Publications

Take a deeper look into all the publications produced by researchers at The Dartmouth Institute.

Scherrer JF, Salas J, Lustman PJ, van den Berk-Clark C, Schnurr PP, Tuerk P, Cohen BE, Friedman MJ, Norman SB, Schneider FD, Chard KM

2018 Aug 8;doi: 10.1001/jamapsychiatry.2018.2028

Posttraumatic stress disorder (PTSD) is associated with an increased risk of type 2 diabetes mellitus (T2DM). Existing literature has adjusted for obesity in combination with other confounders, which does not allow estimating the contribution of obesity alone on the association of PTSD with incident T2DM.

JAMA Psychiatry|2018 Aug 8

Grahl N, Dolben EL, Filkins LM, Crocker AW, Willger SD, Morrison HG, Sogin ML, Ashare A, Gifford AH, Jacobs NJ, Schwartzman JD, Hogan DA

2018 Aug 8;3(4)pii: e00292-18. doi: 10.1128/mSphere.00292-18

Here, we report an approach to detect diverse bacterial and fungal taxa in complex samples by direct analysis of community RNA in one step using NanoString probe sets. We designed rRNA-targeting probe sets to detect 42 bacterial and fungal genera or species common in cystic fibrosis (CF) sputum and demonstrated the taxon specificity of these probes, as well as a linear response over more than 3 logs of input RNA. Culture-based analyses correlated qualitatively with relative abundance data on bacterial and fungal taxa obtained by NanoString, and the analysis of serial samples demonstrated the use of this method to simultaneously detect bacteria and fungi and to detect microbes at low abundance without an amplification step. Compared at the genus level, the relative abundances of bacterial taxa detected by analysis of RNA correlated with the relative abundances of the same taxa as measured by sequencing of the V4V5 region of the 16S rRNA gene amplified from community DNA from the same sample. We propose that this method may complement other methods designed to understand dynamic microbial communities, may provide information on bacteria and fungi in the same sample with a single assay, and with further development, may provide quick and easily interpreted diagnostic information on diverse bacteria and fungi at the genus or species level. Here we demonstrate the use of an RNA-based analysis of specific taxa of interest, including bacteria and fungi, within microbial communities. This multiplex method may be useful as a means to identify samples with specific combinations of taxa and to gain information on how specific populations vary over time and space or in response to perturbation. A rapid means to measure bacterial and fungal populations may aid in the study of host response to changes in microbial communities.

mSphere|2018 Aug 8

Fins JJ, Bernat JL

2018 Aug 8;pii: 10.1212/WNL.0000000000005927. doi: 10.1212/WNL.0000000000005927

This essay complements the scientific and practice scope of the American Academy of Neurology Guideline on Disorders of Consciousness by providing a discussion of the ethical, palliative, and policy aspects of the management of this group of patients. We endorse the renaming of "permanent" vegetative state to "chronic" vegetative state given the increased frequency of reports of late improvements but suggest that further refinement of this class of patients is necessary to distinguish late recoveries from patients who were misdiagnosed or in cognitive-motor dissociation. Additional nosologic clarity and prognostic refinement is necessary to preclude overestimation of low probability events. We argue that the new descriptor "unaware wakefulness syndrome" is no clearer than "vegetative state" in expressing the mismatch between apparent behavioral unawareness when patients have covert consciousness or cognitive motor dissociation. We advocate routine universal pain precautions as an important element of neuropalliative care for these patients given the risk of covert consciousness. In medical decision-making, we endorse the use of advance directives and the importance of clear and understandable communication with surrogates. We show the value of incorporating a learning health care system so as to promote therapeutic innovation. We support the Guideline's high standard for rehabilitation for these patients but note that those systems of care are neither widely available nor affordable. Finally, we applaud the Guideline authors for this outstanding exemplar of engaged scholarship in the service of a frequently neglected group of brain-injured patients.

