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A team of researchers from Nanyang Technological University, Singapore (NTU Singapore), Ngee Ann Polytechnic, Singapore (NP), and the National Heart Centre Singapore (NHCS) have invented a tool that could speed up the diagnosis of cardiovascular diseases.

Powered by artificial intelligence (AI), their innovation uses electrocardiograms (ECGs) to diagnose coronary artery disease, myocardial infarction and congestive heart failure to an accuracy of more than 98.5 per cent.

The joint development of the diagnostic tool is timely, as the number of deaths caused by cardiovascular disease in Singapore has increased over the past three years. According to the Singapore Heart Foundation, 29.3 per cent of all deaths in Singapore in 2019, or almost 1 out of 3 deaths in Singapore, was due to heart diseases or stroke.

The scientists hope that their innovation could support the diagnosis of cardiovascular diseases in clinical settings, specifically while physicians carry out preliminary ECGs, ultimately leading to speedier courses of treatment.

The researchers devised the diagnostic tool by using an AI machine learning algorithm called Gabor-Convolutional Neural Network (Gabor-CNN), which mimics the structure and function of the human brain, enabling computers to learn from past experiences like a human. Using the algorithm, they trained their tool to recognise patterns in patients' ECGs by inputting examples of ECG signals that reflect cardiovascular diseases.

Clinical Associate Professor Tan Ru San, Senior Consultant at the Department of Cardiology, NHCS, who co-authored the study, said: "Our study on a preliminary small group of subjects has demonstrated promising results in terms of the accuracy of using routine ECGs to classify some common cardiovascular conditions. Although confirming the specific disease still requires additional testing, our diagnostic tool will allow physicians to triage patients more efficiently and to streamline the number and type of downstream confirmatory tests."

Associate Professor Eddie Ng Yin Kwee from NTU's School of Mechanical and Aerospace Engineering, who co-led the study, said: "Scientists and physicians have been exploring AI techniques to aid in disease diagnosis. Our diagnostic tool is the first to use GaborCNN to allow for ECG signals to be directly entered into the system for analysis, and could lead to advancements in the pursuit of merging AI with medical solutions. Our proposed system is equipped to be validated with bigger database and has the potential to aid the clinicians to screen for cardiovascular diseases using ECGs."

Dr U Rajendra Acharya, Senior Faculty Member from Ngee Ann Polytechnic's School of Engineering said: "Our AI diagnostic tool, which was developed using a small public database, can detect coronary artery disease, myocardial infarction and congestive heart failure using ECG signals accurately. It has the potential to aid clinicians in the screening of cardiovascular diseases quickly, speed up the delivery of treatment and reduce costs for patients."

The study was published in the peer-reviewed scientific journal Computers in Biology and Medicine in May.

Using AI to aid in detecting heart disease

To test their diagnostic tool, the researchers obtained ECG signals from both healthy individuals and patients with prevalent cardiovascular diseases.

In a pilot study, the researchers used the tool to analyse ECG signals from 92 healthy individuals, as well as seven patients with coronary artery disease, 148 patients with myocardial infarction and 15 patients with congestive heart failure.

Clin Assoc Prof Tan added: "Our AI-enhanced tool could automatically identify ECG signals associated with healthy people and patients with the different cardiovascular diseases with an accuracy of more than 98.5 per cent. Heart disease is a leading cause of death worldwide, and affects not only the heart but other major parts of the body. Early detection prevents complications such as heart failure, stroke, kidney disease and artery disease."

Elaborating on the role of AI in disease detection, Assoc Prof Ng added: "AI techniques have the potential to radically improve healthcare solutions, especially in data analysis, offering clinicians novel tools to interpret data and make clinical decisions. AI techniques such as machine learning and deep learning can also improve medical knowledge due to the increase of the volume and complexity of the data, unlocking clinically relevant information."

The team will be working with local hospitals to conduct further trials to validate the clinical use of their new diagnostic AI tool with a larger database of patients. They hope it can be used to complement current techniques of diagnosing cardiovascular diseases such as magnetic resonance imaging (MRI) and coronary angiography.

Osteoporosis is a condition that does not exhibit symptoms until there is a bone fracture, so it is said that there is a high percentage of people who remain unaware of their condition. When people are unaware their bones have weakened, the condition is left untreated, and the recent rise of the elderly population has caused an increase in bone fractures. This has a large societal impact, such as overwhelming medical costs and long-term care. Simple screenings at resident health exams are one way for an increase in osteoporosis detecting without having to go to the hospital. When suspected osteoporosis and osteopenia is properly detected and patients are encouraged to get further evaluation at the hospital, it can receive appropriate treatment. This study developed a novel method to detect untreated osteoporosis through a low-cost, physical function test during a routine health checkup.

Osteoporosis is under-diagnosed and when left untreated, it can lead to serious fractures that can reduce mobility, living function, and is directly linked to life expectancy. With proper treatment, people are more likely to avoid serious fractures. Doctors and physical therapists at Shinshu University Hospital developed a method to detect possible osteoporosis before going to the hospital. If this detection determines that a patient is likely to have osteoporosis, patients will then be encouraged to have a bone-density test at the hospital.

