Month: January 2021

New Method to Pick up Mutations Behind Colorectal Cancer Risks

University of Michigan researchers have developed a method to detect mutations which give rise to colorectal cancer.

Colorectal cancer is the third most common cancer type, and the second most common cause of cancer-related deaths in the United States. Although most cases occur sporadically, some 5 to 10% of cases are hereditary, the most common cause of which is Lynch syndrome. Lynch syndrome results in an 80% increase in the lifetime risk of developing colorectal cancer. Those with a family history of colorectal cancer are advised to start screening before age 45. However, genetic testing for cancer risk does not always provide useful information for those with family history.  

To address this, a new method of genetic testing was developed by Jacob Kitzman, PhD, of the Department of Human Genetics at Michigan Medicine plus together with other colleagues. Since mutations are rare in the human population, determining which one is responsible is difficult, and simply studying one in the lab is too time consuming to be practical.
With deep mutational scanning, the researchers measured the effect of MSH2 mutations, which is one major cause of Lynch syndrome

They deleted the normal copy of MSH2 from human cells with CRISPR-Cas, replacing it with a library of every possible mutation in the MSH2 gene. Each cell in the mix then carried a unique MSH2 mutation. Chemotherapy then killed off only the cells that had a functional variant of MSH2.

The counterintuitive idea, noted Kitzman, is that the surviving cells do not have functioning MSH2—which have mutations that are most likely to cause disease.

“We were basically trying to sit down and make the mutations we could so they could serve as a reference for ones that are newly seen or are amongst the thousands of variants of unknown significance identified in people from clinical testing,” says Kitzman. “Until now, geneticists could not be sure whether these are benign or pathogenic.”

It is hoped that with other patient-specific information, some of these variants could be reclassified, and those individuals advised to undergo more intense screening.

Kitzman said: “One of the next areas that will need some focus in the field of human genetics is to create these sorts of maps for many different genes where there is a clinical connection, so we can be more predictive when variants are found in an individual.”

Source: Medical Xpress

Journal information: Xiaoyan Jia et al, Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk, The American Journal of Human Genetics (2020). DOI: 10.1016/j.ajhg.2020.12.003

Underweight and Gastrointestinal Distress – A Bidirectional Relationship?

An Asian cross-sectional study found that underweight was linked to functional dyspepsia (FD), regardless of the presence of anxiety, although anxiety was additionally associated with FD.

The study by Kee Huat Chuah, MD, of the University of Malaysia in Kuala Lumpur, and colleagues, also found no link between high body mass index (BMI) and other functional gastrointestinal disorders (FGIDs). People with FGIDs often have irritable bowel syndrome, functional dyspepsia, or functional constipation. These conditions affect up to 40% of people at any one point in time, two-thirds will have chronic, fluctuating symptoms. The questionnaire-based study recruited 1002 adult individuals with a median age of 32, with 20.7% having FGID according to the Rome III criteria.

Across different FGIDs, including irritable bowel syndrome (IBS) and functional diarrhea and constipation, FD affected more underweight adults (defined as BMI less than 18.5) compared with a non-FGID control group (13.3% vs 3.5%, P=0.002). Multivariate analysis showed that underweight maintained an independent association with FD, at an odds ratio (OR) of 3.648 (95% CI 1.494-8.905, P=0.004).

The results of a large population study from France were consistent with these findings, which also found that being underweight was independently associated with FD in females.  Diarrhoea may also have been associated with central obesity, but there were too few individuals with diarrhoea to draw conclusions, although a large US population study from 2019 showed that obesity was associated with chronic diarrhoea.

A bidirectional association has been observed in eating disorders (often linked with anxiety disorders) with both a low BMI and FD.  Anxiety and/or eating disorders may have caused FD subjects to have a low BMI.

William D Chey, MD, of Michigan Medicine, who was not involved with the research, said the results were interesting and that they could be applicable to the US population since obesity rates are comparable to those in Malaysia.

“But I do agree it’s important to consider whether these observations are cause or effect,” Chey commented. “In other words, FD might cause people to lose weight or thin people might be more prone to developing FD. I do think there’s face validity to these observations. Remember that patients with functional dyspepsia that have meal-related symptoms of fullness and early satiety are unable to eat very much without feeling ill.”

Patients with postprandial distress syndrome often lose weight as a result, Chey continued. “On the other hand, patients with anorexia often have measurable abnormalities in gastric emptying, but that’s not to say all FD patients have eating disorders. My point is that certain non-GI conditions associated with weight loss can also be associated with abnormal GI function.”

