Citations

Abstract The 2013 discovery of calreticulin ( CALR ) mutations in myeloproliferative neoplasms was attended by their association with longer survival in primary myelofibrosis (PMF). Subsequent studies have suggested prognostic distinction between type 1/like and type 2/like CALR mutations and detrimental effect from triple‐negative mutational status. Among 709 Mayo Clinic patients with PMF, 467 (66%) harbored JAK2 , 112 (16%) CALR type 1/like, 24 (3.4%) CALR type 2/like, 38 (5.4%) MPL mutations and 68 (10%) were triple‐negative. Survival was longer with type 1/like CALR , compared to JAK2 (HR 2.6, 95% CI 1.9‐3.5), type 2/like CALR (HR 2.5, 95% CI 1.4‐4.5), MPL (HR 1.8, 95% CI 1.1‐2.9) and triple‐negative mutational status (HR 2.4, 95% CI 1.6‐3.6), but otherwise similar between the non‐type 1/like CALR mutational states ( P = .41). In multivariable analysis, the absence of type 1/like CALR ( P < .001; HR 2, 95% CI 1.4‐2.7), presence of ASXL1 / SRSF2 mutations ( P < .001; HR 1.9, 95% CI 1.5‐2.4) and DIPSS‐plus ( P < .001) were each predictive of inferior survival. Furthermore, among 210 patients with ASXL1 / SRSF2 mutations, survival was significantly longer in the presence vs. absence of type 1/like CALR mutations (median 5.8 vs. 2.9 years; P < .001). Triple‐negative status did not disclose additional prognostic information for overall or leukemia‐free survival. The observations regarding the prognostic distinction between CALR mutation variants were validated in an external cohort of 386 patients from the University of Florence Careggi hospital. We conclude that type 1/like CALR mutations in PMF not only predict superior survival, but also partially amend the detrimental effect of high molecular risk mutations.

Key Clinical Message This case report describes an individual with brain calcifications, cognitive decline, motor dysfunction, and hypocalcaemia. Exome sequencing revealed a previously reported variant in the CASR gene and a variant of uncertain significance in PDGFRB . The clinical phenotype is likely explained by the CASR variant, but we discuss how the PDGFRB variant could also participate in the phenotype.

Type 2 diabetes is an emerging global health epidemic. Foundations for new therapies are arising from understanding interactions between body systems. Bone‐derived factors that reduce RANKL (receptor activator of NF‐kappa B ligand) signaling in the liver may prevent insulin resistance and the onset of type 2 diabetes. Here we demonstrate that deletion of the epigenetic regulator, Hdac3, in Osx1‐expressing osteoprogenitors prevents insulin resistance induced by high fat diet by increasing serum and skeletal gene expression levels of osteoprotegerin (Opg), a natural inhibitor of RANKL signaling. Removal of one Opg allele in mice lacking Hdac3 in Osx1+ osteoprogenitors increases the insulin resistance of the Hdac3‐deficient mice on a high fat diet. Thus, Hdac3‐depletion in osteoblasts increases expression of Opg, subsequently preserving insulin sensitivity. The Hdac inhibitor vorinostat also increased Opg transcription and histone acetylation of the Opg locus. These results define a new mechanism by which bone regulates systemic insulin sensitivity.

65 Background: Cholangiocarcinoma (CC) accounts for approximately 3% of all gastrointestinal cancers and have a poor incident to mortality rate. The incidence in the United States (US) is 2,000-3,000 cases annually, with this rate steadily increasing during the last twenty years; this trend is not solely observed in US but also seen in Europe, Australia and Japan. The highest incidence is seen in Southeast Asia due to parasitic infection. CC presents many challenges to healthcare professionals due to the anatomic nature of CC (Lowe et al, 2015). The worldwide increase in incidence of CC is indication for the essential development of nursing practice guidelines underpinned by expert evidence and knowledge and regarding the key aspects of care. Methods: A collaboration of nursing professionals representing major cancer research institutions from around the country and the United Kingdom worked together to identify key aspects of care, the aim being to develop Clinical Nursing Practice Guidelines. The process included an exhaustive literature review using Pubmed, Uptodate, Medline, and CINAHL databases; submission of respective institutional practices; group consensus on guideline content, evidence-based scoring assignment and approval by the Cholangiocarcinoma Medical Advisory Board. Results: The guidelines developed include the care of the patient: (1) with external biliary drains and internal bile duct stents, (2) with intractable nausea and vomiting resulting from disease process, (3) with fatigue resulting from disease process, (4) undergoing chemotherapy, (5) undergoing photon radiation, (6) undergoing radiation on a clinical trial, and (7) preparing for liver transplantation. The purpose of the guidelines are to advance the scientific knowledge of the symptoms experienced, quality of life of patients with CCA, establish standards in patient care, and improve quality of care and satisfaction for patients diagnosed with CC. Conclusions: Creation of evidence-based guidelines will provide a springboard for expanded competent knowledge and a model to test for improvement in the care and quality of life of the patient with CC.

