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Article ; Online: Constrained optimization of divisional load in hierarchically organized tissues during homeostasis.

Ashcroft, Peter / Bonhoeffer, Sebastian

2022 Volume 19, Issue 187, Page(s) 20210784

Abstract: It has been hypothesized that the structure of tissues and the hierarchy of differentiation from stem cell to terminally differentiated cell play a significant role in reducing the incidence of cancer in that tissue. One specific mechanism by which this ... ...

Abstract	It has been hypothesized that the structure of tissues and the hierarchy of differentiation from stem cell to terminally differentiated cell play a significant role in reducing the incidence of cancer in that tissue. One specific mechanism by which this risk can be reduced is by minimizing the number of divisions-and hence the mutational risk-that cells accumulate as they divide to maintain tissue homeostasis. Here, we investigate a mathematical model of cell division in a hierarchical tissue, calculating and minimizing the divisional load while constraining parameters such that homeostasis is maintained. We show that the minimal divisional load is achieved by binary division trees with progenitor cells incapable of self-renewal. Contrary to the protection hypothesis, we find that an increased stem cell turnover can lead to lower divisional load. Furthermore, we find that the optimal tissue structure depends on the time horizon of the duration of homeostasis, with faster stem cell division favoured in short-lived organisms and more progenitor compartments favoured in longer-lived organisms.
MeSH term(s)	Cell Differentiation ; Cell Division ; Homeostasis ; Models, Biological ; Mutation ; Stem Cells
Language	English
Publishing date	2022-02-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2156283-0
ISSN	1742-5662 ; 1742-5689
ISSN (online)	1742-5662
ISSN	1742-5689
DOI	10.1098/rsif.2021.0784
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Article ; Online: Correcting for Antibody Waning in Cumulative Incidence Estimation from Sequential Serosurveys.

Kadelka, Sarah / Bouman, Judith A / Ashcroft, Peter / Regoes, Roland R

American journal of epidemiology

2023

Abstract: Serosurveys are a widely used tool to estimate the cumulative incidence, i.e. the fraction of a population that have been infected by a given pathogen. These surveys rely on serological assays that measure the level of pathogen-specific antibodies. ... ...

Abstract	Serosurveys are a widely used tool to estimate the cumulative incidence, i.e. the fraction of a population that have been infected by a given pathogen. These surveys rely on serological assays that measure the level of pathogen-specific antibodies. Because antibody levels are waning, the fraction of previously infected individuals that have sero-reverted increases with time past infection. To avoid underestimating the true cumulative incidence, it is therefore essential to correct for waning antibody levels. We present an empirically-supported approach for sero-reversion correction in cumulative incidence estimation when sequential serosurveys are conducted in the context of a newly emerging infectious disease. The correction is based on the observed dynamics of antibody titers in sero-positive cases and validated using several in silico test scenarios. Furthermore, through this approach we revise a previous cumulative incidence estimate, which relies on the assumption of an exponentially-declining probability of sero-reversion over time, of SARS-CoV-2 of 76% in Manaus, Brazil, by October 2020 to 47.6% (43.5% - 53.5%). This estimate has implications e.g. for the proximity to herd immunity in Manaus in late 2020.
Language	English
Publishing date	2023-11-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2937-3
ISSN	1476-6256 ; 0002-9262
ISSN (online)	1476-6256
ISSN	0002-9262
DOI	10.1093/aje/kwad226
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Article ; Online: Test-trace-isolate-quarantine (TTIQ) intervention strategies after symptomatic COVID-19 case identification.

Ashcroft, Peter / Lehtinen, Sonja / Bonhoeffer, Sebastian

PloS one

2022 Volume 17, Issue 2, Page(s) e0263597

Abstract: The test-trace-isolate-quarantine (TTIQ) strategy, where confirmed-positive pathogen carriers are isolated from the community and their recent close contacts are identified and pre-emptively quarantined, is used to break chains of transmission during a ... ...

