Over the past 21 years of opioid overdose deaths in the US, whether an area is urban or rural has played a role in where opioid-involved overdose deaths have occurred, reports a new study published in JAMA Network Open. But there will no longer be a distinction between these, the study suggests – and there will be a dramatic increase in opioid-related overdoses.
The reason opioid overdoses have reached historical highs comes from combining synthetic opioids with stimulants such as cocaine and methamphetamines, a lethal cocktail that is hard to reverse during an overdose, the study authors said.
“I’m sounding the alarm because, for the first time, there is a convergence and escalation of acceleration rates for every type of rural and urban county,” said corresponding author Lori Post, director of the Buehler Center for Health Policy and Economics at Northwestern University Feinberg School of Medicine. “Not only is the death rate from an opioid at an all-time high, but the acceleration of that death rate signals explosive exponential growth that is even larger than an already historic high.”
Using methods developed to track COVID outbreaks, the study examined geographic trends in opioid-involved overdose deaths between 1999 and 2020 to determine if geography played a role in the three waves and the theorised fourth wave of America’s opioid crisis.
Near the end of the available data from 2020, overdose deaths in rural areas were escalating faster than in urban areas, according to the study. A visualization of the data illustrates that between 2019 and 2020, rates of opioid-involved overdose deaths converged while escalating for the first time across six types of rural and urban counties, Post said.
“We have the highest escalation rate for the first time in America, and this fourth wave will be worse than it’s ever been before,” Post said. “It’s going to mean mass death.”
The study authors examined toxicology reports and found people are using fentanyl (50 to 100 times more potent than morphine) and carfentanil (approximately 100 times more potent than fentanyl) combined with methamphetamines and cocaine. The result is a powerful and lethal cocktail that can even evade help from overdose-reversing drugs like naloxone.
“The stronger the drugs, the harder it is to revive a person,” said study co-author Alexander Lundberg, assistant professor of emergency medicine at Feinberg. “The polysubstance use complicates an already dire situation.”
“It appears that those who have died from opioid overdoses had been playing pharmacist and trying to manage their own dosing,” Post said. “This is a bigger problem because you have people misusing cocaine and methamphetamines along with an opioid, so you have to treat two things at once, and the fentanyl is horribly volatile.”
“The only path forward is to increase awareness to prevent opioid use disorders and to provide medication-assisted treatment that is culturally appropriate and non-stigmatising in rural communities,” Post said.
A study published in the JAMA Oncology looking at the correlation between daily insulin dose and cancer incidence among patients with type 1 diabetes has found that higher insulin dose is positively associated with cancer incidence and that the association is stronger among those with insulin resistance.
“In patients with type 1 diabetes, our results show that traditional metabolic factors such as obesity (represented by body mass index), sugar control (by Haemoglobin A1c), and blood pressure control do not associate with cancer incidence,” study leader Dr Yuanjie Mao Mao said. “However, cancer incidence was higher for those who took larger dose of insulin. Our results implied that clinicians might need to balance the potential cancer risk when treating patients with type 1 diabetes on a high daily insulin dose or that improving insulin sensitivity may be preferred than simply increasing the insulin dose.”
To conduct the study, Dr Mao collaborated with Wenjun Zhong, PhD, an epidemiologist of Merck Research Labs, to analyse the associations of more than 50 common risk factors in 1303 patients with type 1 diabetes whose data were collected over 28 years. A variety of databases were drawn upon and analysed, including he Diabetes Control and Complications Trial (DCCT.) which was was a controlled clinical trial originating with 1441 patients with type 1 diabetes who were randomised into conventional diabetes therapy or intensive therapy to assess whether reducing hyperglycaemia would decrease the risk of complications of type 1 diabetes.
Mao also found that age and sex are associated with cancer incidence when evaluated separately and that a daily insulin dose posed a higher risk of cancer than age, especially a higher insulin dose. According to the paper, when the daily insulin dose is classified into three groups, low: less than 0.5; medium: greater than or equal to 0.5 or lower than 0.8; and high: greater than or equal to 0.8 units/kg per day, the hazard ratios were significantly higher in the high dose versus the low dose group. Cancer incidence was 2.11, 2.87, and 2.91 per 1000 persons in the low, medium, and high insulin dose groups, respectively.
