Day: September 13, 2022

Categories : Environmental EffectsTags : Leave a comment

Humans Create Their own Pollution-cleaning Zone

On By ModernMedia
Source: Paul Wong on Unsplash

People typically spend 90% of their lives indoors or in vehicles, exposed to a multitude of chemicals from various sources, from vehicle exhausts to fumes from cooking and cleaning. The human body is also a potent emitter of chemicals from its own breath and skin. One of nature’s cleaners for these chemicals is hydroxyl (OH) radicals, primarily formed when UV radiation in sunlight interacts with ozone and water vapour. However, glass windows filter out UV radiation, lowering the indoor concentration of OH radicals.

Indoors, on the other hand, the air is of course far less affected by direct sunlight and rain. Since UV rays are largely filtered out by glass windows it has been generally assumed that the concentration of OH radicals is substantially lower indoors than outdoors and that ozone, leaking in from outdoors, is the major oxidant of indoor airborne chemical pollutants.

OH radicals are formed from ozone and skin oils

However, now it has been discovered that high levels of OH radicals can be generated indoors, simply due to the presence of people and ozone. This has been shown by a team led by the Max Planck Institute for Chemistry in cooperation with researchers from the USA and Denmark.

“The discovery that we humans are not only a source of reactive chemicals, but we are also able to transform these chemicals ourselves was very surprising to us,” said Nora Zannoni, first author of the study, now at the Institute of Atmospheric Sciences and Climate in Bologna, Italy. “The strength and shape of the oxidation field are determined by how much ozone is present, where it infiltrates, and how the ventilation of the indoor space is configured,” adds the scientist from Jonathan Williams’ team. The levels the scientists found were even comparable to outside daytime OH concentrations levels.

The oxidation field is generated by the reaction of ozone with oils and fats on the skin, especially the unsaturated triterpene squalene, which constitutes about 10% of the skin lipids that protect the skin and keep it supple. The reaction releases a host of gas phase chemicals with double bonds that further react with ozone to generate OH radicals. These squalene degradation products were characterised and quantified, with the total OH reactivity determined in parallel enabling the OH levels to be quantified empirically.

The experiments were conducted at the Technical University of Denmark (DTU) in Copenhagen. Four test subjects stayed in a special climate-controlled chamber under standardized conditions. Ozone was added to the chamber air inflow in a quantity that was not harmful to humans but representative of higher indoor levels. The team determined the OH values before and during the volunteers’ stay both with and without ozone present.

In order to understand how the human-generated OH field looked like in space and time during the experiments, results from a detailed multiphase chemical kinetic model from the University of California, Irvine were combined with a computational fluid dynamics model from Pennsylvania State University, both based in the USA. After validating the models against the experimental results, the modeling team examined how the human-generated OH field varied under different conditions of ventilation and ozone, beyond those tested in the laboratory. From the results, it was clear that the OH radicals were present, abundant, and forming strong spatial gradients.

“Our modeling team is the first and currently the only group that can integrate chemical processes between the skin and indoor air, from molecular scales to room scales,” said Manabu Shiraiwa, a professor at UC Irvine who led the modeling part of the new work. “The model makes sense of the measurements — why OH is generated from the reaction with the skin.”

Shiraiwa added that there remain unanswered questions, like the way humidity levels impact the reactions the team traced. “I think this study opens up a new avenue for indoor air research,” he said.

Adapt test methods for furniture and building materials

“We need to rethink indoor chemistry in occupied spaces because the oxidation field we create will transform many of the chemicals in our immediate vicinity. OH can oxidise many more species than ozone, creating a multitude of products directly in our breathing zone with as yet unknown health impacts. This oxidation field will also impact the chemical signals we emit and receive,” said project leader Jonathan Williams, “and possibly help explain the recent finding that our sense of smell is generally more sensitive to molecules that react faster with OH.”

The new finding also has implications for our health: Currently, chemical emissions of many materials and furnishings are being tested in isolation before they are approved for sale. However, it would be advisable to also conduct tests in the presence of people and ozone, says atmospheric chemist Williams. This is because oxidation processes can lead to the generation of respiratory irritants such as 4-oxopentanal (4-OPA) and other OH radical-generated oxygenated species, and small particles in the immediate vicinity of the respiratory tract. These can have adverse effects, especially in children and the infirm.

