The effect of supplementary grass silage and standard concentrate on milk fat fatty acid composition and iodine value when cows are fed a whole rapeseed-based concentrate at pasture

peer-reviewedThe use of grass silage and concentrates to supplement fresh grass intake is commonly practised in dairy systems. However, the effects of such supplementation within a dietary regime designed to produce a spreadable butter are unknown. Sixteen Holstein Friesian cows were used in an incomplete changeover design to investigate the effect on milk fat of supplementation with grass silage (GS) or standard concentrate (SC) when offering a concentrate based on whole rapeseed at pasture (RC+G). A control diet of fresh grass and standard concentrate (SC+G) was also included. Diet had no effect (P > 0.05) on milk yield or on the lactose concentration of milk. The iodine value (IV; grams of iodine per 100 g milk fat) of milk fat with the RC+G diet was greater (43.9, P < 0.05) than with the SC+G diet (39.9). The iodine value of milk fat was reduced (P < 0.05) when RC+G+GS was offered (41.5 g/100g), but not when RC+G+SC was offered (43.1 g/100g), compared with when RC+G was offered. The proportion of unsaturated fatty acids in milk fat was higher (P < 0.05) when the RC+G diet was offered compared with either RC+G+GS or RC+G+SC. If supplementary feedstuffs are to be used in combination with a wholerapeseed- based concentrate and pasture, then inclusion of standard concentrate would be preferred over grass silage because the negative impact on the iodine value of milk fat was less. However, further research is required to investigate the effect on IV of milk fat when a standard concentrate supplement is offered at levels that increase milk yield

Dissection of drug resistance mechanisms in FGFR2 mutant endometrial cancer.

PhDMutations in FGFR2 are common in a subset of endometrial carcinomas. Given the emergence of small molecule inhibitors specific to this receptor tyrosine kinase, FGFR2 is an attractive therapeutic target. However, compensatory and adaptation mechanisms limit the clinical utility of compounds that target nodes in the receptor tyrosine kinase network. Here, we analysed the impact of FGFR inhibition in endometrial cancer cells and observed the emergence of a resistant population in an FGFR2-mutant cell line. To understand the mechanisms underlying this adaptation response, we used a phosphoproteomics approach to measure the kinase network in an unbiased manner. These experiments led to the identification of an AKT-related compensatory mechanism underpinning this resistance. Further dissection of this resistance mechanism utilising gene expression analysis showed PHLDA1, a negative regulator of AKT, was significantly down-regulated in resistant cells. This was further confirmed at the protein level. siRNA knockdown of PHLDA1 conferred immediate drug resistance in the FGFR2-mutant endometrial cancer cell line. Therefore, we identified PHLDA1 down-regulation as a mediator of drug resistance in FGFR2 mutant cancer cells, the first demonstration of the role of PHLDA1 in the acquisition and maintenance of drug resistance. Using a 3D physiomimetic model, we demonstrated that AKT inhibition alone also led to generation of a drug-resistant population. Most importantly, dual-drug therapy inhibited proliferation and induced cell death. Our data highlight how mass spectrometry and microarray gene expression analysis can complement each other in the identification of novel resistance mechanisms in cancer cells. These data suggest that combination treatment of FGFR2-mutant endometrial cancers, targeting both FGFR2 and AKT, represents a promising therapeutic approach.Cancer Research U

Public target interventions to reduce the inappropriate use of medicines or medical procedures: a systematic review.

BACKGROUND: An epidemic of health disorders can be triggered by a collective manifestation of inappropriate behaviors, usually systematically fueled by non-medical factors at the individual and/or societal levels. This study aimed to (1) landscape and assess the evidence on interventions that reduce inappropriate demand of medical resources (medicines or procedures) by triggering behavioral change among healthcare consumers, (2) map out intervention components that have been tried and tested, and (3) identify the "active ingredients" of behavior change interventions that were proven to be effective in containing epidemics of inappropriate use of medical resources. METHODS: For this systematic review, we searched MEDLINE, EMBASE, the Cochrane Library, and PsychINFO from the databases' inceptions to May 2019, without language restrictions, for behavioral intervention studies. Interventions had to be empirically evaluated with a control group that demonstrated whether the effects of the campaign extended beyond trends occurring in the absence of the intervention. Outcomes of interest were reductions in inappropriate or non-essential use of medicines and/or medical procedures for clinical conditions that do not require them. Two reviewers independently screened titles, abstracts, and full text for inclusion and extracted data on study characteristics (e.g., study design), intervention development, implementation strategies, and effect size. Data extraction sheets were based on the checklist from the Cochrane Handbook for Systematic Reviews. RESULTS: Forty-three studies were included. The behavior change technique taxonomy v1 (BCTTv1), which contains 93 behavioral change techniques (BCTs), was used to characterize components of the interventions reported in the included studies. Of the 93 BCTs, 15 (16%) were identified within the descriptions of the selected studies targeting healthcare consumers. Interventions consisting of education messages, recommended behavior alternatives, and a supporting environment that incentivizes or encourages the adoption of a new behavior were more likely to be successful. CONCLUSIONS: There is a continued tendency in research reporting that mainly stresses the effectiveness of interventions rather than the process of identifying and developing key components and the parameters within which they operate. Reporting "negative results" is likely as critical as reporting "active ingredients" and positive findings for implementation science. This review calls for a standardized approach to report intervention studies. TRIAL REGISTRATION: PROSPERO registration number CRD42019139537

