Italy: MOH Statement on First LPAI H9N2 Human Case in Europe (imported)

 
#19,096

With a hat tip to Pathfinder on FluTrackers who posted a media story, I've tracked down the Italian MOH's statement on what appears to be the first H9N2 human infection to be reported in Europe.

Details are vague, but this appears to have been someone who recently arrived from a `non-European' country where they were likely exposed. 

At least one media report identifies the patient as a 'a boy who returned from Africa and was hospitalised a few days after his arrival at Milan Malpensa', although I have yet to find official confirmation.

First the MOH's statement, after which I'll have a bit more. 

(Translated)

Influenza A (H9N2) virus case identified in Lombardy. Routine surveillance and prevention procedures activated.

Press release number 8
Press release date March 25, 2026

The Ministry of Health informs that the Lombardy Region has identified a case of infection with the low-pathogenicity avian influenza A(H9N2) virus of animal origin, in a frail person with concomitant illnesses, who came from a non-European country where he contracted the infection, and is currently hospitalized.

This is the first human case of H9N2 avian influenza detected in Europe. Based on the scientific information available to date, infection occurs through direct exposure to infected poultry or contaminated environments or materials. Human cases are characterized by mild illness, and human-to-human transmission has never been reported.

All the required checks were promptly carried out and the relevant contacts were identified, as part of the ordinary prevention and surveillance activities.

The Ministry of Health immediately activated coordination with the Lombardy Region, the Istituto Superiore di Sanità, and the national reference laboratory expert group, and ensured the coordination and updating of the relevant international bodies.

Currently, no critical issues have been identified and the situation is being constantly monitored.

While 90% of the human H9N2 cases reported have come from China, we've seen sporadic cases in places like Cambodia, Vietnam, and India. We've also seen a handful of cases in Africa (4 in Egypt, 1 in Senegal, and the most recent in Ghana).

The Asian Y280/G57 lineages have shown increasing signs of mammalian adaptation (see EM&I: Enhanced Replication of a Contemporary Avian Influenza A H9N2 Virus in Human Respiratory Organoids)), while the African and Middle Eastern Lineages (mostly European G1-like) are older and less evolved.

Worth noting, LPAI H9N2 has also been detected in African bats (see Preprint: The Bat-borne Influenza A Virus H9N2 Exhibits a Set of Unexpected Pre-pandemic Features).

Given their relatively scarcity outside of Asia, WGS (Whole Gene Sequencing) and antigenic characterization of this latest case will be of considerable interest.

Nature Comms: Post-pandemic Changes in Population Immunity Have Reduced the Likelihood of Emergence of Zoonotic Coronaviruses

Photo Credit NIAID

#19,095

One of the key questions in our post-pandemic world is how much immunity have we gained against other emerging coronaviruses due to our continual exposure to  SARS-CoV-2 and/or COVID vaccines over the past 6 years?

It is not an easy question to answer for a lot of reasons, including:

• First and foremost, COVID is a sarbecovirus, which is just one type of coronavirus. MERS-CoV is another (Merbecovirus), which uses an entirely different receptor cell, making cross-immunity unlikely. 

• Second, even among sarbecoviruses there are at least 4 lineages (clade 1a, 1b, 2, & 3); SARS-CoV was clade 1a, while SARS-CoV-2 was clade 1b. Clades 2 & 3 are more antigenically distant.

• Third, COVID immunity wanes relatively quickly.  While re-exposures or vaccinations can `boost' immunity, variant drift and/or declining vaccine uptake could erode immunity. 

In other words, there are a lot of moving parts.  But in a world teeming with literally dozens of known coronaviruses circulating in the wild (see here, here, here, and here), any cross-immunity is better than none. 

All of which brings us to a new study, published in Nature Comms, where researchers tested cross‑neutralisation of four zoonotic sarbecovirus spikes using human sera from naïve, infected, vaccinated, and hybrid immunity groups.

All four test viruses (SARS‑CoV, Rs4084, GX/P1E, RaTG13) belonged to either clade 1a or 1b, had relatively high spike similarity to SARS-CoV-2, and known ACE2 usage.  Of the 4 tested, the 2002 SARS-CoV showed the least cross-neutralization (30%), while RaTG13 showed the most (79%).

Whether, and how much, cross immunity would extend to more antigenically distant - or non-ACE binding - coronaviruses is unknown. 

