Engaging with stakeholders to inform the development of a decision-support tool for the NHS health check programme: qualitative study.

BACKGROUND: The NHS Health Check Programme is a risk-reduction programme offered to all adults in England aged 40-74 years. Previous studies mainly focused on patient perspectives and programme delivery; however, delivery varies, and costs are substantial. We were therefore working with key stakeholders to develop and co-produce an NHS Health Check Programme modelling tool (workHORSE) for commissioners to quantify local effectiveness, cost-effectiveness, and equity. Here we report on Workshop 1, which specifically aimed to facilitate engagement with stakeholders; develop a shared understanding of current Health Check implementation; identify what is working well, less well, and future hopes; and explore features to include in the tool. METHODS: This qualitative study identified key stakeholders across the UK via networking and snowball techniques. The stakeholders spanned local organisations (NHS commissioners, GPs, and academics), third sector and national organisations (Public Health England and The National Institute for Health and Care Excellence). We used the validated Hovmand "group model building" approach to engage stakeholders in a series of pre-piloted, structured, small group exercises. We then used Framework Analysis to analyse responses. RESULTS: Fifteen stakeholders participated in workshop 1. Stakeholders identified continued financial and political support for the NHS Health Check Programme. However, many stakeholders highlighted issues concerning lack of data on processes and outcomes, variability in quality of delivery, and suboptimal public engagement. Stakeholders' hopes included maximising coverage, uptake, and referrals, and producing additional evidence on population health, equity, and economic impacts. Key model suggestions focused on developing good-practice template scenarios, analysis of broader prevention activities at local level, accessible local data, broader economic perspectives, and fit-for-purpose outputs. CONCLUSIONS: A shared understanding of current implementations of the NHS Health Check Programme was developed. Stakeholders demonstrated their commitment to the NHS Health Check Programme whilst highlighting the perceived requirements for enhancing the service and discussed how the modelling tool could be instrumental in this process. These suggestions for improvement informed subsequent workshops and model development.

Overview of Current and Future First-Line Systemic Therapy for Metastatic Clear Cell Renal Cell Carcinoma.

OPINION STATEMENT: Treatment of metastatic clear cell renal cancer (mccRCC) has seen substantial progress over the last 20 years, with many regulatory approvals since 2006 culminating in a substantial increase to overall survival (OS). Six therapies are currently available for first-line use, with additional treatments currently being tested in this setting, some of which are expected to be approved soon based on new data from the CABOSUN and CheckMate-214 trials. Based on the available evidence, we strongly believe that vascular endothelial growth factor tyrosine kinase inhibitor (VEGF-TKI) therapy over mechanistic target or rapamycin (mTOR; formerly known as mammalian target of rapamycin) inhibitor therapy is the most effective first-line option regardless of risk category assignment. High-dose interleukin-2 (HDIL-2) therapy remains a reasonable treatment option in patients with Eastern Cooperative Oncology Group (ECOG) performance status 0-1 and have minimal comorbid conditions. In the near future, these agents are likely to be surpassed by cabozantinib and by combination immune checkpoint inhibitor therapy with nivolumab and ipilimumab. Independent review has recently confirmed superiority of first-line cabozantinib over sunitinib in a phase 2 trial of 157 patients with intermediate or poor risk mccRCC (progression-free survival [PFS] 8.6 vs 5.3 months, hazard ratio [HR] 0.48, p = 0.0008). In a separate study of 1096 patients treated with either upfront sunitinib or the combination of nivolumab and ipilimumab, those with intermediate and poor risk had significant improvement in both PFS (11.6 vs 8.4 months, HR 0.82, p = 0.0331) and OS (not reached vs 26 months, p < 0.0001). Responses were greater in patients with positive programmed death receptor ligand-1 (PD-L1) tumor staining, and pending regulatory approval may become standard of care in untreated patients with intermediate to poor risk disease with positive PD-L1 status. This likely represents the beginning of additional novel immunotherapy combinations for the first-line treatment of mccRCC.

Novel androgen axis systemic therapies for metastatic hormone-sensitive prostate cancer.

