A prospective cohort study examining the association of claw anatomy and sole temperature with the development of claw horn disruption lesions in dairy cattle.

Foot characteristics have been linked to the development of sole lesions (sole hemorrhage and sole ulcers) and white line lesions, also known as claw horn disruption lesions (CHDL). The objective of this study was to examine the association of claw anatomy and sole temperature with the development of CHDL. A cohort of 2,352 cows was prospectively enrolled from 4 UK farms and assessed at 3 time points: before calving (T1-precalving), immediately after calving (T2-calving), and in early lactation. At each time point body condition score was recorded, a thermography image of each foot was taken for sole temperature measurement, the presence of CHDL was assessed by veterinary surgeons, and an ultrasound image was taken to retrospectively measure the digital cushion and sole horn thickness. Additionally, at the postcalving time point, foot angle and heel depth were recorded. Four multivariable logistic regression models were fit to separately examine the relationship of precalving and postcalving explanatory variables with the development of either white line lesions or sole lesions. Explanatory variables tested included digital cushion thickness, sole horn thickness, sole temperature, foot angle, and heel depth. Farm, parity, body condition score, and presence of lesion at the time of measurement were also included in the models. A thicker digital cushion shortly after calving was associated with decreased odds of cows developing sole lesions during early lactation (odds ratio [OR]: 0.74, 95% confidence interval [CI]: 0.65-0.84). No association was found between digital cushion thickness and development of white line lesions. Sole temperature after calving was associated with increased odds of the development of sole lesions (OR: 1.03, 95% CI: 1.02-1.05), and sole temperature before and after calving was associated with the development of white line lesions (T1-precalving OR: 1.04, 95% CI: 1.01-1.07; T2-calving OR: 0.96, 95% CI: 0.93-0.99). Neither foot angle nor heel depth was associated with the development of either lesion type. However, an increased sole horn thickness after calving reduced the odds of cows developing sole lesions during early lactation (OR: 0.88, 95% CI: 0.83-0.93), highlighting the importance of maintaining adequate sole horn when foot trimming. Before calving, animals with a lesion at the time of measurement and a thicker sole were more likely to develop a sole lesion (OR: 1.23, 95% CI: 1.09-1.40), compared with those without a sole lesion. The results presented here suggest that white line and sole lesions may have differing etiopathogenesis. Results also confirm the association between the thickness of the digital cushion and the development of sole lesions, highlight the association between sole horn thickness and sole lesions, and challenge the potential importance of foot angle and heel depth in the development of CHDL.

Supportive Self-Management Program for People With Chronic Headaches and Migraine: A Randomized Controlled Trial and Economic Evaluation.

BACKGROUND AND OBJECTIVES: Chronic headache disorders are a major cause of pain and disability. Education and supportive self-management approaches could reduce the burden of headache disability. We tested the effectiveness of a group educational and supportive self-management program for people living with chronic headaches. METHODS: This was a pragmatic randomized controlled trial. Participants were aged 18 years or older with chronic migraine or chronic tension-type headache, with or without medication overuse headache. We primarily recruited from general practices. Participants were assigned to either a 2-day group education and self-management program, a one-to-one nurse interview, and telephone support or to usual care plus relaxation material. The primary outcome was headache related-quality of life using the Headache Impact Test (HIT)-6 at 12 months. The primary analysis used intention-to-treat principles for participants with migraine and both baseline and 12-month HIT-6 data. RESULTS: Between April 2017 and March 2019, we randomized 736 participants. Because only 9 participants just had tension-type headache, our main analyses were on the 727 participants with migraine. Of them, 376 were allocated to the self-management intervention and 351 to usual care. Data from 586 (81%) participants were analyzed for primary outcome. There was no between-group difference in HIT-6 (adjusted mean difference = -0.3, 95% CI -1.23 to 0.67) or headache days (0.9, 95% CI -0.29 to 2.05) at 12 months. The Chronic Headache Education and Self-management Study intervention generated incremental adjusted costs of £268 (95% CI, £176-£377) (USD383 [95% CI USD252-USD539]) and incremental adjusted quality-adjusted life years (QALYs) of 0.031 (95% CI -0.005 to 0.063). The incremental cost-effectiveness ratio was £8,617 (USD12,322) per QALY gained. DISCUSSION: These findings conclusively show a lack of benefit for quality of life or monthly headache days from a brief group education and supportive self-management program for people living with chronic migraine or chronic tension-type headache with episodic migraine. TRIAL REGISTRATION INFORMATION: Registered on the International Standard Randomized Controlled Trial Number registry, ISRCTN79708100 16th December 2015 doi.org/10.1186/ISRCTN79708100. The first enrollment was April 24, 2017. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a brief group education and self-management program does not increase the probability of improvement in headache-related quality of life in people with chronic migraine.

