A study shows they do – but without causing cognitive decline
Photo by Towfiqu barbhuiya: https://www.pexels.com/photo/person-feeling-pain-in-the-knee-11349880/
Total joint replacement is a proven treatment to relieve chronic knee pain, but there have been concerns raised that particles from the device may migrate to the brain and cause memory problems. New research from Rush University shows that may not be a worry.
In a study published by Acta Biomaterialia, researchers found that particles in some people with total joint replacements traveled to the brain but did not cause cognitive decline.
Researchers did find an association of cobalt, a key element of most implants, with more Alzheimer’s disease pathology in the brain.
The particles, called wear debris, are caused by friction and movement in the joint, or, in some cases, corrosion. The newer materials used in joint replacements today make this less likely to occur.
“Implants have a very specific combination of metals such as cobalt, and when they show up together in one particle in the brain in the exact same composition that the implant is, we know it can’t come from any other source,” said Robin Pourzal, PhD, associate professor and director of implant materials analysis.
“For years, we’ve known that particles can deposit in tissues surrounding the joint, but this is the first study to look at the particles deposited in the brain.”
In working with Puja Agarwal, PhD, in the Rush Alzheimer’s Disease Center, the team took a closer look at what was happening cognitively in this group of people
The study included data collected among 701 deceased participants in the ongoing Memory and Aging Project conducted by David Bennett, MD, which include older adults residing in the greater Chicago area. The participants had no dementia at the beginning of the study and were followed annually with cognitive assessments using a 19-test battery, a standard collection of memory and thinking skill tests.
A total of 229 people in the study had a total hip, knee or shoulder replacement. The control group was made up of 472 people who had no total joint replacement. Due to a higher likelihood of the metal cobalt being found in total hip replacement, the participants were studied in two groups: 146 with hip replacements and 83 with knee or shoulder replacements.
Pourzal notes that the collaboration was led by faculty members from the Department of Orthopedic Surgery, including leaders from Rush Orthopedic Research, in collaboration with colleagues from the Rush Alzheimer’s Disease Center and international partners.
“Total joint arthroplasty remains one of the most successful and life-changing interventions in modern medicine. But it does suggest that wear particles from the implant, particularly in certain hip replacements involving accelerated wear, may travel beyond the joint and warrant further study.”
Research coauthored by a University of Miami Business School professor links more frequent cannabis use to fewer days of good mental health, particularly among men.
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More frequent cannabis use is associated with fewer days of good mental health among adults, particularly men, according to a study coauthored by a University of Miami Business School professor.
Michael T. French, professor and chair of the Department of Health Management and Policy, and Weiwei Chen, an economist at Kennesaw State University, examined how cannabis use relates to self-reported overall, physical and mental health. Their study was published in Medical Care Research and Review.
“People have some preconceived notions about alcohol and other drug use, including how they affect individuals, society and governments,” said French. “I believe this paper is another example of how our preconceived notions aren’t always correct, especially when it comes to cannabis use and related policies.”
The study examined the relationship between cannabis use and overall physical and mental health, added French, who has spent much of his career studying substance use policies and risky behaviours.
Cannabis use has become more prevalent as additional states pass medical and recreational cannabis laws. In April, FDA-approved cannabis medications and cannabis sold under state medical licences were moved out of the Schedule I classification they shared with heroin and into Schedule III, a category for drugs with accepted medical uses and a moderate risk of dependence, such as ketamine and Tylenol with codeine.
French and Chen applied statistical techniques to data on cannabis use, health status and other individual characteristics from the 2016–2023 Behavioral Risk Factor Surveillance System. The analysis included adults from 38 states and found that more days of cannabis use were associated with fewer days of good mental health among younger adults, particularly men. Results for adults 65 and older were mixed and often not statistically significant.
The main analyses did not find a consistent relationship between cannabis use and physical health in either age group. The authors caution that this does not mean cannabis use carries no physical health risks.
“Although medical use of marijuana has numerous benefits, the cannabis industry, just like the pharmaceutical industry or the medical-device industry, tends to emphasize all the advantages of their products without a full assessment of the potential consequences,” said French. “Objective academic researchers and other scientists without a predetermined agenda can provide unbiased analyses of the true costs and benefits.
“As articulated in the paper, we are presenting our findings without advocating for a particular policy or law. Policymakers can use our results to formulate more informed initiatives that consider the full spectrum of pros and cons associated with cannabis use.”