The team called for further studies of longitudinal design to explore whether anxiety causes a low BMI in FD or vice versa. Limitations included not being population based, with the cohort being mostly hospital and university staff members. In addition, the data on psychological disorders came from a subgroup of original participants in the study’s second phase; the number of participants with functional diarrhoea was low; the cross-sectional design did not allow for causality; and the questionnaire only asked about dietary habits.

Source: MedPage Today

Journal information: Beh KH, et al “The association of body mass index with functional dyspepsia is independent of psychological morbidity: a cross-sectional study” PloS One 2021; doi: 10.1371/journal.pone.0245511.

Obesity Adds to Alzheimer Severity

In addition to it being a risk factor for many known chronic diseases, obesity is an additional burden on cerebral health and may also be associated with the progression of Alzheimer’s disease, according to a new study from the University of Sheffield and the University of Eastern Finland.  

The study used multimodal neural imaging and showed that obesity may contribute to the vulnerability of neural tissue, while maintaining a healthy weight helped to maintain brain structure in mid dementia Alzheimer’s disease.

Alzheimer’s disease is a neurodegenerative disease which accounts for two thirds of dementia in over 65s, is the sixth leading cause of death in the United States and there is no cure at present.  

Lead author Professor Annalena Venneri from the University of Sheffield’s Neuroscience Institute and NIHR Sheffield Biomedical Research Centre, said: “More than 50 million people are thought to be living with Alzheimer’s disease and despite decades of ground breaking studies and a huge global research effort we still don’t have a cure for this cruel disease.

“Prevention plays such an important role in the fight against the disease. It is important to stress this study does not show that obesity causes Alzheimer’s, but what it does show is that being overweight is an additional burden on brain health and it may exacerbate the disease.”

She added that it was important to educate people early on in their lives as it was too late to wait until the 60s to lose weight as the disease lurks in the backgrounds.

The researchers examined MRI scans of the brains of 47 patients diagnosed with mild Alzheimer’s disease dementia, 68 patients with mild cognitive impairment, and 57 individuals who were cognitively healthy. Using three complementary, computational techniques, they studied the brain’s anatomy, blood flow and also the brain’s fibres.

They compared gray matter volume, white matter integrity, cerebral blood flow and obesity. Grey matter volume decreases in Alzheimer’s. In patients with mild Alzheimer’s, an association was found with obesity and grey matter volume around the right temporoparietal junction, suggesting obesity creates a neural vulnerability in cognitively impaired patients. The study also found that maintaining a healthy weight may help preserve brain structure in structure in the presence of age and disease-related weight loss.

Joint author Dr Matteo De Marco from the University of Sheffield’s Neuroscience Institute, said: “Weight-loss is commonly one of the first symptoms in the early stages of Alzheimer’s disease as people forget to eat or begin to snack on easy-to-grab foods like biscuits or crisps, in place of more nutritional meals.

“We found that maintaining a healthy weight could help preserve brain structure in people who are already experiencing mild Alzheimer’s disease dementia. Unlike other diseases such as cardiovascular disease or diabetes, people don’t often think about the importance of nutrition in relation to neurological conditions, but these findings show it can help to preserve brain structure.”

Source: Medical Xpress

Journal information: Manmohi D. Dake et al, Obesity and Brain Vulnerability in Normal and Abnormal Aging: A Multimodal MRI Study, Journal of Alzheimer’s Disease Reports (2021). DOI: 10.3233/ADR-200267

Ivermectin Approved to Treat COVID in SA on Limited Basis

Ivermectin, which has some reports of high effectiveness in limited studies, has received approval from the SA government to be used under strict control for compassionate use.  

Dr Boitumelo Semete-Makokotlela, head of the South African Health Products Regulatory Authority (SAHPRA), said that practitioners applying to use the drug will be considered case-by-case.

Ivermectin has a long history of use as an antiparasitic treatment in animals, while in humans it’s used as an anthelmintic drug that is usually indicated for filarial and resistant scabies infections. While the World Health Organization has suggested the drug has encouraging effects on coronavirus, although it hasn’t been properly evaluated yet.

“We absolutely share everyone’s desperation at this point,” said Helen Rees, SAHPRA chairwoman. “So the question about ivermectin and self-medication goes back to what everyone in the scientific community is saying. And that is, we don’t know if it works and we don’t know if it doesn’t work. That’s why we need to get data.”

Physicians in Zimbabwe are reportedly treating COVID with ivermectin in combination with silver nanoparticles – normally used as an algaecide – to great success.

Rees, however, warned South Africans that people self-medicating “need to be very careful because we don’t have any information about the quality of what you’re taking.”

