Culture

Washington, DC / New Delhi, India - Researchers at CDDEP recently published 'Improving vaccination coverage and timeliness through periodic intensification of routine immunization: evidence from Mission Indradhanush' where they evaluated the performance of India's Mission Indradhanush (MI) child vaccination campaign -- a periodic intensification of the routine immunization program.

Each year, 1.2 million Indian children die, accounting for a fifth of global under-5 deaths. Over 400,000 of these deaths are from vaccine-preventable diseases. An estimated 38% of Indian children under the age of two years were not-fully-immunized in 2016. Additionally, vaccinated children received 23%-35% of the doses of polio, diphtheria-pertussis-tetanus DPT, bacillus Calmette-Guérin (BCG), and measles vaccines at later than recommended ages. Low vaccination coverage and frequently delayed vaccinations stand in juxtaposition with India's rapid economic growth in recent decades.

In December 2014, the Government of India launched Mission Indradhanush (MI), with the objective of increasing full immunization coverage. MI was a periodic intensification of the routine immunization (PIRI) program which targeted unvaccinated and under-vaccinated children by allocating more resources to underserved areas. The program was implemented in 528 districts--with low initial full immunization coverage and high dropout rates--in four phases during March 2015-July 2017. An estimated 25.5 million children across India were vaccinated under MI in this time. Despite the substantial resources allocated towards this program, there has been a lack of robust estimates of its true impact.

The study reports on associations between the first and second phases of the MI program, and routine vaccination coverage and timing outcomes by employing difference-in-difference (DID) regression analysis which incorporates a rich set of socioeconomic and healthcare access indicators. The authors find that the full immunization rate was 27% higher among children under 2 years old residing in districts that received the campaign during both phase 1 and 2 (intervention group) as compared with those residing elsewhere (control group). The rate of receiving all vaccines at recommended ages was 8% higher in the intervention group. Receiving doses of oral polio vaccine (OPV) birth dose, OPV dose 1 (OPV1), OPV2, OPV3, BCG, and hepatitis B birth dose vaccines were 9%, 9%, 11%, 16%, 5%, and 19% higher in the intervention group than the control group, respectively. However, the study did not find improved vaccination rates for children who resided in a district that only received treatment in either phase 1 or 2.

According to the lead author of the study, Amit Summan, "Our findings hold tremendous importance for India's Universal Immunization Program. In the short term, MI-like programs could substantially boost vaccine coverage and on-time delivery rates. However, their long-term sustainability and resource allocation decisions for immunization will need to be evaluated further".

Main points

Strong evidence that patients with pre-existent mental disorders are twice as likely to die or be hospitalised after SARS-CoV-2 infection

Psychotic and mood disorders are linked with COVID-19-associated mortality, as are exposure to antipsychotic and anxiolytic treatments.

Patients with substance use disorders are at increased risk of hospitalisation.

In the largest systematic review and meta-analysis to date on COVID-19 outcomes in individuals with psychiatric disorders, the odds of dying or being hospitalized following COVID-19 infection were determined to be twice as high in comparison to persons without mental disorders.* The study also found ICU admission rates were not affected. This work, initiated by the Immuno-NeuroPsychiatry Network of the European College of Neuropsychopharmacology, is published today in the peer-reviewed journal Lancet Psychiatry**.

The study compiles data from 33 studies from 22 countries, comprising 1 469 731 patients with COVID-19, of whom 43 938 had mental disorders. Twenty-three studies were included in a random-effects meta-analysis of crude and adjusted odds ratios for COVID-19 related mortality, hospitalization, and ICU admission in individuals with comorbid pre-existent mental disorders, investigating different diagnostic groups and classes of psychiatric drugs. Individuals with psychotic disorders and mood disorders, as well as patients receiving treatment with antipsychotics or anxiolytics (anxiety reducing drugs) appear as the most vulnerable groups for COVID-19-associated mortality. Patients with substance use disorders were also at increased risk for hospitalization following COVID-19.

The authors of the paper call for national and international health authorities to take concerted action by offering priority vaccination to patients with severe mental illness, intellectual disability, and substance use disorders, and highlight the urgency of actions to counteract possible reduced access to care.

Corresponding author, Dr Livia De Picker (from the University Psychiatric Hospital Campus Duffel, Belgium) said:

"Together with many colleagues from national and international psychiatric associations, we have been advocating for priority SARS-CoV-2 vaccination of patients with severe mental illness. However, it quickly became apparent that a lack of high-quality evidence on the mortality and hospitalization risks of patients with mental disorders was blocking implementation of our recommendations by healthcare policymakers. In several countries, pleas to change the vaccination strategy were discarded by national health authorities with the argument that the current scientific evidence did not distinguish particular groups of psychiatric patients who have a very high risk for severe Covid-19, hospitalizations, ICU admittance and death due to Covid-19. This paper offers precisely this, and shows that pre-existing mental disorders, in particular psychotic and mood disorders, and exposure to antipsychotics and anxiety-reducing drugs are associated with COVID-19 mortality. With this new evidence, not taking action is no longer an option."

"Importantly, our data revealed a striking contrast in patients with severe mental illness. Patients with psychotic disorders in particular were affected by the highest mortality risk, but did not have increased risk of hospital admission. We know these patients face important barriers to physical healthcare, and our results suggest reduced access to care could have contributed to the increased mortality seen in this group. Public health authorities need to take targeted action to ensure maximum vaccination uptake for all groups of at-risk patients identified in this study. Close monitoring and adequate hospital referral in patients with psychiatric disorders who develop COVID-19 is needed to counteract possible reduced access to care."

