Core Funding Research Articles

A noncanonical NF-kB - β-catenin signaling axis in dendritic cells instructs gut inflammation

Abstract Dendritic cells (DCs) balance intestinal homeostasis against inflammatory insults. In particular, the noncanonical NF-kB pathway, which activates RelB:p52 heterodimers, has been implicated in DC differentiation. However, if DC-intrinsic noncanonical signaling modulates DC function in the inflamed gut remains unclear. Here we report that genetic ablation of the noncanonical signaling in DCs accumulated regulatory T cells in the lamina propria and associated lymph nodes, restraining inflammation in the colitogenic gut. Our mechanistic investigation revealed that an impaired RelB:p52 gene function, rather unexpectedly, augmented the abundance of active β-catenin via impairment of the β-catenin destruction complex. In turn, β-catenin transcriptionally upregulated Raldh2, imparting a retinoic acid gene signature and tolerogenic functions to noncanonical NF-kB-deficient DCs. Indeed, mice possessing DC-intrinsic noncanonical signaling defects exhibited an increased frequency of β-catenin +DCs in the gut and resilience to chemical induced experimental colitis. Taken together, we chart a novel crosstalk between noncanonical NF-kB signaling and the β-catenin pathway that instructs tolerogenic DC functions and modulates inflammation in the gut. National Institute of Immunology Core funding and BT/PR36631/BRB/10/1862/2020, Department of Biotechnology (DBT).

Microwave hyperthermia represses human papillomavirus oncoprotein activity and induces cell death due to cell stress in 3D tissue models of anogenital precancers and cancers

Hyperthermia is a well-accepted cancer therapy. Microwaves provide a very precise, targeted means of hyperthermia and are currently used to treat plantar warts caused by cutaneous-infective human papillomaviruses (HPVs). Other HPV genotypes infecting the anogenital mucosa cause genital warts or preneoplastic lesions or cervical cancer. Effective, non-ablative therapies for these morbid HPV-associated lesions are lacking. The molecular consequences of microwave treatment were investigated in invitro cultured three-dimensional HPV-positive cervical tumour tissues, and tissues formed from HPV-infected normal immortalised keratinocytes. Microwave energy delivery to tissues was quantified. Quantitative reverse transcriptase PCR was used to quantify mRNA expression. Immunohistochemistry and fluorescence immunostaining was used to assess protein expression. Microwave energy deposition induced sustained, localised cell death at the treatment site. There was a downregulation in levels of HPV oncoproteins E6 and E7 alongside a reduction in cellular growth/proliferation and induction of apoptosis/autophagy. HSP70 expression confirmed hyperthermia, concomitant with induction of translational stress. The data suggest that microwave treatment inhibits tumour cell proliferation and allows the natural apoptosis of HPV-infected cells to resume. Precision microwave delivery presents a potential new treatment for treating HPV-positive anogenital precancerous lesions and cancers. Funding was through an Innovate UK Biomedical Catalyst grant (ID# 92138-556187), a Chief Scientist Office grant (TCS/19/11) and core support from Medical Research Council (MC_ UU_12014) core funding for the MRC-University of Glasgow Centre for Virus Research.

Rethinking Social Security Protection with a Digital Mindset: Cases of PSSSF and NSSF in Tanzania

This study examined the use of computerized systems in Social Security Funds (SSFs) in Tanzania. The primary data used for the study were derived using structured questionnaires. Descriptive statistics was used in data analysis. Using a case study design within the quantitative approach, this study examined the types of computerized systems used in Social Security Funds. Findings revealed that the Social Security Scheme in Tanzania is undergoing transformation. It is moving towards a ‘<i>Digital Pension</i>.” In many SSF offices computers, networks, the Internet, and World Wide Web are increasingly used to capture, process, store, and track members’ remittances. More specifically, computerized systems used include Members Management Information System (MMIS), Core Fund Management System (CFMS), “<i>Mobile Taarifa”</i> through mobile phones, Automated Finger Print Identification Systems, Information Kiosks, self-help portal, benefits calculators and Fund Identification Management System (FIMS). They relieve members from visiting and queuing for long hours at SSF offices for a service they would get in a minute all by themselves. Computerization is mostly used for improving the process of issuing benefits. There is a need for using technology for increasing coverage. The government should encourage citizens to use mobile phones to open their pension accounts linked to National IDs.

Durvalumab (MEDI 4736) with extended neoadjuvant regimens in rectal cancer: A randomised phase II trial (PRIME-RT).

