Estimating Patient-Specific Relative Benefit of Adding Biologics to Conventional Rheumatoid Arthritis Treatment: An Individual Participant Data Meta-Analysis.

IMPORTANCE Current evidence remains ambiguous regarding whether biologics should be added to conventional treatment of rheumatoid arthritis for specific patients, which may cause potential overuse or treatment delay. OBJECTIVES To estimate the benefit of adding biologics to conventional antirheumatic drugs for the treatment of rheumatoid arthritis given baseline characteristics. DATA SOURCES Cochrane CENTRAL, Scopus, MEDLINE, and the World Health Organization International Clinical Trials Registry Platform were searched for articles published from database inception to March 2, 2022. STUDY SELECTION Randomized clinical trials comparing certolizumab plus conventional antirheumatic drugs with placebo plus conventional drugs were selected. DATA EXTRACTION AND SYNTHESIS Individual participant data of the prespecified outcomes and covariates were acquired from the Vivli database. A 2-stage model was fitted to estimate patient-specific relative outcomes of adding certolizumab vs conventional drugs only. Stage 1 was a penalized logistic regression model to estimate the baseline expected probability of the outcome regardless of treatment using baseline characteristics. Stage 2 was a bayesian individual participant data meta-regression model to estimate the relative outcomes for a particular baseline expected probability. Patient-specific results were displayed interactively on an application based on a 2-stage model. MAIN OUTCOMES AND MEASURES The primary outcome was low disease activity or remission at 3 months, defined by 3 disease activity indexes (ie, Disease Activity Score based on the evaluation of 28 joints, Clinical Disease Activity Index, or Simplified Disease Activity Index). RESULTS Individual participant data were obtained from 3790 patients (2996 female [79.1%] and 794 male [20.9%]; mean [SD] age, 52.7 [12.3] years) from 5 large randomized clinical trials for moderate to high activity rheumatoid arthritis with usable data for 22 prespecified baseline covariates. Overall, adding certolizumab was associated with a higher probability of reaching low disease activity. The odds ratio for patients with an average baseline expected probability of the outcome was 6.31 (95% credible interval, 2.22-15.25). However, the benefits differed in patients with different baseline characteristics. For example, the estimated risk difference was smaller than 10% for patients with either low or high baseline expected probability. CONCLUSIONS AND RELEVANCE In this individual participant data meta-analysis, adding certolizumab was associated with more effectiveness for rheumatoid arthritis in general. However, the benefit was uncertain for patients with low or high baseline expected probability, for whom other evaluations were necessary. The interactive application displaying individual estimates may help with treatment selection

Predicting the treatment response of certolizumab for individual adult patients with rheumatoid arthritis: protocol for an individual participant data meta-analysis.

BACKGROUND A model that can predict treatment response for a patient with specific baseline characteristics would help decision-making in personalized medicine. The aim of the study is to develop such a model in the treatment of rheumatoid arthritis (RA) patients who receive certolizumab (CTZ) plus methotrexate (MTX) therapy, using individual participant data meta-analysis (IPD-MA). METHODS We will search Cochrane CENTRAL, PubMed, and Scopus as well as clinical trial registries, drug regulatory agency reports, and the pharmaceutical company websites from their inception onwards to obtain randomized controlled trials (RCTs) investigating CTZ plus MTX compared with MTX alone in treating RA. We will request the individual-level data of these trials from an independent platform (http://vivli.org). The primary outcome is efficacy defined as achieving either remission (based on ACR-EULAR Boolean or index-based remission definition) or low disease activity (based on either of the validated composite disease activity measures). The secondary outcomes include ACR50 (50% improvement based on ACR core set variables) and adverse events. We will use a two-stage approach to develop the prediction model. First, we will construct a risk model for the outcomes via logistic regression to estimate the baseline risk scores. We will include baseline demographic, clinical, and biochemical features as covariates for this model. Next, we will develop a meta-regression model for treatment effects, in which the stage 1 risk score will be used both as a prognostic factor and as an effect modifier. We will calculate the probability of having the outcome for a new patient based on the model, which will allow estimation of the absolute and relative treatment effect. We will use R for our analyses, except for the second stage which will be performed in a Bayesian setting using R2Jags. DISCUSSION This is a study protocol for developing a model to predict treatment response for RA patients receiving CTZ plus MTX in comparison with MTX alone, using a two-stage approach based on IPD-MA. The study will use a new modeling approach, which aims at retaining the statistical power. The model may help clinicians individualize treatment for particular patients. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number pending (ID#157595)

Optimal duration of antibiotic treatment for community-acquired pneumonia in adults: a systematic review and duration-effect meta-analysis.

