Publications

Publication: Nature

L. Peruzzotti-Jametti, C. M. Willis, G. Krzak, R. Hamel, L. Pirvan, R.-B. Ionescu, J. A. Reisz, H. A. Prag, M. E. Garcia-Segura, V. Wu, Y. Xiang, B. Barlas, A. M. Casey, A. M. R. van den Bosch, A. M. Nicaise, L. Roth, G. R. Bates, H. Huang, P. Prasad, A. E. Vincent, C. Frezza, C. Viscomi, G. Balmus, Z. Takats, J. C. Marioni, A. D’Alessandro, M. P. Murphy, I. Mohorianu & S. Pluchino

13 March 2024

Summary

Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark of several chronic neurological diseases, including multiple sclerosis. Distinct metabolic and mitochondrial features guide the activation and the diverse functional states of myeloid cells. However, how these metabolic features act to perpetuate inflammation of the central nervous system is unclear. Here, using a multiomics approach, we identify a molecular signature that sustains the activation of microglia through mitochondrial complex I activity driving reverse electron transport and the production of reactive oxygen species.

Publication: Nature

Minna K. Karjalainen, Savita Karthikeyan, Clare Oliver-Williams, Eeva Sliz, Elias Allara, Wing Tung Fung, Praveen Surendran, Weihua Zhang, Pekka Jousilahti, Kati Kristiansson, Veikko Salomaa, Matt Goodwin, David A. Hughes, Michael Boehnke, Lilian Fernandes Silva, Xianyong Yin, Anubha Mahajan, Matt J. Neville, Natalie R. van Zuydam, Renée de Mutsert, Ruifang Li-Gao, Dennis O. Mook-Kanamori, Ayse Demirkan, Jun Liu, China Kadoorie Biobank Collaborative Group, Estonian Biobank Research Team, FinnGen, …Johannes Kettunen

6 March 2024

Summary

Genome-wide association analyses using high-throughput metabolomics platforms have led to novel insights into the biology of human metabolism. This detailed knowledge of the genetic determinants of systemic metabolism has been pivotal for uncovering how genetic pathways influence biological mechanisms and complex diseases. Researchers present a genome-wide association study for 233 circulating metabolic traits quantified by nuclear magnetic resonance spectroscopy in up to 136,016 participants from 33 cohorts. 

Publication: JAC-Antimicrobial Resistance

Nick K Jones, Brian Tom, Constantinos Simillis, John Bennet, Stavros Gourgiotis, Jo Griffin, Helen Blaza, Shuaib Nasser, Stephen Baker, Theodore Gouliouris

16 February 2024

Summary

Being labelled as allergic to penicillin has been associated with an increase in the risk of infection after surgery in a number of studies in USA, Canada and France. This is thought to be due to the use of inferior antibiotic regimens for preventing infection at the time of surgery. We studied a large cohort of patients that had undergone gastrointestinal surgery at Addenbrooke’s Hospital to see if this observation could be generalised to a UK population, where the range of preventative antibiotic regimens in routine use differs significantly. We found no evidence of association between penicillin allergy labels and likelihood of surgical site infection in this cohort, suggesting significant international variation in the impact of penicillin allergy labels on patients.

Publication: The Lancet

Nurulamin M Noor, James C Lee, Simon Bond, Francis Dowling, Biljana Brezina, Kamal V Patel, Tariq Ahmad, Paul J Banim, James W Berrill, Rachel Cooney, Juan De La Revilla Negro, Shanika de Silva, Shahida Din, Dharmaraj Durai, John N Gordon, Prof Peter M Irving, Matthew Johnson, Alexandra J Kent, Klaartje B Kok, Prof Gordon W Moran, Craig Mowat, Pritash Patel, Prof Chris S Probert, Tim Raine, Rebecca Saich, Abigail Seward, Dan Sharpstone, Melissa A Smith, Sreedhar Subramanian, Sara S Upponi, Alan Wiles, Horace R T Williams, Prof Gijs R van den Brink, Prof Séverine Vermeire, Prof Vipul Jairath, Prof Geert R D’Haens, Prof Eoin F McKinney, Paul A Lyons, Prof James O Lindsay, Nicholas A Kennedy, Prof Kenneth G C Smith, Prof Miles Parkes,  

22 February 24

Summary

A large-scale clinical trial of treatment strategies for Crohn’s disease has shown that offering early advanced therapy to all patients straight after diagnosis can drastically improve outcomes, including by reducing the number of people requiring urgent abdominal surgery for treatment of their disease by ten-fold. Read the full news story.

