National Institute of Health (NIH) scientists have made a significant breakthrough in understanding how “bad” cholesterol, known as low-density lipoprotein-cholesterol or LDL-C, builds up in the body. The researchers were able to show for the first time how the main structural protein of LDL binds to its receptor – a process that starts the clearing of LDL from the blood – and what happens when that process gets impaired.
The findings, published in Nature, further the understanding of how LDL contributes to heart disease, the world’s leading cause of death, and could open the door to personalising LDL-lowering treatments like statins to make them even more effective.
“LDL is one of the main drivers of cardiovascular disease which kills one person every 33 seconds, so if you want to understand your enemy, you want to know what it looks like,” said Alan Remaley, MD, PhD, co-senior author on the study who runs the Lipoprotein Metabolism Laboratory at NIH’s National Heart, Lung, and Blood Institute.
Until now scientists have been unable to visualise the structure of LDL, specifically what happens when it links up with its receptor, a protein known as LDLR. Typically, when LDL binds to LDLR, the process of clearing LDL from the blood begins. But genetic mutations can prevent that work, causing LDL to build up in the blood and get deposited into the arteries as plaque, which can lead to atherosclerosis, a precursor for heart disease.
In the new study, the researchers were able to use high-end technology to get a view of what’s happening at a critical stage of that process and see LDL in a new light.
“LDL is enormous and varies in size, making it very complex,” explained Joseph Marcotrigiano, PhD, chief of the Structural Virology Section in the Laboratory of Infectious Diseases at NIH’s National Institute of Allergy and Infectious Diseases and co-senior author on the study. “No one’s ever gotten to the resolution we have. We could see so much detail and start to tease apart how it works in the body.”
Using cryo-electron microscopy, the researchers were able to see the entirety of the structural protein of LDL when it bound to LDLR. Then, with AI-driven protein prediction software, they were able to model the structure and locate the known genetic mutations that result in increased LDL.
The researchers found that many of the mutations that mapped to the location where LDL and LDLR connected, were associated with familial hypercholesterolaemia (FH). FH is marked by defects in how the body uptakes LDL into its cells, and people with it have extremely high levels of LDL and can have heart attacks at a very young age. They found that FH-associated variants tended to cluster in particular regions on LDL.
The study findings could open new avenues to develop targeted therapies aimed at correcting these kinds of dysfunctional interactions caused by mutations. But, as importantly, the researchers said, they could also help people who do not have genetic mutations, but who have high cholesterol and are on statins, which lower LDL by increasing LDLR in cells. By knowing precisely where and how LDLR binds to LDL, the researchers say they may now be able to target those connection points to design new drugs for lowering LDL from the blood.
Air pollution is a well-known risk factor for respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) – but its contribution to lower respiratory infections is less well known, especially in adults. To address this, a team from the Barcelona Institute for Global Health (ISGlobal), a centre supported by the ”la Caixa” Foundation, assessed the effect of air pollution on hospital admissions for lower respiratory infections in adults, and which subgroups that could be particularly vulnerable to these infections. The results have been published in the journalEnvironment International.
The research shows that long-term exposure to particulate matter (PM2.5 and PM10), nitrogen dioxide (NO2) and ozone (O3) air pollution is associated with more hospital admissions for lower respiratory tract infections in adults. The associations were stronger in men, people over 65 years of age and those diagnosed with hypertension.
The study involved 3 800 000 adults from the COVAIR-CAT cohort, a large cohort of 7.7 million people based on the health system of Catalonia. The research team used exposure models to estimate annual average concentrations of PM2.5, PM10, NO2 and ozone during the warm season (May-September) between 2018 and 2020 at the participants’ residences. Information on hospital admissions, mortality and comorbidities was obtained from various administrative databases. The study included hospital admissions for all lower respiratory infections and, separately, the subgroup of hospital admissions for influenza and pneumonia. A statistical model was then used to assess the association between air pollution and hospital admissions.
“The association between air pollution and hospital admissions for lower respiratory tract infections was observed even at pollution levels below current EU air quality standards,” says Anna Alari, ISGlobal researcher and first author of the study. “It is crucial to adopt stricter air quality standards, as more ambitious measures to reduce air pollution would decrease hospital admissions and protect vulnerable populations,” she adds.
Stronger association in men and people over 65
The association between air pollution and hospitalisations for lower respiratory tract infections was more pronounced in people over 65 years of age or with comorbidities, compared with younger people or those without comorbidities. Specifically, elevated levels of air pollution were associated with approximately three times higher rates of hospital admissions for lower respiratory infections among people aged 65 years and older compared with younger people.
