Northern Hospital

Machine learning (ML) is a burgeoning field of medicine with huge resources being applied to fuse computer science and statistics to medical problems. Proponents of ML extol its ability to deal with large, complex and disparate data, often found within medicine and feel that ML is the future for biomedical research, personalized medicine, computer-aided diagnosis to significantly advance global health care. However, the concepts of ML are unfamiliar to many medical professionals and there is untapped potential in the use of ML as a research tool. In this article, we provide an overview of the theory behind ML, explore the common ML algorithms used in medicine including their pitfalls and discuss the potential future of ML in medicine.

BACKGROUND: Comprehensive national joint replacement registries with well-validated data offer unique opportunities for examining the potential future burden of hip and knee osteoarthritis (OA) at a population level. This study aimed to forecast the burden of primary total knee (TKR) and hip replacements (THR) performed for OA in Australia to the year 2030, and to model the impact of contrasting obesity scenarios on TKR burden. METHODS: De-identified TKR and THR data for 2003-2013 were obtained from the Australian Orthopaedic Association National Joint Replacement Registry. Population projections and obesity trends were obtained from the Australian Bureau of Statistics, with public and private hospital costs sourced from the National Hospital Cost Data Collection. Procedure rates were projected according to two scenarios: (1) constant rate of surgery from 2013 onwards; and (2) continued growth in surgery rates based on 2003-2013 growth. Sensitivity analyses were used to estimate future TKR burden if: (1) obesity rates continued to increase linearly; or (2) 1-5% of the overweight or obese population attained a normal body mass index. RESULTS: Based on recent growth, the incidence of TKR and THR for OA is estimated to rise by 276% and 208%, respectively, by 2030. The total cost to the healthcare system would be $AUD5.32 billion, of which $AUD3.54 billion relates to the private sector. Projected growth in obesity rates would result in 24,707 additional TKRs totalling $AUD521 million. A population-level reduction in obesity could result in up to 8062 fewer procedures and cost savings of up to $AUD170 million. CONCLUSIONS: If surgery trends for OA continue, Australia faces an unsustainable joint replacement burden by 2030, with significant healthcare budget and health workforce implications. Strategies to reduce national obesity could produce important TKR savings.

OBJECTIVE: Machine learning (ML) and artificial intelligence (AI) are rapidly becoming the most talked about and controversial topics in radiology and medicine. Over the past few years, the numbers of ML- or AI-focused studies in the literature have increased almost exponentially, and ML has become a hot topic at academic and industry conferences. However, despite the increased awareness of ML as a tool, many medical professionals have a poor understanding of how ML works and how to critically appraise studies and tools that are presented to us. Thus, we present a brief overview of ML, explain the metrics used in ML and how to interpret them, and explain some of the technical jargon associated with the field so that readers with a medical background and basic knowledge of statistics can feel more comfortable when examining ML applications. CONCLUSION: Attention to sample size, overfitting, underfitting, cross validation, as well as a broad knowledge of the metrics of machine learning, can help those with little or no technical knowledge begin to assess machine learning studies. However, transparency in methods and sharing of algorithms is vital to allow clinicians to assess these tools themselves.