Tailoring childhood immunisation services in a socioeconomically disadvantaged community in New South Wales, Australia: a cost analysis.

BACKGROUND: Using the World Health Organization's 'Guide to Tailoring Immunization Programmes' (TIP), a three-step program was developed by health services in partnership with a marginalised community in New South Wales, Australia. The aim was to improve immunisation rates of 1-year-old children. For Step 1, nurses identified and monitored local children overdue for immunisation from a national register, and sent parents or family doctors reminders by mail or telephone. For Step 2, parents were offered appointments at a local health centre; and for Step 3, they were offered home visits. METHODS: An economic costing study was undertaken to examine the program's resource use. Costs were collected between 1 June 2020 and 31 May 2021. Case records were obtained for 139 children. RESULTS: A total of 56 children became up to date after receiving TIP services; most after receiving Step 1 services (n =37). Total annual costs (A$) for the program were $34250 or $246 per case; or $612 per case becoming up to date. At $44 per case and $98 per case becoming up to date, Step 1B: personalised reminders, was the lowest costing step. Sensitivity analysis showed a possible 8% program savings through employment of nurses with a lower salary and use of video conference meetings. CONCLUSION: This study provides information to the local health provider on the cost of TIP alongside their community-based programs. It also identified ways in which TIP could be made more cost-effective. Decision-makers can use this information to consider whether the investment in TIP is recommended.

Prospective cohort study of the association between early lactation mastitis and the presence of sole ulcers in dairy cows.

BACKGROUND: The objective of this study was to investigate the association between (sub)clinical mastitis (CM) in the first 30 days in milk (DIM) and the presence of sole ulcers (SU) later in lactation. METHODS: Holstein cows and heifers were examined for presence of sole haemorrhage and SU before calving, in the first 14 days postcalving and in early lactation (after 30 DIM). CM episodes and somatic cell counts (SCC) measurements were obtained from farm records. Multivariable logistic regression was used for data analysis. RESULTS: Odds of SU in early lactation were 2.44 times greater (95% confidence interval [CI] 0.97-5.54) in cows that had CM in the first 30 DIM compared to cows that did not have CM in the first 30 DIM. When cows that had SU precalving or at the calving check were excluded from the dataset, an association of CM in the first 30 DIM with later presence of SU was no longer statistically significant but the same numeric trend still existed (odds ratio [OR] 2.25, 95% CI 0.81-5.34). The odds of SU in early lactation were 1.70 times greater in cows that had high SCC compared to cows that did not have high SCC in the first 100 DIM (95% CI 1.13-2.55). CONCLUSION: An association was found between CM in the first 30 DIM and presence of SU in early lactation (after 30 DIM). Elucidating the mechanism behind this relationship could improve our understanding of the aetiopathogenesis of both diseases and lead to new preventive strategies.

Assessing Knowledge, Beliefs, and Behaviors around Antibiotic Usage and Antibiotic Resistance among UK Veterinary Students: A Multi-Site, Cross-Sectional Survey.

Antimicrobial resistance (AMR) is a profound threat to human and animal health. Antimicrobial prescribing behaviours are influenced by psychological factors such as knowledge, beliefs, and emotions. As future antimicrobial prescribers, it is important to understand beliefs about AMR and stewardship among veterinary (vet) students. This cross-sectional online survey assessed vet students' self-reported behavior, knowledge, and beliefs in specific relation to antibiotic resistance (ABR) and antibiotic usage. Participants were early years (first- and second-year; n = 460) and later-years (third- and fourth-year; n = 113) undergraduate vet students from three UK universities. Self-reported antibiotic-related behaviors were responsible among most students. Knowledge about ABR and stewardship was moderate among early years students and good among later years students. Vet students typically believed that vets had less responsibility for both causing and preventing ABR than other groups (animal owners, human medics, and the public). This study offers evidence that vet students (along with other groups) tend to lay greater responsibility for ABR/AMR outside of their own profession, which may impact their future prescribing behaviors. It is vital that AMR and antimicrobial stewardship are embedded across veterinary curricula, and that the One Health nature of the challenge posed by AMR is emphasized to encourage shared responsibility across all stakeholder groups, thereby helping to reduce 'other-blaming' for AMR.

Seasonal calving UK dairy herds: A farmer survey of fertility and veterinary services.