Abstract	The test-trace-isolate-quarantine (TTIQ) strategy, where confirmed-positive pathogen carriers are isolated from the community and their recent close contacts are identified and pre-emptively quarantined, is used to break chains of transmission during a disease outbreak. The protocol is frequently followed after an individual presents with disease symptoms, at which point they will be tested for the pathogen. This TTIQ strategy, along with hygiene and social distancing measures, make up the non-pharmaceutical interventions that are utilised to suppress the ongoing COVID-19 pandemic. Here we develop a tractable mathematical model of disease transmission and the TTIQ intervention to quantify how the probability of detecting and isolating a case following symptom onset, the fraction of contacts that are identified and quarantined, and the delays inherent to these processes impact epidemic growth. In the model, the timing of disease transmission and symptom onset, as well as the frequency of asymptomatic cases, is based on empirical distributions of SARS-CoV-2 infection dynamics, while the isolation of confirmed cases and quarantine of their contacts is implemented by truncating their respective infectious periods. We find that a successful TTIQ strategy requires intensive testing: the majority of transmission is prevented by isolating symptomatic individuals and doing so in a short amount of time. Despite the lesser impact, additional contact tracing and quarantine increases the parameter space in which an epidemic is controllable and is necessary to control epidemics with a high reproductive number. TTIQ could remain an important intervention for the foreseeable future of the COVID-19 pandemic due to slow vaccine rollout and highly-transmissible variants with the potential for vaccine escape. Our results can be used to assess how TTIQ can be improved and optimised, and the methodology represents an improvement over previous quantification methods that is applicable to future epidemic scenarios.
MeSH term(s)	Basic Reproduction Number ; COVID-19/epidemiology ; COVID-19/transmission ; Contact Tracing ; Discriminant Analysis ; Humans ; Quarantine
Language	English
Publishing date	2022-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0263597
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Article ; Online: An Analysis of Healthcare Usage & Place of Death in England for All Adults Who Died in 2021/22.

Wiltshire, Justine / Grout, Jacqueline / Krotosky, Mike / Gerry, Peter / Ashcroft, Peter / White, Rachel / Lillis, Ash / Betteley, Adrienne / Minton, Ollie

The American journal of hospice & palliative care

2024 , Page(s) 10499091241247183

Abstract: Objective: We wanted to examine the healthcare use and non-elective activity in the UK population of expected deaths over an 1-year period to highlight and examine the reasons for variation. We did this to identify areas to focus interventions or ... ...

Abstract	Objective: We wanted to examine the healthcare use and non-elective activity in the UK population of expected deaths over an 1-year period to highlight and examine the reasons for variation. We did this to identify areas to focus interventions or resources on to reduce unnecessary emergency care use at the end of life. Methods and analysis: We assembled a data set of approximately 400 000 adults who died in England in the financial year 2021/22 (April 2021-March 2022). Any adults classified as a 'sudden death' were excluded. We used available data to ensure outcome measures were relevant used expert consensus to agree what to examine. We recorded place of death and examined urgent care in terms of admissions in the last year and 90 days of life. We also used recorded hospital care days as elective and non-elective usage. Results: There were over 400 000 decedents included in our regression models. Close to half died in hospital (44%). Three-quarters (77%) had at least one day of unplanned hospital care in the 90 days before they died, and half (56%) had at least one day of planned hospital care. Conclusion: Reliance on urgent care for those approaching end-of-life may indicate poor care planning and integration of services. A relatively modest increase in the amount of community care a person receives at end-of-life can substantially reduce the likelihood of dying in hospital. Those with a cancer cause of death are far less likely to die in hospital.
Language	English
Publishing date	2024-04-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	1074344-3
ISSN	1938-2715 ; 1049-9091
ISSN (online)	1938-2715
ISSN	1049-9091
DOI	10.1177/10499091241247183
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Article ; Online: A qualitative examination of primary care team's participation in the distribution of the COVID-19 vaccination.