In addition, exposure to elevated levels of NO2, PM2.5 or PM10 (but not O3) was associated with about a 50% increase in hospital admissions in men, while the association was about 3% higher in women.
The team observed the same pattern for hospital admissions for influenza or pneumonia, but with smaller associations compared to lower respiratory infections. “This may be due to the influence of available vaccines against the pathogens responsible for influenza and most cases of pneumonia,” says Cathryn Tonne, senior author of the study.
These results give hope to stroke patients worldwide who may not be able to access thrombolytic medications within the approved time window, which in China is within 4.5 hours, said the trial’s principal investigator Min Lou, MD, PhD, a professor at the Second Affiliated Hospital of Zhejiang University’s School of Medicine in China.
In the US, alteplase is approved to treat stroke within three hours of symptom onset and is recommended for use up to 4.5 hours for select patients. Other research has indicated it may also work well in some patients 4.5 to 9 hours after stroke onset.
Researchers enrolled 372 stroke patients whose symptoms began 4.5 hours to 24 hours earlier. They used widely available CT perfusion imaging (advanced brain scanning) to confirm that these patients still had brain tissue that could recover with treatment. Participants were randomised to receive alteplase, while the other received standard stroke care of antiplatelet therapy at the discretion of the investigator, based on the Chinese Guidelines for Diagnosis and Treatment of Acute Ischemic Stroke 2018. Functional recovery was assessed at 90 days.
“We believe these findings mean more people may return to normal or near-normal lives after a stroke, even if they receive treatment later than originally thought beneficial,” Lou said. “This method of treatment could become the new standard, especially in hospitals that use CT perfusion imaging. This technology helps health care professionals see how blood flows in different parts of the brain after an ischemic stroke. This could extend treatment eligibility to millions more patients across the globe.”
The study found:
40% of participants treated with alteplase had little to no disability after 90 days, compared to 26% of those who received standard care – a 54% higher chance of functional recovery.
Less than 3% of participants in either group received rescue mechanical clot removal as an additional treatment.
Rates of death were the same (10.8%) for both groups.
The risk of brain bleeding was higher among those who received alteplase than among participants who did not (3.8% vs. 0.5%), but researchers believe this is a manageable risk.
“We also need to look more closely at how safe and effective other clot-dissolving medications, like tenecteplase, are when given after a stroke, especially beyond the usual time frames. It’s also important to learn if our findings apply to other groups of people, especially in areas with different stroke risks and health care resources,” Lou explained.
Study limitations include the that both participants and researcher knew which treatment was being given, which could have introduced bias, and results may not be generalizable to patients outside of China.
Study design, background and details:
The study enrolled 372 stroke patients in a multicenter, prospective, randomized trial at 26 stroke centers in China.
The patient’s average age was 72 years, and 43% were women.
The trial used widely available CT perfusion imaging software to gauge salvageable brain tissue, making the findings more applicable to real-world clinical settings.
Enrolled patients were assigned to the alteplase group or a standard medical treatment group.
The primary outcome was a score of 0 or 1 on the modified Rankin scale, which scores disability from 0 (no symptoms) to 6 (death) at 90 days.
Study co-authors, funding and disclosures are available in the abstract.
Breast cancer is the world’s most prevalent cancer. Although earlier detection and targeted treatment have resulted in high survival rates, many breast cancer survivors experience fear of cancer recurrence. For some survivors this fear is occasional, for others it is persistent and often debilitating.
A new study of breast cancer survivors has found this psychosocial challenge impacts almost every important domain of their lives – the emotional, behavioural, cognitive, relational and professional. A larger number of domains was affected, and they were affected more frequently in those with greater fear of recurrence.
“Study participants were reportedly disease free and trying to rebuild their lives during their post-treatment survivorship,” said senior author Shelley Johns, PsyD, a researcher-clinician with the Regenstrief Institute, the Indiana University School of Medicine and the IU Melvin and Bren Simon Comprehensive Cancer Center. “Our findings provide clarity about how breast cancer survivors are impacted by fear of recurrence and insight into how they cope with this understandable fear.”
The impact of fear of recurrence ranged from mildly to severely disruptive. Women experiencing mild fear reported sporadic occurrences. Those with significant fear described it as persistent and/or easily triggered across multiple life domains.
Disturbed sleep prior to mammograms was reported by survivors with mild fear, while frequent need to absent themselves from social activities, get into bed and pull the blanket over their eyes to avoid thinking about cancer was an example of severe, also known as clinical, fear of recurrence. Approximately 74 percent of study participants were experiencing clinical fear of recurrence.