Source: Max Planck Institute for Chemistry

Categories : PaediatricsTags : Leave a comment

Anti-diarrhoeal Drug Loperamide Could Treat Autism Symptoms

On By ModernMedia
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Source: Pixabay CC0

At present, there are no effective treatments for the core symptoms of autism spectrum disorder (ASD), which included difficulties with socialising and communicating. Using a computer analysis, researchers have discovered that a common anti-diarrhoeal drug may have potential in treating the social difficulties associated with ASD. Their findings are reported in the journal Frontiers in Pharmacology.

By looking at how different drugs affected ASD-related proteins in a computer model, they identified potential candidates to treat it. The most promising candidate was a commonly used antidiarrhoeal drug called loperamide was , and the researchers have an interesting hypothesis about how it may work to treat ASD symptoms, some of the most common of which involve difficulties with social interaction and communication.

“There are no medications currently approved for the treatment of social communication deficits, the main symptom in ASD,” said Dr Elise Koch of the University of Oslo, lead author on the study. “However, most adults and about half of children and adolescents with ASD are treated with antipsychotic drugs, which have serious side effects or lack efficacy in ASD.”

Repurposing drugs as new treatments

In an effort to find a new way to treat ASD, the researchers turned to drug repurposing, which involves exploring existing drugs as potential treatments for a different condition. The approach has plenty of benefits, as there is often extensive knowledge about existing drugs in terms of their safety, side-effects and the biological molecules that they interact with in the body.

To identify new treatments for ASD, the researchers used a computer-based protein interaction network. Such networks encompass proteins and the complex interactions between them. It is important to account for this complexity when studying biological systems, as affecting one protein can often have knock-on effects elsewhere.

The researchers constructed a protein interaction network that included proteins associated with ASD. By investigating existing drugs and their interaction with proteins in the network, the team identified several candidates that counteract biological process underlying ASD.

The most promising drug is called loperamide, which is commonly used for diarrhea. While it might seem strange that an anti-diarrhoeal drug could treat core ASD symptoms, the researchers have developed a hypothesis about how it may work.

From an upset gastrointestinal system to ASD

Loperamide binds to and activates a protein called the μ-opioid receptor, which is normally affected by opioid drugs, such as morphine. Along with the effects that you would normally expect from an opioid drug, such as pain relief, the μ-opioid receptor also affects social behavior.

In previous studies, genetically engineered mice that lack the μ-opioid receptor demonstrated social deficits similar to those seen in ASD. Interestingly, drugs that activate the μ-opioid receptor helped to restore social behaviors.        

These results in mice highlight the tantalising possibility that loperamide, or other drugs that target the μ-opioid receptor, may represent a new way to treat the social symptoms present in ASD, but further work is required to test this hypothesis. In any case, the current study demonstrates the power of assuming that old drugs may indeed learn new tricks.

Source: Frontiers Blog

Categories : Ethics and LawTags : Leave a comment

Reinstate Whistleblower – Court Orders Eastern Cape Health MEC

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By Tania Broughton

The health department in the Eastern Cape has been ordered to reinstate a “whistleblower”. She was removed from her job in a district human resources office after she raised the alarm about a colleague attempting to get her niece short-listed for a job.

Eastern Cape Labour Court Judge Zolashe Lallie found that “an occupational detriment” had been committed against Vuyelwa Thelma Tanda. The judge ruled that in terms of the Protected Disclosures Act, Tanda had made a “protected disclosure” when she reported the attempted nepotism to her boss.

The judge ordered that she be compensated with R162 402 and that she must be given back her job.

Read the full judgment here

Tanda was initially employed as a data capturer at the Motherwell Community Health Centre. In January 2014, she was seconded to the human resources department in the district office, where she, and two fellow employees, were responsible for managing recruitment and selection processes. They had to report to the deputy director of human resources management, Charmain Jaggers, who in turn reported to the director, Mzoli Njalo.

In January 2018, the department advertised several administrative clerk posts and received a large number of applicants. Njalo’s wife, Phumla Njalo, who was also employed by the department, chaired the shortlisting panel.

The following day, Tanda’s colleague, Princess Makhulume, “got upset” and questioned why her niece had not been shortlisted.

