Digital Therapeutics Care Utilizing Genetic and Gut Microbiome Signals for the Management of Functional Gastrointestinal Disorders: Results From a Preliminary Retrospective Study.

Diet and lifestyle-related illnesses including functional gastrointestinal disorders (FGIDs) and obesity are rapidly emerging health issues worldwide. Research has focused on addressing FGIDs via in-person cognitive-behavioral therapies, diet modulation and pharmaceutical intervention. Yet, there is paucity of research reporting on digital therapeutics care delivering weight loss and reduction of FGID symptom severity, and on modeling FGID status and symptom severity reduction including personalized genomic SNPs and gut microbiome signals. Our aim for this study was to assess how effective a digital therapeutics intervention personalized on genomic SNPs and gut microbiome signals was at reducing symptomatology of FGIDs on individuals that successfully lost body weight. We also aimed at modeling FGID status and FGID symptom severity reduction using demographics, genomic SNPs, and gut microbiome variables. This study sought to train a logistic regression model to differentiate the FGID status of subjects enrolled in a digital therapeutics care program using demographic, genetic, and baseline microbiome data. We also trained linear regression models to ascertain changes in FGID symptom severity of subjects at the time of achieving 5% or more of body weight loss compared to baseline. For this we utilized a cohort of 177 adults who reached 5% or more weight loss on the Digbi Health personalized digital care program, who were retrospectively surveyed about changes in symptom severity of their FGIDs and other comorbidities before and after the program. Gut microbiome taxa and demographics were the strongest predictors of FGID status. The digital therapeutics program implemented, reduced the summative severity of symptoms for 89.42% (93/104) of users who reported FGIDs. Reduction in summative FGID symptom severity and IBS symptom severity were best modeled by a mixture of genomic and microbiome predictors, whereas reduction in diarrhea and constipation symptom severity were best modeled by microbiome predictors only. This preliminary retrospective study generated diagnostic models for FGID status as well as therapeutic models for reduction of FGID symptom severity. Moreover, these therapeutic models generate testable hypotheses for associations of a number of biomarkers in the prognosis of FGIDs symptomatology.

Leveraging Genomic Associations in Precision Digital Care for Weight Loss: Cohort Study.

BACKGROUND: The COVID-19 pandemic has highlighted the urgency of addressing an epidemic of obesity and associated inflammatory illnesses. Previous studies have demonstrated that interactions between single-nucleotide polymorphisms (SNPs) and lifestyle interventions such as food and exercise may vary metabolic outcomes, contributing to obesity. However, there is a paucity of research relating outcomes from digital therapeutics to the inclusion of genetic data in care interventions. OBJECTIVE: This study aims to describe and model the weight loss of participants enrolled in a precision digital weight loss program informed by the machine learning analysis of their data, including genomic data. It was hypothesized that weight loss models would exhibit a better fit when incorporating genomic data versus demographic and engagement variables alone. METHODS: A cohort of 393 participants enrolled in Digbi Health's personalized digital care program for 120 days was analyzed retrospectively. The care protocol used participant data to inform precision coaching by mobile app and personal coach. Linear regression models were fit of weight loss (pounds lost and percentage lost) as a function of demographic and behavioral engagement variables. Genomic-enhanced models were built by adding 197 SNPs from participant genomic data as predictors and refitted using Lasso regression on SNPs for variable selection. Success or failure logistic regression models were also fit with and without genomic data. RESULTS: Overall, 72.0% (n=283) of the 393 participants in this cohort lost weight, whereas 17.3% (n=68) maintained stable weight. A total of 142 participants lost 5% bodyweight within 120 days. Models described the impact of demographic and clinical factors, behavioral engagement, and genomic risk on weight loss. Incorporating genomic predictors improved the mean squared error of weight loss models (pounds lost and percent) from 70 to 60 and 16 to 13, respectively. The logistic model improved the pseudo R2 value from 0.193 to 0.285. Gender, engagement, and specific SNPs were significantly associated with weight loss. SNPs within genes involved in metabolic pathways processing food and regulating fat storage were associated with weight loss in this cohort: rs17300539_G (insulin resistance and monounsaturated fat metabolism), rs2016520_C (BMI, waist circumference, and cholesterol metabolism), and rs4074995_A (calcium-potassium transport and serum calcium levels). The models described greater average weight loss for participants with more risk alleles. Notably, coaching for dietary modification was personalized to these genetic risks. CONCLUSIONS: Including genomic information when modeling outcomes of a digital precision weight loss program greatly enhanced the model accuracy. Interpretable weight loss models indicated the efficacy of coaching informed by participants' genomic risk, accompanied by active engagement of participants in their own success. Although large-scale validation is needed, our study preliminarily supports precision dietary interventions for weight loss using genetic risk, with digitally delivered recommendations alongside health coaching to improve intervention efficacy.

