Baylor Research Institute

Waddimba, A. C., D. C. Mohr, H. B. Beckman and M. M. Meterko (2020). “Physicians’ perceptions of autonomy support during transition to value-based reimbursement: A multi-center psychometric evaluation of six-item and three-item measures.” PLoS One 15(4): e0230907.

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BACKGROUND: Successive health system reforms have steadily eroded physician autonomy. Escalating accountability demands placed on physicians concurrent with diminishing autonomy plus widespread “cost cutting” endanger clinical work-life quality and, in turn, threaten patient-care quality, safety, and continuity. This has engendered a renewed emphasis on bettering physician work-life to safeguard patient care. Research indicates that autonomy support could be an effective intervention point in this dynamic, and that improving healthcare practitioners’ experience of autonomy can promote better patient outcomes. New measures of autonomy support towards physicians during systemic/organizational transformation are thus needed. OBJECTIVE: We investigated the validity and reliability of two versions of a brief measure of physicians’ perceptions of autonomy support. DESIGN: Psychometric evaluation of practitioners’ responses to a theory-based, pilot-tested, multi-center, cross-sectional survey-questionnaire. PARTICIPANTS: Physicians serving in California, Massachusetts, or upstate New York clinical practices implementing pay-for-performance incentives were eligible. We obtained responses from 1,534 (35.14%) of 4,365 physicians surveyed. ANALYSIS: We randomly partitioned the study sample equitably into derivation and validation subsamples. We conducted parallel analysis, inter-item/point-biserial correlations, and item-response-theory-based graded response modeling on six autonomy support items. Three items with the highest (a) point-biserial correlations, (b) item-level discrimination and (c) information capture were used to construct a short-form (3-item) version of the full (6-item) autonomy scale. We utilized exploratory structural equation modeling and confirmatory factor analysis to establish the factor structure and construct validity of the full-length and short-form scales before comparing their factor invariance, reliability and interrater agreement across physician subgroups. FINDINGS: All six autonomy support items loaded highly onto one factor accounting for the majority of variance and demonstrating good data fit. The three most discriminating and informative items loaded equally well onto a single factor with similar goodness-of-fit to the data. The three-item scale correlated highly with its six-item parent, showing equally high sensitivity and specificity in discriminating high autonomy support. Variability in scores nested predominantly at within- rather than between-subgroup levels. CONCLUSIONS AND IMPLICATIONS: Our data supported the factor structure, construct validity, internal consistency, and reliability of six- and three-item autonomy support scales. These brief tools are easily incorporated into multi-dimensional questionnaires at relatively low cost.

Kumano, K., M. Takita, S. Vasu, C. Darden, M. Lawrence, E. Beecherl, A. Gupta, N. Onaca and B. Naziruddin (2020). “Impact of microbial contamination of the islet product during total pancreatectomy with islet autotransplantation.” J Hepatobiliary Pancreat Sci 27(4): 211-218.

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BACKGROUND: The combined use of interleukin-1beta and tumor necrosis factor-alpha blockers in the peritransplant period has improved outcomes of total pancreatectomy with islet autotransplantation (TPIAT). However, these drugs may suppress the immune system, resulting in severe infection. METHODS: We retrospectively investigated the impact of microbial-contaminated islet product on posttransplant complications and metabolic outcomes of TPIAT patients receiving the IL-1beta and TNF-blockade treatment at our center. RESULTS: Among 108 TPIAT patients, 37 patients (34%) received contaminated products. Preoperative stent treatment and fibrosis score were independent risk factors for the contamination. There were no significant differences between the contaminated and noncontaminated product groups in posttransplant infectious complication rate, length of hospitalization, or readmission rate. However, islet equivalents (P < .0001) and insulin independence rate (P = .036) at 6 months were significantly lower for patients receiving contaminated product. CONCLUSIONS: These results suggest that combined anti-inflammatory drug use is safe and well tolerated in TPIAT patients who receive contaminated islet product and does not increase the rate of infectious complications; however, contaminated islet product is associated with poor metabolic outcomes.