What they found was cross‑neutralisation increases with number of vaccine doses and is highest in hybrid immunity (hx of infection & vaccination).  They write:

The highest levels of cross-neutralisation were consistently observed in patients with hybrid immunity, suggesting that vaccine breakdown infections by immune evasive SARS-CoV-2 variants may have a strong protective effect against SARS-CoV-X infection, and that vaccination should be encouraged even in patients with a history of prior infection. In unvaccinated individuals with a history of infection, the strength of cross-neutralisation was lower than in patients with hybrid immunity and was determined by the SARS-CoV-2 infecting strain.

This is consistent with findings that protection conferred by natural infection varies over time and is influenced by the antigenic evolution of SARS-CoV-2, with pre-Omicron infections offering durable immunity, and immunity following Omicron infection waning more rapidly, likely due to increased immune escape38. 

Using this data, the researchers then modeled how COVID and a hypothetical new “SARS‑CoV‑X” might spread in a population like Scotland’s, and determined that our current global immunity makes it more difficult for a SARS-like (ACE-receptor-using) virus to establish itself compared to a naïve community.

Not impossible, but apparently it provides a non-trivial barrier. 

This is a detailed, complex, and nuanced study and deserves to be read in its entirety, as I've only scratched the surface. I'll have a bit more after the break.

Post-pandemic changes in population immunity have reduced the likelihood of emergence of zoonotic coronaviruses

Ryan M. Imrie, Laura A. Bissett, Savitha Raveendran, Maria Manali, Julien A. R. Amat, Laura Mojsiejczuk, Nicola Logan, Andrew Park, Marc Baguelin, Mafalda Viana, Brian J. Willett & Pablo R. Murcia 

Nature Communications volume 17, Article number: 2248 (2026) Cite this article

Abstract

Infections by endemic viruses, and the vaccines used to control them, often provide cross-protection against related viruses, potentially altering the transmission dynamics and likelihood of emergence of new zoonotic viruses with pandemic potential. Here, we investigate how population immunity after the COVID-19 pandemic has impacted the likelihood of emergence of a novel sarbecovirus, termed SARS-CoV-X. 

To this end, we combined empirical cross-neutralisation data with mathematical modelling to identify key immunological and epidemiological factors shaping sarbecovirus emergence. We show that sera from individuals with different COVID-19 immunological histories contained cross-neutralising antibodies against the spike (S) protein of multiple zoonotic sarbecoviruses. 

Simulations parameterised by these data predict that the likelihood of emergence of a novel sarbecovirus has been reduced significantly by population cross-immunity, with outcomes determined by the extent of cross-protection and R0 of the novel virus.

Preventative vaccination against SARS-CoV-X using available COVID-19 vaccines can help resist emergence even in the presence of co-circulating SARS-CoV-2. However, a theoretical vaccine with high specificity to SARS-CoV-2 can increase emergence probability by suppressing SARS-CoV-2 prevalence and, by extension, levels of natural cross-protection. 

Overall, SARS-CoV-2 circulation and vaccination have generated widespread immunity against related sarbecoviruses, creating an immunological barrier to novel sarbecovirus emergence in humans.

(Continue . . . ) 

While these findings appear to do little to negate the threat from MERS-CoV (see (Referral) Nature: Human MERS-CoV cases are falling but pose an ongoing pandemic threat), it does suggest that we likely now carry some degree of protection against a narrow - but important - range of sarbecoviruses.

While not exactly a get-out-of-pandemic-free card - when it comes to emerging viruses - any amount of immunity has to beat no immunity at all. 

Preprint: Mapping global emergence of pathogens with epidemic and pandemic potential . . .

 

#19,094

We've a preprint today from the WHO and international partners which attempts to map the global emergence of pathogens with epidemic and pandemic potential.

This is an ambitious project, and in its first iteration is limited to 17 priority pathogens drawn heavily from the 2017-2018 WHO List Of Blueprint Priority Diseases and 2024's Pathogens Prioritization Report.

As a result, disease threats from some regions of the world (e.g. Americas, Western Pacific, Europe) may be under represented. In this preprint, sub-Saharan Africa and South Asia are identified as high risk areas. 

