Past approaches and future directions for targeting tumor hypoxia in squamous cell carcinomas of the head and neck

AbstractRecurrent squamous cell carcinoma of the head and neck (SCCHN) carries a poor prognosis. Tumor hypoxia (TH) has been implicated as one of many factors contributing to SCCHN recurrence. TH leads to radiation resistance by reversing radiation-induced DNA damage. Effective strategies to overcome TH may improve outcomes in patients with SCCHN. We searched the English literature on PubMed and reviewed the reference sections of key articles related to TH (publications spanning from the early 1900s to the present). We summarized the underlying theory of TH in SCCHN, methods for quantifying it, and the numerous therapies developed to modulate it. We included articles that set the foundation of TH as a theory and the most relevant articles published within the last 15 years related to TH quantification and therapeutic targeting. Despite extensive research, targeting TH in SCCHN has not become a part of routine clinical practice in North America, and we analyze the pitfalls in hypoxia research that have led to this failure. We propose that future studies should test a combined approach of targeting the immune system in addition to cellular pathways rendered aberrant in TH and should include development of novel surrogate markers of TH and/or TH imaging

Effect of farm system and milk urea phenotype on milk yield and milk composition of dairy cows in Canterbury

To investigate the effect of farm system, and cow selection for milk urea nitrogen (MUN), on milk yield and milk composition, a farmlet study was carried out between October 2018 and May 2019 in Lincoln, Canterbury. A farm system with a low stocking rate and low N fertiliser input (LSR, 2.9 cows/ha) sown with a conventional ryegrass clover and plantain diverse pastures was compared with a farm system with a moderate stocking rate and moderate N fertiliser (MSR, 3.9 cows/ha) using conventional ryegrass and white clover pastures and supplementing 3 kg DM/cow/d as crushed barley grain. Each farmlet had total herd size of 40 mixed-age HF x J spring-calving dairy cows which included six cows selected solely for a high MUN or a low MUN. There was no effect of farm system on milk fat, protein or lactose content but MUN was lower in LSR compared with MSR. Milk production was also lower for LSR (466 vs 429±12.4 kg MS/cow/ha, P<0.05), owing to poorer quality diet in mid lactation. Cows selected for low MUN tended to produce less milk compared with high MUN cows (4478 vs 3987±174 kg/cow, P<0.10) though this was partially offset by increased protein content in milk of low MUN cows. Farm system and animal selection for MUN have a greater impact on milk yield than on milk composition

Time, monetary and other costs of participation in family-based child weight management interventions: qualitative and systematic review evidence.

BACKGROUND: Childhood overweight and obesity have health and economic impacts on individuals and the wider society. Families participating in weight management programmes may foresee or experience monetary and other costs which deter them from signing up to or completing programmes. This is recognised in the health economics literature, though within this sparse body of work, costs to families are often narrowly defined and not fully accounted for. A societal perspective incorporating a broader array of costs may provide a more accurate picture. This paper brings together a review of the health economics literature on the costs to families attending child weight management programmes with qualitative data from families participating in a programme to manage child overweight and obesity. METHODS: A search identified economic evaluation studies of lifestyle interventions in childhood obesity. The qualitative work drew on interviews with families who attended a weight management intervention in three UK regions. RESULTS: We identified four cost-effectiveness analyses that include information on costs to families. These were categorised as direct (e.g. monetary) and indirect (e.g. time) costs. Our analysis of qualitative data demonstrated that, for families who attended the programme, costs were associated both with participation on the scheme and with maintaining a healthy lifestyle afterwards. Respondents reported three kinds of cost: time-related, social/emotional and monetary. CONCLUSION: Societal approaches to measuring cost-effectiveness provide a framework for assessing the monetary and non-monetary costs borne by participants attending treatment programmes. From this perspective, all costs should be considered in any analysis of cost-effectiveness. Our data suggest that family costs are important, and may act as a barrier to the uptake, completion and maintenance of behaviours to reduce child obesity. These findings have implications for the development and implementation of child weight initiatives in particular, in relation to reducing inequalities in health

Wnt2 and WISP-1/CCN4 induce intimal thickening via promotion of smooth muscle cell migration

