Nevin Manimala

Liver Transpl. 2021 Jul 15. doi: 10.1002/lt.26231. Online ahead of print.

ABSTRACT

With advances in computing and information technology, large healthcare research databases are becoming increasingly accessible to investigators across the world. These rich, population-level data sources can serve many purposes, such as to generate ‘Real World Evidence’, to enhance disease phenotyping, or to identify unmet clinical needs, among others. This is of particular relevance to the study of patients with end-stage liver disease (ESLD) – a socioeconomically and clinically heterogeneous population that is frequently under-represented in clinical trials. This review describes the recommended ‘best practices’ in the execution, reporting and interpretation of large database clinical epidemiology research in hepatology. The advantages and limitations of selected data sources are reviewed, as well as important concepts on data linkages. The appropriate classification of exposures and outcomes is addressed, and the strategies needed to overcome limitations of the data and minimize bias are explained as they pertain to patients with ESLD and/or liver transplant (LT) recipients. Lastly, selected statistical concepts are reviewed, from model building to analytic decision-making and hypothesis testing. The purpose of this review is to provide the practical insights and knowledge needed to ensure successful and impactful research using large clinical databases in the modern era, and advance the study of ESLD and LT.

PMID:34265178 | DOI:10.1002/lt.26231

Clin Pharmacol Drug Dev. 2021 Jul 15. doi: 10.1002/cpdd.996. Online ahead of print.

ABSTRACT

Pharmacokinetics, safety, and tolerability of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg were assessed in this phase 1, single-arm, open-label, single-dose study in fasted healthy male (n = 4) and female (n = 8) participants of Japanese heritage. Participants received a single dose of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg after an 8-hour fast, with safety assessments and blood samples for pharmacokinetic parameters collected through 72 hours after dosing. Geometric mean maximum plasma concentrations were 5.22 μg/mL (time to maximum concentration [t_max ], 1.01 hours) for abacavir, 4.13 μg/mL (t_max , 3.50 hours) for dolutegravir, and 3.35 μg/mL (t_max , 2.98 hours) for lamivudine. Geometric mean area under the concentration-time curve values were 18.20, 71.60, and 16.60 μg • h/mL for abacavir, dolutegravir, and lamivudine, respectively. No adverse events were reported, and no clinically significant findings were observed in laboratory values, physical examinations, or 12-lead electrocardiographic parameters. Single-tablet administration of abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg was well tolerated in Japanese participants. Exposure to abacavir and lamivudine was comparable with that seen in previous studies. A modest increase in exposure to dolutegravir vs previous clinical studies was observed but is not expected to impact the clinical management of HIV-1 or increase the risk for adverse events.

PMID:34265164 | DOI:10.1002/cpdd.996

J Genet Couns. 2021 Jul 15. doi: 10.1002/jgc4.1444. Online ahead of print.

ABSTRACT

In recent years, it has become apparent that patients expect genetic counselors to be able to address questions about insurance coverage for genetic testing and perform ‘genesurance’ tasks in and out of genetic counseling sessions. Anecdotally, many genetic counseling graduate programs have begun to incorporate genesurance training in some capacity. However, the amount, modality, and potential barriers to this training had not been previously studied; therefore, this study aimed to elucidate current graduate program practice regarding genesurance. Program Directors of Accreditation Council for Genetic Counseling (ACGC) accredited programs who had students enrolled as of July 2019 (n = 50) were recruited through the Association of Genetic Counseling Program Directors (AGCPD) listserv and invited to complete an anonymous electronic survey via Qualtrics. Program Directors (PDs) from 25 ACGC accredited programs located in the United States completed the survey and were included in the analysis, responses from two ACGC Canadian programs were excluded due to small sample size and differences in healthcare systems. Responses were analyzed using descriptive statistics and open-ended responses were coded utilizing latent qualitative content analysis. The majority of respondents from the United States, 96.0% (24/25), report incorporating genesurance training into their curriculum utilizing a variety of training modalities including classroom, clinical, and online experiences. Most (81.0%) felt their trainees were adequately or very prepared to discuss genesurance issues. Despite varied methods of teaching modalities, PDs identified barriers to providing this training, including time constraints within the curriculum, lack of interest in the subject, as well as acknowledging the constantly changing landscape of billing and insurance. Despite these barriers, a baseline understanding of the impact of insurance on offering genetic testing and insight into how insurance impacts clinical practice may be beneficial to genetic counseling trainees, as it reflects the current genetic counselor’s workflow and practice patterns.