BACKGROUND: There is a lack of literature concerning dairy farmers' use of veterinary services and how satisfied they are with them. This study aimed to fill this gap for seasonal calving UK herds, with a focus on fertility, and included farmer perceived barriers to veterinary involvement. METHODS: A cross-sectional questionnaire (convenience sample), with 166 useable responses. RESULTS: Opportunities exist for further veterinary involvement in seasonal herds. Areas vets are least involved in currently are nutrition, breeding and genetics, growth rate monitoring and infrastructure changes. Current veterinary input was rated neutral or poor value by 21% of respondents. Over 90% of farmers want vets to ask questions to elicit their needs. Frequently mentioned barriers were 'lack of veterinary knowledge of our system', 'not enough cost-benefit of veterinary involvement' and 'we get our fertility information elsewhere'. Along with clinical ability and being approachable, 'understanding our system' and being 'proactive' were qualities participants most valued in a vet. After cost, 'pushing sales and interventions' were the least liked. CONCLUSION: Findings highlight the critical importance of clearly demonstrating the full cost-benefit of veterinary services to farmers. The results contain many details concerning farmer perceptions and values that can help veterinary businesses to strengthen existing services and develop new services.

Improved childhood immunization coverage using the World Health Organization's Tailoring Immunization Programmes guide (TIP) in a regional centre in Australia.

In 2017 the World Health Organization's Tailoring Immunization Programmes guide (TIP) was used to identify pockets of low immunization coverage in Australia. The regional centre of Maitland had high numbers and rates of children who were overdue for scheduled vaccinations (2016, n = 344, 37.7%). Families were not opposed to immunization but had conflicting priorities or experienced service access barriers. A tailored strategy was developed including friendly, personalised reminders, outreach appointments and home visiting for those families most in need. Research translation was not quick and easy. A process evaluation identified areas where more support was needed to advance the strategy. Coverage rates have increased from 62.3% (2016) to 86.2% (2020). The number of overdue children has decreased even during COVID-19 restrictions when health services expected families would avoid primary care services. The TIP approach is valuable for improving childhood immunization coverage and is being utilised in other communities with low coverage.

Understanding doctors' emergency department antibiotic prescribing decisions in children with respiratory symptoms in the UK: a qualitative study.

OBJECTIVE: Exploration of the factors that influence hospital doctors' antibiotic prescribing decisions when treating children with respiratory symptoms in UK emergency departments. METHODS: A qualitative study using semistructured interviews based on a critical incident technique with 21 physicians of different grades and specialties that treat children in the UK. Interviews were audio-recorded then transcribed verbatim and analysed using thematic analysis. RESULTS: Four themes were identified. These themes illustrate factors which influence clinician prescribing. The three principal themes were authorities, pressures and risk. The fourth transcending theme that ran through all themes was clinician awareness and complicity ('knowing but still doing'). CONCLUSIONS: Hospital doctors prescribe antibiotics even when they know they should not. This appears to be due to the influence of those in charge or external pressures experienced while weighing up the immediate and longer term risks but clinicians do this with full insight into their actions. These findings have implications for invested parties seeking to develop future antimicrobial stewardship programmes. It is recommended that stewardship interventions acknowledge and target these themes which may in turn facilitate behaviour change and antimicrobial prescribing practice in emergency departments.

Motivations and Barriers for Veterinarians When Facilitating Fertility Management on UK Dairy Farms.

It is economically essential, but challenging, for dairy farmers to manage bovine fertility. Vets can help farmers to improve fertility, and this is cost-effective bringing benefits for production, animal health and welfare, and the environment. However, the extent to which vets are involved in fertility varies considerably between farms, for reasons that are unclear. This study investigated the motivators and barriers that vets perceive when trying to increase their involvement with fertility management on UK dairy farms. Interviews were conducted with 20 vets and four themes identified. The first, "clinical baggage," highlighted vets' disillusionment due to past experiences of low uptake of their advice by farmers. Consequently, some vets made assumptions about farmer needs and behaviours, and exhibited ageist stereotyping. These issues, along with concerns and fatigue associated with repeatedly offering the same advice which was not acted upon, negatively influenced vets' engagement with farmers. The second theme "stuck in the comfort zone" revealed a loss of enthusiasm by some senior vets, whilst others lacked confidence to engage due to perceived gaps in their knowledge. Vets also reported farmers not perceiving their problems and lack of farm data or facilities, as barriers. The "vet-farmer relationship" theme highlighted building trust and developing strong relationships which were key drivers for vets to proactively engage and to "go the extra mile" for their clients. The final theme "money matters" explored vets' motivations to improve their clients' profitability and included the future sustainability of their own businesses. Our themes provide useful insight into the challenges vets face and provide key areas that can be targeted in future interventions to improve veterinary involvement in fertility management. For example, post-graduate training and support for vets needs to consider factors such as reflection, mentorship, stereotyping, relationships, communication, and leadership skills. This type of postgraduate support is currently limited for vets and requires investment from stakeholders if improvements in production, animal health and welfare, and the environment are to be achieved. Our findings are informative for facilitating veterinary involvement in any disease context, and are relevant for stakeholders including governments, educators, charities, farmer representatives, environmentalists, and veterinary leaders.

