A new study using mouse models describes an orally administered small-molecule drug that reduces lowers cholesterol by 70% by preventing the degradation of low-density lipoprotein (LDL) receptors. Published in Cell Reports, the findings point to a previously unrecognised strategy for managing cholesterol – one which may also impact cancer treatments.
“Cholesterol lowering is one of the most important therapies we have to prolong life and protect people from heart disease, which is still the number one cause of morbidity and mortality in the Western world,” said senior author Jonathan S. Stamler, MD, professor at Case Western Reserve School of Medicine.
“Statins only lower cholesterol so far. This is a drug class that we think would represent a new way to lower cholesterol, a new way to hit PCSK9.”
Study Findings
Central to cholesterol regulation are LDL receptors, which sit at the surface of liver cells and remove cholesterol from the blood, thereby lowering serum levels. PCSK9 in the bloodstream controls the number of LDL receptors by marking them for degradation. Therefore, agents that inhibit PCSK9 increase the number of LDL receptors that remove cholesterol.
Nitric oxide is a molecule that is known to prevent heart attacks by dilating blood vessels. In the new study, Stamler and colleagues show that nitric oxide can also target and inhibit PCSK9, thus lowering cholesterol. They identify a small molecule drug that functions to increase nitric oxide inactivation of PCSK9. Mice treated with the drug display a 70% reduction in LDL cholesterol.
Beyond Cholesterol to Cancer
In addition to impacting the field of cholesterol metabolism, the findings may impact patients with cancer, as emerging evidence suggests targeting PCSK9 can improve the efficacy of cancer immunotherapies.
“PCSK9 not only targets LDL receptors for degradation, it also mediates the degradation of MHC 1 on lymphocytes, which is used for recognition of cancer cells” said Stamler. “PCSK9 is effectively preventing your lymphocytes from recognising cancer cells. So, if you inhibit PCSK9, you can boost the body’s cancer surveillance. There may be an opportunity one day to apply these new drugs to that need.”
A study of COVID transmissions in a Taiwanese quarantine hotel revealed that SARS-CoV-2 can spread through cracks in walls and floors, according to findings published in Emerging Infectious Diseases.
The researchers investigated a cluster of SARS-CoV-2 infections in a quarantine hotel in Taiwan in December 2021. This happened amidst a succession of outbreaks in quarantine hotels involving the Omicron variant. The cluster involved three patients who lived in nonadjacent rooms on different floors, and who had no direct contact during their stay.
All three had tested negative by RT-PCR for SARS-CoV-2 within 72 hours before arrival to Taiwan and by deep-throat saliva RT-PCR upon arrival at the airport. None had left their rooms at any point during the stay in the hotel. No other guest or staff member at the hotel had tested positive since the month prior to the start of the investigation.
By directly exploring the space above the room ceilings, the researchers revealed residual tunnels, wall defects, and truncated pipes between their rooms. To see how the rooms were interconnected, they performed a simplified tracer-gas experiment, using ethanol. Aerosol transmission through structural defects in floors and walls in this poorly ventilated hotel was the most likely route of virus transmission.
This event demonstrated the high transmissibility of Omicron variants, even across rooms and floors, through structural defects. “Our findings emphasise the importance of ventilation and integrity of building structure in quarantine facilities,” the authors concluded.
In a study published in The LancetGlobal Health, an international team of researchers has found that influenza vaccines greatly reduce both pneumonia and cardiovascular complications in people with heart failure.
“If you have heart failure, you should get your flu shot because it can save your life – that is what we found in this study,” said the study’s principal investigator Mark Loeb. “It is underappreciated that influenza vaccine can save people from cardiovascular death.”
The study showed that over the entire year the influenza vaccine reduced pneumonia by 40% and hospitalisation by 15% in patients with HF. During influenza season in autumn and winter, the influenza vaccine reduced deaths by 20% in these patients.
Data gathered during flu season also showed the vaccine helped protect against cardiovascular complications, such as heart attacks and strokes.
Trial investigators tracked more than 5000 patients with HF in 10 countries across Africa, Asia and the Middle East, where few people have regular influenza vaccination. They received either an influenza vaccine or a placebo annually between June 2015 and November 2021.
While the flu has long been associated with an increased risk of life-threatening cardiovascular events, Loeb said that people with heart failure are already vulnerable to poor health outcomes. Patients with the condition have a 50% chance of dying within five years, while 20% are hospitalised for cardiovascular complications every year.