This document is complementary to an Expert Review Document on Optical Coherence Tomography (OCT) for the study of coronary arteries and atherosclerosis.1 The goal of this companion manuscript is to provide a practical guide framework for the appropriate use and reporting of the novel frequency domain (FD) OCT imaging to guide interventional procedures, with a particular interest on the comparison with intravascular ultrasound (IVUS).1–4 In the OCT Expert Review Document on Atherosclerosis, a comprehensive description of the physical principles for OCT imaging and time domain (TD) catheters (St Jude Medical, Westford, MA, USA) was provided.1 The main advantage of FD-OCT is that the technology enables rapid imaging of the coronary artery, using a non-occlusive acquisition modality. The FD-OCT catheter (DragonflyTM; St Jude Medical) employs a single-mode optical fibre, enclosed in a hollow metal torque wire that rotates at a speed of 100 r.p.s. It is compatible with a conventional 0.014″ angioplasty guide wire, inserted into a short monorail lumen at the tip. The frequency domain optical coherence tomography lateral resolution is improved in comparison with TD-OCT, while the axial resolution did not change. These features, together with reduced motion artefacts and an increased maximum field of view up to 11 mm, have significantly improved both the quality and ease of use of OCT in the catheterization laboratory.3,4 However, the imaging depth of the FD-OCT is still limited to 0.5–2.0 mm.5 The main obstacle to the adoption of TD-OCT imaging in clinical practice is that OCT cannot image through a blood field, and therefore requires clearing or flushing of blood from the lumen.1 The 6 Fr compatible DragonflyTM FD-OCT catheter is so far the only one in the market, as two other systems from Volcano and Terumo, which have function similar to the DragonflyTM, are not yet available. The DragonflyTM catheter is first advanced over a regular guide wire, distal to the region of interest. A dedicated marker, located 10 mm distal to the OCT lens, enables the pull-back starting point selection. The acquisition of an OCT image sequence requires a bolus of crystalloid solution (usually contrast) injected through the guiding catheter. The acquisition speed can be set up in a range between 5 and 40 mm/s, based on the used OCT system. Most expert users advocate the use of automated contrast injection to optimize the image quality. The previous experience with TD and FD-OCT technology shows OCT acquisition to be safe,1,4,6 effective,1,4,6–8 and highly reproducible for the assessment of the luminal areas and length.9–11 A fair correlation between OCT and IVUS quantitative measurements of the lumen areas was reported,9–11 despite comparative studies showing that IVUS tends to slightly overestimate lumen areas, while stent and neointimal areas are slightly higher on OCT.9–11 Frequency domain optical coherence tomography image quality depends on an accurate acquisition technique and proper guiding catheter engagement is needed to optimize directional contrast flushing. Metallic stent struts are highly reflective structures that lead to specular reflection with the excessive signal usually resulting in ‘blooming’ of the strut surface. Optical coherence tomography shows only the reflection of the luminal surface of the stent strut and is unable to provide a direct measurement of the strut thickness.8,12 Two features indicate a strut: a highly reflective spot and/or an associated shadow behind the strut. The presence of only one of these two defining features is sufficient for strut identification. For bioresorbable stents, the assessment of the whole thickness is possible, since light can usually penetrate non-metallic materials. They can be followed by serial images; the degradation process, characterized by the presence of empty spaces replacing stent struts, was documented for the first generation design,13 but was not visible with the second-generation model, which maintains its mechanical properties.14 Based on preliminary unpublished data, the bioabsorbable magnesium stent has different properties; it is visible after implantation and tends to disappear at the follow-up due to magnesium degradation. Stent overlap occurs in the cross sections in which two superimposed layers of stent struts are visible (Figure 1). Incomplete stent apposition or malapposition occurs if there is a separation of a stent strut from the vessel wall. Malapposition can be addressed at a cross-section level and expressed as an area, or can be evaluated at the strut level analysis.15 In the latter case, it is defined as a measured distance greater than the strut thickness for bare metal stents or greater than the sum of the thickness of the strut plus polymer for drug eluting stents (DES)8,15 (Figure 2). Acute malapposition is diagnosed immediately after stent deployment (Figure 1),14 late malapposition at the follow-up, while late acquired malapposition requires the comparison of the post-intervention and follow-up images. Intra-stent tissue protrusion is defined as tissue prolapsed between stent struts extending inside a circular arc connecting adjacent struts (Figure 3).16 A thrombus is identified as an intra-luminal mass, with no direct continuity with the surface of the vessel wall or as a highly backscattered luminal protrusion in continuity with the vessel wall and resulting in signal-free shadowing.17 However, the discrimination between a tissue prolapse and intra-stent thrombosis is not simple and sufficiently validated. A dissection flap is a linear rim of tissue with a clear separation from the vessel wall, plaque, or the stent struts.18 Dissections are also frequent at the stent edges (Figure 4) and are defined by their longitudinal extension (mm), circumferential extension (degrees or quadrants), and width. Left panel: Stent overlapping in the left anterior descending artery. Despite an optimal angiographic result, optical coherence tomography shows a malapposition of the proximal edge of the distal stent, with a 430 µ distance from the inner (arrow heads) to the outer struts (arrows). Right panel: the optical coherence tomography image of the same cross section obtained after additional high pressure inflation with a non-compliant oversized balloon shows a correction of the malapposition. An optical coherence tomography cross section of a stent immediately following implantation in the right coronary artery. The stent struts are clearly visible. There are struts that are apposed to the vessel wall. However, what is clearly evident is a group of stent struts (between 4 and 12 o'clock) which are grossly malapposed to the vessel wall. Optical coherence tomography cannot penetrate through metallic structures and hence only shows the endoluminal aspect of the stent strut. To be classified as malapposed, the strut must not be in contact with the vessel wall with the distance between the endoluminal aspect and the vessel wall greater than the known thickness of the stent strut itself, including the polymer thickness (arrow in the right panel and dotted line in the left panel with a magnified view). Examples of intra-stent thrombotic formations and a plaque prolapse. (A and B) A tissue protrusion. Arrows show tissue prolapsed between stent struts and extending inside a circular arc, connecting adjacent struts. (C) Intra-luminal globular protrusions at stent strut locations with no direct continuation from the surface of the vessel wall (arrows). (D) A marked intra-stent thrombosis observed in a drug eluting stents at a late follow-up. Arrows show an intra-stent mass with an irregular inner border. Images in (A) and (D) were obtained with frequency domain optical coherence tomography, those in (B) and (C) with time domain optical coherence tomography. Left panel: Cypher stent deployed in the mid-right coronary artery with an optimal final angiographic result. Optical coherence tomography (right inferior panels) shows a moderate dissection distal to the stent ending, missed by angiography. The distance between the rim of the dissection and the vessel wall is 250 µm (line), slightly above the resolution of intravascular ultrasound, while the circumferential extension of the plaque dissection is 90°. The right upper panels are obtained at the stent minimum lumen area and show a well-apposed stent with an MLA of 6.82 mm2. Unlike angiography, IVUS identifies calcium with high accuracy,19 but is unable to measure its thickness.1 Infrared light penetrates calcium better, but calcific components with a thickness >1–1.3 mm or a deep intra-plaque location can prove impossible to penetrate. In the presence of an important circumferential calcification direct stenting should be avoided and the strategy can span from a careful pre-dilatation to test expansion, to cutting balloons for very short calcific rings or to pre-treatment with a rotational atherectomy.19,20 As OCT accurately measures the radial and longitudinal extension of a lipid pool, its use may be encouraged to also predict the risk of embolization of plaque components;1 this is in line with the previous experience with VH-IVUS.21,22 Unlike angiography or IVUS, OCT holds promise in identifying thrombi, measuring their dimensions and guiding their removal23 (Figures 5 and 6). The figure shows optical coherence tomography potentialities to detect components of ruptured plaques. Left panel shows a suboccluded right coronary artery in a patient with an inferior myocardial infarction. Optical coherence tomography cross sections (B) and (C) were obtained at the site of a plaque rupture and show a plaque with mixed composition (calcium + lipid) (arrow). At the shoulder of the plaque, at the site of minimum thickness of the fibrous cap (arrow head), an intra-luminal thrombotic formation is shown (dotted arrow). (A) A severe reduction in the lumen area due to a marked concentric thrombotic formation. As the penetration of optical coherence tomography through a thrombus is limited, vessel media cannot be studied (arrow). The application of a score based on the semi-quantitative assessment of a thrombus (number of the involved quadrants on