INTRODUCTION:Autonomic dysreflexia (AD), a condition of critically raised blood pressure, is a severe complication of spinal cord injury. Primary (essential) hypertension may present with similar blood pressure levels to AD, though the causes, pathophysiology, presentation and treatment will differ. CASE PRESENTATION:We report a case of a 74-year-old patient with a C1 spinal injury, who developed primary (essential) hypertension during her rehabilitation phase of care, requiring extensive investigations for autonomic dysreflexia. Despite this, no underlying cause was found; essential hypertension was subsequently confirmed with 24-hour ambulatory blood pressure monitoring. Treatment with an ACE inhibitor was introduced to good effect. DISCUSSION:Essential hypertension can affect patients with spinal injury, even though most patients with higher level injuries (particularly cervical spinal cord injuries) are expected to have low resting baseline hypotension. Relevant features of this are presented within this case; a set of criteria to differentiate essential hypertension from autonomic dysreflexia are also proposed.

High-level spinal cord injuries are often associated with autonomic impairment, which can result in orthostatic hypotension and syncope. Persistent autonomic dysfunction can manifest with disabling symptoms including recurrent syncopal events. We describe a case of autonomic failure resulting in recurrent syncopal events in a tetraplegic 66-year-old man.

The development of nanoparticle agents for MRI-guided radiotherapy is growing at an increasing pace, with clinical trials now underway and many pre-clinical evaluation studies ongoing. Gadolinium and iron-oxide-based nanoparticles remain the most clinically advanced nanoparticles to date, although several promising candidates are currently under varying stages of development. Goals of current and future generation nanoparticle-based contrast agents for MRI-guided radiotherapy include achieving positive signal contrast on T1-weighted MRI scans, local radiation enhancement at clinically relevant concentrations and, where applicable, avoidance of uptake by the reticuloendothelial system. Exploiting the enhanced permeability and retention effect or the use of active targeting ligands on nanoparticle surfaces is utilised to promote tumour uptake. This review outlines the current status of promising nanoparticle agents for MRI-guided radiation therapy, including several platforms currently undergoing clinical evaluation or at various stages of the pre-clinical development process. Challenges facing nanoparticle agents and possible avenues for current and future development are discussed.

A set of mild conditions for the N-1-difluoromethylation of ethyl 6-((tert-butyldiphenylsilyl)oxy)-1H-indazole-3-arboxylate (1) with chlorodifluoromethane (CHClF2) on large scale (up to 33 g) is described. An optimized N-1difluoromethylation of the functionalized indazole 1 was achieved, under an atmosphere of CHClF2 (balloon) in the presence of NaH and catalytic amounts of NaI and 18-crown-6 ether at a moderate temperature (40 degrees C). This procedure provides a safe and convenient alternative to existing approaches that require high pressures and/or the use of NaH in DMF at high temperatures that would present a safety concern when operating on a large scale. This method was extended to the N-difluoromethylation of indazole, benzotriazole, imidazole, indole and pyrazole derivatives, all of which bear an ester group.

BACKGROUND:The objective of the study is to describe temporal trends and regional variations in the use of knee magnetic resonance imaging (MRI), knee arthroscopy and total knee replacement surgery in Australians older than 55 years.METHODS:Design: A retrospective descriptive study using routinely collected administrative data.MAIN OUTCOME MEASURES:Age-standardized rates of knee MRI, knee arthroscopy and knee replacement surgery from 2003 to 2017.RESULTS:Knee MRI rates increased from 216/100 000 in 2003, to 1509/100 000 in 2017 (sevenfold relative increase). Knee arthroscopy rates initially increased from 372/100 000 in 2003 to a maximum of 475/100 000 in 2011, before declining to 283/100 000 in 2017. Knee joint replacement surgery increased from 535/100 000 in 2003 to 840/100 000 in 2017 (57% relative increase). The use of MRI increased in all regions of Australia but to differing extents. Knee arthroscopy rates declined in all regions from 2011, but to differing extents. Knee joint replacement surgery increased at roughly the same rate across Australia.CONCLUSION:Knee arthroscopy rates increased before declining modestly in more recent years, most likely in response to evidence against its effectiveness. Knee MRI rates have continued to increase despite consistent recommendations against their routine use in the evaluation of knee pain. Future research could investigate potential drivers of the increased use of MRI, and of the continued use of arthroscopy. Further exploration of the extent to which either procedure explains the increase in numbers of knee joint replacements is also warranted.

