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Two simple tests could help to pinpoint cause of stroke

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CCBS researchers suggest that detecting the cause of the deadliest form of stroke could be improved by a simple blood test added alongside a routine brain scan.
CCBS researchers Dr Mark Rodrigues, Professor Rustam Al-Shahi Salman and colleagues have published  findings suggesting that a genetic test for APOE combined with a CT scan could be used to detect stroke caused by intracerebral haemorrhage (ICH).
ICH accounts for up to 50 per cent of all strokes worldwide. Around half of those affected die within one year.
ICH can be caused by a condition called cerebral amyloid angiopathy (CAA). CAA is caused by a build-up of a protein known as amyloid in the walls of blood vessels in the brain. It is linked to a higher risk of further strokes and dementia.
The researchers used computed tomography (CT) scans in more than 100 patients who died following their first ICH. They collected blood samples to test the APOE gene, which is linked to CAA.
By combining simple CT scan images with a genetic blood test, researchers could accurately spot if an ICH had been caused by CAA.
Combining the test with a brain scan could provide key genetic information that may help identify those most at risk from a second stroke.
This new approach could help identify people who are at higher risk after their ICH, revolutionising the way doctors manage this type of stroke.
It could also improve ICH diagnosis in developing countries, as CT scanning and blood testing are available worldwide.
Identifying the cause of a brain haemorrhage is important to planning patient care. Our findings suggest that the combination of routine CT scanning with APOE gene testing can identify those whose ICH has been caused by CAA – a group who may be more at risk of another ICH or dementia.
University of Edinburghwww.ed.ac.uk/clinical-brain-sciences/news/news-jan-jun-2018/simple-tests-detect-cause-ich
 

Smartphone app keeps an ‘eye’ on daily tuberculosis therapy

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Johns Hopkins researchers report success with a smart phone video-based app that substitutes for a daily in-person visit by a health care worker required for tuberculosis treatment known as directly observed therapy, or DOT. The preliminary study showed that the app may be less costly and may improve privacy concerns raised by patients compared to in-person visits.
“We believe video DOT offers an alternative that appears to be as effective as an in-person daily visits by health care workers to assure compliance with drug treatment, but also empowers patients to manage their TB without added stress,” says Samuel Holzman, M.D., a research fellow in the department of infectious diseases at the Johns Hopkins University School of Medicine.
Tuberculosis is one of the few diseases in the U.S. with state and federal provisions outlining recommended and sometimes required measures to ensure that patients adhere to treatment. These recommendations include provisions for home or hospital based isolation or occasionally forced isolation for infectious individuals. Treatment for tuberculosis is effective and benefits not only the patient, but also the public by reducing the chances of ongoing transmission.
The reason for these mandates, says Holzman, is the disease’s virulence. Unlike the flu or the common cold, Mycobacterium tuberculosis, the bacteria that causes infectious tuberculosis, can hang in the air for extended periods when expelled by the coughs or saliva of patients, spreading to others across a room or through a building’s ventilation. Many people with active TB also have relatively few symptoms, allowing the bacteria to spread before a diagnosis is made.
Tuberculosis is typically treated for six months with a battery of daily antibiotics that include a multidrug combination that can be challenging patients to take. The number of side-effects related to the drugs and the motivation needed to continue the long treatment courses can cause patients to stop their treatment early without appropriate monitoring and strong support. Treatments become even more intensive when caring for multidrug or extensively drug-resistant TB, which require additional antibiotics and can take up to two years to bring under control.
 As such, most local health departments in the U.S. require that health care workers observe patients taking their medications to document that they were taken correctly and to monitor for side-effects. In most cases, in-person DOT is conducted five days a week on weekdays and is therefore costly and resource-intensive for local departments of health who absorb the costs associated with treatment.
Nonetheless, this practice helps to support patients through the difficult regimen and provides clinicians a means of tracking a patient’s progress and in-person DOT is the standard of care for TB treatment in the US and globally.  However, DOT has the potential to be logistically challenging for patients and is viewed by some patients as stigmatizing or interfering with their autonomy and privacy.
“In an era when we are focused on patient centred care, having to meet a health provider every single day is logistically challenging and can be personally invasive,” says Maunank Shah, M.D., Associate Professor of Medicine in the Department of Infectious Diseases at the Johns Hopkins University School of Medicine.
To test the effectiveness of video DOT, the researchers conducted a pilot study utilizing the widely-available smartphone application developed by emocha Mobile Health in conjunction with Shah and other clinician-scientists at the Johns Hopkins University School of Medicine.
28 adult TB patients being treated at three health departments in Maryland participated in the pilot study.  These patients had their therapy monitored using the emocha video DOT application in lieu of in-person visits by a health care worker.
The researchers found that patient adherence to treatment was approximately the same between the video DOT and in-person DOT, 94 percent and 98 percent respectively.  As importantly, when including weekends and holidays in the assessment of adherence, the researchers found that the overall proportion of prescribed doses that were verified through observation was 6 percent higher with video DOT compared to in-person DOT.
The researchers also sought to assess the app’s acceptability to patients and clinicians by conducting qualitative interviews and surveys. Ten patients and sixteen staff were interviewed and/or completed surveys after the study.  One hundred percent of the patients felt that the emocha platform was ‘easy to use’ and preferred it over in-person DOT. Staff were largely in agreement with these results and 94 percent reported they believed that video DOT was ‘effective for monitoring patient adherence’.  The researchers also reported several common themes during in depth interviews that focused on the added convenience and increased flexibility of using video DOT. Another prominent theme was the impression that in-person DOT could risk patient privacy.