the cross-sectional optical coherence tomography images) and the longitudinal extension of the thrombus itself. By applying this semi-quantitative grading, in each cross section, a thrombus is classified as absent or subtending 1, 2, 3, or 4 quadrants. The score is then calculated as the sum of each cross-section score. In angiographically hazy lesions, OCT often detects ruptured plaques with a thrombus attached to the site of rupture of the fibrous caps over a partially emptied lipid pool.1,6 Under these circumstances, the decision for the need to proceed with treatment can stem more from these morphological observations than from the absolute measurement of the lumen area. A technical drawback of both TD-OCT and FD-OCT in this application is that a plaque located at the very ostium of the left or right coronary arteries cannot be accurately imaged.1 As for IVUS, preliminary data indicate that OCT can change the operator's intention to treat, avoiding unnecessary interventional procedures or modifying the strategy in some cases.6,24,25 As FD-OCT probes have a slightly thinner profile than IVUS probes and pull-back imaging can be done at very high speeds (normally 20 mm/s), a significant fraction of severely diseased target lesions can be imaged without causing luminal obstruction, with symptomatic ischaemia being less likely. However, in the presence of subocclusive lesions the OCT probe can cause a luminal obstruction and it can be more convenient to perform OCT after gentle pre-dilatation. A number of IVUS studies attempted to characterize the appearance of vulnerable plaques. Recently, the PROSPECT trial, based on a signal radiofrequency analysis of the IVUS backscatter, showed for the first time that IVUS can identify plaques with a risk of events at 3 years.26 OCT, due to its high accuracy in the detection of superficial plaque components, can directly measure the fibrous cap thickness and can possibly detect plaques with a risk of a rupture with greater accuracy. The utility of a combined approach based on the use of OCT and VH-IVUS has been recently proposed to better characterize deep lesion components.27,28 Possibly, in the near future, a real-time application of OCT algorithms to characterize plaque components and identify local signs of inflammation will facilitate OCT detection of plaque vulnerability.29,30 Optical coherence tomography easily enables the comparison of the minimal stent area with the reference area, which is the most often used IVUS criterion for optimal stent expansion. The demonstration of the usefulness of an IVUS-guided approach of a bare metal stent expansion to reduce restenosis is more by meta-analyses31 than by single randomized studies.32,33 There is some evidence that IVUS guidance can improve the clinical outcome in the presence of left main disease34 and tackles the occurrence of thrombosis.35,36 The ability of OCT to address luminal areas and identify underexpansion, malapposition, uneven stent strut distribution, or small intra-stent thrombotic formations makes the technique a very attractive tool for the prevention of thrombosis. However, future studies are required to determine whether OCT is as useful or more useful than IVUS in this regard. Acute malapposition can contribute to a stent thrombosis by disturbing the normal laminar blood flow along the vessel wall, by promoting the deposition of platelets and fibrin37 and reducing re-endothelialization and neointima formation.38 However, to date, IVUS data suggest that acute and late-stent malapposition do not increase the risk of major adverse cardiac events.39,40 Nevertheless, both studies detected a surprisingly small number of malapposed stents (<7.2%) using the IVUS-derived criterion of at least one malapposed strut. Optical coherence tomography studies following stent implantation have demonstrated a much greater proportion of malapposed struts, even after optimal high-pressure post-dilatation, with this phenomenon being particularly evident in regions of stent overlap,41 after deployment of DES or long stents, and in type C lesions.15 In patients with acute coronary syndromes, the occurrence of an in-stent tissue protrusion, due to the presence of residual thrombus, is a common finding on OCT1,8,42 that may elevate the risk for an acute and subacute stent thrombosis. The need of serial OCT acquisitions to guide the selection of balloons and stents and to correct underexpansion means repeated contrast injections which may significantly increase the total amount of procedural contrast. The main drawback of OCT is its inability, unlike IVUS, to outline the vessel architecture, and measure the external elastic membrane, and the longitudinal extent of plaque burden in lesions with thicknesses exceeding 1.0–1.5 mm (Figure 7). This drawback may have some clinical implications, as the accepted criterion for the identification of reference segments by IVUS is a plaque burden <40%.33 Therefore, the pre-intervention use of OCT to select the appropriate stent size and length in diffusely diseased vessels is questionable. Optical coherence tomography is very well versed at detecting microstructures in close proximity to the vessel wall. Its limited tissue penetration (<1.5 mm), however, means that the extent of plaque is unable to be determined. In this example, diffuse, poorly reflective tissue is seen consistent with a lipid rich plaque (arrow), however, its extent beyond 1 mm from the vessel wall is limited. Optical coherence tomography has an easier application for the treatment of late in-stent restenosis because the strong reflective power of the stent struts allows their detection through thick layers of hyperplasia, allowing optimal sizing of high-pressure balloons to correct underexpansion and facilitating the use of cutting balloons.15 Delayed healing and poor endothelialization are common findings in the pathological specimens of vessels treated with DES,43 and recent post-mortem studies demonstrated that a late-stent thrombosis was strongly associated with the ratio of uncovered/total stent struts.44 Several experimental and clinical studies have demonstrated the high correlation between OCT and histological measurements of tissue coverage of stent struts,45,46 although OCT is unable to identify the endothelium.1 In a subanalysis of the ODESSA trial, 8% of the stented segments with no detectable neointima by IVUS were found to have neointimal coverage by OCT.41 Follow-up OCT data revealed that most of the DES, including those with a biodegradable polymer, were covered with thin neointima, but few revealed complete coverage.47–51 Incomplete stent apposition without neointimal hyperplasia was significantly associated with the presence of an OCT-detected thrombus at the follow-up, and may constitute a potent substrate for a late-stent thrombosis;52 however, so far a subclinical thrombus has not been related to the risk of major adverse cardiac events.53 Furthermore, incomplete stent apposition and the absence of OCT tissue coverage are more frequently found in the setting of acute coronary syndromes, particularly after DES deployment (Figure 8).54 It is difficult to offer any recommendation at this stage for the use of OCT for the late follow-up of individual patients but anecdotal cases of OCT application to rule out the need for the prolongation of a dual antiplatelet treatment in patients requiring undeferrable surgery have been reported. The main application is, at present, the comparison of different stent platforms, assuming that a more uniform strut coverage could improve the late outcome. Malapposed struts tend not to heal with tissue coverage unlike well-apposed ones. Optical coherence tomography images obtained 1 month after Taxus stent deployment in the right coronary artery. Optical coherence tomography showed malapposition of the drug eluting stents with many struts not adhering at the vessel wall. The vast majority of malapposed struts (from a to l) were uncovered while only two of them (arrows) had some tissue coverage. On the other hand the two well-apposed struts (m, n) were covered. Optical coherence tomography is being increasingly used as a surrogate method for evaluating stents.15 The ability to provide serial images and analyse a large number of OCT cross section and stent struts represent an advantage over standard histopathology. Core laboratory OCT image analysis should, however, be performed according to a standardized methodology and after a deep of the OCT suggest to address images not only at a strut but including also cross-sectional and in-stent level to study an in-stent coverage and individual incomplete stent Furthermore, if automated should be to reduce and for each strut on malapposition, presence of thrombotic and tissue prolapse should be have been so far by OCT and data on and for the are not available. As a the following can be to stent struts the pull-back image covered covered by tissue with at least of the strut the level of the luminal covered covered by tissue and with the strut located above the level of the luminal uncovered apposed for those not covered by tissue but the vessel uncovered and malapposed for those not covered by tissue and not the vessel OCT different of stent a of An intra-stent thrombus is shown as an in-stent globular appearance and can be In the presence of stent malapposition, the lumen area should be into an in-stent lumen area and an lumen area. overlapping segments and lesions with major should be Optical coherence tomography enables an accurate vessel lumen and stent a high image quality with pull-back procedural and patient Optical coherence tomography into stenting procedures that be missed using conventional angiography or will lead to or complementary with to IVUS in guiding coronary particularly in the of DES, to be to the for this was by of has from St Jude has from St Jude Medical, and and from and has from Volcano and St Jude and from Volcano and has from St Jude Medical, and and is a for has from and from and and has from has and from St Jude has and from St Jude has and from Terumo, and and is an has from St Jude and has and out for St Jude has from St Jude

