The method by which a baby was delivered is associated with how its immune system will respond to pneumococcal and meningococcal vaccinations, according to a study in Nature Communications. After vaccination, babies born naturally had higher antibody levels than those born via Caesarian section.
Experts say the findings could help to inform conversations about C-sections between expectant mothers and their doctors, and shape the design of more tailored vaccination programmes.
Researchers studied the relationship between gut microbes and antibody levels after vaccination in a cohort of 120 babies, who were vaccinated at 8 and 12 weeks against lung infections and meningitis.
The researchers tracked the development of the gut microbiome in the child’s first year of life and their immune response to the vaccines by testing saliva samples at 12 and 18 months.
Research was carried out by a team from the University of Edinburgh, Spaarne Hospital and University Medical Centre in Utrecht and the National Institute for Public Health and the Environment in The Netherlands.
In the 101 babies tested for antibodies as a result of the vaccine that protects against lung infections, the investigators found double the antibody levels in babies delivered naturally compared with those delivered by C-section.
Breastfeeding was linked with 3.5 times higher antibody levels compared with formula-fed children who had been delivered naturally.
Levels of antibodies as a result of the vaccine that protects against meningitis were tested in 66 babies. Experts found the levels of antibodies were 1.7 times higher for naturally delivered babies, regardless of breastfeeding, compared with those delivered via C-section.
The gut microbiome is seeded at birth, developing rapidly over the first few months of life, and is influenced mostly by delivery mode, breastfeeding, and antibiotic use.
The team found a clear relationship between microbes in the gut of those babies and levels of antibodies.
For example, among a host of bacteria in the gut, high levels of two in particular — Bifidobacterium and E. Coli — were associated with a high antibody response to the vaccine that protects against lung infections.
High levels of E. Coli were also linked with a high antibody response to the vaccine that protects against meningitis.
The baby acquires the Bifidobacterium and E.coli bacteria through natural birth and human milk is needed to provide the sugars for these bacteria to thrive on.
The team concludes that the babies’ microbiome in early life contributes the immune system’s response to the vaccines and sets the level of protection against certain infections in childhood.
Vaccination schedules could also be adjusted based on mode of delivery or an analysis of the baby’s microbiome in the future, experts say.
Dr Emma de Koff, first author and microbiology trainee at the Amsterdam University Medical Center, said: “We expected to find a link between the gut microbiome and the babies’ vaccine responses, however we never thought to find the strongest effects in the first weeks of life.”
Professor Debby Bogaert study lead and Chair of Paediatric Medicine at the University of Edinburgh said “I think it is especially interesting that we identified several beneficial microbes to be the link between mode of delivery and vaccine responses. In the future, we may be able to supplement those bacteria to children born by C-section shortly after birth through, for example, mother-to-baby ‘faecal transplants’ or the use of specifically designed probiotics.”
The European Medicines Agency’s safety committee (PRAC) has recommended measures to minimise the risk of serious side effects associated with Janus kinase (JAK) inhibitors used to treat several chronic inflammatory disorders. These side effects include cardiovascular conditions, blood clots, cancer and serious infections.
The Committee recommended that these medicines should be used in the following patients only if no suitable treatment alternatives are available: those aged 65 years or above, those at increased risk of major cardiovascular problems (such as heart attack or stroke), those who smoke or have done so for a long time in the past and those at increased risk of cancer.
The Committee also recommended using JAK inhibitors with caution in patients with risk factors for blood clots in the lungs and in deep veins (venous thromboembolism, VTE) other than those listed above. Further, the doses should be reduced in some patient groups who may be at risk of VTE, cancer or major cardiovascular problems.
The recommendations follow a review of available data, including the final results from a clinical trial of the JAK inhibitor tofacitinib and preliminary findings from an observational study involving baricitinib, another JAK inhibitor. During the review, the PRAC sought advice from an expert group of rheumatologists, dermatologists, gastroenterologists and patient representatives.
The review confirmed tofacitinib increases the risk of major cardiovascular problems, cancer, VTE, serious infections and death due to any cause when compared with TNF-alpha inhibitors. The PRAC has now concluded that these safety findings apply to all approved uses of JAK inhibitors in chronic inflammatory disorders (rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis and alopecia areata).
The product information for JAK inhibitors used to treat chronic inflammatory disorders will be updated with the new recommendations and warnings. In addition, the educational material for patients and healthcare professionals will be revised accordingly. Patients who have questions about their treatment or their risk of serious side effects should contact their doctor.
More about the medicines
The Janus kinase inhibitors subject to this review are abrocitinib, filgotinib, baricitinib, upadacitinib and tofacitinib. These medicines are used to treat several chronic inflammatory disorders (rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, axial spondyloarthritis, ulcerative colitis, atopic dermatitis and alopecia areata). The active substances in these medicines work by blocking the action of enzymes known as Janus kinases. These enzymes play an important role in the process of inflammation that occurs in these disorders. By blocking the enzymes’ action, the medicines help reduce the inflammation and other symptoms of these disorders.