Dr Semete-Makokotlela said that clear guidelines for the rollout would be given tomorrow. She added that SAHPRA granted the health department permission to distribute the Oxford/AstraZeneca COVID vaccine, the first one for SA. It is also currently reviewing applications from Johnson & Johnson and Pfizer, but has yet to receive an application from Moderna, she said.

Source: BusinessTech

Novavax COVID Vaccine only 49.4% Effective in SA

On Thursday, Novavax announced that its vaccine was 89% effective, according to its UK trials which had 15 000 participants. However, its SA trials showed a much lower effectiveness of 49.4%, believed to be caused by the SA COVID variant B.1.351 (aka 501.V2). 

The company conveyed the information in a press release, with a detailed journal publication still to come. The SA trial had 4400 participants, and the observed protection varied depending on HIV status. In people who were HIV negative, the vaccine conferred 60% protection. If the vaccination trial included a representative proportion of HIV positive adult South Africans, it may mean that its effectiveness for this vulnerable segment is very low.

“The higher efficacy of the vaccine in the UK than in South Africa is because the variants circulating in SA are less sensitive to vaccine induced immune responses,” said Professor Shabir Madhi, Executive Director of the Vaccines and Infectious Diseases Analytics Research Unit (VIDA) at Wits, and principal investigator in the Novavax COVID vaccine trial in SA.

“Nevertheless, the 60% reduced risk against Covid-19 illness in vaccinated individuals in South Africans underscores the value of this vaccine to prevent illness from the highly worrisome variant currently circulating in South Africa, and which is spreading globally. This is the only Covid-19 vaccine for which we now have objective evidence that it protects against the variant dominating in South Africa.”

Novavax is pressing ahead with a trial involving 30 000 participants in the United States and Mexico, and has shared data with the UK’s pharmaceutical regulator. It is not clear whether the data from the US and Mexico trial will be required before the vaccine receives approval there. Meanwhile on Friday, the Johnson & Johnson vaccine developed by its subsidiary Janssen has been shown to be 66% effective. It is a single dose vaccine with minimal refrigeration requirements, making it very important for the logistical challenge of vaccinations in developing countries. Since Aspen would be producing some of the doses locally, the SA government had been in talks with Johnson & Johnson to secure some of those vaccines for SA use. However, there are signs that it too is less effective against the B.1.351 variant.

Source: Business Insider

Opioid Deaths Drop when Cannabis Stores are Near

A new US study suggests that opioid-related mortality rates fall in counties where there are legal cannabis stores.

Cannabis was first legalised for medical use in the US in 1996; recreational legalisation began in 2012 with a number of states following suit. Previous research on the effect of legal access to cannabis on opioid overdose mortality had produced conflicting results, with a 2014 study showing a slow increase in deaths, but a subsequent study showing that it reversed over time.

Data on opioid mortality for adults 21 and over was drawn from 2014-2018 CDC data, and a website called Weedmaps for cannabis dispensary details in the 23 states plus the District of Columbia where cannabis dispensaries were allowed to operate as of 2017.

The number of cannabis dispensaries in a county was negatively related to log-transformed age-adjusted opioid mortality rate (β -0.17, 95% CI -0.23 to -0.11). An increase in the number of storefront dispensaries from one to two was linked to a 17% reduction in death rates of all opioid types, and an increase from two to three stores was associated with a further 8.5% drop in mortality.

Eight states plus the District of Columbia allowed recreational storefronts and 15 allowed only medical dispensaries. An increase in medical dispensaries from one to two resulted in a 15% drop in mortality rate; an increase in recreational dispensaries from one to two led to an 11% drop.

Co-author Balázs Kovács, PhD, of Yale University School of Management, said: “We find this relationship holds for both medical dispensaries, which serve only patients who have a state-approved medical card or doctor’s recommendation, as well as for recreational dispensaries, which sell to adults 21 years and older.”

An accompanying editorial pointed out that the relationship was not clear, noting that were was no evidence of substitution. Additionally, individual experiences of benefits and harms could not be inferred.

Although findings are suggestive of a possible link between the increased prevalence of cannabis dispensaries and reduced opioid-related mortality, they do not show causality, Kovács emphasised. “While we find a particularly strong association between the prevalence of storefront dispensaries and fentanyl-related opioid deaths, it is not clear whether cannabis use and fentanyl mortality rates are more specifically linked, or if the strength of the association is due to the rise in fentanyl use and mortality rates during the study period,” he said. 
He added that the potential harms of cannabis, including cognitive development of adolescents, schizophrenia and other medical conditions, and public safety risks, should not be ignored.
Source:MedPage TodayJournal information:  Hsu G and Kovács B “Association between county level cannabis dispensary counts and opioid related mortality rates in the United States: panel data study” BMJ 2021; DOI: 10.1136/bmj.m4957.