IMPORTANCE: Effective therapy has not been established for patients with agitated delirium receiving mechanical ventilation. OBJECTIVE: To determine the effectiveness of dexmedetomidine when added to standard care in patients with agitated delirium receiving mechanical ventilation. DESIGN, SETTING, AND PARTICIPANTS: The Dexmedetomidine to Lessen ICU Agitation (DahLIA) study was a double-blind, placebo-controlled, parallel-group randomized clinical trial involving 74 adult patients in whom extubation was considered inappropriate because of the severity of agitation and delirium. The study was conducted at 15 intensive care units in Australia and New Zealand from May 2011 until December 2013. Patients with advanced dementia or traumatic brain injury were excluded. INTERVENTIONS: Bedside nursing staff administered dexmedetomidine (or placebo) initially at a rate of 0.5 µg/kg/h and then titrated to rates between 0 and 1.5 µg/kg/h to achieve physician-prescribed sedation goals. The study drug or placebo was continued until no longer required or up to 7 days. All other care was at the discretion of the treating physician. MAIN OUTCOMES AND MEASURES: Ventilator-free hours in the 7 days following randomization. There were 21 reported secondary outcomes that were defined a priori. RESULTS: Of the 74 randomized patients (median age, 57 years; 18 [24%] women), 2 withdrew consent later and 1 was found to have been randomized incorrectly, leaving 39 patients in the dexmedetomidine group and 32 patients in the placebo group for analysis. Dexmedetomidine increased ventilator-free hours at 7 days compared with placebo (median, 144.8 hours vs 127.5 hours, respectively; median difference between groups, 17.0 hours [95% CI, 4.0 to 33.2 hours]; P = .01). Among the 21 a priori secondary outcomes, none were significantly worse with dexmedetomidine, and several showed statistically significant benefit, including reduced time to extubation (median, 21.9 hours vs 44.3 hours with placebo; median difference between groups, 19.5 hours [95% CI, 5.3 to 31.1 hours]; P < .001) and accelerated resolution of delirium (median, 23.3 hours vs 40.0 hours; median difference between groups, 16.0 hours [95% CI, 3.0 to 28.0 hours]; P = .01). Using hierarchical Cox modeling to adjust for imbalanced baseline characteristics, allocation to dexmedetomidine was significantly associated with earlier extubation (hazard ratio, 0.47 [95% CI, 0.27-0.82]; P = .007). CONCLUSIONS AND RELEVANCE: Among patients with agitated delirium receiving mechanical ventilation in the intensive care unit, the addition of dexmedetomidine to standard care compared with standard care alone (placebo) resulted in more ventilator-free hours at 7 days. The findings support the use of dexmedetomidine in patients such as these. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01151865.