John Hopkins Universitywww.hopkinsmedicine.org/news/media/releases/smartphone_app_keeps_an_eye_on_daily_tuberculosis_therapy

Paradigm shift in the diagnosis of diabetes

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A completely new classification of diabetes that also predicts the risk of serious complications and provides treatment suggestions. The Swedes are now seeing the first results of ANDIS – a study covering all newly diagnosed diabetics in southern Sweden.
The major difference from today’s classification is that type 2 diabetes actually consists of several subgroups, the results indicate.
“This is the first step towards personalised treatment of diabetes”, says Leif Groop, physician and professor of diabetes and endocrinology at Lund University in Sweden.
“Current diagnostics and classification of diabetes are insufficient and unable to predict future complications or choice of treatment”, explains Professor Leif Groop, who initiated the study. He believes that the results represent a paradigm shift in how to view the disease in the future. “Today, diagnoses are performed by measuring blood sugar. A more accurate diagnosis can be made by also considering the factors accounted for in ANDIS (All New Diabetics In Skåne).”
Since 2008, the researchers have monitored 13 720 newly diagnosed patients between the ages 18 and 97. By combining measurements of, for example, insulin resistance, insulin secretion, blood sugar levels (BMI, HbA1c, GADA, HOMA-B and HOMA-IR) and age at onset of illness, the researchers were able to distinguish five distinct clusters that differ from today’s classification.
In addition to a more refined classification, the researchers also discovered that the different groups are more or less at risk of developing various secondary diseases.
“This will enable earlier treatment to prevent complications in patients who are most at risk of being affected”, says Emma Ahlqvist, associate professor and lead author of the publication.
The ANDIS classification:
Group 1, SAID (severe autoimmune diabetes): essentially corresponds to type 1 diabetes and LADA (latent autoimmune diabetes in adults), and is characterised by onset at young age, poor metabolic control, impaired insulin production and the presence of GADA antibodies.
Group 2, SIDD (severe insulin-deficient diabetes): includes individuals with high HbA1C, impaired insulin secretion and moderate insulin resistance. Group 2 had the highest incidence of retinopathy.
Group 3, SIRD (severe insulin-resistant diabetes): is characterised by obesity and severe insulin resistance. Group 3 had the highest incidence of kidney damage – the secondary disease producing the highest costs to society.
Group 4, MOD (mild obesity-related diabetes): includes obese patients who fall ill at a relatively young age.
Group 5, MARD (mild age-related diabetes): is the largest group (about 40%) and consists of the most elderly patients.
“The most insulin resistant patients (Group 3) have the most to gain from the new diagnostics as they are the ones who are currently most incorrectly treated”, says Professor Leif Groop.
The researchers subsequently repeated the analysis in a further three studies from Sweden and Finland.
“The outcome exceeded our expectations and highly corresponded with the analysis from ANDIS. The only difference was that Group 5 was larger in Finland than in Skåne. The disease progression was remarkably similar in both groups”, says Leif Groop.
Lund University Diabetes Centrewww.ludc.lu.se/article/paradigm-shift-in-the-diagnosis-of-diabetes

