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Reported specificity was very high in the two studies that reported specificity results (range: 85% 95%). Overall sensitivity and specificity results were not presented but the authors noted that 17. Statistically significant increases in sensitivity were reported for all readers but mixed results were reported for specificity (although the difference in specificity was not significant). Retrospective studies for women recalled assessment and symptomatic women Garayoa et al. Increases were usually in the range of a couple of percentage points, but results were not significant. Retrospective studies of women presenting for screening and symptomatic women Tagliafico et al. Six different strategies were investigated which varied in terms of modalities used and number of reads. These results came from a subset of a large prospective study, still the patient data included was relatively not that small (n=163). Retrospective studies: diagnostic pathway unknown Similar findings were reported in Mariscotti et al. Instead, it presents findings from more recent studies (particularly those published since 1 January 2016) and specific additional findings not clearly reported in the systematic reviews. Further information about the implementation considerations of this approach are discussed in Chapter 6. Likewise, differences in specificity were also reported, with lower rates in Heywang-Kobrunner et al. The differences between these two studies (even though they draw on almost the same cohort) are most likely due differences between the two imaging protocols. Also, it is likely that the studies themselves may be underpowered accurately detect sensitivity and specificity. Given this and the lack of statistical difference in key study metrics, Brandt et al. Systematic reviews and narrative literature review Systematic review: Garcia-Leon et al. Reduction in inter-observer variability and increases in inter-observer agreement are likely translate higher quality clinical care. This literature review will only comment on study findings relating inter-observer agreement (not decisions recall asymptomatic women assessment). Regardless of study diagnostic pathway, studies reported increases in inter-observer agreement (and therefore decreases inter-observer variation) of about 25%. Reviewing data from women presenting for screening and the work-up of symptomatic women, Galati et al. Reported intraclass correlation coefficient between any two readers was between 0. While both attending and fellow radiologists agreement improved, greater improvement in agreement was seen for the more experienced radiologists (increase in kappa of 0. Table 8: Additional studies reporting on inter-reader agreement/variation Study Study details Results Fornvik et al. Inter-reader agreement was lower for density and microcalcifications (but the study only had a small number of these which could explain the difference). Even though it is a 2D image, the reconstruction process removes further noise creating a clearer image. Samples sizes varied between 31 women and more than 4500 participants, although most studies had fewer than 400 participants. One early narrative literature review (Tingberg & Zackrisson, 2011) reported on a small 2008 study by Andersson et al. In 99 Japanese women with pathologically-proven breast cancer, two radiologists rated 75. Prospective studies of mixed study populations (asymptomatic and symptomatic women) Two studies (Bahrs et al.

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Network meta-analysis synthesizes information from a network of trials, which helps interpret the randomized evidence and can rank treatments from different trials. All outcomes from our present analysis were consistent with our previous report and strengthened data solidity by reducing confidence or credibility intervals. Additional trials of lpnb relative regimens are not probable change the results, but pzmb relative trials are required improve evidence solidity. German Breast Group, Neu-Isenburg, 2 3 4 Germany; Emergency County Hospital Cluj, Cluj-Napoca, Romania; Amgen, Inc. Here we report results from the single switch treatment arm in the adjuvant phase of the corresponding clinical study. We aimed investigate the cardiotoxicity in the 1 year treatment and follow-up period. Based on the dosage form and strengths available, dose modification may lead drug wastage when the dose cannot be split or saved for later use. Palbociclib starting daily dose, average daily dose, and dosing patterns (dosing modifications and sequences) were reported. The economic burden of drug wastage was estimated by multiplying the number of days with drug wastage. Conclusion: Over a short observation period, dose modifications, mostly dose reductions, were relatively frequent, and potential resulting drug wastage was associated with a substantial economic burden. Table 1: Palbociclib dosing patterns and sequences First line Second line Third line Starting dose (mg daily), N (%) 75 7 (3. Additionally, premature discontinuation of trastuzumab may lead poorer cancer outcomes. Treatment consisted of trastuzumab 6 mg/kg every 3w and palbociclib 200 mg daily for 2w and 1w off. Univariate Cox regression analyses evaluating luminal subtype, age, performance status, treatment line, type of biopsy and endocrine treatment were evaluated. In the primary analysis for the Cohort I randomized stage only, median follow-up was 8 months. Inducing tumor response and delaying disease progression is of critical need in pts with liver metastases (mets). There were no dose-limiting toxicities in either arm at the dose levels evaluated; dose escalation is ongoing. Secondary and exploratory endpoints included efficacy, pharmacokinetics, and biomarkers. Most common reasons for treatment discontinuation in the full population were disease progression (23. However, few studies have described the efficacy of other drugs in combination with pertuzumab plus trastuzumab. The median age was 56 years (23?70), and 8 (16%) and 41 (84%) pts were treated in first and second-line settings, respectively. The median relative dose intensities of eribulin, trastuzumab, and pertuzumab were 93. Body: Background: Older adults are less likely be included in clinical trials leading the approval of novel cancer treatments. Patients completed a pre-treatment geriatric assessment including measures of function, comorbidity, cognition, nutrition, and psychosocial status. The toxicity risk score was not found be significantly related with treatment toxicity, which may be explained by the very low incidence of G3 events. Here we present overall survival data according therapy lines, patient and tumor characteristics. Patients of all therapy lines with any kind of treatment are eligible for this registry. Here we report on the comparison of overall survival data for different patient groups. Only for the analysis of the effect of therapy line on overall survival the complete dataset was used. All further analyses were done only for the subset of first line treated patients with a total of 127 events. Conclusion this breast registry included patients over all therapy lines however mainly during the 1st line of therapy.