He went on to explain that specifically, women carry a higher risk than men; however, it was unclear what risk factors may contribute to the higher cancer incidence in type 1 diabetes.
“We know that people with type 1 diabetes have a higher incidence of cancer compared to people without diabetes,” Liz Beverly, Ph.D. co-director of the diabetes institute and professor in the Heritage College, said. “Dr. Mao’s research identifies a potential mechanism to explain this association. His findings will lead to continued research in this area and potential policy changes in cancer screening and insulin dosing recommendations.”
Although previous studies have concluded that patients with diabetes have a higher risk of cancer in general, this is the first study to explore the associated cancer incidence factors in type 1 diabetes.
“Type 1 diabetes accounts for an estimated five to 10 percent of all diabetes cases, and recent studies in type 1 diabetes also found a higher incidence of certain cancers such as stomach, liver, pancreas, endometrium and kidney cancers in the population compared with the general population,” Mao explained. “Whereas, in type 2 diabetes, increased risk is attributed to metabolic factors such as obesity, chronic inflammation status, and insulin resistance.”
Although the results of the study suggest that the higher the dose of insulin, the higher the cancer incidence, Dr Mao says further investigation is still necessary.
Changing the order of treatments given to breast cancer patients could reduce side effects resulting from mastectomy and improve outcomes, according to a clinical feasibility trial, published in The Lancet Oncology.
In the study, researchers found that switching the sequence of treatments given to breast cancer patients was safe, without any increase in complications and could lead to patients receiving faster and more effective care compared to current methods.
Thirty-three women with breast cancer requiring a mastectomy and post-mastectomy radiotherapy, were recruited to the primary radiotherapy and deep inferior epigastric perforator flap reconstruction for patients with breast cancer (PRADA) trial between January 2016 and December 2017. They were also eligible for a breast reconstruction using tissue from another part of their body.
They were given chemotherapy followed by radiotherapy before having a mastectomy and a breast reconstruction. The team found that this approach was feasible and safe. They also found that side effects were low and that 12 months after surgery patients reported high levels of satisfaction with their breast reconstruction.
Lead author Daniel Leff said: “We believe that, in the long term, this approach will improve patients’ mental and physical wellbeing with higher quality of life scores and satisfaction with their reconstructed breasts compared to current care. It also means that many patients who are currently denied reconstruction due to concerns of further complications due to radiotherapy may be able to get access to this treatment in future.”
Patients with blood cancers have an impaired immune system due to their disease and its treatment, putting them at risk of severe COVID infection and a reduced COVID vaccination response. In a recent study published in CANCER, less than half of patients with haematologic malignancies including leukaemia, lymphoma, and multiple myeloma mounted detectable antibodies after initial COVID vaccination, but 56% of ‘nonresponders’ produced antibodies after receiving a booster dose.
For the study, Thomas Ollila, MD, and colleagues retrospectively analysed antibody responses to initial and booster COVID vaccination in 378 patients with hematologic malignancies.
Anti-SARS-CoV-2 antibodies were detected in the blood of 181 patients (48%) after initial vaccination with one of three FDA-authorised or approved COVID vaccines, and patients with active cancer or those recently treated with an immune cell–depleting therapy were least likely to produce these antibodies. Among patients who did not mount an antibody response following initial vaccination, responses were observed after a booster dose in 48 of 85 (56%) patients who were assessed.
By the end of February 2022, 33 patients (8.8%) developed a COVID infection, with three COVID-related deaths (0.8%). Although there was no significant link between post-vaccination antibody response and incidence of COVID infection, no patient with antibody responses died from COVID
Also, no patient who received tixagevimab plus cilgavimab was diagnosed with a COVID infection. Tixagevimab and cilgavimab are antibody therapies that bind to non-overlapping portions of the SARS-CoV-2 spike protein, preventing the virus from binding to and infecting cells. The FDA authorised the combination therapy for emergency use during the COVID pandemic as a way to help prevent COVID infection in certain individuals.
