Open notes sounds great, but will a provider's documentation change? An exploratory study of the effect of open notes on oncology documentation.

OBJECTIVE: The effects of shared clinical notes on patients, care partners, and clinicians ("open notes") were first studied as a demonstration project in 2010. Since then, multiple studies have shown clinicians agree shared progress notes are beneficial to patients, and patients and care partners report benefits from reading notes. To determine if implementing open notes at a hematology/oncology practice changed providers' documentation style, we assessed the length and readability of clinicians' notes before and after open notes implementation at an academic medical center in Boston, MA, USA. MATERIALS AND METHODS: We analyzed 143 888 notes from 60 hematology/oncology clinicians before and after the open notes debut at Beth Israel Deaconess Medical Center, from January 1, 2012 to September 1, 2016. We measured the providers' (medical doctor/nurse practitioner) documentation styles by analyzing character length, the number of addenda, note entry mode (dictated vs typed), and note readability. Measurements used 5 different readability formulas and were assessed on notes written before and after the introduction of open notes on November 25, 2013. RESULTS: After the introduction of open notes, the mean length of progress notes increased from 6174 characters to 6648 characters (P < .001), and the mean character length of the "assessment and plan" (A&P) increased from 1435 characters to 1597 characters (P < .001). The Average Grade Level Readability of progress notes decreased from 11.50 to 11.33, and overall readability improved by 0.17 (P = .01). There were no statistically significant changes in the length or readability of "Initial Notes" or Letters, inter-doctor communication, nor in the modality of the recording of any kind of note. CONCLUSIONS: After the implementation of open notes, progress notes and A&P sections became both longer and easier to read. This suggests clinician documenters may be responding to the perceived pressures of a transparent medical records environment.

Autologous stem cell transplantation after anti-PD-1 therapy for multiply relapsed or refractory Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) can be curative for patients with relapsed/refractory Hodgkin lymphoma (HL). Based on studies suggesting that anti-PD-1 monoclonal antibodies (mAbs) can sensitize patients to subsequent chemotherapy, we hypothesized that anti-PD-1 therapy before ASCT would result in acceptable outcomes among high-risk patients who progressed on or responded insufficiently to ≥1 salvage regimen, including chemorefractory patients who are traditionally considered poor ASCT candidates. We retrospectively identified 78 HL patients who underwent ASCT after receiving an anti-PD-1 mAb (alone or in combination) as third-line or later therapy across 22 centers. Chemorefractory disease was common, including 42 patients (54%) refractory to ≥2 consecutive systemic therapies immediately before anti-PD-1 treatment. Fifty-eight (74%) patients underwent ASCT after anti-PD-1 treatment, while 20 patients (26%) received additional therapy after PD-1 blockade and before ASCT. Patients received a median of 4 systemic therapies (range, 3-7) before ASCT, and 31 patients (41%) had a positive pre-ASCT positron emission tomography (PET) result. After a median post-ASCT follow-up of 19.6 months, the 18-month progression-free survival (PFS) and overall survival were 81% (95% CI, 69-89) and 96% (95% confidence interval [CI], 87-99), respectively. Favorable outcomes were observed for patients who were refractory to 2 consecutive therapies immediately before PD-1 blockade (18-month PFS, 78%), had a positive pre-ASCT PET (18-month PFS, 75%), or received ≥4 systemic therapies before ASCT (18-month PFS, 73%), while PD-1 nonresponders had inferior outcomes (18-month PFS, 51%). In this high-risk cohort, ASCT after anti-PD-1 therapy was associated with excellent outcomes, even among heavily pretreated, previously chemorefractory patients.

Leukemia vaccine overcomes limitations of checkpoint blockade by evoking clonal T cell responses in a murine acute myeloid leukemia model.

We have developed a personalized vaccine whereby patient derived leukemia cells are fused to autologous dendritic cells, evoking a polyclonal T cell response against shared and neo-antigens. We postulated that the dendritic cell (DC)/AML fusion vaccine would demonstrate synergy with checkpoint blockade by expanding tumor antigen specific lymphocytes that would provide a critical substrate for checkpoint blockade mediated activation. Using an immunocompetent murine leukemia model, we examined the immunologic response and therapeutic efficacy of vaccination in conjunction with checkpoint blockade with respect to leukemia engraftment, disease burden, survival and the induction of tumor specific immunity. Mice treated with checkpoint blockade alone had rapid leukemia progression and demonstrated only a modest extension of survival. Vaccination with DC/AML fusions resulted in the expansion of tumor specific lymphocytes and disease eradication in a subset of animals, while the combination of vaccination and checkpoint blockade induced a fully protective tumor specific immune response in all treated animals. Vaccination followed by checkpoint blockade resulted in upregulation of genes regulating activation and proliferation in memory and effector T cells. Long term survivors exhibited increased T cell clonal diversity and were resistant to subsequent tumor challenge. The combined DC/AML fusion vaccine and checkpoint blockade treatment offers unique synergy inducing the durable activation of leukemia specific immunity, protection from lethal tumor challenge and the selective expansion of tumor reactive clones.