Publication: The British Journal of Psychiatry

Axel A. S. Laurell, Ashwin V. Venkataraman, Tatjana Schmidt, Marcella Montagnese, Christoph Mueller,
Robert Stewart, Jonathan Lewis, Clare Mundell, Jeremy D. Isaacs, Mani S. Krishnan, Robert Barber, Timothy Rittman and Benjamin R. Underwood

18 January 2024

Summary

Clinical researchers at Cambridgeshire and Peterborough NHS Foundation Trust and South London and Maudsley NHS Foundation Trust have collaborated to model how many patients might receive new treatments for Alzheimer’s disease currently under review.

Using data on eligible patients from both Trusts and scaling up, the team estimate that a maximum of 30,000 people using dementia services around the country would be suitable for these potential treatments and that NHS providers could provide them on a small scale if approved. Read the full news story.

Publication: Lancet Microbe

Francesc Coll, Theodore Gouliouris, Beth Blane, Corin A Yeats, Kathy E Raven, Catherine Ludden, Fahad A Khokhar, Hayley J Wilson, Leah W Roberts, Ewan M Harrison, Carolyne S Horner, Le Thi Hoi, Nguyen Thi Hoa, Nguyen Vu Trung, Nicholas M Brown, Prof Mark A Holmes, Prof Julian Parkhill, P Mili Estee Török, Prof Sharon J Peacock,

11 January 2024

Summary

A team of scientists at the Cambridge University Hospitals NHS Foundation Trust, University of Cambridge, Wellcome Sanger Institute and the London School of Hygiene and Tropical Medicine have gone a step forward by establishing the agreement between culture-based laboratory methods and genome sequencing for antibiotic resistance determination in Enterococcus faecium, one of the top 10 bacterial pathogens with the highest mortality burden globally. The team curated a set of over 200 genetic markers that most accurately predict resistance to 12 different, clinically relevant antibiotics in a collection of over 4,000 E. faecium strains. For key antibiotics such as ampicillin, ciprofloxacin, vancomycin and linezolid, the team reported very high diagnostic accuracy, and improved accuracy for the detection of resistance to other antibiotics compared to previous state-of-the-art predictive methods. In addition, the authors implemented the antibiotic resistance predictions on Pathogenwatch

Publication: Nature

M. Fejzo, N. Rocha, I. Cimino, S. M. Lockhart, C. J. Petry, R. G. Kay, K. Burling, P. Barker, A. L. George, N. Yasara, A. Premawardhena, S. Gong, E. Cook, D. Rimmington, K. Rainbow, D. J. Withers, V. Cortessis, P. M. Mullin, K. W. MacGibbon, E. Jin, A. Kam, A. Campbell, O. Polasek, G. Tzoneva, F. M. Gribble, G. S. H. Yeo, B. Y. H. Lam, V. Saudek, I. A. Hughes, K. K. Ong, J. R. B. Perry, A. Sutton Cole, M. Baumgarten, P. Welsh, N. Sattar, G. C. S. Smith, D. S. Charnock-Jones, A. P. Coll, C. L. Meek, S. Mettananda, C. Hayward, N. Mancuso & S. O’Rahilly

Summary

13 December 2023

A Cambridge-led study supported by the NIHR Cambridge BRC has shown why many women experience nausea and vomiting during pregnancy – and why some women become so sick they need to be admitted to hospital. The culprit is a hormone produced by the fetus – a protein known as GDF15. But how sick the mother feels depends on a combination of how much of the hormone is produced by the fetus and how much exposure the mother had to this hormone before becoming pregnant. Read the full news story.

Publication: BJOG

Yasmina Al Ghadban, Yuheng Du, D. Stephen Charnock-Jones, Lana X. Garmire, Gordon C. S. Smith, Ulla Sovio

20 November 2023

Summary

This study identified metabolites from the blood of pregnant mothers that are predictive of spontaneous preterm birth. The results require validation in external populations.

Publication: Nature Microbiology

29 November 2023

Francesca Gaccioli, Katie Stephens, Ulla Sovio, Flora Jessop, Hilary S. Wong, Susanne Lager, Emma Cook, Marcus C. de Goffau, Kirsty Le Doare, Sharon J. Peacock, Julian Parkhill, D. Stephen Charnock-Jones, Gordon C. S. Smith

Summary:

One in 200 newborns is admitted to a neonatal unit with sepsis caused by a bacteria commonly carried by their mothers – much greater than the previous estimate, say Cambridge researchers. The team has developed an ultra-sensitive test capable of better detecting the bacteria, as it is missed in the vast majority of cases. Read the full news story.

Publication: BJOG

Yasmina Al Ghadban, Yuheng Du, D. Stephen Charnock-Jones, Lana X. Garmire, Gordon C. S. Smith, Ulla Sovio

20 November 2023

Summary

This study identified metabolites from the blood of pregnant mothers that are predictive of spontaneous preterm birth. The results require validation in external populations.

