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Item ADAM8 is expressed widely in breast cancer and predicts poor outcome in hormone receptor positive, HER-2 negative patients(BMC, 2023-08-11) Pianetti, Stefania; Miller, Kathy D.; Chen, Hannah H.; Althouse, Sandra; Cao, Sha; Michael, Steven J.; Sonenshein, Gail E.; Mineva, Nora D.; Biostatistics and Health Data Science, School of MedicineBackground: Breast malignancies are the predominant cancer-related cause of death in women. New methods of diagnosis, prognosis and treatment are necessary. Previously, we identified the breast cancer cell surface protein ADAM8 as a marker of poor survival, and a driver of Triple-Negative Breast Cancer (TNBC) growth and spread. Immunohistochemistry (IHC) with a research-only anti-ADAM8 antibody revealed 34.0% of TNBCs (17/50) expressed ADAM8. To identify those patients who could benefit from future ADAM8-based interventions, new clinical tests are needed. Here, we report on the preclinical development of a highly specific IHC assay for detection of ADAM8-positive breast tumors. Methods: Formalin-fixed paraffin-embedded sections of ADAM8-positive breast cell lines and patient-derived xenograft tumors were used in IHC to identify a lead antibody, appropriate staining conditions and controls. Patient breast cancer samples (n = 490) were used to validate the assay. Cox proportional hazards models assessed association between survival and ADAM8 expression. Results: ADAM8 staining conditions were optimized, a lead anti-human ADAM8 monoclonal IHC antibody (ADP2) identified, and a breast staining/scoring control cell line microarray (CCM) generated expressing a range of ADAM8 levels. Assay specificity, reproducibility, and appropriateness of the CCM for scoring tumor samples were demonstrated. Consistent with earlier findings, 36.1% (22/61) of patient TNBCs expressed ADAM8. Overall, 33.9% (166/490) of the breast cancer population was ADAM8-positive, including Hormone Receptor (HR) and Human Epidermal Growth Factor Receptor-2 (HER2) positive cancers, which were tested for the first time. For the most prevalent HR-positive/HER2-negative subtype, high ADAM8 expression identified patients at risk of poor survival. Conclusions: Our studies show ADAM8 is widely expressed in breast cancer and provide support for both a diagnostic and prognostic value of the ADP2 IHC assay. As ADAM8 has been implicated in multiple solid malignancies, continued development of this assay may have broad impact on cancer management.Item Antenna Design and SAR Analysis on Human Head Phantom Simulation for Future Clinical Applications(Scientific Research Publishing, 2017-09) Perez, Felipe Pablo; Bandeira, Joseph Paul; Morisaki, Jorge J.; Krishna Peddinti, Seshasai Vamsi; Salama, Paul; Rizkalla, James; Rizkalla, Maher E.; Medicine, School of MedicineBackground The rapid development of a variety of devices that emit Radiofrequency Electromagnetic fields (RF-EMF) has sparked growing interest in their interaction with biological systems and the beneficial effects on human health. As a result, investigations have been driven by the potential for therapeutic applications, as well as concern for any possible negative health implications of these EM energies [-]. Recent results have indicated specific tuning of experimental and clinical RF exposure may lead to their clinical application toward beneficial health outcomes []. Method In the current study, a mathematical and computer simulation model to analyze a specific RF-EMF exposure on a human head model was developed. Impetus for this research was derived from results of our previous experiments which revealed that Repeated Electromagnetic Field Stimulation (REMFS) decreased the toxic levels of beta amyloid (Aβ) in neuronal cells, thereby suggesting a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). Throughout development of the proposed device, experimental variables such as the EM frequency range, specific absorption rate (SAR), penetration depth, and innate properties of different tissues have been carefully considered. Results RF-EMF exposure to the human head phantom was performed utilizing a Yagi-Uda antenna type possessing high gain (in the order of 10 dbs) at a frequency of 64 MHz and SAR of 0.6 W/Kg. In order to maximize the EM power transmission in one direction, directors were placed in front of the driven element and reflectors were placed behind the driven element. So as to strategically direct the EM field into the center of the brain tissue, while providing field linearity, our analysis considered the