In sleeve gastrectomy (SG), about 80% of the stomach is removed to reduce obesity and its complications. It has been observed to be associated with bone loss in adolescents, prompting a prospective study published in the Journal of Bone and Mineral Research, that revealed through imaging tests that SG decreases strength and bone mineral density of the lumbar spine in adolescents and young adults.
The researchers followed 29 adolescents and young adults with obesity underwent SG and 30 were without surgery over 12 months. At baseline and 12 months, participants underwent computed tomography of the lumbar spine for bone assessments and magnetic resonance imaging of the abdomen and thigh for body composition assessments.
Participants in the SG group lost an average of 34.3 kg 12 months after surgery, whereas weight was unchanged in controls. There were significant reductions in abdominal fat tissue and thigh muscle in the SG group compared with controls. Also, bone strength and bone mineral density decreased in the SG group compared with controls. Reductions in bone strength and bone mineral density were associated with reductions in body mass index, abdominal fat tissue, and muscle.
“Weight loss surgery is very effective in treating obesity and obesity-associated comorbidities in adolescents and young adults with obesity; however, it can cause loss of bone density and strength. We hope that our study raises awareness of the importance of bone health after weight loss surgery, so physicians can make sure that children eat a healthy diet with enough calcium and vitamin D and engage in weight-bearing activity to build up muscle mass, which is good for bones,” said corresponding author Miriam A. Bredella, MD, of Massachusetts General Hospital.
A study published in BJU International found that while adherence to healthy diets seems to have no effect on prostate cancer risk, following an unhealthy ‘Western’ diet may increase the risk of developing aggressive prostate cancer.
The study assessed the diets of 15 296 men recruited in Spain in from 1992–1996. Among these men, 609 prostate cancer cases were identified during a median follow-up of 17 years. Diets were categorised as Western, Prudent, or Mediterranean. The Western dietary pattern consisted of a high intake of high-fat dairy products, processed meat, refined grains, sweets, caloric drinks, convenience food, and sauces, and a low intake of low-fat dairy products and whole grains. The Prudent dietary pattern was characterised by a high intake of low-fat dairy products, vegetables, fruits, whole grains, and juices. The Mediterranean dietary pattern represented a high intake of fish, vegetables, legumes, boiled potatoes, fruits, olives, and vegetable oil, and a low intake of juices.
No effect over prostate cancer risk was detected for the Prudent and Mediterranean dietary patterns, but detrimental effect was observed with the Western dietary pattern. This effect was only observed for aggressive tumors.
“Our results indicate that avoiding unhealthy dietary habits could be the best nutritional strategy to prevent aggressive prostate cancer,” said lead author Adela Castelló-Pastor, PhD, of the Carlos III Institute of Health and CIBERESP, in Spain. “Substituting the intake of Western-type diet products by products characteristic of the Mediterranean diet could also decrease the risk of other chronic diseases,” added co–senior author Marina Pollán, PhD, of the Carlos III Institute of Health and CIBERESP, in Spain.
“The information provided by the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition – or EPIC – has contributed to improving scientific knowledge of the relationship between diet and cancer and other chronic diseases,” added co–senior author Maria-José Sánchez, MD, PhD, lecturer at the Andalusian School of Public Health, scientific director at ibs.GRANADA and researcher at CIBERESP, in Spain.
Storing donor lungs for transplant at 10°C markedly increases the length of time the organ can live outside the body, according to results of a trial were published in the New England Journal of Medicine Evidence. These findings will help reduce the strain on hospitals, reduce waitlists and possibly eliminate the need to bump other surgeries for a lung transplant.
The multicentre, non-randomised clinical trial study of 70 patients demonstrated that donor lungs remained healthy and viable for transplant up to four times longer compared to storage at the current standard of ice cooler preservation of around 4°C. The study was led by a team of scientists at the Toronto Lung Transplant Program in UHN’s Ajmera Transplant Centre.
“The clinical impact of this study is huge,” says lead author Dr Marcelo Cypel, Surgical Director of the Ajmera Transplant Centre and a surgeon within UHN’s Sprott Department of Surgery.
“It’s a paradigm shift for the practice of lung transplant. I have no doubt that this will become the gold standard practice of lung preservation for the foreseeable future.”