Some JAK inhibitors are used to treat myeloproliferative disorders; the review did not include these medicines. The review also did not cover the use of baricitinib in the short-term treatment of COVID, which is under assessment by EMA.
Photo by Reproductive Health Supplies Coalition on Unsplash
Hormonal contraceptives are safe and highly effective at preventing pregnancy, but their impact on the developing bodies of teenage girls, especially their brains, is not well understood.
New research in young rats links the synthetic hormones found in birth control pills, patches and injections with disordered signal transmission between cells in the prefrontal cortex, which is still developing during adolescence. Compared to control rats, the animals receiving hormonal contraceptives also produced higher levels of the stress hormone corticosterone, which is similar to cortisol in humans.
The Ohio State University scientists began investigating the prefrontal cortex, where mood is regulated, because some previous research has associated early adolescent use of hormonal contraceptives with adulthood depression risk. But the most important thing, the researchers said, is learning how birth control affects the developing brain so individuals can weigh the risks and benefits of their reproductive health choices.
“Birth control has had a major positive impact for women’s health and autonomy – so it’s not that we’re suggesting adolescents should not take hormonal contraceptives,” said senior study author Benedetta Leuner, associate professor of psychology at Ohio State.
“What we need is to be informed about what synthetic hormones are doing in the brain so we can make informed decisions – and if there are any risks, then that’s something that needs to be monitored. Then if you decide to use hormonal birth control, you would pay more attention to warning signs if you knew of any possible mood-related side effects.”
The research poster was presented to at Neuroscience 2022, the annual meeting of the Society for Neuroscience.
An estimated 2 in 5 teenage girls in the US have sexual intercourse between age 15 and 19, and the vast majority use a contraceptive, mostly condoms. Of those using birth control, almost 5% use hormonal contraceptives, also known as long-acting reversible contraceptives. These products are also prescribed to treat acne and heavy periods.
Despite their popularity, “there isn’t a lot known about how hormonal birth control influences the teen brain and behaviour,” said co-author Kathryn Lenz, associate professor of psychology at Ohio State. “Adolescence is a crucially under-investigated period of dramatic brain change and dramatic hormonal change that we really haven’t understood.”
The researchers gave a combination of synthetic estrogen and progesterone typically found in hormonal contraceptives to female rats for three weeks beginning about a month after they were born, an age equivalent to early adolescence in humans. Researchers confirmed the drugs disrupted the animals’ reproductive cycling — these birth control products work by stopping ovaries from producing hormones at levels necessary to generate eggs and making the uterine lining inhospitable for an egg to implant.
Blood samples showed the treated rats were producing more corticosterone than untreated animals, a sign that they were stressed. And after being subjected to and recovering from an experimental stressor, the treated rats’ corticosterone level remained high. Their adrenal glands were also larger, suggesting their stress hormone production was consistently higher than that of control animals.
An analysis of gene activation markers in the animals’ prefrontal cortex showed a decrease in excitatory synapses in that region of treated rats’ brains compared to controls, but no change to inhibitory synapses — a phenomenon that could set up an imbalance of normal signaling patterns and result in altered behavior. The loss of only excitatory synapses in the prefrontal cortex has been linked to exposure to chronic stress and depression in previous research.
“What this means for the function of particular circuits, we don’t know yet. But this gives us a clue of where to look next in terms of what the functional outcomes might be,” Lenz said.
The researchers are moving forward with additional studies targeting hormonal contraceptive effects on the brain between puberty and late adolescence – a tricky time to study the developing brain because it is undergoing constant change, Leuner said. The reasons behind the drugs’ effects are an open question, as well.
“These are synthetic hormones, so are they affecting the brain because of their synthetic properties, or are they affecting the brain because they’re blocking the naturally produced hormones?” she said. “It’s a difficult question to answer, but an important one.”
Researchers say that leprosy may hold to the key to safe and effective organ regeneration, after discovering that leprosy can double the size of livers in armadillos by stimulating normal, healthy growth.
Their findings, published in the journal Cell Reports, reveal a previously unknown interaction of the leprosy bacterium with its host, in this study, an armadillo – the only one known one besides humans that the disease may manifest in.
The researchers found that leprosy appears to rewind the developmental clock of liver cells, effectively reprogramming them to be in an ‘adolescent’ state.
Regenerative medicine aims for ‘grown to order’ organs to replace those damaged by disease or age, but organ development is an extremely complex process which takes place in vivo and so far only limited progress has been made using in vitro models. The liver, a highly resilient organ, stops regenerating once it reaches its original size, making it difficult to study regeneration pathways.
Leprosy, also referred to as Hansen disease, is a chronic granulomatous infection generally caused by Mycobacterium leprae and Mycobacterium lepromatosis, both of which primarily affect the skin and peripheral nerves. It also has the ability to convert body tissues from one type to another.
Researchers infected four cloned armadillos with the bacteria, and observed the growth of their livers. The bacteria enlarged the liver, basically give themselves more room – and this was accomplished in a way that left the livers perfectly functional and healthy.
