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Gravitational waves are expected to be radiated by supermassive black hole binaries formed during galaxy mergers. A stochastic superposition of gravitational waves from all such binary systems would modulate the arrival times of pulses from radio pulsars. Using observations of millisecond pulsars obtained with the Parkes radio telescope, we constrained the characteristic amplitude of this background, Ac,yr, to be <1.0 × 10–15 with 95% confidence. This limit excludes predicted ranges for Ac,yr from current models with 91 to 99.7% probability. We conclude that binary evolution is either stalled or dramatically accelerated by galactic-center environments and that higher-cadence and shorter-wavelength observations would be more sensitive to gravitational waves.

ObjectiveDespite growing interest in children and young people’s (CYP) perspectives on healthcare, they continue to be excluded from many patient experience surveys. This study investigated the feasibility of, and additional information gained by, measuring CYP experiences of a recent hospital admission.DesignCross-sectional analysis of national survey data.SettingInpatients aged 8–15 years in eligible National Health Service hospitals, July–September 2014.Participants6204 parents/carers completed the parent section of the survey. The CYP section of the survey was completed by CYP themselves (n=3592), parents (n=849) or jointly (n=1763).Main outcome measuresPain relief, involvement, quality of staff communication, perceived safety, ward environment, overall experience.AnalysesSingle-measures intraclass correlations (ICCs) were used to assess the concordance between CYP and parent responses about the same inpatient episode. Multilevel logistic regression models, adjusted for individual characteristics, were used to compare the odds of positive responses when the CYP section of the survey was completed by parents, by CYP themselves or jointly.ResultsThe CYP section of the survey was completed independently by 57.8% of CYP. Agreement between CYP and parent responses was reasonably good for pain relief (ICC=0.61 (95% CI 0.58 to 0.63)) and overall experience (ICC=0.70 (95% CI 0.68 to 0.72)), but much lower for questions comparing professionals’ communication with CYP and with their parents (ICC range=0.28 (95% CI 0.24 to 0.32) to 0.51 (95% CI 0.47 to 0.54)). In the regression models, CYP were significantly less likely than parents to report feeling safe (adjusted OR (AOR)=0.54 (95% CI 0.38 to 0.76)), involvement in decisions (AOR=0.66 (95% CI 0.46 to 0.94)) or adequate privacy (AOR=0.68 (95% CI 0.52 to 0.89)).ConclusionsIncluding CYP (8–15 years) in patient experience surveys is feasible and enhances what is known from parents’ responses.

The blue shark ( Prionace glauca ) is a widely distributed pelagic predator that undergoes ontogenetic morphological changes that reflect ecological and functional adaptations. Investigating this aspect could provide powerful tools for elucidating the patterns of trait variation and their significance in relation to environmental conditions. This study explores morphometric variation and its ecomorphological implications in the Mediterranean blue shark population using linear and geometric morphometric analyses. A total of 119 specimens (64 females, 55 males), spanning from juvenile (total lengths [TLs] 85.4–149.8 cm in females and 82.9–121.2 cm in males) to adult (TLs 150.4–333.1 cm in females and 133.2–206.8 cm in males) stages, were analysed through a set of 30 linear measurements. Linear morphometric analysis identified significant differences between the juvenile and subadult/adult groups, particularly in the anterior body region and pectoral fin measurements. Geometric morphometric results revealed that juveniles have a more heterocercal caudal fin shape, which transitions to a less heterocercal form in adults, with a proportionally larger ventral lobe. The first dorsal fin showed positive allometry, becoming higher. The observed ontogenetic differences could improve energy efficiency and manoeuvrability. This aligns with the diel vertical migrations (DVM) of larger individuals and their need for sustained swimming during long‐distance migrations, as well as the enhanced manoeuvrability required by juveniles, notably for predator avoidance. These morphological changes likely reflect adaptations to changing energy requirements and locomotion needs throughout life stages. Although blue sharks maintain a generalist diet across ontogeny, these adaptations may optimise feeding efficiency and swimming performance, particularly in adults. This study highlights the interplay between ontogeny, morphology and ecological function, shedding light on the selective pressures that shape the life history strategies of blue sharks. The findings emphasise the importance of integrating ontogenetic perspectives into ecomorphological studies to better understand the evolutionary adaptations of pelagic sharks.