A computerised, retrospective study of 818 patients with sarcoidosis was analysed to study the prognosis of each individual manifestation of the disease. The good prognosis of erythema nodosum, acute arthritis and bilateral hilar lymphadenopathy was confirmed, though 16 per cent of patients presenting with erythema nodosum pursued a chronic course. Cor pulmonale and nephrocalcinosis reflected the poorest prognosis while lupus pernio and sarcoidosis of the mucosa of the upper respiratory tract rarely resolved. Bone sarcoidosis also implied chronicity but in four of 31 patients there was no clinical evidence of disease activity two years after the initial diagnosis, although naturally the bone radiograph was still abnormal. Hepatomegaly carried a worse prognosis than splenomegaly, or indeed, than the finding of pulmonary mottling without hilar glands--a stage three chest radiograph.

Abstract

Abstract Objective Electroencephalography (EEG) interpretations through visual (by human raters) and automated (by computer technology) analysis are still not reliable for the diagnosis of non-convulsive status epilepticus (NCSE). This study aimed to identify typical pitfalls in the EEG analysis and make suggestions as to how those pitfalls might be avoided. Methods We analyzed the EEG recordings of individuals who had clinically confirmed or suspected NCSE. Epileptiform EEG activity during seizures (ictal discharges) were visually analyzed by two independent raters. We investigated whether unreliable EEG visual interpretations quantified by low inter-rater agreement can be predicted by the characteristics of ictal discharges and individuals’ clinical data. In addition, the EEG recordings were automatically analyzed by in-house algorithms. To further explore the causes of unreliable EEG interpretations, two epileptologists analyzed EEG patterns most likely misinterpreted as ictal discharges based on the differences between the EEG interpretations through the visual and automated analysis. Results Short ictal discharges with a gradual onset (developing over 3 seconds in length) were liable to be misinterpreted. An extra 2 minutes of ictal discharges contributed to an increase in the kappa statistics of > 0.1. Other problems were the misinterpretation of abnormal background activity (slow wave activities, other abnormal brain activity, and the ictal-like movement artifacts), continuous interictal discharges, and continuous short ictal discharges. Conclusion A longer duration criterion for NCSE-EEGs than 10 seconds that commonly used in NCSE working criteria is needed. Using knowledge of historical EEGs, individualized algorithms, and context-dependent alarm thresholds may also avoid the pitfalls.

Muscle atrophy is caused by an imbalance in contractile protein synthesis and degradation which can be triggered by various conditions including Type 2 Diabetes Mellitus (T2DM). Reduced muscle quality in patients with T2DM adversely affects muscle function, the capacity to perform activities of daily living, quality of life and ultimately may increase the risk of premature mortality. Systemic inflammation initiated by obesity and prolonged overnutrition not only contributes to insulin resistance typical of T2DM, but also promotes muscle atrophy via decreased muscle protein synthesis and increased ubiquitin-proteasome, lysosomal-proteasome and caspase 3- mediated protein degradation. Emerging evidence suggests that the inflammation-sensitive Nuclear Factor κ B (NF-κB) and Signal Transducer and Activator of Transcription 3 (STAT3) pathways may contribute to muscle atrophy in T2DM. In contrast, exercise appears to be an effective tool in promoting muscle hypertrophy, in part due to its effect on systemic and local (skeletal muscle) inflammation. The current review discusses the role inflammation plays in muscle atrophy in T2DM and the role of exercise training in minimising the effect of inflammatory markers on skeletal muscle. We also report original data from a cohort of obese patients with T2DM compared to age-matched controls and demonstrate that patients with T2DM have 60% higher skeletal muscle expression of the atrophy transcription factor FoxO1. This review concludes that inflammatory pathways in muscle, in particular, NF-κB, potentially contribute to T2DM-mediated muscle atrophy. Further in-vivo and longitudinal human research is required to better understand the role of inflammation in T2DM-mediated atrophy and the anti-inflammatory effect of exercise training under these conditions.