This study was conducted by a random sampling of the Resident Register. Results are expected to be closer to the actual demographic of the general population than surveys targeting hospital patients and specific volunteers. The osteoporosis detection method used the combination of BMI and a two-step test which is performed by taking two maximum-stride steps and calculating the distance in centimeters divided by the body height in centimeters. This showed a high osteoporosis detection capability that even FOSTA could not achieve, despite the cost of the test being close to zero. The study which targeted postmenopausal women who are at high risk for primary osteoporosis found that if any of the following is true, TST

The epidemiological survey "Obuse Study" is a large cohort study, and the second screening will continue. The ultimate goal, says the corresponding author, Dr. Shota Ikegami is "to present a new model for realizing a healthy society in a super-aged society while conducting a comprehensive health evaluation, not limited to osteoporosis, centered on locomotor examinations and sharing this finding with the world."

Below please find link(s) to new coronavirus-related content published today in Annals of Internal Medicine. All coronavirus-related content published in Annals of Internal Medicine is free to the public. A complete collection is available at https://annals.org/aim/pages/coronavirus-content.

Experts offer suggestions for curtailing emerging "black fungus" syndemic in India
Free full text: https://www.acpjournals.org/doi/10.7326/M21-2354

Experts suggest limited and careful use of corticosteroids as one of several strategies to curtail the syndemic of mucormycosis, or "black fungus," a fungal infection characterized by blackening or discoloration over the face, breathing difficulties, and other serious symptoms, that has recently emerged in India. A commentary from Washington University School of Medicine and the University of Massachusetts Medical School is published in Annals of Internal Medicine.

Having diabetes and other conditions that compromise the immune system puts patients at increased risk for mucormycois, as does receipt of immunosuppressive chemotherapy including corticosteroids. Mortality is high, especially if diagnosis and prompt initiation of medical and surgical therapy are delayed. Currently, India has more than 65 million adults with diabetes and is experiencing a second wave of COVID-19 with 28.2 million cases reported. In the midst of this crisis, a "syndemic" of rhino-orbito-cerebral mucormycosis infections has arisen, with nearly 9,000 cases reported.

The commentary authors recommend several strategies for preventing and managing this syndemic of mucormycosis. Nonpharmacological measures, such as masking policies and social distancing, should be taken to reduce risk for transmission of SARSCoV-2 and widespread vaccination should be implemented, as soon as possible. For those infected with SARS-CoV-2, preventing mucormycosis is crucial. This means avoiding exposure to the fungi that cause mucormycosis and limiting the use of corticosteroids and antibiotics, which have been overused in India, thus far. Glucocorticoids have no benefit in patients who do not require respiratory support, as they predispose them to mucormycosis and increase blood glucose levels in persons with prediabetes and diabetes, prevalent conditions in India. As such, the authors suggest that stronger restrictions on over-the-counter sales of systemic corticosteroids and antibiotics should also be considered. Those issued for hydroxychloroquine in March 2020 contributed to reduced hydroxychloroquine sales during the first wave of the pandemic.

A minimally-invasive procedure that targets the nerves near the kidney has been found to significantly reduce blood pressure in hypertension patients, according to the results of a global multicentre clinical trial led in the UK by researchers at Queen Mary University of London and Barts Health NHS Trust.

The study, published in The Lancet and presented at the American College of Cardiology meeting, suggests that the procedure could offer hope to patients with high blood pressure who do not respond to recommended treatments (resistant hypertension), and are at greatly increased risk of cardiovascular diseases, including stroke and heart attack.

The international clinical trial tested a one-hour procedure called 'renal denervation', which uses ultrasound energy to disrupt the nerves between the kidneys and the brain that carry signals for controlling blood pressure.

The study investigated 136 patients who were randomised to receive either renal denervation or a 'sham procedure' - the surgical equivalent of a placebo. The UK trial site at St Bartholomew's Hospital was the largest patient recruiter in the world, with patients also taking part in the United States, France, Germany, the Netherlands and Belgium

The trial showed that renal denervation led to a significant and safe blood pressure lowering effect after two months in patients who were on at least three different blood pressure lowering medications. It was found to reduce blood pressure by 8.0 mmHg, which was a 4.5 mmHg greater drop when compared with patients who had the sham procedure.

Additionally, there were no safety concerns in either the renal denervation or sham groups.

UK Principal Investigator Professor Melvin Lobo from Queen Mary University of London and Barts Health NHS Trust said: "This is probably one of the most important studies in the field of hypertension emerging in the pandemic era. It is conceivable that renal denervation could become a treatment option for patients with hypertension in the very near future and the National Institute for Health and Care Excellence (NICE) will be re-evaluating the technology based upon the recent datasets in the coming months."

Dr Manish Saxena from Queen Mary University of London and Barts Health NHS Trust said, who ran the study at St Bartholomew's Hospital, added: "Resistant hypertension patients often suffer from organ damage, including damage to the heart, eyes and kidneys, have poor quality of life and are at a higher risk of cardiovascular events and death.

