Search

Mixed models are a useful way of analysing longitudinal data. Random effects terms allow modelling of patient specific deviations from the overall trend over time. Correlation between repeated measurements are captured by specifying a joint distribution for all random effects in a model. Typically, this joint distribution is assumed to be a multivariate normal distribution. For Gaussian outcomes misspecification of the random effects distribution usually has little impact. However, when the outcome is discrete (e.g. counts or binary outcomes) generalised linear mixed models (GLMMs) are used to analyse longitudinal trends. Opinion is divided about how robust GLMMs are to misspecification of the random effects. Previous work explored the impact of random effects misspecification on the bias of model parameters in single outcome GLMMs. Accepting that these model parameters may be biased, we investigate whether this affects our ability to classify patients into clinical groups using a longitudinal discriminant analysis. We also consider multiple outcomes, which can significantly increase the dimensions of the random effects distribution when modelled simultaneously. We show that when there is severe departure from normality, more flexible mixture distributions can give better classification accuracy. However, in many cases, wrongly assuming a single multivariate normal distribution has little impact on classification accuracy. [ABSTRACT FROM AUTHOR]

Objective Comorbidities influence disease assessment in axial spondyloarthritis (axSpA), but their association with response to TNF inhibitors (TNFi) is unclear. We examined associations between comorbidity history at TNFi initiation and: (i) change in disease indices over time; (ii) binary response definitions; and (iii) time to treatment discontinuation. Methods We studied participants starting their first TNFi from a national axSpA register. Comorbidity categories were created from 14 physician-diagnosed conditions and compared against: change in disease indices over time using linear mixed effects models; BASDAI50/2 (50% or 2-unit reduction) and BASDAI < 4 at 6 months using logistic models; and time to treatment discontinuation using Cox models. Models were adjusted for age, gender, BMI, deprivation and education. Results In total, 994 were eligible for analysis (68% male, mean age 45 years); 21% had one comorbidity and 11% had ≥2. Baseline disease severity was higher in those with comorbidities across all indices, but absolute improvement over time was comparable for BASDAI and spinal pain. Participants with ≥2 comorbidities had smaller absolute improvement in BASFI and quality of life. This group also had numerically reduced odds of achieving BASDAI50/2 [odds ratio (OR) 0.81; 95% CI: 0.45, 1.45] and BASDAI < 4 (OR 0.57; 95% CI: 0.32, 1.04). Treatment discontinuation was increased in those with two comorbidities [hazard ratio (HR) 1.32; 95% CI: 0.88, 2.00] and ≥3 comorbidities (HR 2.18; 95% CI: 1.20, 3.93) compared with none. Conclusions Participants with multiple comorbidities had poorer treatment outcomes, particularly increased treatment discontinuation and poorer improvements in function and quality of life. These results inform clinicians and educate patients about response to the first TNFi given comorbidity burden. [ABSTRACT FROM AUTHOR]

Objective Whether comorbidities influence disease activity assessment in axial SpA (axSpA) is unclear. Comorbidities inflate DAS28 in rheumatoid arthritis through the patient global score. We examined whether axSpA disease activity measures are differentially affected, and whether comorbidities inflate the AS disease activity score (ASDAS) through the patient global component. Methods We used baseline data from the British Society for Rheumatology Biologics Register for AS, including 14 physician diagnosed comorbidities. Linear models were used to compare disease activity (BASDAI, spinal pain, ASDAS) and ESR/CRP according to comorbidity count, adjusted for age, gender, BMI, smoking, socioeconomic status, and education. The same models were used to examine whether the patient global score was associated with comorbidities, additionally adjusting for other ASDAS components. Results The number of participants eligible for analysis was 2043 (67% male, mean age 49 years); 44% had at least one comorbidity. Each additional comorbidity was associated with higher BASDAI by 0.40 units (95% CI: 0.27, 0.52) and spinal pain by 0.53 (95% CI: 0.37, 0.68). Effect size for ASDAS (0.09 units; 95% CI: 0.03, 0.15) was not clinically significant. ESR and CRP were not associated with comorbidity count. Depression, heart failure and peptic ulcer were consistently associated with higher disease activity measures, but not CRP/ESR. Patient global was associated with comorbidity count, but not independently of other ASDAS components (P  = 0.75). Conclusion Comorbidities were associated with higher patient reported disease activity in axSpA. Clinicians should be mindful of the potential impact of comorbidities on patient reported outcome measures and consider additionally collecting ASDAS when comorbidities are present. [ABSTRACT FROM AUTHOR]