Lungs available for transplant are currently limited by the length of time a donor organ can be kept viable. Increasing storage time allows for viable donor lungs to come from greater distances, increasing the potential for greater numbers of lungs becoming available for transplant and overcoming many of the hurdles around transplant logistics.
“In transplant, we still see a critical shortage of organs and people dying on the waitlist because there are not enough lungs to be transplanted,” says Dr Cypel, who is also a professor in the Division of Thoracic Surgery, Department of Surgery at the University of Toronto.
“It’s a great accomplishment to see that our research is now having an impact, and that we can actually have more cases done at our centre, with continued outstanding clinical results.
“Better organ preservation also means better outcomes for patients.”
Transplant surgeries could become planned procedures
The trial took place over 18 months at UHN’s Toronto General Hospital, the Medical University of Vienna, and Hospital Universitario Puerta de Hierro-Majadahonda in Madrid.
“The ability to extend the lifespan of the donor organ poses several advantages,” says study first author Dr Aadil Ali, adjunct scientist at the Toronto General Hospital Research Institute.
“Ultimately, these advantages will allow for more lungs to be utilised across farther geographies and the ability to improve recipient outcomes by converting lung transplantation into a planned rather than urgent procedure.”
Some advantages of this new 10°C standard for lung storage include the potential to reduce or eliminate the 24/7 schedule and urgency of lung transplant procedures. By increasing the length of time donor lungs are viable, transplant surgeries could become planned procedures, which avoids bumping scheduled surgeries and overnight transplantation.
The study also suggests the new preservation temperature will allow more time to optimise immunologic matching between donor and recipients, and the possibility of performing lung transplantation in a semi-elective rather than urgent fashion.
Scientists predict that we are entering the era of pandemics.
A sustainable global commitment to pandemic preparedness is instrumental to maintaining the upper hand and winning the battle.
In collaboration with the Abbott Pandemic Defense Coalition, CERI unveiled a new genomics facility to help identify, analyse and test infectious diseases in Africa to enable early detection and rapid responses to potential viral threats.
With the increasing rates of urbanisation, global travel and climate change, infectious disease experts predict the world is entering a new era of pandemics. In response to this, Abbott founded the Abbott Pandemic Defense Coalition which comprises of 20 scientific and public health organisations from across the globe who are committed to detecting and responding to emerging viral threats.
Since its launch in 2021, the global Coalition has partnered with organisations in Africa to build up the network and capabilities in the region. The Centre for Epidemic Response and Innovation (CERI) at Stellenbosch University is one of the recent partners, who recently unveiled a new genomics facility that will enable early detection and the rapid response to emerging threats in Africa in collaboration with the Abbott Pandemic Defense Coalition.
“No one organisation, network or country is strong enough to effectively fight against viral pathogens,” says Mary Rodgers, principal scientist at Abbott’s diagnostics business. “We therefore must have an ongoing global commitment to pandemic preparedness – and key to that is collaboration across the private and public sectors to detect and have a rapid response to emerging threats. Our partnership with CERI will expand testing capacity to continue research in understanding how known viruses are spreading in order to identify new viral outbreaks, so that we can stop them from becoming the next pandemic.”
New Technology to Detect Viral Threats in Africa
The state-of-the-art genomics facility is equipped with new technology such as the Metagenomics Next Generation Sequencing which is revolutionising how viruses are discovered – creating a genome that once took years to complete can now be sequenced and analysed in a day or two. The genomics center will also have access to Abbott’s diagnostics molecular lab testing capabilities to provide fast and scalable molecular testing, as well as provide researchers the ability to create molecular tests for new and emerging viral threats.
Professor Tulio de Oliveira, director of CERI concludes, “The partnership with the Abbott Pandemic Defense Coalition will help train Africa’s next generation of virus hunters and public health experts in cutting-edge sequencing, bioinformatics, and other technologies so that they can track and identify viruses faster and smarter. The launch of this new genomics facility is a testament to our shared commitment to advancing scientific knowledge and protecting public health in Africa.”
The South African Health Products Regulatory Authority (SAHPRA) issued media statements on 4 August 2022 and 12 September 2022, relating to two fatal cases of Guillain-Barré syndrome (GBS) following vaccination with COVID-19 Vaccine Janssen. SAHPRA has been informed of a third fatal case of GBS following vaccination with the same vaccine.
