Nevin Manimala

Methods Mol Biol. 2021;2249:261-280. doi: 10.1007/978-1-0716-1138-8_15.

ABSTRACT

Biomarkers are characteristics that are measured as indicators of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions. Biomarkers may serve a number of important uses, particularly in diagnosis and prognosis of disease, and as surrogates for clinical outcomes of disease (i.e., outcomes that measure how patient survives, functions, or feels). Establishing the validity of a given biomarker for a specific role requires the conduct of carefully designed clinical studies in which the biomarker and the outcome of interest are measured independently. The design and analysis of such studies is discussed. Surrogate outcomes in clinical trials consist of events or biomarkers intended to reflect important clinical outcomes. Surrogate outcomes may offer advantages in providing statistically robust estimates of treatment effects with smaller sample sizes. However, to be useful, surrogate outcomes have to be validated to ensure that the effect of therapy on them truly reflects the effect of therapy on the important clinical outcomes of interest.

PMID:33871849 | DOI:10.1007/978-1-0716-1138-8_15

Methods Mol Biol. 2021;2249:229-245. doi: 10.1007/978-1-0716-1138-8_13.

ABSTRACT

The study of patient-reported outcomes, now common in clinical research, had its origins in social and scientific developments during the latter twentieth century. Patient-reported outcomes comprise functional and health status, health-related quality of life, and quality of life. The terms overlap and are used inconsistently, and these terms should be distinguished from expressions of preference regarding health states. Regulatory standards from the USA and European Union provide some guidance regarding reporting of patient-reported outcomes. Determining that patient-reported outcomes measurement is important depends in part on the balance between subjective and objective outcomes of the health problem under study. Instrument selection depends to a large extent on practical considerations. A number of instruments can be identified that are frequently used in particular clinical situations. The domain coverage of commonly used generic short forms varies substantially. Individualized measurement of quality of life is possible, but resource intensive. Focus groups are useful, not only for scale development but also to confirm the appropriateness of existing instruments.Under classical test theory, validity and reliability are the critical characteristics of tests. Under item response theory, validity remains central, but the focus moves from the reliability of scales to the relative levels of traits in individuals and items’ relative difficulty. Plans for clinical studies should include an explicit model of the relationship of patient-reported outcomes to other parameters, as well as define the magnitude of difference in patient-reported outcomes that will be considered important. It is particularly important to minimize missing patient-reported outcome data; to a limited extent, a variety of statistical techniques can mitigate the consequences of missing data.

PMID:33871847 | DOI:10.1007/978-1-0716-1138-8_13

Methods Mol Biol. 2021;2249:213-227. doi: 10.1007/978-1-0716-1138-8_12.

ABSTRACT

When analyzing the results of a trial, the primary outcome variable must be kept in clear focus. In the analysis plan, consideration must be given to comparing the characteristics of the subjects, taking account of differences in these characteristics, intention-to-treat analysis, interim analyses and stopping rules, mortality comparisons, composite outcomes, research design including run-in periods, factorial, stratified and crossover designs, number needed to treat, power issues, multivariate modeling, subgroup analysis, competing risks, and hypothesis-generating analyses.

PMID:33871846 | DOI:10.1007/978-1-0716-1138-8_12

Methods Mol Biol. 2021;2249:103-124. doi: 10.1007/978-1-0716-1138-8_7.

ABSTRACT

Statistical models are used to study the relationship between exposure and disease while accounting for the potential role of other factors’ impact upon outcomes. This adjustment is useful to obtain unbiased estimates of true effects or to predict future outcomes. Statistical models include a systematic and an error component. The systematic component explains the variability of the response variable as a function of the predictors and is summarized in the effect estimates (model coefficients). The error element of the model represents the variability in the data unexplained by the model and is used to build measures of precisions around the point estimates (Confidence Intervals).

PMID:33871841 | DOI:10.1007/978-1-0716-1138-8_7

Methods Mol Biol. 2021;2249:1-16. doi: 10.1007/978-1-0716-1138-8_1.

ABSTRACT

Clinical epidemiology is the science of human disease investigation with a focus on diagnosis, prognosis, and treatment. The generation of a reasonable question requires definition of patients, interventions, controls, and outcomes. The goal of research design is to minimize error, ensure adequate samples, measure input and output variables appropriately, consider external and internal validities, limit bias, and address clinical as well as statistical relevance. The hierarchy of evidence for clinical decision-making places randomized controlled trials (RCT) or systematic review of good-quality RCTs at the top of the evidence pyramid. Prognostic and etiologic questions are best addressed with longitudinal cohort studies.

