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Understanding long-term persistence and variability in species populations can help to predict future survival, growth and distribution; however, sustained observations are exceedingly rare. We examine and interpret a remarkable record of the calcareous brown alga Padina pavonica (Phaeophyceae) at its northern limit on the south coast of England (50°N, 1–3°W) from 1680 to 2014, which is probably the longest compilation and review of any marine algal species. Over this period, which extends from the middle of the Little Ice Age to the present, there has been considerable variability in temperature and storminess. We identified a significant number of site extinctions in the second half of the nineteenth century, which coincided with cooler conditions and stormier weather. To interpret these changes, we measured recruitment, growth and production of tetraspores at sheltered and exposed sites in 2012–2014, years which had low and high spring temperatures. Potential spore production was greater at the sheltered site due to a longer growing period and survival of larger fronds. Delayed growth in the cooler spring resulted in smaller fronds and lower potential production of tetraspores by early summer. Yet in the warmer year, rapid initial growth caused higher sensitivity to damage and dislodgement by summer storms, which also limited potential spore production. Antagonistic responses to multiple stressors and disturbances make future predictions of survival and distribution difficult. Fronds of Padina pavonica are sensitive to both temperature and physical disturbances, yet vegetative perennation appears to have enabled population persistence and explained the longevity of remaining populations.

The goal of this dissertation was to investigate three new curve comparison metrics, the Rescigno Index, fl, and the Chinchilli Metric as tools to compare pharmacokinetic profiles for the assessment of assess relative bioavailability (BA) and bioequivalence (BE). The specific objectives were to (1) compare the relative sensitivity of the new metrics to detect differences in AUC and Cmax as a function of the pharmacokinetics of the drug products, and (2) to estimate relative bioavailability and bioequivalence. Methods. Retrospective analysis of experimental data and Monte Carlo simulations of bioequivalence trials were used to evaluate the relative sensitivity of the metrics to detect profile differences. The experimental data study involved determining the degree of discordance with typical criteria when judging individual profiles to be the same or different, and then examining the relationship between the degree of discordance and the pharmacokinetics of the drug product. The simulation studies involved determining the proportion of clinical studies failing bioequivalence under different pharmacokinetic models. Product bioequivalence was estimated using data from 35 typical 2 treatment-2 period bioequivalence study experimental datasets. Three different bioequivalence limits were applied to the curve metrics. Results. The new metrics more effectively detect differences in absorption time lags but less effectively detect differences in Cmax under some conditions. The relative sensitivity to Cmax depends on the shape of the curve, where increasing the ka(ref)/ke(ref) increases the disparity across the metrics. The curve metrics show increased sensitivity to variability in disposition, elimination, and random residual error, but comparable sensitivity to differences in bioavailability. Fourteen of the 35 studies failed typical criteria (AUC and Cmax). Applying bioequivalence iimits of 25%, 21 and 26 studies failed the Chinchilli and fl criteria respectively. At the 30% limit, 14 and 20 studies failed the Chinchilli and fl criteria respectively. The specific studies failing each criterion varied. The within-subject variability of the Chinchilli Metric was higher than Cmax. Both the Chinchilli Metric and fl showed a tendency toward extreme values. Conclusions. The metrics differ in pharmacokinetic sensitivities and differ in statistical properties. There are advantages and disadvantages associated with these differences.

Bacillus cereus isolates have been described harboring Bacillus anthracis toxin genes, most notably B. cereus G9241, and capable of causing severe and fatal pneumonias. This report describes the characterization of a B. cereus isolate, BcFL2013, associated with a naturally occurring cutaneous lesion resembling an anthrax eschar. Similar to G9241, BcFL2013 is positive for the B. anthracis pXO1 toxin genes, has a multi-locus sequence type of 78, and a pagA sequence type of 9. Whole genome sequencing confirms the similarity to G9241. In addition to the chromosome having an average nucleotide identity of 99.98% when compared to G9241, BcFL2013 harbors three plasmids with varying homology to the G9241 plasmids (pBCXO1, pBC210 and pBFH_1). This is also the first report to include serologic testing of patient specimens associated with this type of B. cereus infection which resulted in the detection of anthrax lethal factor toxemia, a quantifiable serum antibody response to protective antigen (PA), and lethal toxin neutralization activity.