The study was initiated by the ImmunoNeuroPsychiatry Network of the European College of Neuropsychopharmacology. Author and director of the Network, Professor Marion Leboyer (University of Paris Est Créteil, France) said,

"This high-quality study was created through the concerted efforts of many international colleagues working together. Further work is needed to determine the causes of the poor COVID-19 outcomes in psychiatric patients, which might reflect biological processes, such as immune-inflammatory alterations related to the psychiatric disorders. In particular the impact of psychopharmacological treatments requires further study. We found that exposure to antipsychotic and anxiolytic drug treatments initiated before contracting COVID-19 was associated with severe COVID-19 outcomes. Antipsychotics might increase cardiovascular and thromboembolic risks, interfere with an adequate immune response, and cause interactions with drugs used to treat COVID-19. Benzodiazepines are associated with respiratory risk, and are known to be associated with all-cause mortality. By contrast, some antidepressants were recently shown to have protective effects. In addition, social and lifestyle factors such as diet, physical inactivity, social isolation, high alcohol and tobacco use, and sleep disturbances, and a higher prevalence of somatic comorbidities might also have detrimental effects on COVID-19 prognosis."

An international research team led by YAO Zhonghua from the Institute of Geology and Geophysics of the Chinese Academy of Sciences (IGGCAS) has explained the cause of Jupiter's X-ray aurorae, a mystery that has puzzled scientists for 40 years.

The findings were published in Science Advances on July 9.

It is the first time planetary researchers have described the entire causality chain for Jupiter's X-ray auroral flares. The mechanism in producing X-ray auroral flares at Jupiter may have potential applications in X-ray astronomy.

The X-ray auroral spectra tell us these aurorae are produced by heavy ions with energies in the mega electron volt range. But how they are formed and why these ions enter Jupiter's atmosphere was previously unknown.

To understand the energetic processes associated with Jupiter's polar emissions, researchers organized, over the last four years, a series of paradigm-shifting observation campaigns from Earth in tandem with in situ measurements by ESA's flagship X-ray observatory, XMM-Newton, and NASA's Juno spacecraft. These efforts included the most extensive X-ray campaign and the most extensive Hubble Space Telescope campaign ever conducted for Jupiter.

Using these tools, the researchers were able to probe the physics behind the phenomenon and reveal the processes that lead planets to produce X-ray aurorae.

"These are strikingly similar to the processes of producing ion aurorae on Earth, suggesting that ion aurorae share common mechanisms across planetary systems, despite temporal, spatial and energetic scales varying by orders of magnitude," said YAO Zhonghua, first author of the study.

"What we see in the Juno data is this beautiful chain of events. We knew that the auroral ions are stored in the magnetosphere, originated from the volcanic activities of Jupiter's moon Io. In the magnetosphere, now we see the magnetic compression happen, the electromagnetic ion cyclotron wave triggered, the ions, and then a pulse of ions traveling along the field line. A few minutes later, XMM sees a burst of X-rays," said William Dunn from University College London, who co-led the study.

It is noteworthy that Jupiter's X-ray auroral flares are often correlated with ultraviolet auroral flares, which are the most common auroral form. Indeed, the study of the latter may benefit from the wealth of Hubble Space Telescope data acquired through this research. "The discovery of Jupiter's X-ray processes may have implications for our understanding of stunning ultraviolet auroral flares," said Denis Grodent from the University of Liege, a co-author of the study.

The ability to predict and interpret modifications of ribonucleic acid (RNA) has been a welcome advance in biochemistry research.

However, existing predictive approaches have a key drawback--they can only predict a single type of RNA modification without supporting multiple types or providing insightful interpretation of their prediction results.

Researchers from Xi'an Jiaotong-Liverpool University, led by Dr Jia Meng, have addressed this issue by developing a model that supports 12 RNA modification types, greatly expanding RNA research prediction and interpretation.

"To the best of our knowledge, these 12 are the only widely occurring RNA modifications that can be profiled transcriptome-wide with existing base-resolution technologies. This makes them highly desirable for reliable large-scale prediction," Dr Meng said.

Transcriptomes are the set of all RNA transcripts in a cell. By analysing these sequences, researchers can understand which genes are turned 'on' or 'off' in the cells and related tissues.

The research proved the efficacy of their MultiRM model--described by Dr Meng as an attention-based multi-label neural network approach for integrated prediction and interpretation of RNA modifications from the primary RNA sequence. Attention mechanisms weigh the contributions of inputs to optimise the process of learning target results.

The study states that the primary purpose of the MultiRM research is to establish an interpretable predictor that could achieve state-of-the-art accuracy when identifying these RNA modifications and primary RNA sequences.

The prediction method helps researchers understand the sequence-dependent mechanisms of RNA modification, cuts wet-lab experiment costs and provides insights into the regulatory circuit of RNA metabolism.

The approach is still primarily for fundamental research only, Dr Meng said. The tool, however, may help scientists design more efficient RNA therapeutics.

"It is hard to predict which diseases will benefit from the research, but studies indicate the enzymes of m6A RNA methylation play a key role in leukaemia, lung cancer and breast cancer," he said.

To get the multiple, simultaneous predictions, the researchers used a multitask-learning framework that integrates the prediction tasks for all the 12 RNA modifications into a single prediction task, Dr Meng said.

"Existing tools focused on the interpretation of the model," he said. "The MultiRM model provides a more comprehensive view of the epitranscriptomes and discovers underlying mechanisms of the prediction results."