Is the sexual behaviour of young people in sub-Saharan Africa influenced by their peers? A systematic review.

Adolescents in sub-Saharan Africa are highly vulnerable to HIV, other sexually transmitted infections (STIs) and unintended pregnancies. Evidence for the effectiveness of individual behaviour change interventions in reducing incidence of HIV and other biological outcomes is limited, and the need to address the social conditions in which young people become sexually active is clear. Adolescents' peers are a key aspect of this social environment and could have important influences on sexual behaviour. There has not yet been a systematic review on the topic in sub-Saharan Africa. We searched 4 databases to find studies set in sub-Saharan Africa that included an adjusted analysis of the association between at least one peer exposure and a sexual behaviour outcome among a sample where at least 50% of the study participants were aged between 13 and 20 years. We classified peer exposures using a framework to distinguish different mechanisms by which influence might occur. We found 30 studies and retained 11 that met quality criteria. There were 3 cohort studies, 1 time to event and 7 cross-sectional. The 11 studies investigated 37 different peer exposure-outcome associations. No studies used a biological outcome and all asked about peers in general rather than about specific relationships. Studies were heterogeneous in their use of theoretical frameworks and means of operationalizing peer influence concepts. All studies found evidence for an association between peers and sexual behaviour for at least one peer exposure/outcome/sub-group association. Of all 37 outcome/exposure/sub-group associations tested, there was evidence for 19 (51%). There were no clear patterns by type of peer exposure, outcome or adolescent sub-group. There is a lack conclusive evidence about the role of peers in adolescent sexual behaviour in Sub-Saharan. We argue that longitudinal designs, use of biological outcomes and approaches from social network analysis are priorities for future studies

Sample Size Calculations for Population Size Estimation Studies Using Multiplier Methods With Respondent-Driven Sampling Surveys.

BACKGROUND: While guidance exists for obtaining population size estimates using multiplier methods with respondent-driven sampling surveys, we lack specific guidance for making sample size decisions. OBJECTIVE: To guide the design of multiplier method population size estimation studies using respondent-driven sampling surveys to reduce the random error around the estimate obtained. METHODS: The population size estimate is obtained by dividing the number of individuals receiving a service or the number of unique objects distributed (M) by the proportion of individuals in a representative survey who report receipt of the service or object (P). We have developed an approach to sample size calculation, interpreting methods to estimate the variance around estimates obtained using multiplier methods in conjunction with research into design effects and respondent-driven sampling. We describe an application to estimate the number of female sex workers in Harare, Zimbabwe. RESULTS: There is high variance in estimates. Random error around the size estimate reflects uncertainty from M and P, particularly when the estimate of P in the respondent-driven sampling survey is low. As expected, sample size requirements are higher when the design effect of the survey is assumed to be greater. CONCLUSIONS: We suggest a method for investigating the effects of sample size on the precision of a population size estimate obtained using multipler methods and respondent-driven sampling. Uncertainty in the size estimate is high, particularly when P is small, so balancing against other potential sources of bias, we advise researchers to consider longer service attendance reference periods and to distribute more unique objects, which is likely to result in a higher estimate of P in the respondent-driven sampling survey

Statistical design and analysis plan for an impact evaluation of an HIV treatment and prevention intervention for female sex workers in Zimbabwe: a study protocol for a cluster randomised controlled trial.

