Tag: statistics

Proc Natl Acad Sci U S A. 2021 Aug 3;118(31):e2020402118. doi: 10.1073/pnas.2020402118.

ABSTRACT

To mimic the mechanical response of passive biological cilia in complex fluids, we study the bending dynamics of an anchored elastic fiber submitted to a dilute granular suspension under shear. We show that the bending fluctuations of the fiber accurately encode minute variations of the granular suspension concentration. Indeed, besides the stationary bending induced by the continuous phase flow, the passage of each single particle induces an additional deflection. We demonstrate that the dominant particle/fiber interaction arises from contacts of the particles with the fiber, and we propose a simple elastohydrodynamics model to predict their amplitude. Our results provide a mechanistic and statistical framework to describe particle detection by biological ciliated systems.

PMID:34326246 | DOI:10.1073/pnas.2020402118

J Immunother Cancer. 2021 Jul;9(7):e002851. doi: 10.1136/jitc-2021-002851.

ABSTRACT

BACKGROUND: The modified Glasgow Prognostic Score (mGPS) is a composite biomarker that uses albumin and C reactive protein (CRP). There are multiple immune checkpoint inhibitor (ICI)-based combinations approved for metastatic renal cell carcinoma (mRCC). We investigated the ability of mGPS to predict outcomes in patients with mRCC receiving ICI.

METHODS: We retrospectively reviewed patients with mRCC treated with ICI as monotherapy or in combination at Winship Cancer Institute between 2015 and 2020. Overall survival (OS) and progression-free survival (PFS) were measured from the start date of ICI until death or clinical/radiographical progression, respectively. The baseline mGPS was defined as a summary score based on pre-ICI values with one point given for CRP>10 mg/L and/or albumin<3.5 g/dL, resulting in possible scores of 0, 1 and 2. If only albumin was low with a normal CRP, no points were awarded. Univariate analysis (UVA) and multivariate analysis (MVA) were carried out using Cox proportional hazard model. Outcomes were also assessed by Kaplan-Meier analysis.

RESULTS: 156 patients were included with a median follow-up 24.2 months. The median age was 64 years and 78% had clear cell histology. Baseline mGPS was 0 in 36%, 1 in 40% and 2 in 24% of patients. In UVA, a baseline mGPS of 2 was associated with shorter OS (HR 4.29, 95% CI 2.24 to 8.24, p<0.001) and PFS (HR 1.90, 95% CI 1.20 to 3.01, p=0.006) relative to a score of 0; this disparity in outcome based on baseline mGPS persisted in MVA. The respective median OS of patients with baseline mGPS of 0, 1 and 2 was 44.5 (95% CI 27.3 to not evaluable), 15.3 (95% CI 11.0 to 24.2) and 10 (95% CI 4.6 to 17.5) months (p<0.0001). The median PFS of these three cohorts was 6.7 (95% CI 3.6 to 13.1), 4.2 (95% CI 2.9 to 6.2) and 2.6 (95% CI 2.0 to 5.6), respectively (p=0.0216). The discrimination power of baseline mGPS to predict survival outcomes was comparable to the IMDC risk score based on Uno’s c-statistic (OS: 0.6312 vs 0.6102, PFS: 0.5752 vs 0.5533).

CONCLUSION: The mGPS is prognostic in this cohort of patients with mRCC treated with ICI as monotherapy or in combination. These results warrant external and prospective validation.

PMID:34326170 | DOI:10.1136/jitc-2021-002851

Eur Respir J. 2021 Jul 29:2003969. doi: 10.1183/13993003.03969-2020. Online ahead of print.

ABSTRACT

BACKGROUND: Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3).

OBJECTIVE: To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response.

METHODS: The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (pediatric cases/controls: 134/35; adult cases/controls: 149/31). Exacerbation of allergic airway disease in mice was induced by sensitising to OVA, challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor, Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (CF, n=14) and CF with allergic broncho-pulmonary aspergillosis (ABPA, n=9) as well as severe allergic, uncontrolled asthmatics (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed by the Asthma Control Test.

RESULTS: Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in CF plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic odds ratio 31.5).

CONCLUSION: C4Ma3 level depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.

