Nevin Manimala

Trials. 2022 Aug 9;23(1):645. doi: 10.1186/s13063-022-06536-x.

ABSTRACT

INTRODUCTION: Alliance for Clinical Trials in Oncology (Alliance) coordinated trials utilize Medidata Rave® (Rave) as the primary clinical data capture system. A growing number of innovative and complex cancer care delivery research (CCDR) trials are being conducted within the Alliance with the aims of studying and improving cancer-related care. Because these trials encompass patients, providers, practices, and their interactions, a defining characteristic of CCDR trials is multilevel data collection in pragmatic settings. Consequently, CCDR trials necessitated innovative strategies for database development, centralized data management, and data monitoring in the presence of these real-world multilevel relationships. Having real trial experience in working with community and academic centers, and having recently implemented five CCDR trials in Rave, we are committed to sharing our strategies and lessons learned in implementing such pragmatic trials in oncology.

METHODS: Five Alliance CCDR trials are used to describe our approach to analyzing the database development needs and the novel strategies applied to overcome the unanticipated challenges we encountered. The strategies applied are organized into 3 categories: multilevel (clinic, clinic stakeholder, patient) enrollment, multilevel quantitative and qualitative data capture, including nontraditional data capture mechanisms being applied, and multilevel data monitoring.

RESULTS: A notable lesson learned in each category was (1) to seek long-term solutions when developing the functionality to push patient and non-patient enrollments to their respective Rave study database that affords flexibility if new participant types are later added; (2) to be open to different data collection modalities, particularly if such modalities remove barriers to participation, recognizing that additional resources are needed to develop the infrastructure to exchange data between that modality and Rave; and (3) to facilitate multilevel data monitoring, orient site coordinators to the their trial’s multiple study databases, each corresponding to a level in the hierarchy, and remind them to establish the link between patient and non-patient participants in the site-facing NCI web-based enrollment system.

CONCLUSION: Although the challenges due to multilevel data collection in pragmatic settings were surmountable, our shared experience can inform and foster collaborations to collectively build on our past successes and improve on our past failures to address the gaps.

PMID:35945621 | DOI:10.1186/s13063-022-06536-x

Orphanet J Rare Dis. 2022 Aug 9;17(1):310. doi: 10.1186/s13023-022-02453-z.

ABSTRACT

BACKGROUND: Leber hereditary optic neuropathy (LHON) is the most common mitochondrial disorder, frequently resulting in acute or subacute severe bilateral central vision loss. Vitamin B12 deficiency is also a known cause of optic neuropathy through mitochondrial dysfunction. Here we evaluated the prevalence and clinical significance of vitamin B12 deficiency in a large cohort of LHON patients and asymptomatic mutation carriers from a tertiary referral center.

METHODS: From the Munich LHON prospective cohort study, participants included all LHON patients and asymptomatic LHON mutation carriers, who were recruited between February 2014 and March 2020 and consented to participate. Neurological, general, and ophthalmological examinations were regularly performed, as were laboratory tests. Vitamin B12 deficiency was diagnosed if serum vitamin B12 was below 201 pg/mL, or if 201-339 pg/mL plus low serum holotranscobalamin or elevated serum methylmalonic acid or elevated total plasma homocysteine.

RESULTS: We analyzed 244 subjects, including 147 symptomatic LHON patients (74% males) and 97 asymptomatic mutation carriers (31% males). Median age at study baseline was 34 years (range 5-82 years). The prevalence of vitamin B12 deficiency was higher for LHON mutation carriers than for the general population in all age categories. This was statistically significant for the LHON mutation carriers under 65 years (21% vs. 5-7%, p = 0.002). While vitamin B12 deficiency prevalence was not statistically different between LHON patients and asymptomatic mutation carriers, its clinical correlates, e.g., macrocytosis and polyneuropathy, were more frequent in the subgroup of LHON patients. Excessive alcohol consumption was a significant predictor of vitamin B12 deficiency (p < 0.05).

CONCLUSIONS: The high prevalence of vitamin B12 deficiency in LHON mutation carriers, both asymptomatic mutation carriers and LHON patients, highlights the need for regular vitamin B12 screening in this population, in order to ensure early treatment, aiming for better outcomes. Our study is not conclusive regarding vitamin B12 deficiency as determinant for disease conversion in LHON, and further research is warranted to disentangle the role of vitamin B12 in the pathophysiology and prognosis of LHON.

PMID:35945620 | DOI:10.1186/s13023-022-02453-z

BMC Med. 2022 Aug 10;20(1):254. doi: 10.1186/s12916-022-02445-7.

