Body

Many antibiotic courses prescribed for common infections treated in English primary care (general practices and community services) exceed the recommended guidelines, reveals a study in The BMJ today.

Treatment courses were 1.3 million days beyond the durations recommended by guidelines, with most excess days due to treatment for respiratory conditions.

Previous studies have found significant over-prescribing of antibiotics in primary care in the UK and elsewhere, write the authors. And overuse of antibiotics adds to increased antibiotic resistance levels, and puts patients at risk of side effects, they say.

But there has been little research on reducing antibiotic overuse by cutting back on prolonged treatment.

So to explore this, researchers from Public Health England (PHE), University of Oxford, and Brighton and Sussex Medical School compared the durations of antibiotic courses prescribed for common infections in English primary care with the guidelines recommended by PHE in 2013.

They used data from general practices contributing to The Health Improvement Network (THIN) database between 2013-2015, including only prescriptions for oral antibiotics linked to one of 13 conditions, including acute sinusitis, acute sore throat, acute cough and bronchitis, pneumonia and acute cystitis.

They excluded chronic and recurrent conditions, as well as repeat prescriptions.

During this time, 931,015 consultations for the 13 common conditions led to antibiotic prescriptions, making up 20% of the total antibiotics prescribed for any condition. The most common conditions were acute cough and bronchitis (386,972), acute sore throat (239,231) and acute otitis media, a middle ear infection (83,054).

The durations of antibiotic treatment were generally not in line with guidance and most of the excess days were due to respiratory conditions, where 80% or more of antibiotic courses exceeded guidelines.

But only 1 in 10 (9.6%) of acute sinusitis prescriptions were longer than the recommended seven days. And for pneumonia 1 in 12 (8.1%) of prescriptions were longer than the recommended 7 days. However, more recent guidance recommends shorter durations for these conditions, the authors say.

For conditions where guidelines recommended longer durations, the proportion of prescriptions beyond the recommendation was significantly lower than for conditions where guidelines advised a short duration.

And although fewer prescriptions exceeded recommended durations for non-respiratory tract conditions, still more than half (54.6%) of the antibiotic prescriptions for acute cystitis among women were for longer than recommended.

There was significant under-treatment for acute prostatitis (inflamed prostate) and acute cystitis among men. For example, over half (52.3%) of courses were shorter than the recommended 28 days for prostatitis and nearly a third (31.8%) of cystitis treatments were under the suggested 7 days.

This is an observational study and the researchers point to some limitations, including that some prescriptions may have been incorrectly linked to certain conditions in the study. And they can't rule out the possibility that some of their findings may be due to other factors that might underlie decisions to prolong treatment.

But the authors say the results were similar when restricting the analyses to patients without underlying conditions. And for most conditions, three quarters or more of the prescribed antibiotics were mentioned in treatment guidelines.

The findings indicate "substantial scope" for reducing antibiotic prescribing through better adherence to recommended durations of treatment, they say, but "highlighting the magnitude of this issue is only the first step," they conclude.

In a linked editorial, Alastair Hay at the University of Bristol comments on the "growing evidence base informing policy on antimicrobial stewardship."

"Both clinicians and patients may need convincing to abandon longer courses of antibiotics, and future campaigns by Public Health England to "Keep Antibiotics Working" could usefully emphasise that when antibiotics are needed, shorter courses are sufficient to kill bacteria and less harmful than longer courses," he concludes.

Delaying or witholding antibiotics for over 65s with symptoms of urinary tract infection (UTI) appears to be associated with higher risk of bloodstream infection (sepsis) and death, finds a study published by The BMJ today.

The findings suggest that older adults (especially men aged over 85) should start taking antibiotics as soon as possible after diagnosis to prevent serious complications.

Urinary tract infection (UTI) is the most common bacterial infection in older patients. But concerns about the spread of antibiotic resistance have led to reductions in antibiotic use in England.

Such a decline in antibiotic use, however, may harm vulnerable older patients who are already more likely to develop UTI-related complications, and there is a lack of good evidence about the treatment of UTIs in primary care.

So a team of UK researchers set out to assess approaches to antibiotic prescribing and subsequent clinical outcomes in elderly patients.

They used primary care data linked to hospital and mortality records across England to analyse over 300,000 UTIs among more than 150,000 patients aged 65 years or older between 2007 and 2015.

The average age of participants was 77 years, most (79%) cases were female, and follow-up was for 60 days after diagnosis.

The researchers then compared outcomes for the 87% of patients who were prescribed immediate antibiotics (on the day of diagnosis), the 6% who had deferred antibiotics (prescription within seven days), and the 7% who had no antibiotics (no record of a prescription within seven days).

After taking account of potentially influential factors, bloodstream infections and mortality rates were significantly higher in the groups with no and with deferred prescriptions, compared with immediate prescriptions

The researchers estimate that on average for every 37 patients not given antibiotics and for every 51 patients whose antibiotic treatment was deferred, one case of sepsis would occur that would not have been seen with immediate antibiotics.

They also found that the rate of hospital admissions was around double (27%) in patients with no and with deferred prescriptions, compared with immediate prescriptions (15%).

Older men, especially those aged over 85 years, and those living in more deprived areas were most at risk.

This is an observational study, and as such, can't establish cause, and the researchers cannot rule out the possibility that unmeasured factors or missing data may have affected the results.

Nevertheless, they say their findings suggest that GPs "consider early prescription of antibiotics for this vulnerable group of older adults, in view of their increased susceptibility to sepsis following UTI and despite a growing pressure to reduce inappropriate antibiotic use."

Particular care is needed for the management of older men, and those in deprived communities, they conclude.

In a linked editorial, Alastair Hay at the University of Bristol says the implications of this study "are likely to be more nuanced than primary care doctors risking the health of older adults to meet targets for antimicrobial stewardship."

However, he agrees that prompt treatment should be offered to older patients, especially men and those living in areas of greater socioeconomic deprivation, and says further research is needed "to establish whether treatment should be initiated with a broad or a narrow spectrum antibiotic and to identify those in whom delaying treatment (while awaiting investigation) is safe."