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Correlation between recurrent subconjunctival hemorrhages and conjunctivochalasis Ingelheim Pharmaceuticals) should obtain. The medical workup of a patient by clinical profile and successful surgical outcome. Virological and epide miological analysis of coxsackievirus A24 variant epidemic of be adjusted. Adenoviral keratoconjunctivi modified, communication and discussion cases that are recurrent or persistent in tis. Bilateral eyelid ecchymo sis and subconjunctival haemorrhage manifesting as presenting. It is not unusual for patients with injury or similar singular event likely does feature in a case of dengue haemorrhagic fever. What we know about ocular uation, assuming the patient is otherwise manifestations of Ebola. One simple systemic investigation up study of ocular and systemic complications of intravit real injection of bevacizumab (Avastin). Even a small drop of ketchup (blood) can temic conditions are usually the causative 2008;36(6):581-2. Natural history of valsalva reti large area by a tight layer of plastic wrap nopathy in an adolescent. Valsalva retinopathy in preg mon household items nearly always helps nancy: a case report. It should only be considered in cases and the tortuosity of vessels of the bulbar conjunctiva. Subconjunctival hemorrhages: cant ophthalmic morbidity adjacent presenting sign for hereditary hemochromatosis. Periorbital ecchymosis and that eye rubbing may increase re and subconjunctival hemorrhage following ear surgery. Subconjunctival hemor ecchymosis and petechial hemorrhages rhage in a patient on dabigatran (Pradaxa). Location and extent hemorrhage renal dysfunction international normalized ratio of of subconjunctival hemorrhage. Recent causes of sub making: hyposphagma prior intravenous tissue plasminogen nant tumors of the conjunctiva may conjunctival hemorrhage. Concisely communicate your diagnosis & treatment plan utilizing an EyeRes Digital Imaging System. The condition may also most notably herpes simplex and syphilis, ingly difficult culture. When patients these remaining viral components are Ophthalmology, oral antiviral medica present with this array of findings in the highly immunogenic and potentiate tions are preferable topical agents due absence of acute inflammation, the disease the formation of cytokines, chemokines potential toxicity associated with tri is said be in the inactive stage. Its characteristic presentation phage inflammatory proteins, monocyte clovir 500mg once daily. However, these drugs are not sufficiently effective in cases of neurosyphilis; therefore, those with late-stage disease first require peni cillin desensitization. Treatment in this case requires oral antivirals as typically addressed with the concurrent well as topical corticosteroid therapy. Today, syphilis is recognized patients, recommending a longer period visual outcome. Predictors of recurrent ophthalmia syndrome, glaucoma, optic 29-31 herpes simplex virus keratitis. Treatment of herpes simplex virus stromal keratitis disk pits, Ehlers-Danlos syndrome. Topical ophthalmic cyclo glaucoma, iris coloboma or retinal/optic presents with frank epithelial ulceration. Bevacizumab as a for the development of secondary open demonstrates a substantially more rapid potent inhibitor of inflammatory corneal angiogenesis and lym angle, primary angle-closure and second phangiogenesis. Subconjunctival bevacizumab for cor tion who develops hearing loss, vertigo, neal neovascularization in herpetic stromal keratitis. Amniotic membrane transplantation viral suppressant therapy, ensure that the combined with antiviral and steroid therapy for herpes necrotiz were found have thicker central corneal ing stromal keratitis. Successful diagnosis and treatment of a single case of bilateral necrotizing kera Pathophysiology 2. A young immunocompetent patient Signs and Symptoms the corneal endothelium and trabecular with bilateral immune stromal keratitis due varicella zoster and A number of corneal anomalies are pres meshwork.