When evidence was overlaid for multiple pathogens in a composite map, our results demonstrate that the greatest potential for emergence of the largest number of pathogens are in locations in sub-Saharan Africa. Our results provide evidence that some areas of South Sudan,for example, are at risk of exposure to emergence of all priority pathogens considered (Figure1). 

Large geographic areas in Western Africa, including Nigeria and Ghana, in Central and in Southern Africa (from Gabon and Cameroon, to the United Republic of Tanzania and Mozambique) similarly have areas with evidence to support emergence potential for the different pathogens evaluated, with important foci for Lassa virus (LASV), Yersinia pestis,monkeypox virus (MPXV), Rift Valley fever virus (RVF), Ebola virus (EBV), and Marburg virus(MARV) present among others.

Outside of Africa, in South Asia our results illustrate support for the emergence potential for the highest numbers of pathogens in Western India, specifically Gujarat and Rajasthan, in South-East Asia, in the Mekong Delta (Cambodia, Lao People’s Democratic Republic, and Viet Nam),Indonesia, and in southern China where there is evidence of emergence potential of a multitude of pathogens, including key foci for DENV, non specific Henipaviruses, CHIKV, and ZIKV.

 I've reproduced the abstract below. Follow the link to read the report in its entirety.  I'll have a bit more after the break.

Mapping global emergence of pathogens with epidemic and pandemic potential to inform and accelerate pandemic prevention, preparedness, readiness and response

David Pigott, Barbara A Han, Adrian A Castellanos, Huong T Chu, Erin N Frame, Narmada Venkateswaran, Oliver J Brady, Ahyoung J Lim, Diana P. Rojas, Sophie von Dobschuetz, Maria D. Van Kerkhove 

doi: https://doi.org/10.64898/2026.03.20.26347940 This article is a preprint and has not been certified by peer review

       PDF 

ABSTRACT

Introduction

Increasing occurrence of epidemics and pandemics and concurrent emergence of different pathogens calls for multi-sectoral, multi-pathogen preparedness actions. Data on various factors that drive emergence of diverse pathogens can inform evidence-based preparedness by identifying geographies at-risk. When leveraging evidence within a One Health approach,multiple pathogens can be addressed simultaneously, thereby strengthening countries’ pandemic preparedness efforts.

Methods

For seventeen priority pathogens (avian influenza viruses, zoonotic coronaviruses including COVID-19, hemorrhagic fever viruses including Ebola, Henipaviruses, and arboviruses including yellow fever and Zika), we identified global evidence on animal reservoirs, vectors,environmental suitability, and reported human cases. We discriminated geospatially recorded pathogen detections from a background sample and constructed maps using these datasets to generate an evidence-based assessment of emergence risk globally.

Results

Seventeen pathogen-specific assessments were combined into a global composite map. Sub-Saharan Africa and South Asia have evidence supporting emergence risk for the greatest number of pathogens (included areas at-risk of all pathogens) and scored highest when strength-of-evidence weightings were factored. The Americas had the lowest tally of considered pathogens. Environmental suitability analyses received the highest weights, reservoir ranges the lowest.

Discussion

Preparedness and readiness must consider the range of global biological threats. Our methodology is capable of incorporating changing evidence on emergence potential for multiple pathogens to identify geographies at higher risk with different pathogen combinations. Our mapscan contribute to existing decision-support structures, guiding shared interventions and strategic allocation of resources for spillover prevention and pandemic preparedness, thereby enhancing local response capacities applying a multidisciplinary approach.

(Continue . . . )

While this report doesn't provide an explicit ranking of pathogens `most likely to succeed' they do point out how widespread (geographically & across species) avian flu and SARS-CoV-2 have become globally.  

Geographic range of emergence risk for epidemic- and pandemic-prone pathogens 

When considering the risk for individual pathogens derived from the synthesis of all pathogen-specific inputs, SARS-CoV-2 and avian influenza virus were widespread in their geographic risk distributions as compared to other pathogens (Supplementary Appendix). Underpinning this broad risk profile is the number of unique species (44 and 303) that have been documented as having been infected by SARS-CoV-2 and HPAI strains, respectively.

Of course, we could be blindsided (again) by something that currently isn't even on our radar.  And yet - incredibly - we have severely degraded much of our global disease surveillance, investigative, and reporting systems (see Flying Blind In The Viral Storm).