For generations, corporate South Africa treated water like as an abundant utility. Facility managers turned on the tap, paid the monthly municipal bill, and gave the resource little further consideration. That luxury is gone. Today, deteriorating municipal infrastructure, frequent water cuts, and declining water quality have transformed water security from an operational concern into a strategic business risk. It is no longer an issue confined to factory floors or facilities departments, but it demands attention at board level. For modern companies, water stewardship is no longer a corporate social responsibility initiative. It is a core leadership duty that directly affects business survival, legal compliance, and long-term success.
Caught between strategic expectations and operational reality
Business leaders are under pressure from both ends of the value chain. From the top down, investors, banks, and strict environmental standards demand complete openness about how much water companies use and how they protect the environment. From the ground up, operational teams face mounting challenges as unreliable municipal supply, infrastructure failures, and water quality concerns disrupt daily activities.
When poor municipal water supply stops production lines or dirty wastewater breaks environmental laws, the financial hit is immediate. Businesses are constantly forced to choose between paying massive fines or spending large sums of money on emergency repairs. Because of this constant pressure, water has permanently shifted from a minor monthly expense into a top business risk.
Knowing your true water footprint
One of the biggest challenges for large organisations is the lack of accurate, consolidated water data. Many organisations operate without a comprehensive understanding, unified view of how much water they consume, where losses occur, how water quality changes across facilities, or what is ultimately discharged into the environment. Without this basic information, setting realistic reduction goals or meeting modern Environmental, Social and Governance (ESG) reporting requirements becomes exceptionally difficult.
To take back control, boards need to know exactly which of their facilities sit in water-stressed areas or depend on fragile local water supplies. Executive leaders must connect with site managers to truly understand how water shortages impact everything from daily manufacturing output to employee health and community relations.
Testing business resilience for a drier future
Protecting a business for the future requires serious planning at the executive level. Boards can no longer assume that municipal water services will remain reliable. Leadership teams must prepare for a range of scenarios, including long municipal outages, water quality that drops below safe working levels, and sharp increases in water tariffs and fines. As South Africa works to fix its national water infrastructure, factoring these rising costs and risks into financial planning is a basic duty for any director.
Forward-thinking companies are discovering that active water stewardship creates real business advantages beyond just avoiding risks. Moving toward a circular water model allows businesses to grow without relying entirely on fresh water. Investing in on-site water recycling, greywater systems, and advanced treatment technology is what enables companies to insulate themselves from municipal supply problems while turning environmental responsibility into operational strength.
Bridging the gap between policy and practice
Protecting a company’s right to operate means connecting high-level company goals with everyday actions on the ground. Effective water stewardship takes a holistic view of the entire water cycle, examining how water enters a facility, how efficiently it is used, how losses are managed, and how responsibly wastewater is treated and discharged.
Partnerships with specialised environmental service providers can help organisations implement advanced filtration systems, optimise treatment processes, improve wastewater management, and deploy innovative water-efficiency solutions. When the private sector takes responsibility for its water use, the benefits go far beyond individual company profits and reputations.
By taking stress off municipal systems, businesses actively help secure water for the surrounding community. Water stewardship is no longer an act of corporate philanthropy. It is a fundamental requirement for organisations seeking to remain competitive, resilient, and sustainable in an increasingly resource-constrained world.
Researchers at The University of Texas MD Anderson Cancer Center found new evidence that BRAF, a protein commonly involved in cancer, plays a key role in developing, amplifying and maintaining chronic pain caused by nerve damage. Using BRAF inhibitors reduced pain sensitivity in preclinical models, suggesting the therapeutic potential of this approach for treating chronic nerve pain.
“Our findings identify the cancer-promoting protein BRAF as a key driver of pathological pain signaling following nerve injury,” Pan said. “Because BRAF inhibitors are already approved for cancer treatment, this discovery raises the possibility of rapidly repurposing existing therapies to reduce the level of pain signals entering the spinal cord and improve patient quality of life.”
How does nerve injury cause chronic pain?
Chronic nerve pain, or neuropathic pain, can come from injury, disease or even life-saving cancer treatments. This pain can be intense and persistent, and it responds poorly to conventional pain medications, negatively affecting patient quality of life.