“Importantly, we looked at low and middle-income countries where 80 per cent of cardiovascular disease occurs and where flu vaccination rates are low.”
Salim Yusuf, executive director of PHRI and an author of the study said: “The flu shot should be part of the standard practise in people with heart failure given how simple, inexpensive and safe it is. Avoiding one sixth of deaths from heart disease and preventing hospitalizations makes it very cost effective and that can have an important public health and clinical impact.”
The study from McMaster University and partners marks the first clinical trial of the flu vaccine’s effectiveness in patients with HF.
The US Centers for Disease Control have released new opioid prescribing guidelines that do not promote strict thresholds for dose and duration of pain medications. The new guidelines, which update and replace the controversial 2016 guidelines, are published in Morbidity and Mortality Weekly Report.
The previous guidelines had been interpreted as imposing strict opioid dose and duration limits and was misapplied by some organisations, leading to a clarification being released in 2019. Other organisations, such as the European Pain Federation, had stated that overly strict guidelines for their own countries were hampering effective pain management.
The 2022 recommendations are voluntary and give clinicians and patients flexibility to support individual care, said Christopher Jones, PharmD, DrPH, MPH, acting director of CDC’s National Center for Injury Prevention and Control in a press briefing. He stressed that they should not be used as a inflexible rule, or applied as a rigid standard of care, or replace clinical judgement on personalised treatment.
“Patients with pain should receive compassionate, safe, and effective pain care,” Jones stated. “We want clinicians and patients to have the information they need to weigh the benefits of different approaches to pain care, with the goal of helping people reduce their pain and improve their quality of life.”
The guidance covers four key areas: opioids initiation for pain, opioid and dosage selection, deciding prescription duration and conducting follow-up, and assessing risk and potential harms of opioids. It also suggests that clinicians work with patients to incorporate plans to mitigate risks, including offering naloxone.
The document indicates opioids should not be considered as first-line or routine therapy for subacute or chronic pain, and points out that, for many kinds of acute pain, non-opioid therapies are often better choices.
“For patients receiving opioids for 1 to 3 months (the timeframe for subacute pain), the 2022 guideline recommends that clinicians avoid continuing opioid treatment without carefully reassessing treatment goals, benefits, and risks in order to prevent unintentional initiation of long-term opioid therapy,” noted Deborah Dowell, MD, MPH and colleagues in a commentary published in the New England Journal of Medicine.
For chronic pain, clinicians should make maximal use of non-opioid therapies and consider initiating opioid therapy only if pain reduction benefits outweigh the risk, Dowell and colleagues noted. When needed, clinicians should initiate opioids at the minimum effective dose, assess risks and benefits before increasing dosage, and avoid raising dosage above levels likely to yield diminishing returns, they added.
The new guideline offers tips for tapering opioids when warranted, but is not intended to lead to rapid opioid tapering or discontinuation, Jones noted. The recommendations do not apply to sickle cell disease-related pain, cancer pain, and palliative or end-of-life care.
The 2022 document incorporated public feedback since the new version was first proposed in February, including patients discussing their experiences with pain or opioid addiction and barriers to pain care.
“The science on pain care has advanced over the past 6 years. During this time, CDC has also learned more from people living with pain, their caregivers, and their clinicians,” said Dowell in a statement. “We’ve been able to improve and expand our recommendations by incorporating new data with a better understanding of people’s lived experiences and the challenges they face when managing pain and pain care.”
“I think I’m in trouble,” came the message through to Professor Veronica Ueckermann one evening during the first surge of COVID-19 in South Africa in the winter of 2020. It was a distressed call made by a 48-year-old theatre nurse who worked alongside Ueckermann in the ICU frontline. Ueckermann, who is also a professor of internal medicine at the University of Pretoria and an ICU specialist, shifted into high gear with other doctors to save their colleague who was diagnosed with COVID-19.
They succeeded.
But what they didn’t know then was that months later the nurse would be ailing from ongoing medical symptoms put down to the catch-all of long-COVID.