Technique identifies lung nodules for resections in patient with osteosarcoma

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In a proof-of-principle case report, researchers announce that targeted fluorescence successfully identified pulmonary metastases in a patient with osteosarcoma, making it easier for surgeons to locate the tumours for resection.
The case study  by Jarrod Predina, Andrew Newton, Charuhas Deshpande, and Sunil Singhal of The Perelman School of Medicine at the University of Pennsylvania, and Philip Low of Purdue University, is notable for its impact on osteosarcoma resection, according to editor-in-chief, Brian Pogue.  
Osteosarcomas express a number of unique molecular markers, including the folate receptor alpha (FRα). This study utilized a near-infrared contrast agent known as OTL38, which binds to pulmonary metastases expressing FRα, and emits in the NIR range.  
In this study, the fluorescence emitted from the contrast agent allowed surgeons to locate both a known lung nodule and a small occult metastases-less than a half a centimetre-that was not visible in preoperative imaging, suggesting that this approach may enable the detection of small or hard-to-locate nodules during minimally invasive resection.  
The drug was safely delivered and no toxicity was observed, the authors reported. Both nodules were successfully resected using real-time fluorescence feedback.  
The authors report that this technique may enhance the surgeon’s ability to perform a variety of oncologic procedures including tumour localization, margin assessment, and intraoperative staging.   "The authors were able to examine the spatial heterogeneity of the folate-dye uptake and show that even though there is a complex uptake pattern, the shapes were representative of the underlying pathology distribution, and therefore provide a reasonable molecular tag for resection margins," said Brian Pogue.  
Initial reports indicate that more than 90% of primary lung cancers accumulate OTL38 and generate tumour fluorescence during minimally invasive pulmonary resection, suggesting that this technique may have application beyond pulmonary osteosarcoma. Future research will explore if this approach could be applicable to other pulmonary malignancies that express the FRα.  
SPIEspie.org/about-spie/press-room/press-releases/molecular-imaging-technique-successfully-identifies-lung-nodules-for-resection-in-patient-with-osteosarcoma

New cardiac catheter combines light and ultrasound to measure plaques

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To win the battle against heart disease, cardiologists need better ways to identify the composition of plaque most likely to rupture and cause a heart attack. Angiography allows them to examine blood vessels for constricted regions by injecting them with a contrast agent before X-raying them. But because plaque does not always result in constricted vessels, angiography can miss dangerous buildups of plaque. Intravascular ultrasound can penetrate the buildup to identify depth, but lacks the ability to identify some of the finer details about risk of plaque rupture.
This new catheter probe combines intravascular ultrasound (IVUS) with fluorescence lifetime imaging (FLIm) to image the tiny arteries of a living heart.
Professor Laura Marcu’s lab in the Department of Biomedical Engineering at UC Davis has now combined intravascular ultrasound with fluorescence lifetime imaging (FLIm) in a single catheter probe that can image the tiny arteries of a living heart. The new catheter can simultaneously retrieve structural and biochemical information about arterial plaque that could more reliably predict heart attacks.
An optical fibre in the catheter sends short laser pulses into surrounding tissue, which fluoresces with tiny flashes of light in return. Different kinds of tissue (collagen, proteins, lipids) emit different amounts of fluorescence.
At the same time, an ultrasound probe in the catheter records structural information about the blood vessel.
The combination FLIm-IVUS imaging catheter provides a comprehensive insight into how atherosclerotic plaque forms, aiding diagnosis and providing a way to measure how plaques shrink in response to therapy.
The new catheter has been tested in living swine hearts and samples of human coronary arteries.
The catheter used in the study is flexible enough to access coronary arteries in a living human following standard procedures. It does not require any injected fluorescent tracers or any special modification of the catheterization procedures.
The new technique could not only improve understanding of mechanisms behind plaque rupture – an event with fatal consequences- but also the diagnosis and treatment of patients with heart disease.
Marcu’s group is currently working to obtain FDA approval to test this new intravascular technology on human patients.

