Qinglin Pei

Direct evidence for BBSome-associated intraflagellar transport reveals distinct properties of native mammalian cilia

Cilia dysfunction underlies a class of human diseases with variable penetrance in different organ systems. Across eukaryotes, intraflagellar transport (IFT) facilitates cilia biogenesis and cargo trafficking, but our understanding of mammalian IFT is insufficient. Here we perform live analysis of cilia ultrastructure, composition and cargo transport in native mammalian tissue using olfactory sensory neurons. Proximal and distal axonemes of these neurons show no bias towards IFT kinesin-2 choice, and Kif17 homodimer is dispensable for distal segment IFT. We identify Bardet–Biedl syndrome proteins (BBSome) as bona fide constituents of IFT in olfactory sensory neurons, and show that they exist in 1:1 stoichiometry with IFT particles. Conversely, subpopulations of peripheral membrane proteins, as well as transmembrane olfactory signalling pathway components, are capable of IFT but with significantly less frequency and/or duration. Our results yield a model for IFT and cargo trafficking in native mammalian cilia and may explain the penetrance of specific ciliopathy phenotypes in olfactory neurons.

Recognition and Treatment of Depressive Symptoms in Parkinson's Disease: The NPF Dataset

Depression is a major determinant of Health Related Quality of Life in PD, but there is limited data on physician recognition of depression and treatment efficacy. We used data obtained from the QII dataset of the National Parkinsons Foundation database to determine whether there was an association between depressive symptoms and utilization of antidepressants and/or mental health services (MHS) in a large cohort of PD patients. We found that prevalence of depressive symptoms remained high in the PD population despite improved physician recognition and treatment initiation.

Variant histology, IgD and CD30 expression in low-risk pediatric nodular lymphocyte predominant Hodgkin lymphoma: A report from the Children's Oncology Group

Histologic prognostic factors have been described for nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). This study examines histologic and immunophenotypic variants in a clinical trial for pediatric NLPHL.

The Effects of Stroke Type, Locus, and Extent on Long-Term Outcome of Gait Rehabilitation The LEAPS Experience

Background. Paresis in stroke is largely a result of damage to descending corticospinal and corticobulbar pathways. Recovery of paresis predominantly reflects the impact on the neural consequences of this white matter lesion by reactive neuroplasticity (mechanisms involved in spontaneous recovery) and experience-dependent neuroplasticity, driven by therapy and daily experience. However, both theoretical considerations and empirical data suggest that type of stroke (large vessel distribution/lacunar infarction, hemorrhage), locus and extent of infarction (basal ganglia, right-hemisphere cerebral cortex), and the presence of leukoaraiosis or prior stroke might influence long-term recovery of walking ability. In this secondary analysis based on the 408 participants in the Locomotor Experience Applied Post-Stroke (LEAPS) study database, we seek to address these possibilities. Methods. Lesion type, locus, and extent were characterized by the 2 neurologists in the LEAPS trial on the basis of clinical computed tomography and magnetic resonance imaging scans. A series of regression models was used to test our hypotheses regarding the effects of lesion type, locus, extent, and laterality on 2- to 12-month change in gait speed, controlling for baseline gait speed, age, and Berg Balance Scale score. Results. Gait speed change at 1 year was significantly reduced in participants with basal ganglia involvement and prior stroke. There was a trend toward reduction of gait speed change in participants with lacunar infarctions. The presence of right-hemisphere cortical involvement had no significant impact on outcome. Conclusions. Type, locus, and extent of lesion, and the loss of substrate for neuroplastic effect as a result of prior stroke may affect long-term outcome of rehabilitation of hemiparetic gait.

Concordance and discordance between measured and perceived balance and the effect on gait speed and falls following stroke

Objective: To ascertain the existence of discordance between perceived and measured balance in persons with stroke and to examine the impact on walking speed and falls. Design: A secondary analysis of a phase three, multicentered randomized controlled trial examining walking recovery following stroke. Subjects: A total of 352 participants from the Locomotor Experience Applied Post-Stroke (LEAPS) trial. Methods: Participants were categorized into four groups: two concordant and two discordant groups in relation to measured and perceived balance. Number and percentage of individuals with concordance and discordance were evaluated at two and 12 months. Walking speed and fall incidence between groups were examined. Main measures: Perceived balance was measured by the Activities-Specific Balance Confidence scale, measured balance was determined by the Berg Balance Scale and gait speed was measured by the 10-meter walk test. Results: Discordance was present for 35.8% of participants at two months post stroke with no statistically significant change in proportion at 12 months. Discordant participants with high perceived balance and low measured balance walked 0.09 m/s faster at two months than participants with concordant low perceived and measured balance (p < 0.05). Discordant participants with low perceived balance and high measured balance walked 0.15 m/s slower than those that were concordant with high perceived and measured balance (p ⩽ 0.0001) at 12 months. Concordant participants with high perceived and measured balance walked fastest and had fewer falls. Conclusions: Discordance existed between perceived and measured balance in one-third of individuals at two and 12 months post-stroke. Perceived balance impacted gait speed but not fall incidence.