“Our findings build on the wealth of literature showing that patients with hematologic malignancies have an impaired response to COVID vaccination. Importantly, we show that many of these patients who did not respond initially will in fact have a response to booster vaccination,” said Dr Ollila. “Moreover, when we looked at outcomes, we found that deaths from COVID in the patient population we reviewed only occurred in those with undetectable antibodies, and nobody who received prophylactic antibody therapy was diagnosed with COVID. This suggests to us the importance of checking antibody levels in these patients and arranging prophylactic antibody therapy.”
Dr. Ollila encourages providing booster vaccines for patients and prioritising prophylactic antibody therapy when indicated. “This is real world evidence that these actions can save lives,” he said.
Professor Resia Pretorius sounds rushed when Spotlight first tracks her down by phone at Heathrow Airport outside London. She is about to board a plane to South Africa after attending a conference, meetings, and symposia in the United Kingdom, all with the purpose of unravelling the complexity of long COVID and how to treat it.
There is no global consensus among researchers and clinicians on a definition for long COVID, there is no adequate diagnostic test for the debilitating condition, and the causes of patients progressing to long COVID are, at this stage, theoretical.
However, Pretorius who heads the Department of Physiological Science at the University of Stellenbosch remains upbeat. Her research group is the first to have reported evidence of inflammatory microclots in blood samples from individuals with long COVID, potentially solving an important piece of the long COVID puzzle.
She says scientific collaboration is intensifying to find answers to long COVID which affects 43% or 100 million people globally post-infection, according to a meta-analysis and systematic review.
Later speaking from Stellenbosch, Pretorius describes herself as a “lab person” who has been trying to find the cause of long COVID since 2020. “I have always been passionate about research. Now, I am working with clinicians and researchers in the UK, the USA, and other parts of the world. I am too worried to miss anything so I am at all of these meetings. There are 40 to 50 researchers globally who talk to each other regularly. We are going to crack this I know. We just have to.”
Causes of long COVID
As explained in a recent article in the journal Science, there are three leading theories scientists are pursuing in an attempt to decipher the effects of post-COVID-19 infection – which leads to an array of symptoms, including shortness of breath, fatigue, headaches, palpitations, and impairments in mental health and cognition or brain fog.
One theory is that SARS-CoV-2 stubbornly persists in the body, even after the acute infection passes. Studies have shown that the virus lingers in a wide range of body sites, especially in the nerves and other tissues.
Another theory based on blood samples from COVID-19 patients reveals an immune system in disarray even eight months after first testing positive. The body’s cells do not appear to recover.
Images of micro clots as seen under an electron microscope. PHOTO: Supplied
The third, an area in which Pretorius has distinguished herself internationally, is that COVID-19 is not only a lung disease but significantly affects the vascular (blood flow) and coagulation (blood clotting) systems of the body.
A recent study published in the Cardiovascular Diabetology journal, conducted by Pretorius and colleagues, found that there is significant microclot formation in the blood of both acute COVID-19 and long COVID patients. A microclot is a blood clot that can only be seen through a microscope.
Pretorius explains that in a healthy person clots may form, for example, when you cut yourself. The main clotting protein is a molecule called fibrinogen. “When you’re healthy, it’s in solution. And then when you cut yourself, collagen is exposed, and a little gel called fibrin prevents you from bleeding out. In healthy individuals, the clots are then broken down by a process called fibrinolysis.
Blood samples from patients with long COVID have revealed high levels of various inflammatory molecules trapped in the microclots including fibrinogen and Alpha-2 antiplasmin – a molecule that prevents the breakdown of microclots.
The persistent blood clots essentially result in cells not getting enough oxygen in the tissues to sustain bodily functions. This, Pretorius says, may be central to numerous debilitating symptoms.
In healthy individuals, the body’s plasmin-antiplasmin system maintains a fine balance between blood clotting to prevent blood loss after an injury and fibrinolysis which prevents blood clots from forming.
With high levels of alpha(2)-antiplasmin in the blood of acute COVID-19 patients and individuals suffering from long COVID, the body’s ability to break down the clots is significantly undermined. The blood circulation becomes clogged up.