The study discovered a surprising finding--the RNA modifications show significant positive associations among each other, including those originating from different nucleotides. This suggests regions exist that are intensively modified by multiple RNA modifications, which are likely to be the key regulatory components for the epitranscriptome layer of gene regulation.

How MultiRM was built

MultiRM uses a deep-learning framework on the TensorFlow platform. The researchers' approach accommodates the shared structure of different modifications while fully exploiting their distinct features.

As some modifications are more abundant than others, additional algorithms were used to balance the training data issue in multi-label learning. The researchers then implemented other machine-learning algorithms to create MultiRM's baseline benchmark.

The MultiRM model has implications for other researchers. The research team developed a web server that was designed and made accessible to serve the research community, accessible here.

Researchers can freely download the data, code, and model. It takes as input an RNA sequence and returns the predicted RNA modification sites and the key sequence contents that drive the positive predictions.

Although the risk of a child being admitted to hospital due to COVID-19 is small, a new UK study has found that around 1 in 20 of children hospitalised with COVID-19 develop brain or nerve complications linked to the viral infection.

The research, published in The Lancet Child and Adolescent Health and led by the University of Liverpool, identifies a wide spectrum of neurological complications in children and suggests they may be more common than in adults admitted with COVID-19.

While neurological problems have been reported in children with the newly described post-COVID condition paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS), the capacity of COVID-19 to cause a broad range of nervous system complications in children has been under-recognised.

To address this, the CoroNerve Studies Group, a collaboration between the universities of Liverpool, Newcastle, Southampton and UCL, developed a real-time UK-wide notification system in partnership with the British Paediatric Neurology Association.

Between April 2020 and January 2021, they identified 52 cases of children less than 18 years old with neurological complications among 1,334 children hospitalised with COVID-19, giving an estimated prevalence of 3.8%. This compares to an estimated prevalence of 0.9% in adults admitted with COVID-19.

Eight (15%) children presenting with neurological features did not have COVID-19 symptoms although the virus was detected by PCR, underscoring the importance of screening children with acute neurological disorders for the virus.

Ethnicity was found to be a risk factor, over two thirds of children being of Black or Asian background.

For the first time, the study identified key differences between those with PIMS-TS versus those with non-PIMS-TS neurological complications. The 25 children (48%) diagnosed with PIMS-TS displayed multiple neurological features including encephalopathy, stroke, behavioural change, and hallucinations; they were more likely to require intensive care. Conversely, the non-PIMS-TS 27 (52%) children had a primary neurological disorder such as prolonged seizures, encephalitis (brain inflammation), Guillain-Barré syndrome and psychosis. In almost half of these cases, this was a recognised post-infectious neuro-immune disorder, compared to just one child in the PIMS-TS group, suggesting that different immune mechanisms are at work.

Short-term outcomes were apparently good in two thirds (65%) although a third (33%) had some degree of disability and one child died at the time of follow-up. However, the impacts on the developing brain and longer-term consequences are not yet known.

First author Dr Stephen Ray, a Wellcome Trust clinical fellow and paediatrician at the University of Liverpool said: "The risk of a child being admitted to hospital due to COVID-19 is small, but among those hospitalised, brain and nerve complications occur in almost 4%. Our nationwide study confirms that children with the novel post-infection hyper-inflammatory syndrome PIMS-TS can have brain and nerve problems; but we have also identified a wide spectrum of neurological disorders in children due to COVID-19 who didn't have PIMS-TS. These were often due to the child's immune response after COVID-19 infection."

Joint senior-author Dr Rachel Kneen, a Consultant Paediatric Neurologist at Alder Hey Children's NHS Foundation Trust and honorary clinical Senior Lecturer at the University of Liverpool said: "Many of the children identified were very unwell. Whilst they had a low risk of death, half needed intensive care support and a third had neurological disability identified. Many were given complex medication and treatments, often aimed at controlling their own immune system. We need to follow these children up to understand the impact in the long term."

Joint senior-author Dr Benedict Michael, a senior clinician scientist and MRC Fellow at the University of Liverpool said: "Now we appreciate the capacity for COVID-19 to cause a wide range of brain complications in those children who are hospitalised with this disease, with the potential to cause life-long disability, we desperately need research to understand the immune mechanisms which drive this. Most importantly- How do we identify those children at risk and how should we treat them to prevent lasting brain injury? We are so pleased that the UK government has funded our COVID-CNS study to understand exactly these questions so that we can help inform doctors to better recognise and treat these children."

A scientific review has found evidence that a disruption in blood clotting and the first line immune system could be contributing factors in the development of psychosis.

The article, a joint collaborative effort by researchers at RCSI University of Medicine and Health Sciences, Cardiff University and the UCD Conway Institute, is published in Molecular Psychiatry.

Recent studies have identified blood proteins involved in the innate immune system and blood clotting networks as key players implicated in psychosis.

The researchers analysed these studies and developed a new theory that proposes the imbalance of both of these systems leads to inflammation, which in turn contributes to the development of psychosis.

The work proposes that alterations in immune defense mechanisms - including blood clotting - lead to an increased risk of inflammation, which is thought to contribute to the development of psychosis.

The new theory further refines the prevailing 'two-hit' hypothesis, where early genetic and/or environmental factors disrupt the developing central nervous system (the "first-hit") and increases the vulnerability of the individual to subsequent, late environmental disruptions (the "second-hit").

"Early identification and treatment significantly improves clinical outcomes of psychotic disorders. Our theory may provide a further step to biomarkers of psychosis and allow the identification of therapeutic targets for early and more effective treatment," said Dr Melanie Föcking, joint first author on the paper and Lecturer in Psychiatric Neuroscience at RCSI Department of Psychiatry.