OBJECTIVES: This study sought to evaluate the safety and efficacy of rosuvastatin in preventing contrast-induced acute kidney injury (CI-AKI) in patients with diabetes mellitus (DM) and chronic kidney disease (CKD). BACKGROUND: CI-AKI is an important complication after contrast medium injection. While small studies have shown positive results with statin therapy, the role of statin therapy in prevention of CI-AKI remains unknown. METHODS: We randomized 2,998 patients with type 2 DM and concomitant CKD who were undergoing coronary/peripheral arterial angiography with or without percutaneous intervention to receive rosuvastatin, 10 mg/day (n = 1,498), for 5 days (2 days before, and 3 days after procedure) or standard-of-care (n = 1,500). Patients' renal function was assessed at baseline, 48 h, and 72 h after exposure to contrast medium. The primary endpoint of the study was the development of CI-AKI, which was defined as an increase in serum creatinine concentration ≥0.5 mg/dl (44.2 μmol/l) or 0.25% above baseline at 72 h after exposure to contrast medium. RESULTS: Patients randomized to the rosuvastatin group had a significantly lower incidence of CI-AKI than controls (2.3% vs. 3.9%, respectively; p = 0.01). During 30 days' follow-up, the rate of worsening heart failure was significantly lower in the patients treated with rosuvastatin than that in the control group (2.6% vs. 4.3%, respectively; p = 0.02). CONCLUSIONS: Rosuvastatin significantly reduced the risk of CI-AKI in patients with DM and CKD undergoing arterial contrast medium injection. (Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes [TRACK-D]; NCT00786136).

The frequency of human papillomavirus (HPV) type 16 in premalignant and malignant lesions of the cervix was investigated and compared with the detection of HPV type 6. In cervical intraepithelial neoplasia (CIN) grades I-III HPV 6 was detected in 28% and HPV 16 in 62% of patients whereas 90% of malignant lesions contained HPV 16 only. In the CIN lesions there was an increase in HPV 16 detection as the severity of disease increased while the level of detection of HPV 6 decreased. Only three (18%) of the cervices that were colposcopically and histologically normal contained HPV genomes; although two of these three women had either a history of genital warts or a sexual partner with penile warts.

BACKGROUND: A high incidence of functional decline (deterioration in physical or cognitive function) during hospitalisation of older adults is reported. The role of exercise in preventing these deconditioning effects is unclear. OBJECTIVES: To determine the effect of exercise interventions for acutely hospitalised older medical patients on functional status, adverse events and hospital outcomes. SEARCH STRATEGY: We searched MEDLINE (1966-Feb 2006), CINAHL (1982-Feb 2006), EMBASE (1988 to Feb 2006), Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2006), PEDro (1929- Feb 2006), Current Contents (1993- Feb 2006) and Sports Discus (1830-Feb 2006). The Journal of the American Geriatrics Society was hand searched. Additional studies were identified through reference and citation tracking, personal communications with a content expert and contacting authors of eligible trials. There was no language restriction. SELECTION CRITERIA: Eligible studies were prospective randomised controlled trials (RCT) or prospective controlled clinical trials (CCT) comparing exercise for acutely hospitalised older medical patients to usual care or no treatment controls. DATA COLLECTION AND ANALYSIS: Two independent reviewers extracted data relating to patient and hospital outcomes and assessed the method quality of included studies. Data were pooled in meta-analysis using the relative risk (RR) and absolute risk reduction (ARR) for dichotomous outcomes and the standardised mean difference (SMD) or the weighted mean difference (WMD) for continuous outcomes. MAIN RESULTS: Of 3138 potentially relevant articles screened, 7 randomised controlled trials and 2 controlled clinical trials were included. The effect of exercise on functional outcome measures is unclear. No intervention effect was found on adverse events. Pooled analysis of multidisciplinary interventions that included exercise indicated a small significant increase in the proportion of patients discharged to home at hospital discharge (Relative Risk 1.08, 95% CI 1.03 to 1.14 and Numbers Needed to Treat 16, 95% CI 11 to 43) and a small but important reduction in acute hospital length of stay (weighted mean difference, -1.08 days, 95% CI -1.93 to -0.22) and total hospital costs (weighted mean difference, -US$278.65, 95% CI -491.85 to -65.44) compared to usual care. Pooled analysis of exercise intervention trials found no effect on the proportion of patients discharged to home or acute hospital length of stay. AUTHORS' CONCLUSIONS: There is 'silver' level evidence (www.cochranemsk.org) that multidisciplinary intervention that includes exercise may increase the proportion of patients discharged to home and reduce length and cost of hospital stay for acutely hospitalised older medical patients.

