Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up.

BackgroundNovel second-line treatments are needed for patients with advanced urothelial cancer (UC). Interim analysis of the phase III KEYNOTE-045 study showed a superior overall survival (OS) benefit of pembrolizumab, a programmed death 1 inhibitor, versus chemotherapy in patients with advanced UC that progressed on platinum-based chemotherapy. Here we report the long-term safety and efficacy outcomes of KEYNOTE-045.Patients and methodsAdult patients with histologically/cytologically confirmed UC whose disease progressed after first-line, platinum-containing chemotherapy were enrolled. Patients were randomly assigned 1 : 1 to receive pembrolizumab [200 mg every 3 weeks (Q3W)] or investigator's choice of paclitaxel (175 mg/m2 Q3W), docetaxel (75 mg/m2 Q3W), or vinflunine (320 mg/m2 Q3W). Primary end points were OS and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) by blinded independent central radiology review (BICR). A key secondary end point was objective response rate per RECIST v1.1 by BICR.ResultsA total of 542 patients were enrolled (pembrolizumab, n = 270; chemotherapy, n = 272). Median follow-up as of 26 October 2017 was 27.7 months. Median 1- and 2-year OS rates were higher with pembrolizumab (44.2% and 26.9%, respectively) than chemotherapy (29.8% and 14.3%, respectively). PFS rates did not differ between treatment arms; however, 1- and 2-year PFS rates were higher with pembrolizumab. The objective response rate was also higher with pembrolizumab (21.1% versus 11.0%). Median duration of response to pembrolizumab was not reached (range 1.6+ to 30.0+ months) versus chemotherapy (4.4 months; range 1.4+ to 29.9+ months). Pembrolizumab had lower rates of any grade (62.0% versus 90.6%) and grade ≥3 (16.5% versus 50.2%) treatment-related adverse events than chemotherapy.ConclusionsLong-term results (>2 years' follow-up) were consistent with those of previously reported analyses, demonstrating continued clinical benefit of pembrolizumab over chemotherapy for efficacy and safety for treatment of locally advanced/metastatic, platinum-refractory UC.Trial registrationClinicalTrials.gov: NCT02256436

Recording problems and diagnoses in clinical care: developing guidance for healthcare professionals and system designers

BACKGROUND: Accurate recording of problems and diagnoses in health records is key to safe and effective patient care, yet it is often done poorly. Electronic health record systems vary in their functionality and ease of use, and are not optimally designed for easy recording and sharing of clinical information. There is a lack of professional consensus and guidance on how problems and diagnoses should be recorded. METHODS: The Professional Record Standards Body commissioned work led by the Royal College of Physicians Health Informatics Unit to carry out a literature review, draft guidance, carry out an online consultation and round table discussion, and produce a report including recommendations for systems. A patient workshop was held to explore patient preferences for mechanisms for sharing diagnosis information between primary and secondary care. RESULTS: Consensus was reached among medical specialties on key elements of diagnosis recording, and draft guidance was produced ready for piloting in a variety of care settings. Patients were keen for better ways for diagnosis information to be shared. DISCUSSION: Improving the recording of diagnoses and problems will require a major effort of which the new guidance is only a part. The guidance needs to be embedded in training, and clinical systems need to have improved, standardised functionality. Front-line clinicians, specialist societies, clinical informaticians and patients need to be engaged in developing information models for diagnoses to support care and research, accessible via user-friendly interfaces

Emergency ambulance service involvement with residential care homes in the support of older people with dementia : an observational study

© 2014 Amador et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BACKGROUND: Older people resident in care homes have a limited life expectancy and approximately two-thirds have limited mental capacity. Despite initiatives to reduce unplanned hospital admissions for this population, little is known about the involvement of emergency services in supporting residents in these settings.METHODS: This paper reports on a longitudinal study that tracked the involvement of emergency ambulance personnel in the support of older people with dementia, resident in care homes with no on-site nursing providing personal care only. 133 residents with dementia across 6 care homes in the East of England were tracked for a year. The paper examines the frequency and reasons for emergency ambulance call-outs, outcomes and factors associated with emergency ambulance service use. RESULTS: 56% of residents used ambulance services. Less than half (43%) of all call-outs resulted in an unscheduled admission to hospital. In addition to trauma following a following a fall in the home, results suggest that at least a reasonable proportion of ambulance contacts are for ambulatory care sensitive conditions. An emergency ambulance is not likely to be called for older rather than younger residents or for women more than men. Length of residence does not influence use of emergency ambulance services among older people with dementia. Contact with primary care services and admission route into the care home were both significantly associated with emergency ambulance service use. The odds of using emergency ambulance services for residents admitted from a relative's home were 90% lower than the odds of using emergency ambulance services for residents admitted from their own home. CONCLUSIONS: Emergency service involvement with this vulnerable population merits further examination. Future research on emergency ambulance service use by older people with dementia in care homes, should account for important contextual factors, namely, presence or absence of on-site nursing, GP involvement, and access to residents' family, alongside resident health characteristics.Peer reviewedFinal Published versio