TPS282 Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but many patients still die from distant disease. There is increasing recognition that with neoadjuvant treatment some patients achieve a complete response and may avoid surgical resection. PRIME-RT tests the inclusion of neoadjuvant immunotherapy with the aim of enhancing complete response rates, improving stoma-free survival and reducing distant relapse. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients are randomised to Arm A: short course radiotherapy (25 Gray in 5 fractions) with concomitant durvalumab, followed by durvalumab and FOLFOX chemotherapy, or Arm B: long course chemoradiotherapy (50 Gray to primary tumour, 45 Gray to elective nodes, in 25 fractions with capecitabine) with concomitant durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Bio-specimens including serial tumour biopsies and peripheral blood samples are collected prior to, during, and following treatment to explore the molecular and immunological factors underpinning treatment response. The main trial will recruit up to 42 patients and commence after a safety run-in which is recruiting patients with metastatic disease. After opening in January 2021, the four patients completed the safety run in and the main trial commenced in March 2022. The trial is currently open across 5 UK sites. Up to date recruitment details will be provided at the time of presentation but at the time of writing this is ahead of target. Early recruitment to PRIME-RT has shown that adding immunotherapy in the neoadjuvant setting for LARC is feasible. Furthermore, on treatment biospecimen collection is also feasible across multiple sites. The expectation is that the trial will provide efficacy and safety information which allows the optimal treatment approach to be tested within a larger phase clinical trial. Core funding (Glasgow CRUK CTU) and trial-specific funding (Astrazeneca). Clinical trial: NCT04621370; ISRCTN18138369. Clinical trial information: ISRCTN18138369 .

The impact of Covid-19 pandemic on hospices: A systematic integrated review and synthesis of recommendations for policy and practice

Background: The Covid-19 pandemic resulted in the development of numerous recommendations for practice and policy for specialist palliative care provided by hospices in United Kingdom (UK), as hospices were significantly affected by the pandemic and protections put in place. The aim of this review is to identify and synthesise recommendations or implications for policy and practice that have been generated for adult hospice specialist palliative care during the first 24 months of the Covid-19 pandemic. Methods: AMED, BNI, CINAHL, EMBASE, EMCARE, HMIC, Medline, PsycINFO, PubMed databases were searched for peer-reviewed papers, as well as hand searches for grey literature. Literature relating to hospices and Covid-19 in the UK were included and a thematic synthesis of recommendations for hospice policy and practice was undertaken. Results: 858 articles were identified with 12 meeting the inclusion criteria. Fifty-eight recommendations or implications were identified: 31 for policy, 27 for practice, and 10 covering both. Recommendations were organised under ten themes. There were several recommendations seeking to secure hospice resources to mitigate the short-term impact of the pandemic, as well as those focused on longer-term implications such as core funding. The impact of the pandemic on the quality of hospice care was the focus for numerous recommendations around improving integration of hospice care in the community, provision of bereavement support and better use of Advance Care Plans (ACP). However, there were significant gaps related to carer visitation in hospices, inequities of palliative care, or hospice-at-home services. Conclusion: The Covid-19 pandemic and protections exposed several ongoing policy and practice needs, especially around hospice resources, while generating novel issues for hospices to address. Significant policy gaps remain to be addressed to mitigate the impact of the pandemic on the quality of hospice specialist palliative care.

Earmarked Funding and the Control–Performance Trade-Off in International Development Organizations

AbstractSince the 1990s, the funding of multilateral development assistance has rapidly transformed. Donors increasingly constrain the discretion of international development organizations (IDOs) through earmarked funding, which limits the purposes for which a donor's funds can be used. The consequences of this development for IDOs’ operational performance are insufficiently understood. We hypothesize that increases in administrative burdens due to earmarked funding reduce the performance of IDO projects. The additional reporting required of IDOs by earmarked funds, while designed to enhance accountability, ultimately increases IDOs’ supervision costs and weakens their performance. We first test these hypotheses with data on project costs and performance of World Bank projects using both ordinary-least-squares and instrumental-variable analyses. We then probe the generalizability of those findings to other organizations by extending our analysis to four other IDOs: the African Development Bank (AfDB), Asian Development Bank (ADB), Caribbean Development Bank (CDB), and International Fund for Agricultural Development (IFAD). Using data on the performance of 7,571 projects approved between 1990 and 2020, we find that earmarked funding undermines both cost-effectiveness and project performance across IDOs. Donors seeking value for money may consider allocating more money to core funds rather than to earmarked funds.

The Deep Dementia Phenotyping (DEMON) Network: A global platform for innovation using data science and artificial intelligence.

