Body

MRSA skin infections are often treated with intravenous injection of antibiotics, which can cause significant side effects and promote the development of resistant bacterial strains. To solve these problems, researchers at Karolinska Institutet in Sweden are developing a microneedle patch that delivers antibiotics directly into the affected skin area. New results published in Advanced Materials Technologies show that the microneedle patch effectively reduces MRSA bacteria in the skin.

MRSA (methicillin resistant Staphylococcus aureus) skin infections are potentially lethal, especially in patients with compromised immune systems. Vancomycin is one of the main treatments and is given as an intravenous injection. The reason the antibiotic is not given locally is because of its low ability to penetrate the skin. It is not given orally either because of poor absorption through the gut. The problem with systemic administration is that it often results in significant side effects. Moreover, even when relatively high doses are administered, the local concentration of vancomycin in the skin remains low, which may promote the development of antibiotic resistant strains. Thus, there is a clinical need for local delivery of vancomycin to the skin.

"We have addressed this by using microneedle patches that consist of miniaturised needles made from a polymer that is loaded with the drug," says Jill Ziesmer, PhD student at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet and first author of the study. "Through an innovative microneedle design we could efficiently control the drug amounts delivered into the skin."

The patch is placed on the skin at the site of infection. The barely visible microneedles are so small that they do not reach the pain receptors, which makes the treatment relatively painless. The microneedles' ability to penetrate the skin was studied in skin tissue from piglets and excised human skin. The results show that the drug was effectively delivered into the skin, and most importantly, significantly reduced the MRSA bacterial population.

"If this drug delivery device reaches the clinics, it has the capacity to transform the way skin infections from potentially lethal bacteria are treated with drastic improvements in the quality of life of patients," says Georgios Sotiriou, principal researcher at the Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet and last author of the study.

The researchers will now evaluate the performance of microneedles in animal models of MRSA skin infection. The next step is to further develop the product so that it exerts antimicrobial activity through multiple modes of action in order to improve efficacy.

Microneedles were voted one of the top 10 emerging technologies by World Economic Forum in 2020. They are already in clinical use for administering vaccines and there are many ongoing clinical trials for other uses such as treating diabetes, cancer and neuropathic pain.

"Microneedles for delivery of antibiotics have only been studied recently, however, the successful application of microneedles in other areas gives hope that antibiotic microneedles might open new frontiers in skin infection management," says Georgios Sotiriou.

In a retrospective study of trauma patients over 65 years of age attended by KSS, it was found that, although a number of these patients had sustained a minor injury through seemingly innocuous mechanisms, a high proportion of this group required advanced clinical interventions and subsequent tertiary level care at a major trauma centre.

The study also identified that dispatch time to these patients was typically longer, in particular in instances when KSS's critical care was requested by an ambulance crew already in attendance.

With response time often critical to patient outcomes, the findings suggest that dispatch accuracy to older trauma patients could be improved. Further evaluation is also warranted of how age-dependent triggers for mechanism and physiological parameters could optimise dispatch sensitivity and HEMS utilisation for this group, helping to overcome under-triage.

The research looked at KSS data over a six-year period. During this time:

KSS attended 1321 trauma patients aged over 65 years (median age 75 years);

KSS's dispatch was immediate in 32% of cases, after interrogation by a dispatcher in the Emergency Operations Centre in 43% of cases and following a request from South East Coast Ambulance Service crew from the scene in 25% of cases;

Older age was found to be associated with a longer dispatch interval and was significantly longer in the crew request category (median 37 minutes);

Immediate dispatch to patients with isolated head injuries often resulted in the KSS HEMS team delivering pre-hospital emergency anaesthesia (PHEA, 39%). However, over one third of head injured patients attended by a crew request dispatch also received PHEA (36%).

69% of those head injured patients attended by a crew request were still triaged to a major trauma centre.

Professor Richard Lyon MBE, Associate Medical Director at KSS and Professor of Pre-Hospital Emergency Care at the University of Surrey said: "We know that trauma in older people, particularly simple falls from standing height in patients on blood thinning medication, is becoming increasingly common. Older trauma represents 20% of all major trauma in the UK and projections suggest that by 2040 one in four people will be aged 65 or over. Many of these patients would benefit from early pre-hospital critical care and rapid transfer to a major trauma centre, so it is imperative we optimise dispatch to this group of patients."

"This study has demonstrated that many of these patients do not fulfil the initial criteria for immediate dispatch of HEMS, but that they need advanced interventions and subsequent tertiary level care at major trauma centres."

Advances in healthcare have enabled greater independence and activity in older people. This has led to a greater prevalence of older trauma, with 50% of severely injured patients over the age of 65-years recorded on the Trauma Audit and Research Network (TARN). Inevitably, growing demand is being placed on acute healthcare services.

HEMS, like KSS, provide enhanced pre-hospital medical care to major trauma patients, such as PHEA. Accurate tasking of HEMS to those patients who may benefit most from their advanced critical care interventions is important as this is a highly valuable resource.

Emergency medical dispatchers track an established pathway during a 112/999 call to discern traumatic injuries. The dispatch triggers are largely validated in the adult trauma population and not specifically adapted to the older trauma subgroup. This study has shown that clinical observations of traumatically injured older adults may present with parameters equivalent to younger 'well' adults, and that therefore injury severity is potentially masked to both the caller and clinician, and consequently KSS's dispatch was delayed.

This was particularly notable in falls. A significant proportion of older trauma patients in the study had fallen from standing height (less than two metres). In people who are under 65 years of age, falls of this type can lead to serious injury in 4% of cases. In people over 65 years of age, 30% are likely to experience serious injury, and these incidents are 10 times more likely to cause death.