"While the idea of psychosis resulting from some form of inflammation and immune activation is not new, our data suggest a new understanding and change of focus towards a combined function of the innate immune complement system and coagulation pathways to the progression to psychotic disorder," said Dr Meike Heurich, joint first author on the paper and lecturer at School of Pharmacy and Pharmaceutical Sciences, Cardiff University.

"The works builds on our recent studies which increasingly implicate dysregulation of the complement and coagulation pathways both in and preceding psychotic disorder," said Professor David Cotter, senior author of the paper and Professor of Molecular Psychiatry at RCSI Department of Psychiatry.

Tokyo, Japan - Primary immunodeficiencies, such as severe combined immunodeficiency disease (SCID), occur when the immune system does not work properly, leading to increased susceptibility to various infections, autoimmunity, and cancers. Most of these are inherited and have an underlying genetic causes. A team at TMDU has identified a novel disorder resulting from a mutation in a protein called AIOLOS, which functions through a previously unknown pathogenic mechanism called heterodimeric interference.

The gene family known as IKAROS zinc finger proteins (IKZFs) is associated with the development of lymphocyte, a type of white blood cell involved in the immune response--meaning that mutations in this family can be involved in immune system deficiencies. Most research so far has focused on IKAROS protein, encoded by the gene IKZF1, although the underlying mechanism by which IKAROS mutations cause the deficiencies is not yet fully understood. A mutation in AIOLOS--another member of the IKZF family that is encoded by the gene IKZF3--has now also been revealed to cause a hereditary immune deficiency. In addition to not functioning properly itself, the resultant mutant protein interferes with the functioning of IKAROS protein.

TMDU researchers uncovered this new mechanism while investigating the cause of a previously undescribed inherited B cell deficiency observed in a family of patients. After sequencing all of the protein-coding genes, the team focused their research on AIOLOS as IKAROS is known to be the cause of B cell deficiency. They showed that the mutant form of AIOLOS that was present in this family did not just fail to function, but actively bound to a different DNA sequence than the normal version of the protein.

They went on to use a mouse model that harbors equivalent AIOLOS mutation identified in the patients to outline the underlying pathogenic mechanism. AIOLOS and IKAROS bind together to form a "heterodimer". The mutant form of AIOLOS retained the ability to bind IKAROS but then interfered with the normal function of IKAROS, and led to the heterodimer being recruited to the incorrect regions of the genome.

"This is a novel pathogenic mechanism that we termed heterodimeric interference," says lead author Motoi Yamashita, "where a mutant protein in a heterodimer hijacks the function of the normal partner protein."

The team were then able to rescue some of the immune function in the mouse model by deleting the dimerization domain of the mutant AIOLOS.

"The fact we could rescue the phenotype in our mouse model indicates a potential therapeutic approach," says Tomohiro Morio, senior author. "The deletion of the domain responsible for binding IKAROS in the mutant AIOLOS protein could ameliorate the immunodeficiency observed in the patients."

The discovery of this new pathogenic mechanism, heterodimeric interference, may well help to shed light on many other disease processes such as autoimmunity and cancer development where mutant proteins act in the same way.

URBANA, Ill. - U.S. corn and soybean varieties have become increasingly heat and drought resistant as agricultural production adapts to a changing climate. But the focus on developing crops for extreme conditions has negatively affected performance under normal weather patterns, a University of Illinois study shows.

"Since the 1950s, advances in breeding and management practices have made corn and soybean more resilient to extreme heat and drought. However, there is a cost for it. Crop productivity with respect to the normal temperature and precipitation is getting lower," says Chengzheng Yu, doctoral student in the Department of Agricultural and Consumer Economics (ACE) at the University of Illinois and lead author on the new paper, published in Scientific Reports.

Climate projections indicate a mix of extreme and normal weather patterns in the next 50 years, so crops must perform well under a variety of conditions, explains study co-author Madhu Khanna, ACES distinguished professor of environmental economics in ACE.

"It is not enough to just focus on extreme weather conditions. We can't look at the impacts of climate change in a piecemeal fashion and develop varieties only to cope with certain aspects of it," Khanna states.

Yu, Khanna, and co-author Ruiqing Miao, Auburn University, studied corn and soybean yield from 1951 to 2017 in the eastern part of the U.S., an area where crops can grow without irrigation. Crop yield increased significantly during this period due to a wide range of technological and breeding improvements. But when the researchers isolated the effect of climate-related adaptations, they found significant negative impacts on yield.

While heat and drought tolerance increased yield by 33% for corn and 20% for soybean over this period, the gain was offset by reduced productivity under normal conditions. Overall, maladaptation due to climate-related factors reduced corn and soybean yield by 8% and 67%, respectively, the researchers found.

"There's been this trade-off; crops become better adapted to extreme weather, but less adapted to normal conditions," Khanna says. "Overall, crop yields went up by 100% to 200% over the past decades. We break this down into the components that happened because of climate-related changes, and components that happened irrespective of climate change. And we find the impact of climate-related adaptation has been negative," she explains.

The researchers also projected net effects of climate change adaptation on crop yields by 2050 under a range of warming scenarios. In the most extreme scenarios, weather-adapted variations will perform better. But under less extreme scenarios varieties that perform well in normal climate would be more productive.

Khanna and Yu conclude that crop breeders should focus on developing crop varieties for diverse weather patterns. Flexibility is important for agricultural producers to be well prepared for future conditions.