Acquired constriction ring syndrome as a cause of inconsolable cry in a child: a case report

Acute constriction ring syndrome (ACRS) is a rare clinical condition characterized by formation of a circumferential constriction ring around an appendage or genitalia. Cases are mostly reported in infants and young children. Early recognition and a definitive treatment are of paramount importance in order to avoid irreversible ischemia and possible auto-amputation. We describe a case of a 14-month-old child presented to casualty with a history of refusal to feed and inconsolable cry. Parents noticed a recent swelling of left third toe. On careful examination the child was found to have an acquired constriction ring secondary to a tightly wrapped hair around left third toe. An urgent surgical decompression was done by the orthopaedic team with complete resolution of symptoms. We summarized the pathophysiology of ACRS underlining the need of awareness in treating physicians. The possible medico legal implications should be kept in mind bearing a suggested link with non-accidental injury

In Vivo and Ex Vivo Evaluation of L-Type Calcium Channel Blockers on Acid β-Glucosidase in Gaucher Disease Mouse Models

Gaucher disease is a lysosomal storage disease caused by mutations in acid β-glucosidase (GCase) leading to defective hydrolysis and accumulation of its substrates. Two L-type calcium channel (LTCC) blockers—verapamil and diltiazem—have been reported to modulate endoplasmic reticulum (ER) folding, trafficking, and activity of GCase in human Gaucher disease fibroblasts. Similarly, these LTCC blockers were tested with cultured skin fibroblasts from homozygous point-mutated GCase mice (V394L, D409H, D409V, and N370S) with the effect of enhancing of GCase activity. Correspondingly, diltiazem increased GCase protein and facilitated GCase trafficking to the lysosomes of these cells. The in vivo effects of diltiazem on GCase were evaluated in mice homozygous wild-type (WT), V394L and D409H. In D409H homozygotes diltiazem (10 mg/kg/d via drinking water or 50–200 mg/kg/d intraperitoneally) had minor effects on increasing GCase activity in brain and liver (1.2-fold). Diltiazem treatment (10 mg/kg/d) had essentially no effect on WT and V394L GCase protein or activity levels (<1.2-fold) in liver. These results show that LTCC blockers had the ex vivo effects of increasing GCase activity and protein in the mouse fibroblasts, but these effects did not translate into similar changes in vivo even at very high drug doses

Extra-pair parentage and personality in a cooperatively breeding bird

Why so much variation in extra-pair parentage occurs within and among populations remains unclear. Often the fitness costs and benefits of extra-pair parentage are hypothesised to explain its occurrence; therefore, linking extra-pair parentage with traits such as personality (behavioural traits that can be heritable and affect reproductive behaviour) may help our understanding. Here, we investigate whether reproductive outcomes and success are associated with exploratory behaviour in a natural population of cooperatively breeding Seychelles warblers (Acrocephalus sechellensis) on Cousin Island. Exploratory behaviour correlates positively with traits such as risk-taking behaviour and activity in other wild bird species and might promote extra-pair mating by increasing the rate at which potential extra-pair partners are encountered. We therefore predicted that fast-exploring individuals would have more extra-pair offspring. There is also a potential trade-off between pursuing extra-pair parentage and mate guarding in males. We therefore also predicted that fast-exploring males would be more likely to pursue extra-pair parentage and that this would increase the propensity of their mate to gain extra-pair parentage. We found that neither the total number of offspring nor the number of extra-pair offspring were associated with a male’s or female’s exploratory behaviour. However, there was a small but significant propensity for females to have extra-pair fertilisations in pairs that were behaviourally disassortative. Overall, we conclude that, due to the small effect size, the association between exploratory behaviour and extra-pair paternity is unlikely to be biologically relevant. Significance statement: True genetic monogamy is rare, even in socially monogamous systems, and multiple factors, such as behaviour, social structure, morphology and physiology, determined by the biological system can cause variation in extra-pair parentage (EPP). Therefore, investigating the inherent differences in these factors among individuals could be informative. We investigated whether reproductive outcomes/success are associated with differences in the propensity to explore novel environments/objects in a promiscuous, island-dwelling cooperatively breeding bird, the Seychelles warbler. Our results showed that exploratory behaviour was not associated with the number of offspring produced by an individual, and thus the long-term fitness consequences of different exploratory tendencies did not differ. We also found that the propensity to engage in EPP in females was higher in dissimilar behavioural pairs, but due to the small effect size, we hesitate to conclude that there are personality-dependent mating outcomes in the population