UC Davishttps://tinyurl.com/y7we7uva

Telemedicine provides accurate diagnosis of rare cause of blindness in preemies

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Accurately detecting a rare but devastating cause of blindness in premature babies can be done as effectively with telemedicine as with traditional, in-person eye exams, a study suggests. This is believed to be the first study to directly compare the two approaches.
The finding could enable more blindness-preventing treatment for infants born in rural and other areas where there are few ophthalmologists trained to detect the condition, called retinopathy of prematurity, or ROP. Musician Stevie Wonder went blind due to this condition.
“A lack of access to trained ophthalmologists with experience diagnosing ROP sadly prevents many premature infants from receiving much-needed screening, both in developed and developing countries,” said the study’s lead researcher, Michael F. Chiang, M.D., a professor of ophthalmology and medical informatics & clinical epidemiology in the OHSU School of Medicine and a paediatric ophthalmologist at OHSU’s Elks Children’s Eye Clinic.
Retinopathy of prematurity is caused by abnormal blood vessel growth near the retina, the light-sensitive portion in the back of an eye.
Some U.S. medical associations recommend an in-person exam, which involves a special magnifying device that shines light into a baby’s dilated eye, to diagnose the condition. But trained professionals aren’t always easy to find in rural areas and developing countries.
The research team compared the accuracy of in-person exams with digital eye images that were remotely evaluated by professionals. They partnered with seven medical institutions to examine the eyes of 281 infants who were at risk for the condition. Each eye was evaluated both in-person and remotely with a wide-angle telemedicine image.
The researchers found there was no difference in the overall accuracy between the two evaluation methods. In-person examiners were found to be slightly better at accurately diagnosing the condition’s later-stage development, but the research team concluded telemedicine could be used to diagnose clinically significant cases of retinopathy of prematurity.
OHSU School of Medicinenews.ohsu.edu/2018/04/06/telemedicine-provides-accurate-diagnosis-of-rare-cause-of-blindness-in-preemies

3D Mammography costs less than digital mammography

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Although digital breast tomosynthesis (DBT), or 3-D mammography, costs more than a digital mammography (DM) screening, it actually may help rein in cancer screening costs, according to preliminary findings (PD7-05) presented by researchers from the Perelman School of Medicine. The group analysed 46,483 screening episodes – a single screening mammogram and all subsequent breast diagnosis related costs for the following year – in two hospitals within the University of Pennsylvania Health System in 2012 and 2013.
“Early detection is critical to saving lives and lowering costs,” said senior author Emily F. Conant, MD, chief of Breast Imaging at Penn Medicine. “Fortunately, breast imaging is more precise than ever thanks to DBT. Despite its higher initial cost, DBT is increasingly being embraced by radiologists nationwide. If you look at expenses associated with breast diagnosis in the following year after initial screening, DBT is more cost effective in terms of health system or population level screening.”
Previous studies modelling outcomes have demonstrated that DBT can be cost effective. In this study, the authors analysed actual costs and patient outcomes within a single health system where both DM and DBT screening occurred. They excluded any episodes in which the patient had a prior breast cancer diagnosis or reached 90 years of age before the end of the follow-up period. DM represented 53 percent of the episodes and DBT represented 47 percent. Fifty three percent of women studied received DM and 47 percent received DBT.
They tested DBT and DM according to four outcomes – true positive (TP), true negative (TN), false positive (FP), and false negative (FN) rates – by comparing the Breast Imaging Reporting and Data System (BI-RADS) score (assigned at screening with data about subsequent cancer diagnosis).
DBT was a more effective screening method. Compared to DM episodes, DBT episodes had lower FP (8.6% vs. 10.8%) and higher TN (90.9% vs. 88.7%, p<0.001) rates. (There were no statistically significant differences between DBT and DM episodes with respect to TP and FN rates.)
Although it screened more effectively, DBT did cost more than DM. Overall, average episode costs were higher for DBT compared to DM ($378.02 vs. $286.62). This difference was driven by higher average screening costs ($215.94 vs. $155.76), which approximated the additional charge for DBT, as well as follow-up costs ($23.67 vs. $12.11). There was no significant difference in costs between DBT and DM episodes within the diagnosis or cancer treatment windows.
DM and DBT episodes had roughly the same average episode costs per woman screened for FP ($67.75 vs. $65.71), FN ($4.63 vs. $5.60) and TP ($85.80 vs. $65.15) outcomes despite the higher cost per individual DBT study. The higher costs for TN ($219.84 vs. $150.16) outcomes approximated the higher CMS (Centers for Medicam and Medicinal Services) charge for DBT.
Penn Medicinehttps://tinyurl.com/y7nemu7g