"There will be a very significant reduction in crop yield for both corn and soybean over the next 50 years under some extreme warming scenarios, even though the crops are supposedly adapted to extreme conditions. There's overall maladaptation, because the crops are not fully adapted to every possible combination of extreme and normal conditions. And the overall impact is going to be very negative," Khanna says. "We need to drastically change how we're adapting our crops so that they're better prepared for the mix of conditions we are likely to encounter in the following years."

New research led by the University of Cambridge suggests that autism can be detected at 18-30 months using the Quantitative Checklist for Autism in Toddlers (Q-CHAT), but it is not possible to identify every child at a young age who will later be diagnosed as autistic. The results are published today in The BMJ Paediatrics Open.

The team at the Autism Research Centre in Cambridge conducted a prospective population screening study of nearly 4,000 toddlers using a parent-report instrument they developed, called the Quantitative Checklist for Autism in Toddlers (Q-CHAT). Toddlers were screened at 18 months and followed up at 4 years.

The Q-CHAT is a revision of the original CHAT first published by the same authors in the 1990s. It retains the key items but includes additional items that examine language development, repetitive and sensory behaviours, as well as other aspects of social communication behaviour. Each of the 25 items contains a range of response options, allowing for the endorsement of a reduced rate of key behaviours. In effect, this 'dimensionalises' each item (using a five-point scale of frequency), allowing for variability in responses and a better understanding of the distributions across the specific traits. The revision was motivated by trying to improve on the accuracy of screening toddlers for autism.

In the new research, in phase one, 13,070 caregivers were invited to complete the Q-CHAT about their child at 18-30 months. 3,770 caregivers returned the Q-CHAT, of whom 121 were invited for an autism diagnostic assessment.

In phase two, the sample was followed up when the children were 4, using the Childhood Autism Screening Test (CAST), and a checklist enquiring whether any of the children had been referred or diagnosed with any developmental conditions, including autism. Autism assessments were made using internationally recognized methods.

The sensitivity (the proportion of autistic children correctly identified by the Q-CHAT as being autistic) of the Q-CHAT in predicting autism at phase two is 44%, and the specificity (the proportion of children who are not autistic and who are correctly identified by the Q-CHAT as not being autistic) is 98%. Results also showed that the 'positive predictive value' (the proportion whose screened positive on the Q-CHAT who were found to be autistic) is 28%.

This study demonstrates that early detection and diagnosis of autism is possible using the Q-CHAT, since all 11 children who were classified as autistic scored at or above the cut-point of 39. The Q-CHAT did not identify all children during toddlerhood who were later diagnosed with autism at age 4. This likely reflects that some autistic children do not show symptoms of sufficient severity until later in childhood.

In other studies the team have found some autistic people do not receive a diagnosis until their teens or even adulthood, perhaps because family support cushions the need for a diagnosis until social demands increase, for example at transition to secondary school or transition to adulthood.

Dr Carrie Allison, Director of Research Strategy at the Autism Research Centre, and who led the study, said: "This study tells us that autism can be detected during the toddler years, and that other children may only be identified as autistic later. Repeat screening and surveillance across development may be a better approach rather than relying on a single time-point."

Professor Tony Charman, Professor of Clinical Child Psychology at Kings College London, and a member of the team, said: "Screening for autism in infancy means that children can be fast-tracked into early intervention, which we know can lead to better outcomes for many children. This is an exciting advance because most other autism screening measures in toddlers have not been subject to rigorous population studies of this kind."

Professor Sir Simon Baron-Cohen, Director of the Autism Research Centre and a member of the team, said: "25 years ago our team was the first to show autism could be screened and diagnosed as young as 18 months of age. This new study shows how our original screening instrument - the CHAT - has been revised into a better instrument - the Q-CHAT, which can pick up children who need an autism diagnosis. Early detection means happier, healthier, children and families because they can be targeted with support."

Northwestern University engineers have developed the first full, three-dimensional (3D), dynamic simulation of a rat's complete whisker system, offering rare, realistic insight into how rats obtain tactile information.

Called WHISKiT, the new model incorporates 60 individual whiskers, which are each anatomically, spatially and geometrically correct. The technology could help researchers predict how whiskers activate different sensory cells to influence which signals are sent to the brain as well as provide new insights into the mysterious nature of human touch.

The research was published last week in the Proceedings of the National Academy of Sciences.

With just a brush of their whiskers, rats can extract detailed information from their environments, including an object's distance, orientation, shape and texture. This keen ability makes the rat's sensory system ideal for studying the relationship between mechanics (the moving whisker) and sensory input (touch signals sent to the brain).

But while the rat whisker system is a widely used simplified model system in sensory neuroscience, it's challenging to study an animal's nervous system as it moves to interact with its natural environment.

"We cannot measure the signals at the base of a real rat's whisker using current technology because, as soon as you embed a sensor, it interferes with the signals themselves," said Northwestern's Mitra Hartmann, the study's senior author. "The only way we can really capture a rat actively sensing its environment under natural conditions is to simulate it."

With potential to overcome these challenges, simulations have become an increasingly important component of neuroscience. By developing WHISKiT, the study authors now have the first complete model of tactile input to a moving sensory system, which shows how rats actively "whisk" and passively sense their complex 3D environments.

"Because none of the individual whiskers works in isolation, WHISKiT is crucial to understanding how the brain processes incoming tactile sensory information," said Nadina Zweifel, the paper's first author. "It's equivalent to a tactile 'camera' that can capture the mechanical signals an animal may acquire while using the whiskers to interact with the environment. That way, we believe that our tool considerably widens the range of possibilities for computational and experimental studies in the future."

