Category: Diseases, Syndromes and Conditions

Categories : Diseases, Syndromes and Conditions New Compounds and TreatmentsTags :

Promising New Lupus Pill Reverses Organ Damage in Mice

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The autoimmune disease lupus has no cure, and current treatment is limited in its effectiveness in reducing symptoms and controlling damage to the body. Now, scientists report they have begun phase 2 clinical trials with a compound that, in mice, not only prevents lupus-like symptoms, but also reverses signs of organ damage caused by the disease and prevents death.

“Few new therapies have succeeded, but we believe our compound could be an effective treatment for lupus,” says Alaric Dyckman, PhD. The disease affects 5 million people worldwide, according to the Lupus Foundation of America. Symptoms include rashes, extreme fatigue, pain, inflammation and deterioration of organs, such as the kidneys and heart, which can lead to death.

The researchers will present their results at the fall meeting of the American Chemical Society (ACS). ACS Fall 2022 is a hybrid meeting being held virtually and in-person Aug. 21–25, with on-demand access available Aug. 26–Sept. 9.

Lupus develops when the immune system attacks the body’s tissues. Years ago, researchers began suspecting that this process involved toll-like receptors (TLRs) 7 and 8, which are cellular proteins that activate the immune system when they detect viral RNA or mistakenly identify a person’s own RNA as a threat.

“Genetic data and evaluations of injectable treatments suggested TLR7 and 8 could be drug targets for lupus. What was missing was an ability to directly block these receptors with small molecules that could be taken orally,” explained Dr Dyckman. So in 2010, he and other scientists at Bristol Myers Squibb (BMS) set out to develop such compounds.

New options would be welcome, since many patients don’t respond fully to current medications. The two approved therapies that were specifically developed for lupus reduce activity of specific immune system components: AstraZeneca’s anifrolumab blocks an interferon receptor, while GlaxoSmithKline’s belimumab reduces the survival of B cells. Other treatments include steroids and other general immune suppressants, anti-malarials, anti-inflammatories and anticoagulants. However, anifrolumab and belimumab must be given by injection or infusion, Dr Dyckman noted, while steroids and general immune suppressants are associated with safety concerns and were not originally designed to treat lupus.

The BMS researchers started by screening the company’s compound collection for molecules that could block TLR7/8 signalling. The team refined the search further to improve interaction with other receptors, and potency, and enablee oral dosing. The resulting compound, afimetoran, binds to the target TLRs, inhibiting their operation to achieve beneficial activity. Like anifrolumab, it interferes with interferon, and like belimumab, it controls damage from overactive B cells. It also inhibits the production of multiple proinflammatory cytokines that cause a lot of tissue damage in lupus.

“With afimetoran, not only could we prevent the development of lupus-like symptoms in mice before their disease onset, but we could actually reverse the symptoms and prevent death in animals that were days or weeks away from succumbing to the disease,” Dr Dyckman said. “We hadn’t seen that reversal with other mechanisms we had evaluated, so we were particularly excited about that finding.” Dr Dyckman said that he believes afimetoran effects together may let it control lupus as well as or better than existing treatments, doing it through an oral route.

Afimetoran also combined well with corticosteroid treatments in mice, so patients might be able to use lower doses of steroids and reducing associated side effects.

Phase 1 clinical trials of afimetoran have been completed. The trials showed that a low, once-daily oral dose was safe in healthy patients and could almost completely block signalling through TLR7/8. And now, a phase 2 trial to test its effectiveness in lupus patients is underway. Because of its mode of action, Dr Dyckman said, it may also work in other autoimmune disorders, such as psoriasis or arthritis.

BMS is testing other compounds against lupus, such as deucravacitinib, an oral, selective tyrosine kinase 2 (TYK2) inhibitor that is moving into phase 3 studies. Other companies are also making progress. Merck, for instance, is evaluating its own oral TLR7/8 blocker, enpatoran, in phase 2 trials.

Despite intensive efforts to develop new therapies over the past several decades, few have succeeded. “So getting a lot of shots on goal is important,” Dr Dyckman said. “Also, lupus is such a heterogeneous disease that it’s unlikely that any single approach will provide relief for all of the patients out there.”