PMID:34326188 | DOI:10.1183/13993003.03969-2020

BMJ Open Respir Res. 2021 Jul;8(1):e000805. doi: 10.1136/bmjresp-2020-000805.

ABSTRACT

BACKGROUND AND OBJECTIVE: A high frequency of infections complicating rheumatoid arthritis (RA) has been reported due to the immunomodulatory effect of RA or to agents with immunosuppressive effects used in its treatment. We aimed to assess clinical and radiological characteristics of pulmonary cryptococcosis in patients with and without RA.

METHODS: We retrospectively reviewed the medical records of 52 patients with pulmonary cryptococcosis and divided them into two groups, those with RA and without RA, and compared clinical characteristics and radiological findings between them.

RESULTS: Eleven (21.2%) of the 52 patients had RA. Median follow-up periods were 51.2 (range: 1.1-258.7) months for patients with RA and 19.1 (range: 0.63-246.9) months for patients without RA. Among the patients with RA, 81.8% were women, with a mean age of 68.1 years. Female sex and respiratory comorbidities were significantly more frequent in patients with RA than in patients without RA. Frequencies of concomitant cryptococcal meningitis and respiratory failure were not different between the groups. There were no significant differences in frequency of any radiological findings, locations and number between the two groups. Among patients with RA, all but one responded well to antifungal treatment. During the antifungal treatment course, one (9.1%) patient with RA died of cryptococcosis. Despite continuing antirheumatic drugs, no patients had recurrence of pulmonary cryptococcosis during follow-up.

CONCLUSION: Other than some differences in background, there were no clinical, radiological or prognostic differences between the patients with and without RA with pulmonary cryptococcosis. The administration of antirheumatic therapy had no negative effect on the clinical course of antifungal treatment.

PMID:34326152 | DOI:10.1136/bmjresp-2020-000805

BMJ Open Respir Res. 2021 Jul;8(1):e000918. doi: 10.1136/bmjresp-2021-000918.

ABSTRACT

Lung volume recruitment manoeuvres are often prescribed to maintain respiratory health in neuromuscular disease. Unfortunately, no current system accurately records delivered dose. This study determined the performance characteristics of a novel, objective, manual lung volume recruitment bag counter (‘the counter’) with bench and healthy volunteer testing, as well as in individuals with neuromuscular disease. We undertook (1) bench test determination of activation threshold, (2) bench and healthy volunteer fidelity testing during simulated patient interface leak and different pressure compressions and (3) comparisons with self-report in individuals with neuromuscular disease. The data are reported as summary statistics, compression counts, percentage of recorded versus delivered compressions and concordance (Cohen’s kappa (K) and absolute agreement). RESULTS: Minimum counter activation pressure under conditions of zero leak was 1.9±0.4 cm H₂O. No difference was observed between the number of repetitions delivered and recorded during high airway pressure condition. Interface leak approximating 25% resulted in underestimation of repetition counts, and once the leak was at 50% or beyond, the counter recorded no activity. Faster sampling frequency collected data with more fidelity. Counter data agreed with diary self-report during community trials (16 participants, 960 participant days, 77% agreement, Cohen’s Κ=0.66 and p<0.001). Disagreement typically favoured more diary reported (18%) than counter (5%) sessions. CONCLUSIONS: The performance characteristics of a new lung volume recruitment counter have been established in both laboratory and community settings. Objective usage and dosage data should accelerate new knowledge development and better translation of lung volume recruitment therapy into policy and practice.

PMID:34326156 | DOI:10.1136/bmjresp-2021-000918

BJGP Open. 2021 Jul 29:BJGPO.2021.0051. doi: 10.3399/BJGPO.2021.0051. Online ahead of print.

ABSTRACT

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease which causes painful discharging nodules and skin tunnels. HS has associations with several systemic diseases, including cardiovascular (CV) disease and anxiety-depression. High levels of chronic morbidity suggest an important role for Primary Care. However, little evidence exists regarding current management of HS and its co-morbidities in UK General Practice.

AIM: To describe current practice amongst UK GPs in treating and referring people with HS DESIGN & SETTING: Web-based survey circulated to UK Primary Care Dermatology Society members and GPs in Forth Valley, Scotland.

METHOD: Survey responses were analysed with descriptive statistics.