A causality assessment of the reported case was conducted by the National Immunisation Safety Expert Committee (NISEC) using the World Health Organization’s (WHO) methodology. Following investigations, the case was classified as a vaccine product-related event. The events reported in the vaccine recipient were consistent with the case definition of GBS and no other likely cause of GBS was identified at the time of illness.
As previously communicated, GBS is a very rare but potentially severe neurological adverse event that is associated with the administration of various vaccines and other medicines and can also be triggered by some bacterial or viral infections, including SARS-CoV-2. Symptoms of GBS range from mild to severe, and may include muscle weakness, muscle pain, numbness, and tingling. In many cases, GBS resolves with no serious after-effects, but in some cases GBS can cause serious or life-threatening problems.
Regulatory authorities have previously investigated reports of GBS associated with COVID-19 vaccines. They concluded that COVID-19 Vaccine Janssen may increase the risk of GBS. GBS is therefore listed as a rare adverse event in the professional information (PI) for COVID-19 Vaccine Janssen.
Investigations and causality assessment of all reported severe adverse events following immunisation (AEFI) with all COVID-19 vaccines are ongoing. The outcomes of these investigations and causality assessments will be shared with the public as soon as they are completed.
Important points to note
COVID-19 vaccines have consistently been shown to prevent severe forms of disease, hospitalisation and death. Based on the currently available evidence, SAHPRA has determined that the benefits of COVID- 19 vaccination far outweigh the very low risk of severe adverse events, including GBS. The public are strongly advised not to delay COVID-19 vaccination if eligible in terms of the national vaccination programme.
SAHPRA urges the public to report any suspected adverse events following the use of all medicines and vaccines. Reporting can be done at a health facility or by downloading the Med Safety App (https://medsafety.sahpra.org.za/), which is available for Android and iOS phones, or by calling the COVID-19 hotline at 0800 029 999. More information regarding AEFIs reported for the COVID-19 vaccines and how to report an AEFI is available from the SAHPRA website: https://aefi-reporting.sahpra.org.za/.
More information regarding AEFIs reported for the COVID-19 vaccines and how to report an AEFI is available from the SAHPRA website: https://aefi-reporting.sahpra.org.za/.
A new study suggests that notion of the body and mind being inextricably intertwined is more than mere abstraction: parts of the brain area that control movement are plugged into networks involved in thinking and planning, and in control of involuntary bodily functions such as blood pressure and heartbeat. The findings represent a literal linkage of body and mind in the very structure of the brain, overturning decades of interpretations.
The research, published in the journal Nature, could help explain some baffling phenomena, such as why anxiety causes people to pace; why stimulating the vagus nerve, which regulates internal organ functions such as digestion and heart rate, may alleviate depression; and why people who exercise regularly report a more positive outlook on life.
“People who meditate say that by calming your body with, say, breathing exercises, you also calm your mind,” said first author Evan M. Gordon, PhD, an assistant professor of radiology at Washington University School of Medicine in St. Louis. “Those sorts of practices can be really helpful for people with anxiety, for example, but so far, there hasn’t been much scientific evidence for how it works. But now we’ve found a connection. We’ve found the place where the highly active, goal-oriented ‘go, go, go’ part of your mind connects to the parts of the brain that control breathing and heart rate. If you calm one down, it absolutely should have feedback effects on the other.”
Gordon and senior author Nico Dosenbach, MD, PhD, an associate professor of neurology, did not set out to answer age-old philosophical questions about the relationship between the body and the mind. They set out to verify the long-established map of the areas of the brain that control movement, using modern brain-imaging techniques.
In the 1930s, neurosurgeon Wilder Penfield, MD, mapped such motor areas of the brain by applying small jolts of electricity to the exposed brains of people undergoing brain surgery, and noting their responses. He discovered that stimulating a narrow strip of tissue on each half of the brain causes specific body parts to twitch. Moreover, the control areas in the brain are arranged in the same order as the body parts they direct, with the toes at one end of each strip and the face at the other. Penfield’s map of the motor regions of the brain – depicted as a homunculus, or “little man” – has become a staple of neuroscience textbooks.