While I can't predict which pathogen will spark the next pandemic, or when that might happen, one thing is all but certain:

That day will come again. And when it does, we'll rue every day we squandered not preparing for it. 

(Referral) Nature: Human MERS-CoV cases are falling but pose an ongoing pandemic threat

 

#19,093

Since the arrival of the COVID pandemic we've witnesses a sharp, and welcome, decline in the number of MERS-CoV cases reported from the Middle East. 

At first, it was thought this respite was due the the `fog' of the pandemic, and shifting surveillance priorities. 

While detection and reporting of cases has always been challenging (see EID Journal: Estimation of Severe MERS Cases in the Middle East, 2012–2016), this decline now seems legit; potentially caused by a combination of:

• Possible limited cross-protection due to COVID (infection and/or vaccination).

• Behavior changes (mask wearing, better hand hygiene, reduced camel contact, etc.) since COVID

• Improved infection control (again, likely driven by COVID) in healthcare facilities, which often accounted for large outbreaks previously.

Encouraging, but none of these changes are guaranteed to be permanent. Over time acquired immunity can wane, behaviors can change, and lapses in infection control can always resume. 

While the number of cases remains low, over the past 12 months we've seen several high-profile reports of spillovers, including France MOH: 2 Travelers Returning From Arabian Peninsula Diagnosed with MERS-CoV  and WHO: Saudi Arabia Reports 9 New MERS-CoV Cases.

Not surprisingly, over the past year we've also seen a resurgence in MERS-CoV-related studies, including:

The Lancet: The Threat of Another Coronavirus Pandemic

Health Sci Rpts (Narrative Review): Pathogenicity and Potential Role of MERS-CoV in the Emergence of “Disease X”

IJID Editorial: Al-Tawfiq on Global Epidemiology and Public Health Challenges of Middle East Respiratory Syndrome Coronavirus (MERS-CoV)

JEGH: Epidemiological Characteristics of MERS-CoV Human Cases, 2012- 2025

JEGH: Al-Tawfiq & Memish On Recurrent MERS-CoV Transmission in Saudi Arabia

All of which brings us to a WHO-authored commentary - published last week in Nature - which warns that the MERS-CoV continues to circulate in dromedary camels in the Middle East, that it appears to maintain its virulence, and it remains a plausible pandemic threat.

Since this is not an Open Access report released under the CC license, I've only posted the link below.  It is free to read, but you may have to set up an account. 

Nevertheless, it is well worth reading in its entirety.  I'll have a bit more after you return.

Comment
Published: 19 March 2026

Human MERS-CoV cases are falling but pose an ongoing pandemic threat

Lorenzo Subissi, James R. Otieno, Asma Abi Mohamed Shah, Laith Jamal Abu-Raddad, Anurag Agrawal, Amna Omair Al Mehairi, Ahmed Mohammed Albarraq,  Amal Barakat, Ismail Mahat Bashir, Leon Caly, Meera Chand, Christian Drosten, Nuno R. Faria, Adeola Fowotade, Anne von Gottberg, Bart L. Haagmans, Baoying Huang, Jason Kindrachuk, Marion P. G. Koopmans, Bette Korber, Yee-Sin Leo,  Placide Mbala-Kingebeni, Nada M. Melhem, Vincent J. Munster, …Maria D. Van Kerkhove 

Nature Health (2026) Cite this article

Human cases of Middle East respiratory syndrome coronavirus (MERS-CoV) have declined in recent years, but continued surveillance and research is needed to understand this trend and mitigate future zoonotic threats.

While MERS-CoV and new variants of SARS-CoV-2 are both plausible candidates for producing the next pandemic, we continue to watch a growing number of novel coronavirus threats in the wild.

Just a few, of many, include:

Preprint: A Divergent Betacoronavirus with a Functional Furin Cleavage Site in South American Bats

J. of Infection: Novel Coronaviruses Identified in Livestock

Viruses: Novel Rodent Coronavirus-like Virus Detected Among Beef Cattle with Respiratory Disease in Mexico

Nature: Study on Sentinel Hosts for Surveillance of Future COVID-19-like Outbreaks

Preprint: Human Cell adaptation of the Swine Acute Diarrhea Syndrome Coronavirus Spike Protein

Recent studies suggest that the frequency, and impact, of pandemics are only expected to increase in the years ahead.