Ideas and Opinions19 February 2019Recognizing the Potential for Overdiagnosis: Are High-Sensitivity Cardiac Troponin Assays an Example?Katy J.L. Bell, MBChB, MMed(Clin Epi), PhD, Jenny Doust, BMBS, PhD, Paul Glasziou, MBBS, PhD, Louise Cullen, MBBS(Hon), PhD, Ian A. Harris, MBBS, MMed(Clin Epi), PhD, Leon Smith, MBBS, Rachelle Buchbinder, MBBS(Hons), MSc, PhD, and Alexandra Barratt, MBBS, MPH, PhDKaty J.L. Bell, MBChB, MMed(Clin Epi), PhDThe University of Sydney, Sydney, New South Wales, Australia (K.J.B., L.S.)Search for more papers by this author, Jenny Doust, BMBS, PhDBond University, Gold Coast, Queensland, Australia (J.D., P.G.)Search for more papers by this author, Paul Glasziou, MBBS, PhDBond University, Gold Coast, Queensland, Australia (J.D., P.G.)Search for more papers by this author, Louise Cullen, MBBS(Hon), PhDUniversity of Queensland, Brisbane, Queensland, Australia (L.C.)Search for more papers by this author, Ian A. Harris, MBBS, MMed(Clin Epi), PhDThe University of Sydney, Ingham Institute of Applied Medical Research, and South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia (I.A.H.)Search for more papers by this author, Leon Smith, MBBSThe University of Sydney, Sydney, New South Wales, Australia (K.J.B., L.S.)Search for more papers by this author, Rachelle Buchbinder, MBBS(Hons), MSc, PhDCabrini Institute and Monash University, Melbourne, Victoria, Australia (R.B.)Search for more papers by this author, and Alexandra Barratt, MBBS, MPH, PhDWiser Healthcare, The University of Sydney, Sydney, New South Wales, Australia (A.B.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/M18-2645 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Overdiagnosis occurs when persons are labeled with a technically correct diagnosis that does not improve health outcomes (1). It is a common unintended consequence of early disease detection in asymptomatic persons but also takes place in persons with mild or ambiguous symptoms. Despite initiatives to prevent overdiagnosis (2), new tests and changes to disease definitions may become established in clinical practice before their potential for overdiagnosis is recognized; as such, reverting to previous approaches may be difficult. In this commentary, we propose questions (Figure) to identify new practices with the potential for overdiagnosis and evaluate the example of using high-sensitivity ...References1. Carter SM, Degeling C, Doust J, Barratt A. A definition and ethical evaluation of overdiagnosis. J Med Ethics. 2016;42:705-14. [PMID: 27402883] doi:10.1136/medethics-2015-102928 CrossrefMedlineGoogle Scholar2. Doust J, Vandvik PO, Qaseem A, Mustafa RA, Horvath AR, Frances A, et al; Guidelines International Network (G-I-N) Preventing Overdiagnosis Working Group. Guidance for modifying the definition of diseases: a checklist. JAMA Intern Med. 2017;177:1020-5. [PMID: 28505266] doi:10.1001/jamainternmed.2017.1302 CrossrefMedlineGoogle Scholar3. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst. 2010;102:605-13. [PMID: 20413742] doi:10.1093/jnci/djq099 CrossrefMedlineGoogle Scholar4. Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med. 2011;171:831-7. [PMID: 21555660] doi:10.1001/archinternmed.2011.178 CrossrefMedlineGoogle Scholar5. de Lemos JA, Drazner MH, Omland T, Ayers CR, Khera A, Rohatgi A, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010;304:2503-12. [PMID: 21139111] doi:10.1001/jama.2010.1768 CrossrefMedlineGoogle Scholar6. Shah ASV, Anand A, Strachan FE, Ferry AV, Lee KK, Chapman AR, et al; High-STEACS Investigators. High-sensitivity troponin in the evaluation of patients with suspected acute coronary syndrome: a stepped-wedge, cluster-randomised controlled trial. Lancet. 2018;392:919-28. [PMID: 30170853] doi:10.1016/S0140-6736(18)31923-8 CrossrefMedlineGoogle Scholar7. de Groot JAH, Naaktgeboren CA, Reitsma JB, Moons KGM. Methodologic approaches to evaluating new highly sensitive diagnostic tests: avoiding overdiagnosis. CMAJ. 2017;189:E64-8. [PMID: 27378465] doi:10.1503/cmaj.150999 CrossrefMedlineGoogle Scholar8. Glasziou P, Irwig L, Deeks JJ. When should a new test become the current reference standard? Ann Intern Med. 2008;149:816-22. [PMID: 19047029] LinkGoogle Scholar9. Lord SJ, Staub LP, Bossuyt PM, Irwig LM. Target practice: choosing target conditions for test accuracy studies that are relevant to clinical practice. BMJ. 2011;343:d4684. [PMID: 21903693] doi:10.1136/bmj.d4684 CrossrefMedlineGoogle Scholar Author, Article, and Disclosure InformationAffiliations: The University of Sydney, Sydney, New South Wales, Australia (K.J.B., L.S.)Bond University, Gold Coast, Queensland, Australia (J.D., P.G.)University of Queensland, Brisbane, Queensland, Australia (L.C.)The University of Sydney, Ingham Institute of Applied Medical Research, and South Western Sydney Clinical School, University of New South Wales, Sydney, New South Wales, Australia (I.A.H.)Cabrini Institute and Monash University, Melbourne, Victoria, Australia (R.B.)Wiser Healthcare, The University of Sydney, Sydney, New South Wales, Australia (A.B.