A head-mounted device that generates an ultra-low frequency ultralow magnetic field has been found to improve the symptoms of four male patients diagnosed with major depressive disorder. Future trials using the device may offer a safe and noninvasive way of treating depression. The results were published in theAsian Journal of Psychiatry.
The presence of a magnetic field with frequencies typically ranging from 0 to 300 Hz is known as an Extremely Low Frequency Magnetic Environment (ELF-ELME). Although the interaction between magnetic fields and biological systems is complex and not well understood, this frequency is believed to stimulate mitochondria and induce their renewal. Since mitochondria generate energy, they offer a potential way to treat many of the symptoms associated with depression such as lethargy.
For this study, the research team led by Professor Toshiya Inada at Nagoya University Graduate School of Medicine and Masako Tachibana of Nagoya University Hospital in Japan enrolled four male Japanese participants diagnosed with depression and receiving treatment between the ages of 18 and 75 years in a clinical trial known as an exploratory first-in human study.
In exploratory studies such as this, both participants and researchers are aware of the treatment being administered. Although the sample size is small and there is no control group, researchers can focus on gathering preliminary data to explore the safety, dosage, and potential efficacy of a new intervention.
Throughout the trial, participants wore a head-mounted magnetic field device that exposed them to ELF-ELME for two hours per day for eight weeks. As predicted, the researchers found that all patients reported a drop in their level of depression.
Although the experiment was an exploratory trial with a limited number of participants and no control group, the findings suggest that larger scale clinical trials are feasible. If such trials prove to be effective, their research could lead to a groundbreaking change in the current clinical practice of depression treatment.
Inada believes that the device has great potential to treat depression more effectively in a patient-centred way. “The magnetic field generated by the device is non-invasive, being 1/4.5 of the Japanese geomagnetic field and less than 1/60 of the International Commission on Non-Ionizing Radiation Protection’s general public exposure standard,” he said, “We anticipate that patients will be able to receive daily home treatment without even being aware of being in a low magnetic field environment.”
He continued: “Compared to current depression treatments, such as long-term antidepressant medications, electroconvulsive therapy, and repetitive transcranial magnetic stimulation, this therapy is superior in terms of convenience and lack of anticipated side effects. We could see our device being used for patients who prefer not to take medication or safely in combination with other treatments.”
The human body has around 600 lymph nodes (LNs) scattered throughout it, small, bean-shaped organs that house various types of blood cells and filter lymph fluid which temporarily swell during infections with viruses or other pathogens. This LN expansion and subsequent contraction can also result from vaccines injected nearby, and in fact is thought to reflect the ongoing vaccine immune response. While researchers have studied the early expansion of LNs following vaccination, they have not investigated whether prolonged LN expansion could affect vaccine outcomes.
Now, for the first time, researchers from Harvard University and the company Genentech found a way to enhance and extend LN expansion, and study how this phenomenon affects both the immune system and efficacy of vaccinations against tumours.
Key to their approach was a biomaterial vaccine formulation that enabled greater and more persistent LN expansion than standard control vaccines. While the oversized LNs maintained a normal tissue organization, they displayed altered mechanical features and hosted higher numbers of various immune cell types that commonly are involved in immune responses against pathogens and cancers. Importantly, “jump-starting” lymph node expansion prior to administering a traditional vaccine against a melanoma-specific model antigen led to more effective and sustained anti-tumour responses in mice. The findings are published in Nature Biomedical Engineering.
“By enhancing the initial and sustained expansion of LNs with biomaterial scaffolds, non-invasively monitoring them individually over long time periods, and probing deeply into their tissue architecture and immune cell populations, we tightly correlate a persistent LN expansion with more robust immune and vaccination responses,” said Wyss Institute Founding Core Faculty member David Mooney, Ph.D., who led the study. “This opens a new front of investigation for immunologists, and could have far-reaching implications for future vaccine developments.” Mooney also is the Robert P. Pinkas Family Professor of Bioengineering at SEAS, and a co-principal investigator of the NIH-funded and Wyss-coordinated Immuno-Engineering to Improve Immunotherapy (i3) Center.
The research team had previously developed biomaterial vaccine formulations, but had not investigated how their vaccines and those developed by others could influence the response of LNs draining leaked tissue fluid at vaccine injection sites, and have an impact on the LNs tissue organisation, different cell types, and their gene expression, which could in turn affect vaccine efficacy. In their new study, they tested a previously developed vaccine formulation that is based on microscale mesoporous silica (MPS) rods that can be injected close to tumours and form a cell-permeable 3D scaffold structure under the skin. Engineered to release an immune cell-attracting cytokine (GM-CSF), and immune cell-activating adjuvant (CpG), and tumour-antigen molecules, MPS-vaccines are able to reprogram recruited so-called antigen-presenting cells that, upon migrating into nearby LNs, orchestrate complex tumour cell-killing immune responses. Their new study showed that there are more facets to that concept.