field distribution for one versus four antennas. Within the provided dimensions of a typical human brain, results of the Bioheat equation within COMSOL Multiphysics version 5.2a software demonstrated less than a 1 m˚K increase from the absorbed EM power.Item Asymptomatic Bacteriuria versus Symptom Underreporting in Older Emergency Department Patients with Suspected Urinary Tract Infection(Wiley, 2020-11) Caterino, Jeffrey M.; Stephens, Julie A.; Camargo, Carlos A., Jr.; Wexler, Randell; Hebert, Courtney; Southerland, Lauren T.; Hunold, Katherine M.; Hains, David S.; Bischof, Jason J.; Wei, Lai; Wolfe, Alan J.; Schwaderer, Andrew; Pediatrics, School of MedicineItem Barriers to Upper Extremity Reconstruction for Patients With Cerebral Palsy(Sage, 2022) Loewenstein, Scott N.; Angulo-Parker, Francisco; Timsina, Lava; Adkinson, Joshua; Surgery, School of MedicineBackground: Reconstructive surgery for upper extremity manifestations of cerebral palsy (CP) has been demonstrated to be safe and effective, yet many potential candidates are never evaluated for surgery. The purpose of this study was to determine barriers to upper extremity reconstruction for patients with CP in a cohort of upper extremity surgeons and nonsurgeons. Methods: We sent a questionnaire to 4167 surgeons and nonsurgeon physicians, aggregated responses, and analyzed for differences in perceptions regarding surgical efficacy, patient candidacy for surgery, compliance with rehabilitation, remuneration, complexity of care, and physician comfort providing care. Results: Surgeons and nonsurgeons did not agree on the literature support of surgical efficacy (73% vs 35% agree or strongly agree, respectively). Both surgeons and nonsurgeons felt that many potential candidates exist, yet there was variability in their confidence in identifying them. Most surgeons (59%) and nonsurgeons (61%) felt comfortable performing surgery and directing the associated rehabilitation, respectively. Neither group reported that patient compliance, access to rehabilitation services, and available financial resources were a major barrier, but surgeons were more likely than nonsurgeons to feel that remuneration for services was inadequate (37% vs 13%). Both groups agreed that surgical treatments are complex and should be performed in the setting of a multidisciplinary team. Conclusions: Surgeons and nonsurgeons differ in their views regarding upper extremity reconstructive surgery for CP. Barriers to reconstruction may be addressed by performing higher level research, implementing multispecialty educational outreach, developing objective referral criteria, increasing surgical remuneration, improving access to trained upper extremity surgeons, and implementing multidisciplinary CP clinics.Item Bedside lung ultrasound for the diagnosis of pneumonia in children presenting to an emergency department in a resource-limited setting(BMC, 2023-01-09) Amatya, Yogendra; Russell, Frances M.; Rijal, Suraj; Adhikari, Sunil; Nti, Benjamin; House, Darlene R.; Emergency Medicine, School of MedicineBackground: Lung ultrasound (LUS) is an effective tool for diagnosing pneumonia; however, this has not been well studied in resource-limited settings where pneumonia is the leading cause of death in children under 5 years of age. Objective: The objective of this study was to evaluate the diagnostic accuracy of bedside LUS for diagnosis of pneumonia in children presenting to an emergency department (ED) in a resource-limited setting. Methods: This was a prospective cross-sectional study of children presenting to an ED with respiratory complaints conducted in Nepal. We included all children under 5 years of age with cough, fever, or difficulty breathing who received a chest radiograph. A bedside LUS was performed and interpreted by the treating clinician on all children prior to chest radiograph. The criterion standard was radiographic pneumonia, diagnosed by a panel of radiologists using the Chest Radiography in Epidemiological Studies methodology. The primary outcome was sensitivity and specificity of LUS for the diagnosis of pneumonia. All LUS images were later reviewed and interpreted by a blinded expert sonographer. Results: Three hundred and sixty-six children were enrolled in the study. The median age was 16.5 months (IQR 22) and 57.3% were male. Eighty-four patients (23%) were diagnosed with pneumonia by chest X-ray. Sensitivity, specificity, positive and negative likelihood ratios for clinician's LUS interpretation was 89.3% (95% CI 81-95), 86.1% (95%CI 82-90), 6.4, and 0.12 respectively. LUS demonstrated