Protein channels in the brain and spinal cord, known as NMDA receptors, help nerve cells communicate. After nerve injury, these NMDA receptors can become hyperactive, amplifying pain signals. To identify potential mechanisms, the researchers explored the role of BRAF on NMDA receptor activity.
What did the researchers find in this study?
Using preclinical models of nerve injury, the researchers discovered that BRAF moved from peripheral sensory nerve cells to their terminals inside the spinal cord, where it activated molecular signals to increase NMDA receptor activity. They also found a correlation between BRAF signaling proteins and NMDA receptors in human spinal cord samples.
These initial results suggested that targeting BRAF could help reduce activity in the NMDA receptors to reduce pain.
Does targeting BRAF reduce pain?
In the preclinical models, the BRAF inhibitor vemurafenib and the MEK inhibitor selumetinib reduced sensitivity to touch, pressure and heat but did not change normal response in models without nerve injury.
Deleting the Braf gene also resulted in less persistent pain sensitivity. Conversely, activating BRAF directly caused pain sensitivity in models that did not have nerve injury, highlighting the key role of BRAF in starting and maintaining neuropathic pain.
What does this mean for patients who have nerve injury and chronic pain?
These results are preclinical, and researchers will need to further examine the appropriate dosing, delivery methods and possible side effects of BRAF inhibitors prior to clinical trials in humans. The researchers also hope to understand how nerve injury triggers the translocation of BRAF from the nerves to the spinal cord.
However, these results suggest that BRAF signalling is associated with NMDA receptor activation in the spinal cord and that currently available BRAF inhibitors have therapeutic potential to treat neuropathic pain.
Emergency diagnosis occurred in more than 20% of patients across multiple conditions, including Parkinson’s disease, schizophrenia, and coronary heart disease
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Patients diagnosed with conditions after an emergency hospital admission or an emergency room visit face a higher risk of death than those diagnosed in non-emergency settings, according to a large population-based study by Emma Whitfield and colleagues from University College London, UK, published August 25th in the open access journal PLOS Medicine.
Cancer diagnoses following emergency hospital care are known to be associated with advanced disease and poor prognosis. However, less is known about the frequency and prognostic outcomes of emergency diagnosis in other conditions.
Using linked primary care, hospital, and mortality records from England for 1.7 million patients diagnosed with one of 13 conditions between 1999 and 2019, the researchers assessed how often patients received a diagnosis following emergency hospital care and compared subsequent outcomes with those of patients diagnosed through non-emergency routes. Conditions included chronic obstructive pulmonary disease (COPD), inflammatory bowel disease (IBD), Parkinson’s disease, multiple sclerosis (MS), rheumatoid arthritis, celiac disease, and schizophrenia.
Emergency diagnosis was common across multiple conditions. More than one in five patients were diagnosed following an emergency presentation in nine of the 13 conditions examined, including more than 30% of patients with Parkinson’s disease and 35% of those with COPD. Across most conditions, patients diagnosed as an emergency experienced substantially poorer outcomes, including higher mortality and longer hospital stays during the year after diagnosis.
After accounting for factors such as age, year of diagnosis, socioeconomic deprivation, comorbidities, and healthcare setting, emergency diagnosis remained strongly associated with an increased risk of death within one year. This association was evident even in conditions that generally have a favourable prognosis, including celiac disease and IBD.
The study shows that emergency diagnosis is a common phenomenon across diverse diseases and is consistently associated with worse outcomes. Future research is needed to understand disease-specific and broader health system factors that contribute to emergency diagnosis as well as whether reducing emergency diagnoses or improving care for patients diagnosed through emergency pathways can lead to better outcomes.
Dr Emma Whitfield, first author, states, “We showed that emergency diagnosis occurred across a wide range of conditions and was consistently associated with a greater risk of death and more time in hospital in the year after diagnosis. Often emergency diagnosis will represent the best standard of care, as illnesses can develop rapidly or have few warning signs. However, the scale of our findings suggest others may reflect difficulties obtaining timely assessment, investigation, or specialist care.
“Behind these figures are patients and families experiencing an unexpected hospital admission, a new diagnosis, and, sometimes, a much more difficult year afterwards.
“Understanding why emergency diagnosis happens could help us identify where earlier diagnosis may be possible or additional support might make a difference.”