TRPV6 as a Putative Genomic Susceptibility Locus Influencing Racial Disparities in Cancer.

It is well established that African Americans exhibit higher incidence, higher mortality, and more aggressive forms of some cancers, including those of breast, prostate, colon, stomach, and cervix. Here we examine the ancestral haplotype of the TRPV6 calcium channel as a putative genomic factor in this racial divide. The minor (ancestral) allele frequency is 60% in people of African ancestry, but between 1% and 11% in all other populations. Research on TRPV6 structure/function, its association with specific cancers, and the evolutionary-ecological conditions that impacted selection of its haplotypes are synthesized to provide evidence for TRPV6 as a germline susceptibility locus in cancer. Recently elucidated mechanisms of TRPV6 channel deactivation are discussed in relation to the location of the allele favored in selection, suggesting a reduced capacity to inactivate the channel in those who have the ancestral haplotype. This could result in an excessively high cellular Ca2+, which has been implicated in cancer, for those in settings where calcium intake is far higher than in their ancestral environment. A recent report associating increasing calcium intake with a pattern of increase in aggressive prostate cancer in African-American but not European-American men may be related. If TRPV6 is found to be associated with cancer, further research would be warranted to improve risk assessment and examine interventions with the aim of improving cancer outcomes for people of African ancestry.

Morquio A syndrome-associated mutations: a review of alterations in the GALNS gene and a new locus-specific database.

Morquio A syndrome (mucopolysaccharidosis IVA) is an autosomal recessive disorder that results from deficient activity of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS) due to alterations in the GALNS gene, which causes major skeletal and connective tissue abnormalities and effects on multiple organ systems. The GALNS alterations associated with Morquio A are numerous and heterogeneous, and new alterations are continuously identified. To aid detection and interpretation of GALNS alterations, from previously published research, we provide a comprehensive and up-to-date listing of 277 unique GALNS alterations associated with Morquio A identified from 1,091 published GALNS alleles. In agreement with previous findings, most reported GALNS alterations are missense changes and even the most frequent alterations are relatively uncommon. We found that 48% of patients are assessed as homozygous for a GALNS alteration, 39% are assessed as heterozygous for two identified GALNS alterations, and in 13% of patients only one GALNS alteration is detected. We report here the creation of a locus-specific database for the GALNS gene (http://galns.mutdb.org/) that catalogs all reported alterations in GALNS to date. We highlight the challenges both in alteration detection and genotype-phenotype interpretation caused in part by the heterogeneity of GALNS alterations and provide recommendations for molecular testing of GALNS.

Protein side-chain modeling with a protein-dependent optimized rotamer library.