Brentuximab vedotin with gemcitabine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm, phase 1–2 trial

BACKGROUND Patients with primary refractory Hodgkins lymphoma or early relapse have a poor prognosis. Although many salvage regimens have been developed, there is no standard of care. Brentuximab vedotin and gemcitabine have been shown to be active in patients with relapsed or refractory Hodgkins lymphoma when used as monotherapy, and each has been successfully used in combination with other agents. Preclinical data suggest that brentuximab vedotin can sensitise lymphoma cells to gemcitabine, supporting the use of the combination. We aimed to define the safety and efficacy of brentuximab vedotin with gemcitabine in children and young adults with primary refractory Hodgkins lymphoma or early relapse. METHODS In this Childrens Oncology Group, multicentre, single-arm, phase 1-2 trial, we recruited patients with Hodgkins lymphoma from hospitals across the USA and Canada. Eligible patients were aged younger than 30 years, had no previous brentuximab vedotin exposure, and had primary refractory disease or relapse of less than 1 year from completion of initial treatment. Each 21-day cycle consisted of 1000 mg/m2 intravenous gemcitabine on days 1 and 8 and intravenous brentuximab vedotin on day 1 at 1·4 mg/kg or 1·8 mg/kg. The primary objectives were to establish the recommended phase 2 dose of brentuximab vedotin in this combination, the safety of the combination, and the proportion of patients who achieved a complete response among those treated at the recommended phase 2 level, within four cycles of treatment. This trial is registered with ClinicalTrials.gov, number NCT01780662. FINDINGS Between Feb 5, 2013, and Aug 19, 2016, 46 patients were enrolled, including one who was found to be ineligible, in the two phases of the study. The recommended phase 2 dose of brentuximab vedotin was 1·8 mg/kg in combination with gemcitabine 1000 mg/m2. 24 (57%) of 42 evaluable patients (95% CI 41-72) given this dose level had a complete response within the first four cycles of treatment. Four (31%) of 13 patients with a partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle 4. By modern response criteria, these were also complete responses (total number with complete response 28 [67%] of 42 [95% CI 51-80]). The most common grade 3-4 adverse events in all 42 participants treated at the recommended phase 2 dose were neutropenia (15 [36%]), rash (15 [36%]), transaminitis (9 [21%]), and pruritus (4 [10%]). There were no treatment-related deaths. INTERPRETATION Brentuximab vedotin with gemcitabine is a safe combination treatment with a tolerable toxicity profile for patients with primary refractory Hodgkins lymphoma or high-risk relapse. The preliminary activity of this combination shown in this trial warrants further investigation in randomised controlled trials. FUNDING National Institutes of Health and the St. Baldricks Foundation.

Outcomes in intermediate-risk pediatric lymphocyte-predominant Hodgkin lymphoma: A report from the Children's Oncology Group

Optimal management of patients with intermediate‐risk lymphocyte‐predominant Hodgkin lymphoma (LPHL) is unclear due to their small numbers in most clinical trials. Childrens Oncology Group AHOD0031, a randomized phase III trial of pediatric patients with intermediate‐risk Hodgkin lymphoma (HL), included patients with LPHL. We report the outcomes of these patients and present directions for future therapeutic strategies.

Results of the AHOD0431 trial of response adapted therapy and a salvage strategy for limited stage, classical Hodgkin lymphoma: A report from the Children's Oncology Group

The Childrens Oncology Group AHOD0431 study evaluated a response‐directed treatment paradigm in which minimal initial chemotherapy and low‐dose radiation was received only by patients who did not achieve a complete remission, and a chemotherapy/low‐dose radiation salvage regimen was received by those who had a protocol‐defined, low‐risk recurrence.

Pericardial effusion in Hodgkin lymphoma: a report from the Children’s Oncology Group AHOD0031 protocol

TO THE EDITOR: Pericardial effusion in patients with Hodgkin lymphoma (HL) occurs in 5% to 24% of patients at diagnosis.[1][1][⇓][2]-[3][3] However, little is known about the incidence, clinical characteristics, and outcomes for these patients. Most cases are clinically silent, and the effusion

Hospitalization and rehospitalization in Parkinson disease patients: Data from the National Parkinson Foundation Centers of Excellence

Background Patients with Parkinson disease (PD) are at high risk of hospital encounters with increasing morbidity and mortality. This study aimed to determine the rate of hospital encounters in a cohort followed over 5 years and to identify associated factors. Methods We queried the data from the International Multicenter National Parkinson Foundation Quality Improvement study. Multivariate logistic regression with backward selection was performed to identify factors associated with hospital encounter prior to baseline visit. Kaplan-Meier estimates were obtained and Cox regression performed on time to hospital encounter after the baseline visit. Results Of the 7,507 PD patients (mean age 66.5±9.9 years and disease duration 8.9±6.4 years at baseline visit), 1919 (25.6%) had a history of a hospital encounter prior to their baseline visit. Significant factors associated with a history of a hospital encounter prior to baseline included race (white race: OR 0.49), utilization of physical therapy (OR 1.47), history of deep brain stimulation (OR 1.87), number of comorbidities (OR 1.30), caregiver strain (OR 1.17 per standard deviation), and the standardized Timed Up and Go Test (OR 1.21). Patients with a history of hospitalization prior to the baseline were more likely to have a re-hospitalization (HR1.67, P<0.0001) compared to those without a prior hospitalization. In addition, the time to hospital encounter from baseline was significantly associated with age and number of medications. In patients with a history of hospitalization prior to the baseline visit, time to a second hospital encounter was significantly associated with caregiver strain and number of comorbidities. Conclusion Hospitalization and re-hospitalization were common in this cohort of people with PD. Our results suggest addressing caregiver burden, simplifying medications, and emphasizing primary and multidisciplinary care for comorbidities are potential avenues to explore for reducing hospitalization rates.