Significant and Distinctive n-Grams in Oncology Notes: A Text-Mining Method to Analyze the Effect of OpenNotes on Clinical Documentation.

PURPOSE: OpenNotes is a national movement established in 2010 that gives patients access to their visit notes through online patient portals, and its goal is to improve transparency and communication. To determine whether granting patients access to their medical notes will have a measurable effect on provider behavior, we developed novel methods to quantify changes in the length and frequency of use of n-grams (sets of words used in exact sequence) in the notes. METHODS: We analyzed 102,135 notes of 36 hematology/oncology clinicians before and after the OpenNotes debut at Beth Israel Deaconess Medical Center. We applied methods to quantify changes in the length and frequency of use of sequential co-occurrence of words (n-grams) in the unstructured content of the notes by unsupervised hierarchical clustering and proportional analysis of n-grams. RESULTS: The number of significant n-grams averaged over all providers did not change, but for individual providers, there were significant changes. That is, all significant observed changes were provider specific. We identified eight providers who were late note signers. This group significantly reduced its late signing behavior after OpenNotes implementation. CONCLUSION: Although the number of significant n-grams averaged over all providers did not change, our text-mining method detected major content changes in specific providers' documentation at the n-gram level. The method successfully identified a group of providers who decreased their late note signing behavior.

Hypomethylating agent alters the immune microenvironment in acute myeloid leukaemia (AML) and enhances the immunogenicity of a dendritic cell/AML vaccine.

Acute myeloid leukaemia (AML) is a lethal haematological malignancy characterized by an immunosuppressive milieu in the tumour microenvironment (TME) that fosters disease growth and therapeutic resistance. Hypomethylating agents (HMAs) demonstrate clinical efficacy in AML patients and exert immunomodulatory activities. In the present study, we show that guadecitabine augments both antigen processing and presentation, resulting in increased AML susceptibility to T cell-mediated killing. Exposure to HMA results in the activation of the endogenous retroviral pathway with concomitant downstream amplification of critical mediators of inflammation. In an immunocompetent murine leukaemia model, guadecitabine negatively regulates inhibitory accessory cells in the TME by decreasing PD-1 (also termed PDCD1) expressing T cells and reducing AML-mediated expansion of myeloid-derived suppressor cells. Therapy with guadecitabine results in enhanced leukaemia-specific immunity, as manifested by increased CD4 and CD8 cells targeting syngeneic leukaemia cells. We have previously reported that vaccination with AML/dendritic cell fusions elicits the expansion of leukaemia-specific T cells and protects against disease relapse. In the present study, we demonstrate that vaccination in conjunction with HMA therapy results in enhanced anti-leukaemia immunity and survival. The combination of a novel personalized dendritic cell/AML fusion vaccine and an HMA has therapeutic potential, and a clinical trial investigating this combination is planned.

Dissociation between urate and blood pressure in mice and in people with early Parkinson's disease.

BACKGROUND: Epidemiological, laboratory and clinical studies have established an association between elevated urate and high blood pressure (BP). However, the inference of causality remains controversial. A naturally occurring antioxidant, urate may also be neuroprotective, and urate-elevating treatment with its precursor inosine is currently under clinical development as a potential disease-modifying strategy for Parkinson's disease (PD). METHODS: Our study takes advantage of a recently completed phase II trial evaluating oral inosine in de novo non-disabling early PD with no major cardiovascular and nephrological conditions, and of three lines of genetically engineered mice: urate oxidase (UOx) global knockout (gKO), conditional KO (cKO), and transgenic (Tg) mice with markedly elevated, mildly elevated, and substantially reduced serum urate, respectively, to systematically investigate effects of urate-modifying manipulation on BP. FINDINGS: Among clinical trial participants, change in serum urate but not changes in systolic, diastolic and orthostatic BP differed by treatment group. There was no positive correlation between urate elevations and changes in systolic, diastolic and orthostatic BP ((p = .05 (in inverse direction), 0.30 and 0.63, respectively)). Between UOx gKO, cKO, or Tg mice and their respective wildtype littermates there were no significant differences in systolic or diastolic BP or in their responses to BP-regulating interventions. INTERPRETATION: Our complementary preclinical and human studies of urate modulation in animal models and in generally healthy early PD do not support a hypertensive effect of urate elevation or an association between urate and BP. FUND: U.S. Department of Defense, RJG Foundation, Michael J. Fox Foundation LEAPS program, National Institutes of Health, American Federation for Aging Research, Parkinson's Disease Foundation Advancing Parkinson's Therapies initiative.