The increasing availability of large high-dimensional data from experimental medicine, population-based and clinical cohorts, clinical trials, and electronic health records has the potential to transform dementia research. Our ability to make best use of this rich data will depend on utilisation of advanced machine learning and artificial intelligence (AI) techniques and collaboration across disciplinary and geographic boundaries. The Deep Dementia Phenotyping (DEMON) Network launched in 20191 to support the growing interest in machine learning and AI. Led by Director Prof David Llewellyn and Deputy Director Dr Janice Ranson, the leadership team additionally includes 5 Theme Leads and 14 Working Group Leads, supported by an international Steering Committee of world-leading academics. Core funding is provided by Alzheimer's Research UK, the Alan Turing Institute and the University of Exeter, with additional support from strategic partners including the UK Dementia Research Institute and the Alzheimer's Society. Grand Challenges were established at a National Strategy Workshop in June 2020. Multidisciplinary Working Groups were formed to coordinate practical activities in seven key areas: Genetics and omics, experimental medicine, drug discovery and trials optimisation, biomarkers, imaging, dementia prevention, and applied models and digital health. Additional Special Interest Groups coordinate topic specific collaborations. Membership on 4th February 2022 comprised 1,321 individuals from 61 countries across 6 continents (see Figure). Areas of expertise include dementia research (904; 68%), data science (692; 52%), clinical practice (244; 18%), industry (162; 12%), and regulation (26; 2%). Individual membership is free, and regular knowledge transfer events are provided including a monthly seminar series, talks and workshops, training, networking, and early career development. Each Working Group meets monthly, with multiple grants, reviews, and original research articles in progress. Eight state of the science position papers are in preparation, resulting from a Symposium held in April 2021. In January 2022, 110 early career researchers participated in the Network's flagship event 'NEUROHACK', a 4-day competitive global hackathon, with pilot grants awarded to those generating the most innovative solutions. The DEMON Network is a rapidly growing global platform for innovation that is supporting the global dementia research community to collaborate. Find out more at demondementia.com.

The Deep Dementia Phenotyping (DEMON) Network: A global platform for innovation using data science and artificial intelligence

AbstractBackgroundThe increasing availability of large high‐dimensional data from experimental medicine, population‐based and clinical cohorts, clinical trials, and electronic health records has the potential to transform dementia research. Our ability to make best use of this rich data will depend on utilisation of advanced machine learning and artificial intelligence (AI) techniques and collaboration across disciplinary and geographic boundaries.MethodThe Deep Dementia Phenotyping (DEMON) Network launched in 20191 to support the growing interest in machine learning and AI. Led by Director Prof David Llewellyn and Deputy Director Dr Janice Ranson, the leadership team additionally includes 5 Theme Leads and 14 Working Group Leads, supported by an international Steering Committee of world‐leading academics. Core funding is provided by Alzheimer’s Research UK, the Alan Turing Institute and the University of Exeter, with additional support from strategic partners including the UK Dementia Research Institute and the Alzheimer’s Society. Grand Challenges were established at a National Strategy Workshop in June 2020. Multidisciplinary Working Groups were formed to coordinate practical activities in seven key areas: Genetics and omics, experimental medicine, drug discovery and trials optimisation, biomarkers, imaging, dementia prevention, and applied models and digital health. Additional Special Interest Groups coordinate topic specific collaborations.ResultMembership on 4th February 2022 comprised 1,321 individuals from 61 countries across 6 continents (see Figure). Areas of expertise include dementia research (904; 68%), data science (692; 52%), clinical practice (244; 18%), industry (162; 12%), and regulation (26; 2%). Individual membership is free, and regular knowledge transfer events are provided including a monthly seminar series, talks and workshops, training, networking, and early career development. Each Working Group meets monthly, with multiple grants, reviews, and original research articles in progress. Eight state of the science position papers are in preparation, resulting from a Symposium held in April 2021. In January 2022, 110 early career researchers participated in the Network’s flagship event ‘NEUROHACK’, a 4‐day competitive global hackathon, with pilot grants awarded to those generating the most innovative solutions.ConclusionThe DEMON Network is a rapidly growing global platform for innovation that is supporting the global dementia research community to collaborate. Find out more at demondementia.com

Study within a review (SWAR).

Study within a review (SWAR).

Exploring the work and organisation of local Healthwatch in England: a mixed-methods ethnographic study

BackgroundLocal Healthwatch organisations are an important part of the landscape of health and care commissioning and provision in England. In addition, local Healthwatch organisations are a key means by which users of services are given voice to influence decisions about health and care commissioning and provision.ObjectiveWe aimed to explore and enhance the operation and impact of local Healthwatch in ensuring effective patient and public voice in the commissioning and provision of NHS services.DesignWe used mixed methods, including a national survey (96/150 responses, 68%); actor network theory-inspired ethnographic data collection in five local Healthwatch organisations (made up of 75 days’ fieldwork, 84 semistructured interviews, 114 virtual interviews, observations during the COVID-19 pandemic and documentary analysis) and serial interviews about experiences during the pandemic with 11 Healthwatch staff and four volunteers who were members of a Healthwatch Involvement Panel (which also guided data collection and analysis). Finally, we ran five joint interpretive forums to help make sense of our data.SettingOur five Healthwatch case study organisations are of varying size and organisational form and are located in different parts of England.ResultsWe found significant variation in the organisation and work of Healthwatch organisations nationally, including hosting arrangements, scale of operations, complexity of relationships with health and care bodies, and sources of income beyond core funding. Key points of divergence that were consequential for Healthwatch activities included the degree of autonomy from host organisations and local understandings of accountability to various constituencies. These points of divergence gave rise to very different modes of operation and different priorities for enacting the nationally prescribed responsibilities of Healthwatch organisations locally. Large variations in funding levels created Healthwatch organisations that diverged not just in scale but in focus. As the COVID-19 pandemic unfolded, Healthwatch found new approaches to giving voice to the views of the public and formed effective relationships with other agencies.RecommendationsWe identified generalisable principles of good practice regarding the collection and communication of evidence. Policy implications relate to (1) the overall funding regime for Healthwatch and potential inequalities in what is available to local populations and (2) the development of Healthwatch’s role given the evolution of local health and care systems since 2012.Future workFuture studies should explore (1) the consequences of the development of integrated care systems for local Healthwatch organisations, (2) Healthwatch in an international comparative perspective, (3) how the response to the COVID-19 pandemic has reconfigured the voluntary sector locally and (4) how Healthwatch responds formally and informally to a newly emerging focus on public health and health inequalities.LimitationsThe survey sought only self-reported information on impact and we were unable to recruit a Healthwatch that hosted several contracts.ConclusionsThe diversity of the Healthwatch network belies its otherwise unitary appearance. This diversity – especially in differential funding arrangements – has considerable implications for equity of access to influencing health and care planning and provision for residents across England.FundingThis project was funded by the National Institute for Health and Care Research (NIHR) Health and Social Care Delivery Research programme and will be published in full inHealth and Social Care Delivery Research; Vol. 10, No. 32. See the NIHR Journals Library website for further project information.