Objective: Systemic light-chain (AL) amyloidosis is an uncommon hematologic plasma cell dyscrasia that is becoming increasingly recognized. Therapeutic agents used in AL amyloidosis overlap with those used in multiple myeloma; however, differences in disease features change treatment efficacy and tolerance. Pharmacists must be cognizant of these distinctions. Herein, this review article provides an up-to-date guide to treatment considerations for systemic AL amyloidosis in both the front-line and relapsed settings. Data sources: A comprehensive literature search was performed using the PubMed/Medline database for articles published through (June 2020) regarding treatments for AL amyloidosis. Search criteria included therapies that are FDA approved for multiple myeloma, as well as investigational agents. This review of chemotherapeutic agents reflects the current clinical practice guidelines endorsed by NCCN along with commentary based on the experience of pharmacists from a tertiary-referral center treating many patients with AL amyloidosis. Data consists of randomized controlled trials, observational cohorts, case reports, and ongoing clinical trials. Data summary: Frontline options discussed here include high-dose melphalan with autologous stem cell transplantation and bortezomib-based regimens. Regarding the relapsed setting, supporting data are compiled and summarized for: bortezomib, ixazomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, elotuzumab, isatuximab, venetoclax, NEOD001, and melflufen. Conclusions: The treatment platform for AL amyloidosis is expanding with novel agents traditionally used in multiple myeloma being adopted and modified for use in AL amyloidosis. The pharmacist's familiarity with the clinical evidence base for these agents and how they fit into standard protocols for AL amyloidosis is critical as dosing and monitoring recommendations are unique from multiple myeloma. [ABSTRACT FROM AUTHOR]

Objective To describe the prevalence of extra-articular manifestations—enthesitis, dactylitis, nail disease, uveitis and IBD—in PsA, and their impact on longitudinal disease outcomes. Methods We searched Medline, PubMed, Scopus and Web of Science using a predefined protocol in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies using imaging to define extra-articular manifestations (EAMs) were excluded. Where possible, we performed meta-analyses of prevalence estimates, reported as percentages (95% CI). Heterogeneity (I2 statistic) was examined according to study characteristics. Results We identified 65 studies amounting to a total of 163 299 PsA patients. Enthesitis was assessed in 29 studies with an average prevalence of 30% (95% CI: 24%, 38%). Dactylitis was reported in 35 studies with an average prevalence of 25% (95% CI: 20%, 31%). Nail disease was present in 60% (95% CI: 52%, 68%) across 26 studies, but definitions were often unclear. Uveitis (3.2%; 95% CI: 1.9%, 5.3%) and IBD (3.3%; 95% CI: 1.5%, 7.1%) were less common. Heterogeneity was high (>95%) in all meta-analyses, but could not be explained by study characteristics. No studies examined the impact of EAMs on longitudinal disease outcomes, except that dactylitis increases radiographic progression. Conclusion Enthesitis, dactylitis and nail disease are highly prevalent in PsA, but not uveitis and IBD. EAM patterns differ from axial SpA despite their shared disease mechanisms, which may help further understand differences between spondyloarthritides. More studies are needed on the impact of EAMs on disease outcomes such as response to treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) is among the most feared complications of chemotherapy by patients. Deviation from clinical practice guidelines may impair the optimal management of CINV. Furthermore, any operational challenges within a healthcare system may pose a barrier to the management of CINV and may place a large time commitment burden on providers. OBJECTIVE: To minimize the incidence of CINV in patients receiving highly emetogenic chemotherapy (HEC) by achieving 90% complete response to antiemetic regimens over 6 months in an outpatient oncology clinic using a pharmacist-run protocol. protocol between November 1, 2017, and April 30, 2018. Pharmacists completed all prior authorizations, prescribed and delivered medications, and provided face-to-face patient counseling. The proportion of complete responses to antiemetic drugs--defined as the absence of any CINV symptom at days 3 and 5 of the chemotherapy cycle--the percentage of patients managed via pharmacist protocol, the rates of patient enrollment submitted by providers, and the time pharmacists spent with patients, were collected as the study metrics. The providers were surveyed before and after the study to evaluate their perceived impact of the pharmacist-run protocol on patient outcomes and provider time. The protocol included 3 plan-do-study-act cycles: first cycle (weeks 1-6), second cycle (weeks 7-12), and third cycle (weeks 8-24). RESULTS: A total of 46 patients and 163 chemotherapy cycles were managed under the pharmacist- run protocol during the 6-month study period. The complete response rates to antiemetic regimens steadily increased over the study period from 65% at baseline to >90% by the end of the study, through utilization of the pharmacist-managed protocol. A mean time of 45.7 minutes per patient was spent by the pharmacists to maintain this protocol for new patients, which was consistent with the time-savings estimated by providers in pre-intervention surveys. CONCLUSION: The implementation of a pharmacist-run protocol led to high rates of complete response to antiemetic drugs (as measured by the absence of CINV) and significant time-savings for providers in an outpatient oncology clinic. This study supports the integration of pharmacy-driven services into healthcare systems to optimize and streamline providers' time in the clinic, by using pharmacists as extenders to prescribe and manage antiemetic drugs. [ABSTRACT FROM AUTHOR]

Objectives: To compare a Bayesian clinical decision support (CDS) dose-optimizing software program with clinician judgement in individualizing vancomycin dosing regimens to achieve vancomycin pharmacokinetic (PK)/pharmacodynamic (PD) targets in a paediatric population.Methods: A retrospective review combined with a model-based simulation of vancomycin dosing was performed on children aged 1 year to 18 years at the University of California, San Francisco Benioff Children's Hospital Mission Bay. Dosing regimens recommended by the clinical pharmacists, 'clinician-guided', were compared with alternative 'CDS-guided' dosing regimens. The primary outcome was the percentage of occasions predicted to achieve steady-state trough levels within the target range of 10-15 mg/L, with a secondary outcome of predicted attainment of AUC24 ≥400 mg·h/L. Statistical comparison between approaches was performed using a standard t-test.Results: A total of n=144 patient occasions were included. CDS-guided regimens were predicted to achieve vancomycin steady-state troughs in the target range on 70.8% (102/144) of occasions, as compared with 37.5% (54/144) in the clinician-guided arm (P<0.0001). An AUC24 of ≥400 mg·h/L was achieved on 93% (112/121) of occasions in the CDS-guided arm versus 72% (87/121) of occasions in the clinician-guided arm (P<0.0001).Conclusions: In a simulated analysis, the use of a Bayesian CDS tool was better than clinician judgement in recommending vancomycin dosing regimens in which PK/PD targets would be attained in children. [ABSTRACT FROM AUTHOR]

Objective The effects of smoking on disease manifestations in axial SpA are inadequately described. Utilizing a large and well-characterized cohort, we investigated the association between smoking and extra-axial manifestations, and smoking and disease severity measures. Methods Baseline data from the British Society for Rheumatology Biologics Register for Ankylosing Spondylitis were explored. Our analyses focused on extra-axial manifestations and other disease severity measures, including scales for fatigue, sleep, anxiety and depression. Logistic and linear models were used to quantify associations between disease characteristics according to smoking status (current/ex/never) and quantity (heavy/light), adjusting for age, gender, BMI, education, deprivation, comorbidities, symptom duration and alcohol status. Results A total of 2031 participants were eligible for the current analysis (68% male, mean age 49 years). Of these, 24% were current and 32% ex-smokers. When compared with non-smokers, current smokers had lower odds of uveitis [OR 0.7, 95% CI 0.5–0.9] and higher odds of psoriasis (ORadj 1.6, 95% CI 1.1–2.3). Ex- and current smokers had incrementally more severe disease than never smokers, with higher BASDAI (β = 0.3, 95% CI 0.1–0.6; β = 0.9, 95% CI 0.6–1.2) and BASFI (β = 0.5, 95% CI 0.2–0.8; β = 1.3, 95% CI 1.0–1.6); similar associations were observed for fatigue, sleep, anxiety and depression. Conclusion In this large cross-sectional study, we observed that smoking is independently associated with an adverse disease profile in axial SpA, including worse fatigue, sleep, anxiety and depression, and higher odds of psoriasis. The paradoxical association between current smoking and reduced odds of uveitis is interesting and warrants further investigation. [ABSTRACT FROM AUTHOR]