Neurology|2018 Aug 8

Buse DC, Lipton RB, Hallström Y, Reuter U, Tepper SJ, Zhang F, Sapra S, Picard H, Mikol DD, Lenz RA

2018 Aug 7;:333102418789072doi: 10.1177/0333102418789072

Background We evaluated the effect of erenumab, a fully human monoclonal antibody that inhibits the canonical calcitonin gene-related peptide receptor, on migraine-related disability, impact, and health-related quality of life among patients with episodic migraine. Methods Patients enrolled in a phase 3, 6-month, double-blind, placebo-controlled study of once-monthly erenumab 70 and 140 mg for migraine prevention (STRIVE) used an eDiary during the baseline and double-blind treatment phases to complete validated, specific questionnaires, including the modified (monthly) Migraine Disability Assessment Questionnaire; Headache Impact Test; and Migraine-Specific Quality of Life Questionnaire-role function-restrictive (MSQ-RFR), -role function-preventive (MSQ-RFP), and -emotional function (MSQ-EF). Results A total of 955 patients were randomized to receive erenumab 70 mg (n = 317), erenumab 140 mg (n = 319), or placebo (n = 319). Erenumab versus placebo resulted in significantly greater improvements in all patient-reported outcomes; changes from baseline were numerically higher with 140 mg erenumab. Improvements occurred rapidly and were maintained over 6 months of treatment. Between-group differences from placebo over months 4-6 for the 70- and 140-mg dose groups were, respectively, -2.1 and -2.8 for modified (monthly) Migraine Disability Assessment Questionnaire, -2.1 and -2.3 for Headache Impact Test, 5.1 and 6.5 for MSQ-RFR, 4.2 and 5.4 for MSQ-RFP, and 5.2 and 6.7 for MSQ-EF ( p < 0.001 for all). Erenumab also significantly reduced the proportion of patients with severe and very severe migraine-related disability and increased the proportion of patients with clinically meaningful improvements in migraine-related impact and health-related quality of life. Conclusion Erenumab reduced migraine disability and impact and improved patients' health-related quality of life, reinforcing its role as a promising new therapy for migraine prevention.

Cephalalgia|2018 Aug 7

Cather C, Brunette MF, Mueser KT, Babbin SF, Rosenheck R, Correll CU, Kalos-Meyer P

2018 Jul 24;268:303-311doi: 10.1016/j.psychres.2018.06.055

Lifetime co-occurring substance use disorders are common at the time of presentation for treatment of a first episode of primary psychosis and persistent substance use disorder (SUD) leads to poorer outcomes. We assessed whether the NAVIGATE program, a coordinated specialty care service that includes optional substance abuse content reduced substance use compared to usual care in 404 individuals in the Recovery After Initial Schizophrenia Episode-Early Treatment Program (RAISE-ETP) study. Participants were randomized to two years of NAVIGATE (n = 223) or usual care (n = 181) and assessed monthly for substance use. At baseline, over one-half (51.7%) of the participants met criteria for a lifetime SUD, including over one-third with alcohol use disorder (36.4%) and with cannabis use disorder (34.7%). Contrary to our hypothesis, there was no treatment group by time interaction effect on days of self-reported substance use over the two-year follow-up. Participant exposure to the substance abuse component of the NAVIGATE program was low, suggesting that modifications to the program and training method for clinicians may be needed. Further research is needed to determine the most effective strategies for addressing substance use disorders in persons recovering from a first episode of psychosis.

Psychiatry Res|2018 Jul 24

Brown JR, Jacobs JP, Alam SS, Thiessen-Philbrook H, Everett A, Likosky DS, Lobdell K, Wyler von Ballmoos MC, Parker DM, Garg AX, Mackenzie T, Jacobs ML, Parikh CR

2018 Aug 4;pii: S0003-4975(18)31058-0. doi: 10.1016/j.athoracsur.2018.06.052

Hospital readmission within 30 days is associated with higher risks of complications, death, and increased costs. Accurate statistical models to stratify the risk of 30-day readmission or death after cardiac surgery could help clinical teams focus care on those patients at highest risk. We hypothesized biomarkers could improve prediction for readmission or mortality.