Derailed peripheral circadian genes in polycystic ovary syndrome patients alters peripheral conversion of androgens synthesis.

Do circadian genes exhibit an altered profile in peripheral blood mononuclear cells (PBMCs) of polycystic ovary syndrome (PCOS) patients and do they have a potential role in androgen excess? Our findings revealed that an impaired circadian clock could hamper the regulation of peripheral steroid metabolism in PCOS women. PCOS patients exhibit features of metabolic syndrome. Circadian rhythm disruption is involved in the development of metabolic diseases and subfertility. An association between shift work and the incidence of PCOS in females was recently reported. This is a retrospective case-referent study in which peripheral blood samples were obtained from 101 control and 101 PCOS subjects. PCOS diagnoses were based on Rotterdam Consensus criteria. This study comprised 101 women with PCOS and 101 control volunteers, as well as Swiss albino mice treated with dehydroepiandrosterone (DHEA) to induce PCOS development. Gene expression analyses of circadian and steroidogenesis genes in human PBMC and mice ovaries and blood were executed by quantitative real-time PCR. We observed aberrant expression of peripheral circadian clock genes in PCOS, with a significant reduction in the core clock genes, circadian locomotor output cycles kaput (CLOCK) (P ≤ 0.00001), brain and muscle ARNT-like 1 (BMAL1) (P ≤ 0.00001) and NPAS2 (P ≤ 0.001), and upregulation of their negative feedback loop genes, CRY1 (P ≤ 0.00003), CRY2 (P ≤ 0.00006), PER1 (P ≤ 0.003), PER2 (P ≤ 0.002), DEC1 (P ≤ 0.0001) and DEC2 (P ≤ 0.00005). Transcript levels of an additional feedback loop regulating BMAL1 showed varied expression, with reduced RORA (P ≤ 0.008) and increased NR1D1 (P ≤ 0.02) in PCOS patients in comparison with the control group. We also demonstrated the expression pattern of clock genes in PBMCs of PCOS women at three different time points. PCOS patients also exhibited increased mRNA levels of steroidogenic enzymes like StAR (P ≤ 0.0005), CYP17A1 (P ≤ 0.005), SRD5A1 (P ≤ 0.00006) and SRD5A2 (P ≤ 0.009). Knockdown of CLOCK/BMAL1 in PBMCs resulted in a significant reduction in estradiol production, by reducing CYP19A1 and a significant increase in dihydrotestosterone production, by upregulating SRD5A1 and SRD5A2 in PBMCs. Our data also showed that CYP17A1 as a direct CLOCK-BMAL1 target in PBMCs. Phenotypic classification of PCOS subgroups showed a higher variation in expression of clock genes and steroidogenesis genes with phenotype A of PCOS. In alignment with the above results, altered expression of ovarian core clock genes (Clock, Bmal1 and Per2) was found in DHEA-treated PCOS mice. The expression of peripheral blood core clock genes in DHEA-induced PCOS mice was less robust and showed a loss of periodicity in comparison with that of control mice. N/A. We could not evaluate the circadian oscillation of clock genes and clock-controlled genes over a 24-h period in the peripheral blood of control versus PCOS subjects. Additionally, circadian genes in the ovaries of PCOS women could not be evaluated due to limitations in sample availability, hence we employed the androgen excess mouse model of PCOS for ovarian circadian assessment. Clock genes were assessed in the whole ovary of the androgen excess mouse model of PCOS rather than in granulosa cells, which is another limitation of the present work. Our observations suggest that the biological clock is one of the contributing factors in androgen excess in PCOS, owing to its potential role in modulating peripheral androgen metabolism. Considering the increasing prevalence of PCOS and the rising frequency of delayed circadian rhythms and insufficient sleep among women, our study emphasizes the potential in modulating circadian rhythm as an important strategy in PCOS management, and further research on this aspect is highly warranted. This work was supported by the RGCB-DBT Core Funds and a grant (#BT/PR29996/MED/97/472/2020) from the Department of Biotechnology (DBT), India, to M.L. B.S.J. was supported by a DST/INSPIRE Fellowship/2015/IF150361 and M.B.K. was supported by the Research Fellowship from Council of Scientific & Industrial Research (CSIR) (10.2(5)/2007(ii).E.U.II). The authors declare no competing interests. N/A.