A few days later Tanda was contacted by Mrs Njalo, who said there had been an oversight in the shortlisting process and instructed her to add the niece’s name to the shortlist.

Tanda refused, saying that HR policies and procedures did not permit her to comply with such an instruction. She explained that the correct procedure was to reconvene the selection panel.

Tanda said she reported the instruction to Jaggers, but she did not want to intervene. Jaggers advised her to call a meeting of the selection panel.

When the meeting was held, the issue remained unresolved, because only Mrs Njalo wanted Makhulume’s niece to be shortlisted.

Tanda again spoke to Jaggers, who again expressed unwillingness to intervene. Ultimately, the selection panel took a final decision not to shortlist Makhulume’s niece.

Shortly after the incident, Tanda said she was reprimanded by Jaggers for attending a memorial service for a nurse and taking files home.

She said Jaggers had given her permission to attend the service – and she denied taking files home.

She was then barred from attending HR staff meetings, removed from the department’s WhatsApp group, and her files were taken away from her.

After Tanda launched a grievance, it was recommended that she be “removed from the HR department”. She left at the end of March 2019 and was given a job as a data capturer at the information section of the district office.

Judge Lallie said Jaggers denied ill-treating or victimising Tanda after she reported Mrs Njalo’s conduct. She said Tanda had become rebellious and failed to perform her duties properly.

Lawyers for the health MEC argued that in terms of the Protected Disclosures Act, a disclosure made in the normal scope of employment could not be protected.

However, Judge Lallie said the argument that Tanda had not made a protected disclosure was not supported by the evidence that Mrs Njalo was “intentionally acting in breach of recruitment procedures” and attempting to give Mkhuluma’s niece an unfair advantage.

“In the circumstances of this case … the report that Mrs Njalo was instructing Tanda to be complicit in nepotism in violation of the recruitment policy constituted a protected disclosure. The report was made in good faith to Jaggers.”

Judge Lallie said it was common cause that Jaggers had refused to intervene in the matter.

Tanda had given a detailed account of how Jaggers victimised her shortly after she made the disclosure. “I cannot accept the version that the relationship between Tanda and Jaggers changed because of Tanda’s misconduct and incompetence. Tanda had worked in the HR office for four years without any complaint,” said the judge.

Judge Lallie said Tanda had been “punished” and that Jaggers had abused her seniority.

“Tanda has proved that solatium (compensation) is due to her as a result of humiliation, hurt and the violation of her right to dignity which she suffered in the hands of Jaggers for making the protected disclosure.”

Judge Lallie ordered compensation equivalent to the pay she would have earned over a period of ten months, at the rate she was earning when she made the protected disclosure, and that she be given back her job, and that the MEC pay her costs.

Republished from GroundUp under a Creative Commons Attribution-NoDerivatives 4.0 International License.

Source: GroundUp

Categories : Cardiovascular DiseaseTags : Leave a comment

SGLT2 Inhibitors may be Effective for All HF Ejection Fractions

On By ModernMedia
Source: Pixabay CC0

Researchers presented new evidence that SGLT2 inhibitors may benefit a wide range of patients with heart failure (HF). At the ESC Congress 2022 in Barcelona, and in simultaneous publications in The New England Journal of Medicine and The Lancet, physician-scientists presented late-breaking research from the largest trial to date of heart failure patients with mildly reduced or preserved ejection fraction (EF).

They showed that dapagliflozin, which had previously been shown to benefit patients with heart failure with reduced ejection fraction (HFrEF), is likely to also reduce cardiovascular death and hospitalisation for patients with mildly reduced or preserved EF, for whom therapeutic options are limited. A meta-analysis that included two clinical trials further strengthened the evidence that this class of drugs may provide protection for a wide range of heart failure patients.

Scott Solomon, MD, at the Brigham, presented results from the AstraZeneca-funded DELIVER trial, a randomised, placebo-controlled trial of dapagliflozin among patients with heart failure with mildly reduced or preserved EF.

“In the largest and most inclusive trial of heart failure with mildly reduced or preserved ejection fraction, we found that treatment with the SGLT2 inhibitor dapagliflozin can benefit patients across the full spectrum of heart failure,” explained Dr Solomon. “These findings establish SGLT2 inhibitors as foundational treatment for patients living with heart failure, regardless of ejection fraction, to help prevent hospitalisation and morbidity and to extend meaningful survival and improve health-related quality of life. These are the outcomes that matter most to patients and to clinicians – to keep patients feeling well and living longer.”