MUC1-C drives myeloid leukaemogenesis and resistance to treatment by a survivin-mediated mechanism.

Acute myeloid leukaemia (AML) is an aggressive haematological malignancy with an unmet need for improved therapies. Responses to standard cytotoxic therapy in AML are often transient because of the emergence of chemotherapy-resistant disease. The MUC1-C oncoprotein governs critical pathways of tumorigenesis, including self-renewal and survival, and is aberrantly expressed in AML blasts and leukaemia stem cells (LSCs). However, a role for MUC1-C in linking leukaemogenesis and resistance to treatment has not been described. In this study, we demonstrate that MUC1-C overexpression is associated with increased leukaemia initiating capacity in an NSG mouse model. In concert with those results, MUC1-C silencing in multiple AML cell lines significantly reduced the establishment of AML in vivo. In addition, targeting MUC1-C with silencing or pharmacologic inhibition with GO-203 led to a decrease in active ß-catenin levels and, in-turn, down-regulation of survivin, a critical mediator of leukaemia cell survival. Targeting MUC1-C was also associated with increased sensitivity of AML cells to Cytarabine (Ara-C) treatment by a survivin-dependent mechanism. Notably, low MUC1 and survivin gene expression were associated with better clinical outcomes in patients with AML. These findings emphasize the importance of MUC1-C to myeloid leukaemogenesis and resistance to treatment by driving survivin expression. Our findings also highlight the potential translational relevance of combining GO-203 with Ara-C for the treatment of patients with AML.

Combination of Myelin Basic Protein Gene Polymorphisms with HLA-DRB1*1501 in Iranian Patients with Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS), as a multifactorial autoimmune disease with complex genetic basis, causes demyelination in the central nervous system via cytokine responses to myelin antigens. Myelin basic protein (MBP) is the main protein component of the myelin sheath. HLA-DRB (human leukocyte antigen-DR beta) alleles, particularly HLA-DRB1*1501, may be of significance in the pathogenesis of MS. OBJECTIVE: To examine the association of HLA-DRB1*1501 alleles and MBP VNTR (variable number tandem repeat) polymorphism with the MS susceptibility in Iranian population. METHODS: Genomic DNA was extracted from peripheral blood. The alleles were determined by the Polymerase Chain Reaction (PCR) method in 259 MS patients and 312 healthy control individuals and analyses were carried out using Fisher's exact test. RESULTS: The frequencies of MBP VNTR genotypes (AA, AB and BB) were 47%, 42% and 11% among patients, and 45%, 43% and 12% in control subjects, respectively. HLA-DRB1*1501 allele was more frequent among patients than healthy individuals (OR=1.65, P=0.0045). The frequency of allele A and genotype A/A was significantly higher among HLA-DRB1*1501 positive patients (61% and 32%) than controls (46% and 19%) (OR=1.88, P=0.0013; A/A vs. B/B: OR=5.09, P=0.0004). The two-locus analysis of the interaction between the MBP VNTR polymorphism and the HLA-DRB1 allele showed that the HLADRB1* 1501/A haplotype was more frequent among MS patients than the healthy controls. CONCLUSION: The interaction between the HLA-DRB1*1501 allele and MBP gene may be considered as a predisposing factor in the development and pathogenesis of MS in the case of gene-gene interaction.

Effectiveness of second-opinion radiology consultations to reassess the cervical spine CT scans: a study on trauma patients referred to a tertiary-care hospital.

