Citations

ABSTRACT Malaria is a potentially life-threatening disease requiring rapid diagnosis and treatment. Although microscopic examination of thick and thin blood films remains the gold standard for laboratory diagnosis, rapid antigen tests and nucleic acid amplification methods may also play a useful role in detection of acute infection. This review discusses the advantages and disadvantages of the commonly used diagnostic methods and provides important practice points for optimal malaria test utilization.

AbstractBackgroundThe Choosing Wisely campaign has called for better engagement of palliative and hospice care services for patients in the emergency department (ED). PREDICT is a clinical prediction tool that was derived in an Australian ED cohort. It assesses a patient's risk of mortality at 1 year to select those who would benefit from advanced care planning. Such goals‐of‐care discussion can improve patients’ ability to communicate what they want out of their healthcare and, in cases of end of life, potentially reduce the number of futile interventions. Using a cutoff of 13 points, PREDICT had a reported 95.3% specificity and 53.9% sensitivity for 1‐year mortality. We externally validated PREDICT and derived a simpler modified PREDICT tool to systematically identify high‐risk patients eligible for goals‐of‐care discussions and palliative care consultation in the ED.MethodsThis was an observational cohort study of a random sample of 927 patients aged 55+ seen in the ED in 2014. We identified advance healthcare directives (AHDs) on file. We summarized diagnostic accuracy of the clinical tool to predict 1‐year mortality using sensitivity, specificity, and area under the curve (AUC). We refined PREDICT using multivariable modeling. We followed reporting guidelines including STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) for cohort studies and Standards for Reporting of Diagnostic Accuracy (STARD).ResultsA total of 927 patients were included: 55.0% were male, 63 (7.0%) were nursing home residents, 389 (42.0%) patients had an AHD in their medical record at the time of ED visit, and 245 (26.4%) were deceased at 1 year. Of the 780 patients with PREDICT scores < 13, a total of 164 (21.0%; 95% confidence interval [CI] = 18.3–24.1) were deceased at 1 year, and of the 147 patients with PREDICT scores ≥ 13, a total of 81 (55.1%; 95% CI = 46.7–63.2) were deceased at 1 year. The AUC of the PREDICT score was 0.717 (95% CI = 0.680–0.754), sensitivity was 33.1% (95% CI = 27.3–39.4), and specificity was 90.3% (95% CI = 87.8–92.4) to predict 1‐year mortality. The modified PREDICT tool resulted in an AUC of 0.709 (95% CI = 0.671–0.747). We decided to select this model as the preferred model, as the variable of intensive care unit (ICU) admission with multiorgan failure can be difficult to assess in the ED and may delay advanced care planning. Reweighting the score did not improve fit or the AUC, so points assigned to each variable were not adjusted.ConclusionPREDICT is an easy tool to administer to be able to identify patients who are at high risk of 1‐year mortality and who could benefit from AHDs, goals‐of‐care discussion, and when appropriate in the context of an end‐of‐life setting, palliative medicine consultation. External validation of PREDICT was successful in our population. We simplified PREDICT and derived a new tool, the modified PREDICT minus ICU tool, without significantly altering the sensitivity, specificity, and AUC for death at 1 year. The next steps include external validation of the newly derived rule and prospective implementation.

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long‐term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long‐term outcome. We identified 781 patients, median age 12 years, with 4,277 person‐years of follow‐up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event‐free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC–inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5‐0.9, and 0.7, 95% confidence interval 0.5‐0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long‐term outcome. Conclusion: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma‐glutamyltransferase, and aspartate aminotransferase‐to‐platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC–inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518–527).