This study showed that, in the majority of these cases, KSS was dispatched once a ground ambulance crew had assessed the patient, leading to a potential delay in providing the patient with advanced critical interventions. In a number of these cases, patients required specialist interventions at the scene and 60% were transferred to a major trauma centre.

Previous research has shown that HEMS can contribute to a survival benefit in these patients , and now this study identifies the need to improve efficiency of HEMS dispatch in the older trauma subgroup.

Professor Richard Lyon continued:

"Advanced interventions provided by HEMS are an unparalleled but scarce resource and it is crucial that dispatch triggers are effective. KSS is a charity, reliant upon public donations and fundraising for the £15 million it costs each year to deliver our service to the 4.8 million people we serve."

"Improving triage is key, so that those patients who need immediate critical care receive it as quickly as possible. Further research is warranted focusing on how age-dependent triggers can improve efficiency along with how live video-transmission may help gauge physiological parameters to expedite dispatch."

The research has been published by Scandinavian Journal of Trauma Resuscitation and Emergency Medicine.

DALLAS - May 10, 2021 - Scientists at UT Southwestern have discovered a key protein that helps the bacteria that causes Legionnaires' disease to set up house in the cells of humans and other hosts. The findings, published in Science, could offer insights into how other bacteria are able to survive inside cells, knowledge that could lead to new treatments for a wide variety of infections.

"Many infectious bacteria, from listeria to chlamydia to salmonella, use systems that allow them to dwell within their host's cells," says study leader Vincent Tagliabracci, Ph.D., assistant professor of molecular biology at UTSW and member of the Harold C. Simmons Comprehensive Cancer Center. "Better understanding the tools they use to make this happen is teaching us some interesting biochemistry and could eventually lead to new targets for therapy."

Tagliabracci's lab studies atypical kinases, unusual forms of enzymes that transfer chemical groups called phosphates onto proteins or lipids, changing their function. Research here and elsewhere has shown that Legionella, the genus of bacteria that cause Legionnaires' disease, is a particularly rich source of these noncanonical kinases. According to the Centers for Disease Control and Prevention, nearly 10,000 cases of Legionnaires' disease were reported in the U.S. in 2018, though the true incidence is believed to be higher.

After identifying a new Legionella atypical kinase named MavQ, Tagliabracci and his colleagues used a live-cell imaging technique combined with a relatively new molecular tagging method to see where MavQ is found in infected human cells, a clue to its function. Rather than residing in a specific location, the researchers were surprised to see that the protein oscillated back and forth between the endoplasmic reticulum - a network of membranes important for protein and lipid synthesis - and bubble- or tube-shaped structures within the cell.

Further research suggests that MavQ, along with a partner molecule called SidP, remodels the endoplasmic reticulum so that Legionella can steal parts of the membrane to help create and sustain the vacuole, a structure that houses the parasite inside cells and protects it from immune attack.

Tagliabracci, a Michael L. Rosenberg Scholar in Medical Research and a Cancer Prevention & Research Institute of Texas (CPRIT) Scholar, says that he suspects other bacterial pathogens may use similar mechanisms to co-opt existing host cell structures to create their own protective dwellings.

Autistic people have far greater risks of long term physical health conditions than others, but the reasons for this remain unclear. New research from the University of Cambridge suggests that unhealthy lifestyle habits may be an important contributing factor. The results are published today in the journal Molecular Autism.

Earlier research suggests that autistic people die 16-35 years younger than expected, and that greater health problems may contribute to this risk. The present study is the first to consider the diet, exercise, and sleep patterns of autistic adults and how these patterns may relate to health outcomes.

The team at the Autism Research Centre in Cambridge developed an anonymous, online survey about lifestyle choices and daily habits, personal medical history, and family medical history. The final study included 1,183 autistic adults and 1,203 non-autistic adults aged 16-90 years.

The results showed that autistic adults were far less likely than non-autistic adults to meet very minimal health recommendations for diet, exercise, and sleep. Autistic adults were also far more likely to have atypical eating patterns (including limited diet) and sleep disturbance. They were more likely to be underweight or obese than non-autistic individuals.

These poor lifestyle habits were associated with greater risk of cardiovascular conditions such as high blood pressure, heart disease, and stroke among autistic males, and this was a stronger association even than a family history of a cardiovascular condition. Though it is not possible to say conclusively that a poorer lifestyle led to cardiovascular problems, the findings provide the first indication that promoting healthy choices regarding diet, exercise, and sleep may help to reduce the excess risks of health conditions in autistic adults.

While the results indicate that there may be other biological or environmental factors that leave autistic individuals at greater risk of health conditions, they also provide a clear target for intervention. Difficulties with maintaining a healthy lifestyle may also have knock-on effects beyond physical health, including limiting opportunities for social interaction (which may centre around mealtimes or exercise), and could contribute to worsening mental health, and affect employment or education.

The lead researcher of the study, Elizabeth Weir, a PhD student at the Autism Research Centre in Cambridge, said: "These findings help us to better understand the experiences of autistic adults, and have wider implications for quality of life. We need to understand the reasons for restricted diet, limited exercise, and lack of sleep, to provide better support. This may include programmes for health education, and additional mental health support or supported living and working schemes."

Dr Carrie Allison, Director of Research Strategy at the Autism Research Centre and a member of the research team, said: "The challenges we see among autistic children regarding lifestyle behaviours extend into adulthood. Given the implications for risk of chronic disease and length of life, it is critical that we work to identify effective strategies for supporting health choices by autistic people of all ages."

Professor Simon Baron-Cohen, Director of the Autism Research Centre and a member of the team, said: "The wider picture suggests that autistic adults experience vulnerability in a variety of contexts, and this is just one new area that we should consider. Seeing that autistic adults are having such a hard time comparatively with healthy lifestyle habits has clear healthcare and policy implications: we need to create new and better support systems tailored to the specific needs of autistic people."