Gordon, Dosenbach and colleagues set about replicating Penfield’s work with functional magnetic resonance imaging (fMRI). They recruited seven healthy adults to undergo hours of fMRI brain scanning while resting or performing tasks. From this high-density dataset, they built individualized brain maps for each participant. Then, they validated their results using three large, publicly available fMRI datasets – the Human Connectome Project, the Adolescent Brain Cognitive Development Study and the UK Biobank – which together contain brain scans from about 50 000 people.
To their surprise, they discovered that Penfield’s map wasn’t quite right. Control of the feet was in the spot Penfield had identified. Same for the hands and the face. But interspersed with those three key areas were another three areas that did not seem to be directly involved in movement at all, even though they lay in the brain’s motor area.
Moreover, the nonmovement areas looked different than the movement areas. They appeared thinner and were strongly connected to each other and to other parts of the brain involved in thinking, planning, mental arousal, pain, and control of internal organs and functions such as blood pressure and heart rate. Further imaging experiments showed that while the nonmovement areas did not become active during movement, they did become active when the person thought about moving.
“All of these connections make sense if you think about what the brain is really for,” Dosenbach said. “The brain is for successfully behaving in the environment so you can achieve your goals without hurting or killing yourself. You move your body for a reason. Of course, the motor areas must be connected to executive function and control of basic bodily processes, like blood pressure and pain. Pain is the most powerful feedback, right? You do something, and it hurts, and you think, ‘I’m not doing that again.'”
Dosenbach and Gordon named their newly identified network the Somato (body)-Cognitive (mind) Action Network, or SCAN. To understand how the network developed and evolved, they scanned the brains of a newborn, a 1-year-old and a 9-year-old. They also analysed data that had been previously collected on 9 monkeys. The network was not detectable in the newborn, but it was clearly evident in the 1-year-old and nearly adult-like in the 9-year-old. The monkeys had a smaller, more rudimentary system without the extensive connections seen in humans.
“This may have started as a simpler system to integrate movement with physiology so that we don’t pass out, for example, when we stand up,” Gordon said. “But as we evolved into organisms that do much more complex thinking and planning, the system has been upgraded to plug in a lot of very complex cognitive elements.”
Clues to the existence of a mind-body network have been around for a long time, scattered in isolated papers and inexplicable observations.
“Penfield was brilliant, and his ideas have been dominant for 90 years, and it created a blind spot in the field,” said Dosenbach, who is also an associate professor of biomedical engineering, of paediatrics, occupational therapy, radiology, and psychological & brain sciences. “Once we started looking for it, we found lots of published data that didn’t quite jibe with his ideas, and alternative interpretations that had been ignored. We pulled together a lot of different data in addition to our own observations, and zoomed out and synthesised it, and came up with a new way of thinking about how the body and the mind are tied together.”
Over a hundred years after the discovery of the neuron by neuroanatomist Santiago Ramón y Cajal, scientists continue to deepen their knowledge of the brain and its development. Now, scientists detail novel insights into how cells in the outer layers of the brain interact immediately after birth during formation of the cerebellum, the brain region towards the back of the skull. Publishing their results in in Science Advances, the scientists demonstrated a novel type of connection between neural precursor cells via nanotubes, even before synapses form.
In 2009, Chiara Zurzolo’s team from the Institut Pasteur identified a novel mechanism for direct communication between neuronal cells in culture via nanoscopic tunnels, known as tunnelling nanotubes. These are involved in the spread of various toxic proteins that accumulate in the brain during neurodegenerative diseases – but may also be tapped for the treatment of diseases or cancers.
In this new study, the researchers discovered nanoscopic tunnels that connect precursor cells in the brain, more specifically the cerebellum – an area that develops after birth and is important for making postural adjustments to maintain balance – as they mature into neurons. These tunnels, although similar in size, vary in shape from one to another: some contain branches while others don’t, some are enveloped by the cells they connect while others are exposed to their local environment. The authors believe these intercellular connections (ICs) may enable the exchange of molecules that help pre-neuronal cells physically migrate across various layers and reach their final destination as the brain develops.
Intriguingly, ICs share anatomical similarities with bridges formed when cells finish dividing. “ICs could derive from cellular division but persist during cell migration, so this study could shed light on the mechanisms allowing coordination between cell division and migration implicated in brain development. On the other hand, ICs established between cells post mitotically could allow direct exchange between cells beyond the usual synaptic connections, representing a revolution in our understanding of brain connectivity. We show that there are not only synapses allowing communication between cells in the brain, there are also nanotubes,” says Dr Zurzolo, senior author and head of the Membrane Traffic and Pathogenesis Unit (Institut Pasteur/CNRS).