"Many high risk patients have to manage multiple prescription medications, which can be difficult to adhere to and poses a significant challenge to our health care system and resources.

"Finding other ways to reduce blood pressure in these difficult-to-treat patients, such as renal denervation, will lower their cardiovascular risk, reduce their medication load, improve their quality of life and ultimately lead to cost savings for the NHS."

49 year old Raenard Gonzalez from Surrey received the procedure as part of the trial. He said: "I've been on blood pressure tablets for around 19 years, and for the last nine years, I've had to take five different tablets every day. It's been so difficult to manage, and the dosage was constantly increased by my consultant. I felt lethargic and it was hard to maintain a healthy weight, as I just had to keep eating to combat the tiredness and keep myself awake. I knew something wasn't right, but there didn't seem to be any other options for me.

"I heard about the trial and felt I had nothing to lose really. It was all quite straightforward, the procedure wasn't that invasive and just involved puncturing the skin, and I was able to go home that day, and didn't feel much pain.

"Since the procedure, I've managed to control my weight, and have so much more energy and motivation. My blood pressure used to stay high after any physical activity, but now, it doesn't matter how much I exert myself, my blood pressure always goes back down, which is great.

"All the medications that I took before the trial have been scrapped and I'm now just taking one triple combination pill. I'm really happy that this treatment may soon be available to other people."

An international coalition of eye researchers used machine learning to develop classification criteria for 25 of the most common types of uveitis, a collection of over 30 diseases characterized by inflammation inside the eye. Together, these diseases are the fifth leading cause of blindness in the United States. The Standardization of Uveitis Nomenclature (SUN) Working Group, funded by the National Eye Institute (NEI), published its classification criteria in the American Journal of Ophthalmology. NEI is part of the National Institutes of Health.

"In the past, clinical research in the field of uveitis has been hampered by the lack of widely-accepted and validated diagnostic criteria," said Douglas A. Jabs, M.D., M.B.A., the SUN project leader and professor of epidemiology and ophthalmology, Johns Hopkins Bloomberg School of Public Health, Baltimore. "These classification criteria are a major step forward for epidemiological studies, translational studies, pathogenesis research, outcomes research, and clinical trials. They hopefully will yield better disease-specific approaches to diagnosis and treatment."

In uveitis, inflammation can be seen in the anterior chamber (anterior uveitis), vitreous (intermediate uveitis), choroid, or retina (posterior uveitis), or all of these (panuveitis). Disease course, complications of uveitis, and the effect on vision vary dependent on the specific disease. Some uveitis appears abruptly and resolves. But many cases are recurrent or chronic, requiring long-term therapy. Symptoms may include floaters, vision loss, pain, and light sensitivity. Uveitis can strike at any age and can have a major impact on quality of life.

Until recently, classification of uveitis was based on the primary location of inflammation. However, types of uveitis affecting the same anatomic location can have different causes, courses, prognoses, and treatment needs. Previous work by the SUN Working Group demonstrated that even uveitis experts can disagree on diagnosis, making apples-to-apples comparisons difficult when conducting clinical research.

"The agreement among uveitis experts on the diagnosis of individual diseases was modest at best. So, we set off to try to provide clarity, using informatics, formal consensus techniques, and technology to assist in classifying each uveitic disease," said Jabs.

The SUN Working Group, a team of nearly 100 international uveitis experts from more than 20 countries and 60 clinical centers, worked together throughout the project, which was conducted in four phases: informatics, case collection, case selection, and machine learning. The researchers used machine learning, a type of artificial intelligence, to help them identify the important characteristics that distinguished each disease.

The informatics phase involved standardizing language to describe each type of uveitis and the mapping of terms to individual diseases. In the case collection phase, the team entered 5,766 cases into a database, averaging 100-250 of each uveitis type. During the case selection phase, committees of nine uveitis experts reviewed the cases and used formal consensus techniques to determine whether they were a specific identifiable disease. Only cases with a more than 75% agreement among experts were included in the final database. The resulting cases (4,046) were put through machine learning using multiple approaches on a subset of the cases ("training set") and the performance of the criteria determined on a second subset of the cases (the "validation set").

The overall performance of the criteria was over 90% within uveitic class, suggesting that the criteria can be used in clinical and translational research. The final step was approval of the proposed criteria by the SUN Working Group.

"The SUN Working Group is excited about this unprecedented effort coming to fruition and the publication of this work, as it should provide the basis for future clinical research in the field of uveitis." concluded Dr. Jabs.

Researchers at Queen Mary University of London have tested an algorithm on 700,000 patient records in east London, to find out if the data routinely collected by GPs can reveal cases of Familial Hypercholesterolemia - a leading cause of heart attack in young people.

Familial Hypercholesterolemia (FH) is a condition passed down through families that causes extremely high levels of cholesterol in the blood. Without treatment, it can lead to a heart attack at a very young age. FH affects 320,000 people in the UK, the vast majority of whom are unaware they have it.