Since it debuted in 2011, the Get SET Early program, which provides pediatricians and parents with a relatively simple process to screen for indicators of autism spectrum disorder (ASD) in children as young as age 1, has steadily grown in use and validation. Early screening and identification of ASD has been linked to more effective treatment.

A new study, published in the April 26, 2021 issue of the Journal of Pediatrics, by researchers at University of California San Diego School of Medicine, further bolsters these findings.

Led by Karen Pierce, PhD, a professor in the Department of Neurosciences who with colleagues created the Get SET Early program, researchers at the UC San Diego Autism Center of Excellence (ACE) assembled a network of 203 pediatricians in the San Diego region who conducted systematic screenings of 59,411 infants or toddlers at their 12-, 18- and 24-month check-ups.

Parents completed a validated questionnaire about their child's use of eye contact, words, gestures and other forms of age-appropriate communication, using either a paper form or an iPad. The final question on the screening tool: "Do you have any concerns about your child's development?" (Yes or No).

Digital screens automatically scored patients as pass or fail. Pediatricians were asked to indicate whether they were referring toddlers who failed a screening for further evaluation and if not, why not.

Overall, 897 children failed the initial screening and received further evaluation at ACE. Within this cohort, 403 received a subsequent diagnosis of ASD. Approximately 60 percent of these children were assessed at their 12-month well baby visits, and received a comprehensive evaluation, diagnosis and treatment referral by age 15 months.

"There is extensive evidence that early therapy can have a positive impact on the developing brain," said Pierce, who is co-director of ACE. "The opportunity to diagnose and thus begin treatment for autism around a child's first birthday has enormous potential to change outcomes for children affected with the disorder. These toddlers, as part of the Get SET Early program began treatment roughly three years earlier than the national average of 52 months."

But the study also revealed some surprising findings: Participating pediatricians referred only 39 percent of toddlers who had failed a screening for additional evaluation.

"Data from the iPads indicated the lack of referral follow-through was because pediatricians thought that the results of the screen were wrong," said Pierce. "But if a parent noted that they were concerned by checking 'yes' on the last question, the referral rate increased to 70 percent.

"These findings underscore the importance of parent participation and input when seeking to detect the earliest signs of ASD or other development delays in young children. If you are a parent and have even minor concerns about how your child is developing, you must speak up. Don't wait. Your voice carries weight."

ASD is now estimated to affect one in every 54 children born in the United States. Multiple studies, including research conducted by Pierce and colleagues have found that simple parent checklists performed as early as a child's first birthday can identify symptoms of ASD. Early diagnoses have been found to be highly stable as early as 14 months.

Pierce said the Get SET Early program, which has expanded to other cities and states with funding from the National Institute of Mental Health, can be adopted by any pediatric office, at virtually no cost.

What has fluid physics to do with the spreading of the Corona virus? Whirlpools and pandemics seem to be rather different things, certainly in terms of comfort. Yet, newest findings about epidemic spreading come from Physics professor Björn Hof and his research group at the Institute of Science and Technology Austria (IST Austria), who specialize in fluids and turbulent flows. When early last year Björn Hof had to cancel his scheduled visit to Wuhan, his wife's hometown, his focus abruptly shifted to epidemic spreading.

"My group normally investigates turbulent flows in pipes and channels", he explains, "Over the last 10 years we have shown that the onset of turbulence is described by statistical models that are equally used to describe forest fires and epidemics." Given this experience, programming an epidemic model was a straightforward exercise for Burak Budanur, the group's theorist and computational expert.

The epidemic curve does not flatten, it collapses

Standard epidemic models suggest that the level of mitigation has a continuous effect on the height of the epidemic peak. "The expectation is that the curve flattens in proportion to the level of social distancing", says Davide Scarselli, main author of the paper. However, when he first simulated epidemics taking limits in testing and contact tracing into account, the picture was a very different one. The maximum of infected people initially decreased as expected but then suddenly collapsed to almost zero as the mitigation level reached a certain threshold. In one limit, approximately half of the people got infected during the epidemic. In the other one only three percent caught the disease. Surprisingly, it was impossible to obtain a result in between these two outcomes: Either there is an outbreak of considerable size, or there is almost none whatsoever.

Failure yields faster than exponential growth

Testing of known contacts (not testing per se) is one of the most powerful ways to slow down an epidemic. However, the number of cases that can be traced every day is limited and so is the number of tests that can be administered. As the researchers found out that exceeding these limits at one point during the epidemic has far-reaching consequences. "If this happens", says Timme, "the disease begins to spread faster in the unchecked areas and this unavoidably causes a super-exponential increase in infections." Already, exponential growth is immense. It means doubling infections every few days. Super-exponential though signifies that even the rate of doubling becomes faster and faster.

As long as this acceleration can be avoided, epidemic curves collapse to a comparably low case level. Interestingly, it matters relatively little whether contact tracing is protected by a small or a large safety margin. The numbers remain comparatively low. If on the other hand the limit is only surpassed by a single case the super-exponential growth causes the total case numbers to jump to a tenfold level.

Marginal differences and disproportionate effects

"Like most nations, Austria didn´t react early against the second wave. Once not all contacts could be traced anymore during last September, it wasn't difficult to predict that case numbers would soon surge at a faster than exponential rate", says Scarselli. While over the last year it has become apparent that an early and decisive response is essential when facing exponential growth, the team's study shows that test limits make timing even more crucial. The difference between success and failure of a lockdown is marginal, or as Budanur puts it: "A policy that would have worked yesterday will not only take much longer to take effect, but it may fail entirely if it is implemented a single day too late." Hof adds: "Most European countries only reacted when health capacity limits became threatened. Actually, policy makers should have paid attention to their contact tracing teams and locked down before this protective shield fell apart."