Source: EurekAlert!

Categories : Diseases, Syndromes and Conditions Obstetrics & GynaecologyTags :

Caesarean Delivery may Increase Risk of Developing Crohn’s Disease

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Photo by Christian Bowen on Unsplash

A population-based study analysing over one million individuals suggests that babies born via caesarean section delivery may face a higher risk of developing Crohn’s disease later in life. The findings, published in Acta Obstetricia et Gynecologica Scandinavica, add to a growing body of evidence on long-term impacts of caesarean section delivery. 

More and more people are being delivered by caesarean section, and there is interest in understanding possible long-term health consequences of this mode of delivery. One possible route is through a lack of the early exposure of the infant to colonising bacteria via a vaginal delivery. Previous studies suggest that infants delivered by CS are at increased risks of disorders involving the immune system, such as asthma and allergies, type 1 diabetes, celiac disease, obesity, immune deficiencies, and leukaemia and other malignancies affecting young people.

In this study, all full-term individuals registered in the Medical Birth Register in Sweden between 1990 and 2000 were followed until 2017. Among 1 102 468 individuals, of whom 11.6% were delivered by caesarean section and 88.4% were vaginally delivered, caesarean section was associated with a 14% higher risk of developing Crohn’s disease after adjusting for confounding factors. No associations between delivery mode and appendicitis, ulcerative colitis, cholecystitis, or diverticulosis were found.

“Our study is the largest in this field, showing new interesting associations between caesarean section and increased risk later in life for Crohn’s disease. We hypothesise that the underlying mechanism could be the gut microbiome, but further studies will have to confirm this,” said senior author Anna Löf Granström, of the Karolinska Institute.

Source: Wiley

Categories : Diseases, Syndromes and Conditions Lab Tests and ImagingTags :

Low Serum Urate Increases Sarcopenia Risk

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Blood sample being drawn
Photo by Hush Naidoo Jade Photography on Unsplash

Adults with low blood levels of urate, the end-product of the purine metabolism in humans, may be at higher risk of sarcopenia and may face a higher risk of early death, according to a new study published in Arthritis & Rheumatology.

Whether or nor low serum urate (SU) levels contribute to adverse outcomes has been the subject of controversy.  The study involved 13 979 participants aged 20 years and older, sourced from the National Health and Nutrition Examination Survey from 1999–2006.

Low serum urate concentrations (<2.5 mg/dL in women; <3.5 mg/dL in men) were associated with low lean mass, underweight BMI (<18.5 kg/m2), and higher rates of weight loss. While low SU was associated with increased mortality (61%) before adjusting for body composition, its effect was reduced and non-significant after adjustment for body composition and weight loss.

“These observations support what many have intuited, namely that people with low serum urate levels have higher mortality and worse outcomes not because low urate is bad for health, but rather that low urate levels tend to occur among sicker people, who have lost weight and have adverse body composition,” explained lead author Joshua F. Baker, MD, MSCE, of the University of Pennsylvania. “While this observational study doesn’t disprove a causal association, it does suggest that great care is needed in interpreting epidemiologic associations between urate levels and health outcomes.”

Source: Wiley

Categories : Diseases, Syndromes and ConditionsTags :

Asymptomatic Detection of Monkeypox Suggests it is More Widespread

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Colourised transmission electron micrograph of monkeypox virus particles (green) cultivated and purified from cell culture. Credit: NIAID

A brief research report in Annals of Internal Medicine documents positive monkeypox virus PCR results found in anal samples taken from asymptomatic MSM (men who have sex with men). These findings suggest that vaccination limited to those with known exposure to the monkeypox virus may not be an effective strategy for preventing infection.

The findings come as the World Health Organization has renamed the variants, or clades, of monkeypox from their previous geographically-derived names to Roman numerals, eg, the former Congo Basin (Central African) clade is now Clade one (I). It is also seeking inputs on a possible new name for the virus in order to avoid stigmatisation.