Objective—Increased vascular smooth muscle cell (VSMC) migration leads to intimal thickening which acts as a soil for atherosclersosis, as well as causing coronary artery restenosis after stenting and vein graft failure. Investigating factors involved in VSMC migration may enable us to reduce intimal thickening and improve patient outcomes. In this study, we determined whether Wnt proteins regulate VSMC migration and thereby intimal thickening. Approach and Results—Wnt2 mRNA and protein expression were specifically increased in migrating mouse aortic VSMCs. Moreover, VSMC migration was induced by recombinant Wnt2 in vitro. Addition of recombinant Wnt2 protein increased Wnt1-inducible signaling pathway protein-1 (WISP-1) mRNA by ≈1.7-fold, via β-catenin/T-cell factor signaling, whereas silencing RNA knockdown of Wnt-2 reduced WISP-1 mRNA by ≈65%. Treatment with rWISP-1 significantly increased VSMC migration by ≈1.5-fold, whereas WISP-1 silencing RNA knockdown reduced migration by ≈40%. Wnt2 and WISP-1 effects were integrin-dependent and not additive, indicating that Wnt2 promoted VSMC migration via WISP-1. Additionally, Wnt2 and WISP-1 were significantly increased and colocated in human coronary arteries with intimal thickening. Reduced Wnt2 and WISP-1 levels in mouse carotid arteries from Wnt2+/− and WISP-1−/− mice, respectively, significantly suppressed intimal thickening in response to carotid artery ligation. In contrast, elevation of plasma WISP-1 via an adenovirus encoding WISP-1 significantly increased intimal thickening by ≈1.5-fold compared with mice receiving control virus. Conclusions—Upregulation of Wnt2 expression enhanced WISP-1 and promoted VSMC migration and thereby intimal thickening. As novel regulators of VSMC migration and intimal thickening, Wnt2 or WISP-1 may provide a potential therapy for restenosis and vein graft failure

Evaluating the impact of a very low-cost intervention to increase practices’ engagement with data and change prescribing behaviour: a randomized trial in English primary care

Background Unsolicited feedback can solicit changes in prescribing. Objectives Determine whether a low-cost intervention increases clinicians’ engagement with data, and changes prescribing; with or without behavioural science techniques. Methods Randomized trial (ISRCTN86418238). The highest prescribing practices in England for broad-spectrum antibiotics were allocated to: feedback with behavioural impact optimization; plain feedback; or no intervention. Feedback was sent monthly for 3 months by letter, fax and email. Each included a link to a prescribing dashboard. The primary outcomes were dashboard usage and change in prescribing. Results A total of 1401 practices were randomized: 356 behavioural optimization, 347 plain feedback, and 698 control. For the primary engagement outcome, more intervention practices had their dashboards viewed compared with controls [65.7% versus 55.9%; RD 9.8%, 95% confidence intervals (CIs): 4.76% to 14.9%, P < 0.001]. More plain feedback practices had their dashboard viewed than behavioural feedback practices (69.1% versus 62.4%); but not meeting the P < 0.05 threshold (6.8%, 95% CI: −0.19% to 13.8%, P = 0.069). For the primary prescribing outcome, intervention practices possibly reduced broad-spectrum prescribing to a greater extent than controls (1.42% versus 1.12%); but again not meeting the P < 0.05 threshold (coefficient −0.31%, CI: −0.7% to 0.1%, P = 0.104). The behavioural impact group reduced broad-spectrum prescribing to a greater extent than plain feedback practices (1.63% versus 1.20%; coefficient 0.41%, CI: 0.007% to 0.8%, P = 0.046). No harms were detected. Conclusions Unsolicited feedback increased practices’ engagement with data, with possible slightly reduced antibiotic prescribing (P = 0.104). Behavioural science techniques gave greater prescribing effects. The modest effects on prescribing may reflect saturation from similar initiatives on antibiotic prescribing. Clinical Trial Registration ISRCTN86418238

Trends and variation in antidepressant prescribing in English primary care: a retrospective longitudinal study

Background Antidepressants are commonly prescribed. There are clear national guidelines in relation to treatment sequencing. This study examines trends and variation in antidepressant prescribing across English primary care. Aim To examine trends and variation in antidepressant prescribing in England, with a focus on: monoamine oxidase inhibitors (MAOIs); paroxetine; and dosulepin and trimipramine. Design & amp; Retrospective longitudinal study using national and practice-level data on antidepressant items prescribed per year (1998–2018) and per month (2010–2019). Method Class- and drug-specific proportions were calculated at national and practice levels. Descriptive statistics were generated, percentile charts and maps were plotted, and logistic regression analysis was conducted. Results Antidepressant prescriptions more than tripled between 1998 and 2018, from 377 items per 1000 population to 1266 per 1000. MAOI prescribing fell substantially, from 0.7% of all antidepressant items in 1998 to 0.1% in 2018. There was marked variation between practices in past year prescribing of paroxetine (median practice proportion [MPP] = 1.7%, interdecile range [IDR] = 2.6%) and dosulepin (MPP = 0.7%, IDR = 1.8%), but less for trimipramine (MPP = 0%, IDR = 0.2%). Conclusion Rapid growth and substantial variation in antidepressant prescribing behaviour was found between practices. The causes could be explored using mixed-methods research. Interventions to reduce prescribing of specific antidepressants, such as dosulepin, could include review prompts, alerts at the time of prescribing, and clinician feedback through tools like OpenPrescribing.net