BACKGROUND: Pragmatic cluster-randomised trials should seek to make unbiased estimates of effect and be reported according to CONSORT principles, and the study population should be representative of the target population. This is challenging when conducting trials amongst 'hidden' populations without a sample frame. We describe a pair-matched cluster-randomised trial of a combination HIV-prevention intervention to reduce the proportion of female sex workers (FSW) with a detectable HIV viral load in Zimbabwe, recruiting via respondent driven sampling (RDS). METHODS: We will cross-sectionally survey approximately 200 FSW at baseline and at endline to characterise each of 14 sites. RDS is a variant of chain referral sampling and has been adapted to approximate random sampling. Primary analysis will use the 'RDS-2' method to estimate cluster summaries and will adapt Hayes and Moulton's '2-step' method to adjust effect estimates for individual-level confounders and further adjust for cluster baseline prevalence. We will adapt CONSORT to accommodate RDS. In the absence of observable refusal rates, we will compare the recruitment process between matched pairs. We will need to investigate whether cluster-specific recruitment or the intervention itself affects the accuracy of the RDS estimation process, potentially causing differential biases. To do this, we will calculate RDS-diagnostic statistics for each cluster at each time point and compare these statistics within matched pairs and time points. Sensitivity analyses will assess the impact of potential biases arising from assumptions made by the RDS-2 estimation. DISCUSSION: We are not aware of any other completed pragmatic cluster RCTs that are recruiting participants using RDS. Our statistical design and analysis approach seeks to transparently document participant recruitment and allow an assessment of the representativeness of the study to the target population, a key aspect of pragmatic trials. The challenges we have faced in the design of this trial are likely to be shared in other contexts aiming to serve the needs of legally and/or socially marginalised populations for which no sampling frame exists and especially when the social networks of participants are both the target of intervention and the means of recruitment. The trial was registered at Pan African Clinical Trials Registry (PACTR201312000722390) on 9 December 2013

Decisions to use antibiotics for upper respiratory tract infections across China: a large-scale cross-sectional survey among university students.

OBJECTIVES: To investigate the decision-making process of Chinese university students with respect to antibiotic use for upper respiratory tract infections (URTIs). DESIGN: A cross-sectional questionnaire study. SETTING: The participants recruited from six universities across all Chinese regions from September to November 2015. PARTICIPANTS: A total of 2834 university students sampled across six Chinese regions who self-reported experiencing symptoms of URTI within the past month completed the survey. OUTCOME MEASURES: The prevalence of decisions for treatment and antibiotic use for URTIs as well as knowledge about antibiotic use were measured by a self-administrated questionnaire. Using regular and multinomial logistic regression a nd adapted health belief model, we identified and measured a number of variables as potential risk factors for antibiotic misuse behaviours in order to explain and predict people's treatment decisions and antibiotic use including knowledge, perceptions, access to antibiotics and cues to action. RESULTS: Of the 2834 university students who self-diagnosed a URTI, 947 (33.4%) self-reported having taken antibiotics; among them, 462 (48.8%) used non-prescription antibiotics, which came principally from left-over prescriptions (29.0%) and over-the-counter purchases at retail pharmacies (67.3%). One in four who sought care pressured their doctors for antibiotics; all received them. Those who perceived greater severity of the disease, had access to antibiotics, perceived benefits of using antibiotics (for the common cold: adjusted OR (aOR)=2.55, 95% CI 1.93 to 3.38 or as anti-inflammatory drugs: aOR=1.35, 95% CI 1.12 to 1.63), and were cued to action (eg, seeing presence of fever: aOR=2.05, 95% CI 1.62 to 2.60 or self-diagnosing their current infection as severe: aOR=1.86, 95% CI 1.41 to 2.45), keeping antibiotics at home (aOR=2.27, 95% CI 1.83 to 2.81) and access to over-the-counter antibiotics (aOR=2.00, 95% CI 1.63 to 2.45), were more likely to misuse antibiotics. CONCLUSIONS: Misconceptions of antibiotic efficacy and easy access to antibiotics-with or without a prescription-were associated with antibiotic misuse among Chinese university students, which calls for context-appropriate multifaceted interventions in order to effectively reduce antibiotic misuse

Effectiveness of testing, contact tracing and isolation interventions among the general population on reducing transmission of SARS-CoV-2: a systematic review