Physics, Astrophysics and Cosmology with Gravitational Waves

Gravitational wave detectors are already operating at interesting sensitivity levels, and they have an upgrade path that should result in secure detections by 2014. We review the physics of gravitational waves, how they interact with detectors (bars and interferometers), and how these detectors operate. We study the most likely sources of gravitational waves and review the data analysis methods that are used to extract their signals from detector noise. Then we consider the consequences of gravitational wave detections and observations for physics, astrophysics, and cosmology.Comment: 137 pages, 16 figures, Published version <http://www.livingreviews.org/lrr-2009-2

Perceived stressors of climate vulnerability across scales in the Savannah zone of Ghana: a participatory approach

Smallholder farmers in sub-Saharan Africa are confronted with climatic and non-climatic stressors. Research attention has focused on climatic stressors, such as rainfall variability, with few empirical studies exploring non-climatic stressors and how these interact with climatic stressors at multiple scales to affect food security and livelihoods. This focus on climatic factors restricts understanding of the combinations of stressors that exacerbate the vulnerability of farming households and hampers the development of holistic climate change adaptation policies. This study addresses this particular research gap by adopting a multi-scale approach to understand how climatic and non-climatic stressors vary, and interact, across three spatial scales (household, community and district levels) to influence livelihood vulnerability of smallholder farming households in the Savannah zone of northern Ghana. This study across three case study villages utilises a series of participatory tools including semi-structured interviews, key informant interviews and focus group discussions. The incidence, importance, severity and overall risk indices for stressors are calculated at the household, community, and district levels. Results show that climatic and non-climatic stressors were perceived differently; yet, there were a number of common stressors including lack of money, high cost of farm inputs, erratic rainfall, cattle destruction of crops, limited access to markets and lack of agricultural equipment that crossed all scales. Results indicate that the gender of respondents influenced the perception and severity assessment of stressors on rural livelihoods at the community level. Findings suggest a mismatch between local and district level priorities that have implications for policy and development of agricultural and related livelihoods in rural communities. Ghana’s climate change adaptation policies need to take a more holistic approach that integrates both climatic and non-climatic factors to ensure policy coherence between national climate adaptation plans and District development plans

Exploration Behaviour Is Not Associated with Chick Provisioning in Great Tits

In biparental systems, members of the same pair can vary substantially in the amount of parental care they provide to offspring. The extent of this asymmetry should depend on the relative costs and benefits of care. Individual variation in personality is likely to influence this trade-off, and hence is a promising candidate to explain differences in care. In addition, plasticity in parental care may also be associated with personality differences. Using exploration behaviour (EB) as a measure of personality, we investigated these possibilities using both natural and experimental data from a wild population of great tits (Parus major). Contrary to predictions, we found no association between EB and natural variation in provisioning behaviour. Nor was EB linked to responsiveness to experimentally increased brood demand. These results are initially surprising given substantial data from other studies suggesting personality should influence investment in parental care. However, they are consistent with a recent study showing selection on EB is weak and highly context-specific in the focal population. This emphasises the difficulty faced by personality studies attempting to make predictions based on previous work, given that personalities often vary among populations of the same species

Cues for Early Social Skills: Direct Gaze Modulates Newborns' Recognition of Talking Faces

Previous studies showed that, from birth, speech and eye gaze are two important cues in guiding early face processing and social cognition. These studies tested the role of each cue independently; however, infants normally perceive speech and eye gaze together. Using a familiarization-test procedure, we first familiarized newborn infants (n = 24) with videos of unfamiliar talking faces with either direct gaze or averted gaze. Newborns were then tested with photographs of the previously seen face and of a new one. The newborns looked longer at the face that previously talked to them, but only in the direct gaze condition. These results highlight the importance of both speech and eye gaze as socio-communicative cues by which infants identify others. They suggest that gaze and infant-directed speech, experienced together, are powerful cues for the development of early social skills