One method of detection is the 'FAMCAT' (Familial Hypercholesterolemia Case Assertation Tool) which analyses data in GP records - including blood test results and family history - to predict who is 'likely' or 'unlikely' to have FH. The result is a long list of patients that GPs can call in for further investigation. This is the first time FAMCAT has been used on data from a large, inner-city, ethnically diverse population.

Dr John Robson, Reader in Primary Care at Queen Mary University of London, said: "There is an urgent need for better methods to detect people who might have FH. We have demonstrated the FAMCAT algorithm can be applied to whole boroughs or cities, using the data we already have in the system to help find those undiagnosed cases. But FAMCAT generates a very long list of possible candidates, and this needs to be assessed for cost-effectiveness. For every confirmed case of FH, FAMCAT found 119 likely candidates all needing investigation - first by the GP, with a detailed family history and examination, then in secondary care for genetic testing and advice.

"It is also unclear whether the algorithm performs equally well at detecting FH in different ethnic groups. We are now planning further research with east London data to investigate this."

PHILADELPHIA (June 7, 2021) - An article written almost 30 years ago helps frame social constructs around the COVID-19 pandemic. By reviewing the essay, an historian of nursing at the University of Pennsylvania School of Nursing (Penn Nursing) extends that construct to include nurses and patients, delivering a local and personal meaning to the epidemic experience.

In an essay in the Bulletin of the History of Medicine, Julie A. Fairman, PhD, RN, FAAN, Endowed Chair, the Nightingale Professor in Honor of Nursing Veterans, and Professor of Nursing at Penn Nursing, reviews Charles Rosenberg's 1992 article about the AIDS epidemic. Using Rosenberg's theme, she further develops the meaning of an epidemic from the nursing perspective.

"Even as we have experienced different kinds of infectious epidemics over the last century (Ebola, AIDS), Rosenberg's three interrelated stages still help us understand, from a sociological perspective, how society constructs the meaning of epidemics and manages policies, structures, and post-epidemic explanations," says Fairman. "Asking the question 'What is an epidemic?' from the perspective of nurses illustrates how a different cast of expert actors generate meanings that can then be part of a broader understanding of epidemics in general."

Fairman argues that the meaning of epidemics from the perspective of nurses, their patients, and their history injects a more layered approach to the question. Where Rosenberg wrote from the perspective of the history of medicine with the intent to understand the relationship between social structure, meaning and ideology, Fairman writes from the perspective of nurses and patients.

"A nursing perspective illustrates the construction of the meaning of an epidemic from the experiences of the patient and professional nurse, from the ground up rather than from the top down," writes Fairman. "It offers different questions exploring the experiences of patients, families, and practitioners, as well as their hopes, expectations, fears, and needs."

"Epidemics from the Perspective of Professional Nursing: Beyond Germs, Public Health, and Pot Banging" is available online.

The COVID-19 pandemic continues to disrupt and end lives around the world, and public health officials worldwide have recognized vaccines as the critical tools required for controlling the COVID-19 death toll and achieving a return to normal life. Several vaccines against COVID-19 are already in use, but the limited supplies of these vaccines and the possibility of safety and efficacy issues of the existing vaccines mean that it is important for scientists to develop more (and even better) vaccines. In fact, as of February 2021, 69 different vaccines are in various phases of clinical development.

One type of vaccine that could prove quite useful is the inactivated vaccine, which contains an inactivated form of the virus. The inactivated virus cannot harm the recipient, but it still serves to trigger an immune response that causes the recipient's immune system to produce antibodies that can later fight off the real virus if need be. Inactivated vaccines have been in use for decades and have several advantages, including a well-documented safety record, well-developed manufacturing processes, and the capacity to present multiple viral proteins for recognition by the immune system. So far, Chinese authorities have issued conditional approval to three different inactivated vaccines for use in controlling the COVID-19 pandemic.

One inactivated vaccine currently in development is the KCONVAC vaccine developed by the Shenzhen Kangtai Biological Products Company and the Beijing Minhai Biotechnology Company. The KCONVAC vaccine is evaluated in ongoing phase 1 and phase 2 clinical trials, which aim to generate preliminary evidence of safety and preliminary evidence of efficacy, respectively. In a paper recently published in Chinese Medical Journal, a team of researchers led by Dr. Wen-Jie Tan of the Chinese Center for Disease Control and Prevention, Dr. Wei-Jin Huang of the China National Institutes for Food and Drug Control, and Dr. Feng-Cai Zhu of the Jiangsu Provincial Center for Disease Control and Prevention explore the existing clinical evidence for KCONVAC's safety and ability to generate an immune response in healthy adults.

The phase 1 trial included 60 healthy Chinese adults, and the phase 2 trial included 500 healthy Chinese adults. In each trial, the participants were randomly assigned to groups that received 5 micrograms of the vaccine, 10 micrograms of the vaccine, or a placebo injection. The phase 2 trial participants received two separate injections administered either two or four weeks apart. Importantly, each trial was double-blind, meaning that neither the participants nor the clinical personnel they interacted with knew which group a participant had been assigned to. This "double-blinding," a common procedure in clinical trials, served to increase the likelihood that any treatment effects would be due to the treatment administered rather than the participants' expectations about what they would experience. "From the phase 1 and 2 trials, we wanted to know how many participants would experience adverse events within 28 days of the injections, and how effective the vaccine would be at inducing the production of antibodies against the novel coronavirus, respectively," reports Dr. Tan.