“As it turns out, the immune-boosting functions of basic MPS-vaccines actively change the state of LNs by persistently enlarging their whole organ structure, as well as changing their tissue mechanics and immune cell populations and functions,” said first-author Alexander Najibi, PhD, who performed his Ph.D. thesis with Mooney.
Probing LNs with ultra-sound and nano-devices
Using high-frequency ultrasound, the team traced individual LNs in MPS-vaccinated mice over 100 days. They identified an initial peak expansion period that lasted until day 20, in which LN volumes increased about 7-fold, significantly greater than in animals that received traditional vaccine formulations. Importantly, the LNs of MPS-vaccinated mice, while decreasing in volumes after this peak expansion, remained significantly more expanded than LNs from traditionally vaccinated mice throughout the 100-day time course.
When Najibi and the team investigated the mechanical responses of the LNs using a nanoindentation device, they found that LNs in MPS-vaccinated animals, although maintaining an overall normal structure, were less stiff and more viscous in certain locations. This was accompanied by a re-organisation of a protein that assembles and controls cells’ mechanically active cytoskeleton. Interestingly, Mooney’s group had shown in an earlier biomaterial study that changing mechanical features of immune cells’ environments, especially their viscoelasticity, affects immune cell development and functions. “It is very well-possible that in order to accommodate the significant growth induced by MPS-vaccines, LNs need to become softer and more viscous, and that this then further impacts immune cell recruitment, proliferation, and differentiation in a feed-forward process,” said Najibi.
From immune cell engagement to vaccine responses
Interestingly, upon MPS-vaccination, the numbers of “innate immune cells,” including monocytes, neutrophils, macrophages, and other cell types that build up the first wave of immune defences against pathogens and unwanted cells, peaked first in expanding LNs. Peaking with a delay were dendritic cells (DCs), which normally transfer information in the form of antigens from invading pathogens and cancer cells to “adaptive immune cells” that then launch subsequent waves of highly specific immune responses against the antigen-producing invaders. In fact, along with DCs, also T and B cell types of the adaptive immune system started to reach their highest numbers. “It was fascinating to see how the distinct changes in immune cell populations that we detected in expanding LNs in response to the MPS-vaccine over time re-enacted a typical immune response to infectious pathogens,” commented Najibi.
Innate immune cells and DCs are also known as “myeloid cells,” which are known to interact with LN tissue during early expansion. To further define the impact of myeloid cells on LN expansion, Mooney’s team collaborated with the group of Shannon Turley, PhD, the VP of Immunology and Regenerative Medicine at Genentech, and an expert in lymph node biology and tumour immunology. “The MPS-vaccine led to extraordinary structural and cellular changes within the lymph node that supported potent antigen-specific immunity,” said Turley.
Using single cell RNA sequencing on myeloid cells from LNs, the groups were able to reconstruct distinct changes in myeloid cell populations during LN expansion, and identified distinct DC populations in durably expanded LNs whose changed gene expression was associated with LN expansion. In addition, the collaborators found that the number of monocytes was increased 80-fold upon MPS-vaccination – the highest increase among all myeloid cell types – and pinpointed subpopulations of “inflammatory and antigen-presenting monocytes” as promising candidates for facilitating LN expansion. In fact, when they depleted specific subpopulations of these types of monocytes from circulating blood of mice after vaccination, the maintenance of LN expansion, and timing of the T cell response to vaccination, was altered.
Finally, the team explored whether LN expansion could enhance the effectiveness of vaccination. “Jump-starting” the immune system in LNs with an antigen-free MPS-vaccine and subsequently administering the antigen in a traditional vaccine format significantly improved anti-tumour immunity and prolonged the survival of melanoma-bearing mice, compared to the traditional vaccine alone. “The priming of lymph nodes for subsequent vaccinations using various formulations could be a low-hanging fruit for future vaccine developments,” said Mooney.
Substance use disorder treatment in the community is a superior alternative to incarceration for offenders with a substance misuse background, according to a recent study evaluating the effectiveness of the contract treatment sanction in Sweden.
Contract treatment refers to a criminal penalty in which the offender voluntarily consents to treatment in accordance with a specific implementation plan.