Prof Georgios Lyratzopoulos, senior author, notes, “Our study was triggered by a concept initially developed in the field of cancer epidemiology which we have applied across a diverse range of other conditions. The consistency of the findings suggests that emergency diagnosis deserves greater attention by researchers and policymakers across disease areas, and a health system-wide approach.
“Cancer policy has shown the value of monitoring emergency diagnosis, but there is currently little comparable evidence for other conditions. Our study provides a starting point for understanding the scale of the issue beyond cancer, although further research is needed before emergency diagnosis can be used as a quality measure in other disease areas.”
Immunotherapies such as CAR T cell therapy are used primarily to treat cancer. In the future, these patient-specific therapies, manufactured from patients’ own immune cells, could also help cure autoimmune diseases. Six patients with particularly severe rheumatoid arthritis have now received this treatment at Charité – Universitätsmedizin Berlin. In Nature Medicine, the researchers report the results from the world’s first clinical trial of its kind: Disease activity decreased substantially in all participants. By the end of the observation period, three of the patients no longer required any medication for rheumatoid arthritis.
Rheumatoid arthritis is a chronic disease in which the immune system mistakenly attacks the body’s own joints. This causes recurrent inflammation and joint swelling and, as the disease progresses, can lead to joint damage. Currently available treatments can usually keep the inflammation under control, but do not cure the disease. Patients therefore require lifelong medication, including anti-inflammatory drugs and medications that suppress the immune system, with all the associated side effects.
In some patients, even several of the newer treatments fail to produce an adequate response. Doctors then call the disease treatment-refractory. For those affected, this means persistent pain, restricted mobility and a substantial impact on quality of life. “One reason could be disease driving B cells – memory cells of the adaptive immune system that may survive in the lymph nodes, bone marrow or joint tissue after an infection, where they produce harmful antibodies directed against the body’s own tissues and repeatedly reignite the inflammation,” explains Prof David Simon, who designed the trial for this patient group together with Prof Gerhard Krönke at Charité’s Department of Rheumatology and Clinical Immunology.
The researchers hope that CAR T cells, patients’ own immune cells genetically modified in the laboratory, could selectively track down the disease driving B cells, even deep within tissues, reset the pathological B-cell memory as fully as possible and thereby effectively give the B-cell system a fresh start.
Cell therapy resets the immune system
Originally developed for cancer treatment, CAR T cells are now being used more widely. In cancer treatment, patients’ immune cells are given a kind of “training” to specifically recognise and eliminate tumour cells; in autoimmune diseases, the aim is instead to direct immune cells toward disease driving memory cells. “The identifying marker on many B cells, both abnormal B cells in cancers of the blood or lymphatic system and disease driving B cells in rheumatoid arthritis, is the surface molecule CD19. You could think of it as a kind of ‘name tag’” explains David Simon. “To enable CAR T cells to detect and eliminate the disease-causing cells, we equip patients’ own immune cells with a receptor that acts like a search sensor for CD19.”
For this type of CD19 CAR T-cell therapy, T cells are first collected from the patient’s blood. These are immune cells that normally recognize and eliminate infected or abnormal cells. In the laboratory, the cells are genetically modified and equipped with the key recognition feature: a chimeric, or artificial, antigen receptor, known as a CAR, that binds specifically to the CD19 molecule. Before the modified immune cells can be returned to the patient in a single infusion, a short course of preparatory chemotherapy is required to create space in the immune system. This temporarily reduces the number of certain immune cells so that the CAR T cells can then multiply effectively and carry out their function. Once returned to the body, the modified immune cells begin searching for the CD19 marker and specifically attack cells that carry it. In doing so, they temporarily eliminate all CD19-positive B cells, allowing the immune system to reset and helping to eliminate even long-lived disease-driving B cells in the joints that would otherwise be difficult to reach.
Will the approach work in difficult-to-treat rheumatoid arthritis?
For the world’s first clinical trial to evaluate the safety and efficacy of a CD19 CAR T-cell therapy in rheumatoid arthritis, the research team at Charité initially enrolled six patients with particularly severe disease. The three women and three men, aged 31 to 69, had received up to eight targeted or biologic therapies over the previous ten years, none of which had been sufficiently effective.
