Category: Statistics

Pharmacoepidemiol Drug Saf. 2021 Mar 6. doi: 10.1002/pds.5220. Online ahead of print.

ABSTRACT

PURPOSE: Current guidelines have no sex-specific dosage advice for metoprolol. To evaluate whether women and men are prescribed the same dose a cohort analysis was performed in the population-based Rotterdam Study (RS). Results were replicated in the Integrated Primary Care Information (IPCI) database of automated general practice data.

METHODS: The mean daily starting doses of metoprolol in both sexes were compared with independent-samples t-tests and a linear regression analysis was used to adjust in the Rotterdam Study for co-variables, notably, cardiovascular comorbidity, migraine, age, SBP, DBP, BMI, socioeconomic status, use of other antihypertensive drugs, smoking, and alcohol. In the IPCI-database, adjustment was for age only.

RESULTS: The mean daily starting dose was statistically significantly lower in women than in men in both the RS and IPCI database, with a mean difference of 4.8 mg (95%CI -7.8,-1.8) and 4.6 mg (95%CI -5.3,-4.0), respectively. Statistical significance remained after adjustment in both databases.

CONCLUSIONS: Women received lower starting doses of metoprolol than men in two independent data collections despite non-sex specific cardiovascular guideline recommendations. This example of real-life pharmacotherapy can lead to a form of confounding by contraindication in pharmacoepidemiology.

PMID:33675258 | DOI:10.1002/pds.5220

J Med Radiat Sci. 2021 Mar 6. doi: 10.1002/jmrs.464. Online ahead of print.

ABSTRACT

INTRODUCTION: Most primary ocular adnexal lymphomas are those involving mucosa-associated lymphoid tissue (MALT). Radiotherapy (RT) dose regimens in the literature vary from the historically used high doses (up to 56 Gy) to lower dose RT. We aimed to examine our institution’s experience with the use of orbital RT for treating early-stage primary ocular adnexal MALT lymphoma (POAML).

METHODS: Patients treated for stage I or II POAML over a 12-year period (July 2006 to June 2018) were identified through institutional databases. Data were retrospectively collated through review of patient records. Descriptive statistical methods were employed to analyse the data.

RESULTS: Eighteen patients (median age of 67; range 44-87yrs) with localised POAML (3 cases of bilateral disease) were identified, resulting in a total of 21 evaluable orbits. Eight (44%) patients were female, and all were documented to be of good performance status (ECOG 0-1). The median follow-up was 34 months (range 8-75 months). The commonest dose fractionation used was 20 Gy in 10 fractions (n = 13 orbits) and a 3D conformal or volumetric modulated arc therapy (VMAT) technique was used in the majority of cases. None of the patients experienced an in-field recurrence. One patient had experienced a contralateral orbital recurrence two years post-unilateral orbital RT for orbital MALT lymphoma. Three patients experienced distant relapse.

CONCLUSION: The use of lower dose orbital RT such as 20 Gy in 10 fractions (or radio biologically equivalent) yields excellent local disease control in the management of ocular adnexal MALT lymphoma. The durability of the response appears to be favourable. Given the indolent nature of the disease and the low levels of toxicity associated with lower dose orbital RT, this regimen remains our favoured approach to the management of localised POAML.

PMID:33675287 | DOI:10.1002/jmrs.464

Orthop Surg. 2021 Mar 5. doi: 10.1111/os.12946. Online ahead of print.

ABSTRACT

OBJECTIVE: To compare the clinical and radiographic outcomes between the Tri-Lock Bone Preservation Stem (BPS) and the conventional standard Corail stem in primary total hip arthroplasty (THA).

METHODS: From March 2012 to May 2014, we retrospectively reviewed 84 patients (104 hips) who received Tri-Lock (BPS) and 84 patients (115 hips) who received conventional standard Corail stem in THA. Their mean ages were 53.12 ± 2.32 years and 52.00 ± 2.11 years, respectively. The clinical outcomes were assessed by Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Pain Visual Analogue Scale (VAS) and Harris Hip Score (HHS). The radiological outcomes were evaluated by the radiological examination. Accordingly, Intraoperative and postoperative complications were observed as well.