ABSTRACT

Adaptive designs are a class of methods for improving efficiency and patient benefit of clinical trials. Although their use has increased in recent years, research suggests they are not used in many situations where they have potential to bring benefit. One barrier to their more widespread use is a lack of understanding about how the choice to use an adaptive design, rather than a traditional design, affects resources (staff and non-staff) required to set-up, conduct and report a trial. The Costing Adaptive Trials project investigated this issue using quantitative and qualitative research amongst UK Clinical Trials Units. Here, we present guidance that is informed by our research, on considering the appropriate resourcing of adaptive trials. We outline a five-step process to estimate the resources required and provide an accompanying costing tool. The process involves understanding the tasks required to undertake a trial, and how the adaptive design affects them. We identify barriers in the publicly funded landscape and provide recommendations to trial funders that would address them. Although our guidance and recommendations are most relevant to UK non-commercial trials, many aspects are relevant more widely.

PMID:35945610 | DOI:10.1186/s12916-022-02445-7

Genome Med. 2022 Aug 9;14(1):85. doi: 10.1186/s13073-022-01094-y.

ABSTRACT

BACKGROUND: Rare diseases collectively affect up to 10% of the population, but often lack effective treatment, and typically little is known about their pathophysiology. Major challenges include suboptimal phenotype mapping and limited statistical power. Population biobanks, such as the UK Biobank, recruit many individuals who can be affected by rare diseases; however, investigation into their utility for rare disease research remains limited. We hypothesized the UK Biobank can be used as a unique population assay for rare diseases in the general population.

METHODS: We constructed a consensus mapping between ICD-10 codes and ORPHA codes for rare diseases, then identified individuals with each rare condition in the UK Biobank, and investigated their age at recruitment, sex bias, and comorbidity distributions. Using exome sequencing data from 167,246 individuals of European ancestry, we performed genetic association controlling for case/control imbalance (SAIGE) to identify potential rare pathogenic variants for each disease.

RESULTS: Using our mapping approach, we identified and characterized 420 rare diseases affecting 23,575 individuals in the UK Biobank. Significant genetic associations included JAK2 V617F for immune thrombocytopenic purpura (p = 1.24 × 10^-13) and a novel CALR loss of function variant for essential thrombocythemia (p = 1.59 × 10^-13). We constructed an interactive resource highlighting demographic information ( http://www-personal.umich.edu/~mattpat/rareDiseases.html ) and demonstrate transferability by applying our mapping to a medical claims database.

CONCLUSIONS: Enhanced disease mapping and increased power from population biobanks can elucidate the demographics and genetic associations for rare diseases.

PMID:35945607 | DOI:10.1186/s13073-022-01094-y

Respir Res. 2022 Aug 9;23(1):202. doi: 10.1186/s12931-022-02126-2.

ABSTRACT

BACKGROUND: The efficacy and safety of complement inhibition in COVID-19 patients is unclear.

METHODS: A multicenter randomized controlled, open-label trial. Hospitalized COVID-19 patients with signs of systemic inflammation and hypoxemia (PaO₂/FiO₂ below 350 mmHg) were randomized (2:1 ratio) to receive standard of care with or without the C5 inhibitor zilucoplan daily for 14 days, under antibiotic prophylaxis. The primary outcome was improvement in oxygenation at day 6 and 15.

RESULTS: 81 patients were randomly assigned to zilucoplan (n = 55) or the control group (n = 26). 78 patients were included in the safety and primary analysis. Most were men (87%) and the median age was 63 years. The mean improvement in PaO₂/FiO₂ from baseline to day 6 was 56.4 mmHg in the zilucoplan group and 20.6 mmHg in the control group (mean difference + 35.8; 95% confidence interval (CI) – 9.4 to 80.9; p = 0.12), an effect also observed at day 15. Day 28 mortality was 9% in the zilucoplan and 21% in the control group (odds ratio 0.4; 95% CI 0.1 to 1.5). At long-term follow up, the distance walked in a 6-min test was 539.7 m in zilucoplan and 490.6 m in the control group (p = 0.18). Zilucoplan lowered serum C5b-9 (p < 0.001) and interleukin-8 (p = 0.03) concentration compared with control. No relevant safety differences between the zilucoplan and control group were identified.

CONCLUSION: Administration of zilucoplan to COVID-19 patients in this proof-of-concept randomized trial was well tolerated under antibiotic prophylaxis. While not reaching statistical significance, indicators of respiratory function (PaO₂/FiO₂) and clinical outcome (mortality and 6-min walk test) suggest that C5 inhibition might be beneficial, although this requires further research in larger randomized studies.