Molecular basis for increased cardiovascular disease in older women

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Researchers have discovered the molecular basis for the increased incidence of cardiovascular diseases in older women. The study found that older women had mitochondrial dysfunction, reduced antioxidant proteins, and increased inflammation.
Previous studies have shown sex differences in the age at which cardiovascular diseases occur. Ischemic heart disease, for example, develops on average seven to ten years later in women compared with men. It occurs three to four times more often in men than in women below the age of 60 years, but after the age of 75, most patients are women.
It is not clear why many women are protected from cardiovascular disease at a young age but are more susceptible after menopause. Estrogen levels may play a role but the mechanism is unknown. This study looked at molecular changes in the cells of the heart that happen with ageing, and how they differ between men and women.
Specifically, the researchers looked at healthy hearts to see if there are sex differences in mitochondrial function and inflammation during ageing. Heart tissue was obtained from seven women and seven men aged 17 to 40 years, and from eight women and nine men aged 50 to 68 years. The researchers measured levels of proteins involved in inflammation and in the function of the mitochondria.
The researchers found that the levels of Sirt1, a protein that is important for the function of the mitochondria, are higher in young women compared to young men. In the older hearts, Sirt1 levels had decreased in women but not in men. Expression of superoxide dismutase 2, an antioxidant protein in the mitochondria, was higher in young females than males but the difference was no longer present with age.
In addition, the expression of catalase, an enzyme that protects cells from oxidative damage, was higher in young females than males but again the difference was lost with age.
With age, female hearts shifted from an anti-inflammatory to a pro-inflammatory environment. Compared to young men, young women had higher levels of anti-inflammatory cytokines such as interleukin 10 – but this difference was lost with age. Levels of macrophages, which promote inflammation, increased with age in women but not in men.
Dr Maria Luisa Barcena De Arellano, scientific researcher, Institute of Gender Medicine, Charité University Medicine Berlin, Germany, said: “Our study provides a molecular explanation for the increased incidence of cardiovascular diseases in older women.”

European Society of Cardiology
https://tinyurl.com/y8zah7gn

Study casts doubt on ketamine nasal sprays for depression

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Researchers from the Black Dog Institute and UNSW Sydney have questioned the efficacy and safety of intranasal ketamine for depression, with their pilot trial stopped early due to poor side effects in patients.
Nasal spray devices have been touted as a promising way to deliver ketamine to patients with treatment-resistant depression, with this application easier to use and less invasive than other clinical delivery methods such as injections.
Yet contrary to previous trials, this latest study reveals the unpredictable nature of intranasal ketamine tolerance from one person to the next.
“It’s clear that the intranasal method of ketamine delivery is not as simple as it first seemed,” said lead author UNSW Professor Colleen Loo, who is based at Black Dog Institute.
“Many factors are at play when it comes to nasal spray ketamine treatments. Absorption will vary between people and can fluctuate on any given day within an individual based on such things as mucous levels in the nose and the specific application technique used.”
The pilot trial aimed to test the feasibility of repeated doses of ketamine through an intranasal device amongst 10 participants with severe depression, ahead of a larger randomised controlled trial.
Participants were first given extensive training in proper self-administration techniques before receiving either a course of eight ketamine treatments or an active control over a period of four weeks, under supervision at the study centre.
Following initial reactions to the nasal spray, the dosage was adjusted amongst study patients to include longer time intervals between sprays.
However, the pilot study was eventually suspended after testing with five participants due to unexpected problems with tolerability. Side effects included high blood pressure, psychotic-like effects and motor incoordination that left some participants unable to continue to self-administer the spray.  
“Intranasal ketamine delivery is very potent as it bypasses metabolic pathways, and ketamine is rapidly absorbed into the bloodstream,” said Professor Loo.
“But as our findings show, this can lead to problems with high peak levels of ketamine in some people causing problematic side effects.
“Other recent studies have questioned whether changes to ketamine’s composition after being metabolised into derivative compounds may actually deliver useful therapeutic effects.
“It remains unclear whether ketamine nasal sprays can be safely relied upon as a treatment for patients with severe depression.”
University of New South Walesnewsroom.unsw.edu.au/news/health/study-casts-doubt-ketamine-nasal-sprays-depression