Erratum: Golding et al. Examining the Effect of Context, Beliefs, and Values on UK Farm Veterinarians' Antimicrobial Prescribing: A Randomized Experimental Vignette and Cross-Sectional Survey. Antibiotics 2021, 10, 445.

The authors wish to make the following corrections to their published paper [...].

Lameness in Beef Cattle: A Cross-Sectional Descriptive Survey of On-Farm Practices and Approaches.

Cattle lameness is a concern to the United Kingdom (UK) cattle industry, negatively impacting upon welfare and production. Previous work involving one small study (n = 21) has identified that some UK beef farmers underestimate lameness prevalence, but also that farmers vary in their perception of the impact of lameness. Knowledge and skills of farmers were identified as a potential concern, and farmer-reported barriers were identified. However, the extent to which these views can be extrapolated is unknown. Therefore, the aim of this study was to produce descriptive results of UK beef farmer lameness-related activities concerning lameness identification, examination, treatment, and prevention. Questionnaires were circulated online and via post. Postal questionnaires were sent to registered Approved Finishing Units (a specific cohort of beef fattening units subject to strict biosecurity measures as part of UK bovine tuberculosis control) and a stratified sample of all registered beef enterprises in England and Wales. Online questionnaires were circulated on social media and via targeted emails asking selected industry bodies and veterinary practices to distribute to farmers. Descriptive results were produced, and thematic analysis was performed on free text responses. There were 532 usable responses, with most farmers self-reporting their current lameness prevalence as zero (mean 1.2%, range 0-20%). Most respondents did not locomotion score cattle, and most reported that it was not safe to examine feet. Most farmers did not use a foot bath, but of those who did, formaldehyde was the most commonly used product. Some farmers reported use of antibiotic foot baths. Most farmers reported dealing with lame animals within 48 h, but some only dealt with severe cases, and some felt that lame animals would get better by themselves. To deal with animals that have an ongoing lameness problem, transportation to slaughter was considered an option by 35% of farmers. It is worth noting, however, that the majority of lame animals would be precluded from transport under UK legislation. Farmers reported staff shortages, as well as a lack of time, training, and knowledge as barriers to lameness prevention and control. Overall, these results suggest that farmers may be underestimating lameness. Diagnosis is likely to be challenging, with unsafe facilities for lifting feet. The reported high threshold by some farmers for attending to a lame animal is a cause for concern, negatively impacting upon animal welfare, but this is also likely to have negative consequences for animal performance and farm profitability. Many participants in this study expressed a desire for farmer training in several aspects relating to lameness prevention and control, and this represents an opportunity for further knowledge exchange regarding lameness in beef cattle.

Examining the Effect of Context, Beliefs, and Values on UK Farm Veterinarians' Antimicrobial Prescribing: A Randomized Experimental Vignette and Cross-Sectional Survey.

Antimicrobial resistance (AMR) is a pressing threat to public and animal health. There is evidence that antimicrobial prescribing and stewardship behaviors by veterinarians (vets) are influenced by non-clinical factors, such as psychological, social, and environmental factors. This study explored the role of context, beliefs, and values on vets' antimicrobial prescribing decisions. UK-based practicing farm vets (n = 97) were recruited to an online study. Using an experimental vignette methodology, vets were randomly assigned across four conditions, to examine the effects of different contexts (pressure on farm economics, the farmer, or the vet-farmer relationship, compared to a control condition) on vets' likelihood of prescribing antibiotics. Vets' beliefs about different groups' responsibility for causing and preventing AMR and vets' values were also measured. Key findings were that context alone, values, and beliefs about groups' responsibilities for causing AMR were not predictive of vets' likelihood of prescribing antibiotics. However, vets' beliefs about groups' responsibilities for preventing AMR were predictive of an increased likelihood of prescribing antibiotics, when vets were exposed to the experimental condition of the vignette in which the vet-farmer relationship was under pressure. Farm vets also believed that different groups have different levels of responsibility for causing and preventing AMR. Results should be interpreted cautiously, given the smaller than planned for sample size, and the possibility for both false negatives and false positives. Further research is needed to explore how these findings could inform antimicrobial stewardship interventions in veterinary medicine.

Diagnostic pathways in multiple myeloma and their relationship to end organ damage: an analysis from the Tackling Early Morbidity and Mortality in Myeloma (TEAMM) trial.