OBJECTIVES To find the optimal treatment duration with antibiotics for community-acquired pneumonia (CAP) in adults. DESIGN Systematic review and duration-effect meta-analysis. DATA SOURCES MEDLINE, Embase and CENTRAL through 25 August 2021. ELIGIBILITY CRITERIA All randomised controlled trials comparing the same antibiotics used at the same daily dosage but for different durations for CAP in adults. Both outpatients and inpatients were included but not those admitted to intensive care units. We imposed no date, language or publication status restriction. DATA EXTRACTION AND SYNTHESIS Data extraction by two independent reviewers. We conducted a random-effects, one-stage duration-effect meta-analysis with restricted cubic splines. We tested the non-inferiority with the prespecified non-inferiority margin of 10% examined against 10 days . The primary outcome was clinical improvement on day 15 (range 7-45 days). SECONDARY OUTCOMES all-cause mortality, serious adverse events and clinical improvement on day 30 (15-60 days). RESULTS We included nine trials (2399 patients with a mean (SD) age of 61.2 (22.1); 39% women). The duration-effect curve was monotonic with longer duration leading to a lower probability of improvement, and shorter treatment duration (3-9 days) was likely to be non-inferior to 10-day treatment. Harmful outcome curves indicated no association. The weighted average percentage of the primary outcome in the 10-day treatment arms was 68%. Using that average, the absolute clinical improvement rates of the following durations were: 3-day treatment 75% (95% CI: 68% to 81%), 5-day treatment 72% (95% CI: 66% to 78%) and 7-day treatment 69% (95% CI: 61% to 76%). CONCLUSIONS Shorter treatment duration (3-5 days) probably offers the optimal balance between efficacy and treatment burden for treating CAP in adults if they achieved clinical stability. However, the small number of included studies and the overall moderate-to-high risk of bias may compromise the certainty of the results. Further research on the shorter duration range is required. PROSPERO REGISTRATION NUMBER CRD 42021273357

Development and validation of prediction model for incident overactive bladder: The Nagahama study.

OBJECTIVES We aimed to develop models to predict new-onset overactive bladder in 5 years using a large prospective cohort of the general population. METHODS This is a secondary analysis of a longitudinal cohort study in Japan. The baseline characteristics were measured between 2008 and 2010, with follow-ups every 5 years. We included subjects without overactive bladder at baseline and with follow-up data 5 years later. Overactive bladder was assessed using the overactive bladder symptom score. Baseline characteristics (demographics, health behaviors, comorbidities, and overactive bladder symptom scores) and blood test data were included as predictors. We developed two competing prediction models for each sex based on logistic regression with penalized likelihood (LASSO). We chose the best model separately for men and women after evaluating models' performance in terms of discrimination and calibration using an internal validation via 200 bootstrap resamples and a temporal validation. RESULTS We analyzed 7218 participants (male: 2238, female: 4980). The median age was 60 and 55 years, and the number of new-onset overactive bladder was 223 (10.0%) and 288 (5.8%) per 5 years in males and females, respectively. The in-sample estimates for C-statistic, calibration intercept, and slope for the best performing models were 0.77 (95% confidence interval 0.74-0.80), 0.28 and 1.15 for males, and 0.77 (95% confidence interval 0.74-0.80), 0.20 and 1.08 for females. Internal and temporal validation gave broadly similar estimates of performance, indicating low optimism. CONCLUSION We developed risk prediction models for new-onset overactive bladder among men and women with good predictive ability

Halo Excitation of 6^6He in Inelastic and Charge-Exchange Reactions

Four-body distorted wave theory appropriate for nucleon-nucleus reactions leading to 3-body continuum excitations of two-neutron Borromean halo nuclei is developed. The peculiarities of the halo bound state and 3-body continuum are fully taken into account by using the method of hyperspherical harmonics. The procedure is applied for A=6 test-bench nuclei; thus we report detailed studies of inclusive cross sections for inelastic $^6$He(p,p')$^6$He$^*$ and charge-exchange $^6$Li(n,p)$^6$He$^*$ reactions at nucleon energy 50 MeV. The theoretical low-energy spectra exhibit two resonance-like structures. The first (narrow) is the excitation of the well-known $2^+$ three-body resonance. The second (broad) bump is a composition of overlapping soft modes of multipolarities $1^-, 2^+, 1^+, 0^+$ whose relative weights depend on transferred momentum and reaction type. Inelastic scattering is the most selective tool for studying the soft dipole excitation mode.Comment: Submitted to Phys. Rev. C., 11 figures using eps