Despite years of effort, the problem of predicting the conformations of protein side chains remains a subject of inquiry. This problem has three major issues, namely defining the conformations that a side chain may adopt within a protein, developing a sampling procedure for generating possible side-chain packings, and defining a scoring function that can rank these possible packings. To solve the former of these issues, most procedures rely on a rotamer library derived from databases of known protein structures. We introduce an alternative method that is free of statistics. We begin with a rotamer library that is based only on stereochemical considerations; this rotamer library is then optimized independently for each protein under study. We show that this optimization step restores the diversity of conformations observed in native proteins. We combine this protein-dependent rotamer library (PDRL) method with the self-consistent mean field (SCMF) sampling approach and a physics-based scoring function into a new side-chain prediction method, SCMF-PDRL. Using two large test sets of 831 and 378 proteins, respectively, we show that this new method compares favorably with competing methods such as SCAP, OPUS-Rota, and SCWRL4 for energy-minimized structures.

Sampling the conformation of protein surface residues for flexible protein docking.

BACKGROUND: The problem of determining the physical conformation of a protein dimer, given the structures of the two interacting proteins in their unbound state, is a difficult one. The location of the docking interface is determined largely by geometric complementarity, but finding complementary geometry is complicated by the flexibility of the backbone and side-chains of both proteins. We seek to generate candidates for docking that approximate the bound state well, even in cases where there is backbone and/or side-chain difference from unbound to bound states. RESULTS: We divide the surfaces of each protein into local patches and describe the effect of side-chain flexibility on each patch by sampling the space of conformations of its side-chains. Likely positions of individual side-chains are given by a rotamer library; this library is used to derive a sample of possible mutual conformations within the patch. We enforce broad coverage of torsion space. We control the size of the sample by using energy criteria to eliminate unlikely configurations, and by clustering similar configurations, resulting in 50 candidates for a patch, a manageable number for docking. CONCLUSIONS: Using a database of protein dimers for which the bound and unbound structures of the monomers are known, we show that from the unbound patch we are able to generate candidates for docking that approximate the bound structure. In patches where backbone change is small (within 1 Å RMSD of bound), we are able to account for flexibility and generate candidates that are good approximations of the bound state (82% are within 1 Å and 98% are within 1.4 Å RMSD of the bound conformation). We also find that even in cases of moderate backbone flexibility our candidates are able to capture some of the overall shape change. Overall, in 650 of 700 test patches we produce a candidate that is either within 1 Å RMSD of the bound conformation or is closer to the bound state than the unbound is.

Factors affecting the utility of the multiple mini-interview in selecting candidates for graduate-entry medical school.

CONTEXT: We wished to determine which factors are important in ensuring interviewers are able to make reliable and valid decisions about the non-cognitive characteristics of candidates when selecting candidates for entry into a graduate-entry medical programme using the multiple mini-interview (MMI). METHODS: Data came from a high-stakes admissions procedure. Content validity was assured by using a framework based on international criteria for sampling the behaviours expected of entry-level students. A variance components analysis was used to estimate the reliability and sources of measurement error. Further modelling was used to estimate the optimal configurations for future MMI iterations. RESULTS: This study refers to 485 candidates, 155 interviewers and 21 questions taken from a pre- prepared bank. For a single MMI question and 1 assessor, 22% of the variance between scores reflected candidate-to-candidate variation. The reliability for an 8-question MMI was 0.7; to achieve 0.8 would require 14 questions. Typical inter-question correlations ranged from 0.08 to 0.38. A disattenuated correlation with the Graduate Australian Medical School Admissions Test (GAMSAT) subsection 'Reasoning in Humanities and Social Sciences' was 0.26. CONCLUSIONS: The MMI is a moderately reliable method of assessment. The largest source of error relates to aspects of interviewer subjectivity, suggesting interviewer training would be beneficial. Candidate performance on 1 question does not correlate strongly with performance on another question, demonstrating the importance of context specificity. The MMI needs to be sufficiently long for precise comparison for ranking purposes. We supported the validity of the MMI by showing a small positive correlation with GAMSAT section scores.

Online CME: an effective alternative to face-to-face delivery.