Healthcare workers’ views on mandatory SARS-CoV-2 vaccination in the UK: A cross-sectional, mixed-methods analysis from the UK-REACH study

SummaryBackgroundSeveral countries now have mandatory SARS-CoV-2 vaccination for healthcare workers (HCWs) or the general population. HCWs’ views on this are largely unknown. Using data from the nationwide UK-REACH study we aimed to understand UK HCW's views on improving SARS-CoV-2 vaccination coverage, including mandatory vaccination.MethodsBetween 21st April and 26th June 2021, we administered an online questionnaire via email to 17 891 UK HCWs recruited as part of a longitudinal cohort from across the UK who had previously responded to a baseline questionnaire (primarily recruited through email) as part of the United Kingdom Research study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH) nationwide prospective cohort study. We categorised responses to a free-text question “What should society do if people do not get vaccinated against COVID-19?” using qualitative content analysis. We collapsed categories into a binary variable: favours mandatory vaccination or not, using logistic regression to calculate its demographic predictors, and its occupational, health, and attitudinal predictors adjusted for demographics.FindingsOf 5633 questionnaire respondents, 3235 answered the free text question. Median age of free text responders was 47 years (IQR 36–56) and 2705 (74.3%) were female. 18% (n = 578) favoured mandatory vaccination (201 [6%] participants for HCWs and others working with vulnerable populations; 377 [12%] for the general population), but the most frequent suggestion was education (32%, n = 1047). Older HCWs (OR 1.84; 95% CI 1.44–2.34 [≥55 years vs 16 years to <40 years]), HCWs vaccinated against influenza (OR 1.49; 95% CI 1.11–2.01 [2 vaccines vs none]), and with more positive vaccination attitudes generally (OR 1.10; 95% CI 1.06–1.15) were more likely to favour mandatory vaccination, whereas female HCWs (OR= 0.79, 95% CI 0.63–0.96, vs male HCWs) and Black HCWs (OR=0.46, 95% CI 0.25–0.85, vs white HCWs) were less likely to.InterpretationOnly one in six of the HCWs in this large, diverse, UK-wide sample favoured mandatory vaccination. Building trust, educating, and supporting HCWs who are hesitant about vaccination may be more acceptable, effective, and equitable.FundingMRC-UK Research and Innovation grant (MR/V027549/1) and the Department of Health and Social Care (DHSC) via the National Institute for Health Research (NIHR). Core funding was also provided by NIHR Biomedical Research Centres.

Determinants of the incidence of non-academic staff in European and US HEIs

In this article, we contribute to the scant literature covering quantitative studies on the determinants of the non-academic staff incidence in higher education institutions by analysing how the proportion of non-academic staff is related to key features such as size, prestige, year of foundation and financial structure of universities. We apply nonlinear regression analysis to compare HEIs across Europe and the USA, taking into account time and cross-country heterogeneity of the two balanced panel datasets concerning European and American universities over a period of 6 years (2011–2016 for Europe and 2012–2017 for the USA). Evidence suggests that in both Europe and the USA, public and larger (if sufficiently large) as well as more research-oriented units are characterised by a higher proportion of non-academic staff. In Europe, we observe an inverted U-shaped effect of the share of non-personnel expenditure and the foundation year on the proportion of non-academic staff, while the proportion of non-academic staff decreases with the share of core and third-party funding. For the USA, we obtain similar findings except that the share of core funding and third-party funding is characterised by a U-shaped effect, and the impact of the share of non-personnel expenditure has no empirical effect on the proportion of non-academic staff. Additionally, we discover that some factors that contribute to the proportion of non-academic staff may constitute indicators of performance, suggesting the need for further research to extend our knowledge on the complex issue of the role played by non-academic staff in university performance.

Durvalumab (MEDI 4736) with extended neoadjuvant regimens in rectal cancer: A randomized phase II trial (PRIME-RT).

TPS231 Background: Advances in multi-modality treatment of locally advanced rectal cancer (LARC) have resulted in low local recurrence rates, but many patients still die from distant disease. There is increasing recognition that with neoadjuvant treatment some patients achieve a complete response and may avoid surgical resection. The PRIME-RT trial tests the inclusion of neoadjuvant immunotherapy with the aim of enhancing complete response rates, improving stoma-free survival and reducing distant relapse. Methods: PRIME-RT is a multi-centre, open label, phase II, randomised trial for patients with newly diagnosed LARC. Eligible patients are randomised to Arm A: short course radiotherapy (25 Gray in 5 fractions) with concomitant durvalumab, followed by durvalumab and FOLFOX chemotherapy, or Arm B: long course chemoradiotherapy (50 Gray to primary tumour, 45 Gray to elective nodes, in 25 fractions with capecitabine) with concomitant durvalumab followed by FOLFOX and durvalumab. The primary endpoint is complete response rate in each arm. Bio-specimens including serial tumour biopsies and peripheral blood samples are collected prior to, during, and following treatment to explore the molecular and immunological factors underpinning treatment response. The main trial will recruit up to 42 patients and commence after a safety run-in (n≥6) which is recruiting patients with metastatic disease. After opening in January 2021, three patients have been treated within the safety run-in; 2 in Arm A and 1 in Arm B. Early recruitment to PRIME-RT has shown that adding immunotherapy in the neoadjuvant setting for LARC is feasible. The expectation is that the trial will provide efficacy and safety information which allows the optimal treatment approach to be tested within a larger phase clinical trial. Funding information Core funding (Glasgow CRUK CTU) and trial specific funding (Astrazeneca). Trial registration Clinicaltrials.gov NCT04621370 (Registered 9 Nov 2020) ISRCTN18138369 (Registered 27 October 2020) Clinical trial information: NCT04621370.

Directions and Prospects of Interaction of the Security Service of Ukraine With the ember-Countries of the Guam Organization in the Sphere of Ensuring Cyber Security and Countering Cyber Threats

Analysis of cyberattacks on the critical information infrastructure of Ukraine, and the fact of its increased complexity and more sophisticated relevant tools show the engagement of unfriendly countries, especially such as the Russian Federation, in destructive activities in Ukrainian cyberspace: in fact, Ukraine has become a testing ground for new cyber weapons and malicious strategies. Considering the cross-border nature of modern cyber threats and the priority of the Euro-Atlantic course of our country, an important vector of the activities of the Security Service of Ukraine has been to establish effective cooperation with international partners in combating cyber terrorism and hybrid aggression in cyberspace. Having this in mind the Security Service of Ukraine has established and maintained a high level of cooperation with intelligence services and law enforcement agencies in Europe, Asia and North America, as well as with key international organizations such as NATO, the OSCE, the Council of Europe, the UNO, the GUAM and others. At the same time, the Security Service of Ukraine has recently taken a proactive role as an initiator of innovations in the field of regional and international cybersecurity in relevant organizations. The issues of international cooperation of the Security Service of Ukraine in the field of cybersecurity within the framework of international and regional organizations were examined by such Ukrainian experts as V. Petrov, V. Khlevytsky, S. Bondarenko, O. Klimchuk, S. Petrov, N. Tkachuk, D. Melnyk and others. At the same time, these works, according to the authors’ opinion, do not reveal the features of international cooperation between the Security Service of Ukraine and the relevant special and law enforcement agencies of the Organization for Democracy and Economic Development GUAM in the field of cybersecurity and countering cyber threats. Given that Ukraine has recently been the object of cyberattacks, the sources of which originate from the Russian Federation, the establishment of the GUAM Regional Cybersecurity Center in Ukraine will help to strengthen the cyber security capacity of GUAM member countries. Moreover, the operation of this centre in our country, taking into account existing strong international contacts of Ukraine with NATO, EU, Council of Europe, OSCE, will help to create additional mechanisms for GUAM member states to exchange best world practices in cybersecurity as well as combating cybercrime, to increase the level of expertise of GUAM member states’ experts in these fields and to help improve the Organization’s image on the international arena. In this regard the Security Service of Ukraine should support the possible deployment of the technological component of the Center on the basis of the GUAM Secretariat in Ukraine, with the purpose of establishing the educational processes, information exchange, as well as remote access of relevant state bodies of GUAM member states. The provision of core funding of the future Center should be worked out within the framework of GUAM’s international cooperation with the USA, Japan, the EU, etc.

Conscience absolutism via legislative amendment

On 30 June 2021, Ohio state Governor, Mike DeWine, signed a Bill which would enact the state's budget for the next two years. In addition to its core funding imperatives, the Bill also contained an amendment significantly expanding entitlements of health care providers to conscientiously object to professional duties to provide controversial health care services. This amendment has been heavily criticised as providing the means to allow health care providers to discriminate against a wide range of persons by denying them access to often contested services such as abortion and contraception. In this paper, we examine the implications of this amendment and situate it in relation to other legislative actions intended to guarantee absolute rights to conscientious objection. In doing so, we argue that the entitlements extended to health care providers by these Bills are overly broad and ignore their potential to allow significant harm to be caused to clients. We then argue that if health care providers should have rights to conscientiously object (a question we do not try an answer here), then any legislation intended to protect such rights should be limited, specific, and parsimonious. Where it is not, the ideological liberty of HCPs treads dangerously on the physical freedom of their clients.