More recently the team has looked into optimal strategies, where lockdowns are used as a preventive tool rather than an emergency brake. A manuscript that outlines the optimal strategy, which minimizes both, the number of infected people and the required lockdown time, is currently in progress.

New research being presented at The European Congress on Obesity (ECO) held online this year, suggests that a measure of body shape should be used alongside body mass index (BMI) to help determine the risk of obesity-related cancers.

BMI is a simple way of measuring body fat from the weight and height of a person. But its reliability is often criticised, because it does not distinguish fat from muscle, or take into account where body fat is stored or an individual's sex or age. Similarly, waist circumference takes into account belly fat, which is linked to several health risks including cardiovascular disease, type-2 diabetes and cancer, but fails to account for height.

A new metric to measure obesity, called 'A body shape index' (ABSI), takes into account an individual's age, sex, weight, height and waist circumference--and it may provide a more accurate estimate of cancer risk than BMI.

To explore this further, researchers from the University of Glasgow and the University of Newcastle, combined data from 442,614 participants (average age 56 years) from the UK Biobank prospective cohort who were followed for an average of 8 years, during which 36,961 individuals were diagnosed with cancer.

Participants were broken down into three groups (tertiles) according to their body shape to examine the associations with the risk of 24 different types of cancer; and to examine ABSI and BMI as predictors of cancer risk. Results were adjusted for age, sex, ethnicity, deprivation, education, income, smoking, alcohol consumption, dietary intake, physical activity, and sedentary time.

The analysis found that body shape and BMI predicted different obesity-related cancer risk in adults. Specifically, ABSI was linked with an increased risk for three cancers. Participants in the highest ABSI tertile were 38% more likely to develop liver cancer, 40% more likely to develop lung cancer, and had a 17% increased risk of bowel cancer, compared to those in the lowest ABSI tertile, regardless of BMI.

However, researchers found that high ABSI and high BMI combined were linked with an increased risk for seven different types of cancer--uterine, oesophageal, liver, stomach, kidney, bowel, breast cancer. For example, participants in the highest ABSI tertile who were also overweight or obese (BMI 25 kg/m2 or over) were at twice the risk of developing uterine cancer than those with the lowest ABSI and normal BMI.

"Our findings underscore the importance of measuring more than just BMI when predicting cancer risk, and suggest that people's body shape may increase their risk of certain cancers", says lead author Dr Carlos Celis-Morales from the University of Glasgow, UK. "Whatever method you use, being overweight or obese is the single biggest preventable cause of cancer after smoking. More urgent actions are needed to help people maintain a healthy bodyweight and shape throughout their lives, starting at an early age."

Having excess body fat can lead to biological changes that alter levels of sex hormones, such as oestrogen and testosterone, cause levels of insulin to rise, and lead to inflammation, all of which have been linked with increased risk of 13 different types of cancer.

This is an observational study, so cannot establish cause, and it is not a representative sample of the UK adult population, so the results cannot be generalised to the general population.

Obesity increases the risk of developing 10 of the most common cancers, regardless of how it is measured, according to a study of more than 400,000 adults in the UK, being presented at The European Congress on Obesity (ECO) held online this year, with central fatness (larger waist and hips) and general obesity (body mass index [BMI] and body fat percentage) associated with similar estimates of cancer risk.

The results suggest that BMI is an adequate measure of cancer risk from excess weight, and there is no advantage in using more complicated or expensive measures such as waist circumference or body fat percentage.

It is well known that being overweight or obese is linked to an elevated risk of some cancers and premature death. However, most of the evidence is based on BMI, and little is known about the association between cancer and other markers of adiposity (eg, central obesity and body fat).

Using data from the UK Biobank prospective cohort study, researchers from the University of Glasgow identified 437,393 adults (54% women; average age 56 years) who were cancer-free, to investigate the risk of developing and dying from 24 cancers according to six markers of obesity: BMI, body fat percentage, waist-to-hip ratio, waist-to-height ratio, and waist and hip circumferences.

The results were adjusted for age, sex, ethnicity, deprivation, education, smoking, alcohol consumption, intakes of fruit and vegetables, red and processed meat, oily fish, physical activity, and sedentary behaviours [1]. After an average of 9 years follow-up, there were 47,882 cases of cancer, and 11,265 cancer deaths.

The researchers found that all six obesity measures were positively and similarly associated with higher risk for 10 cancers. For example, each 4.2 kg/m2 (men) and 5.1 kg/m2 (women) increase in BMI above 25 kg/m2 (defined as being overweight) was linked with higher risk of cancers of the stomach (35% increase), gallbladder (33%), liver (27%), kidney (26%), pancreas (12%), bladder (9%), colorectal (10%), endometrial (73%), uterine (68%), postmenopausal breast (8%), and overall (3%) cancer.

Based on the results, the researchers estimate that if these associations were causal, being overweight or obese could be responsible for around 40% of endometrial and uterine cancers and 29% of gallbladder cancers; and could account for 64%, 46%, and 40% of deaths from these cancers respectively (see figure 8 in link below).

"We observed a linear association - the more severe obesity is, the higher the risk of developing and dying from these cancers, except for postmenopausal breast cancer", says Dr Carlos Celis-Morales from the University of Glasgow, UK, who led the research. "But there was a lot of variation in the effects of obesity on different cancers. This tells us that obesity must affect cancer risk through a different number of processes, depending on the cancer type."