BACKGROUND: The Pharmacotherapies Accreditation Course (PAC) is a continuing medical education (CME) course designed to prepare practitioners for accreditation as pharmacotherapies prescribers for opioid dependence. The course incorporates a preparation stage, a workshop stage and a clinical placement component. The PAC continues to be successfully delivered in face-to-face mode since 2001. From 2003 onwards, an online alternative of the PAC was also implemented. AIMS: The aim of this study was to evaluate the effectiveness of an online alternative to an existing face-to-face CME workshop in preparing practitioners for accreditation as a pharmacotherapies prescriber for opioid dependence. METHODS: Participants were 62 practitioners who undertook the PAC between 2003 and 2006. A pretest/posttest-control group design was used, with outcome measures across the domains of knowledge, skill, and attitudes, together with a course feedback survey for both the online and face-to-face modes of the course. RESULTS: Results demonstrate that the online CME mode was equally as effective as the face-to face mode in preparing participants for their role in the treatment and management of opioid dependence, and was also rated highly by participants. CONCLUSIONS: The findings have implications for the effective design and delivery of e-learning environments for professional practice, in terms of equipping participants with requisite clinical knowledge and skills and facilitating the development of attitudes congruent with professional practice.

Conceptions of problem-based learning: the perspectives of students entering a problem-based medical program.

Effective learning in higher education is associated with students' perceptions of clear goals and standards of an educational program. In programs using problem-based learning (PBL), students' conceptions of what PBL is about could determine how well they perceive the clarity of goals and standards of their program. In this study the authors aim to investigate the relationship between the nature of first-year students' conceptions of PBL and their perceptions of the clarity of goals and standards of a graduate-entry, problem-based medical program. Results are that most students conceive of PBL as mainly working collaboratively to solve and understand a problem, and place less emphasis on PBL as learning independently. There is no relationship between students' conceptions and perceived clarity of course goals and standards. It is suggested that teachers not only need to help students develop their understanding of what PBL is about but also need to help students learn how to self-regulate their learning in PBL programs.

The neurosurgical training curriculum in Australia and New Zealand is changing. Why?

The Neurosurgical Advanced Training curriculum of the Royal Australasian College of Surgeons (RACS) is currently undergoing change. Given the high standard of neurosurgery in Australia and New Zealand, it may be questioned why such change is necessary. However, the curriculum has not kept pace with developments in professional practice, educational practice or educational theory, particularly in the assessment of medical competence and performance. The curriculum must also adapt to the changing training environment, particularly the effects of reduced working hours, reducing caseloads due to shorter inpatient hospital stays and restricted access to public hospital beds and operating theatres, and the effects of sub-specialisation. A formal review of the curriculum is timely.

A model of teaching and learning in the operating theatre.

INTRODUCTION: This paper extends the work of an earlier publication by the same author which reported the findings of a case study designed to investigate how medical students learn and are taught in the operating theatre. The earlier paper was descriptive in nature, examining the challenges students face as learners in theatres. These were conceptualised around 3 key domains: the challenge posed by the physical environment; the challenge of the educational task, and the challenge of managing and negotiating a role as a participant in the professional workplace of theatres. This paper focuses exclusively on the third domain. It presents an interpretive model of teaching and learning in the operating theatre, drawing largely on conceptual frameworks developed within the literature on learning in work-based settings. METHODS: A multimethod strategy included observation in theatres, interviews with students and surgeons, and a student survey. The themes that characterised the case were identified and the relationships among these themes were explored, leading to the development of the model. Symbolic interactionism provided the underlying theoretical framework. CONCLUSION: In any particular theatre session, the way in which learning evolves or is obstructed for any student, and the shape that teaching takes, depends on the interpretations that the student and the surgeon make in 'sizing up' the teaching and learning environment. How surgeons and students interpret and respond to each others' behaviour, style, attitude and even demeanour, has consequences for the way teaching and learning develop. The concepts of legitimacy and trust underpin these interpretations and are central to understanding the processes of teaching and learning in this setting.

Clinical skills in junior medical officers: a comparison of self-reported confidence and observed competence.