RESULTS: 134 UK GPs completed the survey. 71% (n=94) saw at least one patient with HS in the previous month. 94% (n=125) reported confidence in diagnosis, and 87% (n=120) in initial treatment of HS. Most GPs initiated topical treatments and extended courses of oral antibiotic for HS, and many advised regarding adverse lifestyle factors. A minority provided analgesia, or screening for CV disease risk factors and anxiety-depression. Most GPs referred to Dermatology if Secondary Care input was required, with few referrals to specialised multi-disciplinary services.

CONCLUSION: GPs regularly diagnose and manage uncomplicated HS, but screening for important co-morbidities associated with HS is not common practice.

PMID:34326099 | DOI:10.3399/BJGPO.2021.0051

AJNR Am J Neuroradiol. 2021 Jul 29. doi: 10.3174/ajnr.A7236. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: Noninvasive angiography is commonly used to assess the outcome of surgical or endovascular treatment of intracranial aneurysms in clinical series or randomized trials. We sought to assess whether a standardized 3-grade classification system could be reliably used to compare the CTA and MRA results of both treatments.

MATERIALS AND METHODS: An electronic portfolio composed of CTAs of 30 clipped and MRAs of 30 coiled aneurysms was independently evaluated by 24 raters of diverse experience and training backgrounds. Twenty raters performed a second evaluation 1 month later. Raters were asked which angiographic grade and management decision (retreatment; close or long-term follow-up) would be most appropriate for each case. Agreement was analyzed using the Krippendorff α (α_K) statistic, and the relationship between angiographic grade and clinical management choice, using the Fisher exact and Cramer V tests.

RESULTS: Interrater agreement was substantial (α_K = 0.63; 95% CI, 0.55-0.70); results were slightly better for MRA results of coiling (α_K = 0.69; 95% CI, 0.56-0.76) than for CTA results of clipping (α_K = 0.58; 95% CI, 0.44-0.69). Intrarater agreement was substantial to almost perfect. Interrater agreement regarding clinical management was moderate for both clipped (α_K = 0.49; 95% CI, 0.32-0.61) and coiled subgroups (α_K = 0.47; 95% CI, 0.34-0.54). The choice of clinical management was strongly associated with the size of the residuum (mean Cramer V = 0.77 [SD, 0.14]), but complete occlusions (grade 1) were followed more closely after coiling than after clipping (P = .01).

CONCLUSIONS: A standardized 3-grade scale was found to be a reliable and clinically meaningful tool to compare the results of clipping and coiling of aneurysms using CTA or MRA.

PMID:34326106 | DOI:10.3174/ajnr.A7236

J Neurosci. 2021 Jul 29:JN-RM-2459-20. doi: 10.1523/JNEUROSCI.2459-20.2021. Online ahead of print.

ABSTRACT

Many decisions, from crossing a busy street to choosing a profession, require integration of discrete sensory events. Previous studies have shown that integrative decision-making favours more reliable stimuli, mimicking statistically optimal integration. It remains unclear, however, whether reliability biases operate even when they lead to suboptimal performance. To address this issue, we asked human observers to reproduce the average motion direction of two suprathreshold coherent motion signals presented successively and with varying levels of reliability, while simultaneously recording whole-brain activity using electroencephalography. By definition, the averaging task should engender equal weighting of the two component motion signals, but instead we found robust behavioural biases in participants’ average decisions that favoured the more reliable stimulus. Using population-tuning modelling of brain activity we characterised tuning to the average motion direction. In keeping with the behavioural biases, the neural tuning profiles also exhibited reliability biases. A control experiment revealed that observers were able to reproduce motion directions of low-and high-reliability with equal precision, suggesting that unbiased integration in this task was not only theoretically optimal but demonstrably possible. Our findings reveal that temporal integration of discrete sensory events in the brain is automatically and sub-optimally weighted according to stimulus reliability.Significance statement:Many everyday decisions require integration of several sources of information. To safely cross a busy road, for example, one must consider the movement of vehicles with different speeds and trajectories. Previous research has shown that individual stimuli are weighted according to their reliability. Whereas reliability biases typically yield performance that closely mimic statistically optimal integration, it remains unknown whether such biases arise even when they lead to suboptimal performance. Here we combined a novel integrative decision-making task with concurrent brain recording and modelling to address this question. While unbiased decisions were optimal in the task, observers nevertheless exhibited robust reliability biases in both behaviour and brain activity, suggesting that reliability-weighted integration is automatic and dissociable from statistically optimal integration.