PURPOSE OF REVIEW: Upfront docetaxel and androgen deprivation therapy (ADT) has improved outcomes over ADT alone in men with metastatic hormone-sensitive prostate cancer (mHSPC). Here in, we review the emerging role of novel androgen axis inhibitors in the treatment of men with mHSPC. RECENT FINDINGS: Recently two studies, LATITUDE and STAMPEDE arm G, showed improved survival with addition of abiraterone acetate with prednisone or prednisolone to ADT in men with hormone-naïve advanced prostate cancer. SUMMARY: Upfront docetaxel in addition to ADT has been shown to improve survival outcomes in men with high-volume mHSPC. Recently, abiraterone acetate and prednisone or prednisolone and ADT have been shown to improve survival outcomes compared with ADT alone in men with mHSPC. Multiple other novel androgen axis inhibitors are being investigated in this setting, and expected to garner regulatory approval in the near future. Biomarkers predicting response to these agents are urgently needed to optimize treatment selection, not only to improve outcomes but to also minimize cost and toxicities.

Ultrafast properties of femtosecond-laser-ablated GaAs and its application to terahertz optoelectronics.

We report on the first terahertz (THz) emitter based on femtosecond-laser-ablated gallium arsenide (GaAs), demonstrating a 65% enhancement in THz emission at high optical power compared to the nonablated device. Counter-intuitively, the ablated device shows significantly lower photocurrent and carrier mobility. We understand this behavior in terms of n-doping, shorter carrier lifetime, and enhanced photoabsorption arising from the ablation process. Our results show that laser ablation allows for efficient and cost-effective optoelectronic THz devices via the manipulation of fundamental properties of materials.

Travel-Related Behaviors and Health Outcomes of Adolescents Compared with Adults on Short-Term International Service Missions.

With an increasing number of adolescents participating in international travel, little is known about travel-related behaviors and health risks in this age group. In the years 2015-2016, we conducted an anonymous, posttravel, questionnaire-based survey with the aim to compare self-reported practices and travel-related symptoms between adolescents (< 18 years old, N = 87) and adults (≥ 18 years old, N = 149) who came to our travel clinic before their humanitarian missions. They had the same pretravel health education, and traveled together to perform similar activities. In univariate analysis, compared with adults, we found that adolescents reported less prior international travel (P < 0.001), more often wore long-sleeved clothing for malaria prevention (P < 0.001) but less often for sun protection (P = 0.009), more often used insect repellents (P = 0.011), and less often had diarrhea (P = 0.024). All other practices and health outcomes were similar between the groups. Multivariate analyses using Bayesian network show strong associations between adults and prior travel experience, and not wearing long-sleeve clothing for malaria prevention. We also found strong associations between prior international travel and sustaining an injury, and having jet lag, as well as between taking malaria prophylaxis and not having diarrhea. Overall, most practices and health outcomes were similar between age groups. Adolescent age and lack of prior international travel experience did not have significant impacts on practices and health outcomes. Our findings highlight the need for more effective strategies to improve the behaviors and health outcomes in both adolescents and adults.

Is France Once Again Looking for a Scapegoat?

On September 10, 2021, a special tribunal established by the French government launched an inquiry into the activities of former health minister Dr. Agnes Buzyn who was charged with "endangering the lives of others". It is surprising to learn of this accusation and inquiry into the actions of a public health official whose response to the epidemic was, to all appearances, exemplary.

A cost/benefit analysis of clinical trial designs for COVID-19 vaccine candidates.

We compare and contrast the expected duration and number of infections and deaths averted among several designs for clinical trials of COVID-19 vaccine candidates, including traditional and adaptive randomized clinical trials and human challenge trials. Using epidemiological models calibrated to the current pandemic, we simulate the time course of each clinical trial design for 756 unique combinations of parameters, allowing us to determine which trial design is most effective for a given scenario. A human challenge trial provides maximal net benefits-averting an additional 1.1M infections and 8,000 deaths in the U.S. compared to the next best clinical trial design-if its set-up time is short or the pandemic spreads slowly. In most of the other cases, an adaptive trial provides greater net benefits.

Safety evaluation of a strategy to restart elective orthopaedic surgery during the de-escalation phase of the COVID-19 pandemic.