PMID:33871835 | DOI:10.1007/978-1-0716-1138-8_1

Spine Deform. 2021 Apr 19. doi: 10.1007/s43390-020-00283-2. Online ahead of print.

ABSTRACT

OBJECTIVES: To study factors causing postoperative change of PI after surgical correction of ASD and to assess the effect of this variability on postoperative PI-LL mismatch.

BACKGROUND: PI is used as an individual constant to define lumbar lordosis (LL) correction goal (PI-LL < 10). Postoperative changes of PI were shown but with opposite vectors. The impact of the PI variability on the postoperative PI-LL has not been studied.

METHODS: The medical and radiographic data analyzed for patients who underwent long posterior instrumented spinal fusion. Inclusion criteria are age, ≥ 20 years old; ASD due to degenerative disk disease (DDD) or scoliosis (DS); ≥ 3 levels fused; and 2-year follow-up or revision. Studied parameters are LL (L1-S1), PI, sacral slope (SS), pelvic tilt (PT), and PI-LL. Measurement error and postoperative changes were defined. Statistical analysis includes ANOVA, correlation, regression, and risk assessment by odds ratio; P ≤ 0.05 considered statistically significant.

RESULTS: Eighty patients were included: mean age, 62.4 years-old (SD, 11.1); female, 63.7%; mean body mass index (BMI), 27.1 (SD, 5.6). Distribution of patients by follow-ups includes preoperative 100%; postoperative (1-3 weeks), 100%; 11-13 months. 90%; 22-26 months, 58%; and revision: 24%. Pre- versus postoperative PI (∆PI) changed both positively and negatively and the absolute value of change|∆PI| exceeded measurement error (P ≤ 0.05) reaching as high as 31°, and progressed with time; R² dropped from 0.73 to 0.45 (P < 0.001); ∆PI depended on disproportional changes of SS and PT, preoperative PI, and change of LL. Obesity, DS, and absence of sacroiliac fixation increased |∆PI|. The risk of LL insufficient correction (PI-LL > 10°) associated with a |∆PI|> 6°, P = 0.05. Sacroiliac fixation diminished PI variability only during the first postoperative year.

CONCLUSION: Preoperative variability and postoperative instability of PI diminish the applicability of the PI-LL < 10° goal to plan correction of LL. An alternative method is offered.

LEVEL OF EVIDENCE: IV.

PMID:33871832 | DOI:10.1007/s43390-020-00283-2

Ann Nucl Med. 2021 Apr 19. doi: 10.1007/s12149-021-01612-9. Online ahead of print.

ABSTRACT

OBJECTIVE: Astatine (²¹¹At) is a promising alpha emitter as an alternative to iodine (¹³¹I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [²¹¹At]NaAt to determine the FIH dose.

METHODS: [²¹¹At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups.

RESULTS: No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [²¹¹At]NaAt.

CONCLUSIONS: In the extended single-dose toxicity study of [²¹¹At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.

PMID:33871803 | DOI:10.1007/s12149-021-01612-9

J Gastrointest Cancer. 2021 Apr 19. doi: 10.1007/s12029-021-00641-x. Online ahead of print.

ABSTRACT

PURPOSE: Gastric and small intestine are the most common gastrointestinal stromal tumors (GISTs). There are few studies of patients who underwent surgical treatment with disparate findings. We aimed to evaluate the differences between groups and the risk factors for recurrence and mortality.

METHODS: A retrospective study of 96 gastric and 60 small intestine GIST was performed between 1995 and 2015. Both groups were compared in terms of clinicopathologic features, morbidity, recurrence, and mortality. Statistical analysis was performed with SPSS®.

