipolar minifilament. Here, we describe a regulatory mechanism involving direct binding between tail and motor domains and its fundamental role in microtubule sliding. Kinesin-5 tails decrease microtubule-stimulated ATP-hydrolysis by specifically engaging motor domains in the nucleotide-free or ADP states. Cryo-EM reveals that tail binding stabilizes an open motor domain ATP-active site. Full-length motors undergo slow motility and cluster together along microtubules, while tail-deleted motors exhibit rapid motility without clustering. The tail is critical for motors to zipper together two microtubules by generating substantial sliding forces. The tail is essential for mitotic spindle localization, which becomes severely reduced in tail-deleted motors. Our studies suggest a revised microtubule-sliding model, in which kinesin-5 tails stabilize motor domains in the microtubule-bound state by slowing ATP-binding, resulting in high-force production at both homotetramer ends.

AbstractIntroductionAlthough some members of families with autosomal dominant Alzheimer's disease mutations learn their mutation status, most do not. How knowledge of mutation status affects clinical disease progression is unknown. This study quantifies the influence of mutation awareness on clinical symptoms, cognition, and biomarkers.MethodsMutation carriers and non‐carriers from the Dominantly Inherited Alzheimer Network (DIAN) were stratified based on knowledge of mutation status. Rates of change on standard clinical, cognitive, and neuroimaging outcomes were examined.ResultsMutation knowledge had no associations with cognitive decline, clinical progression, amyloid deposition, hippocampal volume, or depression in either carriers or non‐carriers. Carriers who learned their status mid‐study had slightly higher levels of depression and lower cognitive scores.DiscussionKnowledge of mutation status does not affect rates of change on any measured outcome. Learning of status mid‐study may confer short‐term changes in cognitive functioning, or changes in cognition may influence the determination of mutation status.

Background: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought through an international multicenter collaboration. Methods: Patients with either presumed autosomal dominant LQT5 (N = 229) or the recessive Type 2 Jervell and Lange-Nielsen syndrome (N = 19) were enrolled from 22 genetic arrhythmia clinics and 4 registries from 9 countries. KCNE1 variants were evaluated for ECG penetrance (defined as QTc >460 ms on presenting ECG) and genotype-phenotype segregation. Multivariable Cox regression was used to compare the associations between clinical and genetic variables with a composite primary outcome of definite arrhythmic events, including appropriate implantable cardioverter-defibrillator shocks, aborted cardiac arrest, and sudden cardiac death. Results: A total of 32 distinct KCNE1 rare variants were identified in 89 probands and 140 genotype positive family members with presumed LQT5 and an additional 19 Type 2 Jervell and Lange-Nielsen syndrome patients. Among presumed LQT5 patients, the mean QTc on presenting ECG was significantly longer in probands (476.9±38.6 ms) compared with genotype positive family members (441.8±30.9 ms, P <0.001). ECG penetrance for heterozygous genotype positive family members was 20.7% (29/140). A definite arrhythmic event was experienced in 16.9% (15/89) of heterozygous probands in comparison with 1.4% (2/140) of family members (adjusted hazard ratio [HR] 11.6 [95% CI, 2.6–52.2]; P =0.001). Event incidence did not differ significantly for Type 2 Jervell and Lange-Nielsen syndrome patients relative to the overall heterozygous cohort (10.5% [2/19]; HR 1.7 [95% CI, 0.3–10.8], P =0.590). The cumulative prevalence of the 32 KCNE1 variants in the Genome Aggregation Database, which is a human database of exome and genome sequencing data from now over 140 000 individuals, was 238-fold greater than the anticipated prevalence of all LQT5 combined (0.238% vs 0.001%). Conclusions: The present study suggests that putative/confirmed loss-of-function KCNE1 variants predispose to QT prolongation, however, the low ECG penetrance observed suggests they do not manifest clinically in the majority of individuals, aligning with the mild phenotype observed for Type 2 Jervell and Lange-Nielsen syndrome patients.

Abstract Background Breast cancer–related lymphedema (BCRL) is a well-known side effect of cancer and its treatment with wide-ranging prevalence estimates. Objective This study describes associations between breast cancer–related lymphedema (BCRL) signs, symptoms, and diagnosis for women who were African American, white, or had a low income and survived breast cancer. Design This is a cross-sectional, observational study that used a computer-assisted telephone interview. Methods Women who had survived breast cancer were queried on the presence of 5 lymphedema signs and symptoms (edema in the breast, axilla, arm, and/or hand; tissue fibrosis; pitting; hemosiderin staining; heaviness) and whether they had a diagnosis of BCRL. Relationships between signs/symptoms and diagnosis for each group were evaluated with kappa and chi-square statistics. Results The study sample included 528 women who had survived breast cancer (266 white and 262 African American), with 514 reporting complete data on household income; 45% of the latter reported an annual household income of ≤$20,000. Women who were African American or had a low income were nearly twice as likely as women who were white to have any of 8 signs/symptoms of BCRL. Regardless of race and income, &gt;50% of women with all BCRL signs and symptoms reported that they were not diagnosed with BCRL. Limitations The main limitations of our study are the lack of medical chart data and longitudinal design. Conclusions Women who were African American or had a low income and had survived breast cancer had a greater burden of BCRL signs and symptoms than women who were white. The lack of a strong association between BCRL signs, symptoms, and diagnosis suggests that BCRL may be underdiagnosed. These findings suggest that more rigorous screening and detection of BCRL—especially for women who are African American or have a low income—may be warranted. Cancer rehabilitation programs may be able to fill this gap.