Scaling up community-based goat breeding programmes via multi-stakeholder collaboration

Community-based livestock breeding programmes (CBBPs) have emerged as a potential approach to implement sustainable livestock breeding in smallholder systems. In Malawi and Uganda, goat CBBPs were introduced to improve production and productivity of indigenous goats through selective breeding. Scaling up CBBPs have recently received support due to evidence-based results from current implementation and results of CBBPs implemented in other regions of the world. This paper explores strategies for scaling up goat CBBPs in Malawi and Uganda, and documents experiences and lessons learned during implementation of the programme. A number of stakeholders supporting goat-based interventions for improving smallholders’ livelihoods exists. This offers an opportunity for different actors to work together by pooling financial resources and technical expertise for establishment and sustainability of goat CBBPs. Scaling up strategies should be an integral part of the pilot design hence dissemination partners need to be engaged during the design and inception stages of the pilot CBBPs. Creation of self-sustaining CBBPs requires early collaborative programme planning, meaningful investment and long-term concerted and coordinated efforts by collaborating partners. Permanently established actors, like government agencies and research and training institutions, are better placed to coordinate such efforts. The overall goal of the scaling up programme should be creation of a financially sustainable system, in which smallholders are able, on their own, to transact and sustain operations of their local breeding institutions using locally generated revenue/ resources. Since CBBP scaling up is a ‘learning by doing process’, an effective monitoring and evaluation system should be an integral part of the process

Comparative effectiveness of BNT162b2 versus mRNA-1273 covid-19 vaccine boosting in England: matched cohort study in OpenSAFELY-TPP

Objective To compare the effectiveness of the BNT162b2 mRNA (Pfizer-BioNTech) and mRNA-1273 (Moderna) covid-19 vaccines during the booster programme in England. Design Matched cohort study, emulating a comparative effectiveness trial. Setting Linked primary care, hospital, and covid-19 surveillance records available within the OpenSAFELY-TPP research platform, covering a period when the SARS-CoV-2 delta and omicron variants were dominant. Participants 3 237 918 adults who received a booster dose of either vaccine between 29 October 2021 and 25 February 2022 as part of the national booster programme in England and who received a primary course of BNT162b2 or ChAdOx1. Intervention Vaccination with either BNT162b2 or mRNA-1273 as a booster vaccine dose. Main outcome measures Recorded SARS-CoV-2 positive test, covid-19 related hospital admission, covid-19 related death, and non-covid-19 related death at 20 weeks after receipt of the booster dose. Results 1 618 959 people were matched in each vaccine group, contributing a total 64 546 391 person weeks of follow-up. The 20 week risks per 1000 for a positive SARS-CoV-2 test were 164.2 (95% confidence interval 163.3 to 165.1) for BNT162b2 and 159.9 (159.0 to 160.8) for mRNA-1273; the hazard ratio comparing mRNA-1273 with BNT162b2 was 0.95 (95% confidence interval 0.95 to 0.96). The 20 week risks per 1000 for hospital admission with covid-19 were 0.75 (0.71 to 0.79) for BNT162b2 and 0.65 (0.61 to 0.69) for mRNA-1273; the hazard ratio was 0.89 (0.82 to 0.95). Covid-19 related deaths were rare: the 20 week risks per 1000 were 0.028 (0.021 to 0.037) for BNT162b2 and 0.024 (0.018 to 0.033) for mRNA-1273; hazard ratio 0.83 (0.58 to 1.19). Comparative effectiveness was generally similar within subgroups defined by the primary course vaccine brand, age, previous SARS-CoV-2 infection, and clinical vulnerability. Relative benefit was similar when vaccines were compared separately in the delta and omicron variant eras. Conclusions This matched observational study of adults estimated a modest benefit of booster vaccination with mRNA-1273 compared with BNT162b2 in preventing positive SARS-CoV-2 tests and hospital admission with covid-19 20 weeks after vaccination, during a period of delta followed by omicron variant dominance

Effect of pre-exposure use of hydroxychloroquine on COVID-19 mortality: a population-based cohort study in patients with rheumatoid arthritis or systemic lupus erythematosus using the OpenSAFELY platform.