In the phase 1 trial, participants who received the vaccine were no more likely to experience adverse events than participants who received the placebo injections were. The same pattern emerged in the phase 2 trial, and no severe vaccine-related adverse events occurred. In the phase 2 trial, KCONVAC successfully induced antibody production, and antibody production was stronger in participants who received their injections four weeks apart than in those who received their injections two weeks apart.

What's more, as Dr. Huang notes, "these findings show that KCONVAC, both at a 5-microgram dose and a 10-microgram dose, is well tolerated and able to induce robust immune responses in adults and support the testing 5-microgram vaccine doses spaced four weeks apart in an upcoming phase 3 trial."

"With this upcoming phase 3 trial, we hope to provide solid evidence that KCONVAC is safe and capable of reducing a recipient's likelihood of developing COVID-19," states Dr. Zhu. If the phase 3 trial returns positive results, then KCONVAC may become a valuable new tool in the fight to end the COVID-19 pandemic.

Mental health visits for new mothers were 30% higher during the COVID-19 pandemic than before the pandemic, particularly in the first 3 months after giving birth, found new research in CMAJ (Canadian Medical Association Journal). https://www.cmaj.ca/lookup/doi/10.1503/cmaj.210151

"Increased visit rates began in March 2020, although the state of emergency was declared only midway through the month, suggesting that distress related to the pandemic translated into an increased need for care very quickly," writes Dr. Simone Vigod, chief of psychiatry, senior scientist and interim vice president of academics at Women's College Hospital (WCH), and senior adjunct scientist at ICES in Toronto, Ontario, with coauthors.

Postpartum mental illness affects as many as 1 in 5 mothers and can have long-term effects on children and families if it becomes chronic.

Researchers looked at mental health visits by 137,609 people in Ontario during the postpartum period (from date of birth to 365 days after) from March through November 2020 and collected data on age, number of children, neighbour
hood income based on postal codes, neighbourhood ethnic diversity and region of residence based on the province's 34 public health units. They also divided the province into northern and southern public health units.

During the study period, mental health visits to both family physicians and psychiatrists were higher than before the pandemic, especially among parents with anxiety, depression, and alcohol and substance use disorders. People living in northern public health units had relatively low increases after July 2020, perhaps because of fewer COVID-19 restrictions in those areas during the latter period.

The way care was delivered during the pandemic period differed from the period before: 84.8% of postpartum mental health visits were conducted virtually in April 2020 compared with only 3.1% of visits in the prepandemic period.

The authors suggest that increased use of virtual care may have removed barriers to postpartum mental health support, such as the need to travel, find childcare for older children, or manage erratic schedules, enabling more people to seek care.

Patients in the lowest income neighbourhoods had the smallest increase in mental health visits compared with people in other neighbourhoods, which the authors noted with surprise.

"This raises some concern about the potential for unmet need because low-income patients may have greater barriers to accessing care, including difficulty affording the required technology or finding private space to attend virtual appointments (e.g., crowded homes), or less opportunity to attend "live" appointments because of employment in front-line jobs," write the authors.

They recommend targeted approaches to providing mental health supports.

"Health systems should focus proactively on patients from high-risk groups, monitor waiting lists for care, and explore creative solutions to expand system capacity, with special attention to postpartum patients who may be experiencing barriers to care," they advise.

New research indicates that patients hospitalized with active cancer were more likely to die from COVID-19 than those with a history of cancer or those without any cancer diagnosis. The findings published by Wiley early online in CANCER, a peer-reviewed journal of the American Cancer Society, also indicate those with active blood cancers have the greatest risk of death due to COVID-19. Researchers found no increased mortality risk in patients who received cancer treatments in the three months (or longer) prior to hospitalization.

To investigate how cancer, or the various therapies used to treat it, can affect the health of patients who develop COVID-19, a team analyzed the NYU Langone Medical Center's records of 4,184 hospitalized patients who tested positive for SARS-CoV-2, the virus that causes COVID-19. This group included 233 patients with a current, or "active," cancer diagnosis. More patients with an active cancer diagnosis (34.3 percent) were likely to die from COVID-19 than those with a history of cancer (27.6 percent) and those without any cancer history (20.0 percent).

Among patients with active cancer, those with blood-related cancers were at the highest risk of death. Receiving systemic anticancer therapy, including chemotherapy, molecularly targeted therapies, and immunotherapy, within three months prior to hospitalization was not linked to a higher risk of death, and the investigators found no differences based on the types of cancer therapy received.

"We completed a large chart review-based study of patients hospitalized with COVID-19 and found that patients with active cancer, but not a history of cancer, were more likely to die. Notably, however, among those hospitalized with active cancer and COVID-19, recent cancer therapy was not associated with worse outcomes," said senior author Daniel Becker, MD. "People with active cancer should take precautions against getting COVID-19, including vaccination, but need not avoid therapy for cancer."

