For the first time, a study published Proceedings of the National Academy of Sciences (PNAS) has shown a causal association between environmental phthalates and the increased growth of uterine fibroids, the most common tumours among women.
Manufacturers use environmental phthalates in numerous industrial and consumer products, and they’ve also been detected in medical supplies and food. Although they are known to be toxic, they are currently unbanned in the US.
“These toxic pollutants are everywhere, including food packaging, hair and makeup products, and more, and their usage is not banned,” said corresponding study author Dr Serdar Bulun at Northwestern University. “These are more than simply environmental pollutants. They can cause specific harm to human tissues.”
Up to 80% of all women may develop a fibroid tumour during their lifetime, Bulun said. One-quarter of these women become symptomatic with excessive and uncontrolled uterine bleeding, anaemia, miscarriages, infertility and large abdominal tumours necessitating technically difficult surgeries.
The new study found women with a high exposure to certain phthalates such as DEHP (used as a plasticiser to increase the durability of products such as shower curtains, car upholstery, lunchboxes, shoes and more) and its metabolites have a high risk for having a symptomatic fibroid.
Prior epidemiological studies have consistently indicated an association between phthalate exposure and uterine fibroid growth, but this study explains the mechanisms behind that link. The scientists discovered exposure to DEHP may activate a hormonal pathway that activates an environmentally responsive receptor (AHR) to bind to DNA and cause increased growth of fibroid tumors.
“Interestingly, AHR was cloned in the early ’90s as the receptor for dioxin, the key toxin in the agent orange,” Bulun said. “The use of agent orange during the Vietnam war caused significant reproductive abnormalities in the exposed populations; and dioxin and AHR were thought to be responsible for this.”
This new study, Bulun said, provides further evidence to support these theories.
A recent phase 2 clinical trial published in Arthritis & Rheumatologyhas reported promising results for deucravacitinib, an oral inhibitor tyrosine kinase 2 (TYK2) inhibitor, in patients with active lupus.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterised by the presence of antinuclear autoantibodies and diverse clinical manifestations. Treatment often lacks efficacy for SLE patients, and current therapies are associated with undesirable side effects.
TYK2 is an intracellular kinase that mediates signalling of key cytokines involved in the pathogenesis of SLE. A biologic agent targeting the type I interferon (IFN) receptor has been approved in SLE. Deucravacitinib is an oral, selective, allosteric inhibitor of TYK2 that binds the regulatory domain and locks the enzyme in an inactive state distinguishing it from JAK inhibitors that bind the highly conserved active domain
For the trial, adults with active SLE were enrolled from 162 sites in 17 countries. Patients (n = 363) were randomised 1:1:1:1 to receive deucravacitinib 3mg twice daily, 6mg twice daily, 12mg once daily, or placebo. The primary endpoint was SRI-4 and secondary outcomes were assessed on a variety of disease activity measures.
At week 32, the percentage of patients experiencing benefits was 34% with placebo compared with 58%, 50%, and 45% with the respective deucravacitinib regimens.
Rates of adverse events were similar across groups, except higher rates of infections and cutaneous events, including rash and acne, with deucravacitinib treatment. Rates of serious adverse events were comparable, with no deaths, opportunistic infections, tuberculosis infections, major adverse cardiovascular events, or thrombotic events reported.
Some cases of tuberculosis (TB) can be successfully treated in as little as two months – a third of the current standard of six months in South Africa and most other countries. This is according to early findings from the landmark TRUNCATE TB trial presented at last week’s Union World Conference on Lung Health.
Nick Paton, a professor of Infectious Diseases at the National University of Singapore and the chief investigator of the TRUNCATE trial, explains that the standard six-month treatment for drug-susceptible TB (DS-TB) is actually overtreating a lot of people who have the disease. The reason for the six-month mark for TB treatment is that a minority of TB patients need the long treatment regimen to avoid relapse, but the majority would be cured before the six-month mark.
Essentially, it’s a blunt, but generally, effective instrument used to protect a minority of TB patients.
The TRUNCATE trial set out to see if a two-month (eight weeks) novel combination of TB regimens would be feasible when compared to the standard six-month (24 weeks) treatment regimen. According to Paton, trial participants in the experimental arms of the study were initially given eight weeks of treatment, with the option of extending treatment to 10 to 12 weeks if they had persistent clinical disease after the eight-week treatment. If there was still active TB after that, participants were switched to the standard six-month treatment.
Study participants were monitored regularly through follow-up visits, which included TB symptom screening once a month and sputum smear tests every one to three months.