Exercise may play a role in reducing the growth of colon cancer cells according to new research published in The Journal of Physiology. The study found that after a short session of high intensity interval training (HIIT), growth of colon cancer cells was reduced, and this also increased indicators of inflammation.

For a long time, the focus on exercise has been on the positive changes in the body that occur following a longer period of training. However, these findings suggest that the effects following a single session of HIIT, an exercise regime involving short, high energy bursts are also important.

The changes following HIIT suggest that repeated exposure to the acute effects of exercise may contribute to the fight against the cancer. These results reinforce the importance of doing regular exercise and maintaining a physically active lifestyle.

The study conducted by The University of Queensland in conjunction with the University of Waterloo, Ontario, involved colorectal cancer survivors completing either a single session of HIIT or 12 sessions over 4 weeks. Their blood samples were collected either immediately after the single session of exercise or at rest after 4 weeks of training, and were then analysed to study the growth of colon cancer cells.

Importantly the method used to model the colon cancer cells in the laboratory is very different to how they grow in the human body, requiring future research to translate these findings into human tumours.

James Devin, lead author on the research said:

"We have shown that exercise may play a role in inhibiting the growth of colon cancer cells. After an acute bout of HIIT there were specific increases in inflammation immediately after exercise, which are hypothesised to be involved in reducing the number of cancer cells.

This suggests that a physically active lifestyle may be important in tackling human colorectal tumours. We would now like to look at how these changes in growth occur and understand the mechanisms by which biomarkers in the blood can impact cell growth."

The AIDS Clinical Trials Group (ACTG), the world's largest and longest-established HIV research network, funded by NIAID at the U.S. NIH, will make 11 oral and 19 poster presentations at CROI 2019 (Seattle, March 4-7). Several have the potential to influence clinical practice and guidelines for care.

"For more than 30 years, the ACTG has been at the forefront of research to treat HIV and its co-infections and comorbidities," said ACTG Chair Judith Currier, M.D., MSc of the University of California Los Angeles. "These studies represent the breadth of ACTG investigations and offer important insights into the treatment of MDR-TB, how to approach antiretroviral treatment in resource-limited settings, and strategies to address chronic complications of HIV."

Highlights of ACTG presentations at CROI 2019 by topic include the following:

Tuberculosis:

84LB. QT EFFECTS OF BEDAQUILINE, DELAMANID OR BOTH IN MDR-TB PATIENTS: THE DELIBERATE TRIAL (ACTG 5343; CROI Oral Abstract Session 7: TB: From Contact to Cure and Beyond; Wednesday, March 6, 10:00 am - 12:00 pm) Kelly Dooley et al. (kdooley1@jhmi.edu) (presenting Gary Maartens. gary.maartens@uct.ac.za)

FEATURED ON THE WEDNESDAY, MARCH 6 OFFICIAL CROI PRESS CONFERENCE

Bedaquiline and delaminid, the first two novel medications for MDR-TB to be developed in decades, generated extensive excitement when released. However, there is a lingering concern about overlapping toxicities with the two medications, specifically prolongation of the QT interval. This abstract resolves the debate.

82. EARLY BACTERICIDAL ACTIVITY OF HIGH-DOSE ISONIAZID AGAINST MULTI DRUG RESISTANT TB (ACTG 5312 (CROI Oral Abstract Session 7: TB: From Contact to Cure and Beyond; Wednesday, March 6, 10:00 am - 12:00 pm) Kelly Dooley et al. (kdooley1@jhmi.edu)

High-dose isoniazid (INH) 10-15 mg/kg was left off of the World Health Organization guidelines for multidrug-resistant TB recently, due to lack of data about bacteriocidal killing against TB with typical patterns of INH resistance. This abstract provides pivotal data that could impact guidelines.

78. POTENTIAL CONCERN FOR TIMING OF DMPA INJECTION AMONG WOMEN TREATED FOR HIV AND TB (ACTG 5338; CROI Oral Abstract Session 7: TB: From Contact to Cure and Beyond; Wednesday, March 6, 10:00 am - 12:00 pm) Rosie Mngqibisa et al. (mngqibisa@ecarefoundation.com)

Injectable depot medroxyprogesterone acetate (DMPA) is an important hormonal contraceptive for women in resource-limited settings, but we don't know how it interacts with rifampin-based TB therapy. This study provides the first answers about the drug-drug interactions between DMPA and RIF based TB therapy among women on efavirenz-based ART.

Cure, Persistence, and Inflammation:

26. MULTI-DOSE IV ROMIDEPSIN: NO INCREASE HIV-1 EXPRESSION IN PERSONS ON ART, ACTG A5315 (CROI Oral Abstract Session 2: Strategies for HIV Cure; Tuesday, March 5, 10:00 am - 12:00 pm) Deborah McMahon et al. (mcmahond@pitt.edu)

FEATURED ON THE TUESDAY, MARCH 5 OFFICIAL CROI PRESS CONFERENCE

The histone deacetylase inhibitor Romidepsin (RMD) could help in efforts to reverse HIV latency, if the drug induced HIV expression from cells. Unfortunately, this trial showed that RMD did not induce HIV expression among patients on ART as had been hoped.

37 LB. SAFETY, TOLERABILITY AND IMMUNOLOGIC ACTIVITY OF RUXOLITINIB ADDED TO SUPPRESSIVE ART (ACTG 5366 (CROI Oral Abstract Session 3: Noncommunicable Diseases in Treated HIV; Tuesday, March 5, 10:00 am - 12:00 pm) Vincent Marconi et al. (vcmarco@emory.edu)

Ruxolitinib (RUX) is a Janus kinase (Jak) inhibitor that reduces biomarkers of systemic inflammation in people without HIV and has some activity in the laboratory on reducing persistence in ex-vivo models. This abstract provides important new insights on whether RUX can safely reduce the persistent inflammation seen in people living with HIV, even when on suppressive ART.

131. SIROLIMUS REDUCES T CELL CYCLING AND IMMUNE CHECKPOINT MARKER EXPRESSION, ACTG A5337 (CROI Oral Abstract Session 12: HIV/SIV and the Immune System: An Intimate Dance; Thursday, March 7 10:00 am - 12:00 pm) Timothy Henrich et al. (Timothy.Henrich@ucsf.edu)

This abstract shows that continuous use of oral sirolimus, an mTOR inhibitor, modulates CCR5 expression and markers of cell cycling. Safety of this approach is still being evaluated, however.