Purpose The stiffness of a myocardial infarct affects the left ventricular pump function and remodeling. Magnetic resonance elastography (MRE) is a noninvasive imaging technique for measuring soft‐tissue stiffness in vivo. The purpose of this study was to investigate the feasibility of assessing in vivo regional myocardial stiffness with high‐frequency 3D cardiac MRE in a porcine model of myocardial infarction, and compare the results with ex vivo uniaxial tensile testing. Methods Myocardial infarct was induced in a porcine model by embolizing the left circumflex artery. Fourteen days postinfarction, MRE imaging was performed in diastole using an echocardiogram‐gated spin‐echo echo‐planar‐imaging sequence with 140‐Hz vibrations and 3D MRE processing. The MRE stiffness and tensile modulus from uniaxial testing were compared between the remote and infarcted myocardium. Results Myocardial infarcts showed increased in vivo MRE stiffness compared with remote myocardium (4.6 ± 0.7 kPa versus 3.0 ± 0.6 kPa, P = 0.02) within the same pig. Ex vivo uniaxial mechanical testing confirmed the in vivo MRE results, showing that myocardial infarcts were stiffer than remote myocardium (650 ± 80 kPa versus 110 ± 20 kPa, P = 0.01). Conclusions These results demonstrate the feasibility of assessing in vivo regional myocardial stiffness with high‐frequency 3D cardiac MRE. Magn Reson Med 79:361–369, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Abstract Castration resistant prostate cancer (CRPC) is a deadly disease with a poor prognosis. Treatment options for CRPC patients involve taxanes or newly developed drugs targeting the androgen pathway or androgen synthesis, including CYP17 inhibitors. However, response to therapy varies dramatically among patients, which might be due, in part, to tumor heterogeneity. Therefore, understanding of the genomic landscape of CRPC would be important to help achieve better outcomes by developing personalized therapies. One challenge contributing to our lack of therapies for CRPC is a paucity of clinically relevant animal models predictive of response to therapy in human patients. The Prostate Cancer Medically Optimized Genome Enhanced Therapy (PROMOTE) study is a Mayo Clinic prospective trial designed for patients with metastatic CRPC who are treated with abiraterone acetate, a CYP17 inhibitor, over a 12 week period. Fresh tissue from metastatic lesions, primarily bone metastases, was obtained by needle core biopsy before and 12 weeks after initiating abiraterone acetate treatment. The samples were submitted for DNA and RNA sequencing and were also used to generate patient-derived xenograft (PDX) models. PDX models were developed by injecting biopsy samples subcutaneously or under the renal capsule in male non-obese diabetic (NOD)/severe combined immunodeficient (SCID) or NOD/SCID/IL-2γ-receptor null (NSG) mice implanted with 25mg testosterone pellets at the time of tissue implantation and 2 months later. Baseline samples from 103 unique patients as well as second samples from 61 patients post abiraterone acetate treatment were injected into approximately 600 mice. Of the samples for which pathology is currently available, 31% of the biopsies injected into mice were confirmed to include tumor tissue, which may be compared with a figure of 37.5% of samples sent for sequencing. Thus far, we have established 8 PDX models, four from baseline and four from post treatment samples. Seven models were derived from metastatic bone lesions, and one model from a liver metastasis. The tumor tissue in each model was expanded into a second of generation of mice and harvested when the tumors grew. No tumor was expanded more than four times. Genomic and transcriptomic analysis of xenograft tissue from different “generations” of xenograft expansion is ongoing and will be compared with similar data for the original biopsy. The evaluation of treatment response after exposure of these PDX models to different therapies including CYP19 inhibitors, AR blockers and taxanes is ongoing. These PDX models provide a tool for future drug testing and for studying mechanisms of resistance to therapy in CRPC. Citation Format: Fang Xie, Manish Kohli, Yin Ping, Rafael E. Jimenez, Richard M. Weinshilboum, Liewei Wang. Developing patient derived xenograft (PDX) models for metastatic castration resistant prostate cancer (CRPC) during CYP17 inhibitor therapy. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A05.

Abstract Background There are limited reports of severe tricuspid valve stenosis in dogs and limited data regarding treatment and outcome. Objective To evaluate clinical signs, echocardiographic features, and outcome of balloon valvuloplasty (BV) in dogs with severe tricuspid valve stenosis (TVS) in which BV was attempted. Animals Five client-owned dogs with severe TVS. Methods Records were retrospectively reviewed and data collected regarding signalment, clinical signs, diagnostic findings, procedures, and outcome. Results All dogs were Labrador Retrievers. Presenting complaints included episodic weakness/syncope (4/5), abdominal distension (4/5), lethargy (2/5), and exercise intolerance (2/5). The median and range of measurements before BV were as follows: TV mean velocity 1.5 m/s (range 1.4–1.7 m/s); velocity-time integral (VTI) 79.8 cm (42.4–99.1 cm); and TV maximum velocity 2.9 m/s (2.3–3.2 m/s). Measurements (available for 3 of 5 dogs) after BV were as follows: TV mean velocity 1.15 m/s (0.9–1.4 m/s); VTI 44.95 cm (41.4–54.8 cm); and TV maximum velocity 1.15 m/s (1.9–2.3 m/s). The procedure was attempted in all dogs and completed in 4/5 dogs. The largest balloon diameter ranged from 15 mm to 25 mm, and length ranged from 4 cm to 5 cm. Right atrial pressure decreased in 4/5 dogs. All but 1 dog had clinical improvement after BV, but recurrence of clinical signs occurred (2/5). Tricuspid regurgitation worsened in 1 dog culminating in right heart failure and euthanasia. Conclusions and Clinical Importance BV can be an effective treatment; however, clinical signs can recur. Right heart failure due to worsened TR is a potential complication in dogs with pre-existing moderate-to-severe TR.