Researchers from Bichat–Claude Bernard Hospital, Paris, retrospectively performed testing for monkeypox virus on all anorectal swabs that were collected as part of a sexually transmitted infection screening program. This type of screening is performed every three months among MSM with multiple sexual partners who are either taking HIV preexposure prophylaxis (PrEP) or living with HIV and receiving antiretroviral treatment. Of the 200 asymptomatic persons screened that were negative for N. gonorrhoeae and C. trachomatis, 13 (6.5%) samples were PCR positive for monkeypox virus.  Two of the 13 later developed symptoms of monkeypox.

While it is not know whether asymptomatic transmission will play a role in the current worldwide monkeypox epidemic and the mode of human-to-human transmission may provide evidence that asymptomatic or preclinical spread can occur. In an accompanying editorial, Stuart N. Isaacs, MD, at the University of Pennsylvania, suggests that an expanded ring vaccination strategy and other public health interventions in the highest-risk communities are likely needed to help control the outbreak. 

Source: EurekAlert!

Categories : Diseases, Syndromes and ConditionsTags :

A Breakthrough Tinnitus Therapy – on a Smartphone

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Photo by Dylann Hendricks | 딜란 on Unsplash

After 20 years searching for a cure for tinnitus, for which there is no pharmacological treatment, there are ‘encouraging results’ from a clinical trial of a smartphone app therapy, the results of which have been published in Frontiers in Neurology.

The study randomised 61 patients to one of two treatments, the prototype of the new ‘digital polytherapeutic’ or a popular self-help app producing white noise. On average, the group with the polytherapeutic (31 people) showed clinically significant improvements at 12 weeks, while the other group (30 people) did not.

“This is more significant than some of our earlier work and is likely to have a direct impact on future treatment of tinnitus,” said Associate Professor in Audiology at the Universirt of Auckland, Dr Grant Searchfield.

Key to the new treatment is an initial assessment by an audiologist who develops the personalised treatment plan, combining a range of digital tools, based on the individual’s experience of tinnitus.

“Earlier trials have found white noise, goal-based counselling, goal-oriented games and other technology-based therapies are effective for some people some of the time,” says Dr Searchfield.

“This is quicker and more effective, taking 12 weeks rather than 12 months for more individuals to gain some control.”

“What this therapy does is essentially rewire the brain in a way that de-emphasises the sound of the tinnitus to a background noise that has no meaning or relevance to the listener,” Dr Searchfield says.

Audiology research fellow Dr Phil Sanders says the results are exciting and he found running the trial personally rewarding.

“Sixty-five percent of participants reported an improvement. For some people, it was life-changing – where tinnitus was taking over their lives and attention.”

Some people didn’t notice an improvement and their feedback will inform further personalisation, Dr Sanders noted.

Tinnitus is a phantom noise and its causes are complex. It has so far defied successful treatment.

While most people experience tinnitus, or ringing in the ears at least on occasions, around five percent experience it to a distressing degree. Impacts can include trouble sleeping, difficulty carrying out daily tasks and depression.

Dr Searchfield says seeing his patients’ distress and having no effective treatment to offer inspired his research. “I wanted to make a difference.”

The next step will be to refine the prototype and proceed to larger local and international trials with a view to FDA approval.

The researchers hope the app will be clinically available in around six months.

Source: University of Auckland

Categories : Diseases, Syndromes and ConditionsTags :

Chronic Inflammation Link to Low Vitamin D Explains Some Controversies

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Vitamin D pills
Photo by Michele Blackwell on Unsplash

New genetic research shows a direct link between low vitamin D levels and high levels of inflammation, providing an important biomarker to identify people at higher risk of or severity of chronic illnesses with an inflammatory component, such as type 2 diabetes. The findings, published in the International Journal of Epidemiology, also helps to settle some of the controversies surrounding the ‘sunshine vitamin’.

The study drew on genetic data for 294 970 participants in the UK Biobank, using Mendelian randomisation to show the association between vitamin D and C-reactive protein levels, an indicator of inflammation.

University of South Australia’s Dr Ang Zhou, the study’s lead researcher, said that the findings suggest that boosting vitamin D in people with a deficiency may reduce chronic inflammation.

“This study examined vitamin D and C-reactive proteins and found a one-way relationship between low levels of vitamin D and high levels of C-reactive protein, expressed as inflammation.

“Boosting vitamin D in people with deficiencies may reduce chronic inflammation, helping them avoid a number of related diseases.”

The study also raises the possibility that having adequate vitamin D concentrations may mitigate complications arising from obesity and reduce the risk or severity of chronic illnesses with an inflammatory component, such as CVDs, diabetes, and autoimmune diseases.

Senior investigator and Director of UniSA’s Australian Centre for Precision Health, Professor Elina Hyppönen, said that these results offer an explanation for some of the controversies in reported associations with vitamin D.

“We have repeatedly seen evidence for health benefits for increasing vitamin D concentrations in individuals with very low levels, while for others, there appears to be little to no benefit.” Prof Hyppönen said.

“These findings highlight the importance of avoiding clinical vitamin D deficiency, and provide further evidence for the wide-ranging effects of hormonal vitamin D.”

Source: University of South Australia

Categories : Diseases, Syndromes and ConditionsTags :

What Antivirals are Suitable for Monkeypox Treatment?

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Colourised transmission electron micrograph of monkeypox virus particles (green) cultivated and purified from cell culture. Credit: NIAID

In light of the recent spread of monkeypox virus, now declared a public health emergency of international concern by the World Health Organization, there is a need for treatments. In an article published in Clinical Infectious Diseases, authors review three antiviral agents with activity against monkeypox: cidofovir, brincidofovir, and tecovirimat.

Human monkeypox, caused by the monkeypox virus, a member of the genus Orthopoxvirus within the Poxviridae family of double-stranded DNA (dsDNA) viruses, was first described in a baby in the Democratic Republic of Congo in 1970. Since then, it has resulted in multiple outbreaks in Central and West Africa, and occasionally in Europe and North America. Human-to-human transmission in households has been reported, especially among those unvaccinated against smallpox.

Cidofovir
Although cidofovir has broad activity against many DNA viruses including orthopoxviruses, it is only FDA approved for the treatment of cytomegalovirus retinitis. Cidofovir (CDV) is a prodrug, which must first enter host cells, where it is converted into the active form, CDV diphosphate (CDV-pp). CDV-pp has a prolonged intracellular half-life, and slows viral DNA replication by being incorporated into the growing DNA strand. Pharmokinetics suggest poor oral absorption and is available as intravenous infusions.

In humans, CDV has been used to treat ocular cowpox and as a topical treatment for molluscum cantiogosum.

Brincidofovir
Brincidofovir (BCV) is a lipid-conjugated CDV analogue, FDA-approved in 2021 for the treatment of smallpox. Like CDV, BCV has broad activity against dsDNA viruses. It can be be taken up by the small intestines, and unlike CDV, which slowly crosses cellular membranes, brincidofovir readily enters host cells due to its lipophilicity. Inside cells, BCV is converted into CDV and then CDV-pp. CDV-pp reaches higher intracellular concentrations after BCV administration due to its ability to cross cellular membranes more efficiently. Like CDV, BCV has a prolonged intracellular half-life and inhibits viral replication.

In prairie dog models, which exhibit similarity to the human course, BCV improved survival when administered shortly after infection, suggesting that early treatment is important.

Tecovirimat
Tecovirimat was FDA approved in 2018 for the treatment of smallpox, and has activity against orthopoxviruses, but has no notable activity against other dsDNA viruses. Tecovirimat targets a gene which encodes for membrane protein p37, responsible for the formation of extracellular enveloped virus.

The oral route results in better absorption for tecovirimat, and is effective against monkeypox virus in macaques and prairie dogs. Administration within 72 hours of exposure to poxvirus reduced lesion severity and mortality in various animal models.

Tecovirimat synergises with BCV, and was successfully used to treat monkeypox in two human cases.

Conclusion
The authors note that while CDV and BCV inhibit DNA replication, tecovirimat is more specific to orthopoxviruses and prevents enveloped virus formation, stalling cell-cell transmission.

BCV and tecovirimat could be promising therapeutic candidates based on their tolerability profiles, they conclude. More studies are needed to identify those most at risk from monkeypox and establish the optimal initiation time and duration for therapy.

Categories : Diseases, Syndromes and ConditionsTags :

HSV-1 Driven by Ancient Migrations – and Introduction of Kissing

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The HSV-1 virus strain behind facial herpes, commonly known as cold sores, emerged approximately 5000 years ago, according to University of Cambridge-led research published in Science Advances. The virus arose in the wake of vast Bronze Age migrations into Europe from the Steppe grasslands of Eurasia, and associated population booms that boosted transmission.

Two-thirds of the world’s population below the age of 50 now carry HSV-1, manifesting as occasional lip sores. In combination with other ailments – sepsis or even COVID, for example – the virus can be fatal. In 2018, two women died of HSV-1 infection in the UK following Caesarean births.

Herpes has an ancestry dating back millions of years, infecting species from bats to coral. Despite being prevalent among humans today, however, scientists say that ancient examples of HSV-1 were surprisingly hard to find.

According to the study authors of the study, , the Neolithic flourishing of facial herpes detected in the ancient DNA may have coincided with the advent of a new cultural practice imported from the east: romantic and sexual kissing.    

“Facial herpes hides in its host for life and only transmits through oral contact, so mutations occur slowly over centuries and millennia,” said Dr Charlotte Houldcroft, co-senior author.

“We need to do deep time investigations to understand how DNA viruses like this evolve. Previously, genetic data for herpes only went back to 1925.”

The team managed to hunt down herpes in the remains of four individuals stretching over a thousand-year period, and extract viral DNA from the roots of teeth. Herpes often flares up with mouth infections: at least two of the ancient cadavers had gum disease and a third smoked tobacco.

The oldest sample came from an adult male excavated in Russia’s Ural Mountain region, dating from the late Iron Age around 1500 years ago.

Two further samples were local to Cambridge, UK. One a female from an early Anglo-Saxon cemetery a few miles south of the city, dating from 6-7th centuries CE. The other was a young adult male from the late 14th century who had suffered appalling dental abscesses. 

The final sample came from a young adult male excavated in Holland: a fervent clay pipe smoker, most likely massacred by a French attack on his village by the banks of the Rhine in 1672. 

“We screened ancient DNA samples from around 3000 archaeological finds and got just four herpes hits,” said co-lead author Dr Meriam Guellil, from Tartu University’s Institute of Genomics.

“By comparing ancient DNA with herpes samples from the 20th century, we were able to analyse the differences and estimate a mutation rate, and consequently a timeline for virus evolution,” said co-lead author Dr Lucy van Dorp, from the UCL Genetics Institute.     

Co-senior author Dr Christiana Scheib said: “Every primate species has a form of herpes, so we assume it has been with us since our own species left Africa.”

“However, something happened around five thousand years ago that allowed one strain of herpes to overtake all others, possibly an increase in transmissions, which could have been linked to kissing.”

The first known report of kissing is a Bronze Age manuscript from South Asia, and suggest the custom, not found in most human cultures, may have travelled westward with migrations into Europe from Eurasia.   

In fact, centuries later, the Roman Emperor Tiberius tried to ban kissing at official functions to prevent disease spread, a decree that may have been herpes-related.

However, for most of human prehistory, HSV-1 transmission would have been ‘vertical’: passing from infected mother to newborn child.

Source: University of Cambridge

Categories : Diseases, Syndromes and Conditions Healthcare Politics and RegulationsTags :

Despite Disagreement, WHO Sounds Highest Alert for Monkeypox

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Source: Pixabay CC0

On 22 July, World Health Organisation (WHO) director general Dr Tedros Adhanom Ghebreyesus declared the global spread of monkeypox a Public Health Emergency of International Concern (PHEIC) – a move which went against the recommendation of a special committee. This was the first time since the PHEIC’s inception in 2005 that it had done so. The special committee’s reluctance to recommend a PHEIC has previously drawn criticism from public health experts.

The 21 July meeting of WHO’s Emergency Committee, did not reach a consensus on whether to declare the growing monkeypox outbreak a PHEIC; a narrow majority voting against doing so. But Dr Tedros invoked a PHEIC at a press conference the next day in Geneva. “We have an outbreak that has spread around the world rapidly, through new modes of transmission, about which we understand too little and which meets the criteria in the International Health Regulations,” he said.

Data presented during the meeting including modelling which showed the basic reproduction number (R0) to be above 1 among gay or bisexual men, and below 1 in other groups. For example, in Spain, the estimated R0 is 1.8, in the United Kingdom 1.6, and in Portugal 1.4.

In June, the committee first recommended against declaring a PHEIC , which was roundly criticised by epidemiologists and global health experts. Dr Tedros reconvened the group this week and asked it to reconsider the question. Nine members were against declaring a PHEIC and six in favour, Dr Tedros said at the press conference.

According to Science, the Thursday meeting of the expert panel was followed by tense exchanges via email and text messages between its participants.

One of the objections to a PHEIC was that few deaths had been caused by the disease so far and was not spreading in the general population. Another was that a PHEIC could possibly lead to further stigmatisation of men who have sex with men (MSM), the group primarily affected.

Many gay rights and sexual health advocates were for the PHEIC, as it would help raise awareness and help protect the most at-risk group of MSM.

“Although I’m declaring a public health emergency of international concern, for the moment, this is an outbreak that’s concentrated among men who have sex with men, especially those with multiple sexual partners,” Dr Tedros said. “That means that this is an outbreak that can be stopped with the right strategies in the right groups.”

Those who push for declaring a PHEIC also cited the rising number of monkeypox cases (over 15 000) and the countries affected (70), and that many cases are likely still not being picked up. The virus could also potentially establish itself permanently worldwide – indeed, the CDC reported that two children in the US had been infected.

Sources familiar with the deliberations of the committee said the votes for a PHEIC were driven by those with expertise in monkeypox and LGBT health, and those against by more generalist global heath voices.

According to Science, sources familiar with the committee’s deliberation said that those in favour of a PHEIC had monkeypox and LGBT health expertise, and those against were from a global health standpoint.

While a PHEIC can give the WHO some extra powers, it is the loudest level of alert it can sound. Since its creation in 2005, PHEIC has been declared six times: for outbreaks of H1N1 influenza, polio, Zika, COVID (ongoing), and twice for Ebola outbreaks (one ongoing).

Source: Science.org

Categories : Diseases, Syndromes and ConditionsTags :

Monkeypox Symptoms Described in Case Series

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Source: Wikimedia CC0

A large case series on monkeypox was published in The New England Journal of Medicine, which will help direct the limited resources such as vaccines to contain the recent spread of the virus. In the study, clinicians led by Queen Mary University of London identified new clinical symptoms of monkeypox infection, which will aid future diagnosis and help to slow the spread of infection. This is the largest case study series to date, reporting on 528 confirmed monkeypox infections at 43 sites between 27 April and 24 June 2022.

Gay and bisexual men make up 98% of infected persons in the current spread of the virus. While in most cases sexual closeness is the most likely route of transmission, researchers stress that the virus can be transmitted by any close physical contact through large respiratory droplets and potentially through clothing and other surfaces.

There is a global shortage of both vaccines and treatments for human monkeypox infection. The findings of this study, including the identification of those most at risk of infection, will help to aid the global response to the virus. Public health interventions aimed at higher risk of exposure could help to detect and slow the spread of the virus. Recognising the disease, contact tracing and advising people to isolate will be key components of the public health response.  

Many of the infected individuals reviewed in the study presented with symptoms not recognised in current medical definitions of monkeypox. These symptoms include single genital lesions and sores on the mouth or anus. The clinical symptoms are similar to those of sexually transmitted infections (STIs) and can easily lead to misdiagnosis.

In some people, anal and oral symptoms have led to people being admitted to hospital for management of pain and difficulties swallowing. Since misdiagnosis can slow detection, hindering efforts to control the spread of the virus, this information is important for clinicians. This information will help increase diagnoses in persons from at-risk groups present with traditional STI symptoms.

Public health measures – such as enhanced testing and education – should be developed and implemented working with at-risk groups to ensure that they are appropriate, non-stigmatising, and to avoid messaging that could drive the outbreak underground.

Source: Queen Mary University of London