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M18-2645.Corresponding Author: Katy J.L. Bell, MBChB, MMed(Clin Epi), PhD, School of Public Health, Edward Ford Building (A27), The University of Sydney, Sydney, NSW 2006, Australia; e-mail, katy.[email protected]edu.au.Current Author Addresses: Drs. Bell and Barratt: School of Public Health, Edward Ford Building (A27), The University of Sydney, Sydney, NSW 2006, Australia.Drs. Doust and Glasziou: Centre for Research in Evidence-Based Practice, Health Sciences and Medicine, Bond University, Bond, QLD 4229, Australia.Dr. Cullen: Royal Brisbane & Women's Hospital, Butterfield Street, Herston, Brisbane, QLD 4029, Australia.Dr. Harris: Ingham Institute for Applied Medical Research, 1 Campbell Street, Liverpool, NSW 2170, Australia.Dr. Smith: Hornsby Hospital, 36–38 Palmertson Road, Hornsby, NSW 2077, Australia.Dr. Buchbinder: 4 Drysdale Street, Malvern, VIC 3144, Australia.Author Contributions: Conception and design: K.J.L. Bell, J. Doust, I.A. Harris, R. Buchbinder, A. Barratt.Analysis and interpretation of the data: K.J.L. Bell, J. Doust, L. Cullen, I.A. Harris.Drafting of the article: K.J.L. Bell, J. Doust, L. Cullen, I.A. Harris, A. Barratt.Critical revision of the article for important intellectual content: K.J.L. Bell, J. Doust, P. Glasziou, L. Cullen, I.A. Harris, L. Smith, R. Buchbinder, A. Barratt.Final approval of the article: K.J.L. Bell, J. Doust, P. Glasziou, L. Cullen, I.A. Harris, R. Buchbinder, A. Barratt.Statistical expertise: K.J.L. Bell.Obtaining of funding: J. Doust, A. Barratt.Administrative, technical, or logistic support: K.J.L. Bell, P. Glasziou.Collection and assembly of data: K.J.L. Bell.This article was published at Annals.org on 5 February 2019. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited bySimulations found within-subject measurement variation in glycaemic measures may cause overdiagnosis of prediabetes and diabetesEvaluation of the Incremental Value of a Coronary Artery Calcium Score Beyond Traditional Cardiovascular Risk AssessmentImplementation of more sensitive cardiac troponin T assay in a state-wide health serviceRethinking Low-Risk Papillary Thyroid Cancers < 1cm (Papillary Microcarcinomas): An Evidence Review for Recalibrating Diagnostic Thresholds and/or Alternative LabelsOverdiagnosis is increasing the carbon footprint of healthcareJournalists’ views on media coverage of medical tests and overdiagnosis: a qualitative studyReplyOverdiagnosis of Attention-Deficit/Hyperactivity Disorder in Children and AdolescentsThe potential for overdiagnosis and underdiagnosis because of blood pressure variability: a comparison of the 2017 ACC/AHA, 2018 ESC/ESH and 2019 NICE hypertension guidelinesWhy clinicians overtest: development of a thematic frameworkImpact of the Introduction of High-Sensitive Troponin Assay in the Emergency Department: A Retrospective StudyThe carbon footprint of pathology testingEstimating the magnitude of cancer overdiagnosis in AustraliaWhy We Might Not Need to Stress About Ruling Out Inducible Myocardial IschemiaKaty J.L. Bell, MBChB, MMed(Clin Epi), PhD, Christopher Semsarian, MBBS, PhD, MPH, and Jenny Doust, BMBS, PhDEvidence of potential overdiagnosis and overtreatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents: protocol for a scoping reviewSetting clinical performance specifications to develop and evaluate biomarkers for clinical useMedia Coverage of the Benefits and Harms of Testing the Healthy: a protocol for a descriptive study 19 February 2019Volume 170, Issue 4Page: 259-261KeywordsCardiovascular diseasesDisclosureDrug therapyEvidence based medicineHigh sensitivity cardiac troponinIschemiaMyocardial infarctionPrevention, policy, and public healthStatinsTroponin ePublished: 5 February 2019 Issue Published: 19 February 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...