Multiple myeloma is associated with significant early morbidity and mortality, with considerable end organ damage often present at diagnosis. The Tackling EArly Morbidity and Mortality in Multiple Myeloma (TEAMM) trial was used to evaluate routes to diagnosis in patients with myeloma and the relationship between diagnostic pathways, time to diagnosis and disease severity. A total of 915 participants were included in the study. Fifty-one per cent were diagnosed by direct referral from primary care to haematology; 29% were diagnosed via acute services and 20% were referred via other secondary care specialties. Patients diagnosed via other secondary care specialties had a longer diagnostic interval (median 120 days vs. 59 days) without an increase in features of severe disease, suggesting they had a relatively indolent disease. Marked intrahospital delay suggests possible scope for improvement. A quarter of those diagnosed through acute services reported >30 days from initial hospital consultation to haematology assessment. Participants diagnosed through acute services had poorer performance status (P < 0·0001) and higher burden of end organ damage (P < 0·0001) with no difference in the overall length of diagnostic pathway compared to those diagnosed by direct referral (median 59 days). This suggests that advanced disease in patients presenting through acute services predominantly reflects disease aggression.

Reliability of a beef cattle locomotion scoring system for use in clinical practice.

BACKGROUND: Locomotion (lameness) scoring has been used and studied in the dairy industry; however, to the authors' knowledge, there are no studies assessing the reliability of locomotion scoring systems when used with beef cattle. METHODS: A four-point scoring system was developed and beef cattle filmed walking on a firm surface. Eight veterinary researchers, eight clinicians and eight veterinary students were shown written descriptors of the scoring system and four video clips for training purposes, before being asked to score 40 video clips in a random order. Participants repeated this task 4 days later. RESULTS: The intra-observer agreement (the same person scoring on different days) was acceptable with weighted mean Kappa values of 0.84, 0.81 and 0.84 respectively for researchers, clinicians and students. The inter-observer agreement (different people scoring the same animal) was acceptable with weighted Gwet's Agreement Coefficient values of 0.70, 0.69 and 0.64 for researchers, clinicians and students. Most disagreement occurred over scores one (not lame but imperfect locomotion) and two (lame, but not severe). CONCLUSION: This scoring system has the potential to reliably score lameness in beef cattle and help facilitate lameness treatment and control; however, some disagreements will occur especially over scores one and two.

Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT.

BACKGROUND: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months' trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority. OBJECTIVES: To establish whether or not 6 months' adjuvant trastuzumab is non-inferior to 12 months' in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival. DESIGN: This was a Phase III randomised controlled non-inferiority trial. SETTING: The setting was 152 NHS hospitals. PARTICIPANTS: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part. INTERVENTION: Randomisation (1 : 1) to 6 months' or 12 months' trastuzumab treatment. MAIN OUTCOMES: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months' trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months' trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model. RESULTS: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months' trastuzumab and 2043 were randomised to 6 months' trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years' median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority p = 0.01), demonstrating non-inferiority of 6 months' trastuzumab. Congruent results were found for overall survival (non-inferiority p = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority p = 0.03 (disease-free-survival) and p = 0.006 (overall survival)]. Six months' trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients; p = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients; p < 0.0001]. Health economic analysis showed that 6 months' trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months' trastuzumab, and thus there is a high probability that 6 months' trastuzumab is cost-effective compared with 12 months' trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently. LIMITATIONS: The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered. CONCLUSIONS: PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months' adjuvant trastuzumab is non-inferior to 12 months'. Six months' treatment resulted in significantly less cardiac toxicity and fewer severe adverse events. FUTURE WORK: Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned. TRIAL REGISTRATION: Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.

THE BACKGROUND: There are several different types of breast cancer and some are called 'HER2 positive'. These cancers can often be cured by treatment with chemotherapy and a drug called trastuzumab (also known as Herceptin®; Roche, Basel, Switzerland). Although the first trials of trastuzumab used 12 months treatment, we did not know if less treatment could work as well. A small trial in Finland showed that giving trastuzumab for just 9 weeks was also effective. We know that trastuzumab can have some side effects, including heart problems, so it was important to see if we could reduce the length of treatment time, which is usually 12 months. WHAT DID WE DO?: We wanted to find out if we could treat patients safely with 6 months rather than 12 months of trastuzumab. We carried out a clinical trial called PERSEPHONE, in which over 4000 patients with this type of early breast cancer took part. Half of the patients were given 12 months of trastuzumab and half were given 6 months of trastuzumab. WHAT DID WE FIND?: We found that the two groups of patients had very similar benefit from treatment. At 4 years after diagnosis 90.3% of those who had received 12 months of trastuzumab were alive and free of any breast cancer recurrence, compared with 89.5% of those who had received 6 months. In other words, 125 patients would need to be treated with 12 months' trastuzumab rather than 6 months' trastuzumab for one more person to be alive and cancer-free 4 years from diagnosis. THE SIDE EFFECTS?: Severe side effects of trastuzumab were seen on at least one occasion in 24% of 12-month patients compared with 19% of 6-month patients. More patients receiving 12 months of trastuzumab had to stop trastuzumab early because of heart problems (8% of 12-month patients compared with 3% of 6-month patients). WHAT DOES THIS ALL MEAN?: We have shown that 6 months of trastuzumab has similar outcomes to 12 months in treating patients with HER2-positive early breast cancer but with fewer severe side effects, including heart problems, fewer visits to hospital for patients and significant cost savings for the NHS.