RESULTS: The mean follow-up time was 48.23 ± 2.91 months in the Tri-Lock (BPS) group and 49.11 ± 2.11 months in the Corail group, respectively. The bleeding volumes in two groups were comparable (169.22 ± 58.11 mL vs 179.30 ± 59.14 mL, P = 0.003), with more bleeding volume in Corail group patients, while no statistically significance with respect to operation time was observed (65.41 ± 6.24 min vs 63.99 ± 6.33 min, P = 0.567). The rates of intraoperative fracture was 8% for the Corail group while 1% for the Tri-Lock (BPS) group (8% vs 1%, P = 0.030). At final follow-up, no statistical differences in regard to HHS, WOMAC, and Pain VAS were revealed between the two groups (P > 0.05). The rate of thigh pain was higher in Corail group than in Tri-lock (BPS) group (5% vs 0%, P = 0.043). However, incidence of stress shielding in grade 1 was higher in Tri-Lock (BPS) than in the Corail group (76% vs 23%, P < 0.01), while those in grade 2 and 3 were lower compared to the Corail stem (15% vs 28%, P < 0.01; 9% vs 16%, P = 0.008, respectively). Intriguingly, other assessments in relation to radiographic outcomes and postoperative complications were not comparable between the two groups. The Kaplan-Meier survival rate (revision surgery performed for any reason was defined as the end point) was similar between the two groups (P = 0.57), with 98.8% (95% confidence interval, 92.3%-100%) in Tri-lock (BPS) group and 97.6% (95% confidence interval, 94.6%-100%) in Corail group.

CONCLUSIONS: The Tri-Lock (BPS) has similar clinic performances compared to the Corail stem. Furthermore, the Tri-lock (BPS) stem has some advantages in achieving lower incidence of thigh pain, stress shielding and intra-operative fracture. Therefore, we recommend the Tri-lock (BPS) stem as a good alternative in primary total hip arthroplasty, especially taking into account patient factors, including bone deficiency and convenience of extraction of the stem in hip revision.

PMID:33675168 | DOI:10.1111/os.12946

Horm Mol Biol Clin Investig. 2021 Mar 5. doi: 10.1515/hmbci-2020-0097. Online ahead of print.

ABSTRACT

OBJECTIVES: Prader-Willi syndrome (PWS) is a rare genetic syndrome characterized by hyperphagia and early development of morbid obesity. Cardiovascular disease (CVD) and metabolic syndrome (MetS) are major comorbidities in these patients leading to premature death. Inhibitory factor 1 (IF₁) works as a regulatory protein, inhibiting the ATP hydrolase activity of mitochondrial ATP synthase and likely playing a role in lipid metabolism. We aimed to assay IF₁ in adult patients with PWS evaluating any relationship with clinical, genetic and biochemical parameters.

METHODS: We recruited 35 adult patients with genetically confirmed PWS.

RESULTS: IF₁ serum concentration displayed a normal distribution with an average value of 70.7 ± 22.6 pg/mL, a median value of 66.1 pg/mL. It was above the reference range only in one patient. All parameters were compared from both sides of IF₁ median without displaying any significant differences. Patients with normal or low HDL-cholesterol did not present any difference as regards IF₁ levels, which were not different between patients with and without MetS. Non-esterified fatty acids (NEFA) serum levels (r=0.623; p<0.001) showed a statistically significant correlation with IF₁. Cholesterol and its fractions did not present any correlation with IF_1.

CONCLUSIONS: In this study we do not confirm that HDL-cholesterol and IF₁ are correlated, but we show that in adult PWS patients, NEFA are correlated with serum IF_1. This protein could play a role to some extent in determining the complex metabolic alterations in PWS patients.

PMID:33675216 | DOI:10.1515/hmbci-2020-0097

Diagnosis (Berl). 2021 Mar 5. doi: 10.1515/dx-2020-0139. Online ahead of print.

ABSTRACT

OBJECTIVES: Diagnostic Management Teams (DMTs) are one strategy for reducing diagnostic errors. This study examined errors in serology test selection after a positive antinuclear antibody (ANA) test in patients with suspected systemic autoimmune rheumatic disorder (SARD).

METHODS: This retrospective study included 246 patient cases reviewed by our ANA DMT from March to August 2019. The DMT evaluated the appropriateness of tests beyond ANA screening tests (overutilization, underutilization, or both) based on American College of Rheumatology recommendations and classified cases into diagnostic error or no error groups. Errors were quantified, and patient and provider characteristics associated with diagnostic errors were assessed.

RESULTS: Among 246 cases, 60.6% had at least one diagnostic error in test selection. The number of sub-serology tests ordered was 2.4 times higher in the diagnostic error group than in the no error group. The likelihood of at least one diagnostic error was higher in males and African American/Black patients, although the differences were not statistically significant. Providers from general internal medicine, primary care, and non-rheumatology specialties were approximately two times more likely to make diagnostic errors than rheumatology specialists.