We conducted a systematic literature review of general population testing, contact tracing, case isolation and contact quarantine interventions to assess their effectiveness in reducing SARS-CoV-2 transmission, as implemented in real-world settings. We designed a broad search strategy and aimed to identify peer-reviewed studies of any design provided there was a quantitative measure of effectiveness on a transmission outcome. Studies that assessed the effect of testing or diagnosis on disease outcomes via treatment, but did not assess a transmission outcome, were not included. We focused on interventions implemented among the general population rather than in specific settings; these were from anywhere in the world and published any time after 1 January 2020 until the end of 2022. From 26 720 titles and abstracts, 1181 were reviewed as full text, and 25 met our inclusion criteria. These 25 studies included one randomized control trial (RCT) and the remaining 24 analysed empirical data and made some attempt to control for confounding. Studies included were categorized by the type of intervention: contact tracing (seven studies); specific testing strategies (12 studies); strategies for isolating cases/contacts (four studies); and 'test, trace, isolate' (TTI) as a part of a package of interventions (two studies). None of the 25 studies were rated at low risk of bias and many were rated as serious risk of bias, particularly due to the likely presence of uncontrolled confounding factors, which was a major challenge in assessing the independent effects of TTI in observational studies. These confounding factors are to be expected from observational studies during an on-going pandemic, when the emphasis was on reducing the epidemic burden rather than trial design. Findings from these 25 studies suggested an important public health role for testing followed by isolation, especially where mass and serial testing was used to reduce transmission. Some of the most compelling analyses came from examining fine-grained within-country data on contact tracing; while broader studies which compared behaviour between countries also often found TTI led to reduced transmission and mortality, this was not universal. There was limited evidence for the benefit of isolation of cases/contacts away from the home environment. One study, an RCT, showed that daily testing of contacts could be a viable strategy to replace lengthy quarantine of contacts. Based on the scarcity of robust empirical evidence, we were not able to draw any firm quantitative conclusions about the quantitative impact of TTI interventions in different epidemic contexts. While the majority of studies found that testing, tracing and isolation reduced transmission, evidence for the scale of this impact is only available for specific scenarios and hence is not necessarily generalizable. Our review therefore emphasizes the need to conduct robust experimental studies that help inform the likely quantitative impact of different TTI interventions on transmission and their optimal design. Work is needed to support such studies in the context of future emerging epidemics, along with assessments of the cost-effectiveness of TTI interventions, which was beyond the scope of this review but will be critical to decision-making. This article is part of the theme issue 'The effectiveness of non-pharmaceutical interventions on the COVID-19 pandemic: the evidence'

Assessing Bias in Population Size Estimates Among Hidden Populations When Using the Service Multiplier Method Combined With Respondent-Driven Sampling Surveys: Survey Study.

BACKGROUND: Population size estimates (PSEs) for hidden populations at increased risk of HIV, including female sex workers (FSWs), are important to inform public health policy and resource allocation. The service multiplier method (SMM) is commonly used to estimate the sizes of hidden populations. We used this method to obtain PSEs for FSWs at 9 sites in Zimbabwe and explored methods for assessing potential biases that could arise in using this approach. OBJECTIVE: This study aimed to guide the assessment of biases that arise when estimating the population sizes of hidden populations using the SMM combined with respondent-driven sampling (RDS) surveys. METHODS: We conducted RDS surveys at 9 sites in late 2013, where the Sisters with a Voice program (the program), which collects program visit data of FSWs, was also present. Using the SMM, we obtained PSEs for FSWs at each site by dividing the number of FSWs who attended the program, based on program records, by the RDS-II weighted proportion of FSWs who reported attending this program in the previous 6 months in the RDS surveys. Both the RDS weighting and SMM make a number of assumptions, potentially leading to biases if the assumptions are not met. To test these assumptions, we used convergence and bottleneck plots to assess seed dependence of RDS-II proportion estimates, chi-square tests to assess if there was an association between the characteristics of FSWs and their knowledge of program existence, and logistic regression to compare the characteristics of FSWs attending the program with those recruited to RDS surveys. RESULTS: The PSEs ranged from 194 (95% CI 62-325) to 805 (95% CI 456-1142) across 9 sites from May to November 2013. The 95% CIs for the majority of sites were wide. In some sites, the RDS-II proportion of women who reported program use in the RDS surveys may have been influenced by the characteristics of selected seeds, and we also observed bottlenecks in some sites. There was no evidence of association between characteristics of FSWs and knowledge of program existence, and in the majority of sites, there was no evidence that the characteristics of the populations differed between RDS and program data. CONCLUSIONS: We used a series of rigorous methods to explore potential biases in our PSEs. We were able to identify the biases and their potential direction, but we could not determine the ultimate direction of these biases in our PSEs. We have evidence that the PSEs in most sites may be biased and a suggestion that the bias is toward underestimation, and this should be considered if the PSEs are to be used. These tests for bias should be included when undertaking population size estimation using the SMM combined with RDS surveys

Accumulation of Immunity in Heavy-Tailed Sexual Contact Networks Shapes Mpox Outbreak Sizes

Many countries affected by the global outbreak of mpox in 2022 have observed a decline in cases. Our mathematical model accounting for heavy-tailed sexual partnership distributions suggests that mpox epidemics can hit the infection-derived herd immunity threshold and begin to decline with less than 1% of sexually active MSM population infected regardless of interventions or behavioural changes. Consistently, we found that many countries and US states experienced an epidemic peak with cumulative cases of around 0.1-0.5% of MSM population. The observed decline in cases may not necessarily be attributable to interventions or behavioural changes primarily