This is an observational study, so can't establish cause, and the researchers say they cannot rule out the possibility that other unmeasured factors (residual confounding) may have influenced the results. They also note that the study is not a representative sample of the UK adult population, so the results might not be generalisable to the general population.

A study of more than 173,000 women in Denmark, presented at the European Congress on Obesity (ECO) held online this year, suggests that girls with a higher body mass index (BMI) during childhood are less likely than their peers with a lower BMI to develop breast cancer as adults, both before and after the menopause.

The findings contrast with those for adult BMI, which indicate that women who gain weight after menopause have an increased risk of postmenopausal breast cancer. While the authors are unsure why children with a higher BMI appear to be protected against breast cancer, they caution that having overweight or obesity can have many adverse impacts on general health.

"Our results suggest that having a higher BMI during childhood may lower your risk of breast cancer both before and after the menopause. But we must be really clear that weight gain should not be considered as a way of preventing breast cancer", says lead author Dr Dorthe Pedersen from Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark. "There are so many health risks linked with having overweight or obesity, it is vital for women to maintain a healthy weight throughout their lives."

Breast cancer is the most common cancer in women, with around 55,000 women diagnosed every year in the UK alone, and almost 1 in 5 cases developing in those under the age of 50. Previous research has established a link between increased BMI in adult women and a lower risk of breast cancer before the menopause, but an increased risk after menopause. Although a high childhood BMI may be protective against the risk of overall breast cancer, past studies had not been large enough to investigate the link by type menopausal status.

To provide more evidence, Danish researchers analysed data for 173,373 women from the Copenhagen School Health Records Register born between 1930 and 1996 (aged 25 to 91 years now) who had information on height and weight measured at annual school health examinations from ages 7 to 13 years. Cases of breast cancer were identified by linking with the Danish Cancer Registry.

During an average of 33 years of follow-up, 4,051 women were diagnosed with breast cancer before the menopause (at 55 years of age or younger), and 5,942 women after the menopause (after age 55 years).

The analyses suggest "inverse associations" between childhood BMI and breast cancer risk before and after the menopause, which means that breast cancer risks decreased as BMI increased. For example, when comparing two 7 year-old girls with an average height and one z-score difference in BMI (equivalent to 2.4 kg), the girl with the highest BMI had a 7% lower risk of developing pre-menopausal breast cancer and a 10% lower risk of developing post-menopausal breast cancer than the girl with the lower BMI.

The authors say that further studies are needed to uncover the mechanisms underlying these associations. They acknowledge that the findings are associations only, so no conclusions can be drawn about cause and effect, and point to several limitations, including that the study used BMI as a marker of fat mass, but children with the same BMI can have different body fat distributions and overall levels of body fat.

New research presented at this year's European Congress on Obesity (held online, 10-13 May) finds evidence that structures called inflammasomes (a part of the innate immune system that helps to regulate inflammation) could play an important role in the development of obesity-associated colon cancer. The study is by Dr Victoria Catalán and Professor Gema Frühbeck, University Hospital Navarra and CIBEROBN, Instituto de Salud Carlos III, Pamplona, Spain, and colleagues.

Inflammasomes* form part of the innate immune system which provides the first line of defence against pathogens using a wide range of physical, chemical, and biological responses.

Dysregulation of inflammasomes within visceral adipose tissue (VAT - fat that surrounds the organs) and in the colon can trigger prolonged episodes of inflammation, favouring the development of colon cancer (CC). The aim of this study was to explore whether obesity and CC influence the expression of different inflammasomes and their main 'trigger' molecules (called interleukins 1ß and 18), in VAT and in the colon, where they could create a microenvironment favourable for tumour growth.

Tissue samples were obtained from 99 subjects [38 lean (LN), and 61 obese (OB)], who were further classified into those with CC (41), and those without (58). The study revealed for the first time that obesity and CC increase gene expression levels of the proteins NLRP3, NLRP6, ASC, IL1B and NOD2 in VAT.

Gene expression levels of adiponectin were also reduced in VAT in obese subjects as well as those with CC. This may increase the risk of developing conditions such as type 2 diabetes and metabolic syndrome due to adiponectin's role in modulating metabolic processes and improving insulin sensitivity. Conversely, CC was associated with reduced expression of NLRP6 and IL18 in tissue samples taken from the colon.

The team also found evidence of a possible role for inflammasomes in altering the expression levels of proteins involved in maintaining the integrity of the intestinal wall.

The authors conclude: "These findings provide evidence about the potential involvement of inflammasomes in obesity-associated colon cancer by regulating inflammation and the intestinal-barrier integrity."

They add: "Therefore, strategies to restore the functions of immunosurveillance of inflammasome components could represent an interesting target to identify and treat patients with obesity at increased risk for developing colon cancer."

A study presented at this year's European Congress on Obesity (held online, 10-13 May) supports recommendations to avoid pregnancy for 12 months after bariatric (obesity) surgery due to an association with adverse outcomes in pregnancy including an elevated risk of preterm birth. The study is by Dr Laura Heusschen, Vitalys Obesity Clinic, part of Rijnstate Hospital, Arnhem, The Netherlands, and colleagues.

More than half of all female patients who undergo bariatric surgery are of reproductive age, and the resulting weight loss improves fertility, as well as reducing the risk of gestational diabetes and hypertensive disorders during pregnancy. It also lowers the chance of the baby having a high birth weight, which is associated with an increased risk of complications for both mother and child.

Current recommendations for women undergoing bariatric surgery are that they should avoid pregnancy for 12 to 24 months after the operation to avoid problems caused by ongoing active weight loss and an increased risk of malnutrition due to a markedly reduced calorie intake. This is most likely to occur within the first 12 months after surgery and can decrease the nutritional supply to the growing fetus; potentially affecting its development and resulting in a reduced birth weight and greater likelihood of preterm birth.