PMID:34326142 | DOI:10.1523/JNEUROSCI.2459-20.2021

BMJ Open. 2021 Jul 29;11(7):e053212. doi: 10.1136/bmjopen-2021-053212.

ABSTRACT

INTRODUCTION: While healthcare transition (HCT) interventions are recognised as an important area in paediatric rehabilitation, there has been limited research focusing on young people with spinal cord injuries (SCI). In this study, researchers will collaborate with young people with SCI and their parents/caregivers to develop, implement and evaluate the feasibility and acceptability of a HCT intervention aimed at supporting young people with SCI during their transition from paediatric to adult healthcare services.

METHODS AND ANALYSIS: A participatory action research (PAR) approach will be used to co-develop the HCT intervention with young people with SCI aged 14-25 years and their parents/caregivers. Three phases will be conducted to address the five objectives of this study. Phase 1 will use semi-structured interviews to explore young people and parent/caregivers’ experiences of HCT. In Phase 2a, both young people and parent/caregivers will be co-researchers. They will be included in the analysis of the interviews and will be asked to participate in co-design workshops to inform the development of a prototype HCT intervention. In Phase 2b, using focus groups, feedback on the prototype HCT intervention will be collected. In Phase 3, the refined prototype HCT intervention will be implemented, and young people with SCI and parent/caregivers will evaluate the feasibility and acceptability of the HCT intervention in semi-structured interviews. A reference group, including stakeholders and end users, will be consulted at different time points.

ETHICS AND DISSEMINATION: The study has received ethics approval from Western Sydney University Human Research and Ethics Committee (H14029). The researcher will use the results of this study as chapters in a thesis to obtain a Doctor of Philosophy degree. The findings will be disseminated via publication in peer-reviewed journals and will be presented at local, national or international conferences.

TRIAL REGISTRATION NUMBER: ACTRN12621000500853.

PMID:34326059 | DOI:10.1136/bmjopen-2021-053212

Diabetes Care. 2021 Jul 29:dc210531. doi: 10.2337/dc21-0531. Online ahead of print.

ABSTRACT

OBJECTIVE: We aimed to test whether type 2 diabetes (T2D)-associated TCF7L2 genetic variants affect insulin sensitivity or secretion in autoantibody-positive relatives at risk for type 1 diabetes (T1D).

RESEARCH DESIGN AND METHODS: We studied autoantibody-positive TrialNet Pathway to Prevention study participants (N = 1,061) (mean age 16.3 years) with TCF7L2 single nucleotide polymorphism (SNP) information and baseline oral glucose tolerance test (OGTT) to calculate indices of insulin sensitivity and secretion. With Bonferroni correction for multiple comparisons, P values < 0.0086 were considered statistically significant.

RESULTS: None, one, and two T2D-linked TCF7L2 alleles were present in 48.1%, 43.9%, and 8.0% of the participants, respectively. Insulin sensitivity (as reflected by 1/fasting insulin [1/I_F]) decreased with increasing BMI z score and was lower in Hispanics. Insulin secretion (as measured by 30-min C-peptide index) positively correlated with age and BMI z score. Oral disposition index was negatively correlated with age, BMI z score, and Hispanic ethnicity. None of the indices were associated with TCF7L2 SNPs. In multivariable analysis models with age, BMI z score, ethnicity, sex, and TCF7L2 alleles as independent variables, C-peptide index increased with age, while BMI z score was associated with higher insulin secretion (C-peptide index), lower insulin sensitivity (1/I_F), and lower disposition index; there was no significant effect of TCF7L2 SNPs on any of these indices. When restricting the analyses to participants with a normal OGTT (n = 743; 70%), the results were similar.

CONCLUSIONS: In nondiabetic autoantibody-positive individuals, TCF7L2 SNPs were not related to insulin sensitivity or secretion indices after accounting for BMI z score, age, sex, and ethnicity.

PMID:34326068 | DOI:10.2337/dc21-0531