BACKGROUND: The intern year is a key time for the acquisition of clinical skills, both procedural and cognitive. We have previously described self-reported confidence and experience for a number of clinical skills, finding high levels of confidence among Australian junior doctors. This has never been correlated with an objective measure of competence. AIMS AND HYPOTHESIS: We aimed to determine the relationship between self-reported confidence and observed competence for a number of routine, procedural clinical skills. METHODS: A group of 30 junior medical officers in their first postgraduate year (PGY1) was studied. All subjects completed a questionnaire concerning their confidence and experience in the performance of clinical skills. A competency-based assessment instrument concerning 7 common, practical, clinical skills was developed, piloted and refined. All 30 PGY1s then completed an assessment using this instrument. Comparisons were then made between the PGY1s' self-reported levels of confidence and tutors' assessments of their competence. RESULTS: A broad range of competence levels was revealed by the clinical skills assessments. There was no correlation between the PGY1s' self-ratings of confidence and their measured competencies. CONCLUSIONS: Junior medical officers in PGY1 demonstrate a broad range of competence levels for several common, practical, clinical skills, with some performing at an inadequate level. There is no relationship between their self-reported level of confidence and their formally assessed performance. This observation raises important caveats about the use of self-assessment in this group.

Making the most of learning in the operating theatre: student strategies and curricular initiatives.

BACKGROUND: Students in medical programmes around the world are required to attend with their patient in the operating theatre, yet little is known about this area of medical education. Most of the published literature on the operating theatre is normative in character, written from the perspective of the surgeon as teacher. This paper, in contrast, reports the student's perspective as learner. It is an interpretive case study conducted in the department of surgery at an Australian university. METHODS: Research approaches were combined in a multi-method strategy which included in-depth interviews with students and surgeons, observations in operating theatres, group interviews and a student survey. The aim was to understand the student's experience of the theatre as a learning environment, with a view to improving teaching and learning in this setting. FINDINGS: The operating theatre is a challenging place in which to learn. The challenges are conceptualized in this paper around three key domains: the challenge posed by the physical environment and the emotional impact of surgery as work; the challenge of the educational task, and the challenge of managing the social relations of work in the operating theatre. CONCLUSION: Students who report finding the operating theatre a useful experience are those who adopt active strategies to successfully manage their learning across the three domains. The paper describes curricular initiatives that have been introduced in a department of surgery to help more students make the most of their learning in theatres, and goes on to discuss the wider implications of the findings for surgical education beyond this case study.

Preparedness for hospital practice among graduates of a problem-based, graduate-entry medical program.

OBJECTIVE: To compare preparedness for hospital practice between graduates from a problem-based, graduate-entry medical program and those from other programs (undergraduate problem-based and traditional). DESIGN: Survey of graduates (by mailed questionnaire) and organisers of clinical training (by semistructured interview); results were compared with published results of surveys of graduates from other programs. SETTING AND PARTICIPANTS: All graduates of the first intake of the University of Sydney graduate-entry medical program were surveyed at the end of their first intern year (2001), along with the director of clinical training or intern manager at each of the New South Wales hospitals that employed the graduates. MAIN OUTCOME MEASURES: Graduates' self-reported level of preparedness in the eight domains of the Preparation for Hospital Practice Questionnaire; and organisers' opinions of their strengths and weaknesses. RESULTS: 76 of 108 graduates from the graduate-entry program (70%) and organisers of clinical training at all 17 hospitals participated. Graduates from the program felt more prepared than did those from other programs in five of the eight domains assessed (interpersonal skills, confidence, collaboration, holistic care, and self-directed learning) and no less prepared in any domain. Organisers rated the graduates highly, especially in clinical competence, confidence, communication and professional skills. Opinions of interns' knowledge of basic sciences conflicted, with strengths and weaknesses mentioned with equal frequency. CONCLUSION: Graduates from the graduate-entry, problem-based program are at least as well prepared for their intern year as graduates from traditional and undergraduate problem-based programs.