Microclots are generally not found in people who do not have long COVID. Pretorius says you can find them in some other conditions, such as diabetes, “but the difference is the number and the extreme presence of the clots with long COVID, that’s what’s making the difference,” she says.
Insoluble clots
Another difference is that the clots in long COVID are insoluble. When Pretorius tried to dissolve these clots using an enzyme called trypsin in her laboratory, they would not dissolve. They are resistant to fibrinolysis.
Initially, Pretorius was looking at acute COVID-19 infection. We received blood samples from ICU patients and we made blood smears and looked at them under a scanning electron microscope that can enlarge a sample hundreds of thousands of times. We then added a fluorescent dye or marker called Thioflavin T which lights up when there are misfolded proteins. This happens when, for example, the spike protein binds to the soluble fibrinogen molecule making it insoluble.
The SARS-CoV-2 virus is known to bind to ACE2 receptors and TMPRSS receptors which are found on platelets (blood cells that help with clotting). They are also found on the endothelium (the inner-most lining of the blood vessels). By binding to the platelets and the endothelium, the virus sets off a torrent of clotting causing vascular damage.
Pretorius says in early 2021, “I got a report from Harvard collaborators and others to say that patients do not fully recover post-infection and they referred to this as long COVID.
“I said let’s get the samples. We looked at the blood samples and lo and behold we found the clots and they were fully persistent. I was not surprised to find the clots in long COVID because I knew with acute COVID many people were dying because of clots in the lungs and shortness of breath. But, I did not know the extent to which they were present in long COVID.”
“When we did proteomics analysis on the sample, when we looked at the different molecules in the blood, I could not dissolve the sample with typical enzymes. I used a massively abrasive enzyme called Trypsin which dissolves any possible protein. But it could not dissolve these cells. The resilience of these clots, that they simply don’t get dissolved, surprised me,” Pretorius says.
Pretorius recalls that in 2020, several South African clinicians alerted others to COVID-19 not being a typical viral pneumonia but suggested it was also a vascular disease. “At that stage, it was massively controversial with many dismissing this idea saying it’s a virus that affects the lungs and that’s it,” she says.
Pretorius says this was despite papers published overseas in 2020 that concluded COVID-19 was also a vascular disease. “It was made controversial in South Africa but it is now widely accepted that COVID-19 also affects clotting as well as the body’s vasculature (network of blood vessels).”
Pretorius says, “Although the microclot is a theory, it encompasses all of the other suggested causes of long COVID because the spike protein itself can trigger microclots. We have submitted a paper, looking at many more blood samples, where we found inflammatory molecules trapped inside the blood clots which do not break down. We also found antibodies so the theories about immune abnormalities, persistent virus, and microclots are intertwined. All of these can cause organ damage. So if you look at it from a systems biology approach, all of these are valid.”
Many are told that their symptoms are possibly psychological, all in their head, and they are told to get some rest and to stop stressing. Meanwhile, the patients are very ill
Diagnostics
Pretorius says there are no general pathology tests readily available to diagnose people with long COVID.
“People that are desperately ill – bedridden or in wheelchairs – are often given generalised blood tests. They are told that their pathology test results are within normal to healthy ranges. Many are told that their symptoms are possibly psychological, all in their head, and they are told to get some rest and to stop stressing. Meanwhile, the patients are very ill,” she says.
Pretorius says the main reason the traditional laboratory tests do not pick up any of the inflammatory molecules is that they are trapped inside the insoluble microclots. A typical pathology test looks at the soluble content of the blood, so if the molecules are trapped they will be missed.
“We patented a long COVID test which is just a simple microscopy test that is a useable diagnostic method to see if microclots are present,” Pretorius says.
Microscopy methods are not readily available at pathology laboratories. However, Pretorius says, “We have crowd-funded and received funding from the Polybio Research Foundation in America to buy a flow cytometer for our blood lab to develop a flow cytometry method that can be used in the typical pathology labs. So we hope to have a diagnostic that will be readily available in a couple of months.”