AbstractBackgroundCardiac allograft vasculopathy (CAV) remains an important cause of graft failure after heart transplantation (HT). Although many risk factors for CAV have been identified, there are no clinical prediction models that enable clinicians to determine each recipient's risk of CAV.MethodsWe studied a cohort of 14 328 heart transplant recipients whose data were reported to the International Society for Heart and Lung Transplantation Registry between 2000 and 2010. The cohort was divided into training (75%) and test (25%) sets. Multivariable modeling was performed in the test set using variables available at the time of heart transplant using three methods: (i) stepwise Cox proportional hazard, (ii) regularized Cox proportional hazard, and (iii) Bayesian network.ResultsCardiac allograft vasculopathy developed in 4259 recipients (29.7%) at a median time of 3.0 years after HT. The regularized Cox proportional hazard model yielded the optimal performance and was also the most parsimonious. We deployed this model as an Internet‐based risk calculator application.ConclusionsWe have developed a clinical prediction model for assessing a recipient's risk of CAV using variables available at the time of HT. Application of this model may allow clinicians to determine which recipients will benefit from interventions to reduce the risk of development and progression of CAV.

Context.— The diagnosis and grading of acute cellular and antibody-mediated rejection (AMR) in lung allograft biopsies is important because rejection can lead to acute graft dysfunction and/or failure and may contribute to chronic graft failure. While acute cellular rejection is well defined histologically, no reproducible specific features of AMR are currently identified. Therefore, a combination of clinical features, serology, histopathology, and immunologic findings is suggested for the diagnosis of AMR. Objective.— To describe the perspective of members of the Pulmonary Pathology Society (PPS) on the workup of lung allograft transbronchial biopsy and the diagnosis of acute cellular rejection and AMR in lung transplant. Data Sources.— Reports by the International Society for Heart and Lung Transplantation (ISHLT), experience of members of PPS who routinely review lung allograft biopsies, and search of literature database (PubMed). Conclusions.— Acute cellular rejection should be assessed and graded according to the 2007 working formulation of the ISHLT. As currently no specific features are known for AMR in lung allografts, the triple test (clinical allograft dysfunction, donor-specific antibodies, pathologic findings) should be used for its diagnosis. C4d staining might be performed when morphologic, clinical, and/or serologic features suggestive of AMR are identified.

Context Although many studies have demonstrated the benefits of mentoring in academic medicine, conceptual understanding has been limited to studies performed in North America and Europe. An ecological model of mentoring in academic medicine can provide structure for a broader understanding of the role of culture in mentoring. Objective The goal of this study was to explore the role of culture in the development and maintenance of mentoring relationships within the context of the University of Malawi College of Medicine. Methods A qualitative study using in‐depth, semi‐structured interviews and thematic analysis was conducted to explore the meaning of mentorship at the study institution. Criterion sampling was used to identify and recruit medical students, interns, registrars and faculty members. Study team members developed a codebook through open coding and applied it to all interview transcripts. Thematic analysis was used to identify and categorise themes according to an ecological model. Results A total of 46 participants from two major centres in Malawi were interviewed. Themes were identified within three domains: the intrapersonal; the interpersonal, and the institutional. Intrapersonal themes included Malawian politeness, mentoring needs, and friendliness and willingness to help. Interpersonal themes included understanding the role of the mentor, respect for elders, personal and professional boundaries, and perceptions of others. Institutional themes included the supervisor versus mentor, time pressures, tension about the scope of training, and the mentoring cycle. Conclusions This study highlights the strengths of and challenges imposed by culture to the provision of mentoring relationships at the study institution. It also highlights the central role of culture in mentoring and proposes an updated model for mentoring in academic medicine. This model can inform future research on mentoring and may serve as a model in the larger effort to provide faculty development in mentoring across sub‐Saharan Africa.