The SARS-CoV-2 Delta variant emerged shortly after COVID-19 vaccines became available in 2021. We describe SARS-CoV-2 breakthrough infections in a highly vaccinated, well-monitored US Embassy community in Kampala, Uganda. Defining breakthrough infection rates in highly vaccinated populations can help determine public health messaging, guidance, and policy globally.

We have constructed 26-amino acid transmembrane proteins that specifically transform cells but consist of only two different amino acids. Most proteins are long polymers of amino acids with 20 or more chemically distinct side-chains. The artificial transmembrane proteins reported here are the simplest known proteins with specific biological activity, consisting solely of an initiating methionine followed by specific sequences of leucines and isoleucines, two hydrophobic amino acids that differ only by the position of a methyl group. We designate these proteins containing leucine (L) and isoleucine (I) as LIL proteins. These proteins functionally interact with the transmembrane domain of the platelet-derived growth factor β-receptor and specifically activate the receptor to transform cells. Complete mutagenesis of these proteins identified individual amino acids required for activity, and a protein consisting solely of leucines, except for a single isoleucine at a particular position, transformed cells. These surprisingly simple proteins define the minimal chemical diversity sufficient to construct proteins with specific biological activity and change our view of what can constitute an active protein in a cellular context.

There is substantial movement of US refugee populations originating from Africa, Asia, and other parts of the world across all parts of the country, beyond large metropolitan areas and traditional immigration hubs. Counter to expectations that refugees would remain in a given resettlement location for a period of integration and support, many non-resettlement communities have attracted newcomer refugees. The dynamics of early movement of refugees blurs the line between initial resettlement and secondary migration. To study the timing and motivations for refugee secondary migration, we conducted structured quantitative interviews with 92 refugees in Greeley, Colorado. Like many other small agricultural cities across the USA (Marston et al. International Journal of Migration and Residential Mobility, 1(3), 253–268, 2016; Broadway Rural Sociology, 72(4), 560–582, 2007), Greeley has experienced an influx of refugees due to a shift in the meatpacking labor market from immigrant to refugee labor. This study adds to prior research documenting refugee secondary migration (e.g., Marks 2014; Hume and Hardwick Geographical Review, 95(2), 189–209, 2005; Weine et al. Family Process, 50(1), 27–46, 2011) with a larger study sample focused on gathering uniform accounts of refugee migration histories. Our data show that many refugees arrived in Greeley very soon after initial resettlement. Employment and social networks were a draw for most interviewees to move to Greeley; however, many who came for work had not yet found employment or were unemployed after leaving jobs at the meatpacking plant. These and other findings suggest the importance of research on refugee mobility. In an ever-globalizing world, the blurred line between primary and secondary migration necessitates preparation among American communities to maximize refugee integration.

Respiratory distress is common in premature infants. Many of these infants require mechanical ventilatory support for the first few weeks of life, but the best way to deliver this support is not known. In this randomized trial performed in the United Kingdom, there was no difference between the two ventilatory strategies in terms of survival, the need for oxygen treatment at 28 days of life, or other benefits or complications of ventilation. In this trial in very preterm infants, there was no difference between two ventilatory strategies in preventing lung disease. Pulmonary disease continues to be a major cause of illness and death in very preterm infants. Despite the introduction of a number of therapeutic interventions, the incidence of chronic lung disease remains high among such infants. Pulmonary immaturity, high ventilator pressure, and oxygen toxicity are major risk factors for chronic lung disease whose frequency could be reduced through the use of high-frequency oscillatory ventilation. Such ventilation involves the application of rapid oscillatory pressure — at 5 to 15 Hz, or 300 to 900 breaths per minute — superimposed on a continuous distending pressure. Although studies in animals have shown that . . .

ABSTRACTObjectivesTo develop a staff training intervention for agitation in people with severe dementia, reaching end-of-life, residing in nursing homes (NHs), test feasibility, acceptability, and whether a trial is warranted. DesignFeasibility study with pre- and post-intervention data collection, qualitative interviews, and focus groups. SettingThree NHs in South East England with dementia units, diverse in terms of size, ownership status, and location. ParticipantsResidents with a dementia diagnosis or scoring ≥2 on the Noticeable Problems Checklist, rated as “severe” on Clinical Dementia Rating Scale, family carers, and staff (healthcare assistants and nurses). InterventionManualized training, delivered by nonclinical psychology graduates focusing on agitation in severe dementia, underpinned by a palliative care framework. MeasurementsMain outcomes were feasibility of recruitment, data collection, follow-up, and intervention acceptability. We collected resident, family carer, and staff demographics. Staff provided data on resident’s agitation, pain, quality of life, and service receipt. Staff reported their sense of competence in dementia care. Family carers reported on satisfaction with end-of-life care. In qualitative interviews, we explored staff and family carers’ views on the intervention. ResultsThe target three NHs participated: 28 (49%) residents, 53 (74%) staff, and 11 (85%) family carers who were eligible to participate consented. Eight-four percent of staff attended ≥3 sessions, and we achieved 93% follow-up. We were able to complete quantitative interviews. Staff and family carers reported the intervention and delivery were acceptable and helpful. ConclusionsThe intervention was feasible and acceptable indicating a larger trial for effectiveness may be warranted.