“The core [of the strategy] is it’s a very short period of initial treatment, plus you then do the monitoring and pick up people [who relapsed] early,” Paton says.
A total of 674 trial participants were recruited from March 2018 to March 2022 across 18 sites in Thailand, Indonesia, the Philippines, Uganda, and India. Four patients withdrew from the trial and 10 participants died during the trial.
Paton tells Spotlight that the overall death rate was low and there was no difference in the death rate between the standard treatment arm and the TRUNCATE strategy arms. The causes of death were mixed, he adds, and often the precise cause was unknown
For the final results, 660 participants were evaluated at week 96. In other words, about two years of follow-up occurred.
Encouraging results
Paton explains that the trial used the TRUNCATE strategy, which initially involved using four treatment arms containing a novel combination of TB drugs and comparing the results to a control arm consisting of the standard six-month treatment. Later, two TRUNCATE strategy arms were selected to complete the latter half of the study. He notes that it was a pragmatic decision to stop two of the arms, to ensure better data.
“You do substantially cut down the amount of time on treatment overall.”
Professor Nick Paton, chief investigator of the TRUNCATE trial.
In the first of the two remaining experimental arms, 184 study participants received a regimen consisting of high-dose rifampicin (35mg per kg, reduced to 20mg per kg as a precaution following a liver injury-related death), isoniazid, pyrazinamide, ethambutol, and linezolid (600mg). In the second, 189 study participants received a regimen consisting of bedaquiline (400mg/d for two weeks then 200mg three times a week), isoniazid, pyrazinamide, ethambutol, and linezolid (600mg). The standard treatment arm had 181 participants.
In the standard treatment arm, 98% completed treatment and 3% had to be re-treated before week 96.
In the TRUNCATE strategy arms, overall, 91% completed the eight-week treatment and stopped treatment by week 12. 17%, (ranging from 13 to 23% by arm) had re-treatment, and 2% of participants did not complete initial treatment due to withdrawing from the trial, death, or defaulting on treatment.
A comparison of the two experimental TRUNCATE arms with the standard treatment arm showed that the TRUNCATE arm with bedaquiline and linezolid was non-inferior to the standard treatment arm, while the high dose rifampicin and linezolid arm fell just short of meeting the non-inferiority criteria. Efficacy was calculated based on the proportion of unsatisfactory outcomes at week 96. Unsatisfactory outcomes were classified as death, still having active TB, or still being on TB treatment at week 96.
“The idea was that if we added those [unsatisfactory outcomes] up and that was the same in the standard treatment arm as the TRUNCATE strategy arm then that shows that this strategy in principle, can work,” Paton tells Spotlight.
The mean total days on treatment were reduced in the TRUNCATE strategy arms when compared to the standard treatment arm, which was 180 days. For high-dose rifampicin-linezolid, the average total days on treatment was 106 days, and in the bedaquiline-linezolid arm, it was 85 days.
“So, clearly the net effect is to decrease the average time on treatment,” Paton says. “You do substantially cut down the amount of time on treatment overall.”
He adds that the proportion of participants that had Grade 3 or 4 adverse events, serious adverse events, or who died did not differ between the standard treatment arm and the TRUNCATE strategy arm. The proportion of participants with respiratory disability at week 96 also did not differ.
The only cases of acquired drug resistance were two cases observed in the bedaquiline and linezolid arm. This is a frequency of 1.1% according to Paton. One of these participants missed several treatment doses, while the other did not miss any doses. Both were successfully re-treated.
Initially, they wanted to enroll participants who were co-infected with HIV in the later stages of the trial, but none could be enrolled in time, so currently there is no data on how well it works in people living with HIV who also have TB, says Paton.
“The trial has shown that alternatives to systematically over-treating the large majority of people with TB can be successful. This is an important new research direction which has the promise to improve outcomes for patients and programmes,” Paton says. “The strategy may be refined in future to improve outcomes using alternative drug regimens or alternative approaches to monitoring. Ongoing analysis from the trial will further enhance our understanding.”
PK and safety data
At last week’s conference, Christopher Cousins, project leader of the TRUNCATE trial presented the first level of pharmacokinetic (PK) analysis from the trial. The PK results were taken from week eight of the study.
AUC for the high-dose rifampicin was four to six times higher than in the standard dose and exceeded the proposed efficacy targets in the majority of patients.
After fasting overnight, participants took an observed dose of their medication at the trial site and had blood sampling done over a 12-hour period. The data is based on 96 participants in the two experimental arms.