Hartmann is a professor of biomedical and mechanical engineering at Northwestern's McCormick School of Engineering, where she is a member of the Center for Robotics and Biosystems and the Northwestern University Interdepartmental Neuroscience program. Zweifel is a Ph.D. candidate in Hartmann's laboratory.

To develop the new WHISKiT model, the Northwestern team combined more than a decade's worth of experimental data from Hartmann's lab. Because every whisker is slightly different, her group previously calculated the proper geometry (including arc, base diameter and slope) for individual whiskers. After validating models for individual whiskers, the researchers combined the whiskers into a full array.

The resulting model considers the geometry, spatial arrangement and movement of all 60 whiskers (30 on each side) on a rat's face. Each whisker is embedded in a follicle, where the mechanical signals are generated at the base.

WHISKiT also incorporates new data collected from 3D scans that Zweifel captured of rats' natural environments, including in urban alleys, around dumpsters and at drain pipes, across the cities of Chicago and Evanston. The model simulates rats in these natural environments ("whisking" around a drain pipe, for example) as well as in laboratory settings. The researchers found that each typical, exploratory scenario generates a unique pattern of data.

"The tactile signals associated with exploring a complicated drain pipe or dumpster are very different from those associated with exploring a blank wall," Hartmann explained.

The researchers next plan to use the simulation to address several long-standing questions, including how rats can use touch to distinguish between stationary and moving objects and how active whisking compares to passive sensing.

Bat conversations might be light on substance, according to researchers from the University of Cincinnati.

Echoes from bats are so simple that a sound file of their calls can be compressed 90% without losing much information, according to a study published in the journal PLOS Computational Biology.

The study demonstrates how bats have evolved to rely on redundancy in their navigational "language" to help them stay oriented in their complex three-dimensional world.

"If you can make decisions with little information, everything becomes simpler. That's nice because you don't need a lot of complex neural machinery to process and store that information," study co-author Dieter Vanderelst said.

UC researchers suspected that the calls of bats contain redundant information and that bats might use efficient encoding strategies to extract the most relevant information from their echoes. Many natural stimuli encountered by animals have a lot of redundancy. Efficient neural encoding retains essential information while reducing this redundancy.

To test their hypothesis, they built their own "bat on a stick," a tripod-mounted device that emits a pulse of sound sweeping from 30 to 70 kilohertz, a frequency range used by many bats. By comparison, human speech typically ranges from 125 to 300 hertz (or 0.125 to 0.3 kHz).

More than 1,000 echoes were captured in distinct indoor and outdoor environments such as in a barn, in different-sized rooms, among bushes and tree branches and in a garden.

Researchers converted the recorded echoes to a graph of the sound, called a cochleogram. Then they subjected these graphs to 25 filters -- essentially compressing the data. They trained a neural network, a computer system modeled on the human brain, to determine if the filtered graphs still contained enough information to complete a number of sonar-based tasks known to be performed by bats.

They found that the neural network correctly identified the location of the echoes even when the cochleogram was stripped of as much as 90% of its data.

"What that tells us is you can compress that data and still do what you need to do. It also means if you're a bat, you can do this efficiently," said Vanderelst, an assistant professor in UC's College of Arts and Sciences and in the College of Engineering and Applied Science.

Vanderelst said researchers often can infer what bats are doing just by listening to their calls.

"Even if you don't see the bat, you can tell with a high degree of certainty what a bat is doing," he said. "If it calls more frequently, it's looking for something. If the calls are spread out, it's cruising or studying something far away."

Bats produce their ultrasonic calls with a larynx much like ours. But what a voice box. It can contract 200 times a second, making it the fastest known muscle in all mammals.

The nighttime forest can be deafening to people because of its chorus of frogs and drone of insects. But Vanderelst said the ultrasonic frequency by comparison is pretty quiet, allowing bats to hear their own chittering calls that bounce off tree branches and other obstacles during echolocation.

While bats use different chirps for navigating than for communicating with each other, Vanderelst said they're all pretty simple. But human language has lots of built-in redundancy as well, Vanderelst said.

Fr xmpl, cn y rd ths sntnc wth mssng vwls?

"Take out a lot of letters in a sentence and it's still readable," Vanderelst said.

UC graduate Adarsh Chitradurga Achutha, Vanderelst's student, was the study's lead author. Co-authors include Vanderelst's mentor Herbert Peremans at the University of Antwerp, Belgium, and bat expert Uwe Firzlaff with the University of Munich, Germany.

The way bats perceive the world is fascinating both from biological and engineering perspectives, Vanderelst said.

"It's like a riddle, looking at something that shouldn't be able to do what it does. So the question is how?" he said. "It's given me an appreciation for the elegant efficiency underlying this system."

Researchers at Vanderbilt University Medical Center (VUMC) and the Baylor College of Medicine in Houston, Texas, have taken a big step toward developing targeted treatments and vaccines against a family of viruses that attacks the gastrointestinal tract.

Each year in the United States circulating strains of the human norovirus are responsible for approximately 20 million cases of acute gastroenteritis. Hallmark symptoms include severe abdominal cramping, diarrhea and vomiting.

Several vaccine candidates are in clinical trials, but it is unclear how effective they will be, given the periodic emergence of novel norovirus variants. Developing broadly effective vaccines will require an understanding of the genetic diversity of the virus and the mechanisms by which the immune system can neutralize it.

Reporting this week in the journal Nature Communications, the researchers isolated a panel of human monoclonal antibodies from subjects with a history of acute gastroenteritis that are cross-reactive and which neutralize a broad range of norovirus variants in laboratory tests.