Muthiah Vaduganathan, MD MPH, also at the Brigham, presented results from a pre-specified meta-analysis of DELIVER and EMPEROR-Preserved, a large-scale clinical trial of empagliflozin, funded by Boehringer Ingelheim and Eli Lilly.

“Our meta-analysis, encompassing more than 12 000 patients, provides a summary of the totality of the evidence and drives home the message that, when it comes to heart failure, this is a therapy for all,” said Dr Vaduganathan. “These trials included patients across a broad range of ages, race, functional class, sex and medical histories, but regardless of individual characteristics, they benefited consistently from this treatment.”

Dapagliflozin is a sodium-glucose co-transporter-2 (SGLT2) inhibitor, which causes the body to excrete sugar in urine. As well as blood glucose control in diabetes, SGLT-2 inhibitors have been shown to provide significant cardiovascular and kidney disease benefits. The DELIVER trial was designed to determine whether dapagliflozin would decrease cardiovascular morbidity and mortality in patients with heart failure with mildly reduced or preserved EF.

The international trial enrolled patients aged 40 or older and had symptomatic HF with an EF of greater than 40%, including mildly reduced ejection fraction and preserved EF, as well as patients who had previously had reduced EF that had improved to greater than 40%, and in both the outpatient and inpatient setting. More than 6000 participants were randomised to receive dapagliflozin or placebo and followed for a median of 2.3 years. The primary endpoint was a composite of cardiovascular death or worsening heart failure.

Dapagliflozin significantly reduced the primary composite endpoint by 18 percent. In the dapagliflozin group, 11.8% experienced worsening heart failure compared to 14.5% of the placebo group. Cardiovascular death in these groups occurred in 7.4 % and 8.3% of participants, respectively. Key secondary outcomes were also significantly reduced, including total heart failure hospitalisations and total symptom burden.

The meta-analysis used data from DELIVER and EMPEROR-Preserved, with a composite of cardiovascular death or first hospitalisation for heart failure. SGLT2 inhibitors were found to reduce primary outcome risk by 20%. Effects were consistent across subgroups by age, sex, race, body mass index, systolic blood pressure, history of various medical conditions and more.

The team further incorporated data from additional clinical trials with SGLT2 inhibitors, including those performed with dapagliflozin and empagliflozin in patients with HFrEF, and in patients from a clinical trial of the SGLT1/2 inhibitor sotagliflozin. Taken together, the evidence with all these data suggest that patients across the full spectrum of HF benefit from this class of drugs, regardless of EF or care setting.

Limitations were noted by the authors. Black patients made up less than 5% of the patients enrolled in DELIVER; the COVID pandemic limited symptom assessment after March 2020; and subgroups in the trial were underpowered. However, findings were consistent across prespecified subgroups.

“There are more than 64 million people worldwide affected by heart failure, half of whom have mildly reduced or preserved ejection fraction,” said Dr Solomon. “Our goal is to rigorously and scientifically evaluate potential treatments so that we can provide the best evidence-based care to help them lead longer, healthier lives.”

Source: Brigham and Women’s Hospital

Categories : Metabolic DisordersTags : Leave a comment

30-year Diabetes Study Determines HbA1c Threshold for Complications

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Diabetes - person measures blood glucose
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The levels of long-term blood sugar, HbA1c, can be used to accurately determine the risk of a person with type 1 diabetes developing eye- and kidney complications. A Swedish study, published in Diabetes Care, followed individuals after the onset type 1 diabetes for 30 years and showed that this level should under 53mmol/mol (7%).

People with diabetes may experience damage to the small blood vessels in various organs. The reasons for this are unclear, but it has been known since the 1990s that good control of blood sugar levels reduces the risk of complications. It has, however, not been clear what level of long-term sugar, HbA1c, people with type 1 diabetes should have in order to avoid serious damage to blood vessels in the eyes and kidneys.

“Our study determines accurately the levels of long-term sugar that can avoid complications. This knowledge can increase a person’s motivation to keep their blood sugar level under control,” said study leader Hans Arnqvist, professor emeritus at Linköping University.