BMJ Global: Historical Trends Demonstrate a Pattern of Increasingly Frequent & Severe Zoonotic Spillover Events

PNAS Research: Intensity and Frequency of Extreme Novel Epidemics

While I can't tell you what type of emerging disease will spark the next pandemic - or when - it is all but guaranteed to happen again. And very much like we were in the run-up to COVID, the world is nowhere near prepared to go through that again.

Vet Research Comms: First report of serological and molecular detection of influenza A (H1N1) in European bison (Bison bonasus)

 

European Bison - Credit Wikipedia

#19,092

It was 2 years ago this week (March 24th, 2024) that I wrote about Curious Reports of Unknown Disease In Dairy Cows (Texas, Kansas & New Mexico), that in short order would be identified as HPAI H5N1.

HPAI testing appears to have been delayed for several weeks because - up until then - cattle had been considered poorly susceptible to influenza A (see A Brief History Of Influenza A In Cattle/Ruminants), despite successful experimental infection with H5N1.  

Since then we've seen more than 1,000 dairy herds infected with HPAI H5 in the United States, along with spillovers to goats, pigs, and alpacas. Testing remains largely voluntary, however,  and some estimates suggest that significant under-reporting of H5N1 in dairy herds is likely.

Over the past two years we've seen a number of studies suggesting that Influenza A in general (including HPAI H5), can and does infect livestock, including bovines, pigs, and goats.  A few of many studies include:

Netherlands: NOS.NL Reports 5 Dairy Cows Have Now Tested Positive for H5N1

Transboundary & Emerg Inf: Serological Evidence of HPAI (H5N1) in Invasive Wild Pigs in Western Canada,

Preprint: Highly Pathogenic Avian Influenza H5 Virus Exposure in Goats and Sheep (in Pakistan).

Germany FLI: Statement On Experimental Infection Of Dairy Cows With European H5N1 Virus 

Despite this growing resume, much of the world continues to act as if the spillover of HPAI H5 is somehow just an `American problem' - due to an aberrant local strain of the virus - and unlikely to spread beyond our borders.

Last October, WOAH embraced an 11-page OFFLU technical document (see OFFLU Guidelines for High Pathogenicity Avian Influenza Virus Risk Mitigation in Cattle) which - among other things - finally made HPAI in cattle a `reportable disease'. 

But it isn't at all clear how seriously governments and farmers are taking these recommendations - both here in the United States - and around the world.  

Today we've another (admittedly minor) data point; The first detection of influenza A (H1N1pdm) in a European Bison. This comes from a retrospective study, using samples collected between 2017 and 2023, and the positive sample came from 2018.

Almost all of the testing of cattle for HPAI in the United States (and elsewhere) has been conducted on lactating cows, but this detection was in a 4 year-old male bison which lived at a farm in Poland.

This report is notable because it adds yet another wild ruminant species to the list of  influenza A susceptible mammals, and it highlights the risks of bidirectional spillover of IAV at the wildlife-livestock-human interface.

I've just reproduced the abstract. Follow the link to read the report in its entirety. I'll have a brief postscript after the break.

First report of serological and molecular detection of influenza A (H1N1) in European bison (Bison bonasus)

Brief Report
Open access
Published: 21 March 2026
Volume 50, article number 212, (2026)
Veterinary Research Communications

Download PDF

Anna Didkowska, Víctor Martín-Santander, Anna Golke, Marlena Wojciechowska, Wanda Olech, Olga Szaluś-Jordanow, Tomasz Dzieciątkowski, Álex Gómez, Sergio Villanueva-Saz, Ewelina Kwiecień, Pablo Quilez, Krzysztof Anusz & Diana Marteles-Aragüés 

Abstract

Influenza A virus is a zoonotic pathogen capable of infecting a wide range of hosts, yet data on infections in wild ruminants are limited. The European bison (Bison bonasus), Europe’s largest terrestrial mammal, had not previously been identified as a host for Influenza A virus. This study aimed to provide the first molecular and serological evidence of H1N1 pandemic influenza A virus (A/H1N1pdm) infection in European bison, contributing to the understanding of Influenza A virus ecology at the wildlife–livestock interface. 