To achieve these discoveries, the researchers used a three-dimensional (3D) electron microscopy method and brain cells from mouse models to study how the brain regions communicate between each other. Very high resolution neural network maps could thus be reconstructed. The 3D cerebellum volume produced and used for the study contains over 2000 cells. “If you really want to understand how cells behave in a three-dimensional environment, and map the location and distribution of these tunnels, you have to reconstruct an entire ecosystem of the brain, which requires extraordinary effort with twenty or so people involved over 4 years,” said the article’s first author Diego Cordero.
To meet the challenges of working with the wide range of cell types the brain contains, the authors used an AI tool to automatically distinguish cortical layers. Furthermore, they developed an open-source program called CellWalker to characterise morphological features of 3D segments. The tissue block was reconstructed from brain section images. This program being made freely available will enable scientists to quickly and easily analyse the complex anatomical information embedded in these types of microscope images.
The next step will be to identify the biological function of these cellular tunnels to understand their role in the development of the central nervous system and in other brain regions, and their function in communication between brain cells in neurodegenerative diseases and cancers.
Van Andel Institute scientists have pinpointed a key driver of low bone density, a discovery that may lead to improved treatments with fewer side effects for women with osteoporosis. Their findings appear in the journal Science Advances.
Their research reveals that loss of an epigenetic modulator, KDM5C, preserves bone mass in mice. KDM5C works by altering epigenetic ‘marks’, switches that ensure the instructions written in DNA are read in the right time and place.
Several medications are approved to treat osteoporosis but fears of rare, severe side effects often are a barrier for their use. Treatments that leverage the hormone oestrogen also are available, but are only recommended for low-dose, short-term use due in part to associations with cancer risk.
It is well-established that women experience disproportionately lower bone mass than men throughout their lives. Loss of bone mass accelerates with menopause, increasing the risk of osteoporosis and associated fractures for women as they age.
To figure out why this happens, VAI Associate Professors Connie M. Krawczyk, PhD, and Tao Yang, PhD, and their teams looked at the differences in the ways bone is regulated in male and female mice, which share many similarities with humans and are important models for studying health and disease. They focused on osteoclasts, which help maintain bone health by breaking down and recycling old bone.
“Osteoporosis is a common disease that can have debilitating outcomes,” Yang said. “KDM5C is a promising target to treat low bone mass in women because it is highly specific. We’re hopeful that our findings will contribute to improved therapies.”
The researchers found reducing KDM5C disrupted cellular energy production in osteoclasts, which slowed down the recycling process and preserved bone mass. Importantly, KDM5C is linked to X chromosomes, which means it is more active in females than in males.
“Lowering KDM5C levels is like flipping a switch to stop an overactive recycling process. The result is more bone mass, which ultimately means stronger bones,” Krawczyk said. “We’re very excited about this work and look forward to carrying out future studies to refine our findings. At the end of the day, we hope these insights make a difference for people with osteoporosis.”
A preconception and early-pregnancy diet that contains lots of fruit, vegetables, seafood, dairy, eggs and grain may be associated with reducing risk of miscarriage, suggests a new review of research in the journal Fertility and Sterility.
University of Birmingham researchers analysed 20 studies on eating habits in the months before and shortly after conceiving a baby to see whether these studies showed evidence of association with a lower or higher chance of miscarriage. The team conclude that there is evidence to suggest a diet rich in fruit, vegetables, seafood, dairy products, eggs and grain reduces miscarriage risk.
Not surprisingly, these are foods which typically make up ‘healthy’ well-balanced diets, with previous evidence showing that eating a well-rounded diet which is rich in vitamins and minerals during pregnancy is important.
The research review found that, when compared to low consumption, high intake of fruit may be associated with a 61% reduction in miscarriage risk. High vegetable intake may be associated with a 41% reduction in miscarriage risk. For dairy products it is a 37% reduction, 33% for grains, 19% for seafood and eggs.
Led by Dr Yealin Chung, researchers also looked at whether pre-defined dietary types, such as the Mediterranean Diet or Fertility Diet could also be linked to miscarriage risk. They could not find evidence that following any of these diets lowered or raised risk.