Objectives This proposed systematic review will identify the existing evidence on medication‐overuse headache in children and adolescents. Background A number of medications have been shown to be effective for acute treatment of migraine in children and adolescents. However, patients may find they need to use their acute medications more frequently when migraine frequency is high. This has led to concern about their potential to develop medication‐overuse headache. Methods We will search PubMed, Embase, Web of Science, PsycINFO, and Cochrane databases from their inception to present time. We will also search conference proceedings of the last 4 scientific meetings of relevant societies and scan the reference lists of studies identified through the search. Study designs will include case series, cross‐sectional, cohort, case‐control, and interventional studies. Participants will include children and adolescents under 18 years of age with primary headache disorders. We aim to determine whether frequency of acute medication use is associated with headache frequency in children and adolescents. Outcomes of interest include: (1) headache frequency; (2) change in headache frequency, with time and in relationship to use of acute medications; and (3) headache‐related disability. We will also review data addressing treatment/management of medication overuse or medication‐overuse headache in children and adolescents. Relevant comparators will be withdrawal vs reduction of acute medication, initiation of preventive therapy vs no initiation with or without withdrawal of acute medication, and initiation of preventive therapy early vs late. Outcomes of interest include (1) days of acute medication use; (2) headache frequency; (3) change in headache frequency; and (4) headache‐related disability. After screening for inclusion, 2 team members will independently review and extract relevant data, and any discrepancies will be resolved through discussion and arbitration. We will assess risk of bias using appropriate tools (Cochrane Risk of Bias for randomized controlled trials (RCT) and Newcastle‐Ottawa Score for observational studies). Data will be summarized descriptively in text and tables. Results This systematic review will provide an overview of the available evidence on medication‐overuse headache in children and adolescents. Conclusions Findings from this review will aid clinicians by clarifying for them the current state of the evidence base, and will inform design of future research on this topic.

Abstract BACKGROUND No guidelines have been published regarding stereotactic radiosurgery (SRS) in the management of Spetzler-Martin grade I and II arteriovenous malformations (AVMs). OBJECTIVE To establish SRS practice guidelines for grade I-II AVMs on the basis of a systematic literature review. METHODS Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant search of Medline, Embase, and Scopus, 1986-2018, for publications reporting post-SRS outcomes in ≥10 grade I-II AVMs with a follow-up of ≥24 mo. Primary endpoints were obliteration and hemorrhage; secondary outcomes included Spetzler-Martin parameters, dosimetric variables, and “excellent” outcomes (defined as total obliteration without new post-SRS deficit). RESULTS Of 447 abstracts screened, 8 were included (n = 1, level 2 evidence; n = 7, level 4 evidence), representing 1102 AVMs, of which 836 (76%) were grade II. Obliteration was achieved in 884 (80%) at a median of 37 mo; 66 hemorrhages (6%) occurred during a median follow-up of 68 mo. Total obliteration without hemorrhage was achieved in 78%. Of 836 grade II AVMs, Spetzler-Martin parameters were reported in 680: 377 were eloquent brain and 178 had deep venous drainage, totaling 555/680 (82%) high-risk SRS-treated grade II AVMs. CONCLUSION The literature regarding SRS for grade I-II AVM is low quality, limiting interpretation. Cautiously, we observed that SRS appears to be a safe, effective treatment for grade I-II AVM and may be considered a front-line treatment, particularly for lesions in deep or eloquent locations. Preceding publications may be influenced by selection bias, with favorable AVMs undergoing resection, whereas those at increased risk of complications and nonobliteration are disproportionately referred for SRS.

Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate &lt; .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.

AbstractObjectiveTo conduct a systematic literature review of spinal cord stimulation (SCS) for pain.DesignGrade the evidence for SCS.MethodsAn international, interdisciplinary work group conducted literature searches, reviewed abstracts, and selected studies for grading. Inclusion/exclusion criteria included randomized controlled trials (RCTs) of patients with intractable pain of greater than one year’s duration. Full studies were graded by two independent reviewers. Excluded studies were retrospective, had small numbers of subjects, or existed only as abstracts. Studies were graded using the modified Interventional Pain Management Techniques–Quality Appraisal of Reliability and Risk of Bias Assessment, the Cochrane Collaborations Risk of Bias assessment, and the US Preventative Services Task Force level-of-evidence criteria.ResultsSCS has Level 1 evidence (strong) for axial back/lumbar radiculopathy or neuralgia (five high-quality RCTs) and complex regional pain syndrome (one high-quality RCT).ConclusionsHigh-level evidence supports SCS for treating chronic pain and complex regional pain syndrome. For patients with failed back surgery syndrome, SCS was more effective than reoperation or medical management. New stimulation waveforms and frequencies may provide a greater likelihood of pain relief compared with conventional SCS for patients with axial back pain, with or without radicular pain.