good diagnostic accuracy for pneumonia with an area under the curve of 0.88 (95% CI 0.83-0.92). Interrater agreement between clinician and expert ultrasound interpretation was excellent (k = 0.85). Conclusion: Bedside LUS when used by ED clinicians had good accuracy for diagnosis of pneumonia in children in a resource-limited setting.Item CD30 Lateral Flow and Enzyme-Linked Immunosorbent Assays for Detection of BIA-ALCL: A Pilot Study(MDPI, 2023-10-25) Zeyl, Victoria G.; Xu, Haiying; Khan, Imran; Machan, Jason T.; Clemens, Mark W.; Hu, Honghua; Deva, Anand; Glicksman, Caroline; McGuire, Patricia; Adams, William P., Jr.; Sieber, David; Sinha, Mithun; Kadin, Marshall E.; Surgery, School of MedicineIntroduction: Breast Implant-Associated Anaplastic Large Cell Lymphoma (BIA-ALCL) commonly presents as a peri-implant effusion (seroma). CD30 (TNFRSF8) is a consistent marker of tumor cells but also can be expressed by activated lymphocytes in benign seromas. Diagnosis of BIA-ALCL currently includes cytology and detection of CD30 by immunohistochemistry or flow cytometry, but these studies require specialized equipment and pathologists' interpretation. We hypothesized that a CD30 lateral flow assay (LFA) could provide a less costly rapid test for soluble CD30 that eventually could be used by non-specialized personnel for point-of-care diagnosis of BIA-ALCL. Methods: We performed LFA for CD30 and enzyme-linked immunosorbent assay (ELISA) for 15 patients with pathologically confirmed BIA-ALCL and 10 patients with benign seromas. To determine the dynamic range of CD30 detection by LFA, we added recombinant CD30 protein to universal buffer at seven different concentrations ranging from 125 pg/mL to 10,000 pg/mL. We then performed LFA for CD30 on cryopreserved seromas of 10 patients with pathologically confirmed BIA-ALCL and 10 patients with benign seromas. Results: Recombinant CD30 protein added to universal buffer produced a distinct test line at concentrations higher than 1000 pg/mL and faint test lines at 250-500 pg/mL. LFA produced a positive test line for all BIA-ALCL seromas undiluted and for 8 of 10 malignant seromas at 1:10 dilution, whereas 3 of 10 benign seromas were positive undiluted but all were negative at 1:10 dilution. Undiluted CD30 LFA had a sensitivity of 100.00%, specificity of 70.00%, positive predictive value of 76.92%, and negative predictive value of 100.00% for BIA-ALCL. When specimens were diluted 1:10, sensitivity was reduced to 80.00% but specificity and positive predictive values increased to 100.00%, while negative predictive value was reduced to 88.33%. When measured by ELISA, CD30 was below 1200 pg/mL in each of six benign seromas, whereas seven BIA-ALCL seromas contained CD30 levels > 2300 pg/mL, in all but one case calculated from dilutions of 1:10 or 1:50. Conclusions: BIA-ALCL seromas can be distinguished from benign seromas by CD30 ELISA and LFA, but LFA requires less time (<20 min) and can be performed without special equipment by non-specialized personnel, suggesting future point-of-care testing for BIA-ALCL may be feasible.Item Circulating Tumor Cells in Renal Cell Carcinoma: Recent Findings and Future Challenges(Frontiers, 2019-04-05) Santoni, Matteo; Cimadamore, Alessia; Cheng, Liang; Lopez-Beltran, Antonio; Battelli, Nicola; Massari, Francesco; Scarpelli, Marina; Galosi, Andrea Benedetto; Bracarda, Sergio; Montironi, Rodolfo; Pathology and Laboratory Medicine, School of MedicineItem Clinical challenges in diagnosis and treatment of recurrent vulvovaginal candidiasis(Sage, 2022-09-08) Neal, Chemen M.; Martens, Mark G.; Obstetrics and Gynecology, School of MedicineVulvovaginal candidiasis is a common infection associated most often with the overgrowth of the fungal species Candida albicans. Although most women will have at least one episode of vulvovaginal candidiasis in their lifetime, some will experience recurrent infections. Recurrent vulvovaginal candidiasis can significantly impact quality of life, causing both physical and psychological symptoms, and poses a substantial financial burden for women and the health care system. Acute vulvovaginal candidiasis infections are often diagnosed symptomatically by clinicians or self-diagnosed by patients themselves; this can result in over- and underdiagnosis, as well as misdiagnosis, and has the potential to lead to ineffective treatment and incomplete infection resolution. Clinical diagnosis should include confirmatory laboratory tests, including microscopy and fungal culture, especially in women with a history of recurrent vulvovaginal