PMID:34265129 | DOI:10.1002/jgc4.1444

Acta Paediatr. 2021 Jul 15. doi: 10.1111/apa.16032. Online ahead of print.

ABSTRACT

AIM: To examine the factors associated with the risk of neonatal mortality following caesarean births at country-level in sub-Saharan Africa.

METHODS: We used meta-analytic procedure to synthesize the results of most recent nationally representative cross-sectional Demographic and Health Survey (DHS) datasets for 33 sub-Saharan Africa countries conducted between 2010 and 2018. Pooled odds ratio (OR) and 95% confidence intervals (CI) were computed for all countries.

RESULTS: The overall caesarean section (CS) rate was 4.9%, neonatal mortality was 2.8% and Post-CS neonatal mortality was 4.3%. The rates of CS were generally low and only 5 countries had CS rates at or above 10%. The overall pooled result showed a statistically significant increase in the odds of neonatal mortality after a caesarean section (CS) OR 1.7 (95% CI 1.53 – 1.89; I² = 39.3%, p<0.012); such that children delivered via CS were 70% more likely not to survive beyond the first 30 days. Geographical variations existed in the measure of association between caesarean section and neonatal mortality.

CONCLUSION: This paper has provided evidence on the low rates of CS and the associated neonatal mortality risk compared to normal deliveries in sub-Saharan Africa.

PMID:34265122 | DOI:10.1111/apa.16032

Med Phys. 2021 Jul 15. doi: 10.1002/mp.15098. Online ahead of print.

ABSTRACT

PURPOSE: We propose a general framework for quantifying predictive uncertainties of dose-related quantities and leveraging this information in a dose mimicking problem in the context of automated radiation therapy treatment planning.

METHODS: A three-step pipeline, comprising feature extraction, dose statistic prediction and dose mimicking, is employed. In particular, the features are produced by a convolutional variational autoencoder and used as inputs in a previously developed nonparametric Bayesian statistical method, estimating the multivariate predictive distribution of a collection of predefined dose statistics. Specially developed objective functions are then used to construct a probabilistic dose mimicking problem based on the produced distributions, creating deliverable treatment plans.

RESULTS: The numerical experiments are performed using a dataset of 94 retrospective treatment plans of prostate cancer patients. We show that the features extracted by the variational autoencoder capture geometric information of substantial relevance to the dose statistic prediction problem and are related to dose statistics in a more regularized fashion than hand-crafted features. The estimated predictive distributions are reasonable and outperforms a non-input-dependent benchmark method, and the deliverable plans produced by the probabilistic dose mimicking agree better with their clinical counterparts than for a non-probabilistic formulation.

CONCLUSIONS: We demonstrate that prediction of dose-related quantities may be extended to include uncertainty estimation and that such probabilistic information may be leveraged in a dose mimicking problem. The treatment plans produced by the proposed pipeline resemble their original counterparts well, illustrating the merits of a holistic approach to automated planning based on probabilistic modeling.

PMID:34265105 | DOI:10.1002/mp.15098

Br J Clin Pharmacol. 2021 Jul 15. doi: 10.1111/bcp.14985. Online ahead of print.

ABSTRACT

AIM: The Norwegian Association for Clinical Pharmacology in their National Guidelines decreased therapeutic range (TR) of topiramate (TPM) from 5-20 mg/L to 2-10 mg/L. The objective of this study is to ascertain which TR produces better clinical outcomes.

METHODS: Data source were request forms for routine therapeutic drug monitoring of TPM. Concentration dependent adverse drug reactions (ADRs) were evaluated in 1,721 samples taken pre-dose. Seizure frequency analysis was performed in 294 samples of monotherapy.

STATISTICS: Prism 5.0, GraphPad Instatt: One-way Anova with Bonferroni correction for median plasma level (PL). χ2-test with Bonferroni correction for seizure frequency and for distribution of PL according to TR 5-20 mg/L and intervals <2, 2-5, 5-10, 10-20, >20 mg/L.