Ann Thorac Surg|2018 Aug 4

Tran TAN, Linos K, de Abreu FB, Carlson JA

2018 Aug 6;doi: 10.1097/DAD.0000000000001236

Malignant melanoma (MM) may display highly variable phenotypic diversity, sometimes associated with loss of immunohistochemical melanocytic markers and acquisition of nonmelanocytic lineage of differentiation. Primary cutaneous MM with rhabdomyosarcomatous differentiation is extremely rare with only 5 reported cases in the literature. To date, a chronological progression of a MM to rhabdomyosarcoma has not been conclusively documented. A 96-year-old man underwent a re-excision of an "atypical fibroxanthoma" of the forearm, which revealed a small lentigo maligna melanoma associated with a dominant dermal high-grade spindle cell nodule admixed with a population of malignant polygonal epithelioid cells. On immunohistochemical studies, the spindle cells were completely negative for all melanocytic markers, whereas a small population of polygonal neoplastic cells at the periphery was positive for Desmin and Myo-D1, supporting early rhabdomyosarcomatous transformation. Several subsequent re-excisions demonstrated merely nodules of malignant pleomorphic epithelioid cells with rhabdomyosarcomatous differentiation and devoid of melanocytic markers. In addition, both rhabdomyosarcomatous component and original MM displayed identical mutations. Therefore, the histologic, immunohistochemical, and molecular findings documented for the first time a chronological progression from an invasive MM to a pleomorphic rhabdomyosarcoma through an intermediate stage of undifferentiated sarcoma/atypical fibroxanthoma. Interestingly, subsequent recurrences of pure rhabdomyosarcomatous component displayed skip lesions/microsatellitosis, marked tumor-infiltrative lymphocytes, and rare junctional nests of rhabdomyosarcomatous cells in the epidermis, histologic features that were not described in primary cutaneous rhabdomyosarcoma and therefore could serve as morphologic clues to the diagnosis of rhabdomyosarcomatous transformation in an MM.

Am J Dermatopathol|2018 Aug 6

Poryo M, Wissing A, Zemlin M, Aygün A, Ebrahimi-Fakhari D, Geisel J, Schöpe J, Wagenpfeil S, Sauer H, Meyer S

2018 Aug 6;doi: 10.1007/s10354-018-0649-8

To correlate nucleated red blood cell counts and serum lactate concentrations on day 2 and 5 of life with morbidity and mortality in very low birth weight infants and to determine corresponding cutoff values.

Wien Med Wochenschr|2018 Aug 6

Forbes NS, Coffin RS, Deng L, Evgin L, Fiering S, Giacalone M, Gravekamp C, Gulley JL, Gunn H, Hoffman RM, Kaur B, Liu K, Lyerly HK, Marciscano AE, Moradian E, Ruppel S, Saltzman DA, Tattersall PJ, Thorne S, Vile RG, Zhang HH, Zhou S, McFadden G

2018 Aug 6;6(1):78doi: 10.1186/s40425-018-0381-3

In this White Paper, we discuss the current state of microbial cancer therapy. This paper resulted from a meeting ('Microbial Based Cancer Therapy') at the US National Cancer Institute in the summer of 2017. Here, we define 'Microbial Therapy' to include both oncolytic viral therapy and bacterial anticancer therapy. Both of these fields exploit tumor-specific infectious microbes to treat cancer, have similar mechanisms of action, and are facing similar challenges to commercialization. We designed this paper to nucleate this growing field of microbial therapeutics and increase interactions between researchers in it and related fields. The authors of this paper include many primary researchers in this field. In this paper, we discuss the potential, status and opportunities for microbial therapy as well as strategies attempted to date and important questions that need to be addressed. The main areas that we think will have the greatest impact are immune stimulation, control of efficacy, control of delivery, and safety. There is much excitement about the potential of this field to treat currently intractable cancer. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other biological or small molecule drugs. By better understanding and controlling these mechanisms, we will create new therapies that will become integral components of cancer care.

J Immunother Cancer|2018 Aug 6

Thompson JA, Christensen BC, Marsit CJ

2018 Aug 5;19(8)pii: E2296. doi: 10.3390/ijms19082296

Bidirectional gene promoters affect the transcription of two genes, leading to the hypothesis that they should exhibit protection against genetic or epigenetic changes in cancer. Therefore, they provide an excellent opportunity to learn about promoter susceptibility to somatic alteration in tumors. We tested this hypothesis using data from genome-scale DNA methylation (14 cancer types), simple somatic mutation (10 cancer types), and copy number variation profiling (14 cancer types). For DNA methylation, the difference in rank differential methylation between tumor and tumor-adjacent normal matched samples based on promoter type was tested by the Wilcoxon rank sum test. Logistic regression was used to compare differences in simple somatic mutations. For copy number alteration, a mixed effects logistic regression model was used. The change in methylation between non-diseased tissues and their tumor counterparts was significantly greater in single compared to bidirectional promoters across all 14 cancer types examined. Similarly, the extent of copy number alteration was greater in single gene compared to bidirectional promoters for all 14 cancer types. Furthermore, among 10 cancer types with available simple somatic mutation data, bidirectional promoters were slightly more susceptible. These results suggest that selective pressures related with specific functional impacts during carcinogenesis drive the susceptibility of promoter regions to somatic alteration.

Int J Mol Sci|2018 Aug 5

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