Researchers in the current study, known as VISS (Vascular Diabetic Complications in Southeast Sweden), have followed all children and adults under 35 who developed type 1 diabetes during the period 1983–1987 in Southeast Sweden. All 447 newly diagnosed persons in the region during this period were included in the study. The researchers have followed the patients’ HbA1c values, which reflect their average blood sugar levels during a longer period. They have also monitored the development of eye- and kidney damage in these patients for a period of between 32 and 36 years after diagnosis.

In type 1 diabetes, the small blood vessels in the eye are particularly susceptible to damage. Nearly all patients experience small haemorrhages in the eye that do not affect their vision. In some cases, proliferative retinopathy develops, forming new blood vessels which can lead to blindness. The macula of the retina can also be damaged, leading to blurred vision.

While the kidneys are not as sensitive to high blood sugar levels as the eye, the important small blood vessels here can also be damaged, leading to albuminuria. The damage to the kidneys eventually leads to impaired kidney function and, in serious cases, kidney failure.

In healthy individuals, the blood sugar level is very closely controlled, with a maximum HbA1c level of 42mmol/mol (6.0%).

“The results of our study show that people with type 1 diabetes for at least 32 years should keep their mean long-term sugar level below 53mmol/mol (7.0%), if they are to completely avoid serious damage. The risk of eye- and kidney complications increases as the level increases. Our conclusions relate to avoiding complications arising from blood vessel damage. But if a patient has problems with low blood sugar, hypoglycaemia, it’s not possible to control the blood sugar level so strictly,” said Prof Arnqvist.

The target level for HbA1c that is suggested by the results of the VISS study agrees with the individual targets recommended by the American Diabetes Association. In Sweden, target levels are given for groups, rather than individuals.

The previous follow-up by the research group was conducted 20 years after the onset of disease. Now after 30 years, the results show that damage has arisen at lower blood sugar levels than was the case after 20 years.

More patients have experienced damage, despite having blood sugar levels that are not higher than those they have previously had. In other words, it seems that the threshold for developing complications falls gradually with time. This means that the study does not allow any conclusions for the recommended blood sugar levels of people with type 1 diabetes longer than 30 years after diagnosis.

Source: Linköping University

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Prenatal Cannabis Exposure Impacts Persist to Pre-adolescence

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Children
Photo by Ben Wicks on Unsplash

Children who were exposed to cannabis in the womb continue to show elevated rates of symptoms of psychopathology (depression, anxiety and other psychiatric conditions), even as they reach pre-adolescence (aged 11–12), according to research published in JAMA Pediatrics.

The study, led by Ryan Bogdan, associate professor at Washington University in St. Louis, is a follow-up to 2020 research from the Bogdan lab that revealed younger children who had been prenatally exposed to cannabis were slightly more likely to have had, inter alia, sleep problems, lower birth weight and lower cognitive performance.

In both cases, the effect is strongest when looking at exposure to cannabis after the pregnancy is known. To find out whether or not these associations persisted as the children aged, David Baranger, a postdoctoral researcher in the BRAIN Lab, revisited the more than 10 500 children from the 2020 analysis, who were an averaged of 10 years old in 2020.

The data on the children and their mothers came from the Adolescent Brain and Cognitive Development Study (ABCD Study), an ongoing study of nearly 12 000 children, beginning in 2016 when they were 9–10 years old, and their parents or caregivers.

This seemingly small change in age – from 10 to 12 – is an important one. “During the first wave, they were just children. Now they’re edging up on adolescence,” Baranger said. “We know this is a period when a large proportion of mental health diagnoses occur.”

An analysis of the more recent data showed no significant changes in the rate of psychiatric conditions as the children aged; they remain at greater risk for clinical psychiatric disorders and problematic substance use as they enter the later adolescent years.

“Once they hit 14 or 15, we’re expecting to see further increases in mental health disorders or other psychiatric conditions – increases that will continue into the kids’ early 20s,” Baranger said.

Source: University of Washington in St. Louis

Categories : Mental HealthTags : Leave a comment

Explaining the Power of ‘Super-recognisers’

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Image by Mar Lezhava on Unsplash

Some people have the ability to never forget a face, and some help police departments and security agencies identify suspects. It is only now that researchers have come to understand a bit more about this ability, which until now was believed to derive from photographic memory.