Cognitive Function, Obesity and Long-Term HIV Infection:

128. CARDIOVASCULAR RISK SCORES PREDICT LONGITUDINAL COGNITIVE FUNCTION IN OLDER PLHIV (ACTG 5322; CROI Oral Abstract Session 11: Suppressive ART and the CNS: Switches, Outcomes, and Biomarkers; Thursday, March 7 10:00 am - 12:00 pm) Felicia Chow et al. (felicia.chow@ucsf.edu)

Addressing neurocognitive decline in people living with HIV requires targets for intervention. This study shows that the established baseline 10-year cardiovascular risk score predicts longitudinal cognitive function in people living with HIV - - and may provide clinicians with new insights into opportunities to optimize both heart health and brain health.

129. OBESITY IS INDEPENDENTLY ASSOCIATED WITH COGNITIVE DECLINE IN HIV (ACTG 5322; CROI Oral Abstract Session 11: Suppressive ART and the CNS: Switches, Outcomes, and Biomarkers; Thursday, March 7 10:00 am - 12:00 pm) Jeremiah Perez et al. (perez@sdac.harvard.edu)

Much remains to be learned about what contributes to neurocognitive decline in persons living with HIV, and how to prevent or reverse it. In the ACTG 5322 (HALIO) study, both greater age and obesity were independently associated with neurocognitive decline.

This is just one of the many important ACTG abstracts at CROI 2019 highlighting the impact of obesity in HIV disease, including:

669. RISK FACTORS FOR EXCESS WEIGHT GAIN FOLLOWING SWITCH TO INTEGRASE INHIBITOR-BASED ART (ACTG 5322, ACTG 5001; Themed Discussion Session 08, Weight Gain During ART, Wednesday, March 6, 1:30 pm) Jordan Lake et al. (Jordan.E.Lake@uth.tmc.edu)

673. THE IMPACT OF WEIGHT GAIN AND SEX ON IMMUNE ACTIVATION FOLLOWING INITIATION OF ART (NWCS 407; Themed Discussion Session 08, Weight Gain During ART, Wednesday, March 6, 1:30 pm) Sarah Bares et al. (sara.bares@unmc.edu)

384. SEX AND OBESITY ARE ASSOCIATED WITH RESIDUAL VIREMIA IN ART-SUPPRESSED INDIVIDUALS (ACTG 5321; Poster Session P-E09; Mechanisms of Persistence; Thursday, March 7, 2:30 pm) Joshua Cyktor. et al. (jcc114@pitt.edu)

681. CHANGES IN FAT DENSITY AFTER ART INITIATION (NWCS 450; Poster Session P-N3: Adipose Tissue Density and Biology; Thursday, March 7, 2:30 pm) Jordan Lake et al. (Jordan.E.Lake@uth.tmc.edu)

Antiretroviral therapy:

52. PHARMACOGENETICS WORSENS AN ADVERSE ANTIRETROVIRAL-HORMONAL CONTRACEPTIVE INTERACTION (ACTG 5316; CROI Oral Abstract Session O-05: Strange Bedfellows: STIs, Contraception, and Trials of HIV Testing, Tuesday, March 5 10:00 am - 12:00 pm) David Haas et al. (david.haas@vanderbilt.edu)

We already know that efavirenz influences the levels of the birth control products etonogestrol and ethinyl estradiol in injectable implants. This important study looks at whether there are genetic traits we can screen for that influence that interaction.

518. IMPORTANT SEX DIFFERENCES IN OUTCOMES FOR INDIVIDUALS PRESENTING FOR THIRD LINE ART (ACTG 5288; Themed Discussion Session TD-04: Women with HIV: Are Outcomes Different? Tuesday, March 5, 1:30 pm) Catherine Godfrey et al. (cgodfrey@niaid.nih.gov)

This study looked at how to treat people living with HIV on failing 2nd-line ART in low- and middle- income countries. This abstract explores the very important topic of sex differences in safety and outcomes for men and women in that large study.

496. QUALITY OF LIFE AND ADHERENCE AS PREDICTORS OF SECOND-LINE ART VIROLOGICAL FAILURE (ACTG 5373; CROI Poster Session P-H3, Virologic Failures: To Second Line and Beyond, Wednesday, March 6, 2:30 pm). Thiago Torres et al. (thiago.torres@ini.fiocruz.br)

Can quality of life influence adherence when switching to a new regimen? If so, providers can help patients with adherence by focusing more on their overall quality of life.

499. PREDICTORS OF VIROLOGIC OUTCOME WHILE CONTINUING A PI-BASED ART REGIMEN IN ACTG A5288. (CROI Poster Session P-H3, Virologic Failures: To Second Line and Beyond, Wednesday, March 6, 2:30 pm). Robert Salata et al. (ras7@case.edu)

This important presentation provides further evidence of the factors that lead to better or worse outcomes for people failing 2nd line therapy in low- and middle-income countries.

By estimating a statistical model for male and female marathon world record progressions, Dr Angus also found that 1:58.05 is likely the fastest time that any living human being will be able to run this distance.

Published today in Medicine and Science in Sports and Exercise, the American College of Sports Medicine's flagship journal, results show that the chance of a female athlete ever breaking the two-hour mark is less than 1 in 100, with the fastest all-time female marathon time estimated to be 2:05.31.

The study by Monash Business School is the first to address all three related aspects of world record marathon performance in one modelling framework - the sub-two hour limit, the limits of human physiological running capacity and gender equivalence.

It also highlights the potential barriers elite female athletes face in marathon running resulting in a something of a "world record drought", with Paula Radcliffe's 2:15.25 mark, set in 2003, still standing. A 'sub-130 minute' project (2:10.00), advocated in this study, would empower female long-distance athletes.

The marathon has an official distance of 42.195 kilometres (26.219 miles) and was one of the original Olympic events in 1896. More than 800 marathons are held across the world each year, with tens of thousands of participants taking part in this physically gruelling event.

"Breaking the sub-two hour marathon in an official event has attracted growing interest in recent times with commercial and international momentum building," Dr Angus, Associate Professor of Economics at Monash Business School and ultramarathon runner, said.

"Prospects of a male athlete going sub-two hours in an IAAF event, even in the near future, would appear high given that the most recent world record reduced the mark by 78 seconds, and the Nike 'Breaking2' project produced a time just 25 seconds outside this two hour barrier. However, a 13 year wait seems more in line with the evidence."

As part of the study, Dr Angus applied a robust non-linear economic model to all official IAAF world record marathon performances of men and women since 1950 in order to calculate record-breaking prediction intervals.

From there, Dr Angus was able to reconceptualise the 'sub-two hour question' as one of odds - for example, when will a given time be run with 1 in 10, or 10% likelihood.

Using these figures, Dr Angus was then able to determine the limits of human performance for the male and female marathon; the performance gap between the current male and female world record to the limiting times; and the equivalent of the 'sub-two hour' threshold for women and when this will be achieved.

The economic model is, on average, accurate to within 1% for men - or around 70 seconds - across a 66-year period which saw a 19 minute reduction in the world record time. For women, accuracy is within 3% - or roughly 200 seconds - across the same period where the world record dropped by one hour and 22 minutes.

A statistical findings for the sub-two hour male marathon are noted as:

Odds
Chance
When

1 in 4
25%
March 2054

1 in 10
10%
May 2032

1 in 20
5%
June 2024

1 in 50
2%
April 2017

1 in 100
1%
January 2013

1 in 200
0.5%
June 2009

"In other words, if an IAAF marathon were run in May 2032, then I would predict that there is a 10% chance that a runner in that event will break the two hour mark," Dr Angus said.

"The current male world record holder, Eliud Kipchoge from Kenya, is just a fraction outside the sub-two hour mark with a time of 2:01.39 - a record he set at the Berlin Marathon in 2018. By inspecting the prediction lines on my economic model, there was only a 2% chance that the sub-two hour record would be broken at that point in time.

"While a sub-two hour run could occur anytime between now and May 2032, the likelihood of that occurring is extremely rare."

Using the same economic model and 10% likelihood approach, Dr Angus calculated that the likely human performance limit for male and female marathon times is 1:58.05 (performance gap to current world record of 2.9%) and 2:05.31 (performance gap of 8.6%) respectively.

Dr Angus also used the model to identify the equivalent of the sub-two hour marathon for female athletes.

"Based on the equivalent performance gap to the expected all-time fastest time for females, a target of 2:10.00 or the 'sub-130 minute' project would be a reasonable focal point to build international momentum around," Dr Angus said.

However, the study also provides statistical weight to the existence of a quantifiable lack of world record progression in the female marathon over the last decade, in particular, from the African gene pool.

"In my opinion, this finding should cause public and private actors to work harder at reducing barriers and increasing opportunities for elite female athletic performance. The evidence of this study and others like it is that there are likely world-record female marathoners living today, principally in Africa. We just don't yet know who they are," he said.

People who suffer from obesity and type 2 diabetes are more likely to become victims of infectious diseases. Both conditions affect the immune system and hence increase the risk of infections. Scientists have long sought a deeper understanding of the mechanism underlying this weakness in the immune system of obese and diabetic individuals.

A study performed at the University of São Paulo's Biomedical Science Institute (ICB-USP) in Brazil has now demonstrated that the propensity of people with obesity and type 2 diabetes to contract infectious diseases is associated with alterations to neutrophils, which are white blood cells that are part of the immune system and inflammatory response and the first cells to react to the presence of an invasive pathogen in the organism.

Findings from the study have just been published in Scientific Reports, an online journal owned by Springer Nature. The study resulted from the doctoral research of biochemist Wilson Mitsuo Tatagiba Kuwabara and was supervised by biologist Tatiana Carolina Alba-Loureiro, currently at Southern Cross University (UNICSUL).

The study was conducted at ICB-USP in the laboratory formerly led by Professor Rui Curi, currently at Butantan Institute and UNICSUL.

"Kuwabara's research is highly important because it shows that the conditions for insulin resistance, which we call metabolic syndrome, are associated with a major alteration to neutrophils. It also suggests this alteration may explain the susceptibility of obese people and diabetic individuals to infectious processes," Curi said.

Kuwabara recalled that the mechanism that makes obese people and diabetic individuals more vulnerable to severe infectious diseases has always been poorly understood. "We found the answer by investigating what happens in neutrophils to transmembrane protein and toll-like receptor TLR4 when it recognizes the toxin LPS in invading pathogens," he said.

Toll-like receptors (TLRs) are a family of proteins that play a key role in the innate immune system. Impaired activation of TLR4 is a mechanism that can weaken the capacity of immune cells to combat pathogens.

"TLR4 is a membrane receptor and is found in the external membrane of most cells in the organism, but its main role takes place in immune cells. When TLR4 makes contact with invading pathogens, it triggers an immune response by the organism," Kuwabara said.

TLR4 is activated when it comes into contact with gram-negative bacteria. More specifically, TLR4 activation occurs when the receptor detects a toxin called lipopolysaccharide (LPS) in the external membrane of gram-negative bacteria. When this happens, TLR4 tells the organism to produce more inflammatory substances to combat the invading pathogens. LPS is a soluble endotoxin and can also be found in the bloodstream of infected individuals.

Gram-negative bacteria are among the main causes of severe infectious diseases such as chlamydia, brucellosis, salmonellosis, meningitis, cholera, syphilis and bubonic plague, among others.

The study is part of the regular grant project "The role of neutrophils in the inflammatory response during type 2 diabetes mellitus: cellular and molecular mechanisms", for which Alba-Loureiro is principal investigator, and is associated with the Thematic Project "Cellular and molecular mechanisms of insulin resistance and inflammation in obese Wistar rats and lean Goto-Kakizaki rats: causes and associations with diet and physical exercise", for which Curi is principal investigator.

Kuwabara is currently a postdoctoral researcher at ICB-USP, with a scholarship from FAPESP. His research is supervised by Professor José Cipolla Neto.

Experimental models

To understand the TLR4 activation mechanism in obese people and diabetic individuals, Kuwabara performed experiments using two different experimental models with Goto-Kakizaki (GK) and Wistar rats.

The GK rat is a Wistar substrain developed in Japan in the 1970s for the study of diabetes. It spontaneously displays all the classic symptoms of type 2 diabetes, such as insulin resistance, fasting hyperglycemia, hyperinsulinemia, and increased levels of triglycerides and cholesterol in the blood. These rats were especially imported for the experiment at ICB-USP and are the only GK rats in Brazil.

The second model used in the study involved Wistar rats, one of the most commonly used rat strains in scientific studies. In this case, they were fed a high-fat diet (60% of calories from fat) or a control diet for eight weeks. At least eight animals were used in each model.

After eight weeks on the high-fat diet, the Wistar rats exhibited obesity, with liver fat accumulation, glucose intolerance, insulin resistance and inflammation.

To evaluate the neutrophil response to LPS, LPS intratracheal instillation was performed on rats in the models for obesity and type 2 diabetes. A cannula was inserted into the trachea, and LPS in solution was injected directly into the airways.

After six hours, the rats were euthanized to determine the immune system's response to LPS installation in each group. Blood samples were taken, and bronchoalveolar lavage was performed to collect neutrophils from the inflammatory environment.

To analyze the immune response to LPS, neutrophils isolated from the lavage were counted, cytokine and chemokine volumes were measured, and the activity of myeloperoxidase (MPO), an enzyme used as a neutrophil marker, was evaluated.

The researchers found that LPS intratracheal instillation promoted neutrophil migration to the lungs. The number of neutrophils collected in the bronchoalveolar lavage was smaller in the obese rats and GK rats than in the control group. Similarly, the obese rats and GK rats exhibited less MPO activity and lower production of pro-inflammatory cytokines than the control group.

"After LPS stimulation, we observed less viability in neutrophils collected from GK rats. Compared with the control group, blood neutrophils from GK rats showed a higher death rate in terms of cell membrane integrity loss and increased levels of cleaved caspase-3, a protein that plays a key role in cell death," Kuwabara said.

"With regard to the obese rats, we found their neutrophils to be more susceptible to cell death even while circulating in the blood and hence before migrating to the lungs to combat the inflammation induced by LPS instillation."

The data showed that the neutrophil response of GK and obese rats to LPS was impaired, Kuwabara added. In other words, they were LPS-tolerant. "This tolerance may explain the higher death rates in obese patients and diabetic individuals as a result of bacterial infection," he said.

Biochemical reason

According to Curi, the study is important because it succeeded in demonstrating that neutrophils were involved in an augmented inflammatory process in obese and diabetic rats.

"Thus, when the neutrophils come into contact with bacteria, they're unable to respond effectively to these agents. This is how the infectious process is installed," he said.

TLR4 is an essential receptor to the innate immune response, and loss of its activation jeopardizes the inflammatory process and the response to infection.

"Now we know the biochemical reason why obese people and diabetic individuals are more likely to develop diseases. Further research is necessary to find out why TLR4 is inactivated in neutrophils, as described," Curi said.

Women who work more than 55 hours a week are at a higher risk of depression but this is not the case for men, according to a new UCL-led study with Queen Mary University of London.

The study of over 20,000 adults, published today in the BMJ's Journal of Epidemiology & Community Health, found that after taking age, income, health and job characteristics into account, women who worked extra-long hours had 7.3% more depressive symptoms than women working a standard 35-40 week. Weekend working was linked to a higher risk of depression among both sexes.

Women who worked for all or most weekends had 4.6% more depressive symptoms on average compared to women working only weekdays. Men who worked all or most weekends had 3.4% more depressive symptoms than men working only weekdays.

"This is an observational study, so although we cannot establish the exact causes, we do know many women face the additional burden of doing a larger share of domestic labour than men, leading to extensive total work hours, added time pressures and overwhelming responsibilities," explained Gill Weston (UCL Institute of Epidemiology and Health Care), PhD candidate and lead author of the study.

"Additionally women who work most weekends tend to be concentrated in low-paid service sector jobs, which have been linked to higher levels of depression."

The study showed that men tended to work longer hours in paid work than women, and having children affected men's and women's work patterns in different ways: while mothers tended to work fewer hours than women without children, fathers tended to work more hours than men without children.

Two thirds of men worked weekends, compared with half of women. Those who worked all or most weekends were more likely to be in low skilled work and to be less satisfied with their job and their earnings than those who only worked Monday to Friday or some weekends.

Researchers analysed data from the Understanding Society, the UK Household Longitudinal Study (UKHLS). This has been tracking the health and wellbeing of a representative sample of 40,000 households across the UK since 2009.

Information about working hours, weekend working, working conditions and psychological distress was collected from 11,215 working men and 12,188 working women between 2010 and 2012. Depressive symptoms such as feeling worthless or incapable were measured using a self-completed general health questionnaire.

"Women in general are more likely to be depressed than men, and this was no different in the study," Weston said.

"Independent of their working patterns, we also found that workers with the most depressive symptoms were older, on lower incomes, smokers, in physically demanding jobs, and who were dissatisfied at work."

She added: "We hope our findings will encourage employers and policy-makers to think about how to reduce the burdens and increase support for women who work long or irregular hours - without restricting their ability to work when they wish to.

"More sympathetic working practices could bring benefits both for workers and for employers - of both sexes."

AUSTIN, Texas--A new Texas Policy Evaluation Project (TxPEP) study shows that use of medication abortion, also known as "the abortion pill," bounced back in Texas after a March 2016 label change by the US Food and Drug Administration (FDA). The label change impacted the use of mifepristone, one of the two medications used for medication abortion, and essentially nullified the restrictions put in place in 2013 by Texas House Bill 2 (HB 2), legislation that contributed to a large decline in medication abortion use.

This study, published in Contraception and available open access, reports that medication abortion constituted 28% of all abortions before HB 2, 10% after implementation of the HB 2 restrictions, and 33% after the FDA label change. TxPEP collected data directly from licensed non-hospital abortion facilities at three time points and supplemented the data with publicly available abortion statistics from the Texas Department of State Health Services.