347 women completed the study’s open-ended survey:
Many reported feelings of stress, irritability and sadness.
Some said fear of recurrence frequently interrupted their train of thought, for example interfering with their job when their disease popped into their mind.
Survivors who thought that they were more worried than they should be compared to other breast cancer survivors reported feelings of embarrassment.
Some indicated it was too hard to be around their family because they were constantly wondering how many more Christmases and birthdays they were going to have with their children.
The paper’s title includes the phrase, “out of a dark place,” a direct quote from a breast cancer survivor who said that she joined the study to support “getting out of a dark place.”
Other survivors noted the specific impact of fear of cancer recurrence on daily life:
“It motivates me to maintain healthy habits. Such as eating five servings of fruits and vegetables, working out and drinking less alcohol. It also motivates me to maintain mental health and physical health.”
“Whenever I feel any kind of pain or discomfort in the area where I had cancer it concerns me and I feel anxious and irritable.”
“Cancer is all around us. Everything is a trigger. Anniversaries, other family/friends’ diagnosis, commercials about drugs, social media, etc. …it’s a daily thought or a daily emotion.”
“Sit for hours doing nothing, do not turn on TV, sleepless, find hours pass by and I am in the same place just thinking, do not participate in activities, get lost driving because I’m deep in thought, compulsive online shopping, collecting things.”
Survivors offered specifics on their coping mechanisms:
“Just trying to be positive, eat healthy, take my meds, get enough sleep, exercise three times a week, and hope for the best.”
“I try to avoid things that make me think about recurrence. For example, unfollowing social media accounts, fast forwarding or leaving the room when commercials about cancer medications are on.”
“I try not to focus on it. I also speak with family members who have lived with cancer longer than myself.”
“Prayer, meditation, staying in the moment, and focusing on making the best of each day.”
While many survivors cited avoidance of thoughts and feelings as their primary coping behaviour, Dr Johns, a health services researcher and clinical health psychologist, observes that research is needed to probe the function of various coping behaviours’ to determine if they are helpful.
In a question seldom posed to participants in a clinical trial, when asked what they hoped to gain by participating in the study, the majority indicated that they sought senses of purpose, belonging, control and connection with others.
The paper concludes, “Fear of cancer recurrence is one of the most common psychological challenges for cancer survivors. Understanding affected life domains, coping strategies employed prior to intervention, and reasons for seeking guidance can inform the development and implementation of evidence-based interventions to effectively address fear of cancer recurrence among persons living with breast cancer.”
A timely report on governance in South Africa’s healthcare sector released last year identified several serious shortcomings. As the political and administrative wheels again start turning in 2025, we unpack the report and ask if government is paying attention.
The signing of the National Health Insurance (NHI) Bill into law last year, sparked a renewed conversation on how the healthcare sector is governed, making the release of a consensus study on what was needed to achieve good governance and management in the South African healthcare system a few months later particularly timely. Commissioned by the Academy of Science of South Africa (ASSAF), the report was a three-year endeavour led by a panel of experts from multiple fields.
The spark for the project was concerns over the performance of the country’s healthcare system and the Life Esidimeni tragedy in particular, according to the chairperson of the ASSAF report panel Professor Lilian Dudley. The Life Esidimeni tragedy, in which 144 mental healthcare users in Gauteng died due to starvation and neglect, highlighted what the public health medicine specialist described as “not just poor performance but corruption and unethical practices in the health system”.
“There were concerns about the overall governance or oversight and leadership of the health system, and the panel was essentially asked to try and look at some of the challenges, as well as to go over the evidence and make recommendations which could be implemented to address it,” she told Spotlight.
After describing the “magnitude, the spread, and the effects of the governance challenges in the health system” as well as finding examples of where good governance was taking place, the report went on to make eight recommendations on practical strategies to improve the situation. This article focuses on three of these recommendations, so it is by no means exhaustive. The recommendations are interdependent, as is evident from the full report which can be found here.
Good governance is ‘patchy’
Sharon Fonn, Professor of Public Health at the University of the Witwatersrand who also worked on the report, told Spotlight it found that good governance in our healthcare system is “patchy”. She said there were two issues contributing to this: There are some people without the necessary competence and skills or sometimes motivation in key positions, and in some cases dysfunctional or inappropriate systems undermine the best efforts of those who are competent or have the right intentions.
There is no quick fix though. “You need to see this as a 10-year project,” Fonn said. “There’s some political leadership that’s needed, and then there’s some technical interventions that are needed. It’s about having a plan and getting people around the table,” she added.
