Predicting, Preparing for, and Creating the Future: What Will Happen to Internal Medicine?

It is the year 2025. During the past 20 years, internal medicine as a discipline continued to become less prestigious, less respected, and more fragmented. As fewer medical students chose internal medicine as a career, residency programs began to close. Those that remained open filled with fewer graduates of US medical schools but filled with more US citizens who graduated from international medical schools, more graduates of osteopathic medical schools, and more foreign graduates of international medical schools. Due to lack of adequate remuneration and a shift of primary care provision from generalist physicians to nurse practitioners and physician assistants, training in general internal medicine as a patient care specialty ceased. Generalist internal medicine careers have been replaced by tracks designed to foster health services research or academic careers; internal medicine training graduates subspecialty physicians. Although the projected collapse of Medicare in 2019 was avoided, severe cuts in federal funding for undergraduate and graduate medical education programs forced medical schools and residency programs to compete for federal funds. As a result, medical school tuition became prohibitive, for-profit health care systems viewed medical education as a significant cost center and chose to limit the size of their residency programs, and community-based training programs could not withstand the financial pressures and closed. The result was a reduced supply of internists. Furthermore, compliance with the regulatory burden imposed by accrediting organizations—such as the Accreditation Council for Graduate Medical Education—drove individuals from sustained careers in education, further impacting the viability of training programs

Understanding context specificity:the effect of contextual factors on clinical reasoning

Background: Situated cognition theory argues that thinking is inextricably situated in a context. In clinical reasoning, this can lead to context specificity: a physician arriving at two different diagnoses for two patients with the same symptoms, findings, and diagnosis but different contextual factors (something beyond case content potentially influencing reasoning). This paper experimentally investigates the presence of and mechanisms behind context specificity by measuring differences in clinical reasoning performance in cases with and without contextual factors. Methods: An experimental study was conducted in 2018-2019 with 39 resident and attending physicians in internal medicine. Participants viewed two outpatient clinic video cases (unstable angina and diabetes mellitus), one with distracting contextual factors and one without. After viewing each case, participants responded to six open-ended diagnostic items (e.g. problem list, leading diagnosis) and rated their cognitive load. Results: Multivariate analysis of covariance (MANCOVA) results revealed significant differences in angina case performance with and without contextual factors [Pillai's trace = 0.72, F=12.4, df=(6, 29), p Conclusions: Using typical presentations of common diagnoses, and contextual factors typical for clinical practice, we provide ecologically valid evidence for the theoretically predicted negative effects of context specificity (i.e. for the angina case), with large effect sizes, offering insight into the persistence of diagnostic error

Fluorescence and spin properties of defects in single digit nanodiamonds

International audienceThis article reports stable photoluminescence and high-contrast optically detected electron spin resonance (ODESR) from single nitrogen-vacancy (NV) defect centers created within ultrasmall, disperse nanodiamonds of radius less than 4 nm. Unexpectedly, the efficiency for the production of NV fluorescent defects by electron irradiation is found to be independent of the size of the nanocrystals. Fluorescence lifetime imaging shows lifetimes with a mean value of around 17 ns, only slightly longer than the bulk value of the defects. After proper surface cleaning, the dephasing times of the electron spin resonance in the nanocrystals approach values of some microseconds, which is typical for the type Ib diamond from which the nanoparticle is made. We conclude that despite the tiny size of these nanodiamonds the photoactive nitrogen-vacancy color centers retain their bulk properties to the benefit of numerous exciting potential applications in photonics, biomedical labeling, and imaging

Faculty verbal evaluations reveal strategies used to promote medical student performance

Background: Preceptors rarely follow medical students’ developing clinical performance over time and across disciplines. This study analyzes preceptors’ descriptions of longitudinal integrated clerkship (LIC) students’ clinical development and their identification of strategies to guide students’ progress. Methods: We used a common evaluation framework, reporter-interpreter-manager-educator, to guide multidisciplinary LIC preceptors’ discussions of students’ progress. We conducted thematic analysis of transcripts from preceptors’ (seven longitudinal ambulatory preceptors per student) quarterly group discussions of 15 students’ performance over one year. Results: All students’ clinical development progressed, although most experienced obstacles. Lack of structure in the history and physical exam commonly obstructed progression. Preceptors used templates for data gathering, and modeling or experiences in the inpatient setting to provide time and solidify structure. To advance students’ knowledge acquisition, many preceptors identified focused learning topics with their students; to promote application of knowledge, preceptors used reasoning strategies to teach the steps involved in synthesizing clinical data. Preceptors shared accountability for helping students advance as the LIC allowed them to follow students’ response to teaching strategies. Discussion: These results depict preceptors’ perceptions of LIC students’ developmental continuum and illustrate how multidisciplinary preceptors can use a common evaluation framework to identify strategies to improve performance and follow students’ performance longitudinally