CONCLUSIONS: Diagnostic errors in test selection after a positive ANA for patients with suspected SARD were common, although there were fewer errors when ordered by rheumatology specialists. These findings support the need to develop strategies to reduce diagnostic errors in test selection for autoimmunity evaluation and suggest that implementation of a DMT can be useful for providing guidance to clinicians to reduce overutilization and underutilization of laboratory tests.

PMID:33675217 | DOI:10.1515/dx-2020-0139

Pharm Stat. 2021 Mar 6. doi: 10.1002/pst.2106. Online ahead of print.

ABSTRACT

Regulatory agencies typically evaluate the efficacy and safety of new interventions and grant commercial approval based on randomized controlled trials (RCTs). Other major healthcare stakeholders, such as insurance companies and health technology assessment agencies, while basing initial access and reimbursement decisions on RCT results, are also keenly interested in whether results observed in idealized trial settings will translate into comparable outcomes in real world settings-that is, into so-called “real world” effectiveness. Unfortunately, evidence of real world effectiveness for new interventions is not available at the time of initial approval. To bridge this gap, statistical methods are available to extend the estimated treatment effect observed in a RCT to a target population. The generalization is done by weighting the subjects who participated in a RCT so that the weighted trial population resembles a target population. We evaluate a variety of alternative estimation and weight construction procedures using both simulations and a real world data example using two clinical trials of an investigational intervention for Alzheimer’s disease. Our results suggest an optimal approach to estimation depends on the characteristics of source and target populations, including degree of selection bias and treatment effect heterogeneity.

PMID:33675139 | DOI:10.1002/pst.2106

Eur J Neurosci. 2021 Mar 6. doi: 10.1111/ejn.15174. Online ahead of print.

ABSTRACT

Affective-motivational disturbances are highly inconsistent in animal pain models. The reproducibility of the open-field test in assessing anxiety, malaise, or disability remains controversial despite its popularity. While traumatic, persistent, or multi-regional pain models are commonly considered more effective in inducing negative affect or functional impairment, the early psychobehavioral changes before pain chronification are often underexplored. Here, we aimed to clarify the fundamental relationship between hypernociception and passive distress-like behavior using a model of transient inflammatory pain. To minimize latent confounders and increase data consistency, male C57BL/6N mice were habituated to the open-field arena 6 times before receiving the unilateral intraplantar injection of prostaglandin E2 (PGE2) or vehicle. Open-field (40-minute exploration) and nociceptive behavior were evaluated repeatedly along the course of hypernociception in both wild-type and transgenic mice with a known pronociceptive phenotype. To reduce subjectivity, multivariate open-field behavioral outcomes were analyzed by statistical modeling based on exploratory factor analyses, which yielded a 2-factor solution. Within 3 hours after PGE2 injection, mice developed significantly reduced center exploration (factor 1) and a marginally significant increase in their habituation tendency (factor 2), which were not apparent in vehicle-injected mice. The behavioral passivity generally improved as hypernociception subsided. Therefore, transient inflammatory irritation is sufficient to suppress mouse open-field exploratory activity. The apparent absence of late affective-motivational changes in some rodents with prolonged hypernociception may not imply a lack of preceding or underlying neuropsychological alterations. Procedural pain after invasive animal experiments, however small, should be assessed and adequately controlled as a potential research confounder.

PMID:33675141 | DOI:10.1111/ejn.15174

Pharm Stat. 2021 Mar 5. doi: 10.1002/pst.2109. Online ahead of print.

ABSTRACT

The purpose of assessing adverse events (AEs) in clinical studies is to evaluate what AE patterns are likely to occur during treatment. In contrast, it is difficult to specify which of these patterns occurs in each patient. To tackle this challenging issue, we constructed a new statistical model including nonnegative matrix factorization by incorporating background knowledge of AE-specific structures such as severity and drug mechanism of action. The model uses a meta-analysis framework for integrating data from multiple clinical studies because insufficient information is derived from a single trial. We demonstrated the proposed method by applying it to real data consisting of three Phase III studies, two mechanisms of action, five anticancer treatments, 3317 patients, 848 AE types, and 99,546 AEs. The extracted typical treatment-specific AE patterns coincided with medical knowledge. We also demonstrated patient-level safety profiles using the data of AEs that were observed by the end of the second cycle.

PMID:33675157 | DOI:10.1002/pst.2109

J Cachexia Sarcopenia Muscle. 2021 Mar 5. doi: 10.1002/jcsm.12693. Online ahead of print.