Aims: To evaluate our proposed multivariate approach to identify patients who will develop sight‐threatening diabetic retinopathy (STDR) within a 1‐year screen interval, and explore the impact of simple stratification rules on prediction. Materials and methods: A 7‐year dataset (2009‐2016) from people with diabetes (PWD) was analysed using a novel multivariate longitudinal discriminant approach. Level of diabetic retinopathy, assessed from routine digital screening photographs of both eyes, was jointly modelled using clinical data collected over time. Simple stratification rules based on retinopathy level were also applied and compared with the multivariate discriminant approach. Results: Data from 13 103 PWD (49 520 screening episodes) were analysed. The multivariate approach accurately predicted whether patients developed STDR or not within 1 year from the time of prediction in 84.0% of patients (95% confidence interval [CI] 80.4‐89.7), compared with 56.7% (95% CI 55.5‐58.0) and 79.7% (95% CI 78.8‐80.6) achieved by the two stratification rules. While the stratification rules detected up to 95.2% (95% CI 92.2‐97.6) of the STDR cases (sensitivity) only 55.6% (95% CI 54.5‐56.7) of patients who did not develop STDR were correctly identified (specificity), compared with 85.4% (95% CI 80.4‐89.7%) and 84.0% (95% CI 80.7‐87.6%), respectively, achieved by the multivariate risk model. Conclusions: Accurate prediction of progression to STDR in PWD can be achieved using a multivariate risk model whilst also maintaining desirable specificity. While simple stratification rules can achieve good levels of sensitivity, the present study indicates that their lower specificity (high false‐positive rate) would therefore necessitate a greater frequency of eye examinations. [ABSTRACT FROM AUTHOR]

There is an emerging need in clinical research to accurately predict patients' disease status and disease progression by optimally integrating multivariate clinical information. Clinical data are often collected over time for multiple biomarkers of different types (e.g. continuous, binary and counts). In this paper, we present a flexible and dynamic (time-dependent) discriminant analysis approach in which multiple biomarkers of various types are jointly modelled for classification purposes by the multivariate generalized linear mixed model. We propose a mixture of normal distributions for the random effects to allow additional flexibility when modelling the complex correlation between longitudinal biomarkers and to robustify the model and the classification procedure against misspecification of the random effects distribution. These longitudinal models are subsequently used in a multivariate time-dependent discriminant scheme to predict, at any time point, the probability of belonging to a particular risk group. The methodology is illustrated using clinical data from patients with epilepsy, where the aim is to identify patients who will not achieve remission of seizures within a five-year follow-up period. [ABSTRACT FROM AUTHOR]

RUTHERFORD, BLAIR. Working on the margins: black workers, white farmers in postcolonial Zimbabwe. xx, 267 pp., maps, tables, bibliogr. London, New York: Zed Books, 2001. £45.00 (cloth), £15.95 (paper) For [...]