He says the AUC (which represents total drug exposure over time – AUC = area under the curve) for the high-dose rifampicin was four to six times higher than in the standard dose and exceeded the proposed efficacy targets in the majority of patients. This supports the hypothesis that high-dose rifampicin would enhance treatment sterilisation in the eight-week regimen.
The data also showed what seems to be a drug-drug interaction between rifampicin and linezolid, but this didn’t appear to be significant enough to abolish anti-mycobacterial efficacy.
According to Cousins, the bedaquiline concentrations at the end of week eight in the bedaquiline and linezolid arm were comparable to the concentrations seen after 24 weeks of treatment for drug-resistant TB (currently both bedaquiline and linezolid are part of the standard treatment for DR-TB, but not for DS-TB).
When asked how well monitoring participants in the TRUNCATE arms after they stopped treatment was able to detect those who still had active TB disease, Paton tells Spotlight that further analysis of the sputum smears samples will be able to tell us more. The trial used a relatively low-technology approach where a symptom screening and a sputum smear test were used to determine if a participant still had active TB and needed to be re-treated.
“We need to run additional biomarkers, interrogate the data set in more detail to figure out who was cured, who wasn’t cured, over what duration and how well do these other things [sputum smear test and symptom screening] pick it [TB] up,” he says.
He adds that this was a starting point, “but we are likely to be able to do better if we use some of the new biomarker technologies for monitoring”.
Implications of findings
“These results are very exciting as proof of concept – they show it’s possible to shorten treatment for drug-sensitive TB even further,” says Lindsay McKenna, TB Project Co-Director at New York-based Treatment Action Group (TAG). “But we need to optimise the regimen and study this treatment strategy in broader populations, including people living with HIV – none were enrolled in the study – and [in] programme contexts,” she says.
“There are other trials that are being planned that look to proactively (for example, at time of treatment initiation) determine who might benefit from shorter versus longer treatment based on available indicators or risk factors known to be correlated with treatment outcomes, such as disease severity, BMI, and HIV status (called a stratified medicine approach), and to tailor the duration of treatment accordingly,” she adds. “If the latter stratified medicine approach is proven, it will be very interesting to see how these two approaches compare and are viewed by programmes and affected communities.”
Feasibility of shortened regimens
Nerissa Donato the site co-investigator for the Truncate TB trial from the Lung Centre in the Philippines outlined the feasibility and acceptability of the TRUNCATE strategy at last week’s conference. This was based on participant questionnaires, clinician surveys, description data from the trial, and observations from Donato.
“The TRUNCATE strategies were acceptable and feasible in the context of the clinical trial. It can be successfully implemented provided that it is supported by the NTP (national treatment programme) and embraced by trained clinicians,” she says.
She explains the main challenges to implementing the strategy were patients’ concerns about potential side effects and the greater pill burden, but after some discussion participants were comfortable with the regimen due to the possibility of a much shorter treatment regimen. The close following up of participants and follow-up visits required was different from the normal procedure of treating for six months and being discharged from care. But she says participants were generally happy to come back for the follow-up visits.
Clinicians who participated were initially sceptical of whether the regimen was safe and would work but after the trial, they had a more positive view, according to Donato.
She says that in order to implement the strategy in the real world, it would need to be adopted by the NTPs, which will likely require more data on cost-effectiveness.
Need better treatment approaches and regimens
Paton tells Spotlight that somewhere between the two extremes of overtreating TB patients and personalised medicine as seen in high-income countries, there can lie a better treatment option for TB patients. An approach that is less monolithic and instead based on reacting to individual patient needs and responses.
“We need to look at how do we personalise it [TB treatment], but in a way that’s not so high tech so it becomes impossible for programmes,” he says. “At least if you’re monitoring [patients] you’ve got a safety net. If you get it wrong, you just make sure you pick the person up early and re-treat and there shouldn’t be serious harm from that.”
Additional data from the trial will be released in the coming months.
A smartwatch ECG can accurately detect heart failure (HF) in nonclinical environments, according to a study published in Nature Medicine. Researchers analysed Apple Watch ECG recordings with AI to identify patients with ventricular dysfunction. Study participants were able to remotely record their smartwatch ECGs at any time, with the data automatically and securely uploaded to their electronic health records via a smartphone app.