The authors note, however: "Previous studies found no associations between the time from surgery to conception and adverse pregnancy or neonatal outcomes. In fact, most studies confirm that the risk of these outcomes is not increased during the first 12 months after bariatric surgery compared to later pregnancies."

The aim of this retrospective multi-centre cohort study was to evaluate pregnancy and birth outcomes by surgery-to-conception interval and by adherence to the recommendations for gestational weight gain of the National Academy of Medicine.* Births were categorised based on surgery-to-conception interval and gestational weight gain, with the primary outcome variables gestational age at delivery, preterm birth, birth weight, and weight-for-age percentile.

Preterm birth was defined as having a gestation period of less than 37 weeks, while gestation periods of less than 32 weeks were classed as very preterm based on the definition used by the World Health Organization. The relationship between the weight of an infant at birth relative to its gestational age was compared against birth weight charts, adjusted for sex. Those within the top 10% were classified as being large-for-gestational-age (LGA), with the bottom 10% classified as small-for-gestational-age (SGA).

The authors performed a retrospective analysis of 196 single pregnancies in mothers who had previously undergone bariatric surgery using the Roux-en-Y gastric bypass, Sleeve Gastrectomy, or One Anastomosis Gastric Bypass methods. These pregnancies were assigned to one of three groups based on time interval from surgery to conception: early group (?12 months), the middle group (12-24 months) and the late group (>24 months). Gestational weight gain was classified as inadequate, adequate or excessive according to the National Academy of Medicine recommendations.

Despite current recommendations, 23.5% of the women in this study cohort had conceived within 12 months of their operation. These 'early' pregnancies were associated with lower gestational age at delivery (267.1 days vs 272.7 and vs 273.1 days), lower gestational weight gain (-0.9 kg vs +10.2 kg and +10.0 kg), and lower neonatal birth weight (2979 grams vs 3161 grams and 3211 grams) than those in the 'middle' and 'late' groups, respectively.

The authors note: "Although the difference of 200 g in neonatal birth weight is probably not clinically relevant, the lower gestational age in the 'early' group might be alarming as we also found a trend towards more preterm births in this group."

The team also found an association between 'inadequate' gestational weight gain (40.6% were in this category) and lower gestational age at delivery (266.5 days vs 273.8 days) and lower neonatal birth weight (3061 grams vs 3217 grams) compared to pregnancies in the 'adequate' weight gain group. Inadequate gestational weight gain was also associated with a higher rate of preterm births (15.9% vs 6.0%) than pregnancies with adequate gestational weight gain.

The authors conclude: "Our findings support the recommendation to avoid pregnancy for 12 months after bariatric surgery...We should encourage women who wish to conceive after bariatric surgery to avoid pregnancy until their weight has stabilised to minimise the risk of inadequate gestational weight gain. In order to break the vicious cycle of obesity and its health consequences, it is important that future research and clinical care focus on the prevention of babies being born small for gestational age after bariatric surgery."

WASHINGTON, D.C. - Peer reviewed by medical experts that included three U.S. government senior scientists and published in the American Journal of Therapeutics, the research is the most comprehensive review of the available data taken from clinical, in vitro, animal, and real-world studies. Led by the Front Line COVID-19 Critical Care Alliance (FLCCC), a group of medical and scientific experts reviewed published peer-reviewed studies, manuscripts, expert meta-analyses, and epidemiological analyses of regions with ivermectin distribution efforts all showing that ivermectin is an effective prophylaxis and treatment for COVID-19.

"We did the work that the medical authorities failed to do, we conducted the most comprehensive review of the available data on ivermectin," said Pierre Kory, M.P.A., MD, president and chief medical officer of the FLCCC. "We applied the gold standard to qualify the data reviewed before concluding that ivermectin can end this pandemic."

A focus of the manuscript was on the 27 controlled trials available in January 2021, 15 of which were randomized controlled trials (RCT's), the preferred trial of the World Health Organization, U.S. National Institutes of Health, and the European Medicines Agency. Consistent with numerous meta-analyses of ivermectin RCT's since published by expert panels from the UK, Italy, Spain, and Japan, they found large, statistically significant reduction in mortality, time to recovery and viral clearance in COVID-19 patients treated with ivermectin.

To evaluate the efficacy of ivermectin in preventing COVID-19, 3 RCT's and 5 observational controlled trial's including almost 2,500 patients all reported that ivermectin significantly reduces the risk of contracting COVID-19 when used regularly.

Many regions around the world now recognize that ivermectin is a powerful prophylaxis and treatment for COVID-19. South Africa, Zimbabwe, Slovakia, Czech Republic, Mexico, and now, India, have approved the drug for use by medical professionals. The results as seen in this latest study demonstrate that the ivermectin distribution campaigns repeatedly led to "rapid population-wide decreases in morbidity and mortality."

"Our latest research shows, once again, that when the totality of the evidence is examined, there is no doubt that ivermectin is highly effective as a safe prophylaxis and treatment for COVID-19," said Paul E. Marik, M.D., FCCM, FCCP, founding member of the FLCCC and Chief, Pulmonary and Critical Care Medicine at Eastern Virginia Medical School. "We can no longer rely on many of the larger health authorities to make an honest examination of the medical and scientific evidence. So, we are calling on regional public health authorities and medical professionals around the world to demand that ivermectin be included in their standard of care right away so we can end this pandemic once and for all."

PITTSBURGH, May 7, 2021 - In a paper published today in Nature Communications, an international group of collaborators led by researchers at UPMC Children's Hospital of Pittsburgh have identified a genetic cause of a rare neurological disorder marked by developmental delay and loss of coordination, or ataxia.