Prophylactic levofloxacin to prevent infections in newly diagnosed symptomatic myeloma: the TEAMM RCT.

BACKGROUND: Myeloma causes profound immunodeficiency and recurrent serious infections. There are approximately 5500 new UK cases of myeloma per annum, and one-quarter of patients will have a serious infection within 3 months of diagnosis. Newly diagnosed patients may benefit from antibiotic prophylaxis to prevent infection. However, the use of prophylaxis has not been established in myeloma and may be associated with health-care-associated infections (HCAIs), such as Clostridium difficile. There is a need to assess the benefits and cost-effectiveness of the use of antibacterial prophylaxis against any risks in a double-blind, placebo-controlled, randomised clinical trial. OBJECTIVES: To assess the risks, benefits and cost-effectiveness of prophylactic levofloxacin in newly diagnosed symptomatic myeloma patients. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. A central telephone randomisation service used a minimisation computer algorithm to allocate treatments in a 1 : 1 ratio. SETTING: A total of 93 NHS hospitals throughout England, Northern Ireland and Wales. PARTICIPANTS: A total of 977 patients with newly diagnosed symptomatic myeloma. INTERVENTION: Patients were randomised to receive levofloxacin or placebo tablets for 12 weeks at the start of antimyeloma treatment. Treatment allocation was blinded and balanced by centre, estimated glomerular filtration rate and intention to give high-dose chemotherapy with autologous stem cell transplantation. Follow-up was at 4-week intervals up to 16 weeks, with a further follow-up at 1 year. MAIN OUTCOME MEASURES: The primary outcome was to assess the number of febrile episodes (or deaths) in the first 12 weeks from randomisation. Secondary outcomes included number of deaths and infection-related deaths, days in hospital, carriage and invasive infections, response to antimyeloma treatment and its relation to infection, quality of life and overall survival within the first 12 weeks and beyond. RESULTS: In total, 977 patients were randomised (levofloxacin, n = 489; placebo, n = 488). A total of 134 (27%) events (febrile episodes, n = 119; deaths, n = 15) occurred in the placebo arm and 95 (19%) events (febrile episodes, n = 91; deaths, n = 4) occurred in the levofloxacin arm; the hazard ratio for time to first event (febrile episode or death) within the first 12 weeks was 0.66 (95% confidence interval 0.51 to 0.86; p = 0.002). Levofloxacin also reduced other infections (144 infections from 116 patients) compared with placebo (179 infections from 133 patients; p-trend of 0.06). There was no difference in new acquisitions of C. difficile, methicillin-resistant Staphylococcus aureus and extended-spectrum beta-lactamase Gram-negative organisms when assessed up to 16 weeks. Levofloxacin produced slightly higher quality-adjusted life-year gains over 16 weeks, but had associated higher costs for health resource use. With a median follow-up of 52 weeks, there was no significant difference in overall survival (p = 0.94). LIMITATIONS: Short duration of prophylactic antibiotics and cost-effectiveness. CONCLUSIONS: During the 12 weeks from new diagnosis, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced febrile episodes and deaths without increasing HCAIs or carriage. Future work should aim to establish the optimal duration of antibiotic prophylaxis and should involve the laboratory investigation of immunity, inflammation and disease activity on stored samples funded by the TEAMM (Tackling Early Morbidity and Mortality in Myeloma) National Institute for Health Research Efficacy and Mechanism Evaluation grant (reference number 14/24/04). TRIAL REGISTRATION: Current Controlled Trials ISRCTN51731976. FUNDING DETAILS: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 62. See the NIHR Journals Library website for further project information.

WHAT IS THE PROBLEM?: Myeloma is a type of cancer that develops from cells in the bone marrow, called plasma cells, which are part of the immune system. Because myeloma affects the immune system, people who have it are at greater risk of picking up infections. This risk is higher at the start of antimyeloma therapy when the myeloma is active. WHAT DID THE STUDY DO?: The trial looked to see if the risk of getting an infection can be reduced, rather than waiting to see if an infection developed and then treating it. An antibiotic already used all over the world, called levofloxacin was tested. Half of the patients (n = 489) took levofloxacin for 12 weeks and the other half (n = 488) were given a dummy tablet (placebo). The aim was to see if taking levofloxacin at the start of antimyeloma therapy reduced the risk of getting an infection. Alongside this, we evaluated three important groups of antibiotic-resistant bacteria to see whether or not the use of preventative levofloxacin increased the number of these resistant bacteria living in the body. In addition, the overall survival, economic impacts and the impact of using preventative antibiotics on patients' quality of life and response to antimyeloma treatment were evaluated. WHAT DID THE STUDY FIND?: During the 12 weeks from new diagnosis of myeloma, the addition of prophylactic levofloxacin to active myeloma treatment significantly reduced the number of febrile episodes and deaths [134 (febrile episodes alone, n = 112; febrile episodes plus death, n = 7; deaths alone, n = 15) out of 488 (27%) placebo patients vs. 95 (febrile episodes alone, n = 87; febrile episodes plus death, n = 4; deaths alone, n = 4) out of 489 (19%) levofloxacin patients; p = 0.002] without increasing antibiotic-resistant bacteria.