Publication: Stem Cell Reports

Maha Al-Thani Mary Goodwin-Trotma Steven Bel Krushangi Pate Lauren K. Flemin Catheline Vilain, Marc Abramowicz, Stuart M. Allan, Tao Wang, M. Zameel Cader, Karen Horsburgh, Tom Van Agtmael, Sanjay Sinha, Hugh S. Markus, Alessandra Granata,

16 November 2023

Summary
Cambridge scientists have grown small blood vessel-like models in the lab and used them to show how damage to the scaffolding that support these vessels can cause them to leak, leading to conditions such as vascular dementia and stroke.

Publication: Journal of Neuroscience

Rong Ye, Frank H. Hezemans, Claire O’Callaghan, Kamen A. Tsvetanov, Catarina Rua, P. Simon Jones, Negin Holland, Maura Malpetti, Alexander G. Murley, Roger A. Barker, Caroline H. Williams-Gray, Trevor W. Robbins, Luca Passamonti and James B. Rowe

5 September 2023

Parkinson’s disease (PD) and progressive supranuclear palsy (PSP) both impair response inhibition, exacerbating impulsivity. Inhibitory control deficits vary across individuals and are linked with worse prognosis, and lack improvement on dopaminergic therapy. Motor and cognitive control are associated with noradrenergic innervation of the cortex, arising from the locus coeruleus (LC) noradrenergic system.

Here we test the hypothesis that structural variation of the LC explains response inhibition deficits in PSP and PD. Twenty-four people with idiopathic PD, 14 with PSP-Richardson’s syndrome, and 24 age- and sex-matched controls undertook a stop-signal task and ultrahigh field 7T magnetisation-transfer-weighted imaging of the LC. Parameters of ‘race models’ of go- versus stop-decisions were estimated using hierarchical Bayesian methods to quantify the cognitive processes of response inhibition. We tested the multivariate relationship between LC integrity and model parameters using partial least squares. Both disorders impaired response inhibition at the group level. PSP caused a distinct pattern of abnormalities in inhibitory control with a paradoxically reduced threshold for go responses, but longer non-decision times, and more lapses of attention.

The variation in response inhibition correlated with the variability of LC integrity across participants in both clinical groups. Structural imaging of the LC, coupled with behavioural modelling in parkinsonian disorders, confirms that LC integrity is associated with response inhibition and LC degeneration contributes to neurobehavioural changes. The noradrenergic system is therefore a promising target to treat impulsivity in these conditions. The optimisation of noradrenergic treatment is likely to benefit from stratification according to LC integrity.

Publication: Journal of Internal Medicine

Youngwon Kim, Haeyoon Jang, Mengyao Wang, Qiaoxin Shi, Tessa Strain, Stephen J Sharp, Shiu Lun Au Yeung, Shan Luo, Simon Griffin, Nicholas J. Wareham, Katrien Wijndaele, Soren Brage

23 August 2023

Summary

Excess sedentary time (ST) is recognized as an important modifiable risk factor for coronary heart disease (CHD). However, whether the associations of genetic susceptibility with CHD incidence can be modified by replacing wearable-device-measured ST with physical activity (PA) is unknown.

Publication: Molecular Psychiatry

Dr Leonidas Chouliaras, Professor John T. O’Brien

22 August 2023

Early and accurate diagnosis of dementia subtype is critical to improving clinical care and developing better treatments. Structural and molecular imaging has contributed to a better understanding of the pathophysiology of neurodegenerative dementias and is increasingly being adopted into clinical practice for early and accurate diagnosis.

In this review we summarise the contribution imaging has made with particular focus on multimodal magnetic resonance imaging (MRI) and positron emission tomography imaging (PET). Structural MRI is widely used in clinical practice and can help exclude reversible causes of memory problems but has relatively low sensitivity for the early and differential diagnosis of dementia subtypes. 

F-fluorodeoxyglucose PET has high sensitivity and specificity for AD and FTD, while PET with ligands for amyloid and tau can improve the differential diagnosis of AD and non-AD dementias, including recognition at prodromal stages. Dopaminergic imaging can assist with the diagnosis of LBD. The lack of a validated tracer for α-synuclein or TAR DNA-binding protein 43 (TDP-43) imaging remain notable gaps, though work is ongoing.

Emerging PET tracers such as C-UCB-J for synaptic imaging may be sensitive early markers but overall larger longitudinal multi-centre cross diagnostic imaging studies are needed.

Publication: Cell Reports Medicine

Ruth Hanssen, Chiara Auwerx, Maarja Jõeloo, Sadaf Farooqi, Alexandre Reymond, Katherine Lawler

15 August 2023

New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2–3 [BP2–3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10−10) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p = 8.1 × 10−6). We conclude that people with 16p11.2 BP2–3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling.