The disorder, scientists found, is caused by mutations in a protein called GEMIN5--one of the key building blocks of a protein complex that controls RNA metabolism in neurons. No mutations in GEMIN5 were previously linked to any genetic disease.

"It's just like building a house," said senior author Udai Pandey, Ph.D., associate professor of pediatrics, human genetics and neurology at the University of Pittsburgh School of Medicine. "You take out the most important brick at the base and the whole building falls apart."

GEMIN5 is part of a protein complex that regulates a slew of important cellular processes, including development of specialized outgrowths from nerve cells called dendrites and axons. Interestingly, mutations in another key protein of the complex, named survival motor neuron protein, cause a different devastating disorder--spinal muscular atrophy.

To gather material for the study, Pittsburgh researchers contacted pediatricians, geneticists and neurologists from all over the globe, eventually collecting data from 30 patient families in 12 different countries.

Because isolating live neurons from people isn't possible, researchers had to come up with another way of getting samples for future testing. They collected blood samples from pediatric patients who were referred to neurogenetic clinics with undiagnosed neurological symptoms. Blood samples were then processed to isolate cells that, with careful tinkering in the lab, were reprogrammed into neurons.

After comparing genetic material of reprogrammed neurons from sick children with that of unaffected relatives, scientists linked neurologic manifestations of the disease to 26 mutations in the GEMIN5 gene that cause damage to the structure of the protein.

"Children came into the clinic with non-specific symptoms, such as developmental delay and abnormal gait. Their doctors ran all the possible tests, including assessing a child's metabolic function, to no avail--their conditions had no easy explanation," said Deepa Rajan, M.D., assistant professor of pediatrics, Pitt School of Medicine, neurologist at UPMC Children's Hospital and a co-first author of the study. "It was not until we did an extensive genome analysis that we found that these patients had mutations in the GEMIN5 gene."

"Many genetic disorders seem individually rare, but collectively they are relatively common," added Rajan, who also is director of the Neurogenetics Clinic at UPMC Children's Hospital. "We now are able to harness next-generation technology to help diagnose previously undiagnosed children, and each new gene discovery is the start of the journey to understanding each of these diseases better."

Additional experiments linked damage to GEMIN5 protein to disease manifestations more definitively. Scientists found that depleting an analog of human neuronal GEMIN5 protein in fruit flies was deadly if it happened in early stages of the fly's life cycle, or drastically delayed its development if such disruption happened later.

"The most exciting part of being a researcher is working on a project that directly helps families," said Pandey. "We are hopeful that because of our study, neurologists will now consider testing for GEMIN5 mutations and that labs will include GEMIN5 in their testing for ataxic disorders. Genetic diseases are challenging to identify and treat, but if we find a cure, it will make a massive difference in someone's life."

Patients with lasting symptoms of COVID-19 who completed a six week, supervised rehabilitation programme demonstrated significant improvements in exercise capacity, respiratory symptoms, fatigue and cognition, according to researchers at the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre - a partnership between Leicester's Hospitals, the University of Leicester and Loughborough University.

The study, which is published in the journal Chronic Respiratory Disease today (Friday 7 May 2021), followed thirty patients who took part in face-to-face exercise rehabilitation classes twice a week over a period of six weeks. The programme included aerobic exercise, such as walking or using a treadmill, strength training of the arms and legs, and educational discussions to support symptom management based upon the information on the Your COVID Recovery platform.

Researchers found a statistically significant improvement in exercise capacity, as measured by scores of distance travelled and ability to keep going without a rest using incremental and endurance shuttle-walking tests. They also found that fatigue improved by 5 points on the Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue Scale over the six-week period. In addition, participants demonstrated improvement in their overall wellbeing and cognition, as measured by standardised clinical assessment tools.

Participants were referred through a hospital discharge follow-up telephone assessment, at a face-to-face COVID-19 clinic assessment, or via their GP. Individuals were offered the opportunity to take part if they displayed physical and/or psychological symptoms that were affecting their daily activities. Patients were excluded if they demonstrated acute symptoms, or were not medically stable (such as uncontrolled diabetes) or had only symptoms that were deemed unlikely to benefit from a pulmonary rehabilitation programme, such as loss of taste or smell.

Of the participants, there was an even split between men and women, with an average of 58 years. Eighty-seven per cent of participants were admitted to hospital with COVID-19, staying on average 10 days in hospital. Fourteen per cent required mechanical ventilation and were treated in an Intensive Care Unit. Four individuals had a pre-existing respiratory condition, such as asthma or chronic obstructive pulmonary disease (COPD).

Dr Enya Daynes, specialist pulmonary rehabilitation and research physiotherapist at Leicester's Hospitals and lead author of the study, said: "We know that COVID-19 survivors present with a wide variety of symptoms and that a one-size-fits-all approach to managing these would not be appropriate. However, there are some overlap between the needs of COVID-19 survivors and patients who have accessed pulmonary rehabilitation [PR] for other conditions, such as COPD. So we modified our well-established PR course for COVID-19 survivors and measured their symptoms to assess whether the programme could be of potential benefit.

"We found there were significant improvements in clinical outcomes of walking capacity and symptoms of fatigue, cognition and respiratory symptoms - factors that patients tell us most affect their quality of life."

Professor Sally Singh, head of cardiac and pulmonary rehabilitation at Leicester's Hospitals, professor at the University of Leicester and senior author of the paper, said: "This adapted rehabilitation programme for individuals following COVID-19 has demonstrated promising improvements in clinical outcomes. There were no drop-outs due to worsening symptoms and the high completion rate suggests that patients found it to be an acceptable treatment.