Objectives Although the risk of overdiagnosis in cancer screening was identified almost 50 years ago, evidence of cancer overdiagnosis was slow to emerge, and has required development of new approaches and study designs. As a result, responses to mitigate overdiagnosis, and to inform the public and professionals, have been delayed. This meant cancer screening activities became well established in clinical practice and policy before the problem overdiagnosis was recognised, making reversal difficult. It would be beneficial to avoid repeating the same delays outside the cancer setting – whether in the context of screening programs (e.g. gestational diabetes screening among pregnant women) or in managing already symptomatic patients (eg children with ADHD symptoms, adults with joint pain) – so that timely policy responses to overdiagnosis in these settings can be developed. We therefore aimed to identify early ‘indicators’ of potential overdiagnosis. Method We used concepts described in key papers about methods for detecting and quantifying cancer overdiagnosis, the clinical utility of diagnostic tests, and for modifying the definition of diseases, to identify early indicators of potential overdiagnosis. We identified four indicators: 1. Expanded detection of condition/disease; 2. Subclinical forms of the condition/disease; 3. Increasing diagnosis and treatment of condition/disease; and 4. Balance of benefit vs harm of diagnosis/treatment likely to be unfavourable based on existing evidence. We provide an overview of the proposed approach, and illustrate it using two examples that are common in everyday, clinical investigation of non cancer conditions: MRI in the investigation of adult knee pain, and high sensitivity troponin testing in emergency department workup of patients with suspected myocardial infarction. We evaluate and discuss the application of the indicators to these examples, using analysis of routinely collected, local data, and current research evidence. Results Example One: Is there potential overdiagnosis of knee pathology in older Australians? Knee MRI is positive on indicators 1, 2 and 4 for possible overdiagnosis (expanded detection of condition (disease); subclinical forms of the condition (disease); balance of benefit vs harm of diagnosis/treatment likely to be unfavourable). Indicator 3 (increasing diagnosis and treatment of the condition) is inconclusive. Example Two: Is there potential overdiagnosis of Myocardial Infarction in Australians? Non ST Elevation Myocardial Infarction (NSTEMI) meets indicators 1 and 3 (expanded detection of condition (disease); increasing diagnosis and treatment of condition (disease)). Indicators 2 (subclinical forms of the condition (disease)) and 4 (benefit vs harm of diagnosis/treatment likely to be unfavourable) are inconclusive. Conclusions The proposed indicators may have utility in helping to identify possible overdiagnosis sooner than would normally come about through standard processes of surveillance of changes in clinical testing and its impact. We found that in our two examples, more indicators were clearly positive for knee MRI than for hs Tn/NSTEMI, suggesting more evidence of potential overdiagnosis for the former than for the latter. The approach is necessarily different from methods that have been developed for cancer screening because, in non-cancer conditions, patients may be asymptomatic (as in the context of early detection of disease) OR symptomatic yet still at risk of overdiagnosis. These four indicators may help identify tests that warrant the investment of research resources to assess the impact of the new testing patterns and disease definitions on long term, patient-relevant outcomes to avoid harm through overdiagnosis and overtreatment.