Publication: International Journal Geriatric Psychiatry

Anne D. Kershenbaum, Annabel C. Price, Rudolf N. Cardinal, Shanquan Chen, James M. Fitzgerald, Jonathan Lewis, Sinéad Moylett, John T. O’Brien

19 May 2023

Summary

Survival is shorter in Lewy body dementia (LBD, referring to both Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB)) compared with Alzheimer’s disease (AD), but the reasons for this difference are not well established.

Researchers identified cohorts of patients with dementia (male and female AD, PDD, and DLB dementia groups) referred into mental health services and linked to National Health Service (NHS) Hospital Episode Statistics and the Office for National Statistics to identify death dates and proximal cause of death. Among patients with DLB and PDD compared to AD ,those with PDD, especially males with PDD, had the highest hazard ratio for death. Aspiration pneumonia and nervous system causes of death accounted for a significant proportion of the excess deaths in the male PDD group compared to the male AD group. Compared with AD, hazard ratios for nervous system causes of death were significantly elevated in all LBD groups. A range of cause‐of‐death categories were significantly more frequent across the LBD groups, with aspiration pneumonia ,genitourinary causes and other respiratory causes elevated in more than one group

Publication: Nature Immunology

Jing Hua Zhao, David Stacey, Niclas Eriksson, Erin Macdonald-Dunlop, Asa K Hedman et al

18 July 2023

Aberrant inflammatory responses play a role in pathogenesis of many diseases, including autoimmune conditions, cardiovascular diseases and cancers. In this study of genetic influences on inflammation-related proteins, an international team conducted a genome-wide association study of 91 plasma proteins in ~15,000 participants within the SCALLOP Consortium.

Having identified 180 gene-protein associations, they integrated with gene expression and disease genetics to provide insights into disease aetiology, implicating FGF5 in hypertension and cardiovascular disease, and lymphotoxin-α in multiple sclerosis.

The team identified both shared and distinct effects of specific proteins across immune mediated diseases, including directionally discordant functions for CD40 in rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease, and a role for CXCL5 in the aetiology of ulcerative colitis UC but not Crohns disease.

These results provide a powerful resource to understand the role of chronic inflammation in a wide range of diseases and facilitate future drug target prioritisation.

Publication: Innovation in Aging

Chen S, Zhang H, Underwood BR, Wang D, Chen X, Cardinal RN

22 May 2023

Summary

We looked at survey data from 2000-2018 about people aged over 65, with cognitive impairment, and living alone in the United States. We examined their need for support with activities of daily living, and the extent to which such support was provided. We examined trends over time, including trends by gender and by ethnicity.

Publication: Biological Psychiatry: Global Open Science

Annemieke M. Apergis-Schoute, Febe E. van der Flier, Samantha H.Y. Ip, Jonathan W. Kanen, Matilde M. Vaghi, Naomi A. Fineberg, Barbara J. Sahakian, Rudolf N. Cardinal, Trevor W. Robbins

13 July 2023

Summary

People with obsessive-compulsive disorder (OCD) can show both “perseveration” (persisting with an action after it is no longer advantageous) or “shifting” to other actions, depending on the situation they are in. In experimental tests, perseveration was related to the severity of OCD, and improved by medication that influences serotonin neurotransmitter systems.

Publication: Nature Medicine

Agatha A. van der Klaauw, Emily C. Horner, Pehuén Pereyra-Gerber, Utkarsh Agrawal, William S. Foster, Sarah Spencer, Bensi Vergese, Miriam Smith, Elana Henning, Isobel D. Ramsay, Jack A. Smith, Stephane M. Guillaume, Hayley J. Sharpe, Iain M. Hay, Sam Thompson, Silvia Innocentin, Lucy H. Booth, Chris Robertson, Colin McCowan, Steven Kerr, Thomas E. Mulroney, Martin J. O’Reilly, Thevinya P. Gurugama, Lihinya P. Gurugama, Maria A. Rust, Alex Ferreira, Soraya Ebrahimi, Lourdes Ceron-Gutierrez, Jacopo Scotucci, Barbara Kronsteiner, Susanna J. Dunachie, Paul Klenerman, PITCH Consortium, Adrian J. Park, Francesco Rubino, Abigail A. Lamikanra, Hannah Stark, Nathalie Kingston, Lise Estcourt, Heli Harvala, David J. Roberts, Rainer Doffinger, Michelle A. Linterman, Nicholas J. Matheson, Aziz Sheikh, I. Sadaf Farooqi & James E. D. Thaventhiran

11 May 2023

Summary

Clinical trials have shown that COVID-19 vaccines are highly effective at reducing symptoms, hospitalisation and deaths caused by the virus, including for people with obesity. Previous studies have suggested that antibody levels may be lower in vaccinated people who have obesity and that they may remain at higher risk of severe disease than vaccinated people with normal weight. The reasons for this have, however, remained unclear. Read the news story.