In a paper published in Psychological Science, psychologists challenged this view, proving that super-recognisers look at faces just like all of us, but do it faster and more accurately. 

UNSW Sydney researcher and study lead author, Dr James Dunn, explained that when super-recognisers catch a glimpse of a new face, they divide it into parts and then store these in the brain as composite images.

“They are still able to recognise faces better than others even when they can only see smaller regions at a time. This suggests that they can piece together an overall impression from smaller chunks, rather than from a holistic impression taken in a single glance,” Dr Dunn said. 

Co-lead author Dr Sebastien Miellet, University of Wollongong (UOW) expert in active vision, used eye-tracking technology to analyse how super-recognisers scan and process faces and their parts. 

“With much precision, we can see not only where people look but also which bits of visual information they use,” Dr Miellet said.

When studying super-recognisers’ visual processing patterns, Dr Dunn and Dr Miellet realised that contrary to typical recognisers, super-recognisers focused less on the eye region, instead distributing their gaze more evenly than typical viewers, extracting information from other facial features, particularly when learning faces. 

“So the advantage of super-recognisers is their ability to pick up highly distinctive visual information and put all the pieces of a face together like a puzzle, quickly and accurately,” Dr Miellet said. 

The researchers will continue to study the super-recogniser population. Dr Miellet says that one hypothesis is that super-recognisers’ superpower may stem from a particular curiosity and behavioural interest in others. Super-recognisers may also be more empathetic. 

“In the next stages of our study, we’ll equip some super-recognisers and typical viewers with a portable eye tracker and release them onto the streets to observe, not in the lab but in real life, how they interact with the world,” Dr Miellet said. 

Source: University of Wollongong Australia

Categories : General Interest Injury & TraumaTags : Leave a comment

Oldest Known Successful Amputation Dates Back 31 000 Years

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Mariano, Public domain, via Wikimedia Commons

At a site in Borneo, archaeologists have unearthed the oldest case of surgical amputation to date, a remarkable feat of prehistoric medical practice.

Published in Nature, the researchers describe the skeletal remains of a young adult found in a cave in Borneo, who had part of the left lower leg and left foot amputated, probably as a child, at least 31 000 years ago. The person lived for at least another six to nine years after the procedure, surviving into adulthood where they died from an unknown cause, possibly in their 20s.

The prehistoric surgery is a remarkable feat; preventing infections is difficult even in modern surgical amputations.

Study co-lead author, Dr Melandri Vlok, at University of Sydney said the find is “incredibly exciting and unexpected.”

“The discovery implies that at least some modern human foraging groups in tropical Asia had developed sophisticated medical knowledge and skills long before the Neolithic farming transition,” said bioarchaeologist Dr Vlok, an expert in ancient skeletons.

The skeleton of the young adult was carefully buried within LiangTebo cave – located Borneo in East Kalimantan, in a limestone karst area home to some of the world’s earliest dated rock art.

The bones were uncovered by archaeologists just days before borders closed for the COVID pandemic in March 2020. Dr Vlok was invited to study the bones when they were brought back to Australia.

“No one told me they had not found the left foot in the grave,” Dr Vlok said. “They kept it hidden from me to see what I would find.”

As Dr Vlok laid the bones out, the left leg looked withered, and was the size of a child’s, but the individual was an adult. She unwrapped the part of the leg that contained the stump and noticed the cut was clean, well healed and had no evidence of any infection. “The chances the amputation was an accident was so infinitely small,” Dr Vlok said. “The only conclusion was this was stone age surgery.”

Dr Vlok ran to the office to tell her research colleagues what she had found. “I told them I thought it looked like a surgical amputation,” she said. “It wasn’t until then that they said they already knew the foot was missing.” Dr Vlok had just confirmed their suspicions. The foot was never placed in the grave to begin with.

An accident in difficult terrain

While the cause for the amputation was unclear, the individual also had a very well healed neck fracture and trauma to their collar bone that may have occurred during the same event, said Dr Vlok.

“An accident, such as a rock fall may have caused the injuries, and it was clearly recognised by the community that the foot had to be taken off for the child to survive,” she said.

The location of the cave is surrounded by extremely rugged terrain, and accessing the site was challenging, making the individual’s survival after the the surgery even more remarkable. The finding will provide even more insight into prehistoric medicine, the researchers said.