PURPOSE: A second opinion is a valuable resource in confirming proper medical diagnosis and treatment. This study evaluates the effectiveness of second-opinion radiology consultations to reassess the cervical spine computed tomography (CT) scans of the trauma patients referred to our hospital. METHODS: Cervical spine CT scans of 301 consecutive adult trauma patients, who were referred to our hospital from outside institutions, were analyzed. The emergency radiologists at our institution completed the over-read reports on the CT images obtained at the outside facilities. A single radiologist compared the outside- and over-read reports and determined the discrepancy of the radiologic reports. RESULTS: Based on the outside reports, 31% of the CT scans had cervical traumatic injury. In 92% of patients, the first-read and the over-read reports had consistent radiologic findings. About 90% of the positive, and 93% of the negative radiologic findings, were reported consistently in the over-read reports. Our analysis showed that the over-read reporting resulted in reassurance of negative findings in 63%; confirmation of positive findings in 29%; clearing a false diagnosis in 3%; and detection of a missed diagnosis in 5%. A rescan was done in 80% of patients with inconsistent and 20% of patients with consistent findings (P < 0.05). The most common missed radiologic findings in the first-reports were transverse and spinous process fractures and the most common misdiagnoses were dens fractures. CONCLUSION: For a service offering second-opinion consultations on cervical spine trauma, review of outside CT studies improves diagnosis and benefits patient care.

Mycobacterium tuberculosis type II NADH-menaquinone oxidoreductase catalyzes electron transfer through a two-site ping-pong mechanism and has two quinone-binding sites.

Type II NADH-quinone oxidoreductase (NDH-2) catalyzes the transfer electrons from NADH to the quinone pool and plays an essential role in the oxidative phosphorylation system of Mycobacterium tuberculosis (Mtb). The absence of NDH-2 in the mammalian mitochondrial electron transport chain makes this enzyme an attractive target for antibiotic development. To fully establish the kinetic properties of this enzyme, we studied the interaction of Mtb NDH-2 with substrates, NADH, and various quinone analogues and their products in both membrane and soluble environments. These studies, and comparative analyses of the kinetics with thio-NAD(+) and quinone electron acceptors, provided evidence that Mtb NDH-2 catalyzes the transfer electrons from NADH to quinone substrates by a nonclassical, two-site ping-pong kinetic mechanism whereby substrate quinones bind to a site that is distinct from the NADH-binding site. Furthermore, the effects of quinols on Mtb NDH-2 catalytic activity demonstrate the presence of two binding sites for quinone ligands, one favoring the reduced form and the other favoring the oxidized form.

Minor groove binding compounds that jump a gc base pair and bind to adjacent AT base pair sites.

Most A/T specific heterocyclic diamidine derivatives need at least four A/T base pairs for tight binding to the DNA minor groove. Addition of a GC base pair to A/T sequences typically causes a large decrease in binding constant. The ability to target biologically important sequences of DNA could be significantly increased if compounds that could recognize A/T sites with an intervening GC base pair could be designed. The kinetoplast DNA sequence of parasitic microorganisms, for example, contains numerous three A/T binding sites that are separated by a single G. A series of compounds were prepared to target the AAAGTTT sequence as a model system for discovery of "G-jumpers". The new synthetic compounds have two aromatic-amidine groups for A/T recognition, and these are connected through an oxy-methylene linker to cross the GC. CD experiments indicated a minor groove binding mode, as expected, for these compounds. T(max), surface plasmon resonance, and isothermal titration calorimetry experiments revealed 1:1 binding to the AAAGTTT sequence with an affinity that depends on compound structure. Benzimidazole derivatives gave the strongest binding and had generally good solution properties. The binding affinities to the classical AATT sequence were similar to that for AAAGTTT for these extended compounds, but binding was weaker to the AAAGCTTT sequence with two intervening GC base pairs. Binding to both AAAGTTT and AATT was enthalpy driven for strong binding benzimidazole derivatives.

Influence of DNA structure on adjacent site cooperative binding.

Previous NMR studies of Hoechst 33258 with the d(CTTTTGCAAAAG)2 sequence have shown very strong (K2 >> K1) cooperativity between two adjacent binding sites (Searle, M. S.; Embrey, K. J. Nucleic Acids Res. 1990, 18 (13), 3753- 3762). In contrast, surface plasmon resonance (SPR) results with the hairpin analog of the same sequence show significantly reduced cooperativity. In an effort to explain the difference, two-dimensional (2-D) NMR experiments were done on both duplex and hairpin. Hoechst 33258 and an amidine analog, DB183, show very strong cooperativity with the duplex DNA but much weaker cooperativity with the hairpin. The significantly lower thermal melting temperature (Tm) of the duplex (34.8 degrees C) in comparison to its hairpin analog (62.3 degrees C) supports the idea of a dynamic difference between the two DNA structures that can influence cooperativity in binding. These results confirm the role of conformational entropy in positive cooperativity in some DNA interactions.