The key question was whether CAR T cells can track down the disease-driving B cells in the joints and whether the treatment is not only effective but also safe. For the researchers, the results from the first part of the COMPARE trial are highly encouraging: “Disease activity decreased markedly in all six patients. During follow-up of up to one year, three patients were in sustained remission without any medication for rheumatoid arthritis,” reports Gerhard Krönke, who leads the joint Clinical Rheumatology research group at Charité and the German Rheumatology Research Center (DRFZ), a Leibniz Institute. “This is particularly remarkable given that none of the established treatments had previously been able to relieve their symptoms adequately.”
The cell therapy appears to have done more than temporarily curb inflammation in the joints: the modified immune cells also tracked down and eliminated disease-promoting B cells in deeper reservoirs such as the bone marrow, lymph nodes and joint tissue. At regular follow-up visits over the subsequent twelve months, the research team found that levels of the autoantibodies characteristic of rheumatoid arthritis had declined sharply.
David Simon adds: “When the B-cell system later recovered, predominantly naïve B cells that had not yet been shaped by the disease returned. In contrast, the B cells directed against the body’s own tissues that had been present before treatment were no longer detectable in almost all patients, an indication that the treatment may indeed be able to reset the pathological immune memory.” Protective antibodies from previous vaccinations, for example against chickenpox or tetanus, remained detectable. Despite the profound depletion of B cells, protective antibody memory appears to be largely preserved. However, any longer-term effects of the therapy on the immune system still need to be investigated.
Early successes, but still some way to go
The trial shows that, in some patients, a single CAR T-cell treatment can lead to a sustained symptom-free period without medication – a state of disease inactivity known as remission. For selected patients with rheumatoid arthritis who have not responded adequately to treatment, it may in the future be possible to reset the pathological immune memory in a targeted way and thereby stop the persistent inflammation, instead of having to suppress it continuously with drugs.
Nevertheless, CAR T-cell therapy for autoimmune diseases, and for rheumatoid arthritis in particular, remains experimental. There is not yet any long-term experience with this treatment. In addition, responses to the therapy varied among patients in the current trial: some did not achieve a complete response, and in one case the disease returned after an initial medication-free period of remission. In contrast, the researchers consider the safety data obtained thus far to be encouraging. “After the participants received the CD19 CAR T cells, we observed only a temporary, mild-to-moderate cytokine release syndrome (CRS) in all participants, which was readily manageable. There were no severe neurological complications or other serious adverse events, and infections were rare,” explains Dr Marie Luise Hütter-Krönke, Medical Director of the Hematology Early Clinical Trial Unit at Charité’s Department of Hematology, Oncology and Cancer Immunology.
In a second phase of the trial involving ten additional patients, the researchers will compare the new treatment approach with a drug already approved for rheumatoid arthritis that also targets B cells. In this way, they aim to determine whether CAR T cells have a stronger and longer-lasting effect and whether they can indeed reset immune memory. If the new concept is confirmed in this and other, larger trials, it could ultimately become an alternative for patients whose lives are severely affected and for whom no adequate treatment is currently available.
Meta Platforms, the parent company of Facebook and Instagram, has agreed to a record-breaking $18-billion (over R300-billion) settlement in the United States following legal action alleging that its platforms contributed to harm among children and teenagers and failed to do enough to protect young users. The settlement, which involves almost all U.S. states, mandates specific safeguards including default daily limits, nighttime lockouts, and the disabling of notifications during school hours.
While Meta has denied any wrongdoing, the settlement has intensified an already urgent global debate about children’s digital safety. Around the world, governments are taking action, from Australia’s nationwide ban on under-16s to Brazil’s parental consent requirements, the UK’s proposed restrictions, and similar measures being considered in many other countries.
However, as governments and courts grapple with how platforms should protect young users, Pretoria based, Professor Anke de Beer believes the solution must start earlier and closer to home: with education. She is the founder of the Smart Device Licence, a pioneering South African programme designed to teach children and teenagers how to use smart devices safely, responsibly and with greater awareness of the risks they may encounter online before they are given unrestricted access.
“When you give your child a smart device, you don’t just give them access to the world. You give the world access to your child,” says Prof Anke. “The Smart Device Licence is about turning that access into a valuable skill for navigating the digital world responsibly.”
Why this matters now
Children are entering the digital world at increasingly young ages, often gaining access to social media, online gaming, messaging platforms and other digital environments before they fully understand the risks involved. Concerns around cyberbullying, inappropriate content, privacy, online exploitation, excessive device use and digital addiction have made children’s online safety an increasingly important issue for families, schools and policymakers. The latest record action against Meta is one of several developments internationally placing greater scrutiny on how technology platforms operate.