However, a whole diet containing healthy foods overall, or foods rich in antioxidant sources, and low in pro-inflammatory foods or unhealthy food groups may be associated with a reduction in miscarriage risk for women.
A diet high in processed food was shown to be associated with doubling of miscarriage risk.
The studies included in the analysis focused on the peri-conception period, which is before and during the first 3 months of pregnancy. Data collected from a total of 63 838 healthy women of reproductive age was included, with information on their diets typically collected through food frequency questionnaires for each study.
Dr Chung explains:
“Miscarriage is common, with estimates suggesting 1 in 6 pregnancies end in miscarriage, and there are many known causes, from problems with the baby’s chromosomes to infections in the womb.
“Yet nearly 50% of early pregnancy losses remain unexplained and in the absence of a cause, parents often turn to their healthcare providers for guidance on the best ways to be as healthy as possible and reduce the risk of future miscarriages.
“There’s a growing body of evidence to show that lifestyle changes – including changes to diet, stopping smoking and not drinking alcohol – before conceiving and in your pregnancy’s early stages – may have an impact.”
Respiratory syncytial virus (RSV) is a dangerous early childhood viral infection, but results of a vaccine trial promise to change things radically.
A new study published in the New England Journal of Medicine, the world’s most prestigious medical journal, on 5 April that examined the effect of an RSV vaccine on pregnant women found that it reduced the risk of severe lower respiratory tract infections in newborns by 82%.
RSV is the most common cause of acute lower respiratory infection – or pneumonia – in infants. Globally, it was responsible for just over 100,000 deaths (with a lower bound of 84,000 deaths and an upper bound of 126,000 deaths) of children under five in 2019. Of these deaths 45% were infants (younger than six months), and nearly all deaths occurred in lower income countries (half in Africa alone). In an article in Spotlight in June 2022, Professor Cheryl Cohen, head of the Centre for Respiratory Diseases and Meningitis at the National Institute for Communicable Diseases (NICD), said that, pre-COVID, RSV led to 44 615 hospitalisations and 490 deaths in children under five each year in South Africa.
RSV causes cold-like symptoms, but can lead to severe symptoms like pneumonia. At present, there is no licensed RSV vaccine, though the virus was first identified in the 1960s.
The study was a phase three, double-blind trial (which compares a new treatment to standard care, and leads the way to regulatory approval and production) conducted in 18 countries, led by Beate Kampmann, Professor of Paediatric Infection and Immunity at the London School of Hygiene and Tropical Medicine, Shabir Madhi, Dean of the Faculty of Health Sciences and Professor of Vaccinology at the University of the Witwatersrand, and Iona Munjal, Director of Clinical Research & Development at Pfizer. It builds on earlier work by Madhi and others.
Women who were between 24 and 36 weeks pregnant were given an injection of a protein–based vaccine (RSVpreF) and a placebo. Pregnant women can passively transfer their immunity to viruses and diseases to their foetuses in utero.
They were then monitored to see if they suffered a severe RSV-associated lower respiratory tract illness that required medical attention, and if their newborns required medical attention for RSV-associated lower respiratory tract illness up to six months after birth.
A total of 7,358 women participated across the two trial groups, and 7,128 babies were monitored, and no safety concerns were identified over the course of the trial.
In November last year, Pfizer announced that it planned to submit a licence application to the US Food and Drug Administration after trials showed that the vaccine was highly effective at reducing severe RSV cases in the first 90 days of an infant’s life.
In a Twitter thread announcing the results, Madhi said that the next challenge would be to ensure that the vaccine is licensed across lower income countries, where most infant RSV deaths occur. Madhi said that there is a “moral responsibility on pharma to licence [the RSV] vaccine in LMIC [Lower and Middle Income Countries] at [an] affordable price.” Governments in poorer countries, “need to act to protect children in their counties by funding and deploying the vaccine timeously,” he said.
Madhi also informed GroundUp that coincidentally in the same issue of the New England Journal of Medicine, a medicine called nirsevimab was found to protect infants against RSV-associated hospitalisation and severe lower respiratory tract infections. Madhi and his team at Wits also participated in this trial.
This medicine is “administered as a single dose at the onset of RSV season,” Madhi explained. “The two approaches [the vaccine and nirsevimab] will be complementary.”