"The new FDA label has allowed Texas providers to offer medication abortion in a way that is consistent with the best medical evidence, rather than being forced to comply with an outdated label imposed by HB 2," said lead author of the study Sarah Baum, investigator at TxPEP and associate at Ibis Reproductive Health. "This has increased options for Texas women and brought the proportion of medication abortions in the state in alignment with national data."

The label change brought medication abortion prescribing guidelines in line with evidence-based practice, reducing the number of required in-person visits from four to two and extending the period when patients can take the pill from seven weeks of pregnancy to 10 weeks.

"With the label change, many Texas women have regained access to medication abortion, a method some women prefer," said Dr. Kari White, investigator at TxPEP. "However, the smaller network of open facilities in Texas following HB 2 means that some women still need to travel considerable distances just to take a pill that is established to be safe and effective."

About 900,000 reproductive-age women in Texas currently live more than 150 miles from an abortion clinic, in part due to clinic closures brought about by HB 2. There are currently 20 clinics in Texas, down from more than 40 before HB 2 was passed. Additional barriers remain to accessing medication abortion in Texas, including a ban on telemedicine for the provision of medication abortion, a mandatory ultrasound during an in-person visit at least 24 hours before taking the first pill, and prohibition of insurance coverage for abortion.

All forms of Brexit will negatively impact the UK National Health Service (NHS), but the prospect of a No-Deal Brexit presents by far the worst scenario, with negative effects on the health care workforce, NHS financing, availability of medicines and vaccines, sharing of information and medical research, according to a new Health Policy review published in The Lancet.

While the Withdrawal Agreement negotiated between the UK Government and the EU (but not agreed by Parliament) offers a more positive scenario compared to a No-Deal Brexit, there are serious concerns about the negative impact of Brexit on the NHS beyond the transition period, when the Backstop or arrangements envisaged in the Political Declaration on the Future Relationship would come into force.

Under either the Backstop or Political Declaration scenarios, the impact of Brexit on the NHS is only slightly less harmful than the No-Deal scenario, though the exact impacts vary.

In the new analysis, the authors, who are leading experts in public health and law, use the available legal and political texts on four Brexit scenarios to assess the likely impact on fifteen specific aspects of the UK health service.

The four scenarios are a No-Deal Brexit under which the UK leaves the EU on March 29, 2019 without any formal agreement on the terms of the withdrawal, the Withdrawal Agreement including a transition agreement until the end of 2020, the Northern Ireland Protocol's Backstop, and the Political Declaration on the Future Relationship between the UK and EU, which are possible scenarios after the end of the transition period.

Remaining in the EU was not included in the analysis but is better overall for health than any form of Brexit, as was outlined in a previous paper by the same authors in 2017, also published in The Lancet [1].

The authors warn that little evidence exists that the UK is prepared for any of the eventualities set out in their analysis. For instance, the recently published NHS ten-year plan ran to 136 pages, with only two mentions of Brexit, neither of which offered any detail about what it might mean, or how any threats would be addressed.

Professor Martin Mc Kee, co-author from the London School of Hygiene & Tropical Medicine (UK) says: "Some people will dismiss our analysis as "Project Fear". But with just over a month to go to Brexit, we need to move beyond slogans. We have set out the problems in detail, based on the best available evidence. If others disagree, then they owe it to the British people to say why. It just isn't good enough to keep saying that "something will work out" without any details of exactly how." [2]

Recruitment and retention to the health care workforce represents a major challenge post Brexit. The Withdrawal Agreement provides reciprocal arrangements and mutual recognition of professional qualifications up to 2020. But, no provisions for health care workers have been made in the Backstop or Political Declaration. And, under a No-Deal Brexit, the Immigration White Paper proposes a minimum salary threshold of £30,000 per year which could seriously limit immigration of many health workers to the UK.

Under the Withdrawal Agreement, reciprocal health care arrangements (eg via the European Health Insurance Card, EHIC) would remain but only until 2020 as there is no mechanism to continue them subsequently, although some limited bilateral agreements may be possible with time. All reciprocal health care arrangements would cease in 2019 under a No-Deal scenario. This would be particularly harmful to older UK residents and people with pre-existing conditions for whom health insurance cover in the EU would be particularly expensive.

Access to capital financing for NHS infrastructure via the European Investment Bank would be negatively impacted in all scenarios. As one of the largest areas of public expenditure, any negative impact in the UK economy will put additional pressure on NHS financing, and the UK has already seen a slower rate of economic growth than if it had remained in the EU. The idea that Brexit will bring a "deal dividend" has been described as not credible by the Treasury Select Committee.

Given looming crises in several other sectors, including welfare and the criminal justice system, the authors note that concerns about whether the Government can maintain its funding commitments for the NHS are warranted.

Under the Withdrawal Agreement, the continuity of legal provisions will secure supply chains for medicines, vaccines, medical devices and equipment until 2020. Under a No-Deal Brexit, the absence of a legal framework for imports and exports would have an immediate and drastic effect on supply chains. Despite Government reassurance of contingency plans in place, shortages are likely because stockpiling arrangements cannot cope more than a few weeks, proposals that doctors offer "best alternative medication" can be distressing for patients, and some products (such as radioisotopes) cannot be stockpiled.

Under any form of Brexit, the UK will no longer be part of the European Medicines Agency, and while the UK's Medicines and Health products Regulatory Agency will continue to licence medicines, without laws in place to secure regulatory alignment, the UK would become less attractive for global pharma to launch new medicines, potentially meaning launch dates up to 24 months later.

Professor Tamara Hervey, co-author from the School of Law, University of Sheffield (UK) says: "It's critical to be clear about the practical effects of disentangling over 40 years of legal integration. This is not something that can be done hastily without potentially jeopardising people's health. Future legal relations will have quite different effects on the NHS: these should be taken into account when the UK Government, advised by Parliament, makes its post-Brexit choices."

Any form of Brexit will also harm the UK's European and global leadership role in health. Membership of the European Centre for Disease Control is not mentioned in the Withdrawal Agreement, and while the Political Declaration mentions global collaboration on public health, it does not reference European collaboration. UK laws on air pollution, workplace health and safety, and tobacco trade derive from EU law. With the UK having failed to meet standards on air quality, there is concern that the UK might use Brexit to roll back some of these measures.