But platform regulation and landmark settlements are only part of the solution. Children also need to know how to navigate the digital world before they are given a device.
A personal mission becomes a national programme
Prof Anke’s journey from housewife to academic and activist was sparked by a deeply personal family experience involving gaming addiction and its devastating consequences. The experience opened her eyes to the potential risks of unrestricted digital access and the importance of equipping children with the knowledge to make safer choices. What began as a family’s fight for survival became a broader mission to help protect South Africa’s young people.
The Smart Device Licence was developed with input from professionals working across education, psychology and child protection, with the aim of providing children with practical skills they can use in their everyday digital lives, filling the gap left by slow-moving regulation and corporate settlements.
How the Smart Device Licence works
The Smart Device Licence is an interactive e-learning programme covering:
Digital citizenship
Privacy protection
Cyberbullying recognition
Responsible social media use
Healthy device habits
Online safety
Understanding digital risks
There are two levels:
Junior Licence: Designed for primary school learners, focusing on healthy device habits, responsible digital behaviour and avoiding harmful online content.
Senior Licence: Designed for high school learners, covering privacy, adult content, sharing personal images or messages, cyberbullying, responsible online communication and the psychology of digital addiction. Learners complete modules, quizzes and practical exercises. Those who complete the programme receive an official Smart Device Licence certificate. Schools including Rabboni Christian School in Brits are already using the platform. The programme is voluntary. The licence is an educational milestone, not a legal requirement.
Expanding access
The Smart Device Licence is available to schools, parents and learners across South Africa.
“The conversation about children’s digital safety is becoming impossible to ignore,” says Prof Anke. “But we should not wait for a court case, legislation or a crisis, whether in the US or here at home, before we prepare our children. The best time to teach a child how to use a smart device responsibly is before they receive one.”
The licence fee is R115, including VAT, providing access to the programme’s modules, exercises and quizzes. Content will be updated regularly to reflect emerging technologies, digital trends and relevant developments.
A study identifies PANK1 as a previously unknown target of SGLT2 inhibitors, revealing how the medications boost energy production and improve heart function.
Top: ribbon model of PANK1 dimer. Bottom left: zoom-in of pantothenate binding to PANK1. Bottom right: super-imposed binding of AcCoA, showing extension into the PANK1 enzymatic pocket. Credit: University of Pennsylvania
Researchers have discovered that SGLT2 inhibitors, a class of drugs originally developed to treat diabetes and now widely used for heart failure, work by activating a key enzyme that helps heart cells produce and use energy more efficiently. The study, published in Science, potentially solves a longstanding gap in knowledge about these drugs and opening the door to potential new treatments for heart failure.
The study, led by researchers in the Perelman School of Medicine at the University of Pennsylvania, found that SGLT2 inhibitors directly activate an enzyme called PANK1 in heart cells. This activation boosts production of coenzyme A (CoA), a molecule essential for converting nutrients into energy. Researchers found that increasing CoA production improved the ability of human heart cells to contract and relax, two critical functions that are impaired in heart failure.
“Our findings suggest these drugs are helping the failing heart restore its energy-producing capacity,” said senior author Zoltan Arany, MD, PhD, the Samuel Bellet Professor of Cardiology and chair of Physiology at Penn Medicine. “We identified PANK1 as a direct target of these medications and found that activating this pathway makes heart cells work better. This may explain many of the remarkable benefits patients experience with these drugs.”
Figuring out why it works
For years, physicians have known that SGLT2 inhibitors significantly reduce hospitalisations and deaths among heart failure patients, but have struggled to explain exactly why, because the drugs were designed to target the SGLT2 protein which is found in the kidneys, not the heart.
Using human heart tissue from transplant recipients and donors, the researchers found that SGLT2 inhibitors increased the heart’s ability to use multiple fuel sources, including sugars, fats, amino acids, and ketones. The drugs also increased levels of CoA, which plays a central role in cellular energy production. To identify how that happened, the team traced the effect back to PANK1, an enzyme that regulates the first and most important step in CoA production. The researchers demonstrated that the drugs physically bind to PANK1 and activate it.
“The evidence was especially compelling when we found that activating PANK1 alone reproduced many of the benefits of the drugs, while blocking the pathway largely eliminated those benefits,” said Nicholas Forelli, MD, an internal medicine resident in the Arany lab and co-author of the study. “We cannot completely rule out other contributing mechanisms, but the data strongly support PANK1 as a major driver.”