AIMS: To evaluate safety outcomes and patient satisfaction of the re-introduction of elective orthopaedic surgery on 'green' (non-COVID-19) sites during the COVID-19 pandemic. METHODS: A strategy consisting of phased relaxation of clinical comorbidity criteria was developed. Patients from the orthopaedic waiting list were selected according to these criteria and observed recommended preoperative isolation protocols. Surgery was performed at green sites (two local private hospitals) under the COVID-19 NHS contract. The first 100 consecutive patients that met the Phase 1 criteria and underwent surgery were included. In hospital and postoperative complications with specific enquiry as to development of COVID-19 symptoms or need and outcome for COVID-19 testing at 14 days and six weeks was recorded. Patient satisfaction was surveyed at 14 days postoperatively. RESULTS: There were 54 females and 46 males (mean age 44 years, mean body mass index (BMI) 25.6 kg/m2). In all, 56 patients underwent major orthopaedic procedures. There were no exclusions. One patient had a postoperative positive SARS-CoV-2 RT-PCR test but had no typical symptoms of COVID-19 infection and no clinical sequelae. 99% of patients were satisfied with the process and 98% would recommend undergoing elective orthopaedic surgery in the study period. CONCLUSION: In an environment with appropriate infrastructure, patient selection, isolation, screening, and testing, elective orthopaedic surgery is safe during the COVID-19 pandemic, and associated with high patient satisfaction. Further follow-up is required to establish that safety is maintained as the clinical restrictions are eased with the phased approach described.Cite this article: Bone Joint Open 2020;1-8:450-456.

Treatment Decisions for Metastatic Clear Cell Renal Cell Carcinoma in Older Patients: The Role of TKIs and Immune Checkpoint Inhibitors.

Given the underrepresentation of older patients in registration trials for metastatic renal cell carcinoma (mRCC), data to support the use of any particular systemic therapy over others, based on age, is limited. This is further complicated by clinical trials not commonly reporting adverse events by age. Thus, recommendations on treatment of older patients with mRCC are generally extrapolated from data on younger patients enrolled in these trials, which may not be ideal as many older patients are frail, have age-related organ dysfunction, or have multiple medical co-morbidities. In the last decade, the treatment landscape for mRCC has drastically changed with the approval of more than ten targeted therapies, as well as immune checkpoint inhibitors. Thus, treatment selection and sequencing of treatments can be especially challenging for clinicians. We begin this review by analyzing the available efficacy and toxicity data of these treatments in younger and older patients. We also discuss a network meta-analysis that compares the efficacy of these agents in older patients with mRCC. Utilizing this data, we suggest that nivolumab plus ipilimumab and cabozantinib may be favored for first-line treatment of specific populations of older patients. For salvage treatment, we suggest that cabozantinib may be the preferred agent for older patients.

Treatment of metastatic renal cell carcinoma in older patients: A network meta-analysis.

INTRODUCTION: More than half of patients diagnosed with renal cell carcinoma (RCC) are age 65 or older. However, older patients are often unable to meet eligibility criteria for clinical trial enrollment due to multiple factors, such as comorbidities and polypharmacy, which leads to under-representation of this population in clinical trials. Given this, efficacy data from the registration trials may not apply to older patients. Our objective was to evaluate the efficacy of first-line and salvage-line treatment in older patients, and compare efficacy between older and younger patients with metastatic RCC (mRCC). METHODS: Pivotal phase three clinical trials for first-line and salvage-line treatments were included if they reported overall survival (OS) or progression-free survival (PFS) results stratified by age (

High Prevalence of Shigella or Enteroinvasive Escherichia coli Carriage among Residents of an Internally Displaced Persons Camp in South Sudan.

Displaced persons living in camps are at an increased risk of diarrheal diseases. Subclinical carriage of pathogens may contribute to the spread of disease, especially for microbes that require a low infectious dose. Multiplex real-time polymerase chain reaction was performed to detect a panel of 20 bacterial, viral, and protozoal targets, and we report a high prevalence of enteropathogen carriage, including Shigella spp. or enteroinvasive Escherichia coli in 14%, among a sample of 88 asymptomatic individuals in an internally displaced persons camp in South Sudan. Further studies are needed to determine the contribution of such carriage to the spread of disease.