Treatment
Pretorius says colleagues in the United Kingdom have already designed two randomised controlled trials to independently test both coagulation therapy (CLOTT-UK) and Apheresis (CLOTT-Apheresis trial ) in which microclots and inflammatory molecules are filtered out in a dialysis-type treatment. These trials will study whether anticoagulants and Apheresis give long-lasting relief of symptoms. These trials are being planned and researchers are waiting for ethics approval.
In addition, colleagues from the University of Sheffield Hallam and from the University of Manchester have independently set up microclot testing in their labs and they are planning to publish their UK cohort results soon. They are also correlating long COVID severity to microclot presence, says Pretorius.
“It’s been quite a ride. Seeing the devastation of long COVID, I realise why I decided not to be a clinician… handling and hearing all the issues is just so sad,” says Pretorius.
But, she remains determined to help “crack” long COVID.
The fields of Alzheimer’s disease and cancer research have both been shaken by recent investigations which have revealed image falsification and plagiarism. These findings call into question specific avenues of research which have received considerable funding.
Neuroscientist Matthew Schrag, a junior professor studying Alzheimer’s, had already ruffled some feathers criticising the FDA approval of the Alzheimer’s drug Aduhelm when he was approached by an attorney to investigate Simufilam, another Alzheimer’s drug under development.
According to Science, he used funding given to him by the attorney to investigate the data behind the drug’s development. The research focuses on amyloid beta (Aβ) plaques, long thought to be the culprit behind Alzheimer’s.
Schrag identified apparently altered or duplicated images in dozens of journal articles, and sent them to the National Institutes of Health (NIH), which had funded tens of millions of dollars.
The investigation drew him towards a bedrock of modern Alzheimer’s research, a 2006 Nature study by Sylvain Lesné of the University of Minnesota in the laboratory of Karen Ashe, which identified an amyloid beta protein.
Schrag avoids describing the suspicious data as fraud, since that would require unfettered access to the original material. “I focus on what we can see in the published images, and describe them as red flags, not final conclusions,” he said. “The data should speak for itself.”
The work focused on ‘toxic oligomers’, subtypes of Aβ that dissolve in some bodily fluids, a potential Alzheimer’s cause that had gained traction in the early 2000s partly due to their discovery in autopsied Alzheimer’s patients.
Using transgenic mice, the UMN team discovered a previously unknown oligomer species, Aβ*56. They isolated Aβ*56 and injected it into young rats, causing a reduction in cognitive ability.
This discovery, the first to show a direct cause, resulted in an explosion in related research, with related studies receiving $287 million in National Institutes of Health funding in 2021, compared to no funding in 2006.
In concert with molecular biologist Elisabeth Bik, no less than 20 of Lesné’s papers were flagged, 10 of which related to Aβ*56. A finding which some Alzheimer’s experts say calls into question 16 years of amyloid beta research. Some had been suspicious and had failed to replicate the findings, but journals are reluctant to publish research which proves a negative or which contradicts a prominent researcher’s findings.
Cancer research has been dogged by its own crisis with fabricated data, according to an investigative report by Nature. For years, a prominent US cancer-research laboratory run by leading cancer geneticist Carlo Croce at the Ohio State University (OSU) had been dogged by allegations of plagiarism and falsified images. To date 11 papers he has co-authored have been retracted, and 21 have needed corrections.
In 2017, The New York Times first reported on allegations of research misconduct against Croce, when OSU opened inquiries into papers from Croce’s lab. These proceeded to formal investigations, Nature learnt, two of which found multiple instances of research misconduct, including data falsification and plagiarism, by scientists Michela Garofalo and Flavia Pichiorri, in papers they’d authored while in Croce’s laboratory.
Garofalo claimed she did not received proper image manipulation training and Pichiorri said she did not understand plagiarism at the time. They have since moved on from OSU.
OSU declined to charge Croce with misconduct as his involvement did not relate to direct plagiarism or image fabrication, but did note that these cases resulted out of his “poor mentorship and lack of oversight.”
Croce was removed from a number of his positions – for which he attempted to sue – but is still employed by OSU, and many of the papers identified by OSU have not been retracted by their journals.