The discovery may also help explain why SGLT2 inhibitors often begin benefiting heart failure patients within days of starting treatment.
Exciting possibilities ahead
Despite years of research into these medications, the role of PANK1 had gone unnoticed. “Honestly, no one thought to look,” Arany said. “Researchers knew these drugs were doing something important in the heart, but the target responsible for those effects had remained elusive.”
The findings could have important implications for future drug development. While SGLT2 inhibitors are highly effective, they can cause side effects such as urinary tract infections, dehydration, and, in rare cases, diabetic ketoacidosis. “One of the most exciting possibilities is developing drugs that directly target PANK1,” Arany said. “That could allow us to capture the heart benefits while potentially avoiding some of the side effects associated with current therapies. We’re actively working on that now.”
The first-ever European Society of Cardiology Guidelines on the management of cardiovascular disease and chronic kidney disease have been developed in collaboration with the European Renal Association. The new guidelines were published online in the European Heart Journal [1] and presented at ESC Congress 2026 on 29 August.[2]
Chronic kidney disease (CKD) is defined as the presence of abnormalities of kidney structure or function present for at least 3 months, with implications for health.[4] It has been estimated there are around 100 million people in Europe with CKD,[5] all of whom are at increased risk of a wide range of cardiovascular diseases (CVD) as a result of their kidney problem.
“The disability and lifetime lost to each disease are profound, but CKD can accelerate CVD and vice versa, resulting in cardiovascular events and the need for dialysis much earlier in life,” said Task Force Chair, Associate Professor Kevin Damman from University Medical Centre Groningen, Netherlands. “The good news is that there have been major advances over the last few years, which mean there are now several simple treatments that can substantially lower the risk of both cardiovascular and kidney complications.”
Task Force Chair, Professor William Herrington from the University of Oxford, UK, noted: “Many patients with CKD are treated by the cardiology community and the new ESC Guidelines aim to increase the use of kidney function and urine albumin testing in patients with CVD. With improved screening, more at-risk patients can be identified and the most appropriate treatments for both CKD and CVD can be prescribed.”
The Task Force developed the ‘STAMP on CKD’ acronym, which stands for: Screen, Triage, Address CKD Risk, Modify CVD management and Plan health services. The first step is screening all patients with CVD at diagnosis for CKD using blood and urine tests (estimated glomerular filtration rate from blood creatinine plus urine albumin-to-creatinine ratio). A key message on triage is the accurate assessment of risk of kidney failure and accurate assessment of CVD risk using validated scoring systems that incorporate kidney function.
Addressing risk means ensuring the early use of proven cost-effective risk-modifying therapies that have been shown to slow CKD progression and reduce the risk of cardiovascular events. “Early use of drugs called RAS inhibitors and SGLT2 inhibitors alongside statin-based therapy are particularly important and effective,” explained Associate Prof. Damman.
The guidelines highlight key areas where modifications to CVD management are needed in the context of CKD, including recommendations for medications that are permitted in patients who may not be able to clear standard treatments from their bodies due to decreased kidney function.
Finally, appropriate planning of health services ensures that services are set up to recognise high-risk patients and provide timely access to care from cardiologists and nephrologists. “Active and efficient communication between specialties is often necessary due to the complexities associated with CKD,” noted Prof. Herrington. “Engagement of patients and family/caregivers in the multidisciplinary care process also helps to ensure patients’ priorities are met, improve their experience and promote patient-centred care.” A version of the new guidelines for patients aims to give individuals the knowledge and confidence to be involved in shared decision-making with healthcare providers.[3]
The Task Force Chairs concluded, “CVD and CKD are major burdens on patients, healthcare systems and society. The key messages in these guidelines should be noted by all relevant healthcare stakeholders and policymakers, and research planned to fill several gaps in the evidence. Raising awareness will help realise the hope that the guidelines will lead to important individual and societal improvement for those with, or at risk of, CVD and CKD.”
References
[1] 2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease. Eur Heart J. 2026. doi:10.1093/eurheartj/ehag098.
[3] ESC Guidelines for the management of cardiovascular disease and chronic kidney disease: What patients need to know. Available on the Patient Versions of ESC Guidelines webpage.