They describe a conserved, antigenic site on the norovirus that could be used to reformulate vaccine candidates so that they are broadly effective against circulating viral strains. The monoclonal antibodies also could be used to treat or prevent norovirus infection directly or as diagnostic reagents, they added.

Leading the research were the paper's corresponding authors, James Crowe Jr., MD, director of the Vanderbilt Vaccine Center, and B.V. Venkataram Prasad, PhD, the Alvin Romansky Chair in Biochemistry, in collaboration with Mary Estes, PhD, the Cullen Chair and professor of virology at Baylor College of Medicine.

First authors of the paper were Gabriela Alvarado, PhD, formerly of the Crowe lab, now at the National Institute of Allergy and Infectious Diseases, and Wilhelm Salmen, a graduate student in the Prasad lab.

"We were surprised to find naturally occurring antibodies that recognized so many different noroviruses," said Crowe, the Ann Scott Carell Chair and professor of Pediatrics and Pathology, Microbiology & Immunology at VUMC.

"Previously, many experts thought that this would not be possible because of the extreme sequence diversity in the various groups and types of noroviruses in circulation," he said. "The human immune system continues to surprise us in its capacity to recognize diverse virus variants."

"One of the fascinating aspects of this study was the unexpected finding of where the human antibody attacks the virus for neutralization," Prasad said.

"It is exciting to now have human monoclonal antibodies that neutralize many norovirus variants," added Estes.

WHAT:

A new study published in Nature Communications suggests that gene therapy delivered into the brain may be safe and effective in treating aromatic L-amino acid decarboxylase (AADC) deficiency. AADC deficiency is a rare neurological disorder that develops in infancy and leads to near absent levels of certain brain chemicals, serotonin and dopamine, that are critical for movement, behavior, and sleep. Children with the disorder have severe developmental, mood dysfunction including irritability, and motor disabilities including problems with talking and walking as well as sleep disturbances. Worldwide there have been approximately 135 cases of this disease reported.

In the study, led by Krystof Bankiewicz, M.D., Ph.D., professor of neurological surgery at Ohio State College of Medicine in Columbus, and his colleagues, seven children received infusions of the DDC gene that was packaged in an adenovirus for delivery into brain cells. The DDC gene is incorporated into the cells' DNA and provides instructions for the cell to make AADC, the enzyme that is necessary to produce serotonin and dopamine. The research team used magnetic resonance imaging to guide the accurate placement of the gene therapy into two specific areas of the midbrain.

Positron emission tomography (PET) scans performed three and 24 months after the surgery revealed that the gene therapy led to the production of dopamine in the deep brain structures involved in motor control. In addition, levels of a dopamine metabolite significantly increased in the spinal fluid.

The therapy resulted in clinical improvement of symptoms. Oculogyric crises, abnormal upward movements of the eyeballs, often with involuntary movements of the head, neck and body, that can last for hours and are a hallmark of the disease, completely went away in 6 of 7 participants. In some of the children, improvement was seen as early as nine days after treatment. One participant continued to experience oculogyric crises, but they were less frequent and severe.

All of the children exhibited improvements in movement and motor function. Following the surgery, parents of a majority of participants reported their children were sleeping better and mood disturbances, including irritability, had improved. Progress was also observed in feeding behavior, the ability to sit independently, and in speaking. Two of the children were able to walk with support within 18 months after receiving the gene therapy.

The gene therapy was well tolerated by all participants and no adverse side effects were reported. At three to four weeks following surgery, all participants exhibited irritability, sleep problems, and involuntary movements, but those effects were temporary. One of the children died unexpectedly seven months after the surgery. The cause of death was unknown but assessed to be due to the underlying primary disease.

As the Covid-19 pandemic raged, news reports show that sales of electronic air cleaners have surged due to concerns about airborne disease transmission. But a research team at the Georgia Institute of Technology has found that the benefits to indoor air quality of one type of purifying system can be offset by the generation of other pollutants that are harmful to health.

Led by Associate Professor Nga Lee "Sally" Ng in Georgia Tech's School of Chemical and Biomolecular Engineering and the School of Earth and Atmospheric Sciences, the team evaluated the effect of a hydroxyl radical generator in an office setting. Hydroxyl radicals react with odors and pollutants, decomposing them, and hydroxyl radical generators have been marketed to inactivate pathogens such as coronaviruses.

However, Ng's study found that in the process of cleaning the air, the hydroxyl radicals generated by the device reacted with volatile organic compounds present in the indoor space. This led to chemical reactions that quickly formed organic acids and secondary organic aerosols that can cause health problems. Secondary organic aerosols is a major component of PM2.5 (particulate matter with a diameter smaller than 2.5 ?m), and exposure to PM2.5 has been associated with cardiopulmonary diseases and millions of deaths per year.

The paper, "Formation of oxidized gases and secondary organic aerosol from a commercial oxidant-generating electronic air cleaner," is published in the journal Environmental Science and Technology Letters.

While the pandemic has made various types of electronic cleaners increasingly popular, Ng explained that consumers are probably not aware of the secondary chemistry taking place in the air, with the pollutants generated not being directly emitted by the cleaning device itself.

"There are increasing concerns regarding the use of electronic air cleaners as these devices can potentially generate unintended byproducts via oxidation chemistry similar to that in the atmosphere," Ng said.