Importance: Preclinical and clinical studies have suggested a neuroprotective effect of remote ischemic conditioning (RIC), which involves repeated occlusion/release cycles on bilateral upper limb arteries; however, robust evidence in patients with ischemic stroke is lacking. Objective: To assess the efficacy of RIC for acute moderate ischemic stroke. Design, Setting, and Participants: This multicenter, open-label, blinded-end point, randomized clinical trial including 1893 patients with acute moderate ischemic stroke was conducted at 55 hospitals in China from December 26, 2018, through January 19, 2021, and the date of final follow-up was April 19, 2021. Interventions: Eligible patients were randomly assigned within 48 hours after symptom onset to receive treatment with RIC (using a pneumatic electronic device and consisting of 5 cycles of cuff inflation for 5 minutes and deflation for 5 minutes to the bilateral upper limbs to 200 mm Hg) for 10 to 14 days as an adjunct to guideline-based treatment (n = 922) or guideline-based treatment alone (n = 971). Main Outcomes and Measures: The primary end point was excellent functional outcome at 90 days, defined as a modified Rankin Scale score of 0 to 1. All end points had blinded assessment and were analyzed on a full analysis set. Results: Among 1893 eligible patients with acute moderate ischemic stroke who were randomized (mean [SD] age, 65 [10.3] years; 606 women [34.1%]), 1776 (93.8%) completed the trial. The number with excellent functional outcome at 90 days was 582 (67.4%) in the RIC group and 566 (62.0%) in the control group (risk difference, 5.4% [95% CI, 1.0%-9.9%]; odds ratio, 1.27 [95% CI, 1.05-1.54]; P = .02). The proportion of patients with any adverse events was 6.8% (59/863) in the RIC group and 5.6% (51/913) in the control group. Conclusions and Relevance: Among adults with acute moderate ischemic stroke, treatment with remote ischemic conditioning compared with usual care significantly increased the likelihood of excellent neurologic function at 90 days. However, these findings require replication in another trial before concluding efficacy for this intervention. Trial Registration: ClinicalTrials.gov Identifier: NCT03740971.

AIM: Elevation of Troponin after scheduled percutaneous coronary intervention (PCI) is a recognized consequence. We sought to evaluate the prognostic significance and impact of the newly published definition of PCI-related myocardial infarction (MI) according to which any troponin elevation >3 times the upper reference limit identify a peri-procedural MI. METHODS: Search of BioMedCentral, CENTRAL, mRCT and PubMed (updated May 2008). Outcomes of interest were: MACE [the composite of all cause death, MI, repeat target vessel PCI (re-PCI) and coronary artery bypass grafting (CABG)]; single end points were also assessed. RESULTS: Fifteen studies have been included totalling 7578 patients. Troponin elevation occurred in 28.7% of the procedures. The incidence of PCI-related MI according to the new definition was 14.5%. During the hospitalization, any level of raised troponin was associated with an increased risk of MACE [OR 11.29 (3.00-42.48), Number needed to harm (NNH) 5], death [OR 7.16 (1.95-26.27), NNH = 100], MI [OR 30.85 (6.05-157.38), NNH = 4] and re-PCI [OR 4.13 (1.23-13.88), NNH = 50]. Patients with PCI-related MI had an increased risk of death [OR 17.25 (2.71-109.96), NNH = 100] and re-PCI [OR 10.86 (3.2-36.94), NNH = 25]. At follow up of 18 months any troponin elevation was associated with an increased risk of MACE [OR 1.48 (1.12-1.96), NNH = 20], death [OR 2.19 (1.59-3.00), NNH = 50], MI [OR 3.29 (2.71-6.31), NNH = 33] and re-PCI [OR 1.47 (1.06-2.03), NNH = 25]. In patients with PCI-related MI the risk of MACE was further increased: OR 2.25 (1.26-4.00), NNH = 3. An increase of the troponin level below the cut-off was not associated with MACE. CONCLUSION: A diagnosis of MI according to the new guidelines applies to 15% of patients undergoing PCI and these patients are at high risk of further adverse events both during the hospital stay and at 18 months.

There have been considerable advances in understanding the metabolic role of the endothelial lining cells of the blood vessels. Angiotensin-converting enzyme activity is concentrated in these cells, especially those lining the pulmonary circulation. The enzyme exerts control over systemic vascular tone indirectly through the powerful pressor effect of angiotensin II. A number of therapeutic agents are now available which directly inhibit converting enzyme activity and thereby effect a reduction in blood pressure. Macrophages are the source of increased angiotensin-converting enzyme activity commonly found in association with active sarcoidosis. A better understanding of this phenomenon may give fresh insight into this puzzling condition. Pulmonary endothelial metabolism is affected by lung injury and it is likely that in this situation changing activities of serum angiotensin converting enzyme may indicate the extent of damage and the response to therapy. The full clinical significance of serum ACE measurements has yet to be established. However, raised activities have been reported in a number of other conditions and diabetes mellitus and hyperthyroidism are of particular current interest. The numerous methods and reference ranges described in the literature for the measurement of serum ACE activity require further assessment, and there is a clear need for an accepted reference method.