Mimicking subsecond neurotransmitter dynamics with femtosecond laser stimulated nanosystems.

Existing nanoscale chemical delivery systems target diseased cells over long, sustained periods of time, typically through one-time, destructive triggering. Future directions lie in the development of fast and robust techniques capable of reproducing the pulsatile chemical activity of living organisms, thereby allowing us to mimic biofunctionality. Here, we demonstrate that by applying programmed femtosecond laser pulses to robust, nanoscale liposome structures containing dopamine, we achieve sub-second, controlled release of dopamine--a key neurotransmitter of the central nervous system--thereby replicating its release profile in the brain. The fast delivery system provides a powerful new interface with neural circuits, and to the larger range of biological functions that operate on this short timescale.

Pleistocene isolation and recent gene flow in Haliotis asinina, an Indo-Pacific vetigastropod with limited dispersal capacity.

Haliotis asinina is a broadcast-spawning mollusc that inhabits Indo-Pacific coral reefs. This tropical abalone develops through a nonfeeding larval stage that is competent to settle on specific species of coralline algae after 3-4 days in the plankton. Failure to contact an inductive algae within 10 days of hatching usually results in death. These life cycle characteristics suggest a limited capacity for dispersal and thus gene flow. This makes H. asinina particularly suitable for elucidating phylogeographical structure throughout the Indo-Malay Archipelagoes, and eastern Indian and western Pacific Oceans, all regions of biogeographical complexity and high conservation value. We assayed 482 bp of the mitochondrial cytochrome oxidase II gene in 206 abalone collected from 16 geographically discrete sites across the Indian and Pacific Oceans and Indo-Malay Archipelagoes. DNA sequence variation was analysed via population genetics and phylogenetics, and by nested clade analyses (NCA). Our data resolved clear phylogeographical breaks among major biogeographical regions, with sequence divergences ranging from a high of 3.7% and 3.0% between Indian and Pacific sites and Pacific and Indo-Malay sites, respectively, to a low of 1.1% between Indian and Indo-Malay sites. Despite the apparent limited dispersal capacity of H. asinina, no finer scale phylogeographical structure was resolved within the respective biogeographical regions. However, amova and NCA identified several significant associations between haplotypes and geographical distribution, most notably higher gene flow among geographical populations associated with major ocean currents. Our study provides further evidence that larval dispersal capacity alone is not a good predictor of population genetic structure in marine invertebrates. We infer instead that a combination of historical events (long-term barriers followed by range expansion associated with Pleistocene sea level changes) and contemporary processes (gene flow restricted by life history and oceanography) have shaped observed patterns of H. asinina phylogeography.

Social structure in migrating humpback whales (Megaptera novaeangliae).

Although largely solitary, humpback whales exhibit a number of behaviours where individuals co-operate with one another, for example during bubble net feeding. Such cases could be due to reciprocal altruism brought on by exceptional circumstances, for example the presence of abundant shoaling fish. An alternative explanation is that these behaviours have evolved through kin selection. With little restriction to either communication or movement, diffuse groups of relatives could maintain some form of social organization without the need to travel in tight-nit units. To try to distinguish between these hypotheses, we took advantage of the fact that migrating humpback whales often swim together in small groups. If kin selection is important in humpback whale biology, these groups should be enriched for relatives. Consequently, we analysed biopsy samples from 57 groups of humpback whales migrating off Eastern Australia in 1992. A total of 142 whales were screened for eight microsatellite markers. Mitochondrial DNA sequences (371 bp) were also used to verify and assist kinship identification. Our data add support to the notion that mothers travel with their offspring for the first year of the calf's life. However, beyond the presence of mother-calf/yearling pairs, no obvious relatedness pattern was found among whales sampled either in the same pod or on the same day. Levels of relatedness did not vary between migratory phases (towards or away from the breeding ground), nor between the two sexes considered either overall or in the north or south migrations separately. These findings suggest that, if any social organization does exist, it is formed transiently when needed rather than being a constant feature of the population, and hence is more likely based on reciprocal altruism than kin selection.