Ashcroft, Rachelle / Donnelly, Catherine / Lam, Simon / Sheffield, Peter / Hamilton, Bryn / Kemp, Connor / Adamson, Keith / Brown, Judith Belle

BMC primary care

2024 Volume 25, Issue 1, Page(s) 85

Abstract: Background: Primary health care (PHC) has historically led and implemented successful immunization programs, driven by strong relationships with patients and communities. During the COVID-19 pandemic, Canada began its vaccination strategy with mass ... ...

Abstract	Background: Primary health care (PHC) has historically led and implemented successful immunization programs, driven by strong relationships with patients and communities. During the COVID-19 pandemic, Canada began its vaccination strategy with mass immunizations that later included local efforts with PHC providers. This study seeks to understand how PHC contributed to the different phases of the COVID-19 vaccination rollouts in Ontario, Canada's most populous province. Methods: We conducted a descriptive qualitative study with focus groups consisting of PHC providers, administrators, and staff in Ontario. Eight focus groups were held with 39 participants representing geographic diversity across the six Ontario Health regions. Participants reflected a diverse range of clinical, administrative, and leadership roles. Each focus group was audio-recorded and transcribed with transcriptions analyzed using thematic analysis. Results: With respect to understanding PHC teams' participation in the different phases of the COVID-19 vaccination rollouts, we identified five themes: (i) supporting long-term care, (ii) providing leadership in mass vaccinations, (iii) integrating vaccinations in PHC practice sites, (iv) reaching those in need through outreach activities; and (v) PHC's contributions being under-recognized. Conclusions: PHC was instrumental in supporting COVID-19 vaccinations in Ontario, Canada across all phases of the rollout. The flexibility and adaptability of PHC allowed teams to participate in both large-scale and small-scale vaccination efforts.
MeSH term(s)	Humans ; Primary Health Care ; COVID-19 Vaccines/therapeutic use ; Pandemics ; COVID-19/epidemiology ; COVID-19/prevention & control ; Vaccination ; Ontario/epidemiology
Chemical Substances	COVID-19 Vaccines
Language	English
Publishing date	2024-03-14
Publishing country	England
Document type	Journal Article
ISSN	2731-4553
ISSN (online)	2731-4553
DOI	10.1186/s12875-024-02327-2
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Article ; Online: Myeloproliferative Neoplasms: The Long Wait for JAK2-Mutant Clone Expansion.

Luque Paz, Damien / Ashcroft, Peter / Skoda, Radek C

Cell stem cell

2021 Volume 28, Issue 3, Page(s) 359–361

Abstract: Myeloproliferative neoplasms (MPNs) are hematological malignancies caused by somatic mutations originating from a single hematopoietic stem cell (HSC). In this issue of Cell Stem Cell,Van Egeren et al. (2021) used whole-genome sequencing of hematopoietic ...

Abstract	Myeloproliferative neoplasms (MPNs) are hematological malignancies caused by somatic mutations originating from a single hematopoietic stem cell (HSC). In this issue of Cell Stem Cell,Van Egeren et al. (2021) used whole-genome sequencing of hematopoietic colonies to reconstruct the clonal history and time of acquisition of the disease-initiating gene mutation.
MeSH term(s)	Cell Differentiation ; Clone Cells ; Hematologic Neoplasms/genetics ; Hematopoietic Stem Cells ; Humans ; Janus Kinase 2/genetics ; Mutation/genetics ; Myeloproliferative Disorders/genetics
Chemical Substances	JAK2 protein, human (EC 2.7.10.2) ; Janus Kinase 2 (EC 2.7.10.2)
Language	English
Publishing date	2021-03-05
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	2375354-7
ISSN	1875-9777 ; 1934-5909
ISSN (online)	1875-9777
ISSN	1934-5909
DOI	10.1016/j.stem.2021.02.018
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Article ; Online: On the relationship between serial interval, infectiousness profile and generation time.

Lehtinen, Sonja / Ashcroft, Peter / Bonhoeffer, Sebastian

Journal of the Royal Society, Interface

2021 Volume 18, Issue 174, Page(s) 20200756

Abstract: The timing of transmission plays a key role in the dynamics and controllability of an epidemic. However, observing generation times-the time interval between the infection of an infector and an infectee in a transmission pair-requires data on infection ... ...