Primary effusion lymphoma (PEL) is a rare form of aggressive B cell lymphoma caused by Kaposi's sarcoma-associated herpesvirus (KSHV). Current chemotherapy approaches result in dismal outcomes, and there is an urgent need for new PEL therapies. Previously, we established, in a direct xenograft model of PEL-bearing immune-compromised mice, that treatment with the proteasome inhibitor, bortezomib (Btz), increased survival relative to that after treatment with doxorubicin. Herein, we demonstrate that the combination of Btz with the histone deacetylase (HDAC) inhibitor suberoylanilidehydroxamic acid (SAHA, also known as vorinostat) potently reactivates KSHV lytic replication and induces PEL cell death, resulting in significantly prolonged survival of PEL-bearing mice. Importantly, Btz blocked KSHV late lytic gene expression, terminally inhibiting the full lytic cascade and production of infectious virus in vivo. Btz treatment led to caspase activation and induced DNA damage, as evidenced by the accumulation of phosphorylated γH2AX and p53. The addition of SAHA to Btz treatment was synergistic, as SAHA induced early acetylation of p53 and reduced interaction with its negative regulator MDM2, augmenting the effects of Btz. The eradication of KSHV-infected PEL cells without increased viremia in mice provides a strong rationale for using the proteasome/HDAC inhibitor combination therapy in PEL.

Primary effusion lymphoma (PEL) is an aggressive B-cell lymphoma most commonly diagnosed in HIV-positive patients and universally associated with Kaposi's sarcoma-associated herpesvirus (KSHV). Chemotherapy treatment of PEL yields only short-term remissions in the vast majority of patients, but efforts to develop superior therapeutic approaches have been impeded by lack of animal models that accurately mimic human disease. To address this issue, we developed a direct xenograft model, UM-PEL-1, by transferring freshly isolated human PEL cells into the peritoneal cavities of NOD/SCID mice without in vitro cell growth to avoid the changes in KSHV gene expression evident in cultured cells. We used this model to show that bortezomib induces PEL remission and extends overall survival of mice bearing lymphomatous effusions. The proapoptotic effects of bortezomib are not mediated by inhibition of the prosurvival NF-κB pathway or by induction of a terminal unfolded protein response. Transcriptome analysis by genomic arrays revealed that bortezomib down-regulated cell-cycle progression, DNA replication, and Myc-target genes. Furthermore, we demonstrate that in vivo treatment with either bortezomib or doxorubicin induces KSHV lytic reactivation. These reactivations were temporally distinct, and this difference may help elucidate the therapeutic window for use of antivirals concurrently with chemotherapy. Our findings show that this direct xenograft model can be used for testing novel PEL therapeutic strategies and also can provide a rational basis for evaluation of bortezomib in clinical trials.

•Over 100 countries have a nationwide mandatory vaccination policy requiring one or more vaccines.•Of those, 62 countries (59%) also impose one or more penalties against individuals who do not comply.•Educational and financial penalties are the most common types of penalties; severity varies.•Most educational penalties deny school enrollment until vaccination requirements are met. Declining vaccination coverage and increasing hesitancy is a worldwide concern. Many countries have implemented mandatory vaccination policies to promote vaccination. However, mandatory vaccination policies differ significantly by country. Beyond case studies, no comprehensive study has compared these policies or the penalties for non-compliance on a global scale. We conducted extensive keyword, policy, and literature searches to identify mandatory national vaccination policies globally and develop a comprehensive database. A mandatory national vaccination policy was defined as a policy from a national authority that requires individuals to receive at least one vaccination based on age or to access a service. Two reviewers independently evaluated evidence for a mandate and whether non-compliance penalties were incorporated. We categorized penalties into four types, based on the nature of the penalty. These penalties impact an individual’s financial, parental rights, educational (i.e., child's school entry and access), and liberty status. We rated the severity within each category. Of 193 countries investigated, 54% (n = 105) had evidence of a nationwide mandate as of December 2018. The frequency, types, and severity of penalties varied widely across all regions. We found that 59% (n = 62) of countries with national mandates defined at least one penalty for non-compliance with a vaccine mandate. Among those, educational penalties (i.e., limiting a child's entry or ongoing access to school) were the most common (69%; n = 43), with most countries with educational penalties refusing school enrollment until vaccination requirements are met (81%; n = 35). We undertook a comprehensive assessment of national mandatory vaccination policies and identified a diversity of penalties in place to promote compliance. Our results highlight the need to critically evaluate the implementation of non-compliance penalties in order to determine their effectiveness and to define best practices for sustaining high vaccination uptake worldwide.