Dr Nick Fahy, co-author from the Department of Primary Care, University of Oxford (UK), says: "The NHS is at the heart of our national life; it is vital to understand the impact Brexit will have on it. Patients and the people who care for them are facing ever-growing uncertainty and potential disruption to healthcare. The NHS urgently needs clarity and certainty about Brexit." [2]

Finally, Brexit has required the mobilisation of hundreds of civil servants, but the task ahead is immense, requiring Government and Parliament to pass several major pieces of legislation and up to 600 statutory instruments within a month. Meanwhile important legislation, such as social care, has suffered prolonged delays.

The authors note that their analysis is based on the most up to date available legal texts, but is inherently limited by the lack of transparency about the Governments' preparations, the lack of detail in the Political Declaration, and the unprecedented nature of a member state leaving the EU after more than 40 years of membership for which no comparable situation exists.

UCLA scientists have developed a new method to quickly screen hundreds of drugs in order to identify treatments that can target specific tumors.

The approach could help scientists understand how a person's tumor would respond to a certain drug or drug combination, and it could help guide treatment decisions for people with rare and hard-to-treat cancers. A paper detailing the new technique was published in Communications Biology.

"We always focus on how we need new and better drugs to treat cancer," said Alice Soragni, the senior author of the study and a scientist at the UCLA Jonsson Comprehensive Cancer Center. "While that's true, we also have many drugs currently available -- we just haven't been able to figure out who is going to respond to which ones for most of them."

The screening method uses patients' own cells, collected during surgery, to create miniature tumor organoids.

Organoids are simpler, smaller versions of bodily organs or tumors that scientists can grow in a lab to replicate the full-function structures; researchers create them to study diseases and possible treatments.

"We obtain cancer cells directly from surgery and that same day we can seed them to generate tumor organoids," said Soragni, an assistant professor in the division of hematology/oncology at the David Geffen School of Medicine at UCLA and member of the Molecular Biology Institute at UCLA. "We created a miniaturized system that allows the setup of hundreds of wells for testing with minimal manipulation."

After the tumor organoids are established, typically in three to five days, the lab screens hundreds of drugs to determine which ones are effective. The approach developed by Soragni's lab uses an automated feed -- instead of testing one drug at a time, scientists use robots to simultaneously screen hundreds of different treatments. The method is fast and efficient: The entire process, from surgery to final results, can take as little as one to two weeks.

To test the technique, Soragni's team took cells from four patients -- three with ovarian cancer and one with peritoneal cancer -- to grow tumor organoids. The test enabled the researchers to produce personalized snapshots of which drugs were effective for each patient's organoids.

For example, one of the four participants in the study was a woman with an extremely rare type of ovarian cancer. (The specific subtype of cancer is diagnosed in fewer than 200 U.S. women each year.) The organoids developed from her cancer cells responded to a class of drugs called cyclin-kinase inhibitors, which can target cancer by preventing it from growing. Soragni said there are currently no known biomarkers to predict the effect of the specific cyclin-kinase inhibitors identified by the screening on tumor growth. So without the test, it would have been impossible to know that the drugs would work on that specific subtype of cancer.

For many rare types of cancer, scientists know little about drug susceptibilities. But being able to create models of rare tumors in the lab can help scientists identify patients who could benefit the most from a specific treatment. In addition to identifying personalized treatments, the technique could also help scientists select patients to participate in clinical trials for potential new cancer therapies.

"This could become a powerful tool to help guide therapies for people who really have no known treatment options left," Soragni said.

AURORA, Colo. (Feb. 25, 2019) - A survey of Colorado home health care clinicians (HHCs) revealed that 60 percent said they had not received enough information to guide patient treatment while 52 percent said patients often had unrealistic expectations of the kind of care they would receive.

The study, conducted by researchers at the University of Colorado Anschutz Medical Campus, also showed major gaps in communication between hospital and home health care staff, some that could have serious medical consequences.

The study was published today in the Journal of the American Medical Directors Association.

"We have heard of medication errors occurring between hospitals and home health care providers," said the study's lead author Christine D. Jones, MD, MS, assistant professor at the University of Colorado School of Medicine. "As a result, patients can receive the wrong medication or the wrong dose. Some home health providers don't get accurate information about how long to leave a urinary catheter or intravenous line in."

Jones and her colleagues surveyed nurses and staff at 56 HHC agencies throughout Colorado. Participants were sent a 48-question survey covering communication between hospitals and HHCs, patient safety, pending tests, medication schedules, clinician contact and other areas.

More than half said hospitals did not adequately prepare patients for home health care upon discharge. They also said patients often expected a level of home care that was simply not available including extended hours, housekeeping and help with transportation.

Home health care workers with access to electronic health records (EHRs) for referring providers had fewer problems relating to a lack of information about patients, including critical medication data.

They were able to electronically access notes, orders, lab and radiology results and referrals. Some 12 percent of respondents reported positive experiences when accessing the Colorado Regional Health Information Organization (CORHIO, http://www.corhio.org) about hospital admissions.

Yet many did not have access to such information.

"Although almost all (96 percent) indicated that Internet-based access to a patient's hospital record would be at least somewhat useful," Jones said. "Fewer than half reported having access to EHRs for referring hospitals or clinics."

She said the survey revealed problems getting medication doses right due to conflicting information.

"Notably, additional studies have found extremely high rates of medication discrepancies (94 percent - 100 percent) when referring provider and HHC medications lists are compared," Jones said.

The study suggested targeted education of hospital staff about what home health clinicians actually provide to patients and caregivers to avoid frustration.

Jones noted that if these issues are arising in Colorado, they could signify a national problem.

"For hospitals and HHC agencies seeking strategies to improve communication, this study can provide targets for improvement," she said. "Future interventions to improve communication between the hospital and HHC should aim to improve preparation of patients and caregivers to ensure they know what to expect from HHC and to provide access to EHR information for HHC agencies."

Researchers from the University of Alabama at Birmingham Department of Occupational Therapy have published new findings that suggest spending 20 minutes in an urban park will make someone happier regardless of whether they are engaging in exercise or not during the visit.