“Currently, we diagnose ventricular dysfunction – a weak heart pump – through an echocardiogram, CT scan or an MRI, but these are expensive, time consuming and at times inaccessible. The ability to diagnose a weak heart pump remotely, from an ECG that a person records using a consumer device, such as a smartwatch, allows a timely identification of this potentially life-threatening disease at massive scale,” says senior study author Paul Friedman, MD, chair of the Department of Cardiovascular Medicine at Mayo Clinic.
Ventricular dysfunction might not cause symptoms, but affects about 2% of the population and 9% of people over 60. Symptoms may develop with a low ejection fraction, including shortness of breath, a rapid heart rate and swelling in the legs. Early diagnosis is important because once identified, there are numerous treatments to improve quality of life and decrease the risks of heart failure and death.
Mayo researchers interpreted Apple Watch single-lead ECGs by modifying an earlier algorithm developed for 12-lead ECGs that is proven to detect a low ejection fraction.
While the data are early, the modified AI algorithm using single-lead ECG data had an area under the curve of 0.88 to detect low ejection fraction. By comparison, this measure of accuracy is as good as or slightly better than a medical treadmill diagnostic test.
“These data are encouraging because they show that digital tools allow convenient, inexpensive, scalable screening for important conditions. Through technology, we can remotely gather useful information about a patient’s heart in an accessible way that can meet the needs of people where they are,” says first author Zachi Attia, PhD, the lead AI scientist in the Department of Cardiovascular Medicine at Mayo Clinic.
“Building the capability to ingest data from wearable consumer electronics and provide analytic capabilities to prevent disease or improve health remotely in the manner demonstrated by this study can revolutionize health care. Solutions like this not only enable prediction and prevention of problems, but also will eventually help diminish health disparities and the burden on health systems and clinicians,” says co-author Bradley Leibovich, MD, the medical director for the Mayo Clinic Center for Digital Health.
Approximately 420 of the 2454 participants had an echocardiogram within 30 days of logging an Apple Watch ECG in the app. Of those, 16 patients had low ejection fraction confirmed by the echocardiogram, which provided a comparison for accuracy.
WHO today launched new guidelines to improve survival and health outcomes for babies born preterm (< 37 weeks) or small (< 2.5kg). In a significant departure from common clinical practice, the guidelines advise that caregiver skin to skin contact with a caregiver – aka kangaroo mother care – should start immediately after birth, without incubator stabilisation. This reflects the immense health benefits of ensuring caregivers and their preterm babies can stay close, without being separated, after birth.
The guidelines also provide recommendations to ensure emotional, financial and workplace support for families of very small and preterm babies, who can face extraordinary stress and hardship because of intensive caregiving demands and anxieties around their babies’ health.
“Preterm babies can survive, thrive, and change the world – but each baby must be given that chance,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “These guidelines show that improving outcomes for these tiny babies is not always about providing the most high-tech solutions, but rather ensuring access to essential healthcare that is centred around the needs of families.”
Depending on where they are born, there remain significant disparities in a preterm baby’s chances of surviving. While most born at or after 28 weeks in high-income countries go on to survive, in poorer countries survival rates can be as low as 10%.
Most preterm babies can be saved through feasible, cost-effective measures including quality care before, during and after childbirth, prevention and management of common infections, and kangaroo mother care – combining skin to skin contact in a special sling or wrap for as many hours as possible with a primary caregiver, usually the mother, and exclusive breastfeeding.
Previous recommendations for preterm babies were for an initial period of separation from their primary caregiver, with 3–7 days of initial stabilisation in an incubator or warmer. However, research has now shown that starting kangaroo mother care immediately after birth reduces mortality, infections and hypothermia, and improves feeding.
Breastfeeding is also strongly recommended to improve health outcomes for preterm and low birthweight babies, with evidence showing it reduces infection risks compared to infant formula. Where mother’s milk is not available, donor human milk is the best alternative, though fortified ‘preterm formula’ may be used if there are no donor milk banks.
Integrating feedback from families gathered through over 200 studies, the guidelines also advocate for increased emotional and financial support for caregivers. Parental leave is needed to help families care for the infant, the guidelines state, while government and regulatory policies and entitlements should ensure families of preterm and low birthweight babies receive sufficient financial and workplace support.
Earlier this year, WHO released related recommendations on antenatal treatments for women with a high likelihood of a preterm birth. These include antenatal corticosteroids, which can prevent breathing difficulties and reduce health risks for preterm babies, as well as tocolytic treatments to delay labour and allow time for a course of corticosteroids to be completed. Together, these are the first updates to WHO’s preterm and low birth weight guidelines since 2015.
The guidelines were released ahead of World Prematurity Day, which is marked every year on 17th November.