“Contract treatment is an alternative to incarceration. It is mainly used when the offence is deemed to have occurred as a result of substance misuse or some other condition requiring treatment,” says Suvi Virtanen, a University Lecturer in Psychology at the University of Eastern Finland.
A rehabilitation period is always planned based on individual needs. In addition to psychosocial treatment, it may include opioid substitution therapy.
In addition to Sweden, a sanction similar to contract treatment is in use in, e.g., Norway and many EU countries; however, not in Finland. The United States, in turn, has adopted a model of specialised drug courts.
Contract treatment carries a smaller risk of recidivism
Although contract treatment has been in use in Sweden since the late 1980s, its effectiveness has not been studied until now. The present study combined data from the Swedish Prison and Probation Service’s client register with other national registries, including data on visits to specialised health care. The study cohort included 11 893 individuals who were serving a contract treatment sanction between 1999 and 2012, and they were followed up for at least two years.
“With the introduction of contract treatment, criminal behaviour and substance-related adverse health events, such as overdoses and hospitalisations due to psychiatric and somatic reasons, decreased significantly compared to the period before contract treatment,” Virtanen says.
A significant proportion of those sentenced to contract treatment had also served community sanctions and prison sentences. In the within-individual research design, an individual’s risk of recidivism and adverse health events during contract treatment was examined compared to periods when the individual was serving a community sanction or was on parole after a prison sentence.
“The risk of recidivism and adverse health events was lower during contract treatment than during a community sanction or probation,” Virtanen notes.
Providing treatment yields better results than punishment
Substance misuse problems and criminality often go hand in hand. The most effective way to prevent recidivism is to address its root causes, which often are, in one way or another, linked to the use of substances.
“Substance use disorders are increasingly understood as a health issue that should primarily be addressed by means of health care. Usually, prison is not the best place for an individual who needs appropriate treatment and support for recovery,” Virtanen says.
The results of the study provide support for the notion that, from the viewpoint of societal security and public health, providing treatment can lead to better outcomes than penalties that emphasise punishment.
In the future, the researchers intend to study the effectiveness of contract treatment in more recent data.
In an age where healthcare integrity is of the utmost importance, a coalition of industry pioneers and technological trailblazers must lead the charge in driving transformation to combat fraud, waste and abuse (FWA) in the healthcare sector.
As a focal point of discussion on day two of the 2024 BHF Annual Conference, Vusi Makanda, HFMU Deputy Chairperson, and Manager of Fraud Management at Bonitas, set the stage for an interactive discussion on these healthcare issues.
“Collaboration is paramount in addressing the challenges of healthcare FWA, evidenced by the erosion of trust and substantial financial losses highlighting the call for collective action,” says Makanda.
Dr Hleli Nhlapo, MD of the medical schemes division at Dental Information Systems (DENIS), echoed Makanda’s sentiments. To this end, Nhlapo set the scene on the current state of FWA in the healthcare industry, suggesting that it exerts unnecessary pressure on resources while undermining trust between stakeholders.
“Perpetrators are employing increasingly sophisticated tactics, leveraging technology and syndicates to orchestrate large-scale schemes, while regulatory delays and prosecutorial challenges hinder effective resolution,” says Nhlapo. “Despite this, collaboration among healthcare funders has emerged as a crucial solution, with recent initiatives indicating a promising shift towards industry-wide cooperation in addressing these complex challenges.”
Following Nhlapo’s address, Roxane Ferreira, Head of Department at the Association of Certified Fraud Examiners (ACFE), alluded to several global trends in FWA that are plaguing the global industry.
The impact of these is extensive and has led to concerning financial situations for healthcare systems around the world. So much so that Ferreira’s insights suggest that in the United States, it is estimated that as much as $68 billion is lost every year on the back of FWA.
“In South Africa, the problem is not much better, with between R8 billion and R13 billion being lost annually to this. With between 15-35% of all claims submitted regarded as being fraudulent or abusive, the plight is adding approximately R22 billion to the cost of private healthcare,” adds Ferreira.
Healthcare fraud is perpetrated by a variety of actors within the system, ranging from medical scheme staff to service providers and even syndicates. These perpetrators exploit vulnerabilities at different points in the healthcare process, whether through falsifying claims, overbilling or engaging in other deceptive practices.
Moreover, medical scheme members themselves, as well as patients, may also be complicit in fraudulent activities, while brokers and manufacturers can also play a role in facilitating these plans.
Ferreira highlighted the multifaceted approach employed in identifying healthcare fraud, citing that 70% of cases stem from tip-offs or received information, while the remaining 30% are uncovered through data mining, audits and investigations.
“Healthcare fraud encompasses various deceptive practices,” suggests Ferreira. “ Some of the most common ones include merchandising, where pharmacies sell non-healthcare merchandise, but claim for a healthcare service; false claims by claiming for services rendered; ATM scams where doctors submit false claims and provide cash to patients; card farming where members lend their membership cards to non-members; code gaming that involves doctors manipulating billing rules to increase revenue; and lastly, the hospital cash plan fraud that entails doctors and members colluding to arrange unnecessary hospital admissions.”
In response to the escalating challenges of healthcare fraud, Ferreira adds that the sector is increasingly turning to innovative solutions, with the integration of Artificial Intelligence (AI) emerging as a pivotal strategy.
“AI technology offers the capability to analyse large volumes of data rapidly and accurately, enabling the identification of suspicious patterns and behaviours,” she says. “By leveraging AI algorithms, healthcare providers can proactively identify questionable activities, thereby safeguarding resources and maintaining the integrity of healthcare systems”
Using these advanced algorithms, AI can swiftly identify irregularities, such as sudden spikes in billed procedures and visit rates. Furthermore, it can compare billing practices, verify purchases, compare the geographical location of a patient against the practice, and treatments billed for the same or similar treatment by other practices.
In the fight against healthcare FWA, collaboration and technological innovation are emerging as critical pillars. By harnessing advancements such as AI, healthcare systems can effectively detect and prevent fraudulent activities, thus safeguarding resources, upholding the integrity of patient care and rebuilding trust.
The world’s largest study of cerebral palsy (CP) genetics has discovered genetic defects are most likely responsible for more than a quarter of cases in Chinese children, rather than a lack of oxygen at birth as previously thought.
The study, published in Nature Medicine, used modern genomic sequencing and found mutations were significantly higher in CP cases with birth asphyxia, indicating a lack of oxygen could be secondary to the underlying genetic defect. The results are consistent with smaller studies globally.
More than 1500 Chinese children with CP were involved in this collaborative effort between the University of Adelaide and Fudan University Shanghai, Zhengzhou University, Zhengzhou and associates.
The Australian team was led by obstetrician and University of Adelaide’s Emeritus Professor Alastair MacLennan AO and human geneticist, Professor Jozef Gecz.
“24.5 percent of Chinese children in the study had rare genetic variations linked to cerebral palsy. This revelation mirrors our earlier findings in our Australian cerebral palsy cohort, where up to one third of cases have genetic causes,” said Professor Gecz, who is the University of Adelaide’s Head of Neurogenetics at the Adelaide Medical School and the Robinson Research Institute.
“Our research shows at least some babies who experience birth asphyxia and are diagnosed with CP may have improper brain development as a result of the underlying genetic variants rather than a lack of oxygen.
“Crucially, clinically actionable treatments were found in 8.5 percent of cases with a genetic cause. It is exciting to see how genetic pathways to cerebral palsy inform tailored treatments for these individuals.”
Cerebral palsy affects movement and posture and is the most common motor disability in children. The disorder is diagnosed in up to 2 per 1000 children globally and is sometimes in association with epilepsy, autism and intellectual difficulties. Symptoms often emerge during infancy and early childhood and can range from mild to severe.
The research team identified 81 genes with causation mutations in the children with CP. These genes are known to play important roles in neural and embryonic development and may affect the molecular pathways responsible for respiration.
Oxygen deprivation frequently claimed in medical litigation
“A lack of oxygen at birth is often claimed to be the cause of CP in medical litigation following a diagnosis and this has led to the presumption that the condition is preventable with better obstetrics or midwifery. This is simply not the case,” said Professor MacLennan, who has spent the past 30 years advocating that there is little scientific evidence to support the myth that cerebral palsy is due to trauma or lack of oxygen at birth.
Professor MacLennan said frequent litigation has been associated with a high increase in “defensive” caesarean delivery and high insurance premiums for obstetricians.
“These results highlight the need for early genetic testing in children with cerebral palsy, especially those with risk factors like birth asphyxia, to ensure they receive the right medical care and treatment.
“All children with cerebral palsy merit modern genetic screening as early and customised interventions really can make a difference and improve their long-term outcomes,” he said.
Ongoing genetic research is also investigating other types of contributing genetic variation to the cause of CP and, as a result, the researchers expect that the overall genetic diagnosis rate is likely to increase.