[4] Kidney Disease Improving Global Outcomes CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105:S117–S314.
[5] GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395:709–733.
Studies in the behavioural and brain sciences reporting a major sex-dependent effect – that a drug, treatment or other intervention is more effective in one sex than another – are supported by appropriate evidence less than 25% of the time, an analysis finds.
The Proceedings of the National Academy of Sciences (PNAS) published the analysis of 200 recent articles with a claim of a sex- or gender-dependent effect in the title. The articles included studies on human and non-human subjects and spanned six brain-related research areas: behavioural sciences, clinical neurology, neurosciences, psychiatry, psychology and substance abuse.
“We found that studies in psychology had the highest rate of appropriate evidence – 39% of the published papers included statistical evidence to support the claim of a sex difference,” says Donna Maney, corresponding author of the study and professor of psychology at Emory University. “Research in neuroscience had the lowest rate of appropriate evidence, at just 18%.”
The low rate of appropriate evidence in neuroscience is particularly troubling, Maney says. She notes that claims of sex-dependent effects are more numerous in neuroscience, where such reports are currently being published at triple the rate seen in any other field.
“The high number of reports seen in neuroscience may be due to bias – neuroscientists looking harder for sex differences than other scientists,” Maney says. “But most current evidence shows that the brain is one of the least sexually differentiated organs in the body.”
Maney’s team was particularly alarmed by the number of calls for changes in clinical approaches that were based on faulty analyses. Many of the 200 articles they reviewed, for example, called for sex-specific approaches to suicide prevention, stress-related psychiatric disorders, substance-use disorder and psychopathy – all without providing statistical comparisons of effects across sex.
First author of the PNAS paper is Madeline Olivier, who did the work as an Emory student and has since graduated with a BS in psychology.
Summary of findings
In 24% of the 200 papers, the effect compared statistically across sex and the results supported the claim of a sex-dependent effect.
In 9%, the researchers tested for a sex difference, but the results were missing.
In 9.5%, the sex difference in the effect was reported as not statistically significant, which was incompatible with the claim in the title.
In 57.5%, the sexes were not statistically compared — the researchers did not test the claim in the title at all.
A logical error
Maney is a neuroscientist who studies hormonal and genetic influences on behaviour. For more than a decade, she has also focused on investigating how sex differences are tested for and reported in biomedical research.
One issue she emphasises is that, instead of comparing the sexes directly with each other, researchers often test for the effect in each sex separately. Although it might make sense on the surface, the practice reduces the number of subjects to the point where a real effect can be missed. If the effect is detected in one sex but missed in the other, researchers are vulnerable to a logical error: that the effect differs between the sexes, when they have not been directly compared.
To show that the sexes differ, females and males must be directly compared with each other in a statistical test. Most of the articles analysed by Maney and colleagues for the current PNAS paper did not do that. Instead, the researchers relied on the individual, within-sex tests – an invalid way of comparing the sexes that produces the illusion of a difference up to 50% of the time. “It’s no better than flipping a coin,” Maney says.
It’s also easy to miss true sex differences with a subgroup approach. For example, men and women could respond differently to a treatment but when the sample is divided in half and tested separately, the effect could be missed in both.
Maney cites the classic example of a large clinical trial showing that aspirin significantly reduced mortality from heart attacks. To illustrate the problem with the subgroup error, cardiologist Peter Sleight reanalysed the data by dividing participants into subgroups according to their astrological signs. Once the trial was split into 12 zodiac groups, the benefit of aspirin was no longer statistically detectable among the Libras and Geminis.
Sleight’s “findings” demonstrated how dividing a large group into subgroups can make a real effect disappear in some of the groups, even when the treatment is clearly beneficial.
“This problem is not new,” says Maney. “I made the error myself until I learned about it. “Many researchers don’t receive training in how to test whether an effect differs between two groups.”
A simple solution
To provide evidence that an effect differs by sex, the effect must be statistically compared between males and females, Maney emphasises. Only that approach can show sufficient evidence for a sex difference.
She designed an open-source tool, housed on the web at sexdifference.org, to help guide researchers to verify sex-specific effects.
Maney’s interests extend beyond statistical sex comparisons.
“Ultimately,” she says, “I would like to see researchers not treat sex as the most important variable in a biomedical study. Variation in participants’ weights, ages or habits, for example, likely explains variation in the effect of a treatment better than which sex category they are in.”