Accumulation of water in the lungs (lungcongestion) is a common condition in hemodialysis patients, particularly in those at high cardiovascular risk, like those presenting coronary artery disease and/or heart failure. This alteration can be detected in an X-ray image, but cannot be heard easily with a stethoscope. When the congestion becomes so severe that fluid floods the alveoli ('alveolar pulmonary edema'), the sound of rattling breathing can be heard (and without a stethoscope at a later stage). Then, at the latest, pulmonary gas exchange is severely impaired, and the patients experience shortness of breath or even fear of death.

For hemodialysis patients, especially, lung congestion is a strong risk factor for mortality. Between dialysis sessions, all fluid which patients introduce is retained. Severe overhydration may ensue and this can then lead to heart decompensation. The degree of lung congestion can be assessed by ultrasound examination (sonography), and this may be used to adjust fluid removal during hemodialysis and drug therapies.

An international, multicenter study in 363 patients investigated whether such an ultrasound-based approach improves patient outcomes [1]. The primary endpoints were mortality, heart attack and decompensated heart failure. This strategy was compared with standard care in hemodialysis patients with a high cardiovascular risk.

The ultrasound examinations were carried out by the nephrologists themselves after brief instruction via a web platform. Sonographic control examinations were also performed periodically by cardiologists (blinded, i.e. without prior knowledge of the treatment that patients were receiving). The measurement parameters were B-lines in the ultrasound image, indicating fluid accumulation in lung tissue. The target for hemodialysis management was less than 15 sonographic B-lines.

In the sonography group (n=183), the number of B-lines decreased from 15 to nine from the beginning to the end of the study; in the control group (n=180), however, the number increased from 16 to 30 (p=0.002). In the sonography group, 117 patients (78%) reached the target value (

'The lung ultrasound-guided treatment strategy significantly reduced individual secondary, post hoc endpoints: decompensations of heart failure occurred 63% less frequently - and severe cardiovascular events 37% less frequently,' summarizes Dr Torino. Yet, because decompensated heart failure was not the primary end point of the study, new trials are still needed to confirm this finding. 'The fact that this did not significantly affect the composite end point could be due to the fact that decongestion improved gradually during the trial reaching the maximum at the end of the trial. Therefore, there could haven't been sufficient time for the beneficial effect of the lung ultrasound guided treatment to materialize.'

'Ultrasound examinations are available virtually everywhere in the hospital environment and do not take long to perform, so they can be deployed to diagnose and treat an ominous complication like lung congestion in hemodialysis patients.'

IgA nephropathy (IgAN) is a chronic kidney disease occurring in young adults and is one of the most common reasons for kidney transplantation in this age group. IgAN is the most common form of glomerulonephritis (GN), i.e., immunologically induced inflammation of the renal glomeruli. It is characterized by glomerular deposition of immune complexes containing immunoglobulin A (IgA), and by a complex inflammatory response and progressive loss of kidney function. For many decades, IgAN has therefore been treated with anti-inflammatory or strong immunosuppressive agents. However, the STOP-IgAN study and its ten-year follow-up [2, 3] showed that the addition of immunosuppressive therapy to optimal supportive therapy (strict blood pressure control, proteinuria treatment with RAS blockers, dietary and lifestyle measures), has no additional benefit: During the follow-up period, approximately half of all patients reached the primary combined endpoint (progressive loss of renal function > 40%, dialysis requirement or mortality). However, immunosuppression increased the incidence of adverse effects, especially infections. The use of immunosuppressants in IgAN has since been increasingly questioned by experts and should only be applied to rapid-progressive courses. Long-term outcomes are generally unfavorable, so targeted therapy is still urgently needed in addition to optimization of supportive therapy.

It is now known that overactivity of the alternative complement signaling pathway of the immune system plays a role in the pathogenesis of IgAN, thereby increasing the chronic inflammation. Targeted inhibition of this signaling pathway is thus a logical therapeutic approach.

Iptacopan is an oral, highly selective inhibitor of complement factor B and the alternative complement signaling pathway, and has now been investigated in a randomized, double-blind placebo-controlled Phase II clinical trial. In Part 1, 46 IgAN patients received three different doses of iptacopan or placebo for 90 days. A further 66 patients were then treated in Part 2 with four doses of iptacopan or placebo for 180 days. The primary endpoint was the dose-response relationship in the improvement of proteinuria (as a 24-hr urine protein/creatinine ratio). All 112 patients have now been evaluated together (day 90). Secondary endpoints were safety and tolerability, as well as eGFR and biomarkers of the alternative complement signaling pathway. Five groups were compared: iptacopan 10mg (n=20); 50mg (n=19); 100mg (n=22); 200mg (n=26) and placebo (n=25). Four patients (3.6%) had discontinued treatment due to side effects (two in the placebo group and one in the Verum group) or to protocol errors (in one case).