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However, the vast majority of dengue patients present late during their illness, perhaps on days 3 or 4 of fever. Even during clinical studies, patients do not present study staff much earlier. In this respect, a trial of dengue antivirals would have capture patients presenting primary care facilities, where it would be possible enrol patients during the frst two days after the onset of symptoms, whereas hospital admission is more likely occur on days 3 or 4 or later. However, the earlier the presentation with fever, the less likely it is that the diagnosis will be dengue. It would also be ideal test reactions between an anti-dengue drug and other drugs often used treat dengue patients, such as paracetamol. It is likely that a multicentre trial of a candidate dengue antiviral drug would be indicated, which raises a series of issues. For instance, the treatment that dengue cases receive in hospitals is known have a dramatic effect on the disease outcome, and the way clinicians treat dengue cases varies greatly both within and between institutions. In addition, getting physicians document parameters and outcomes carefully in busy clinical situations is often diffcult though not impossible and is clearly essential for any trial. A robust study design with a single protocol followed meticulously at all sites would solve the problem but would be challenging achieve. The greatest burden of dengue in most countries is in children, although in some areas older age groups are also signifcantly affected. The target population for dengue drugs would be all age groups but, because of the problematic nature of clinical trials in children, a drug trial may be better performed in the frst instance in adults (>15 years of age). Although vaccines and drugs for dengue pose signifcant challenges during both product development and feld-testing, tremendous strides have been made recently in both areas. Vaccines against dengue: a review of current candidate vaccines at advanced development stages. Economic impact of dengue fever/dengue hemorrhagic fever in Thailand at the family and population levels. Scientifc consultation on immunological correlates of protection induced by dengue vaccines report from a meeting held at the World Health Organization 17-18 November 2005. Virulence of a live dengue virus vaccine candidate: a possible new marker of dengue virus attenuation. Short report: immune response and occurrence of dengue infection in thai children three eight years after vaccination with live attenuated tetravalent dengue vaccine. Guidelines for the clinical evaluation of dengue vaccines in endemic areas: summary of a World Health Organization technical consultation. A 7-deaza-adenosine analog is a potent and selective inhibitor of hepatitis C virus replication with excellent pharmacokinetic properties. Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention. Proceedings of the National Academy of Sciences of the United States of America, 2007, 104:9422?9427. In vivo enhancement of dengue virus infection in rhesus monkeys by passively transferred antibody. Dengue virus infects macrophages and dendritic cells in a mouse model of infection. Tropism of dengue virus in mice and humans defned by viral nonstructural protein 3-specifc immunostaining. A dengue fever viremia model in mice shows reduction in viral replication and suppression of the infammatory response after treatment with antiviral drugs. Inhibition of dengue virus serotypes 1 4 in vero cell cultures with morpholino oligomers. In vitro resistance selection and in vivo effcacy of morpholino oligomers against West Nile virus. Dengue fever is an infectious disease carried by mosquitoes and caused by any of four related dengue viruses. This disease used be called "break-bone" fever because it sometimes causes severe joint and muscle pain that feels like bones are breaking. Dengue fever is found mostly during and shortly after the rainy season in tropical and subtropical areas of the Caribbean and Central and South America, Africa, Southeast Asia and China, India, the Middle East, Australia and the South and Central Pacific.