"There has been concern that rehabilitation may worsen or trigger symptoms of post-viral fatigue and that exercise therapy may exacerbate fatigue. The exercise element of this programme is progressed by staff experienced in delivering pulmonary and cardiac rehabilitation programmes in line with patient's symptoms throughout the programme. Our results did not show that fatigue worsened among the group of patients on the study, and that many of their symptoms improved. This suggests an adapted pulmonary rehabilitation courses can be part of a spectrum of patient-centred and holistic approaches to treating the many different presentations of lasting COVID symptoms."

The research team acknowledges that as a cohort study there is no control group of people with similar symptoms who did not embark on the modified pulmonary rehabilitation course to offer a comparison and that further studies with a larger patient population are needed to confirm their preliminary findings.

More than ever, patients are using telehealth to ask doctors and nurses about worrying blood-pressure readings, nauseating migraines and stubborn foot ulcers. But for patients with chronic conditions, how frequent should telehealth appointments be? Can that frequency change? Under what conditions?

West Virginia University researcher Jennifer Mallow is trying to answer these questions. In a new project, she and her colleagues completed a systematic review of studies that dealt with telehealth and chronic conditions. They found that--in general--telehealth services benefitted patients more if they continued for about a year, rather than ending after six months or so. But perhaps their most significant finding was just how much we have left to discover.

"As researchers, we recognized there is a gap in the current science," said Mallow, an associate professor in the School of Nursing's Adult Health Department. "We don't know how much or how often telehealth should be used to impact outcomes yet. So, we needed to do the work in order to push what we know about telehealth forward."

Their findings appear in E-Health Telecommunication Systems and Networks.

The systematic review included "quasi-experimental" tests as well as randomized controlled trials. It encompassed three types of telehealth services: synchronous (including real-time videoconferencing), asynchronous (such as exchanging messages) and remote patient monitoring (reviewing readings from devices like glucometers).

Regardless of the form telehealth took, Mallow and her team found that it produced positive results in patients who received the services for 51 weeks. In contrast, telehealth durations of 37 or 38 weeks produced mixed or neutral results.

But the data weren't plentiful enough for the researchers to draw any conclusions about the best dose of telehealth to improve care effectiveness, quality, safety and cost. For instance, how often--and for how long--should a patient with diabetes use remote patient monitoring to submit her blood sugar readings to her healthcare provider? What if her readings have been healthy and stable for a month? What if they've worsened for a week? What if she has high blood pressure in addition to diabetes?

"Even though we've been doing the ramp-up of telehealth for over a year, we still don't have the answers to these questions," Mallow said. "It's because this is implementation science. This is not work that's done in the lab. So, my plea--during the booming amount of work that's being done in telehealth research--is that we need to measure dose in standard and specific ways."

Mallow and her team are doing just that. As part of the "Take Me Home, West Virginia" program, they are delivering telehealth services to West Virginians, tracking those services and identifying how they influence particular health metrics.

The program is federally funded by the Centers for Medicare and Medicaid Services. It supports state Medicaid programs--including the West Virginia Department of Health and Human Resources' Bureau for Medical Services--to give older adults and people with disabilities a greater choice in where they get long-term care.

"We're collecting information related to dose," Mallow said. "How long do we spend with participants? What are the nurses doing, and how long does it take them? How long does it take us to review remote patient monitoring? Are we talking to patients on the phone? As we collect this information in a standard way, we can begin to make those links between dose and outcome."

Ben Klos--a registered nurse, faculty member in the School of Nursing and member of Mallow's research team--provides clinical services to the telehealth patients through the "Take Me Home, West Virginia" program. He spends much of his time reviewing telehealth patients' records and following up with them when symptoms arise.

"Our participants get sent a tablet, which helps them collect their vitals--mostly blood pressure, pulse and oxygen levels--and asks them disease-specific questions," Klos said. "If I see an abnormality in their vitals or answers, I call and check on them. For us, dosing helps us understand how long an intervention should be to benefit the patient while preventing device fatigue."

Another part of Klos' job is calling patients every two weeks to collect survey data about their alcohol use and signs of anxiety, depression and loneliness. Those phone calls can be especially important for patients with more than one chronic condition because, as a group, those patients score higher than average on measures of loneliness.

"We know that people with multiple chronic conditions have higher loneliness scores and that these scores are linked to functional decline, depressive symptoms and poorer physical health outcomes, including higher blood pressure," said Laurie Theeke, a professor and director of the Ph.D. Program at the School of Nursing, and part of the research team. "Using telehealth to connect with chronically lonely people in a way that works to diminish loneliness and enhance their perception of belonging could be key to improving measures of chronic illness control."

Telehealth could also be key to addressing some of the health problems that bedevil West Virginia. The state consistently has some of the highest rates of diabetes, obesity, coronary heart disease, COPD and other chronic conditions. In addition, it ranks sixth in the nation for poverty.

"Lack of access to healthcare services, transportation options and social supports are social determinants of health that have contributed to health disparities such as heart disease, diabetes and depression in West Virginia," said Steve Davis, an associate professor in the School of Public Health who was involved with the study. "Telehealth has the potential to address these service and support gaps."

For instance, telehealth could improve rural patients' access to medical specialists--like cardiologists, neurologists, endocrinologists and psychiatrists--whose offices are a long drive away.

That's particularly important because, as the Association of American Medical Colleges reports, three out of five federally designated health-professional-shortage areas are in rural locations.

"If you're going to use telehealth for chronic conditions, the various professional bodies need to come out with recommendations for when and how often," Mallow said. "The American Diabetes Association might say you should see your patients in person at least once per year to do a foot exam but could use telehealth for other follow-up care, for example. But before they do that, we need rigorous research studies so that they can make those determinations."