ABSTRACT

BACKGROUND: Muscle atrophy is a common pathology associated with disuse, such as prolonged bed rest or spaceflight, and is associated with detrimental health outcomes. There is emerging evidence that disuse atrophy may differentially affect males and females. Cellular mechanisms contributing to the development and progression of disuse remain elusive, particularly protein turnover cascades. The purpose of this study was to investigate the initial development and progression of disuse muscle atrophy in male and female mice using the well-established model of hindlimb unloading (HU).

METHODS: One hundred C57BL/6J mice (50 male and 50 female) were hindlimb suspended for 0 (control), 24, 48, 72, or 168 h to induce disuse atrophy (10 animals per group). At designated time points, animals were euthanized, and tissues (extensor digitorum longus, gastrocnemius, and soleus for mRNA analysis, gastrocnemius and extensor digitorum longus for protein synthesis rates, and tibialis anterior for histology) were collected for analysis of protein turnover mechanisms (protein anabolism and catabolism).

RESULTS: Both males and females lost ~30% of tibialis anterior cross-sectional area after 168 h of disuse. Males had no statistical difference in MHCIIB fibre area, whereas unloaded females had ~33% lower MHCIIB cross-sectional area by 168 h of unloading. Both males and females had lower fractional protein synthesis rates (FSRs) within 24-48 h of HU, and females appeared to have a greater reduction compared with males within 24 h of HU (~23% lower FSRs in males vs. 40% lower FSRs in females). Males and females exhibited differential patterns and responses in multiple markers of protein anabolism, catabolism, and myogenic capacity during the development and progression of disuse atrophy. Specifically, females had greater mRNA inductions of catabolic factors Ubc and Gadd45a (~4-fold greater content in females compared with ~2-fold greater content in males) and greater inductions of anabolic inhibitors Redd1 and Deptor with disuse across multiple muscle tissues exhibiting different fibre phenotypes.

CONCLUSIONS: These results suggest that the aetiology of disuse muscle atrophy is more complicated and nuanced than previously thought, with different responses based on muscle phenotypes and between males and females, with females having greater inductions of atrophic markers early in the development of disuse atrophy.

PMID:33675163 | DOI:10.1002/jcsm.12693

Exp Physiol. 2021 Mar 6. doi: 10.1113/EP089431. Online ahead of print.

ABSTRACT

NEW FINDINGS: What is the central question of this study? To explore the relationship between proteins in skeletal muscle and adipose tissue determined at rest and peak rates of fat oxidation in men and women. What is the main finding and its importance? Resting content of proteins in skeletal muscle involved in triglyceride hydrolysis and mitochondrial lipid transport are more strongly associated with peak fat oxidation rates than proteins related to lipid transport, or hydrolysis in adipose tissue. Whilst females display higher relative rates of fat oxidation than males, this was unexplained by the proteins measured in this study, suggesting other factors determine sex-differences in fat metabolism.

ABSTRACT: This study explored key proteins involved in fat metabolism that may associate with peak fat oxidation (PFO) and account for sexual dimorphism in exercise fuel metabolism. Thirty-six healthy adults [15 females; age 40 (11); V̇O₂ peak 42.5 (9.5) mL⋅kg BM^-1 ⋅min^-1 ; means±SD] completed two exercise tests to determine PFO via indirect calorimetry. Resting adipose tissue and/or skeletal muscle biopsies were obtained to determine the protein content of adipose tissue PLIN1, CGI-58, HSL, ATGL, ACSL1, CPT1b and oestrogen receptor α (ERα), and skeletal muscle FABPpm, ATGL, ACSL1, CTP1b and ERα. Moderate strength correlations were found between PFO (mg⋅kg FFM^-1 ⋅min^-1 ) and the protein content of ATGL [r_s = 0.41 (0.03-0.68), P<0.05] and CPT1b [r_s = 0.45 (0.09-0.71), P<0.05] in skeletal muscle. No other statistically significant bivariate correlations were consistently found. Females had a greater relative PFO compared to males: 7.1±1.9 vs 4.5±1.3 and 7.3±1.7 vs 4.8±1.2 mg⋅kg FFM^-1 ⋅min^-1 )] in the adipose tissue (n = 14) and skeletal muscle (n = 12) sub-groups, respectively (p<0.05). No statistically significant sex differences were found in the content of these proteins. The regulation of PFO may involve processes relating to intramyocellular triglyceride hydrolysis and mitochondrial fatty acid transport, and adipose tissue is likely to play a more minor role than muscle. Sex differences in fat metabolism are likely to be due to factors other than the resting content of proteins in skeletal muscle and adipose tissue relating to triglyceride hydrolysis and fatty acid transport. This article is protected by copyright. All rights reserved.

PMID:33675111 | DOI:10.1113/EP089431