Levofloxacin prophylaxis in patients with newly diagnosed myeloma (TEAMM): a multicentre, double-blind, placebo-controlled, randomised, phase 3 trial.

BACKGROUND: Myeloma causes profound immunodeficiency and recurrent, serious infections. Around 5500 new cases of myeloma are diagnosed per year in the UK, and a quarter of patients will have a serious infection within 3 months of diagnosis. We aimed to assess whether patients newly diagnosed with myeloma benefit from antibiotic prophylaxis to prevent infection, and to investigate the effect on antibiotic-resistant organism carriage and health care-associated infections in patients with newly diagnosed myeloma. METHODS: TEAMM was a prospective, multicentre, double-blind, placebo-controlled randomised trial in patients aged 21 years and older with newly diagnosed myeloma in 93 UK hospitals. All enrolled patients were within 14 days of starting active myeloma treatment. We randomly assigned patients (1:1) to levofloxacin or placebo with a computerised minimisation algorithm. Allocation was stratified by centre, estimated glomerular filtration rate, and intention to proceed to high-dose chemotherapy with autologous stem cell transplantation. All investigators, patients, laboratory, and trial co-ordination staff were masked to the treatment allocation. Patients were given 500 mg of levofloxacin (two 250 mg tablets), orally once daily for 12 weeks, or placebo tablets (two tablets, orally once daily for 12 weeks), with dose reduction according to estimated glomerular filtration rate every 4 weeks. Follow-up visits occurred every 4 weeks up to week 16, and at 1 year. The primary outcome was time to first febrile episode or death from all causes within the first 12 weeks of trial treatment. All randomised patients were included in an intention-to-treat analysis of the primary endpoint. This study is registered with the ISRCTN registry, number ISRCTN51731976, and the EU Clinical Trials Register, number 2011-000366-35. FINDINGS: Between Aug 15, 2012, and April 29, 2016, we enrolled and randomly assigned 977 patients to receive levofloxacin prophylaxis (489 patients) or placebo (488 patients). Median follow-up was 12 months (IQR 8-13). 95 (19%) first febrile episodes or deaths occurred in 489 patients in the levofloxacin group versus 134 (27%) in 488 patients in the placebo group (hazard ratio 0·66, 95% CI 0·51-0·86; p=0·0018. 597 serious adverse events were reported up to 16 weeks from the start of trial treatment (308 [52%] of which were in the levofloxacin group and 289 [48%] of which were in the placebo group). Serious adverse events were similar between the two groups except for five episodes (1%) of mostly reversible tendonitis in the levofloxacin group. INTERPRETATION: Addition of prophylactic levofloxacin to active myeloma treatment during the first 12 weeks of therapy significantly reduced febrile episodes and deaths compared with placebo without increasing health care-associated infections. These results suggest that prophylactic levofloxacin could be used for patients with newly diagnosed myeloma undergoing anti-myeloma therapy. FUNDING: UK National Institute for Health Research.

Improving child immunisation rates in a disadvantaged community in New South Wales, Australia: a process evaluation for research translation.

The World Health Organization's Tailoring Immunization Programmes approach was used to develop a new strategy to increase child vaccination coverage in a disadvantaged community in New South Wales, Australia, including reminders, outreach and home visiting. After 18 months, the strategy hasn't been fully implemented. A process evaluation was conducted to identify barriers and facilitators for research translation. Participants included child health nurses, Population Health staff, managers and general practitioners. The Capability-Opportunity-Motivation model of behaviour change (COM-B) was used to develop questions. Twenty-four participants took part in three focus groups and four interviews. Five themes emerged: (i) designing and adopting new ways of working is time-consuming and requires new skills, new ways of thinking and changes in service delivery; (ii) genuine engagement and interaction across fields and institutions helps build capacity and strengthen motivation; (iii) implementation of a new strategy requires clarity; who's doing what, when and how?; (iv) it is important not to lose sight of research findings related to the needs of disadvantaged families; and (v) trust in the process and perseverance are fundamental. There was strong motivation and opportunity for change, but a need to enhance service capability. Areas requiring support and resources were identified.

6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE): 4-year disease-free survival results of a randomised phase 3 non-inferiority trial.