New antifungal provides hope in fight against superbugs

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Microscopic yeast have been wreaking havoc in hospitals around the world—creeping into catheters, ventilator tubes, and IV lines—and causing deadly invasive infection. One culprit species, Candida auris, is resistant to many antifungals, meaning once a person is infected, there are limited treatment options. But in a recent Antimicrobial Agents and Chemotherapy study, researchers confirmed a new drug compound kills drug-resistant C. auris, both in the laboratory and in a mouse model that mimics human infection.
APX001, the prodrug of the active moiety APX001A, is currently in clinical development by Amplyx Pharmaceuticals. It works through a novel mechanism of action. Unlike other antifungal agents that poke holes in yeast cell membranes or inhibit sterol synthesis, the new drug targets an enzyme called Gwt1, which is required for anchoring critical proteins to the fungal cell wall. This means C. auris can’t grow properly and has a harder time forming drug-resistant fungal biofilms that are a stubborn source of hospital outbreaks. Gwt1 is highly conserved across fungal species, suggesting the new drug could treat a broad range of fungal infections.
“The drug is first in a new class of antifungals, which could help stave off drug resistance. Even the most troublesome strains are unlikely to have developed workarounds for its mechanism of action,” said study lead Mahmoud A. Ghannoum, PhD, professor of dermatology at Case Western Reserve University School of Medicine and director of the Center for Medical Mycology at Case Western Reserve University and University Hospitals Cleveland Medical Center.
In the new study, Ghannoum’s team tested the drug against 16 different C. auris strains, collected from infected patients in Germany, Japan, South Korea, and India. When they exposed the isolates to the new drug, they found it more potent than nine other currently available antifungals. According to the authors, the concentration of study drug needed to kill C. auris growing in laboratory dishes was “eight-fold lower than the next most active drug, anidulafungin, and more than 30-fold lower than all other compounds tested.”
The researchers also developed a new mouse model of invasive C. auris infection for the study. Said Ghannoum, “To help the discovery of effective drugs it will be necessary to have an animal model that mimics this infection. Our work helps this process in two ways: first we developed the needed animal model that mimics the infection caused by this devastating yeast, and second, we used the developed model to show the drug is effective in treating this infection.”
Ghannoum studied immunocompromised mice infected with C. auris via their tail vein—similar to very sick humans in hospitals who experience bloodstream infections. Infected mice treated with APX001 and anidulafungin had significant reductions in kidney and lung fungal burden two days post-treatment, compared to control animals. APX001 also significantly decreased fungal burden in the brain, consistent with brain penetration, whereas reduction with anidulafungin did not reach significance. The results suggest the new drug could help treat even the most invasive infections.
According to Ghannoum, the most exciting element of the study is that it brings a promising antifungal one step closer to patients. It helps lay the foundation for phase 2 clinical trials that study that study the safety and efficacy of new drugs in patients with fungal infections. There is an urgent need for such studies, as C. auris infection has become a serious threat to healthcare facilities worldwide—and resistance to commercially available antifungal drugs is rising.
Case Western Reserve University Medical Schoolcasemed.case.edu/cwrumed360/news-releases/release.cfm?news_id=906&news_category=8

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