RESULTS: Better seizure control was found in children both in whole cohort (without seizure 49% vs 37% adults), as well as in monotherapy (56% vs 44%), in children with PL 5-20 mg/L vs <5 mg/L (65% vs 44%) and in children with PL 5-10 mg/L vs <2 mg/L (63 vs 14%). PL in seizure-free patients did not differ from those with seizure. Seizure control was poorer in the period 2003-2005 compared to 2006-2011. ADRs reported in 38 samples (2.8%) were without relation to PL.

CONCLUSIONS: Change of TR is not recommended.

PMID:34265104 | DOI:10.1111/bcp.14985

Cancer. 2021 Jul 15. doi: 10.1002/cncr.33801. Online ahead of print.

ABSTRACT

BACKGROUND: Breast cancer is the most common cancer among women in the United States. However, data on spatial disparities in survival for breast cancer are limited in the country. This study estimated 5-year relative survival (RS) of female breast cancer and examined the spatial variations across the contiguous United States.

METHODS: Women newly diagnosed with breast cancer in 2003-2010 in the United States were identified from the National Cancer Database and followed up through 2016. The crude 5-year RS at the county level was estimated and adjusted for patients’ key sociodemographic and clinical factors. To account for spatial effects, the RS estimates were smoothed using the Bayesian spatial survival model. A local spatial autocorrelation analysis with the Getis-Ord Gi* statistics was applied to identify geographic clusters of low or high RS.

RESULTS: Clusters of low RS were identified in more than 15 states covering 671 counties, mostly in the southeast and southwest regions, including Georgia, Alabama, Mississippi, Louisiana, Arkansas, Oklahoma, and Texas. Approximately 30% of these clusters can be explained by patients’ characteristics: Race, insurance, and stage at diagnosis appeared to be the major attributable factors.

CONCLUSIONS: Significant spatial disparity in female breast cancer survival was found, with low RS clusters identified in Georgia, Alabama, Mississippi, Louisiana, Arkansas, Oklahoma, and Texas. Policies and interventions that focus on serving Black women, improvements in insurance coverage, and early detection in these areas could potentially mitigate the spatial disparities.

PMID:34265081 | DOI:10.1002/cncr.33801

Swiss Med Wkly. 2021 Jul 7;151:w20525. doi: 10.4414/smw.2021.20525. eCollection 2021 Jul 5.

ABSTRACT

OBJECTIVE: The Swiss Diabetes Registry (SwissDiab) is a multicentre, longitudinal, observational study of outpatients with diabetes receiving treatment at tertiary care centres. The aim of this study was to evaluate the representativeness of the participants at the study centre in the Division of Endocrinology and Diabetes at the Cantonal Hospital of St Gallen by comparing diabetes-related characteristics of participating and nonparticipating patients.

METHODS: The study included 493 SwissDiab participants enrolled between 1 January 2010 and 31 December 2016 and 640 nonparticipating patients treated at the centre during the same time period. For participants and nonparticipating patients, demographic characteristics, clinical findings, blood chemistry and medication were retrieved from the SwissDiab baseline visit and the medical record &plusmn;6 months from the first available outpatient visit to the clinic for diabetes-related care within the study period. Nonparticipating patients were further divided into three subgroups: (i) excluded from SwissDiab, or having received (ii) &ge;6 months or (iii) &lt;6 months of prior diabetes treatment at the centre. Differences in diabetes-related clinical characteristics were determined using simple bivariate (nonparametric) statistical analyses stratified by diabetes mellitus type 1 and type 2.

RESULTS: Compared with nonparticipants, participants smoked less (diabetes mellitus type 1: 24% vs 45%; diabetes mellitus type 2: 21% vs 29%), had higher educational attainment (diabetes mellitus type 1: 39% vs 21%; and diabetes mellitus type 2: 25% vs 18%) and lower glycated haemoglobin levels (diabetes mellitus type 1: 7.2% vs 7.8%; diabetes mellitus type 2: 7.2% vs 8.1%). In diabetes mellitus type 2, the proportion of females (30% vs 38%) and a migration background (36% vs 49%) were lower among participants. (All p-values &lt;0.05.) In a stratified analysis SwissDiab participants had slightly better controlled diabetes than nonparticipating patients with &ge;6 months of prior treatment, whereas the diabetes of patients recently referred to the clinic (with &lt;6 months of prior treatment) and patients excluded from participation in SwissDiab were less well controlled.