The psychosexual sequelae of diagnosis and treatment of pre-invasive cervical atypia were assessed in three groups of women. The first group included 30 women referred to a colposcopy clinic with an abnormal cervical smear indicating cervical intraepithelial neoplasia (CIN), the second comprised 50 women who were traced as sexual partners of men with penile human papillomavirus (HPV) infection; 26 of them had histologically proven cervical atypia and 24 had no such evidence. The third group included 25 women traced as partners of men with non-specific urethritis and who did not have cervical disease. Before and after questionnaires assessed six aspects of sexual behaviour and responses before diagnosis and 6 months after treatment in women with cervical atypia. These were compared with answers given by women investigated and treated, if necessary, as partners of men with sexually transmitted disease (control group). There were statistically significant adverse psychosexual sequelae associated with diagnosis and treatment of pre-invasive cervical epithelial disease.

All schizophrenic symptoms remitted completely in six out of 14 adults who had not responded to phenothiazine drugs and who were then given propranolol. Another patient improved markedly and four improved moderately. Two had minimal or transient improvement, and one left hospital unchanged after a short, severe, toxic reaction. The six with complete remissions all began to improve within a few days of starting propranolol and the florid symptoms remitted completely after three to 26 days. They were stabilized on a daily dose of 500-3,500 mg of propranolol and at the time of writing had remained well for up to six months. Two patients who stopped propranolol after their symptoms remitted relapsed severely within a few days. Toxic effects (ataxia, visual hallucinations, and confusional states) were related to the rate of increase rather than to the absolute dose of propranolol. After the procedure was modified unwanted effects were usually mild or absent.

OBJECTIVE: To evaluate the effect of the 6-PACK programme on falls and fall injuries in acute wards. DESIGN: Cluster randomised controlled trial. SETTING: Six Australian hospitals. PARTICIPANTS: All patients admitted to 24 acute wards during the trial period. INTERVENTIONS: Participating wards were randomly assigned to receive either the nurse led 6-PACK programme or usual care over 12 months. The 6-PACK programme included a fall risk tool and individualised use of one or more of six interventions: "falls alert" sign, supervision of patients in the bathroom, ensuring patients' walking aids are within reach, a toileting regimen, use of a low-low bed, and use of a bed/chair alarm. MAIN OUTCOME MEASURES: The co-primary outcomes were falls and fall injuries per 1000 occupied bed days. RESULTS: During the trial, 46 245 admissions to 16 medical and eight surgical wards occurred. As many people were admitted more than once, this represented 31 411 individual patients. Patients' characteristics and length of stay were similar for intervention and control wards. Use of 6-PACK programme components was higher on intervention wards than on control wards (incidence rate ratio 3.05, 95% confidence interval 2.14 to 4.34; P<0.001). In all, 1831 falls and 613 fall injuries occurred, and the rates of falls (incidence rate ratio 1.04, 0.78 to 1.37; P=0.796) and fall injuries (0.96, 0.72 to 1.27; P=0.766) were similar in intervention and control wards. CONCLUSIONS: Positive changes in falls prevention practice occurred following the introduction of the 6-PACK programme. However, no difference was seen in falls or fall injuries between groups. High quality evidence showing the effectiveness of falls prevention interventions in acute wards remains absent. Novel solutions to the problem of in-hospital falls are urgently needed. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12611000332921.

Patients with chronic, refractory irritable bowel syndrome (n = 102) were entered into a randomised controlled trial of psychotherapy versus supportive listening. Independent physical and psychological assessments were carried out at the beginning and end of the 12-week trial. For women, psychotherapy was found to be superior to supportive listening, in terms of an improvement in both physical and psychological symptoms. There was a similar trend for men, but this did not reach significance. Following completion of the trial, patients in the control group were offered psychotherapy; 33 accepted and following treatment experienced a marked improvement in their symptoms; ten declined. At follow-up one year later, those patients who had received psychotherapy remained well, patients who had dropped out of the trial were unwell with severe symptoms, and most of the controls who declined psychotherapy had relapsed. This study shows that psychotherapy is feasible and effective in the majority of irritable bowel syndrome patients with chronic symptoms unresponsive to medical treatment.

BACKGROUND: Increasing frailty is associated with risk of mortality and functional decline in hospitalized older adults, but there is no consensus on the best screening method for use by non-geriatricians. The objective of this study is to determine whether the clinical frailty scale (CFS) can be used to identify patient baseline frailty status in the acute general medical setting when used by junior medical staff using information obtained on routine clinical assessment. METHODS: This was a prospective cohort study in an acute general medical unit. All patients aged 65 and over admitted to a general medical unit during August and September 2013 were eligible for the study. CFS score at baseline was documented by a member of the treating medical team. Demographic information and outcomes were obtained from medical records. The primary outcomes were functional decline and death within three months. RESULTS: Frailty was assessed in 95 % of 179 eligible patients. 45 % of patients experienced functional decline and 11 % died within three months. 40 % of patients were classified as vulnerable/mildly frail, and 41 % were moderately to severely frail. When patients in residential care were excluded, increasing frailty was associated with functional decline (p = 0.011). Increasing frailty was associated with increasing mortality within three months (p = 0.012). CONCLUSIONS: A high proportion of eligible patients had the frailty measure completed, demonstrating the acceptability of the CFS to clinicians. Despite lack of training for medical staff, increasing frailty was correlated with functional decline and mortality supporting the validity of the CFS as a frailty screening tool for clinicians.