RESULTS: Eighty-one gastric GISTs and 56 small intestine GISTs underwent surgical treatment. Gastrointestinal bleeding was the most common cause of emergency surgery being more frequent in gastric GIST (P = 0.009); however, emergency surgery was indicated more frequently in the small intestinal GIST (P = 0.004) and was mostly due to perforation (P = 0.009). With a median follow-up of 66.9 (39.7-94.8) months, 28 (20.4%) patients had recurrence. A mitotic index > 5 (P ≤ 0.001) and the intestinal location (P = 0.012) were significantly associated to recurrence. Tumor size > 15 cm (P = 0.001) and an age of ≥ 75 years (P = 0.014) were associated to mortality. On univariate analysis, higher mean values of Ki-67 were associated to higher mortality (P = 0.0032). Small intestine GIST presented lower disease-free survival (DFS) than that of gastric GIST (65.7% vs 90.8%) with P = 0.003. The overall survival (OS) of gastric and small intestine GIST was 74.7% and 71.6%, respectively (P = 0.68).

CONCLUSION: Small intestine GIST received emergency surgery more frequently showing lower DFS and same OS than that of gastric GIST. We found that Ki-67 could be a prognostic factor. Further studies are necessary to assess whether Ki-67 is a prognostic risk factor for GISTs.

PMID:33871798 | DOI:10.1007/s12029-021-00641-x

Endocrine. 2021 Apr 19. doi: 10.1007/s12020-021-02730-0. Online ahead of print.

ABSTRACT

PURPOSE: Sodium-glucose cotransporter 2 inhibitors increase glucagon secretion by pancreatic alpha cells and the susceptibility to ketoacidosis. On the other hand, growth hormone (GH) stimulates peripheral lipolysis and provides free fatty acids (FFA) for ketogenesis; however, it remains unresolved whether GH directly impacts hepatic ketogenesis. We aimed to investigate the role of physiologic GH levels in promoting ketogenesis in prediabetic or type 2 diabetic patients under empagliflozin treatment.

METHODS: Sixteen patients (11 women, 5 men) with prediabetes or type 2 diabetes mellitus, aged 55.6 ± 4.7 years and with a mean BMI of 30.7 ± 4.8 kg/m² and HbA1c 7.1 ± 1.6% (means ± SD), participated in this study. All of them were submitted to three mixed-meal tests: they received placebo at -60 min (test 1), and empagliflozin 25 mg (test 2, 21st day) and empagliflozin 25 mg plus pegvisomant 30 mg were administered subcutaneously 36 h before (test 3, 28th day). After test 1, all patients were instructed to take empagliflozin 25 mg daily.

RESULTS: The empagliflozin treatment decreased the plasma concentrations of glucose by 14% (P < 0.01), FFA by 23% (P < 0.01), and the insulin/glucagon ratio by 26% (P < 0.01), and it increased β-hydroxybutyrate by 44% (P < 0.05). The GH receptor block by pegvisomant restored the plasma β-hydroxybutyrate to baseline levels.

CONCLUSIONS: We conclude that GH has a direct effect on promoting the ketogenesis environment in patients treated with empagliflozin.

PMID:33871793 | DOI:10.1007/s12020-021-02730-0

J Clin Monit Comput. 2021 Apr 19. doi: 10.1007/s10877-021-00704-1. Online ahead of print.

ABSTRACT

Almost since its introduction pulse oximetry was known to overestimate oxygen saturation in cases of carbon monoxide poisoning or elevated methemoglobin (metHb) levels. To eliminate this dangerous behavior some manufacturers have added additional LED emitters to try to increase the number of measured hemoglobin species and to improve measurement accuracy, but have not been very successful. We hypothesized that the use of narrow-band laser light sources would make accurate and precise measurement of the four primary species of hemoglobin possible, even in cases of elevated levels of carboxyhemoglobin (COHb). Calibration and verification studies were performed on a tissue simulator that employed an artificial finger pulsating with whole human blood. This simulator allowed safe generation of 165 different combinations of the levels of oxyhemoglobin (O₂Hb), COHb, metHb, and reduced hemoglobin (RHb) for calibration of the laser-based pulse oximeter. A follow-on study used 56 mixed hemoglobin levels for verification and statistical analysis of the performance of this device. This laser-based pulse oximeter measured all four species of hemoglobin accurately and precisely (A_RMS ≤ 1.8%) for metHb levels in the clinically normal range. At elevated metHb levels the device continued to provide accurate and precise measurements of metHb and RHb (A_RMS ≤ 1.7%). The use of monochromatic laser light sources can create a new generation of highly accurate, multi-parameter, pulse oximeters.

PMID:33871764 | DOI:10.1007/s10877-021-00704-1