Foundations for good governance are present but no longer ‘fit-for-purpose’
To contextualise governance within the healthcare system, the report needed to look at the past, according to Dudley. She explained that democratic South Africa “inherited a very flawed, fragmented health system, which was not being governed in order to address the needs of the majority of the population”. Thus, a lot of work had been done after 1994 to set up a unified healthcare system and establish systems and structures to lay foundations for good governance. “But we seem to have lost the plot along the way,” she said.
“One of our key findings was that there were some foundations that were put in place, but they would not be effective as governance structures and were no longer fit for purpose,” Dudley said. “Even though we have some structure, some systems, they are not really supporting and promoting the kind of governance that is needed.” In this regard, Dudley points to key legislation and policies such as the National Health Act (NHA) and the White Paper on Transformation for the Health system.
“The other context within which we are operating is the overall political environment, and health is political at the end of the day with levels of political interference,” Dudley added. “[H]aving the right people, the right competence and the right ethics in place has been a problem because a lot of senior managers in the health system are not necessarily accountable to the people they serve”.
The report stated that a conflict between two pieces of legislation – the Public Finance Management Act (PFMA) and the Public Services Act (PSA) – could be contributing to some of these problems with senior leadership and so-called “cadre deployment” in some provincial health systems. At issue are apparent contradictions and overlaps between the roles of purely political appointments, such as Members of the Executive Committees (MECs) for health, and those of senior officials like heads of health departments.
The PFMA is legislation aimed at regulating the financial management of government and providing for the responsibilities of the persons entrusted with that financial management. According to the report, the Act grants the power and responsibility for financial management, service delivery and human resource management to “accounting officers”, who are either the Head of Department or the Director-General – depending on the level of government being referred to.
By contrast, according to the ASSAF report, the PSA aims to regulate the organisation and administration of the public service, grants Ministers and MECs in the provinces the power of “executive authority” giving them the authority to, among other things, appoint people to government positions.
It is not unusual to have contradictions between pieces of legislation that were developed at different times and by different Ministers or Departments, Dr Andy Gray, a senior lecturer in the Division of Pharmacology at the University of KwaZulu-Natal’s School of Health Sciences, told Spotlight.
He said Section 38 of the PMFA describes the responsibilities of “accounting officers”, which is clearly describing a managerial function. However, every Head of Department is also subject to governance by a minister. The PSA repeats the same definition for an accounting officer as the PMFA but adds an additional definition for an executive authority.
Within the PSA, who the executive officer is depends on the level of government being referred to, for example in relation to “a provincial department or a provincial government component within an Executive Council portfolio”, the executive officer will be the member of the Executive Council responsible for that portfolio.
In the case of a provincial health department, this would mean the MEC for Health is an executive officer, who is granted by this Act all the powers and duties necessary for, among other things, “the recruitment, appointment, performance management, transfer, dismissal and other career incidents of employees of that department”.
“That does appear to contradict the separation between management and governance, so the ASSAF criticism appears to be valid,” Gray said.
Another function of governance that has not been working as it should, according to Dudley, has been the community participation aspect. She said that the NHA has delegated a lot of the power and responsibility for enabling community participation to the provincial governments. And in the cases where provincial governments have created appropriate regulations for the health committees that allow for community participation, it’s still inadequate.
As summarised by the report, the lack of clarity between these three Acts – NHA, PFMA, and PSA – “have contributed to conflicting mandates between politicians and senior managers in the public health sector, across levels of government, and between the health sector and structures for community representation”.
Legislation needs to be refined
To address some of these issues, the report recommended updating legislation and governance structures “to insulate them from vested interests and give them executive rather than merely advisory functions”.
To do so, it called for making accountability structures more effective by amending the conflicts within legislation that weaken or undermine the delegation of governance. This includes, among other steps, aligning the PFMA and the PSA, as well as clarifying and strengthening the way the NHA delegates authority between levels of government, particularly to health districts and health facilities.
The report also proposes taking steps to strengthen community governance structures like clinic committees, hospital boards and other entities. This included, among other things, reforming legislation to ensure “harmonised policies on roles and functions of such structures across all provinces” and extending community participation structures to the private sector. It also called for a common policy defining the “criteria and processes for appointments, role and functions, reimbursement of community committee members for costs, induction, and continuous capacity building”.
Systems are not working
Also hindering good governance, according to Fonn, is dysfunctional systems, such as overly complicated procurement processes and ineffective information systems. She said that whenever a problem arose with procurement, another layer of control was added, making the systems impossible to navigate.
“It must be possible to review it and to work out a more manageable process around procurement. And procurement is particularly important because it’s sort of what keeps things turning over. It’s also the space where vested interests can be exercised,” Fonn said.