Abstract: Longitudinal discriminant analysis (LoDA) can be used to classify patients into prognostic groups based on their clinical history, which often involves longitudinal measurements of various clinically relevant markers. Patients' longitudinal data is first modelled using multivariate generalised linear mixed models, allowing markers of different types (e.g. continuous, binary, counts) to be modelled simultaneously. We describe three approaches to calculating a patient's posterior group membership probabilities which have been outlined in previous studies, based on the marginal distribution of the longitudinal markers, conditional distribution and distribution of the random effects. Here we compare the three approaches, first using data from the Mayo Primary Biliary Cirrhosis study and then by way of simulation study to explore in which situations each of the three approaches is expected to give the best prediction. We demonstrate situations in which the marginal or random‐effects approach perform well, but find that the conditional approach offers little extra information to the random‐effects and marginal approaches. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs) are an effective therapy for various cancers; however, they can induce immune-related adverse events (irAEs) as a side effect. Myocarditis is an uncommon, but fatal, irAE caused after ICI treatments. Currently, the mechanism of ICI-associated myocarditis is unclear. Here, we show the development of myocarditis in A/J mice induced by anti-PD-1 monoclonal antibody (mAb) administration alone without tumor cell inoculation, immunization, or viral infection. Mice with myocarditis have increased cardiac infiltration, elevated cardiac troponin levels, and arrhythmia. Anti-PD-1 mAb treatment also causes irAEs in other organs. Autoimmune T cells recognizing cardiac myosin are activated and increased in mice with myocarditis. Notably, cardiac myosin-specific T cells are present in naive mice, showing a phenotype of antigen-experienced T cells. Collectively, we establish a clinically relevant mouse model for ICI-associated myocarditis and find a contribution of cardiac myosin-specific T cells to ICI-associated myocarditis development and pathogenesis. [Display omitted] • PD-1 inhibitor treatment alone causes myocarditis development in A/J mice • Cardiac-myosin-specific T cells drive PD-1 inhibitor-induced myocarditis in mice • Cardiac-myosin-specific autoimmune T cells are present in naive mouse hearts • Cardiac-myosin-specific autoimmune T cells express PD-1 during naive conditions Won et al. demonstrate that PD-1 inhibitor treatment alone induces myocarditis in A/J mice, creating a mouse model for immune-checkpoint-inhibitor-associated myocarditis. Cardiac myosin-specific autoreactive T cells drive the pathogenesis of PD-1 inhibitor-induced myocarditis in mice. PD-1-expressing cardiac myosin-specific T cells are present in the heart during naive conditions. [ABSTRACT FROM AUTHOR]

A survey was conducted to assess pressure management practices in water distribution systems. Most of the surveyed utilities agreed on the need to avoid low-pressure episodes (< 20 psi). However, 56% of the utilities had no requirements for the maximum pressure delivered to customers, and 67% did not manage peak pressures in their systems. Only 13% of surveyed systems conducted pressure monitoring at critical locations--e.g., sites of highest or lowest pressure. Approximately 50% of systems reported at least one occurrence of negative pressure during the previous year; however, many more incidents of low and/or negative pressure may have gone undetected. The authors recommend that distribution system pressures be monitored in at least two locations in each pressure zone, representing the highest and lowest pressures. The recording interval could be set to 5-10 min with a 10-s sampling interval. Impulse recording (when available) should be enabled to capture momentary pressure changes. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) is a progressive disease for which there is no disease modifying therapy. Vitamin K levels and vitamin K antagonism have been associated with risk and progression of OA which may have direct implications for clinical management, but these observational findings are susceptible to confounding. We aimed to estimate the causal association between vitamin K and OA risk using Mendelian randomisation (MR). We used data from the largest genome-wide association study (GWAS) of OA to date (up to 826,690 individuals) to estimate the effect of genetically predicted vitamin K level (instrumented using four variants derived from a GWAS of 2,138 individuals) on risk of all OA types, knee, hip, spine, hand OA, and total joint replacement. We employed the inverse-variance weighted method for the primary analysis and, in a series of sensitivity analyses, adjusted for sub-genome wide significant instruments and tested for potential bias from pleiotropy. We showed that genetically predicted vitamin K levels were not causally associated with risk of OA overall (OR 0.98 per unit increase in log-transformed vitamin K1; 95%CI 0.96-1.01), knee (OR 0.98; 0.92-1.03), hip (OR 0.97; 0.88-1.07), spine (OR 0.97; 0.90-1.04), hand OA (OR 0.97; 0.91-1.04) or joint replacement (OR 0.96; 0.89-1.04). Results were similar across all sensitivity analyses. We found little evidence of a causal association between genetically predicted vitamin K and OA risk. Larger genetic and interventional studies of vitamin K are required to confirm our findings. [ABSTRACT FROM AUTHOR]