PMID:35945604 | DOI:10.1186/s12931-022-02126-2

Trials. 2022 Aug 9;23(1):637. doi: 10.1186/s13063-022-06583-4.

ABSTRACT

BACKGROUND: Dysmenorrhea is one of the most common disorders among young women. Medicinal herbs are one of the alternative methods for the treatment of dysmenorrhea. This study will investigate the effect of Rosa foetida extract, along with self-care behavior education on primary dysmenorrhea among female students of Babol University of medical sciences.

METHODS/DESIGN: A randomized clinical trial will be performed on single students, aged 18 to 24 years. The research samples will be divided into three groups. The students will receive self-care behavior education on dysmenorrhea. Following the education, two of the groups will receive Rosa foetida extract capsules and placebo capsules in two consecutive cycles every 8 h for two successive days, respectively. The capsules will have similar physical appearance. The third group will not receive any medication. Data will be collected through demographic characteristic questionnaire, visual analog scale, dysmenorrhea self-care behaviors scale questionnaire, pictorial chart, and menstrual distress scale questionnaire. In order to determine and compare the effect of pharmacological and educational interventions on the severity of dysmenorrhea in groups, an ANOVA analysis of variance test with repeated measures will be used by SPSS software version 22.

DISCUSSION: The results will show the effects of Rosa foetida extract along with self-care behavior education on primary dysmenorrhea, and beneficial effects that may be found in the trial of this plant may be of use for women with the same problem.

ETHICS AND DISSEMINATION: The study is approved by the Ethics Committee of Babol University of Medical Sciences (IR.MUBABOL.REC.1397.059).

TRIAL REGISTRATION: IRCT 20190318043086N1. Registered on 14 June 2019.

PMID:35945594 | DOI:10.1186/s13063-022-06583-4

BMC Oral Health. 2022 Aug 9;22(1):338. doi: 10.1186/s12903-022-02368-y.

ABSTRACT

BACKGROUND: The Tanaka and Johnson equation is commonly used in mixed dentition analysis. However, the analysis is based on a Caucasian population making clinical decisions challenging when used in different ethnic groups. This study developed a prediction equation based on a Kenyan population.

DESIGN: A descriptive cross-sectional study done in 68 13-17 years old Kenyans of African descent in two boarding secondary schools. Alginate impressions were taken, study models obtained, and mesiodistal tooth-widths measured on upper and lower study models from the first molar to the contralateral first molar. Descriptive statistics, paired t-tests and independent t-tests were conducted and Pearson product-moment correlation coefficients calculated (p < 0.05).

RESULTS: The mean age was 13.78 years (SD ± 0.70), females were 59%. The mesiodistal tooth-widths of the permanent canines and premolars were different between males and females (p ˂ 0.1). The Tanaka and Johnston equation significantly under-estimated the mesiodistal tooth-widths of the permanent canines and premolars (p ˂ 0.05). The addition of lower first permanent molars to the permanent lower incisors provided higher correlation coefficients than the Tanaka Johnston equation.

CONCLUSIONS: A new equation that includes the permanent lower incisors and first permanent molars as predictor teeth seems to be more suitable for mixed dentition analysis for this Kenyan population. A larger study is needed to validate these findings.

PMID:35945576 | DOI:10.1186/s12903-022-02368-y

BMC Oral Health. 2022 Aug 9;22(1):337. doi: 10.1186/s12903-022-02373-1.

ABSTRACT

BACKGROUND: The Sense of Coherence (SOC) construct has been used worldwide in oral health research, but rigorous factor analyses of the scale are scarce. We aim to test the dimensional structure of the Brazilian short version of the SOC scale with 13 items.

METHODS: This study is a secondary analysis of four independent cross-sectional Brazilian studies on oral health, using the 13-items SOC scale. Sample 1 was conducted on 1760 mothers and 1771 adolescents. Sample 2 comprised 1100 adults. Sample 3 had 720 adults and older individuals. Sample 4 comprised 664 adolescent students. Confirmatory Factor Analysis (CFA) was conducted on sample 1 to compare two models: 3-factor versus 1-factor. Because they were refuted, Exploratory Factor Analysis was implemented in samples 2 and 3. Modified models were tested in sample 4 using CFA. All analyses were conducted with MPlus version 7.11.