Measuring the impact of COVID-19 on sexual and reproductive health in the UK: web-panel surveys with qualitative follow-up

BackgroundThe UK's National Surveys of Sexual Attitudes and Lifestyles (Natsal) have been done every 10 years since 1990, and provide a key data source to underpin sexual and reproductive health policy. The COVID-19 pandemic disrupted many lifestyle aspects, triggering an urgent need for population-level data on sexual behaviour, relationships, and service use at a time when gold-standard, in-person, household-based surveys with probability sampling were not feasible. We designed the Natsal-COVID study to understand the effect of COVID-19 on the nation's sexual and reproductive health. MethodsData were collected over 4 months (survey wave one; July 29 to Aug 10, 2020) and 1 year (wave two; March 27 to April 26, 2021) after the announcement of the UK's first lockdown (March 23, 2020). Data were collected online via web-panel surveys administered by Ipsos MORI. Eligible participants were UK residents aged 18–59 years, and the samples included a boost of those aged 18–29 years. Questions covered participants' sexual behaviour, relationships, and sexual and reproductive health service use. Quotas and weighting were used to achieve a quasi-representative sample of the UK general population. Participants meeting criteria of interest and agreeing to be recontacted were selected for qualitative follow-up interviews over the months of October and November, 2020. Comparisons were made with contemporaneous national probability surveys (2019 Annual Population Survey and 2018 Health Survey for England) and Natsal-3 (2010–12) to understand bias in sociodemographic characteristics, general health, and sexual behaviours. We obtained ethical approval from the ethics committees of the University of Glasgow College of Medical, Veterinary & Life Sciences College (reference 20019174) and the London School of Hygiene & Tropical Medicine Research (reference 22565). Findings6654 participants completed wave one of the study, of which 45 (0·7%) completed qualitative interviews. A further 6658 participants completed wave two, of which 2098 (31·5%) were wave one participants. Compared with probability surveys, the weighted Natsal-COVID participants were more educated, less sexually experienced, and in poorer health. In wave one, we found that 20·8% of respondents (95% CI 19·3–22·3%) reported using sexual and reproductive health services in the first 4 months of lockdown, whereas 9·7% (8·6–10·8%) reported difficulty accessing services. Wave two allowed for the generation of 1-year estimates, including of chlamydia testing (5·4% [4·7–6·2%]), HIV testing (7·2% [6·4–8·1%]), and cervical cancer screening (10·3% [9·2–11·6%]). Qualitative interviews suggested that participants often required repeated attempts to access sexual and reproductive health services. InterpretationNatsal-COVID rapidly collected quasi-representative population data to evaluate the population-level effect of COVID-19 and lockdown measures on sexual and reproductive health in the UK and to inform sexual and reproductive health policy. Although less representative than the decennial Natsals, Natsal-COVID will complement national surveillance data and Natsal-4 (planned for 2022). FundingNatsal is a collaboration between University College London (UK), the London School of Hygiene & Tropical Medicine (UK), the University of Glasgow (UK), Örebro University Hospital (Sweden), and NatCen Social Research (UK). The Natsal Resource, which is supported by the Wellcome Trust (via grant number 212931/Z/18/Z), with contributions from the UK's Economic and Social Research Council and National Institute for Health Research, supports the Natsal-COVID study through funding from the University College London COVID-19 Rapid Response Fund and the MRC/CSO Social and Public Health Sciences Unit (Core funding, grant numbers MC_UU_00022/3 and SPHSU18). The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Dairy intake and risk of major cardiovascular events: a prospective cohort study of 0.5 million Chinese adults

Abstract Background Evidence on the association between dairy consumption and risk of cardiovascular disease has been highly inconsistent, with findings suggesting either harmful, neutral or beneficial effects. In addition, a very large majority of the previous studies on this topic were conducted among populations in Europe and North America who usually consume a higher amount of dairy products and very few data, particularly prospective data, come from China where the dairy consumption level is low. Purpose We therefore investigated the associations between intake of dairy products and incidence of several major types of cardiovascular diseases in Chinese adults. Methods During 2004–2008, the prospective China Kadoorie Biobank Study recruited slightly over 0.5 million adults from ten diverse regions (five urban and five rural) across China. Information on the consumption frequency of dairy products was collected at baseline and periodic resurveys, using a validated interviewer-administered laptop-based questionnaire. Over a mean follow-up of 10.9 years, there were 47,128 incident ischaemic heart disease events, 43,481 ischaemic strokes and 9749 intracerebral haemorrhages among 489,595 study participants, who did not report a prior history of cardiovascular disease at baseline. Cox regression analyses were performed to estimate multivariable-adjusted hazard ratios (HRs) for incident events associated with dairy intake. Results Overall, 69.3% of participants reported never or rare consumption (i.e. non-consumers) and 11.3% of them reported regular consumption (i.e. ≥4 days/week) of dairy products, with milk accounting for the largest proportion of total dairy intake (∼77%). Male and female regular dairy consumers had 2.1/1.5 and 1.7/1.1 mmHg lower systolic/diastolic blood pressure, respectively compared to non-consumers. In a subset (∼18,000) of participants with blood lipid levels measured, regular dairy consumers had ∼0.1 mmol/L higher LDL levels than non-consumers. After adjusting for a range of potential confounders, including sociodemographic and lifestyle factors, BMI and other dietary factors, dairy consumption was positively and significantly associated with risk of ischaemic heart disease, with the adjusted HR per 50 g/day increase in usual dairy consumption being 1.11 (95% confidence interval [CI] 1.09–1.14). Dairy consumption was not significantly associated with risk of ischemic stroke but was inversely associated with risk of intracerebral haemorrhage, with each 50 g/day increase in usual dairy consumption being associated with 17% lower risk (HR 0.83, 0.78–0.88). These associations remained significant after additional adjustment for systolic blood pressure. Conclusion In this large study of Chinese adults, higher intake of dairy products was associated with a higher risk of ischaemic heart disease but a lower risk of intracerebral haemorrhage. The exact mechanisms underlying such associations require further investigation. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The CKB baseline survey and the first re-survey were supported by the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up has been supported by Wellcome grants to Oxford University (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z) and grants from the National Key Research and Development Program of China (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) and from the National Natural Science Foundation of China (91843302). The UK Medical Research Council (MC_UU_00017/1,MC_UU_12026/2 MC_U137686851), Cancer Research UK (C16077/A29186; C500/A16896) and the British Heart Foundation (CH/1996001/9454), provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University for the project.