candidiasis, who are more likely than women with vulvovaginal candidiasis to be infected with less-common Candida species or with azole-resistant strains. With proper diagnosis, most acute vulvovaginal candidiasis episodes can be successfully treated; however, women with recurrent vulvovaginal candidiasis may require long-term maintenance therapy. US-based guidelines recommend ⩽6 months of maintenance fluconazole treatment, but infection recurs in up to 50% of women treated. There are currently no US Food and Drug Administration–approved treatments for recurrent vulvovaginal candidiasis; however, several promising treatments for recurrent vulvovaginal candidiasis are in development.Item Concordance between DSM-IV and DSM-5 criteria for delirium diagnosis in a pooled database of 768 prospectively evaluated patients using the delirium rating scale-revised-98(BioMed Central, 2014-09-30) Meagher, David J.; Morandi, Alessandro; Inouye, Sharon K.; Ely, Wes; Adamis, Dimitrios; Maclullich, Alasdair J.; Rudolph, James L.; Neufeld, Karin; Leonard, Maeve; Bellelli, Giuseppe; Davis, Daniel; Teodorczuk, Andrew; Kreisel, Stefan; Thomas, Christine; Hasemann, Wolfgang; Timmons, Suzanne; O’Regan, Niamh; Grover, Sandeep; Jabbar, Faiza; Cullen, Walter; Dunne, Colum; Kamholz, Barbara; Van Munster, Barbara C.; De Rooij, Sophia E.; De Jonghe, Jos; Trzepacz, Paula T.; Department of Psychiatry, School of MedicineBackground The Diagnostic and Statistical Manual fifth edition (DSM-5) provides new criteria for delirium diagnosis. We examined delirium diagnosis using these new criteria compared with the Diagnostic and Statistical Manual fourth edition (DSM-IV) in a large dataset of patients assessed for delirium and related presentations. Methods Patient data (n = 768) from six prospectively collected cohorts, clinically assessed using DSM-IV and the Delirium Rating Scale-Revised-98 (DRS-R98), were pooled. Post hoc application of DRS-R98 item scores were used to rate DSM-5 criteria. ‘Strict’ and ‘relaxed’ DSM-5 criteria to ascertain delirium were compared to rates determined by DSM-IV. Results Using DSM-IV by clinical assessment, delirium was found in 510/768 patients (66%). Strict DSM-5 criteria categorized 158 as delirious including 155 (30%) with DSM-IV delirium, whereas relaxed DSM-5 criteria identified 466 as delirious, including 455 (89%) diagnosed by DSM-IV (P <0.001). The concordance between the different diagnostic methods was: 53% (ĸ = 0.22) between DSM-IV and the strict DSM-5, 91% (ĸ = 0.82) between the DSM-IV and relaxed DSM-5 criteria and 60% (ĸ = 0.29) between the strict versus relaxed DSM-5 criteria. Only 155 cases were identified as delirium by all three approaches. The 55 (11%) patients with DSM-IV delirium who were not rated as delirious by relaxed criteria had lower mean DRS-R98 total scores than those rated as delirious (13.7 ± 3.9 versus 23.7 ± 6.0; P <0.001). Conversely, mean DRS-R98 score (21.1 ± 6.4) for the 70% not rated as delirious by strict DSM-5 criteria was consistent with suggested cutoff scores for full syndromal delirium. Only 11 cases met DSM-5 criteria that were not deemed to have DSM-IV delirium. Conclusions The concordance between DSM-IV and the new DSM-5 delirium criteria varies considerably depending on the interpretation of criteria. Overly-strict adherence for some new text details in DSM-5 criteria would reduce the number of delirium cases diagnosed; however, a more ‘relaxed’ approach renders DSM-5 criteria comparable to DSM-IV with minimal impact on their actual application and is thus recommended.Item Decision and discovery in defining 'disease'(Springer, 2007) Schwartz, Peter H.The debate over how to analyze the concept of disease has often centered on the question of whether to include a reference to values, in particular the ‘disvalue’of diseases, or whether to avoid such notions. ‘Normativists,’such as King ([1954], 1981) and Culver and Gert (1982) emphasize the undesirability of diseases, while ‘Naturalists,’ most prominently Christopher Boorse (1977, 1987, 1997), instead require just the presence of biological dysfunction. The debate between normativism and naturalism often deteriorates into stalemate, with each side able to point out significant problems with the other. It starts to look as if neither approach can work. In this paper, I argue that the standoff stems from deeply questionable assumptions that have been used to formulate the opposing positions and guide the debate. In the end, I propose an alternative set of guidelines that offer a more constructive way to devise and compare theories.