The US Food and Drug Administration (FDA) and National Institutes of Health (NIH) share a mutual interest in facilitating efficient, well-designed clinical studies of drugs, devices, and biological products. Recent advances in science and technology, as well as innovative approaches to research design and methodology, provide opportunities to enhance efficiency in medical product development and improve participant engagement in clinical trials. Recent initiatives across the FDA and NIH focus on evidence modernization approaches. Fostering appropriate use of novel designs and sources of evidence, such as real-world data (RWD) to support marketing authorizations and satisfy postapproval study requirements, may be enhanced by using consensus terminology for innovative study designs. To facilitate effective communication within the scientific community, FDA and NIH formed an interagency collaborative initiative to define clinical research terms related to innovative study designs, with a focus on studies using RWD, for FDA-regulated medical products or broader research and foster a shared understanding of terms across the clinical research ecosystem. The FDA-NIH Modernizing Research and Evidence (MoRE) Glossary Working Group (MGWG) was initiated in April 2023 to evaluate terms inadequately defined within the clinical research community that would benefit from development of a consensus definition. The MGWG conducted a landscape evaluation of common innovative design terminology that may lack clarity or concordance. Subsequently, the MGWG reviewed whether and how existing regulations, guidance, and policies use or define such terms. Following the landscape evaluation, the MGWG engaged in rigorous review to seek consensus definitions. In addition, federal agencies sought public input via a request for information before publishing the included terms and definitions. The MGWG developed the MoRE Consensus Definitions, comprising 40 clinical research terms and definitions related to innovative clinical study designs that support scientific, patient, clinical, and regulatory decision-making. The MoRE Consensus Definitions are intended to facilitate effective communication about clinical research and enable transparency around innovative clinical study designs. This publication makes available the glossary developed through this collaboration and serves as an accessible resource for the clinical research enterprise. Furthermore, as clinical research is continuously evolving, additional efforts may focus on emerging new vocabulary and evolving use of current terms to benefit medical product development.

IntroductionTourette syndrome and chronic tic disorder are common, disabling childhood-onset conditions. Guidelines recommend that behavioural therapy should be offered as first-line treatment for children with tics. However, there are very few trained behaviour therapists for tics and many patients cannot access appropriate care. This trial investigates whether an internet-delivered intervention for tics can reduce severity of symptoms.Methods and analysisThis parallel-group, single-blind, randomised controlled superiority trial with an internal pilot will recruit children and young people (aged 9–17 years) with tic disorders. Participants will be randomised to receive 10 weeks of either online, remotely delivered, therapist-supported exposure response prevention behavioural therapy for tics, or online, remotely delivered, therapist-supported education about tics and co-occurring conditions. Participants will be followed up mid-treatment, and 3, 6, 12 and 18 months post randomisation.The primary outcome is reduction in tic severity as measured on the Yale Global Tic Severity Scale total tic severity score. Secondary outcomes include a cost-effectiveness analysis and estimate of the longer-term impact on patient outcomes and healthcare services. An integrated process evaluation will analyse quantitative and qualitative data in order to fully explore the implementation of the intervention and identify barriers and facilitators to implementation. The trial is funded by the National Institute of Health Research (NIHR), Health Technology Assessment (16/19/02).Ethics and disseminationThe findings from the study will inform clinicians, healthcare providers and policy makers about the clinical and cost-effectiveness of an internet delivered treatment for children and young people with tics. The results will be submitted for publication in peer-reviewed journals. The study has received ethical approval from North West Greater Manchester Research Ethics Committee (ref.: 18/NW/0079).Trial registration numbers ISRCTN70758207 and NCT03483493; Pre-results.