Concurrent pulmonary zygomycosis and Mycobacterium tuberculosis infection: a case report

A non-smoking 77-year old gentleman of Indian origin was admitted with a 4-month history of intermittent night sweats, haemoptysis and 6 kg of weight loss. CT scan of thorax demonstrated a 2.5 cm mass in the right middle lobe with multiple small nodules within the right lung and confirmed the presence of mediastinal and hilar lymph nodes

Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases

Aims The genetic cause of cardiac conduction system disease (CCSD) has not been fully elucidated. Whole-exome sequencing (WES) can detect various genetic variants; however, the identification of pathogenic variants remains a challenge. We aimed to identify pathogenic or likely pathogenic variants in CCSD patients by using WES and 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines as well as evaluating the usefulness of functional studies for determining them. Methods and Results We performed WES of 23 probands diagnosed with early-onset (<65 years) CCSD and analyzed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. We focused on rare variants (minor allele frequency < 0.1%) that were absent from population databases. Five probands had protein truncating variants in EMD and LMNA which were classified as “pathogenic” by 2015 ACMG standards and guidelines. To evaluate the functional changes brought about by these variants, we generated a knock-out zebrafish with CRISPR-mediated insertions or deletions of the EMD or LMNA homologs in zebrafish. The mean heart rate and conduction velocities in the CRISPR/Cas9-injected embryos and F2 generation embryos with homozygous deletions were significantly decreased. Twenty-one variants of uncertain significance were identified in 11 probands. Cellular electrophysiological study and in vivo zebrafish cardiac assay showed that 2 variants in KCNH2 and SCN5A, 4 variants in SCN10A, and 1 variant in MYH6 damaged each gene, which resulted in the change of the clinical significance of them from “Uncertain significance” to “Likely pathogenic” in 6 probands. Conclusions Of 23 CCSD probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%). Functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants in patients with CCSD. SCN10A may be one of the major genes responsible for CCSD. Translational Perspective Whole-exome sequencing (WES) may be helpful in determining the causes of cardiac conduction system disease (CCSD), however, the identification of pathogenic variants remains a challenge. We performed WES of 23 probands diagnosed with early-onset CCSD, and identified 12 pathogenic or likely pathogenic variants in 11 of these probands (48%) according to the 2015 ACMG standards and guidelines. In this context, functional analyses of a cellular electrophysiological study and in vivo zebrafish cardiac assay might be useful for determining the pathogenicity of rare variants, and SCN10A may be one of the major development factors in CCSD

Drop Formation and Breakup of Low Viscosity Elastic Fluids: Effects of Molecular Weight and Concentration

Submitted to Phys. FluidsThe dynamics of drop formation and pinch-off have been investigated for a series of low viscosity elastic fluids possessing similar shear viscosities, but differing substantially in elastic properties. On initial approach to the pinch region, the viscoelastic fluids all exhibit the same global necking behaviour that is observed for a Newtonian fluid of equivalent shear viscosity. For these low viscosity dilute polymer solutions, inertial and capillary forces form the dominant balance in this potential flow regime, with the viscous force being negligible. The approach to the pinch point, which corresponds to the point of rupture for a Newtonian fluid, is extremely rapid in such solutions, with the sudden increase in curvature producing very large extension rates at this location. In this region the polymer molecules are significantly extended, causing a localised increase in the elastic stresses, which grow to balance the capillary pressure. This prevents the necked fluid from breaking off, as would occur in the equivalent Newtonian fluid. Alternatively, a cylindrical filament forms in which elastic stresses and capillary pressure balance, and the radius decreases exponentially with time. A (0+1)-dimensional FENE dumbbell theory incorporating inertial, capillary and elastic stresses is able to capture the basic features of the experimental observations. Before the critical ‘pinch time’ tp , an inertial-capillary balance leads to the expected 2/3-power scaling of the minimum radius with time, Rmin ∼ (tp − t)^2/3. However, the diverging deformation rate results in large molecular deformations and rapid crossover to an elasto-capillary balance for times t > tp. In this region the filament radius decreases exponentially with time Rmin ~exp[(tp - t) / λ1], where λ1 is the characteristic time constant of the polymer molecules. Measurements of the relaxation times of PEO solutions of varying concentrations and molecular weights obtained from high speed imaging of the rate of change of filament radius are significantly higher than the relaxation times estimated from Rouse-Zimm theory, even though the solutions are within the dilute concentration region as determined using intrinsic viscosity measurements. The effective relaxation times exhibit the expected scaling with molecular weight but with an additional dependence on the concentration of the polymer in solution. This is consistent with the expectation that the polymer molecules are in fact highly extended during the approach to the pinch region (i.e. prior to the elasto-capillary filament thinning regime) and subsequently as the filament is formed they are further extended by filament stretching at a constant rate until full extension of the polymer coil is achieved. In this highly-extended state, inter-molecular interactions become significant producing relaxation times far above theoretical predictions for dilute polymer solutions under equilibrium conditions.Australian Research Counci

Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival

<p>Abstract</p> <p>Introduction</p> <p>Although systemic T-cell responses against tumor antigens and tumor infiltration by T cells have been investigated in colorectal cancer (CRC), the initiation of spontaneous immune responses <it>in situ </it>is not well understood. Macrophages and dendritic cells (DC) play an important role as a link between innate and adaptive immune response. The aim of the present study was to analyze macrophage and DC infiltration in CRC and to investigate whether there is a correlation to systemic T-cell response, regulatory T cell (Treg) infiltration, and survival.</p> <p>Methods</p> <p>Immunohistological staining was performed with nine markers for macrophages and DC (CD68, CD163, S100, CD11c, CD208, CD209, CD123, CD1a, Langerin) in 40 colorectal cancer samples from patients, in whom the state of systemic T-cell responses against tumor-associated antigens (TAA) and Treg infiltration had previously been determined.</p> <p>Results</p> <p>All specimens contained cells positive for CD68, CD163, S100 and CD1a in epithelial tumor tissue and tumor stroma. Only a very few (less than median 3/HPF) CD123+, CD1a+, CD11c+, CD 208+, CD209+, or Langerin+ cells were detected in the specimens. Overall, we found a trend towards increased infiltration by S100-positive DC and a significantly increased number of stromal S100-positive DC in patients without T-cell response. There was an increase of stromal S100 DC and CD163 macrophages in limited disease (S100: 11.1/HPF vs. 7.3/HPF, p = 0.046; CD163: 11.0/HPF vs. 8.1/HPF, p = 0.06). We found a significant, positive correlation between S100-positive DC and FOXP3-positive Tregs. Survival in patients with high DC infiltration was significantly better than that in those with low DC infiltration (p < 0.05). Furthermore, we found a trend towards better survival for increased infiltration with CD163-positive macrophages (p = 0.07).</p> <p>Conclusion</p> <p>The present <it>in situ </it>study adds new data to the discussion on the interaction between the innate and adoptive immune system. Our data strongly support the hypothesis that tumor-infiltrating DC are a key factor at the interface between innate and adaptive immune response in malignant disease. Tumor infiltrating S100-positive DC show an inverse relationship with the systemic antigen-specific T-cell response, a positive correlation with regulatory T cells, and a positive association with survival in CRC. These data put tumor-infiltrating DC at the center of the relevant immune response in CRC.</p

Design of experiments to study the impact of process parameters on droplet size and development of non-invasive imaging techniques in tablet coating

Atomisation of an aqueous solution for tablet film coating is a complex process with multiple factors determining droplet formation and properties. The importance of droplet size for an efficient process and a high quality final product has been noted in the literature, with smaller droplets reported to produce smoother, more homogenous coatings whilst simultaneously avoiding the risk of damage through over-wetting of the tablet core. In this work the effect of droplet size on tablet film coat characteristics was investigated using X-ray microcomputed tomography (XμCT) and confocal laser scanning microscopy (CLSM). A quality by design approach utilising design of experiments (DOE) was used to optimise the conditions necessary for production of droplets at a small (20 μm) and large (70 μm) droplet size. Droplet size distribution was measured using real-time laser diffraction and the volume median diameter taken as a response. DOE yielded information on the relationship three critical process parameters: pump rate, atomisation pressure and coating-polymer concentration, had upon droplet size. The model generated was robust, scoring highly for model fit (R2 = 0.977), predictability (Q2 = 0.837), validity and reproducibility. Modelling confirmed that all parameters had either a linear or quadratic effect on droplet size and revealed an interaction between pump rate and atomisation pressure. Fluidised bed coating of tablet cores was performed with either small or large droplets followed by CLSM and XμCT imaging. Addition of commonly used contrast materials to the coating solution improved visualisation of the coating by XμCT, showing the coat as a discrete section of the overall tablet. Imaging provided qualitative and quantitative evidence revealing that smaller droplets formed thinner, more uniform and less porous film coats