Abstract	The timing of transmission plays a key role in the dynamics and controllability of an epidemic. However, observing generation times-the time interval between the infection of an infector and an infectee in a transmission pair-requires data on infection times, which are generally unknown. The timing of symptom onset is more easily observed; generation times are therefore often estimated based on serial intervals-the time interval between symptom onset of an infector and an infectee. This estimation follows one of two approaches: (i) approximating the generation time distribution by the serial interval distribution or (ii) deriving the generation time distribution from the serial interval and incubation period-the time interval between infection and symptom onset in a single individual-distributions. These two approaches make different-and not always explicitly stated-assumptions about the relationship between infectiousness and symptoms, resulting in different generation time distributions with the same mean but unequal variances. Here, we clarify the assumptions that each approach makes and show that neither set of assumptions is plausible for most pathogens. However, the variances of the generation time distribution derived under each assumption can reasonably be considered as upper (approximation with serial interval) and lower (derivation from serial interval) bounds. Thus, we suggest a pragmatic solution is to use both approaches and treat these as edge cases in downstream analysis. We discuss the impact of the variance of the generation time distribution on the controllability of an epidemic through strategies based on contact tracing, and we show that underestimating this variance is likely to overestimate controllability.
MeSH term(s)	COVID-19/epidemiology ; COVID-19/transmission ; Contact Tracing ; Humans ; Models, Biological ; SARS-CoV-2 ; Time Factors
Language	English
Publishing date	2021-01-06
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2156283-0
ISSN	1742-5662 ; 1742-5689
ISSN (online)	1742-5662
ISSN	1742-5689
DOI	10.1098/rsif.2020.0756
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Article ; Online: Test-trace-isolate-quarantine (TTIQ) intervention strategies after symptomatic COVID-19 case identification.

Peter Ashcroft / Sonja Lehtinen / Sebastian Bonhoeffer

PLoS ONE, Vol 17, Iss 2, p e

2022 Volume 0263597

Abstract	The test-trace-isolate-quarantine (TTIQ) strategy, where confirmed-positive pathogen carriers are isolated from the community and their recent close contacts are identified and pre-emptively quarantined, is used to break chains of transmission during a disease outbreak. The protocol is frequently followed after an individual presents with disease symptoms, at which point they will be tested for the pathogen. This TTIQ strategy, along with hygiene and social distancing measures, make up the non-pharmaceutical interventions that are utilised to suppress the ongoing COVID-19 pandemic. Here we develop a tractable mathematical model of disease transmission and the TTIQ intervention to quantify how the probability of detecting and isolating a case following symptom onset, the fraction of contacts that are identified and quarantined, and the delays inherent to these processes impact epidemic growth. In the model, the timing of disease transmission and symptom onset, as well as the frequency of asymptomatic cases, is based on empirical distributions of SARS-CoV-2 infection dynamics, while the isolation of confirmed cases and quarantine of their contacts is implemented by truncating their respective infectious periods. We find that a successful TTIQ strategy requires intensive testing: the majority of transmission is prevented by isolating symptomatic individuals and doing so in a short amount of time. Despite the lesser impact, additional contact tracing and quarantine increases the parameter space in which an epidemic is controllable and is necessary to control epidemics with a high reproductive number. TTIQ could remain an important intervention for the foreseeable future of the COVID-19 pandemic due to slow vaccine rollout and highly-transmissible variants with the potential for vaccine escape. Our results can be used to assess how TTIQ can be improved and optimised, and the methodology represents an improvement over previous quantification methods that is applicable to future epidemic scenarios.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Stochastic Gene Expression Influences the Selection of Antibiotic Resistance Mutations.