BACKGROUND: Adjuvant trastuzumab significantly improves outcomes for patients with HER2-positive early breast cancer. The standard treatment duration is 12 months but shorter treatment could provide similar efficacy while reducing toxicities and cost. We aimed to investigate whether 6-month adjuvant trastuzumab treatment is non-inferior to the standard 12-month treatment regarding disease-free survival. METHODS: This study is an open-label, randomised phase 3 non-inferiority trial. Patients were recruited from 152 centres in the UK. We randomly assigned patients with HER2-positive early breast cancer, aged 18 years or older, and with a clear indication for chemotherapy, by a computerised minimisation process (1:1), to receive either 6-month or 12-month trastuzumab delivered every 3 weeks intravenously (loading dose of 8 mg/kg followed by maintenance doses of 6 mg/kg) or subcutaneously (600 mg), given in combination with chemotherapy (concurrently or sequentially). The primary endpoint was disease-free survival, analysed by intention to treat, with a non-inferiority margin of 3% for 4-year disease-free survival. Safety was analysed in all patients who received trastuzumab. This trial is registered with EudraCT (number 2006-007018-39), ISRCTN (number 52968807), and ClinicalTrials.gov (number NCT00712140). FINDINGS: Between Oct 4, 2007, and July 31, 2015, 2045 patients were assigned to 12-month trastuzumab treatment and 2044 to 6-month treatment (one patient was excluded because they were double randomised). Median follow-up was 5·4 years (IQR 3·6-6·7) for both treatment groups, during which a disease-free survival event occurred in 265 (13%) of 2043 patients in the 6-month group and 247 (12%) of 2045 patients in the 12-month group. 4-year disease-free survival was 89·4% (95% CI 87·9-90·7) in the 6-month group and 89·8% (88·3-91·1) in the 12-month group (hazard ratio 1·07 [90% CI 0·93-1·24], non-inferiority p=0·011), showing non-inferiority of the 6-month treatment. 6-month trastuzumab treatment resulted in fewer patients reporting severe adverse events (373 [19%] of 1939 patients vs 459 [24%] of 1894 patients, p=0·0002) or stopping early because of cardiotoxicity (61 [3%] of 1939 patients vs 146 [8%] of 1894 patients, p<0·0001). INTERPRETATION: We have shown that 6-month trastuzumab treatment is non-inferior to 12-month treatment in patients with HER2-positive early breast cancer, with less cardiotoxicity and fewer severe adverse events. These results support consideration of reduced duration trastuzumab for women at similar risk of recurrence as to those included in the trial. FUNDING: UK National Institute for Health Research, Health Technology Assessment Programme.

Shared Goals, Different Barriers: A Qualitative Study of UK Veterinarians' and Farmers' Beliefs About Antimicrobial Resistance and Stewardship.

Although much research has investigated the drivers of inappropriate antimicrobial prescribing in human medicine, equivalent research in veterinary medicine is in its infancy. This qualitative study used a critical incident approach to explore farm veterinarians' (vets) and farmers' beliefs about antimicrobial use and antimicrobial stewardship. Semi-structured interviews were conducted with 13 vets and 12 farmers in the UK, who worked mostly with beef cattle, dairy cattle and sheep, but a minority also worked with pigs or poultry. An inductive thematic analysis was conducted to explore how vets and farmers understood their responsibilities toward stewardship and antimicrobial resistance (AMR) and to identify key similarities and differences between the professions. The analysis generated four themes: "A shared conflict between ideals and behaviour," "Barriers to stewardship: the vets' perspective," "Barriers to stewardship: the farmers' perspective," and "A shared ambivalence: ownership vs. other-blaming." Vets and farmers demonstrated good understanding of stewardship but their treatment decisions are not always aligned to stewardship principles. Various barriers to improving antimicrobial stewardship were discussed by vets and farmers, but they placed differing emphasis on specific barriers. Faced with these barriers and an awareness that antimicrobial usage is not always aligned to stewardship principles, vets and farmers expressed frustration and a sense of ambivalence toward stewardship, and also engaged in other-blaming for the problem of AMR. In conclusion, vets and farmers in this study seem motivated to be antimicrobial stewards but feel challenged by the day-to-day reality of their jobs; they experience ambivalence toward their responsibilities for AMR, which may negatively impact their motivation to always act as antimicrobial stewards. Successfully tackling AMR will require change at the individual-, group-, and societal-level. Future interventions to improve antimicrobial usage in livestock farming could be situated within a social ecological framework, where other-blaming between professions is seen as a result of the interplay between psychological and contextual factors. Other-blaming could be reduced using a social identity approach; a common ingroup identity could be created by encouraging vets and farmers to focus on their common goal, namely a shared desire to promote animal welfare through optimal antimicrobial stewardship.