Associations of red meat, poultry, fish and egg intake with risk of cardiovascular disease: an 11-year prospective study of the China Kadoorie Biobank

Abstract Background Higher red meat intake and lower fish intake have been associated with increased risk of cardiovascular disease (CVD), while the relevance of poultry and egg intake for CVD incidence remains inconclusive. Furthermore, most of the prospective evidence comes from studies in the Western populations, with limited data from China where the CVD patterns are largely different. Purpose We therefore investigated the associations of red meat, poultry, fish and egg intake with risks of several major types of CVD in Chinese adults. Methods The China Kadoorie Biobank is a prospective study which recruited ∼512,000 adult participants from ten diverse localities during 2004–08. At baseline and periodic resurveys, information on the consumption frequency of major food groups was collected using a validated interviewer-administered laptop-based questionnaire, together with medical history, socio-demographic and other lifestyle factors. During an average follow-up of 10.9 years, 47,128 incident ischaemic heart disease events, 43,481 ischaemic strokes and 9749 intracerebral haemorrhages were recorded among 489,595 participants, who did not have a prior history of CVD at baseline. Cox regression was used to calculate adjusted hazard ratios (HRs) relating dietary exposures to CVD risk. Results There were 47.2%, 1.4%, 9.0% and 24.1% of participants at baseline who regularly consumed (i.e. ≥4 days/week) red meat, poultry, fish and eggs, respectively. After adjusting for potential confounders, including body mass index and other dietary factors under study, egg consumption was significantly associated with lower risks of ischaemic heart disease and ischaemic stroke, with each 50 g/day increase in estimated habitual egg consumption being associated with 18% (HR 0.82, 95% confidence interval [CI] 0.75–0.90) and 24% lower risks (HR 0.76, 95% CI 0.69–0.84), respectively. Inverse associations were also observed between intakes of red meat, fish and eggs and risk of intracerebral haemorrhage, with adjusted HRs for 50 g/day higher intake being 0.84 (95% CI 0.74–0.97), 0.86 (95% CI 0.74–0.99) and 0.42 (95% CI 0.34–0.51), respectively. Conclusion This large prospective study of Chinese adults showed that higher intake of eggs was associated with lower risks of ischaemic heart disease and ischaemic stroke. Moreover, higher intakes of red meat, fish and eggs were each associated with a lower risk of intracerebral haemorrhage. Further investigation of the potential mechanisms that underlie the observed associations is required. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The CKB baseline survey and the first re-survey were supported by the Kadoorie Charitable Foundation in Hong Kong. The long-term follow-up has been supported by Wellcome grants to Oxford University (212946/Z/18/Z, 202922/Z/16/Z, 104085/Z/14/Z, 088158/Z/09/Z) and grants from the National Key Research and Development Program of China (2016YFC0900500, 2016YFC0900501, 2016YFC0900504, 2016YFC1303904) and from the National Natural Science Foundation of China (91843302). The UK Medical Research Council (MC_UU_00017/1,MC_UU_12026/2 MC_U137686851), Cancer Research UK (C16077/A29186; C500/A16896) and the British Heart Foundation (CH/1996001/9454), provide core funding to the Clinical Trial Service Unit and Epidemiological Studies Unit at Oxford University for the project. MG. Kakkoura is supported by the Wellcome Trust, Our Planet Our Health (Livestock, Environment and People - LEAP) (205212/Z/16/Z).

The Innovation Delusion: How Our Obsession with the New Has Disrupted the Work That Matters Most

The Innovation Delusion: How Our Obsession with the New Has Disrupted the Work That Matters Most