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Digital enhancement of the images at 47 computer workstations may also improve the accuracy of mammographic interpretation. In particular, increased contrast resolution improves the detection of low contrast lesions in radiographically dense breasts. Hand-held ultrasound has been used as a diagnostic tool 51 evaluate women with breast masses and has been promoted by some as a screening tool. All four of the advanced imaging technologies considered in this assessment generate multiple two dimensional images representing slices of the breast. This is particularly relevant in mammographically dense breasts because breast cancers may be obscured by superimposed dense tissue. The system uses computational algorithms generate detailed cross-sectional views of the breast. Mammography requires repositioning of the breast and mammography system for each Institute for Clinical & Economic Review, 2014 Page 7 desired view. It is particularly useful differentiate fluid filled cysts from solid masses (cysts are rarely cancerous). Advantages of ultrasound include the ability evaluate tissue that is dense on mammography without additional ionizing radiation, which can potentially increase the risk for future cancers. It is also perceived be more comfortable than mammography because it does not require compression of the breasts. There are also concerns about the operator dependency and reproducibility of the examinations. At a minimum, the breast radiologist needs be available review static images saved by the performing technologist in real time so that additional images can be acquired if necessary. A breast-shaped transducer is placed on the compressed breast and automatically scans the entire breast. The entire procedure, including patient preparation, takes about 15 52 minutes complete. The radiologist can review the scan independently using software that displays the images individually or sequentially in a movie mode. Breast compression is performed using the same device and technique as conventional mammography. The tomograms can be displayed individually (similar enhanced conventional mammograms) or in a dynamic movie mode. Currently, a standard digital image is also acquired, so 54,55 the total dose is approximately twice that of digital mammography alone. This technology is still in development and was not used in studies considered in this assessment. A true positive is a positive imaging assessment that is followed by a diagnosis of invasive or in situ breast cancer within 12 months. A false positive is a positive imaging result that is not followed by a cancer diagnosis within 12 months. The cancer detection rate is the number of cancers detected by a positive test divided by the number of screening tests performed for consistency and ease of comparison, we will report it as the number of breast cancers detected per 1000 screening examinations. The most common statistics reported by scientists evaluating the diagnostic performance of a test are the sensitivity and specificity. The sensitivity is calculated among women with disease: it is defined as the number of positive tests in women with breast cancer divided by the total number of women with breast cancer and is usually reported as a percentage. In studies of breast imaging, the standard has been follow women for one year after the screening examination and count any cancers found during that period as interval cancers. Interval cancers are also known as false negatives because the test was negative, but cancer was likely present. True negatives are the negative test results that remain negative during follow-up. The interval cancers are added the screen-detected cancers give the total number of women with breast cancer for the calculation of these statistics.

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Outbreak Response Plan for Hospitals There have been an increasing number of dengue outbreaks in many parts of the country. Therefore, having a hospital emergency response plan for dengue outbreaks is vital in early diagnosis and appropriate clinical management of cases minimize complications and deaths. Assess bed occupancy in each unit (with a view identifying additional beds during outbreaks)? Laboratory facilities As the first step, with the available resources, hospitals should develop and strengthen their capacity screen and triage suspected dengue patients at the outpatient departments. Hospital staff including doctors, nurses and other categories should be trained and assigned appropriate duties in case of an outbreak. It is essential conduct regular training for medical staff based on the current guidelines on clinical management of dengue fever and dengue haemorrhagic fever. Following essential medicines, supplies, equipment and services should be available in the hospitals providing in-ward care for patients with dengue haemorrhagic fever: Medicines:? More complicated patients will need blood sugar, liver function tests, renal function tests, serum electrolytes (including serum calcium), blood gases, coagulation assays, chest x-rays & ultrasonography. Thrombocytopenia and Platelet Transfusion in Dengue Haemorrhagic Fever and Dengue Shock Syndrome. Clinical Practice Guidelines on Management of Dengue infection in Adults (Revised 2nd Edition), Ministry of Health, Malaysia, 2010. Comprehensive guidelines for prevention and control of dengue and dengue haemorrhagic fever. Guidelines on Clinical Management of Dengue Fever / Dengue Haemorrhagic Fever, Epidemiology Unit, Ministry of Health, 2005. Guidelines on Management of Dengue Fever / Dengue Haemorrhagic Fever, Epidemiology Unit Ministry of Health, Sri Lanka, 2010. However, the association was inconclusive due the variation association between obesity and dengue severity in the results of earlier studies. Therefore, we conducted a systematic review and meta among pediatric patients: A systematic review and meta-analysis. At least two authors independently conducted the literature search, selecting eligible studies, and Accepted: January 23, 2018 extracting data. This is an open access article distributed under the terms of the Creative Commons Attribution License, which Findings permits unrestricted use, distribution, and We obtained a total of 13,333 articles from the searches. For the final analysis, we reproduction in any medium, provided the original author and source are credited. Three cohort studies, two case control studies, and one cross-sectional study found an association between obesity and Data Availability Statement: All relevant data are within the paper and its Supporting Information dengue severity. Our meta-analysis revealed Funding: this study was supported by the that there was 38 percent higher odds (Odds Ratio = 1. This review found that obesity is a risk factor for dengue severity among children. The result Competing interests: the authors have declared highlights and improves our understanding that obesity might influence the severity of den that no competing interests exist. Author summary Dengue fever, an Aedes mosquito-borne viral infection, is a self-limiting or asymptomatic viral infection. In its severe form, severe dengue, the symptoms include organ failure, life threatening bleeding, and shock. Patients with obesity were found be at higher risks of developing complications and severe dengue infection compared non-obese patients. Our systematic review and meta-analysis critically compared the available shreds of evi dence related obesity and severe forms of dengue infection. A total of fifteen studies that include nine cohort studies, five case-control studies, and one cross-sectional study were reviewed explore the association between obesity and dengue severity. The results indicated that obese patients have higher odds of developing severe dengue infection com pared non-obese patients. This review highlighted the importance of obesity in the pro gression of dengue infection.