Sun, Lei / Ashcroft, Peter / Ackermann, Martin / Bonhoeffer, Sebastian

Molecular biology and evolution

2019 Volume 37, Issue 1, Page(s) 58–70

Abstract: Bacteria can resist antibiotics by expressing enzymes that remove or deactivate drug molecules. Here, we study the effects of gene expression stochasticity on efflux and enzymatic resistance. We construct an agent-based model that stochastically ... ...

Abstract	Bacteria can resist antibiotics by expressing enzymes that remove or deactivate drug molecules. Here, we study the effects of gene expression stochasticity on efflux and enzymatic resistance. We construct an agent-based model that stochastically simulates multiple biochemical processes in the cell and we observe the growth and survival dynamics of the cell population. Resistance-enhancing mutations are introduced by varying parameters that control the enzyme expression or efficacy. We find that stochastic gene expression can cause complex dynamics in terms of survival and extinction for these mutants. Regulatory mutations, which augment the frequency and duration of resistance gene transcription, can provide limited resistance by increasing mean expression. Structural mutations, which modify the enzyme or efflux efficacy, provide most resistance by improving the binding affinity of the resistance protein to the antibiotic; increasing the enzyme's catalytic rate alone may contribute to resistance if drug binding is not rate limiting. Overall, we identify conditions where regulatory mutations are selected over structural mutations, and vice versa. Our findings show that stochastic gene expression is a key factor underlying efflux and enzymatic resistances and should be taken into consideration in future antibiotic research.
MeSH term(s)	Drug Resistance, Bacterial/genetics ; Gene Expression ; Models, Genetic ; Mutation ; Selection, Genetic
Language	English
Publishing date	2019-08-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	998579-7
ISSN	1537-1719 ; 0737-4038
ISSN (online)	1537-1719
ISSN	0737-4038
DOI	10.1093/molbev/msz199
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Article ; Online: Preparing medical students for a pandemic: a systematic review of student disaster training programmes.

Ashcroft, James / Byrne, Matthew H V / Brennan, Peter A / Davies, Richard Justin

Postgraduate medical journal

2020 Volume 97, Issue 1148, Page(s) 368–379

Abstract: Objective: To identify pandemic and disaster medicine-themed training programmes aimed at medical students and to assess whether these interventions had an effect on objective measures of disaster preparedness and clinical outcomes. To suggest a ... ...

Abstract	Objective: To identify pandemic and disaster medicine-themed training programmes aimed at medical students and to assess whether these interventions had an effect on objective measures of disaster preparedness and clinical outcomes. To suggest a training approach that can be used to train medical students for the current COVID-19 pandemic. Results: 23 studies met inclusion criteria assessing knowledge (n=18, 78.3%), attitude (n=14, 60.9%) or skill (n=10, 43.5%) following medical student disaster training. No studies assessed clinical improvement. The length of studies ranged from 1 day to 28 days, and the median length of training was 2 days (IQR=1-14). Overall, medical student disaster training programmes improved student disaster and pandemic preparedness and resulted in improved attitude, knowledge and skills. 18 studies used pretest and post-test measures which demonstrated an improvement in all outcomes from all studies. Conclusions: Implementing disaster training programmes for medical students improves preparedness, knowledge and skills that are important for medical students during times of pandemic. If medical students are recruited to assist in the COVID-19 pandemic, there needs to be a specific training programme for them. This review demonstrates that medical students undergoing appropriate training could play an essential role in pandemic management and suggests a course and assessment structure for medical student COVID-19 training. Registration: The search strategy was not registered on PROSPERO-the international prospective register of systematic reviews-to prevent unnecessary delay.
MeSH term(s)	COVID-19/epidemiology ; COVID-19/prevention & control ; COVID-19/transmission ; Curriculum ; Disaster Medicine/education ; Education, Medical, Undergraduate ; Humans
Keywords	covid19
Language	English
Publishing date	2020-06-09
Publishing country	England
Document type	Journal Article ; Systematic Review
ZDB-ID	80325-x
ISSN	1469-0756 ; 0032-5473
ISSN (online)	1469-0756
ISSN	0032-5473
DOI	10.1136/postgradmedj-2020-137906
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