Positive patient experience is associated with improved patient outcomes, but efforts to improve patient experience are often underprioritized, especially with respect to pediatric care. To address this challenge, leaders at several US children's hospitals established the Pediatric Experience Collaborative (PEC) in 2016 to leverage their collaboration and scale to optimize patient, family, and provider experiences. Since then, the PEC has steadfastly incorporated the patient and family perspective in all its endeavors (e.g., installing a family member as one of the organization's co-chairs); has created both structured opportunities and unstructured opportunities for learning and connection; and has embarked on multi-institutional research among its 20 + members, beginning with a survey on the impact of video visits in the immediate aftermath of the COVID-19 pandemic. Having achieved success through this collaborative model, the PEC is preparing for its next phase of growth by concentrating on three key objectives: expanding the evidence base for best practices in pediatric patient experience (PPX), elevating the national importance of PPX within the healthcare industry, and strengthening the national PPX community.

Aims: We previously reported effects of the CMCA intervention in reducing social and commercial access to alcohol by youth, and reducing alcohol use by 18‐20‐year‐olds. This paper reports on effects of CMCA on arrests and car crashes. Design: CMCA was a group‐randomized trial that implemented and evaluated a community‐organizing effort to change community policies and practices to reduce youth access to alcohol. Seven Midwestern communities were randomly assigned to the intervention condition and eight communities were assigned to the control condition. Intervention: For 2.5 years, a part‐time community organizer worked in each of the seven intervention communities with local public officials, enforcement agencies, alcohol merchants, the media, schools and other community groups to reduce youth access to alcohol. Measurement: We collected annual arrest and quarterly traffic crash data for the years 1987‐1995, providing a 6‐year baseline and 3 years of data during the intervention. Data were stratified into two target age groups (15‐17 and 18‐20) and a control group (age 21 and over). Analyses used random‐coefficient models because we had repeated observations for each unit of assignment in a group‐randomized trial with heterogeneous trends across communities. Findings: We observed net declines in the intervention communities for all arrest and traffic crash indicators. The decline was statistically significant for DUI arrests among 18‐20‐year‐olds and approached significance for DUI arrests and disorderly conduct violations among 15‐17‐year‐olds. Conclusions: Together with previously published results from this study, the results reported here suggest that a community‐organizing approach to limit youth access to alcohol may be effective, at least for selected end‐points and subgroups. We conclude that this approach may be useful, but that a longer intervention period is required to increase effectiveness.

Objective: To evaluate the effects of lowering prices and increasing availability on sales of healthy foods and beverages from 33 vending machines in 4 bus garages as part of a multicomponent worksite obesity prevention intervention. Methods: Availability of healthy items was increased to 50% and prices were lowered at least 10% in the vending machines in two metropolitan bus garages for an 18-month period. Two control garages offered vending choices at usual availability and prices. Sales data were collected monthly from each of the vending machines at the four garages. Results: Increases in availability to 50% and price reductions of an average of 31% resulted in 10% to 42% higher sales of the healthy items. Employees were mostly price responsive for snack purchases. Conclusions: Greater availability and lower prices on targeted food and beverage items from vending machines was associated with greater purchases of these items over an 18-month period. Efforts to promote healthful food purchases in worksite settings should incorporate these two strategies.

Background Associations between hours worked per week and Body Mass Index (BMI), food intake, physical activity, and perceptions of eating healthy at work were examined in a sample of transit workers. Methods Survey data were collected from 1086 transit workers. Participants reported hours worked per week, food choices, leisure-time physical activity and perceptions of the work environment with regard to healthy eating. Height and weight were measured for each participant. Multivariate linear and logistic regressions were conducted to examine associations between work hours and behavioral variables. Associations were examined in the full sample and stratified by gender. Results Transit workers working in the highest work hour categories had higher BMI and poorer dietary habits, with results differing by gender. Working 50 or more hours per week was associated with higher BMI among men but not women. Additionally, working 50 or more hours per week was significantly associated with higher frequency of accessing cold beverage, cold food, and snack vending machines among men. Working 40 or more hours per week was associated with higher frequency of accessing cold food vending machines among women. Reported frequency of fruit and vegetable intake was highest among women working 50 or more hours per week. Intake of sweets, sugar sweetened beverages, and fast food did not vary with work hours in men or women. Physical activity and perception of ease of eating healthy at work were not associated with work hours in men or women. Conclusions Long work hours were associated with more frequent use of garage vending machines and higher BMI in transit workers, with associations found primarily among men. Long work hours may increase dependence upon food availability at the worksite, which highlights the importance of availability of healthy food choices.