The analysis showed a statistically significant dose-response effect of iptacopan versus placebo (p=0.038), with a 23% decrease in proteinuria under 200 mg iptacopan versus placebo at 90 days. Renal function (eGFR) showed a trend to stabilization, and biomarkers also improved (functional serum complement activity, concentration of complement factor Bb, and urinary excretion of soluble C5b-9 were measured). Side effects were mild (92%) to moderate (8%); there were no serious adverse effects. The most common side effects were headache (11.6%), back pain (6.3%), diarrhea (6.3%), vomiting (6.3%), but not related to the dose taken.

'This is the first study to report the safety and efficacy of targeted alternative complement pathway inhibition in IgAN patients, with the results showing a significant dose-dependent reduction in proteinuria and a trend to eGFR stabilization,' comments Dr Barratt. 'Iptacopan was also well tolerated and resulted in inhibition of various biomarkers of alternative pathway activity, supporting its further evaluation in the ongoing Phase III (APPLAUSE-IgAN) trial.'

LA JOLLA, CALIF. - June 7, 2021 - A preclinical study led by scientists at Sanford Burnham Prebys has established that AAV8-TNAP-D10--a gene therapy that replaces a key enzyme found in bone--may be a safe and effective single-dose treatment for hypophosphatasia (HPP). The study, published in the Journal of Bone and Mineral Research and performed in a murine model of the disease, further supports advancing the therapy toward human clinical trials.

"This is the most promising gene therapy study to date demonstrating a successful increase in life span, and improvement of the skeletal and dental abnormalities associated with HPP, without signs of side effects in other organs," says José Luis Millán, Ph.D., professor in the Human Genetics Program at Sanford Burnham Prebys. "We're hopeful that this research will lead to a curative therapy--an alternative for patients who must currently undergo multiple injections of medication per week, often associated with injection-site reactions, to maintain their health."

HPP--also known as soft bone disease--is an inherited, rare bone condition of broad-ranging severity that causes life-threatening disease in approximately one per 100,000 live births. Depending on the severity of the skeletal disease, symptoms can include deformity of the limbs and chest, pneumonia, and recurrent fractures. Although there is currently no cure for HPP, patients may benefit from injections of asfotase alfa--a mineral-targeted form of the missing enzyme called TNAP--which is an FDA-approved therapy based on Millán's more than 20 years of pioneering research on the enzyme and characterized in his laboratory for preclinical efficacy.

The new study evaluated the efficacy of a single intramuscular injection of AAV8-TNAP-D10 in a murine model of infantile HPP. AAV8-TNAP-D10 extended the life span of the mice; and no ectopic calcifications--a potential side effect of the current therapy--were observed in the kidneys, aorta, coronary arteries or brain of the treated mice. AAV8-TNAP-D10 is an adeno-associated virus gene construct that incorporates the gene encoding mineral-targeted TNAP-D10.

"This is a much-needed advance in the field of HPP research," says Deborah Fowler, founder and president of Soft Bones, a leading advocacy group dedicated to the community of patients, caregivers and families living with HPP. "Our patients vary in severity, and there remains a significant unmet need for those unable to receive treatment and those who experience administration challenges with the chronic therapy."

"Our research efforts are committed to improving the lives of people affected by HPP," says Millán. "I'm grateful to the many individuals who enabled this latest study--from the National Institutes of Health, which has generously funded our research since the 1980s, to the collaborators and lab members who are instrumental in our scientific advances. "This work is the culmination of more than 10 years of collaborative efforts with gene therapy experts Professor Takashi Shimada and Dr. Koichi Miyake from Nippon Medical School in Tokyo, to identify the best vector and route of delivery of the TNAP-D10 encoding vector to treat HPP," adds Millán.

C3 glomerulopathy (C3G) is a very rare immunological (or more precisely: complement-mediated) inflammation of the glomeruli. Due to progressive renal dysfunction, many such patients have to go on dialysis or receive a kidney transplant after about ten years. C3G has to date been treated by lowering blood pressure and proteinuria and by non-specific immunosuppression. In order to compare different therapeutic approaches in the future, a 'European Register for C3 glomerulopathy and immune-complex-mediated MPGN', in which cases are systematically registered, was initiated in 2015.

Pathogenetic dysregulation in the 'alternative complement signaling pathway' of the immune system leads to glomerular deposits of complement factor C3 (a protein). Permanent overactivation of the signaling cascade also causes elevated levels of the C5 and C5a factors. C5a is a potent inflammatory mediator that acts via the associated C5a receptor. In preclinical studies, C3G progression was markedly slowed with the selective C5a receptor inhibitor avacopan.

The ACCOLADE study conducted a randomized, double-blind placebo-controlled investigation into the use of avacopan in C3G patients. For 26 weeks, they received either 30 mg of orally administered avacopan twice daily (n=28), or placebo (n=29). The C3G Histologic Index (C3HI 'Disease Activity Score') was used to measure changes in histology over time by means of repeat kidney biopsies (higher values indicating severe disease). Secondary endpoints were the histologic disease chronicity score (degree of fibrosis), the glomerular filtration rate (eGFR), and proteinuria (UPCR - urinary protein to creatinine ratio).