“It’s a case study, but it was also very close to my heart,” says Ueckermann, who has become a specialist and researcher on the long-term effects of COVID. She recently presented on long-COVID during a webinar of the South African Academy of Family Physicians. “The nursing sister had numerous comorbidities, including a raised BMI, diabetes, hypertension, and asthma. When her symptoms didn’t get better, the hospital just wanted to have her medically boarded because they couldn’t be sure when she would be well enough to work again,” says Ueckermann.
She is cautious too, pointing out that there’s still little definitively known about long-COVID and new research is only in its infancy. Much of the difficulty lies in the wide-ranging symptoms and how individuals are affected. There are also varying recovery times, different underlying conditions and susceptibilities, and the reality that many people are simply not diagnosed. It makes the term “long-COVID” an umbrella term for everything from brain fog or mental confusion and fatigue to depression and shortness of breath and chest pains. Others also describe general body aches and continued loss of smell and taste.
The post-COVID condition
In October 2022, the World Health Organization (WHO) released a factsheet that states that between 10% and 20% of people who are diagnosed with COVID-19 continue to have symptoms beyond three months of first getting ill and develop what the WHO refers to as post-COVID condition. Many more people say symptoms plague them still even after nearly two years.
“The condition can be debilitating, causing disabling symptoms and functional deficits. It can significantly impact people’s ability to work, engage and participate fully in family and community life. Mental health effects can directly result from long-COVID, but may also develop due to prolonged suffering and distress caused by the condition,” reads the WHO factsheet.
The WHO’s recommended treatment, however, is non-specific, stating: “Post-COVID-19 condition can be supported with help from their families, peers, employers, and the community and they can also benefit from tailored rehabilitation.”
According to the National Institute for Communicable Diseases (NICD), “Every long-COVID patient is different, as such, every patient will need treatment specific to their symptoms which can be managed by their family doctor or clinic. There are no drugs to prevent long-COVID. Long-COVID is not a contraindication to vaccination, and COVID-19 vaccination may even sometimes improve long-COVID symptoms. Long-COVID is treated by slow, stepwise rehabilitation, and appropriate management of symptoms.”
Greater awareness and education needed
Ueckermann agrees with the WHO’s call for greater awareness and education so patients feel heard and supported. Many people resort to joining online support groups through platforms like Facebook. They share their challenges and stories and give each other support when they feel misunderstood and frustrated that they can’t get well and doctors can’t help. Ueckermann says there needs to be help for patients’ individual needs because not finding solutions will add to mounting pressure on the healthcare system.
“Because of COVID disruptions, many cancers are now presenting at later stages. There are cases of TB and other illnesses that were neglected. And now we have long-COVID that requires diagnosis after diagnosis for exclusion so all of this drives up costs,” she says.
lung There are other associated costs for people who cannot work or are performing sub-optimally trying to work while feeling unwell. Children affected by long-COVID do worse at school and lose interest in their sports and other activities that they used to enjoy, she says.
Last year, Spotlight reported on a dedicated long-COVID clinic at Groote Schuur Hospital in Cape Town. As far as we could establish, such specialised long-COVID clinics are very rare in South Africa.
“Long-COVID remains inaccurately defined and as a result, standard treatment guidelines for the condition as a whole have not yet been developed,” says Foster Mohale, Spokesperson for the National Department of Health. “However, standard treatment guidelines to address the symptoms and conditions associated with long-COVID are in place,” he says. “These guidelines guide assessment and treatment, and provide criteria for referral from primary healthcare to more specialised services.”
Mohale adds that the burden of disease is of “enormous concern and needs to be better understood and quantified”. But says the department’s data shows that visits by adults to public sector primary healthcare facilities remain below pre-pandemic levels, which suggests that any increase in the burden of disease has not resulted in an increased burden on health services. He also emphasises the need to have up-to-date vaccinations, adding that “people who are vaccinated are less likely to develop long-COVID”.
Research ongoing
Ueckermann says it’s a positive development that as awareness is growing, so are studies, including studies by the Medical Research Council and many of the country’s universities. She says scientists are looking at everything from the role of green tea extracts and the use of SSRIs (Selective serotonin reuptake inhibitors) that are commonly used to treat depression.
“These are all ongoing studies, so we have to wait to see the data coming through but it’s promising that everyone is trying to understand exactly what this long-COVID is and the most important thing is that we continue making this a greater area of priority in healthcare,” she says. It matters for the growing number of patients, or for her colleague who she says still needs help to get from “doing better,” to fully recovered.