Factor XIa (FXIa) is a blood coagulation enzyme that is involved in the amplification of thrombin generation. Mounting evidence suggests that direct inhibition of FXIa can block pathologic thrombus formation while preserving normal hemostasis. Preclinical studies using a variety of approaches to reduce FXIa activity, including direct inhibitors of FXIa, have demonstrated good antithrombotic efficacy without increasing bleeding. On the basis of this potential, we targeted our efforts at identifying potent inhibitors of FXIa with a focus on discovering an acute antithrombotic agent for use in a hospital setting. Herein we describe the discovery of a potent FXIa clinical candidate, 55 (FXIa Ki = 0.7 nM), with excellent preclinical efficacy in thrombosis models and aqueous solubility suitable for intravenous administration. BMS-962212 is a reversible, direct, and highly selective small molecule inhibitor of FXIa.

Total body irradiation (TBI) treatments are used to treat the whole body in preparation for hematopoietic stem cell (or bone marrow) transplantation. Our standard clinical regimen is a 12 Gy in 6 fraction, bi-daily technique using 6 MV X-rays at an extended Source-to-Surface distance (SSD) of 300 cm. Utilizing these characteristics, the beam dose rate is reduced below 7 cGy/min as is standard for TBI treatment. Dose received by the patient is monitored using optically stimulated luminescent dosimetry (OSLD). This work presents some practical calibration corrections based on time-dependant factors for OSLD calibration related to TBI procedure. Results have shown that a negligible difference is seen in OSL sensitivity for 6 MV X-rays irradiated in standard SSD (100 cm) and high dose rate (600 cGy/min) conditions compared to extended SSD (300 cm) and low TBI dose rate (6 cGy/min) conditions. Results have also shown that whilst short term signal fading occurs in the OSL after irradiation at a high dose rate (37% reduction in signal in the first 15 min), thereafter, negligible differences are seen in the OSL signal between 600 and 7 cGy/min irradiations. Thus a direct comparison can be made between calibration OSLs and clinical TBI OSLs between 15 min and 2 h. Finally a table is presented to provide corrections between calibration OSL readout and clinical TBI dose readout for a period up to 7 days. Combining these three results allows users to pre-irradiate their calibration OSLs at standard dose rate and SSD, up to 1 week prior to clinical treatment, and still provide accurate in-vivo dosimetry. This can help with time saving and work efficiency in the clinic.

The synthesis, structural activity relationships (SAR), and selectivity profile of a potent series of phenylalanine diamide FXIa inhibitors will be discussed. Exploration of P1 prime and P2 prime groups led to the discovery of compounds with high FXIa affinity, good potency in our clotting assay (aPPT), and high selectivity against a panel of relevant serine proteases as exemplified by compound 21. Compound 21 demonstrated good in vivo efficacy (EC50 = 2.8 μM) in the rabbit electrically induced carotid arterial thrombosis model (ECAT).

Cone beam computed tomography (CBCT) is now widely used to image radiotherapy patients prior to treatment for the purpose of accurate patient setup. However each CBCT image delivered to a patient increases the total radiation dose that they receive. The measurement of the dose delivered from the CBCT images is not readily performed in the clinic. In this study, we have used commercially available optically stimulated luminescence (OSLD) dosimeters to measure the dose delivered by the Varian OBI on a radiotherapy linear accelerator. Calibration of the OSLDs was achieved by using a therapeutic X-ray unit. The dose delivered by a head CBCT scan was found to be 3.2 ± 0.3 mGy which is similar in magnitude to the dose of a head computed tomography (CT) scan. The results of this study suggest that the radiation hazard associated with CBCT is of a similar nature to that of conventional CT scans. We have also demonstrated that the OSLDs are suitable for these low X-ray dose measurements.

Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2′ group provided compound 32 with FXIa Ki = 6.7 nM and modest oral exposure in dogs.

Nanoparticle contrast agents offer the potential to significantly improve existing methods of cancer diagnosis and treatment. Advantages include biocompatibility, selective accumulation in tumor cells, and reduced toxicity. Considerable research is underway into the use of nanoparticles as enhancement agents for radiation therapy and photodynamic therapy, where they may be used to deliver treatment agents, produce localized enhancements in radiation dose and selectively target tumor cells for localized damage. This paper reviews the current status of nanoparticles for cancer treatment and presents preliminary results of a pilot study investigating titanium dioxide nanoparticles for dual-mode enhancement of computed tomography (CT) imaging and kilovoltage radiation therapy. Although titanium dioxide produced noticeable image contrast enhancement in the CT scans, more sensitive detectors are needed to determine whether the nanoparticles can also produce localized dose enhancement for targeted radiation therapy.