The researchers suggest that, as with other body tissues, the bacteria-induced partial reprogramming also works in adult liver in vivo, turning hepatocytes into liver progenitor-like cells leading to proliferation and subsequent re-differentiation in the microenvironment created by the bacteria.
Prof Anura Rambukkana, from the University of Edinburgh’s centre for regenerative medicine described the discover as “completely unexpected”.
“It is kind of mind-blowing,” Prof Rambukkana told the BBC. “How do they do that? There is no cell therapy that can do that.”
An immune response that likely evolved to help fight infections appears to be the mechanism that drives human immunodeficiency virus (HIV) into a latent state, lurking in cells only to erupt anew, according to research published in the journal Nature Microbiology. The findings help explain why HIV particularly stealthy, but could also apply to other viral infections.
“HIV has proven to be incurable because of a small number of latently HIV-infected T-cells that are untouched by both antiviral drugs and the immune response,” said senior author Bryan R. Cullen, PhD, professor at Duke University School of Medicine.
“These cells, which are very long lived, can spontaneously emerge from latency and start producing HIV even years after infection, thus necessitating the life-long use of antiretrovirals,” Cullen said. “The origin of these latently infected cells has remained unknown despite considerable effort.”
The findings offer important insights, pointing to a protein complex called SMC5/6, which is involved in a host cell’s chromosome function and repair.
HIV enters the body, infects the immune system’s CD4+ T-cells, then makes a genome-length DNA molecule that it integrates into a host cell chromosome where it is then copied to generate viral RNAs and proteins.
If this so-called DNA provirus is prevented from integrating into the host cell DNA, for example by a drug that blocks this process, then it fails to make any viral RNAs and proteins and becomes inert. In contrast, DNA proviruses that are able to integrate are normally able to drive a productive HIV infection.
Cullen and his team found that, in a small number of infected cells, the SMC5/6 protein complex initiates a process that silences the DNA provirus before it integrates into a host cell chromosome. These proviruses remain inert even after integration and result in latent infections, lying low until prompted to erupt into an active infection.
“Our research suggests that latency results not from any intrinsic properties of the infecting HIV but rather from an unfortunate side effect of a cellular innate immune response that probably evolved to silence invasive foreign DNA,” Cullen said.
The researchers found that a molecule that shuts down SMC5/6’s silencing action showed promising results as a potential therapeutic strategy as it inhibited the establishment of latent HIV infections. Reactivated proviruses are vulnerable to natural immune system responses and anti-retroviral drugs.
“Although antiretroviral therapies can reduce the viral load in AIDS patients to below the level of detection, these drugs fail to eradicate HIV-1,” Cullen said. “While there has been considerable effort expended on trying to develop therapies that can activate latent HIV-1 and help antiretroviral therapies clear the body of infectious virus, this effort has so far failed to identify drugs that are both effective and non-toxic. Our study represents a potentially important step toward achieving this goal.”
“Clearly, understanding the mechanism that results in HIV-1 latency may provide insights into how latent HIV-1 proviruses can be reactivated and then destroyed,” Cullen said.
A study of obese adults with nonalcoholic fatty liver disease (NAFLD) and morbid obesity has shown that those who underwent bariatric surgery suffered far fewer extreme cardiovascular events subsequently.
Reporting their results in JAMA Network Open, the researchers, reported that these obese patients (BMI > 40) undergoing bariatric surgery had a 49% lower risk of developing adverse cardiovascular events.
“The findings provide evidence in support of bariatric surgery as an effective therapeutic tool to lower elevated risk of cardiovascular disease for select individuals with obesity and NAFLD,” said Vinod K. Rustgi, profesor at Rutgers Robert Wood Johnson Medical School. “These finding are tremendously impactful for many reasons.”
NAFLD, and a more advanced form known as NASH, are rapidly increasing causes of liver disease which occur because of excessive fat storage in the liver. As such it is common in obesity and type 2 diabetes.
In the study, researchers analysed outcomes data, using a medical insurance database, from 2007 to 2017. Of 230 million covered individuals, 86 964 adults between the ages of 18 and 64 who had obesity and NAFLD were identified. Of those, 68% were female, 35% underwent bariatric surgery and 65% received nonsurgical care.
Bariatric surgery patients experienced a 49% decrease in the risk of developing major cardiovascular events such as heart attacks, heart failure or ischemic strokes. They were also far less likely to experience angina, atherosclerotic events or arterial blood clots.
The association between bariatric surgery and risk reduction of developing cardiovascular disease has not been studied to this level of detail before, the researchers said.
There is growing evidence that bariatric surgery, because of the weight reduction it brings about in patients, offers definitive health benefits. A study conducted by Rustgi and colleagues, published in the journal Gastroenterology in March 2021, showed that bariatric surgery can also significantly reduce the risk of cancer, especially obesity-related, in obese individuals with NAFLD. Importantly, these cancers included colorectal, pancreatic, endometrial, thyroid cancer, multiple myeloma and hepatocellular carcinoma.
“Although bariatric surgery is a more aggressive approach than lifestyle modifications, it may be associated with other benefits, such as improved quality of life and decreased long-term health care burden,” Rustgi said.
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.