Two types of air cleaning technologies are commonly used to remove indoor pollutants such as particles or volatile organic compounds and to inactivate pathogens: mechanical filtration and electronic air cleaners that generate ions, reactive species, or other chemical products such as photocatalytic oxidation, plasma, and oxidant-generating equipment (e.g., ozone, hydroxyl radical), among others.

Ng's team selected a hydroxyl generator for the study. They measured the oxygenated volatile organic compounds and the chemical composition of particles generated by the device in an office on the Georgia Tech campus.

While previous research reported pollutant formation from various electronic air cleaners (ionizers, plasma systems, photocatalytic systems with ultraviolet lamps, etc.), Ng believes that her team's study is the first to monitor the chemical composition of secondary pollutants in both gas and particle phases during the operation of an electronic device that dissipates oxidants in a real-world setting.

Advanced instrumentation made Ng's study possible. Gas-phase organic compounds were measured using a high-resolution time-of-flight chemical ionization mass spectrometer, purchased through a National Science Foundation major instrumentation grant. The study received support from Georgia Tech's Covid-19 Rapid Response fund.

Ng noted that future studies on air cleaning technology should not be limited to inactivation of viruses or reduction of volatile organic compounds, but should also evaluate potential oxidation chemistry and the formation of unintended harmful gaseous and particulate chemicals.

"More studies need to be conducted on the effects of these devices in a variety of environments," Ng said.

"Electronic air cleaners greatly rose in prominence because of the pandemic, and now there are a lot of these devices out there. Millions of dollars are being spent on these devices by businesses and schools. The market is huge.

"Our results show that care must be taken when choosing an adequate and appropriate air cleaning technology for a particular environment and task," she said.

Ng stressed the importance of future studies concerning the unintended effects of electronic purifiers, as these devices are not currently well regulated and do not have testing standards.

"There needs to be more peer-reviewed scientific data on electronic air cleaners," Ng said. "We hope that additional studies will lead to more government guidelines and regulation."

A team of researchers from the University of Maryland has 3D printed a soft robotic hand that is agile enough to play Nintendo's Super Mario Bros. - and win!

The feat, highlighted on the front cover of the latest issue of Science Advances, demonstrates a promising innovation in the field of soft robotics, which centers on creating new types of flexible, inflatable robots that are powered using water or air rather than electricity. The inherent safety and adaptability of soft robots has sparked interest in their use for applications like prosthetics and biomedical devices. Unfortunately, controlling the fluids that make these soft robots bend and move has been especially difficult - until now.

The key breakthrough by the team, led by University of Maryland assistant professor of mechanical engineering Ryan D. Sochol, was the ability to 3D print fully assembled soft robots with integrated fluidic circuits in a single step.

"Previously, each finger of a soft robotic hand would typically need its own control line, which can limit portability and usefulness," explains co-first author Joshua Hubbard, who performed the research during his time as an undergraduate researcher in Sochol's Bioinspired Advanced Manufacturing (BAM) Laboratory at UMD. "But by 3D printing the soft robotic hand with our integrated fluidic transistors, it can play Nintendo based on just one pressure input."

As a demonstration, the team designed an integrated fluidic circuit that allowed the hand to operate in response to the strength of a single control pressure. For example, applying a low pressure caused only the first finger to press the Nintendo controller to make Mario walk, while a high pressure led to Mario jumping. Guided by a set program that autonomously switched between off, low, medium, and high pressures, the robotic hand was able to press the buttons on the controller to successfully complete the first level of Super Mario Bros. in less than 90 seconds.

"Recently, several groups have tried to harness fluidic circuits to enhance the autonomy of soft robots," said recent Ph.D. graduate and co-first author of the study Ruben Acevedo, "but the methods for building and integrating those fluidic circuits with the robots can take days to weeks, with a high degree of manual labor and technical skill."

To overcome these barriers, the team turned to "PolyJet 3D Printing," which is like using a color printer, but with many layers of multi-material 'inks' stacked on top of one another in 3D.

"Within the span of one day and with minor labor, researchers can now go from pressing start on a 3D printer to having complete soft robots - including all of the soft actuators, fluidic circuit elements, and body features - ready to use," said study co-author Kristen Edwards.

The choice to validate their strategy by beating the first level of Super Mario Bros. in real time was motivated by science just as much as it was by fun. Because the video game's timing and level make-up are established, and just a single mistake can lead to an immediate game over, playing Mario provided a new means for evaluating soft robot performance that is uniquely challenging in a manner not typically tackled in the field.

In addition to the Nintendo-playing robotic hand, Sochol's team also reported terrapin turtle-inspired soft robots in their paper. The terrapin happens to be UMD's official mascot, and all of the team's soft robots were printed at UMD's Terrapin Works 3D Printing Hub.

Another important benefit of the team's strategy is that it's open source, with the paper open access for anyone to read as well as a link in the supplementary materials to a GitHub with all of the electronic design files from their work.

"We are freely sharing all of our design files so that anyone can readily download, modify on demand, and 3D print - whether with their own printer or through a printing service like us - all of the soft robots and fluidic circuit elements from our work," said Sochol. "It is our hope that this open-source 3D printing strategy will broaden accessibility, dissemination, reproducibility, and adoption of soft robots with integrated fluidic circuits and, in turn, accelerate advancement in the field."

At present, the team is exploring the use of their technique for biomedical applications including rehabilitation devices, surgical tools, and customizable prosthetics. As Sochol is a faculty affiliate of the Fischell Department of Bioengineering as well as a member of both the Maryland Robotics Center and the Robert E. Fischell Institute for Biomedical Devices, the team has an exceptional environment to continue advancing their strategy to address pressing challenges in biomedical fields.