The patients had been diagnosed with C3G 46-48 months on average before enrollment; in the avacopan group, the mean eGFR was 76.27 ml/min/1.73 m2; proteinuria (> 1 g/g) was present in 76.9% of patients. In the placebo group, eGFR was 73.42 ml/min/1.73 m2, while 69.2% had proteinuria (> 1 g/g).

At 26 weeks, the C3HI activity score improved by 0.2% in the avacopan group, but worsened by 20.6% in the placebo group. The C3HI chronicity score increased by 31.7% in the avacopan group and by 57.5% in the placebo, which equates to an absolute change of 0.8 versus 1.6, respectively. The eGFR changes were also statistically significant; in the avacopan group, eGFR increased by 4.8% on average and decreased in the placebo group by 5.9% (p=0.02). Patients with a previous eGFR less than 60 ml/min/1.73 m2 benefited particularly from the therapy, as their eGFR increased by 13% (compared to a 6.1% decrease for placebo). Proteinuria also improved in the avacopan group. The tolerability and safety profile of avacopan did not differ on the whole from placebo.

'In patients with C3 glomerulopathy, targeted therapy aimed at the complement system provides the best possible route to slow disease progression,' explains Dr Bomback. 'In addition, the more selectively we target the causal disease mechanisms in the immune system, as was done in this study at the C5a receptor with avacopan, the less the immune system as a whole is suppressed, which should also yield not only more effective but also less toxic therapies.'

'Targeted immunomodulation is already used to treat various diseases and will play an increasingly important role in the future if we want to treat C3G effectively yet safely.'

A new study from the University of Chicago and Scripps Research Institute shows that during the last great pandemic--2009's H1N1 influenza pandemic--people developed strong, effective immune responses to stable, conserved parts of the virus. This suggests a strategy for developing universal flu vaccines that are designed to generate those same responses, instead of targeting parts of the virus that tend to evolve rapidly and require a new vaccine every year.

Influenza is an elusive and frustrating target for vaccines. There are two main types of flu virus that can infect humans, which evolve rapidly from season to season. When developing seasonal flu vaccines, health officials try to anticipate the predominant variation of the virus that will circulate that year. These predictions are often slightly off. Sometimes new, unexpected variants emerge, which means the vaccine may not be very effective. To avoid this, the ultimate goal of many flu researchers is to develop a universal vaccine that can account for any virus strain or variation in a given year, or even longer.

The new study, published June 2 in Science Translational Medicine, was led by UChicago immunologists Jenna Guthmiller, PhD, and Patrick Wilson, PhD, along with structural biologists Julianna Han, PhD, and Andrew Ward, PhD, from Scripps Research Institute. They studied the immune responses of people who were first exposed to the 2009 H1N1 pandemic flu virus, either from infection or a vaccine.

The researchers saw that the immune systems of these people recalled memory B cells from their childhood that produced broadly neutralizing antibodies against highly conserved parts on the head of a protein called hemagglutinin (HA) -- a virus surface protein that attaches to receptors on host cells. These antibody responses were very effective at combatting the virus, and because they targeted conserved parts of the HA protein--meaning they don't change very often--they could provide an enticing target for a vaccine to generate those same robust immune responses.

In a separate 2020 study, Guthmiller and colleagues found so-called polyreactive antibodies that can bind to several conserved sites on the flu virus. Now, the new study reveals more details about the conditions that can recall the same strong immune responses as this first exposure.

"That's the exciting thing about this study," Guthmilller said. "Not only have we found these broadly neutralizing antibodies, but now we know of a way to actually induce them."

The only problem is that on subsequent encounters with the virus or a vaccine, the body doesn't generate those same super-effective antibodies. Instead, for reasons that are unclear, the immune system tends to target newer variations on the virus. That may be effective at the time, but isn't very helpful down the road when another, slightly different version of influenza comes along.

"When people encounter that virus a second or third time, their antibody response is pretty much completely dominated by antibodies against those more variable parts of the virus," Guthmiller said. "So that's the uphill battle that we continue to face with this."

The trick to getting around this is to design a vaccine that recreates that initial encounter with H1N1, using a version of the HA protein that keeps the conserved, powerful antibody-inducing components, and replaces the variable parts with other molecules that won't distract the immune system.

"Structural studies were essential to delineate the conserved areas on the HA protein," said Han, who was co-first author of the new study and received her doctorate from the Committee on Microbiology at UChicago. "Now these data can be used to fine-tune vaccine targets."

In roughly the past century, two of the four flu pandemics have been caused by H1N1 influenza, including the 1918 Spanish flu pandemic that killed as many as 100 million people. Yet the findings of this study are reassuring in the fight against possible future pandemics caused by other H1 viruses.

"The odds of there being another pandemic within our lifetime caused by an H1 virus is quite high," Guthmiller said. "Just knowing that we actually have the immune toolkit ready to protect ourselves is encouraging. Now it's just a matter of getting the right vaccine to do that."