Moderate Alcohol Has an Immediate Effect on the Heart

One or two drinks a day may make for a healthy heart, but people with atrial fibrillation (AFib) may experience immediate impacts, as a new study reveals.

University of California, San Francisco (UCSF) researchers found that alcohol immediately changed the electrical properties driving heart muscle contraction in patients undergoing a treatment for AFib. These subjects were randomised to receive an infusion of alcohol maintained at the lower limit of legal intoxication, An equal number of control subjects who instead received a placebo infusion did not have this occur. The work was published January 27, 2021 in the Journal of the American College of Cardiology: Clinical Electrophysiology,

Senior study author Gregory Marcus, MD, professor of medicine in the Division of Cardiology at UCSF explained: “The acute impact of exposure to alcohol is a reduction in the time needed for certain heart muscle cells in the left atrium to recover after being electrically activated and to be ready to activated again, particularly in the pulmonary veins that empty into the left atrium.”    

AFib is the most common cardiac rhythm disorder, affecting some 1% of the world’s population, and is characterised by tachyarrhythmia. It is caused by abnormal electrical activity in the atria of the heart, making them fibrillate. This causes the atria to pump blood inefficiently, leading to feelings of the heart pounding, fluttering or skipping a beat. Due to turbulence caused by the irregular rhythm, a clot could form which could lead to a stroke. This results in some 158 000 deaths in the US annually. Other negative impacts include fatigue, weakness, dizzy lightheadedness, difficulty breathing and chest pain.

The study patients were undergoing a catheter ablation procedure. This is commonly used to suppress AFib by severing the electrical connection between the pulmonary veins and the left atrium. This areas was also the area noted to be affected by alcohol in the study.

Preparation for the ablation therapy required installation of catheters and electrodes in the heart chambers to monitor and pace the heart, and destroy selected tissue. The study measured refractory time before cells could again transmit electrical signals, and conduction speeds, as well as a stimulus inducing more AFib events. Electrical conduction speed and induced AFib events did not vary, but a 12 millisecond delay was seen in tissue around the pulmonary vein in the alcohol infusion group.

“Although epidemiological studies have found an association between self-reported alcohol consumption and the development of an atrial fibrillation diagnosis, ours is the first study to point to a mechanism through which a lifestyle factor can acutely change the electrical properties of the heart to increase the chance of an arrhythmia,” Marcus said. The same changes caused by alcohol infusion in the study have earlier been associated with episodes of AFib in previous computer models and animal studies, he said.
“Patients should be aware that alcohol can have immediate effects that are expected to increase risk for arrhythmias,” Marcus concluded.

However, in a separate study, injecting ethanol into the vein of Marshall when performing a catheter ablation seemed to increase the odds of treatment success compared to catheter ablation alone.

Source: MedicalXpress

EU Demands AstraZeneca Vaccine Produced by UK Plants

In another twist to the EU’s seemingly never-ending vaccine procurement problems, the EU health minister has demanded that vaccine production from AstraZeneca’s UK operations be sent to EU countries to make up for the company’s shortfall at its two European plants. 

EU health commissioner Stella Kyriakides dismissed AstraZeneca’s argument that it the UK take precedence.

“We reject the logic of first come, first served,” the commissioner declared. “That may work at the neighbourhood butcher’s [shop] but not in contracts and not in our advanced purchase agreements. There’s no priority clause in the purchase agreements.”

The Anglo-Swedish company had triggered fury in Brussels when it was revealed that it would only be able to deliver 25% of the agreed vaccine doses when they received approval as expected this Friday. However, AstraZeneca assured the UK government that it would meet its commitment of supplying 2 million doses a week. UK government sources insisted that only once AstraZeneca had fulfilled its order to provide the UK with 100 million doses would its vaccine production be allowed to be released to serve other countries.

The EU meanwhile is flagging far behind, with only 2% of its adult population vaccinated compared to 10% of the UK’s. Kyriakides pointed out that in its contract with AstraZeneca, four European plants were listed as suppliers and two of those were located in the UK, and she expected them to work for EU citizens.

An AstraZeneca spokesperson said: “Each supply chain was developed with input and investment from specific countries or international organisations based on the supply agreements, including our agreement with the European commission.

“As each supply chain has been set up to meet the needs of a specific agreement, the vaccine produced from any supply chain is dedicated to the relevant countries or regions and makes use of local manufacturing wherever possible.”

Kyriakides said the argument was unacceptable, emphasising that the company had a moral duty to treat the EU similarly to the UK, adding that there was no “priority clause” that would justify UK residents benefiting first from doses made there.