Accurate information is another essential component of the health system that overall isn’t working very well, though there are exceptions. Fonn explained that the report found functional information systems in some provinces. Part of what can be done to improve governance, she said, is to take what worked in those instances and try to replicate or adapt it to work in other provinces.
Need functional fit-for-purpose systems
One of the recommendations in the report is to “surround managers and leaders with functional fit-for purpose systems (including human resources, procurement, health information systems) so that they can do their work”.
Part of this was a call to improve procurement processes by simplifying the existing overly complex and sometimes contradictory rules and delegating more of the actual procurement to facilities and district or sub-district managers.
“Overly complex procurement systems are inhibiting decentralisation, as the complexity of existing rules makes it difficult for decentralised managers,” the report stated. “This does not mean that every facility should be issuing its own medicine tenders, but there is no reason why strong sub-district offices or larger facilities should not be ordering supplies off transversal tenders without multiple layers of high-level signoff.”
Some of the suggested reforms include greater development and use of electronic systems like electronic catalogues, stock management systems, ordering systems and e-procurement systems. It also suggested including medical supplies and medical equipment in transversal tenders to achieve economies of scale.
The report also advocated for giving health institutions greater power, where appropriate, over hiring, firing and disciplinary procedures. “Within labour law and labour agreements, space must be made to allow managers to follow agreed procedures without sacrificing the public value mission of the service,” it stated.
Implementing the electronic National Health Information System of South Africa (NHISSA) was also identified by the report as an urgent priority so that patient-linked data can be collected.
Alleged lack of vision and stewardship by the National Department of Health
Another trend observed by the panelists, Fonn said, is an overall lack in a vision of the healthcare system that is being communicated by government – particularly the National Department of Health. She used the example of the NHI, where the government has been, as she described it, “unable to communicate that [NHI] in a way that captures the public imagination and in a way that makes sense to people on the ground who are actually [healthcare] providers”.
“The argument from government is that the NHI Act is simply setting in place the fund, that’s all it’s supposed to do. I understand that…and it’s a legitimate argument. The problem is then that doesn’t tell people what it means,” she added. “It’s that kind of lack of stewardship, lack of communicating a vision.”
Fonn also pointed out an apparent reluctance by the National Department of Health to engage with stakeholders and instead foster a “command-and-control environment”.
Another layer of this issue is that the healthcare system is set up in a way that makes the National Department of Health responsible for steering the system but, according to Fonn, they haven’t done this effectively and have focused on the wrong things.
“The way the South African health system is set up currently is that the National Department [of Health] is responsible for stewarding the system, for making sure that the right legislation exists, the right checks and balances exist, and the right controls exist,” said Fonn.
“I think that at least in part, they haven’t [fulfilled that responsibility]. It’s a complex thing to do so I’m not suggesting it’s easy. But I don’t think they’ve had their eye on the right place,” she said.
“What our report does acknowledge is that there are many good people in the health system who actually want to see improvements, who are committed to good leadership and management and governance,” Fonn said. “But I think we need leadership to kind of show the way and one of the first things that we felt was important was to revisit what our public values are, what are the social goals that we want to set for the health system, and can we all agree on that and move towards that? [We need] that kind of leadership and stewardship from the political and national government level.”
Mixed response from government
Spotlight asked the National Department of Health and Minister of Health Dr Aaron Motsoaledi for their responses to the report and its findings. The spokesperson for the health department indicated he had only been able to access an abstract of the report and would not be able to respond without seeing the full report. A copy of the report was then sent to the spokesperson, but no response or comment was received by the time of publication (more than a week later).
However, according to Dudley, the report was presented last year to the Minister of Health, senior managers in the provinces, and health MECs.
“There was actually quite a bit of interest from the new MECS [for health] … the MECs were quite keen to hear more about it, engage more about it and wanted to know what we need to do to actually respond and to start implementing some of these recommendations,” she said.
By comparison, Dudley said there was less interest from the National Department of Health.
She however pointed out that the burden of changing governance in the healthcare system doesn’t rest entirely on the health department’s shoulders.
“There are multiple stakeholders that need to take action, we do try to emphasise that in the report. Yes, government and politicians do have particular roles, but everybody has a role,” Dudley said.
These include academic institutions, she said, which need to ensure when training health professionals and leaders they are provided with the kind of competencies that will improve the management, leadership and governance of the health system.
Research institutions also have a role to play in addressing some of the unanswered questions around governance and how to implement interventions that can bring about change. Civil Society will also have a part to play through activism to hold those in positions of power to account.