CONCLUSION: The observed differences in clinical characteristics between study participants and nonparticipating patients indicate that SwissDiab is likely to overestimate the state of diabetes care and management. The results highlight the need to improve recruitment of females and patients with a migration background in diabetes mellitus type 2.

PMID:34265071 | DOI:10.4414/smw.2021.20525

J Food Prot. 2021 Jul 15. doi: 10.4315/JFP-21-028. Online ahead of print.

ABSTRACT

Based upon regulatory and food industry-driven food safety standards, there is a need for rapid, accurate methods for assessing sanitary conditions. A commonly utilized assay is based on the assessment of the biochemical molecule, adenosine triphosphate (ATP). A more recent assay (AXP) targets the cumulative presence of ATP and its dephosphorylated homologues, adenosine diphosphate (ADP) and adenosine monophosphate (AMP). Yet, there is little information that compares the practical performance of these two assays. This work examined these two assay types with a comparative study in a Grade A dairy foods processing plant and a licensed and inspected meat processing facility. A total of 1,920 concomitant analyses were conducted with main variables of assay type, processing facility type and hygiene zone category. Statistical process control methodology was used to calculate 95% confidence control limits (CL); data beyond those limits were considered contamination events. Results demonstrated that, overall, the AXP assay detected contamination events approximately two times more often than the ATP-only based assay. This increase in the rate of contamination event detection was especially more prevalent in the meat processing facility where, across all hygienic zones, there were 38 vs. 85 contaminations events detected for the ATP and AXP assays, respectively. Across hygiene zones, the AXP data displayed either an equal or increased incidence of soil detection compared to data from the ATP assay. This study provides applied evidence that assays solely dependent on ATP concentrations are less able to detect soil contaminants under conditions that favor ATP dephosphorylation reactions.

PMID:34265064 | DOI:10.4315/JFP-21-028

J Clin Endocrinol Metab. 2021 Jul 15:dgab518. doi: 10.1210/clinem/dgab518. Online ahead of print.

ABSTRACT

CONTEXT: Craniopharyngioma is a sellar tumor associated with high rates of pituitary deficiencies (~98%) and hypothalamic obesity (~50%).

OBJECTIVE: To determine the efficacy regarding long-term weight loss after bariatric surgery in obese craniopharyngioma patients with hypothalamic dysfunction.

DESIGN: Retrospective case control study.

SETTING: Multicenter international study.

PATIENTS AND PARTICIPANTS: Obese craniopharyngioma patients (N = 16; of which 12 women) with a history of bariatric surgery [12 Roux-en-Y gastric bypass, 4 sleeve gastrectomy; median age of 21 years (range 15-52), median follow-up 5.2 years (range 2.0-11.3)] and age/sex/surgery/BMI-matched obese controls (N = 155).

MAIN OUTCOME MEASURES: Weight loss and obesity-related comorbidities up to 5 years after bariatric surgery were compared and changes in hormonal replacement therapy evaluated.

RESULTS: Mean weight loss at 5-year follow-up was 22.0% (95% CI 16.1, 27.8) in patients versus 29.5% (28.0, 30.9) in controls (P = 0.02), which was less after Roux-en-Y gastric bypass (22.7% [16.9, 28.5] vs. 32.0% [30.4, 33.6]; P = 0.003) but at a similar level after sleeve gastrectomy (21.7% [-1.8, 45.2] vs. 21.8% [18.2, 25.5]; P = 0.96). No major changes in endocrine replacement therapy were observed after surgery. One patient died (unknown cause). One patient had long-term absorptive problems.

CONCLUSIONS: Obese patients with craniopharyngioma had a substantial mean weight loss of 22% at 5-year follow-up after bariatric surgery, independent of type of bariatric surgery procedure. Weight loss was lower than in obese controls after Roux-en-Y gastric bypass. Bariatric surgery appears effective and relatively safe in the treatment of obese craniopharyngioma patients.

PMID:34265053 | DOI:10.1210/clinem/dgab518