Ye, M., C. Goudot, T. Hoyler, B. Lemoine, S. Amigorena and E. Zueva (2020). “Specific subfamilies of transposable elements contribute to different domains of T lymphocyte enhancers.” Proc Natl Acad Sci U S A 117(14): 7905-7916.

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Transposable elements (TEs) compose nearly half of mammalian genomes and provide building blocks for cis-regulatory elements. Using high-throughput sequencing, we show that 84 TE subfamilies are overrepresented, and distributed in a lineage-specific fashion in core and boundary domains of CD8(+) T cell enhancers. Endogenous retroviruses are most significantly enriched in core domains with accessible chromatin, and bear recognition motifs for immune-related transcription factors. In contrast, short interspersed elements (SINEs) are preferentially overrepresented in nucleosome-containing boundaries. A substantial proportion of these SINEs harbor a high density of the enhancer-specific histone mark H3K4me1 and carry sequences that match enhancer boundary nucleotide composition. Motifs with regulatory features are better preserved within enhancer-enriched TE copies compared to their subfamily equivalents located in gene deserts. TE-rich and TE-poor enhancers associate with both shared and unique gene groups and are enriched in overlapping functions related to lymphocyte and leukocyte biology. The majority of T cell enhancers are shared with other immune lineages and are accessible in common hematopoietic progenitors. A higher proportion of immune tissue-specific enhancers are TE-rich compared to enhancers specific to other tissues, correlating with higher TE occurrence in immune gene-associated genomic regions. Our results suggest that during evolution, TEs abundant in these regions and carrying motifs potentially beneficial for enhancer architecture and immune functions were particularly frequently incorporated by evolving enhancers. Their putative selection and regulatory cooption may have accelerated the evolution of immune regulatory networks.

Singhal, N. K., S. Sternbach, S. Fleming, K. Alkhayer, J. Shelestak, D. Popescu, A. Weaver, R. Clements, B. Wasek, T. Bottiglieri, E. J. Freeman and J. McDonough (2020). “Betaine restores epigenetic control and supports neuronal mitochondria in the cuprizone mouse model of multiple sclerosis.” Epigenetics Mar 9:1-16. [Epub ahead of print].

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Methionine metabolism is dysregulated in multiple sclerosis (MS). The methyl donor betaine is depleted in the MS brain where it is linked to changes in levels of histone H3 trimethylated on lysine 4 (H3K4me3) and mitochondrial impairment. We investigated the effects of replacing this depleted betaine in the cuprizone mouse model of MS. Supplementation with betaine restored epigenetic control and alleviated neurological disability in cuprizone mice. Betaine increased the methylation potential (SAM/SAH ratio), levels of H3K4me3, enhanced neuronal respiration, and prevented axonal damage. We show that the methyl donor betaine and the betaine homocysteine methyltransferase (BHMT) enzyme can act in the nucleus to repair epigenetic control and activate neuroprotective transcriptional programmes. ChIP-seq data suggest that BHMT acts on chromatin to increase the SAM/SAH ratio and histone methyltransferase activity locally to increase H3K4me3 and activate gene expression that supports neuronal energetics. These data suggest that the methyl donor betaine may provide neuroprotection in MS where mitochondrial impairment damages axons and causes disability.

Schiffmann, R., J. Sevigny, A. Rolfs, E. H. Davies, O. Goker-Alpan, M. Abdelwahab, A. Vellodi, E. Mengel, E. Lukina, H. W. Yoo, T. Collin-Histed, A. Narita, T. Dinur, S. Revel-Vilk, D. Arkadir, J. Szer, M. Wajnrajch, U. Ramaswami, E. Sidransky, A. Donald and A. Zimran (2020). “The definition of neuronopathic Gaucher disease.” J Inherit Metab Dis Apr 3. [Epub ahead of print].

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Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form-Gaucher type 2-from the subacute or chronic form-Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials