Tag: 21/4/21

Night Shifts Increase Risk of Infection

Shift working and irregular working hours can affect our health and disrupt immune response, especially in men, according to new research from the University of Waterloo.

These health-related issues occur because the body’s circadian rhythm can be disrupted by inconsistent changes in the sleep-wake schedule and feeding patterns often caused by shift work. To study this, researchers at Waterloo developed a mathematical model to investigate how a disruption in the circadian clock affects the immune system in fighting off illness.

“Because our immune system is affected by the circadian clock, our ability to mount an immune response changes during the day,” said Anita Layton, professor of Applied Mathematics, Computer Science, Pharmacy and Biology at Waterloo. “How likely are you to fight off an infection that occurs in the morning than midday? The answer depends on whether you are a man or a woman, and whether you are among [the] quarter of the modern-day labor force that has an irregular work schedule.”

The researchers created new computational models, separately for men and women, which simulate the interplay between the circadian clock and the immune system. The model is composed of the core clock genes, their related proteins, and the regulatory mechanism of pro- and anti-inflammatory mediators. By adjusting the clock, the models can simulate male and female shift-workers.

The researchers’ simulation results demonstrate that the immune response varies with the time of infection. The model simulation indicates that the time just before people go to sleep is the “worst” time to get an infection. At this point during the day, the human body is least prepared to produce the pro- and anti-inflammatory mediators needed during an infection. An individual’s sex also impacts the effect significantly.

“Shift work likely affects men and women differently,” said Stéphanie Abo, a PhD candidate in Waterloo’s Department of Applied Mathematics. “Compared to females, the immune system in males is more prone to overactivation, which can increase their chances of sepsis following an ill-timed infection.”

Source: Medical Xpress

More information: Stéphanie M. C. Abo et al. Modeling the circadian regulation of the immune system: Sexually dimorphic effects of shift work, PLOS Computational Biology (2021). DOI: 10.1371/journal.pcbi.1008514

Predicting the Next Viral Pandemic

A group of experts has argued that trying to survey all of the viruses in the animal kingdom is a futile effort, and that we should rather focus on those most likely to cross over at the interface of humans and animals.

The observation that most of the viruses that cause human disease come from other animals has led some researchers to attempt “zoonotic risk prediction” to second-guess the next virus to cause a global pandemic. 
Zoonotic viruses, those that cross over from animal species into humans, have caused epidemics and pandemics in humans for centuries. This is exactly what is occurring today with the COVID pandemic: SARS-CoV-2—the coronavirus that causes the disease—emerged from an animal species, albeit which one is not yet known.

An essay published April 20th in the open access journal PLOS Biology, led by Dr Michelle Wille at the University of Sydney, Australia with co-authors Jemma Geoghegan and Edward Holmes outlines the great challenges in zoonotic risk prediction.

The authors argue that these zoonotic risk predictions are of limited value, and will not be able to predict which virus will cause the next great pandemic. Instead, they reason, the human-animal interface should be the target for intensive viral surveillance.

A key question is whether it is possible to predict which animal or which virus group will most likely cause the next pandemic. This has led to “zoonotic risk prediction,” in which researchers attempt to determine which virus families and host groups are most likely to carry potential zoonotic and/or pandemic viruses.

Dr Wille and her colleagues identified several key problems with zoonotic risk prediction attempts.

Firstly, they’re based on very small data sets. Despite decades of work, less than 0.001% of all viruses have likely been identified, even from the mammalian species from which the next pandemic virus is expected to emerge.

Second, these data are also already highly biased in favour of those the most infectious viruses  of humans or agricultural animals, or are already known to be zoonotic. Most animals have in fact not been surveyed for viruses, and that viruses evolve so quickly that any such surveys will soon be out of date and therefore be of limited value.

The authors instead argue that a new approach is needed, not trying to futilely survey all the viruses in the wild but instead undertaking extensive sampling at the animal-human interface. This would enable the detection of novel viruses as soon as they appear in humans. This kind of enhanced surveillance could help us forestall the next pandemic.

Source: Phys.Org

Journal information: Wille M, Geoghegan JL, Holmes EC (2021) How accurately can we assess zoonotic risk? PLoS Biol 19(4): e3001135. doi.org/10.1371/journal.pbio.3001135

Lipid-wrapped Peptide Sends Chemo Drugs Deep into Tumours

A study has shown that a peptide wrapped in a fatty liposome capsule can deliver chemotherapy drugs deep into tumour sites.

University of Minnesota researcher Hongbo Pang led a cross-institutional study on improving the efficacy of nucleotide-based drugs against prostate cancer and bone metastasis.  

The researchers looked at whether liposomes (enclosures of fatty molecules), when integrated with the iRGD peptide (which binds strongly to tumour blood vessels), will help concentrate antisense oligonucleotides (ASOs, a type of nucleolytic drug) into primary prostate tumours and its bone metastases.

More importantly, they investigated whether this system helps more drugs across the vessel wall and deeply into the tumor tissue. This is critical because, although nucleotide drugs have unique advantages in treating tumours and other diseases, they often struggle to cross the blood vessels and penetrate the tumour tissue, where their targets reside. Their clinical applicability and efficacy is hampered as a result. Even typical chemotherapeutic agents only penetrate 3-5 cancer cell diameters deep.

“Our system demonstrates a good ability to deliver more ASOs into both primary tumor tissue and bone metastases — which is the primary site for prostate cancer metastasis. This further translates into a significant improvement of ASO efficacy to inhibit the growth of primary tumor and bone metastases,” said study leader Hongbo Pang, assistant professor at the College of Pharmacy, and member of the Masonic Cancer Center. “We expect this system to become a universal carrier system, to improve the clinical efficacy of ASOs and other nucleotide drugs.”

The study found that iRGD-liposomes can increase the tumor accumulation and vascular/tissue penetration of ASOs against the disease-driving gene of prostate cancer. It also found that the ability of ASOs to inhibit primary tumours and bone metastases growth was significantly improved with iRGD-liposomes. A long-term tumour inhibition study was also performed, which showed that iRGD-liposomes significantly extends the AR-ASO suppression of primary tumor growth.

Pang and his team concluded that iRGD-liposomes are proven as a desirable delivery system for ASOs, and could enhance the clinical efficacy of nucleotide drugs in cancer therapies.

Source: News-Medical.Net

Journal information: Guan, J., et al. (2021) iRGD‐Liposomes Enhance Tumor Delivery and Therapeutic Efficacy of Antisense Oligonucleotide Drugs against Primary Prostate Cancer and Bone Metastasis. Advanced Functional Materials. doi.org/10.1002/adfm.202100478.

Refining the Genetic Heritage of South Africans for Better Medicine

A new study from Wits University challenges the idea that all South-Eastern-Bantu speaking groups are a single genetic group.

The South-Eastern-Bantu (SEB) language family includes isiZulu, isiXhosa, siSwati, Xitsonga, Tshivenda, Sepedi, Sesotho and Setswana. Almost 80% of South Africans speak one of these as their first language and their origins can be traced to West-Central Africa farmers whose descendants over the past two millennia southwards, finally reaching Southern Africa.

Since then, settling and population movements and interaction with Khoe and San communities, as other SEB speakers, ultimately resulted in distinct Southern African languages such as isiZulu, isiXhosa and Sesotho. But despite these linguistic differences, these groups of people are treated as one group in genetic studies.

Genetic disease studies rely on understanding the genetic diversity of population. If two genetically distinct populations are treated as one, errors could occur when finding disease genes, especially for complex diseases like hypertension and diabetes.

Dr Dhriti Sengupta  and Dr  Ananyo Choudhury in the Sydney Brenner Institute for Molecular Bioscience (SBIMB) at Wits University were joint lead authors of the paper published in Nature Communications. 

“South Eastern Bantu-speakers have a clear linguistic division – they speak more than nine distinct languages – and their geography is clear: some of the groups are found more frequently in the north, some in central, and some in southern Africa. Yet despite these characteristics, the SEB groups have so far been treated as a single genetic entity,” said Dr Choudhury.

The study found that SEB speaking groups are too different to be treated as a single genetic unit.

“So if you are treating say, Tsonga and Xhosa, as the same population – as was often done until now – you might get a completely wrong gene implicated for a disease,” said Sengupta.

The study aimed to find out whether the SEB speakers are indeed a single genetic entity or if they have enough genetic differences to be grouped into smaller units.

Genetic data from more than 5000 participants speaking eight different southern African languages were generated and analysed. Participants were recruited from research sites in Gauteng, Mpumalanga, and Limpopo province.

The study detected major variations in genetic contribution from the Khoe and San into SEB speaking groups; some groups have received a lot of genetic influx from Khoe and San people, while others have had a very little genetic exchange with these groups.

This variation ranged on average from about 2% in Tsonga to more than 20% in Xhosa and Tswana, suggesting that  SEB speaking groups are too different to be treated as a single genetic unit.

“The study showed that there could be substantial errors in disease gene discovery and disease risk estimation if the differences between South-Eastern-Bantu speaking groups are not taken into consideration,” said Dr Sengupta.

The genetic data also show major differences in the history of these groups over the last 1000 years, with genetic exchanges occurring at different points in time. These genetic differences are distinctive enough to affect the outcomes of biomedical genetic research.

Dr Sengupta cautioned that ethnolinguistic identities are complex and broad conclusions extrapolated should not from the findings regarding genetic differences.

“Although genetic data showed differences [separation] between groups, there was also a substantial amount of overlap [similarity]. So while findings regarding differences could have huge value from a research perspective, they should not be generalised,” she said.

A common approach to identify if a genetic variant causes or predisposes a disease is to compare occurrence of many genetic variants in individuals with a disease (eg, hypertension or diabetes) against healthy individuals. If there is a difference in frequency in a variant between two sets, the genetic variant is assumed to be perhaps linked to the disease.

“However, this approach depends entirely on the underlying assumption that the two groups consist of genetically similar individuals. One of the major highlights of our study is the observation that Bantu-speakers from two geographic regions – or two ethnolinguistic groups – cannot be treated as if they are the same when it comes to disease genetic studies,” said Dr Choudhury.

Future studies, especially those testing a small number of variants, need to be more nuanced and have balanced ethnolinguistic and geographic representation, he said.

Professor Michèle Ramsay, director of the SBIMB and corresponding author of the study, says: “The in-depth analysis of several large African genetic datasets has just begun. We look forward to mining these datasets to provide new insights into key population histories and the genetics of complex diseases in Africa”.

Source: Wits University

Journal reference: Sengupta, D., et al. (2021) Genetic substructure and complex demographic history of South African Bantu speakers. Nature Communications.doi.org/10.1038/s41467-021-22207-y.

Epidurals Do Not Increase Autism Risk for Babies

A Canadian study showed that children born to mothers who used epidural analgesia during labour were not at increased risk of developing autism spectrum disorder (ASD).

Epidural analgesia is administered into the epidural space around the spinal cord, typically during labour. Besides easing pain and reducing the use of other analgesics, it has also been shown to lower cortisol levels, expedite the return of bowel function, decrease the incidence of PE and DVT in the postoperative period, and reduce hospital stays.

Epidural analgesia is used by 73% of pregnant women in the U.S. for pain during labour. Since the US incidence of ASD increased from 0.66% in 2002 to 1.85% in 2016, there have been more efforts to identify environmental factors that put children at risk, the researchers said.

Elizabeth Wall-Wieler, PhD, of the University of Manitoba in Winnipeg, and colleagues drew from population datasets and included vaginal deliveries of singleton babies born in Canada from 2005 to 2016, following children from birth up until 2019.

Of the more than 123 000 infants included in the study, approximately 38% were exposed to epidural analgesia during delivery, and about 80 000 had a sibling in the study cohort. The mean age of mothers was 28 years. The children’s median age at their first diagnosis of ASD was 4 years. Births with epidural analgesia were more likely to be nulliparous or involve other factors such as foetal distress.
About 2.1% of children exposed to epidural labour analgesia (ELA) later developed ASD, compared with 1.7% who were not exposed, the team reported. But after factor adjustments, the researchers found no association between epidural analgesia and childhood ASD risk, they wrote in JAMA Pediatrics.

“This finding is of clinical importance in the context of pregnant women and their obstetric and anesthesia care professionals who are considering ELA during labor,” Dr Wall-Wieler and colleagues noted.

The group’s results contrast with Qiu et al.’s recent study that found a 37% increased risk of autism in children whose mothers used epidural analgesia during their delivery. Their study did not account for key perinatal factors, such as induction of labor, labor dystocia, and foetal distress, and drew criticism from five medical societies for possible residual confounding.

Dr Wall-Wieler and colleagues said that ELA is “recognized as the most effective method of providing labor analgesia,” adding that future qualitative research should assess how their findings — as well as the prior ones — have altered the perceptions about the perceived risk of ASD in offspring among both pregnant women and healthcare providers.

In an accompanying editorial, Gillian Hanley, PhD, of the University of British Columbia in Vancouver, and colleagues said that given the concerns stemming from previous findings, “it thus comes with some relief that Wall-Wieler et al found no association when controlling for key maternal sociodemographic and perinatal factors.”

“Epidural labor analgesia is an extremely effective approach to obstetric analgesia,” Dr Hanley’s group noted. “We have a collective responsibility to understand whether it is a safe option that sets a healthy developmental pathway well into childhood.”

The researchers observed an association between ELA and autism risk before accounting for confounders; but after controlling for all maternal sociodemographic, pre-pregnancy, pregnancy and perinatal factors, there was no longer a correlation.

In an analysis of siblings, researchers again observed a null association after controlling for all confounders and family fixed effects. Siblings who were exposed to epidural analgesia had a 2% cumulative risk of developing autism, and unexposed siblings had a risk of 1.6%.

The accuracy of inpatient and outpatient diagnostic codes for ASD, as well as coding for ELA was acknowledged as a study limitation by the researchers, as well as a lack of data describing epidural analgesia drug doses.

Source: MedPage Today

Journal information: Wall-Wieler E, et al “Association of epidural labor analgesia with offspring risk of autism spectrum disorders” JAMA Pediatr 2021; DOI: 10.1001/jamapediatrics.2021.0376.

Mechanism of AstraZeneca Blood Clotting Detailed in Study

Red blood cells. CC0 Creative Commons

A new study into rare cases of blood clots in the brain with low platelets seen in some patients after vaccination has been published in the New England Journal of Medicine.

The research team behind the study were the first clinicians in the UK to spot the link between the Oxford/AstraZeneca vaccine and rare cases of blood clotting along with a low platelet count, before identifying the correct diagnostic test for the syndrome. They recommended the treatment approach which avoids the use of heparin, an anticoagulant typically used to treat normal blood clots.

The researchers detailed the cases of 23 patients, who all presented with thrombosis and thrombocytopenia after receiving the AstraZeneca vaccine, and none of whom had underlying conditions which would predispose them to blood clots.

The presence of the PF4 antibody (platelet factor 4) was detected in almost all cases (21 out of 23). In rare instances, these antibodies are triggered by the blood-thinning drug heparin, a syndrome known as heparin-induced thrombocytopenia (HIT). However, HIT was ruled out because none of the patients in this study received heparin.

The investigators therefore concluded that they were seeing a heparin-independent PF4-dependent syndrome in the setting of the AstraZeneca vaccine. They cautioned that this syndrome needs to be identified quickly if present, because its treatment is very different to that of blood clots with low platelet counts.

Co-author Professor Tom Solomon commented: “Although it is a very rare side effect, this issue of clots in the brain and elsewhere combined with blood abnormalities following COVID-19 immunization is extremely important. It is critical we understand the disease mechanisms so we can provide the best treatment for patients. Here at the University we are part of a national program collecting information on such patients.”

The researchers stressed that vaccination is still the key means to end the pandemic, and everyone should continue to receive a vaccine when offered one.

Source: Medical Xpress

Journal information: Marie Scully et al. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination, New England Journal of Medicine (2021). DOI: 10.1056/NEJMoa2105385