BACKGROUND: Hydroxychloroquine has been shown to inhibit entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into epithelial cells in vitro, but clinical studies found no evidence of reduced mortality when treating patients with COVID-19. We aimed to evaluate the effectiveness of hydroxychloroquine for prevention of COVID-19 mortality, as opposed to treatment for the disease. METHODS: We did a prespecified observational, population-based cohort study using national primary care data and linked death registrations in the OpenSAFELY platform, which covers approximately 40% of the general population in England, UK. We included all adults aged 18 years and older registered with a general practice for 1 year or more on March 1, 2020. We used Cox regression to estimate the association between ongoing routine hydroxychloroquine use before the COVID-19 outbreak in England (considered as March 1, 2020) compared with non-users of hydroxychloroquine and risk of COVID-19 mortality among people with rheumatoid arthritis or systemic lupus erythematosus. Model adjustment was informed by a directed acyclic graph. FINDINGS: Between Sept 1, 2019, and March 1, 2020, of 194 637 people with rheumatoid arthritis or systemic lupus erythematosus, 30 569 (15·7%) received two or more prescriptions of hydroxychloroquine. Between March 1 and July 13, 2020, there were 547 COVID-19 deaths, 70 among hydroxychloroquine users. Estimated standardised cumulative COVID-19 mortality was 0·23% (95% CI 0·18 to 0·29) among users and 0·22% (0·20 to 0·25) among non-users; an absolute difference of 0·008% (-0·051 to 0·066). After accounting for age, sex, ethnicity, use of other immunosuppressive drugs, and geographical region, no association with COVID-19 mortality was observed (HR 1·03, 95% CI 0·80 to 1·33). We found no evidence of interactions with age or other immunosuppressive drugs. Quantitative bias analyses indicated that our observed associations were robust to missing information for additional biologic treatments for rheumatological disease. We observed similar associations with the negative control outcome of non-COVID-19 mortality. INTERPRETATION: We found no evidence of a difference in COVID-19 mortality among people who received hydroxychloroquine for treatment of rheumatological disease before the COVID-19 outbreak in England. Therefore, completion of randomised trials investigating pre-exposure prophylactic use of hydroxychloroquine for prevention of severe outcomes from COVID-19 are warranted. FUNDING: Medical Research Council

Measuring the impact and costs of a universal group based parenting programme : protocol and implementation of a trial

Background Sub-optimal parenting is a common risk factor for a wide range of negative health, social and educational outcomes. Most parenting programmes have been developed in the USA in the context of delinquency prevention for targeted or indicated groups and the main theoretical underpinning for these programmes is behaviour management. The Family Links Nurturing Programme (FLNP) focuses on family relationships as well as behaviour management and is offered on a universal basis. As a result it may be better placed to improve health and educational outcomes. Developed in the UK voluntary sector, FLNP is popular with practitioners, has impressed policy makers throughout the UK, has been found to be effective in before/after and qualitative studies, but lacks a randomised controlled trial (RCT) evidence base. Methods/Design A multi-centre, investigator blind, randomised controlled trial of the FLNP with a target sample of 288 south Wales families who have a child aged 2-4 yrs living in or near to Flying Start/Sure Start areas. Changes in parenting, parent child relations and parent and child wellbeing are assessed with validated measures immediately and at 6 months post intervention. Economic components include cost consequences and cost utility analyses based on parental ranking of states of quality of life. Attendance and completion rates and fidelity to the FLNP course delivery are assessed. A nested qualitative study will assess reasons for participation and non-participation and the perceived value of the programme to families. By the end of May 2010, 287 families have been recruited into the trial across four areas of south Wales. Recruitment has not met the planned timescales with barriers including professional anxiety about families entering the control arm of the trial, family concern about video and audio recording, programme facilitator concern about the recording of FLNP sessions for fidelity purposes and delays due to the new UK research governance procedures. Discussion Whilst there are strong theoretical arguments to support universal provision of parenting programmes, few universal programmes have been subjected to randomised controlled trials. In this paper we describe a RCT protocol with quantitative and qualitative outcome measures and an economic evaluation designed to provide clear evidence with regard to effectiveness and costs. We describe challenges implementing the protocol and how we are addressing these