RESULTS: CFA of sample 1 resulted in an unacceptable fit (RMSEA = 0.12;CFI = 0.78; TLI = 0.73; and WRMR = 3.28) for 1-factor model and 3-factor (RMSEA = 0.10; CFI = 0.87; TLI = 0.84; and WRMR = 2.50). The EFA on samples 2 and 3 showed, respectively, two eigenvalues greater than 1 (4.11 and 1.56) and (4.32 and 1.42), but the scale items soc1, soc2 and soc3 formed an uninterpretable second factor. Another CFA, using sample 4, showed acceptable model fit after removing those three items and also soc11 (RMSEA = 0.05; CFI = 0.98; TLI = 0.99; and WRMR = 0.71).

CONCLUSION: The results indicate that the SOC-13 scale needs further adjustments. The one-factor model with nine items showed a good statistical fit, but the implications of excluding items should be further investigated, considering the scale’s content validity, cross-cultural adaptation and theoretical background.

PMID:35945574 | DOI:10.1186/s12903-022-02373-1

BMC Med Educ. 2022 Aug 9;22(1):610. doi: 10.1186/s12909-022-03678-z.

ABSTRACT

BACKGROUND: Complete denture, as an important restoration method for edentulism, is difficult to study for beginners, especially in linking the theory with clinical practice.

OBJECTIVE: This study was aimed to compare the teaching effects between case-based learning combined with Rain Classroom teaching and traditional lecture method in the clinical course of complete denture prosthesis for undergraduate interns.

METHODS: In a course called “Problems and treatment strategies of complete denture after wearing”, interns were divided into two groups: one for traditional lecture-based teaching with PowerPoint slideshow (the control group, n = 28); and the other for case-based learning combined with Rain Classroom teaching, which published information before class, discussed specific clinic cases in class and got real-time interns’ feedback via WeChat (the test group, n = 22). Both groups received the same exam and questionnaire survey after class. The Q&A participation of interns in class, theoretical test scores and questionnaire survey responses were used to evaluate the teaching effects. An independent sample t-test and the chi-square test or Fisher’s exact test were used for statistical analysis in this study.

RESULTS: The Q&A participation of interns in the test group was much better than that of the control group. The average score on the theoretical test after class in the test group (72.14 ± 12.24) was significantly higher than that in the control group (61.29 ± 20.12) (P < 0.05). In the test group, 94.54% (21/22) of the interns preferred the new teaching mode.

CONCLUSION: Case-based learning combined with Rain Classroom teaching is helpful to enliven the classroom atmosphere, inspire studying enthusiasm, and achieve a good learning effect in both theory and clinical practice related to complete denture prosthesis.

PMID:35945563 | DOI:10.1186/s12909-022-03678-z

J Anim Sci Biotechnol. 2022 Aug 10;13(1):94. doi: 10.1186/s40104-022-00741-z.

ABSTRACT

BACKGROUND: Carnitine facilitates the flux of long-chain fatty acids for hepatic mitochondrial beta-oxidation, which acts to ameliorate the negative energy balance commonly affecting high-yielding dairy cows. Inflammation triggered by lipopolysaccharide (LPS) load can however pose a challenge to the metabolic integrity via the expression of pro-inflammatory mediators, leading to immune system activation and respective metabolic alterations. The effect of enhanced carnitine availability on hepatic metabolome profiles during an inflammatory challenge has not yet been determined in dairy cows. Herein, Holstein cows were supplemented with 25 g/d rumen-protected carnitine from 42 d prepartum until 126 d postpartum (n = 16) or assigned to the control group with no supplementation during the same period (n = 14). We biopsied the liver of the cows before (100 d postpartum) and after (112 d postpartum) an intravenous injection of 0.5 µg/kg LPS. Liver samples were subjected to a targeted metabolomics analysis using the AbsoluteIDQ p180 Kit (Biocrates Life Sciences AG, Innsbruck, Austria). RESULTS: Multivariate statistical analyses revealed that hepatic metabolome profiles changed in relation to both the carnitine supplementation and the LPS challenge. Comparing the metabolite profiles on 100 d, carnitine increased the concentration of short- and long-chain acyl-carnitines, which may be explained by an enhanced mitochondrial fatty acid shuttle and hence greater energy availability. The LPS injection affected hepatic metabolite profiles only in the carnitine supplemented group, particularly altering the concentration of biogenic amines.

CONCLUSIONS: Our results point to interactions between an acute hepatic inflammatory response and biogenic amine metabolism, depending on energy availability.

PMID:35945561 | DOI:10.1186/s40104-022-00741-z