We retrospectively analysed 335 serum samples collected from European bison between 2017 and 2023 using a commercial ELISA detecting antibodies against all Influenza A virus subtypes. Tissue samples (heart and liver) from ELISA-positive animal were further tested by RT-qPCR targeting hemagglutinin (HA) and neuraminidase (NA) genes of A/H1N1pdm, A/H3N2, and A/H5N1. PCR-positive products were sequenced for confirmation.

Seroprevalence of Influenza A virus was 0.3% (1/335; 95% CI: 0.02–1.71). Influenza A virus RNA (A/H1N1pdm) was detected in the heart and liver tissue of a 4-year-old captive male from Borecka Forest, culled in 2018. The animal exhibited pulmonary congestion, emphysema, and posthitis at necropsy. 

This study provides the first molecular and serological confirmation of H1N1pdm infection in European bison. The findings highlight the potential susceptibility of this species to Influenza A virus and raise questions about possible transmission routes, including spillover from domestic animals or humans.

(Continue . . . )

We saw similar detections of (of non-HPAI) influenza A reported in steers and bulls last year in Virology: Detection of Antibodies Against Influenza A Viruses in Cattle, where the authors wrote:

Our results demonstrate that IAVs other than H5N1 can infect cattle, infections are not limited to dairy cows, and that bovine infections with swine and human IAVs have occurred prior to the H5N1 outbreaks.

All results highlight the value in monitoring IAV epidemiology in cattle, as the viruses might adapt to cattle and/or reassort with the currently circulating H5N1 HPAIV, increasing risk to humans.

Yesterday, in Referral: (OFFLU Report) Beyond poultry: Rethinking monitoring and control of HPAI H5Nx anticipating spillover risks for mammals, we saw renewed calls for enhanced surveillance of farmed animals: particularly cattle, goats, sheep, fur bearing mammals, and pigs. 

Last December more than 30 countries participated in a WPRO Table-Top Exercise Crystal: A `Bovine' Novel Flu Outbreak Scenario;' one which envisioned an epidemic that would have been considered by many as bordering on the absurd just 24 months ago.

 

Today, due to the speed at which HPAI is evolving, it is all too plausible.

Referral: (OFFLU Report) Beyond poultry: Rethinking monitoring and control of HPAI H5Nx anticipating spillover risks for mammals.

 

WOAH SitRep #79

#19,091

Yesterday OFFLU - the WOAH/FAO joint network of expertise on avian influenza - published a paper from some of the most recognizable names in influenza research, that offers practical steps for combating the growing threat from HPAI H5Nx.

In a nutshell, the authors posit that we can no longer afford to think of HPAI H5Nx as simply an avian or poultry-centric disease. Its epidemiology has changed in recent years to permit sustained, year-round carriage in aquatic birds, and increased spillover to multiple mammals species. 

They argue that surveillance and reporting systems must be adapted to protect animal and human health. They warn that `. . . dedicated HPAI surveillance strategies targeting wild and domestic mammals are largely absent in most countries.' 

They also find the most critical surveillance gap is among farmed mammals, a topic we've covered often (see OFFLU Guidelines for High Pathogenicity Avian Influenza Virus Risk Mitigation in Cattle).

The authors then present a framework for creating a `spillover prevention plan' utilizing a One Health approach. One that focuses prevention and surveillance on four groups of mammals:

• Mammals housed in groups (livestock, fur farms, zoos, catteries)
• Companion animals (cats, dogs, etc.)
• Free‑ranging mammals (wild and feral)
• Humans with relevant exposures.

As I can find no explicit copyright notice anywhere in the PDF, I'm reluctant to quote extensively from the paper. However, since it is relatively short (7-pages), I can highly recommend following the link to read it its entirety.  

Beyond poultry: Rethinking monitoring and control of HPAI H5Nx anticipating spillover risks formammals.March 2026 

This document was developed by OFFLU, the Network of Expertise on Animal Influenza established by the World Organisation for Animal Health (WOAH) and the Food and Agriculture Organization of the United Nations (FAO), through its Wildlife and Avian Technical Activities. 

Authors and Affiliations Lineke Begeman* 1,2, Fabien Filaire* 1,2, Lorcan Carnegie1 , Martin Beer3 , Francesco Bonfante4 , Nicola Lewis5,6, Guillaume Fournie6,7,8 , Erik A Karlsson9 (OFFLU Vice-Chair), Marcela Uhart10 (OFFLU Chair), Ron Fouchier2 , Thijs Kuiken2 (*contributed equally).