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It should be emphasized that, date, there is no evidence that a vaccine recipient who has received a candidate vaccine has subsequently succumbed severe disease. Rather, vaccine recipients have shown evidence of immunity for varying lengths of time. Nonetheless, the risk of immune enhancement by a candidate vaccine must be evaluated through prolonged follow-up of vaccinated cohorts. Phase 4, or post-marketing, trials will be particularly important for dengue for the same reason. Likewise, long term evaluation of volunteers will be required demonstrate lack of evidence for immune enhancement/severe disease. Trials need take place in multiple countries particularly in both Asia and the Americas due the distinct epidemiological characteristics and the viruses circulating in each region. The greatest burden of disease is found in distinct age groups in different countries, and the methodology of capturing clinical events may differ by age group and between countries. The epidemic peak 140 varies somewhat in timing and exact location from year year even in endemic countries; thus, long-term dengue surveillance data about the potential vaccine testing Chapter 6. New avenues site(s) is crucial and, even so, the unpredictability of timing and location adds a level of complexity calculations of trial sample size. Depending on cost-effectiveness and the outcome of fnancial and operational analysis, countries may decide introduce dengue vaccines into the national immunization programmes for routine administration. If the vaccine is be used for infants, the dengue vaccination will need be carried out on a schedule compatible with other vaccines. Interference between dengue vaccine and other vaccines likely be given in the same time period must be ruled out. If the vaccine is be delivered older age groups, proper contact points will need be established deliver the vaccine effectively and ensure post-marketing surveillance. In addition, vaccine presentation, packaging and stability requirements should be compatible with large-scale use. To maximize the effect of vaccination, the potential impact of a vaccine on dengue transmission needs be studied. A number of modelling approaches are being taken address this and other similar issues, as well as the characteristics of the mosquito population transmitting the virus and climatographic parameters. This observation suggests that progress serious dengue disease and adverse morbidity may be reversed by 141 administering potent and safe small molecule compounds that target essential steps in Dengue: Guidelines for diagnosis, treatment, prevention and control virus replication early during the disease, thereby lowering the viral load substantially. This hypothesis requires feld-testing when a suitable anti-dengue agent is discovered. The importance of targets such as the viral protease and polymerase have been studied by reverse genetics using infectious clones validate them as targets for drug discovery. The feld is also benefting from new insights afforded by x-ray crystallography and cryo-electron microscopy data. In the past fve years alone, seven new 3-D structures of dengue proteins have been solved and nine structures of other favivirus proteins have become available. Based on these, a number of in silico and high through-put screens have been and are being undertaken, yielding several lead compounds so far (19). They include the proprietary libraries of pharmaceutical and biotechnology companies, focused libraries of compounds synthesized specifc targets. Distinct classes of inhibitors are being explored, such as substrate and transition-state-based as well as non substrate-based inhibitors. Early preclinical in vivo testing can be conducted in certain mouse models of dengue infection. Initial studies of such compounds in mice against the related West Nile virus have been reported (29). In addition, cellular targets are under consideration, as is the idea of incorporating multiple targets in one formulation so as delay the possible development of resistance. As more is understood about the mechanism of severe dengue 142 disease, animal models that reproduce specifc manifestations may be useful for testing anti-dengue drugs. It can also reproduce antibody-dependent enhancement of infection and disease (17) and is currently being used test compounds that target disease phenotypes such as vascular leak. The minimal target product profle includes oral route of administration, frequency of dosing of once per day, stability in the face of heat and humidity, a long shelf-life, and low/reasonable cost of goods and ease of formulation allow a reasonably priced product (18).

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