According to the study, published in International Journal of Environmental Health Research, urban parks have been recognized as key neighborhood places that provide residents with opportunities to experience nature and engage in various activities. Through contact with the natural environment and engagement in health-promoting and/or social and recreational activities in parks, users experience physical and mental health benefits such as stress reduction and recovery from mental fatigue.

Principle investigator Hon K. Yuen, Ph.D., OTR/L, professor in the UAB Department of Occupational Therapy, said the original intent of the project was to validate previous research findings on the impact of park visit on emotional well-being, and evaluate the contribution of choosing to participate in physical activity in the park in relation to emotional well-being after the park visit.

"Overall, we found park visitors reported an improvement in emotional well-being after the park visit," said Yuen. "However, we did not find levels of physical activity are related to improved emotional well-being. Instead, we found time spent in the park is related to improved emotional well-being."

Co-author and chair of the department Gavin R. Jenkins, Ph.D., OTR/L, said this means that potentially all people can benefit from time in a park. If you cannot be physically active due to aging, a disability or any other limitations, the study implies a person can still gain health benefits just from a visit to a local park.

Participants of the study were adult visitors to one of the three urban parks -- Overton, Jemison and Cahaba River Walk Parks -- in Mountain Brook, Alabama. Data were collected from 98 adult park visitors; four visitors reported that they participated in this study twice. Data from the second participation were excluded, resulting in 94 unique participants participating in the study. These parks were selected for the study because they were the three main public parks in Mountain Brook and had a relatively high volume of visitors daily.

Yuen said several limitations of the study included the lack of objective data to measure emotional health and confining the study to just three urban parks in a six-month data collection period.

Although a small study, Jenkins said the significance of these findings helps reinforce the need for more urban parks and the conservation of those that already exist.

"There is increasing pressure on green space within urban settings," said Jenkins. "Planners and developers look to replace green space with residential and commercial property. The challenge facing cities is that there is an increasing evidence about the value of city parks but we continue to see the demise of theses spaces."

SAN FRANCISCO, C.A. -- Regular dietary peanut consumption after completing oral immunotherapy (OIT) or sublingual immunotherapy (SLIT) for peanut allergy may provide continued protection against accidental exposures to the allergen, according to a new study led by Edwin Kim, MD, who presented the findings at the annual American Academy of Allergy, Asthma and Immunology (AAAAI) conference in San Francisco.

The observational study followed 55 people who had completed OIT or SLIT peanut immunotherapy trials at UNC-Chapel Hill and were desensitized to between 300 mg and 5,000 mg of peanut - with 300 mg representing one peanut kernel. Desensitization increases the amount of peanut it takes to cause an allergic reaction, decreasing the likelihood of a severe reaction caused by accidental peanut exposure.

"People just want to know that they are protected," said Kim, assistant professor of medicine and pediatrics at the UNC School of Medicine and director of the UNC Food Allergy Initiative. "They don't necessarily want to eat large amounts of their allergen, they just want a level of reassurance that if a restaurant cook makes a mistake or a food label is wrong, they won't have a severe allergic reaction."

After completing their immunotherapy trial, participants were encouraged to introduce foods containing peanuts into their diets with a goal of about 300 mg of peanut each day. As part of their long-term follow-up, participants were asked to report how much they ate, how often they ate it and how they felt afterward.

The majority of participants continued regularly eating peanuts daily for up to eight years after completing immunotherapy. Among those still eating peanuts, the median amount of daily consumption was 600 mg. No reactions from accidental ingestions were reported for the 55 participants, but ten people reported allergic reactions to the daily peanut foods they introduced into their diet. The majority of reactions were mild and treated with antihistamines, however three reactions required epinephrine and two required EMS. Although these more significant reactions were infrequent, it is a reminder that incorporation of dietary peanut in this capacity should only be done under the guidance of an allergist.

"One of the big questions out there now is, 'what does life after immunotherapy look like?'" said Kim. "That's what we were trying to answer with this research, and it appears that eating these small amounts of peanut is safe, can improve quality of life, and may help to maintain desensitization."

Kim says more longitudinal studies need to be done, but he and colleagues are hopeful this research can be applied to other types of food allergies.

SAN FRANCISCO - Children exclusively breastfed for the first three months of life had significantly lower odds of having eczema at age 6 compared with peers who were not breastfed or were breastfed for less time, according to preliminary research presented during the American Academy of Allergy, Asthma & Immunology 2019 Annual Meeting.

Eczema is a chronic condition characterized by extremely itchy skin that, when scratched, becomes inflamed and covered with blisters that crack easily. While genes and the environment are implicated in this inflammatory disease, many questions remain unanswered, such as how best to prevent it. According to the Centers for Disease Control and Prevention (CDC), breastfed infants have reduced risks for developing many chronic conditions, including asthma and obesity.

"The evidence that being exclusively breastfed protects children from developing eczema later in life remains mixed," says Katherine M. Balas, BS, BA, a clinical research assistant at Children's National and the study's lead author. "Our research team is trying to help fill that data gap."

Balas and colleagues tapped data collected in Infant Feeding Practices Study II, a longitudinal study co-led by the CDC and the Food and Drug Administration (FDA) from 2005 to 2007, as well as the agencies' 2012 follow-up examination of that study cohort. This study first tracked the diets of about 2,000 pregnant women from their third trimester and examined feeding practices through their babies' first year of life. Their follow-up inquiry looked at the health, development and dietary patterns for 1,520 of these children at 6 years of age.

About 300 of the children had been diagnosed with eczema at some point in their lives, and 58.5 percent of the 6-year-olds had eczema at the time of the CDC/FDA Year Six Follow-Up. Children with higher socioeconomic status or a family history of food allergies had higher odds of being diagnosed with eczema.

"Children who were exclusively breastfed for three months or longer were significantly less likely (adjusted odds ratio: 0.477) to have continued eczema at age 6, compared with peers who were never breastfed or who were breastfed for less than three months," Balas adds. "While exclusive breastfeeding may not prevent kids from getting eczema, it may protect them from experiencing extended flare-ups."