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.
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.
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.
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.
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this manuscript, we analyze a data set containing information on children with Hodgkin Lymphoma (HL) enrolled on a clinical trial. Treatments received and survival status were collected together ...with other covariates such as demographics and clinical measurements. Our main task is to explore the potential of machine learning (ML) algorithms in a survival analysis context in order to improve over the Cox Proportional Hazard (CoxPH) model. We discuss the weaknesses of the CoxPH model we would like to improve upon and then we introduce multiple algorithms, from well-established ones to state-of-the-art models, that solve these issues. We then compare every model according to the concordance index and the Brier score. Finally, we produce a series of recommendations, based on our experience, for practitioners that would like to benefit from the recent advances in artificial intelligence.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background
Chemotherapy-induced peripheral neuropathy (CIPN) is an under-recognized complication of several chemotherapy agents used as part of curative-intent therapy for Hodgkin Lymphoma (HL). In ...the absence of validated self- or proxy-report measures for children and adolescents, CIPN reporting has relied on clinician rating, with grading scales often restricted to severe manifestations. In a proof-of-concept study, we assessed the feasibility and psychometric performance of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx), a unidimensional CIPN symptom scale widely used adults with CIPN, in pediatric HL at risk for CIPN.
Methods
Youth (11+ years) and parents of all children (5–17.9 years) with newly diagnosed high-risk HL enrolled on Children’s Oncology Group AHOD1331 (NCT02166463) were invited to complete the FACT-GOG-Ntx and a health-related quality of life (HRQL) measure at pre-treatment (Time 1), and during cycles 2 (Time 2) and 5 (Time 3) of chemotherapy during the first half of study accrual. Clinical grading of CIPN by providers was also assessed using the Balis Pediatric Neuropathy Scale. We evaluated Cronbach’s alpha, construct validity, and agreement between raters. Change in FACT-GOG-Ntx scores over time was assessed using a repeated measures model.
Results
306 patients had at least one completed FACT-GOG-Ntx with time-specific completion rates of > 90% for both raters. Cronbach’s alpha was > 0.7 for youth and parent-proxy report at all time points. Correlations between FACT-GOG-Ntx and HRQL scores were moderate (0.41–0.48) for youth and parent-proxy raters across all times. Youth and parent-proxy raters both reported worse FACT-GOG-Ntx scores at Time 3 for those who had clinically-reported CIPN compared to those who did not. Agreement between raters was moderate to high. Compared to baseline scores, those at Time 3 were significantly lower for youth (β = − 2.83,
p
< 0.001) and parent-proxy raters (β = − 1.99,
p
< 0.001).
Conclusions
High completion rates at all time points indicated feasibility of eliciting youth and parent report. Psychometric performance of the FACT-GOG-Ntx revealed acceptable reliability, evidence of validity, and strong inter-rater agreement, supporting the use of this self- or proxy-reported measure of CIPN in youth with high-risk HL exposed to tubulin inhibitors, as part of a Phase 3 clinical trial.
Clinical trial information
: Clinical Trials Registry, NCT02166463. Registered 18 June 2014,
https://clinicaltrials.gov/ct2/show/study/NCT02166463
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.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Many HIV research projects are plagued by the high missing rate of selfreported information during data collection. Also, due to the sensitive nature of the HIV research data, privacy protection is ...always a concern for data sharing in HIV studies.
This paper applies a data masking approach, called triple-matrix masking 1, to the context of HIV research for ensuring privacy protection during the process of data collection and data sharing.
Using a set of generated HIV patient data, we show step by step how the data are randomly transformed (masked) before leaving the patients' individual data collection device (which ensures that nobody sees the actual data) and how the masked data are further transformed by a masking service provider and a data collector. We demonstrate that the masked data retain statistical utility of the original data, yielding the exactly same inference results in the planned logistic regression on the effect of age on the adherence to antiretroviral therapy and in the Cox proportional hazard model for the age effect on time to viral load suppression.
Privacy-preserving data collection method may help resolve the privacy protection issue in HIV research. The individual sensitive data can be completely hidden while the same inference results can still be obtained from the masked data, with the use of common statistical analysis methods.
To describe characteristics of Parkinson's disease by sex and determine if differences in disease progression exist.
Longitudinal, observational study.
Twenty-one National Parkinson Foundation ...Centers of Excellence.
People (N = 4,679; 63% men and 37% women) with idiopathic Parkinson's disease.
Demographic and clinical data at enrollment and after 1 year were collected. We defined progression as a 1-year change in the following functional health outcome measures: (a) health-related quality of life (Parkinson's Disease Questionnaire-39), (b) Timed Up and Go test, (c) cognitive function, and (d) number of medications. We compared baseline characteristics between men and women. Then, linear regression models were built to assess the independent contribution of sex to progression.
At baseline, women were significantly more likely to be older and have greater disease severity and more comorbidities than men despite similar duration of disease. This finding corresponded to worse function as assessed by the Parkinson's Disease Questionnaire-39 and Timed Up and Go test but not to number of medications and cognitive function. After 1 year, declines across all functional measures except delayed recall occurred. No significant changes in Parkinson's Disease Questionnaire-39, Timed Up and Go, number of medications, or verbal fluency between men and women occurred. Women had a more significant improvement in delayed recall than men.
Numerous small baseline differences occurred between men and women with PD, although differences in markers of progression were few. Findings suggest that clinical manifestations and prognosis appear similar by sex under the same treatment conditions.
In vivo hypoxanthine–guanine phosphoribosyltransferase (HPRT)-deficient T cells (MT) from melanoma patients are enriched for T cells with in vivo clonal amplifications that traffic between blood and ...tumor tissues. Melanoma is thus a model cancer to test the hypothesis that in vivo MT from cancer patients can be used as immunological probes for immunogenic tumor antigens. MT were obtained by 6-thioguanine (TG) selection of lymphocytes from peripheral blood and tumor tissues, and wild-type T cells (WT) were obtained analogously without TG selection. cDNA sequences of the T cell receptor beta chains (TRB) were used as unambiguous biomarkers of in vivo clonality and as indicators of T cell specificity. Public TRB were identified in MT from the blood and tumor of different melanoma patients. Such public TRB were not found in normal control MT or WT. As an indicator of T cell specificity for melanoma, the >2600 MT and WT TRB, including the public TRB from melanoma patients, were compared to a literature-derived empirical database of >1270 TRB from melanoma-reactive T cells. Various degrees of similarity, ranging from 100% conservation to 3-amino acid motifs (3-mer), were found between both melanoma patient MT and WT TRBs and the empirical database. The frequency of 3-mer and 4-mer TRB matching to the empirical database was significantly higher in MT compared with WT in the tumor (p=0.0285 and p=0.006, respectively). In summary, in vivo MT from melanoma patients contain public TRB as well as T cells with specificity for characterized melanoma antigens. We conclude that in vivo MT merit study as novel probes for uncharacterized immunogenic antigens in melanoma and other malignancies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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