Source: University of Sydney

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‘Striking’ Colon Cancer Trial Data gets Standing Ovation

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In a clinical trial, nearly every one of the 112 patients with mismatch repair-deficient (dMMR) colon cancer achieved a pathologic response with just two cycles of neoadjuvant immunotherapy, prompting a presentation panellist to describe it as “striking data” – though a note of caution was given.

Patients in the NICHE-2 single-arm study received PD-1 plus CTLA-4 blockade – nivolumab plus ipilimumab, and successfully underwent surgical resection, 98% on time, meeting the study’s primary safety endpoint, reported Myriam Chalabi, MD, at the at the European Society for Medical Oncology (ESMO) annual congress.

And with a median follow-up of 13.1 months, the disease-free survival (DFS) rate was 100%, said Dr Chalabi of the Netherlands Cancer Institute in Amsterdam. She pointed out that, by this point, the expected rate for this patient population was about 15%. The primary efficacy endpoint for the trial is DFS at 3 years, with success defined as a rate of 93% (data are expected next year).

A standing ovation erupted when Dr Chalabi displayed the waterfall plot showing the depth of pathologic response with just four weeks of nivolumab plus ipilimumab.

Credit: NICHE-2 Study

Among the 107 patients evaluable for efficacy, all but one had a pathologic response, 95% had a major pathologic response (MPR), and 67% had a pathologic complete response (pCR), ie no residual viable tumour in both the primary tumour bed and lymph nodes.

“As you can appreciate, the pathologic regression observed was near-complete or complete in almost all patients,” she said.

In contrast, pathologic response rates in the range of 5% to 7% for this population have been shown in prior trials involving neoadjuvant chemotherapy, said Chalabi.

Some 10–15% of colon cancers are classified as dMMR, she explained, which are highly sensitive to immune checkpoint inhibitors, where a number of agents have been approved for the metastatic setting.

The first to comment in Q&A, Alexander Eggermont, MD, PhD, stressed the potential impact of the findings, saying that patients with dMMR tumours scheduled for resection “should be taken off the surgical program.”

“They should be sent to the medical oncologist for the first dose of ipi/nivo,” he said. “We will live the day that they will not undergo surgery anymore after these schedules – that’s the next step.”

A multicentre, single-arm study, NICHE-2 enrolled 112 patients with previously untreated non-metastatic dMMR colon cancer undergoing surgery. The first cycle of neoadjuvant treatment included ipilimumab (1mg/kg) and nivolumab (3mg/kg). The second cycle, given two weeks later, was limited to nivolumab alone. After the first dose, median time to surgery was 5.4 weeks.

The trial defined pathologic response as 50% or less residual viable tumour; MPR was defined as 10% or less residual viable tumour, and included patients with pCRs in the primary tumour but viable tumour in the lymph nodes.

The median age of patients was 60, and 58% were women. About three-fourths had high-risk stage III disease, 13% had low-risk stage III disease, and 13% had stage I/II disease. About half had radiologic high-risk disease (both T4 and N2), said Dr Chalabi, and abdominal wall involvement was common.

When asked whether randomised data would be needed to make this approach standard, Dr Chalabi pointed out the group with T4 tumours.

“I wouldn’t want to randomise those patients,” she said. “Surgeons usually would prefer to have some type of downstaging before continuing on to surgery in order to increase the chances of achieving tumour-free resection margins and also to limit the extent of surgery needed to achieve that.”

The case for randomisation is stronger in earlier disease, she said, but if recurrences can be prevented even in stages where recurrence is more rare, such as stage II tumours (about 10% at 3 years), “we’re curing 10% more patients.”

A little less than a third of patients had Lynch syndrome, and pCRs were more frequent in this subset (78% vs 58% in those with sporadic tumours). Immune-related adverse events (AEs) were reported in 61% of patients, with 4% being grade 3/4.

When the prospect of a NICHE-3 trial came up, Dr Chalabi said that it ideally would have been an international study to validate the approach. However, a subsequent trial is being developed and will likely involve nivolumab plus anti-LAG-3 relatlimab, “which is a shame,” she noted.

“If we do get similar responses with nivolumab and anti-LAG-3, then that may be an avenue to test organ-sparing approaches with that combination in this population,” she added.

Source: MedPage Today