Germany meanwhile has said that it is facing 10 weeks of vaccine shortage.
However, there is encouraging news as Israel reported a 92% effectiveness with the Pfizer/BioNTech vaccine outside trials. Only 31 of 163 000 Israelis caught COVID within ten days of the innoculation reaching its full strength. None were hospitalised.

Source: The Guardian

New Study Challenges the Need for Some Post-surgical Opioids

Doctors must carefully weigh the pain relief value of opioids for patients against their potential for misuse and inducing opioid addiction even in patients with no history of substance abuse. Now, a new study challenges current practice by showing the effectiveness of an approach that takes a middle way to giving opioids.

Some 16 million people around the world suffer from opioid use disorder, which can result from opioid administration from surgery and for chronic pain. Opioids are highly addictive, with tolerance reached in days and addiction can occur within a matter of weeks, so there is every incentive to minimise exposure of patients to these effective but potentially dangerous medications.

To investigate the effectiveness of minimising opioid use, a team from Michigan Medicine at the University of Michigan conducted a study with 620 patients who had surgery in hospitals across Michigan, had their anaesthetic usage tracked, and filled in surveys within one to three months following their surgeries. The patients were split equally into two groups.
The first group received pre-surgery counseling emphasising non-opioid pain treatment as their first option. Some patients in this group received small, “just in case” prescriptions, but a third of them didn’t receive any opioid prescription at all after surgery.

The patients in the other group received standard care, that is, receiving the usual amount of opioids prescribed after such operations. The prescriptions received in fact were larger than in the opioid sparing group. Most patients didn’t take all of the pills, which if left lying around could be used inappropriately.

Patients in the two groups had the same surgery: either gallbladder removal, full or partial thyroid removal or hernia repair. However, both groups reported equal levels of quality of life and satisfaction with care when followed-up. Most surprisingly, the opioid-sparing group reported less pain overall.

First author Maia Anderson, MD, a resident in the U-M Department of Surgery, said: “It’s so exciting to think about the potential for opioid sparing postoperative pathways to not only reduce the risk of opioids for our patients, but also to substantially decrease the risk of opioid diversion into our communities.”

Senior author Ryan Howard, MD, Surgical Resident, Michigan Medicine commented: “We know that opioids pose serious risks to patients after surgery. We can protect patients from those risks by reducing or eliminating opioids after surgery. But that idea always raises the concern that patients will have uncontrolled pain and feel miserable. This study suggests that’s not the case – patients who get small opioid prescriptions, or even no prescription, are just as satisfied with their recovery after surgery.”

Source: News-Medical.Net

Journal information: Anderson, M., et al. (2020) Patient-Reported Outcomes After Opioid-Sparing Surgery Compared With Standard of Care. JAMA Surgery.

Six Key Takeaways of SA’s Vaccination Programme

From a webinar held by the Department of Health late Wednesday night, there are six key points that were learned about the government’s vaccination programme.

1: To receive a vaccine, people will need an internet connection, cellphone and an ID. The internet connection is needed for self-enrolment on the Electronic Vaccine Data System (EVDS), and the cellphone is needed to receive an SMS detailing the time and place for vaccination. An ID book is required for identification. After the second vaccination (if a two-dose vaccine), an “electronic vaccination certificate” can be accessed from the EVDS. No mention was made of alternatives for those without ID books or internet access to the EVDS.

2: Private doctors and nurses will be paid R50 to R60 per shot administered. However, the government would prefer to use public healthcare facilities wherever possible.

3: Medical aids will pay double or triple for the vaccine doses. As reported in early January, medical aid schemes will pay for some of the costs of achieving herd immunity. The single exit price (SEP) of vaccines will be higher. Whether medical aids cover the number of additional doses for uninsured people at 1:1 or 2:1 is yet to be determined.

4: Mines have significant vaccination capacity – assuming they have enough doses on hand. The head of health for the Minerals Council, Thuthula Balfour, explained: “We’ve actually worked out that the industry can administer about 60 000 to 80 000 vaccines a day, so within two months we could vaccinate between 2.5 million to 3 million people.” This would equate to some five extra people per mineworker.

5: Rural clinics without generators will not receive vaccines. The distribution will use a hub-and-spoke model with hubs that are able to guarantee security and available electricity receiving vaccine stocks.

6: The auditor-general is already involved, to forestall corruption. Health Minister Zweli Mkhize said that “all the approaches that we’re taking to make sure that at the end of it they can give us a sense of checks and balances they are going to suggest as we deal with the risks associated with this process.”

Source: Business Insider