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis

Clinical implications of serum neurofilament in newly diagnosed MS patients: a longitudinal multicentre cohort study

BACKGROUND: We aim to evaluate serum neurofilament light chain (sNfL), indicating neuroaxonal damage, as a biomarker at diagnosis in a large cohort of early multiple sclerosis (MS) patients. METHODS: In a multicentre prospective longitudinal observational cohort, patients with newly diagnosed relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) were recruited between August 2010 and November 2015 in 22 centers. Clinical parameters, MRI, and sNfL levels (measured by single molecule array) were assessed at baseline and up to four-year follow-up. FINDINGS: Of 814 patients, 54.7% (445) were diagnosed with RRMS and 45.3% (369) with CIS when applying 2010 McDonald criteria (RRMS[2010] and CIS[2010]). After reclassification of CIS[2010] patients with existing CSF analysis, according to 2017 criteria, sNfL levels were lower in CIS[2017] than RRMS[2017] patients (9.1 pg/ml, IQR 6.2-13.7 pg/ml, n = 45; 10.8 pg/ml, IQR 7.4-20.1 pg/ml, n = 213; p = 0.036). sNfL levels correlated with number of T2 and Gd+ lesions at baseline and future clinical relapses. Patients receiving disease-modifying therapy (DMT) during the first four years had higher baseline sNfL levels than DMT-naïve patients (11.8 pg/ml, IQR 7.5-20.7 pg/ml, n = 726; 9.7 pg/ml, IQR 6.4-15.3 pg/ml, n = 88). Therapy escalation decisions within this period were reflected by longitudinal changes in sNfL levels. INTERPRETATION: Assessment of sNfL increases diagnostic accuracy, is associated with disease course prognosis and may, particularly when measured longitudinally, facilitate therapeutic decisions

DeepWAS: multivariate genotype-phenotype associations by directly integrating regulatory information using deep learning

Genome-wide association studies (GWAS) identify genetic variants associated with traits or diseases. GWAS never directly link variants to regulatory mechanisms. Instead, the functional annotation of variants is typically inferred by post hoc analyses. A specific class of deep learning-based methods allows for the prediction of regulatory effects per variant on several cell type-specific chromatin features. We here describe "DeepWAS", a new approach that integrates these regulatory effect predictions of single variants into a multivariate GWAS setting. Thereby, single variants associated with a trait or disease are directly coupled to their impact on a chromatin feature in a cell type. Up to 61 regulatory SNPs, called dSNPs, were associated with multiple sclerosis (MS, 4,888 cases and 10,395 controls), major depressive disorder (MDD, 1,475 cases and 2,144 controls), and height (5,974 individuals). These variants were mainly non-coding and reached at least nominal significance in classical GWAS. The prediction accuracy was higher for DeepWAS than for classical GWAS models for 91% of the genome-wide significant, MS-specific dSNPs. DSNPs were enriched in public or cohort-matched expression and methylation quantitative trait loci and we demonstrated the potential of DeepWAS to generate testable functional hypotheses based on genotype data alone. DeepWAS is available at https://github.com/cellmapslab/DeepWAS

Treatment choices and neuropsychological symptoms of a large cohort of early MS

Objective To assess clinical characteristics, distribution of disease-modifying treatments (DMTs), and neuropsychological symptoms in a large cohort of patients with early-stage MS. Methods The German National MS Cohort is a multicenter prospective longitudinal cohort study that has recruited DMT-naive patients with clinically isolated syndrome (CIS) and relapsing-remitting MS (RRMS) since 2010. We evaluated their baseline characteristics and the prevalence of neuropsychological symptoms. Results Of 1,124 patients, with a 2.2: 1 female-to-male ratio and median age at onset of 31.71 years (interquartile range [IQR]: 26.06-40.33), 44.6% and 55.3% had CIS and RRMS, respectively. The median Expanded Disability Status Scale (EDSS) score at baseline was 1.5 (IQR: 1.0-2.0). A proportion of 67.8% of patients started DMT after a median time of 167.0 days (IQR 90.0-377.5) since the first manifestation. A total of 64.7% and 70.4% of the 762 patients receiving early DMT were classified as CIS and RRMS, respectively. Fatigue, depressive symptoms, and cognitive dysfunction were detected in 36.5%, 33.5%, and 14.7% of patients, respectively. Conclusion Baseline characteristics of this large cohort of patients with early, untreated MS corroborated with other cohorts. Most patients received early DMT within the first year after disease onset, irrespective of a CIS or RRMS diagnosis. Despite the low EDSS score, neuropsychological symptoms affected a relevant proportion of patients

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis