Each successive generation of X-ray machines has opened up new frontiers in science, such as the first radiographs and the determination of the structure of DNA. State-of-the-art X-ray sources can ...now produce coherent high-brightness X-rays of greater than kiloelectronvolt energy and promise a new revolution in imaging complex systems on nanometre and femtosecond scales. Despite the demand, only a few dedicated synchrotron facilities exist worldwide, in part because of the size and cost of conventional (accelerator) technology. Here we demonstrate the use of a new generation of laser-driven plasma accelerators, which accelerate high-charge electron beams to high energy in short distances, to produce directional, spatially coherent, intrinsically ultrafast beams of hard X-rays. This reduces the size of the synchrotron source from the tens of metres to the centimetre scale, simultaneously accelerating and wiggling the electron beam. The resulting X-ray source is 1,000 times brighter than previously reported plasma wigglers and thus has the potential to facilitate a myriad of uses across the whole spectrum of light-source applications.
Aim
Continuous subcutaneous insulin infusion (CSII) is increasingly used in clinical practice for the management of selected patients with Type 1 diabetes. Several cost‐effectiveness studies ...comparing CSII vs. multiple insulin injections (MDI) have been reported. The aim was systematically to review these analyses and test the hypothesis that CSII is a cost‐effective use of healthcare resources across settings.
Methods
A literature review was performed using MEDLINE, Cochrane Library and other databases. No time limit or language restrictions were applied. After two rounds of screening, 11 cost‐effectiveness analyses were included in the final review, of which nine used the CORE Diabetes Model. A narrative synthesis was conducted and mean cost effectiveness calculated.
Results
CSII was considered cost‐effective vs. MDI in Type 1 diabetes in all 11 studies in 8 countries, with a mean (95% CI) incremental cost effectiveness ratio of €30 862 (17 997–43 727), US$40 143 (23 409–56 876) per quality‐adjusted life year (QALY) gained. CSII was associated with improved life expectancy and quality‐adjusted life expectancy (0.4–1.1 QALYs in adults), driven by lower HbA1c and lower frequency of hypoglycaemic events vs. MDI. CSII was associated with higher lifetime direct costs due to higher treatment costs but this was partially offset by cost‐savings from reduced diabetes‐related complications.
Conclusions
Published cost‐effectiveness analyses show that in Type 1 diabetes CSII is cost‐effective vs. MDI across a number of settings for patients who have poor glycaemic control and/or problematic hypoglycaemia on MDI, with cost‐effectiveness highly sensitive to the reduction in HbA1c and hypoglycaemia frequency associated with CSII.
The initial microbial colonization of tooth surfaces is a repeatable and selective process, with certain bacterial species predominating in the nascent biofilm. Characterization of the initial ...microflora is the first step in understanding interactions among community members that shape ensuing biofilm development. Using molecular methods and a retrievable enamel chip model, we characterized the microbial diversity of early dental biofilms in three subjects. A total of 531 16S rRNA gene sequences were analyzed, and 97 distinct phylotypes were identified. Microbial community composition was shown to be statistically different among subjects. In all subjects, however, 4-h and 8-h communities were dominated by Streptococcus spp. belonging to the Streptococcus oralis/Streptococcus mitis group. Other frequently observed genera (comprising at least 5% of clone sequences in at least one of the six clone libraries) were Actinomyces, Gemella, Granulicatella, Neisseria, Prevotella, Rothia, and VEILLONELLA: Fluorescence in situ hybridization (FISH) confirmed that the proportion of Streptococcus sp. sequences in the clone libraries coincided with the proportion of streptococcus probe-positive organisms on the chip. FISH also revealed that, in the undisturbed plaque, not only Streptococcus spp. but also the rarer Prevotella spp. were usually seen in small multigeneric clusters of cells. This study shows that the initial dental plaque community of each subject is unique in terms of diversity and composition. Repetitive and distinctive community composition within subjects suggests that the spatiotemporal interactions and ecological shifts that accompany biofilm maturation also occur in a subject-dependent manner.
Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations in thirteen
CLN
genes. Mutations in one
...CLN
gene,
CLN5
, cause variant late-infantile NCL, with an age of onset between 4 and 7 years. The CLN5 protein is ubiquitously expressed in the majority of tissues studied and in the brain, CLN5 shows both neuronal and glial cell expression. Mutations in CLN5 are associated with the accumulation of autofluorescent storage material in lysosomes, the recycling units of the cell, in the brain and peripheral tissues. CLN5 resides in the lysosome and its function is still elusive. Initial studies suggested CLN5 was a transmembrane protein, which was later revealed to be processed into a soluble form. Multiple glycosylation sites have been reported, which may dictate its localisation and function. CLN5 interacts with several CLN proteins, and other lysosomal proteins, making it an important candidate to understand lysosomal biology. The existing knowledge on CLN5 biology stems from studies using several model organisms, including mice, sheep, cattle, dogs, social amoeba and cell cultures. Each model organism has its advantages and limitations, making it crucial to adopt a combinatorial approach, using both human cells and model organisms, to understand CLN5 pathologies and design drug therapies. In this comprehensive review, we have summarised and critiqued existing literature on CLN5 and have discussed the missing pieces of the puzzle that need to be addressed to develop an efficient therapy for CLN5 Batten disease.
Summary
We present the main findings of the 5th National Audit Project on accidental awareness during general anaesthesia. Incidences were estimated using reports of accidental awareness as the ...numerator, and a parallel national anaesthetic activity survey to provide denominator data. The incidence of certain/probable and possible accidental awareness cases was ~1:19 600 anaesthetics (95% CI 1:16 700–23 450). However, there was considerable variation across subtypes of techniques or subspecialties. The incidence with neuromuscular blockade was ~1:8200 (1:7030–9700), and without it was ~1:135 900 (1:78 600–299 000). The cases of accidental awareness during general anaesthesia reported to 5th National Audit Project were overwhelmingly cases of unintended awareness during neuromuscular blockade. The incidence of accidental awareness during caesarean section was ~1:670 (1:380–1300). Two thirds (82, 66%) of cases of accidental awareness experiences arose in the dynamic phases of anaesthesia, namely induction of and emergence from anaesthesia. During induction of anaesthesia, contributory factors included: use of thiopental; rapid sequence induction; obesity; difficult airway management; neuromuscular blockade; and interruptions of anaesthetic delivery during movement from anaesthetic room to theatre. During emergence from anaesthesia, residual paralysis was perceived by patients as accidental awareness, and commonly related to a failure to ensure full return of motor capacity. One third (43, 33%) of accidental awareness events arose during the maintenance phase of anaesthesia, most due to problems at induction or towards the end of anaesthesia. Factors increasing the risk of accidental awareness included: female sex; age (younger adults, but not children); obesity; anaesthetist seniority (junior trainees); previous awareness; out‐of‐hours operating; emergencies; type of surgery (obstetric, cardiac, thoracic); and use of neuromuscular blockade. The following factors were not risk factors for accidental awareness: ASA physical status; race; and use or omission of nitrous oxide. We recommend that an anaesthetic checklist, to be an integral part of the World Health Organization Safer Surgery checklist, is introduced as an aid to preventing accidental awareness. This paper is a shortened version describing the main findings from 5th National Audit Project – the full report can be found at http://www.nationalauditprojects.org.uk/NAP5_home#pt.
Aging as a passage of discovery and engagement From bestselling author Parker J. Palmer comes a brave and beautiful book for all who want to age reflectively, seeking new insights and life-giving ...ways to engage in the world. “Age itself,” he says, “is no excuse to wade in the shallows. It's a reason to dive deep and take creative risks.” Looking back on eight decades of life—and on his work as a writer, teacher, and activist—Palmer explores what he's learning about self and world, inviting readers to explore their own experience. In prose and poetry—and three downloadable songs written for the book by the gifted Carrie Newcomer—he meditates on the meanings of life, past, present, and future. “The laws of nature that dictate sundown dictate our demise. But how we travel the arc toward the sunset of our lives is ours to choose: will it be denial, defiance, or collaboration?” With compassion and chutzpah, gravitas and levity, Palmer writes about cultivating a vital inner and outer life, finding meaning in suffering and joy, and forming friendships across the generations that bring new life to young and old alike.
Objectives
The economic burden of multimorbidity is considerable. This review analyzed the methods of cost-of-illness (COI) studies and summarized the economic outcomes of multimorbidity.
Methods
A ...systematic review (2000–2016) was performed, which was registered with Prospero, reported according to PRISMA, and used a quality checklist adapted for COI studies. The inclusion criteria were peer-reviewed COI studies on multimorbidity, whereas the exclusion criterion was studies focusing on an index disease. Extracted data included the definition, measure, and prevalence of multimorbidity; the number of included health conditions; the age of study population; the variables used in the COI methodology; the percentage of multimorbidity vs. total costs; and the average costs per capita.
Results
Among the 26 included articles, 14 defined multimorbidity as a simple count of 2 or more conditions. Methodologies used to derive the costs were markedly different. Given different healthcare systems, OOP payments of multimorbidity varied across countries. In the 17 and 12 studies with cut-offs of ≥2 and ≥3 conditions, respectively, the ratios of multimorbidity to non-multimorbidity costs ranged from 2–16 to 2–10. Among the ten studies that provided cost breakdowns, studies with and without a societal perspective attributed the largest percentage of multimorbidity costs to social care and inpatient care/medicine, respectively.
Conclusion
Multimorbidity was associated with considerable economic burden. Synthesising the cost of multimorbidity was challenging due to multiple definitions of multimorbidity and heterogeneity in COI methods. Count method was most popular to define multimorbidity. There is consistent evidence that multimorbidity was associated with higher costs.
Internet-accessed sexually transmitted infection testing (e-STI testing) is increasingly available as an alternative to testing in clinics. Typically this testing modality enables users to order a ...test kit from a virtual service (via a website or app), collect their own samples, return test samples to a laboratory, and be notified of their results by short message service (SMS) or telephone. e-STI testing is assumed to increase access to testing in comparison with face-to-face services, but the evidence is unclear. We conducted a randomised controlled trial to assess the effectiveness of an e-STI testing and results service (chlamydia, gonorrhoea, HIV, and syphilis) on STI testing uptake and STI cases diagnosed.
The study took place in the London boroughs of Lambeth and Southwark. Between 24 November 2014 and 31 August 2015, we recruited 2,072 participants, aged 16-30 years, who were resident in these boroughs, had at least 1 sexual partner in the last 12 months, stated willingness to take an STI test, and had access to the internet. Those unable to provide consent and unable to read English were excluded. Participants were randomly allocated to receive 1 text message with the web link of an e-STI testing and results service (intervention group) or to receive 1 text message with the web link of a bespoke website listing the locations, contact details, and websites of 7 local sexual health clinics (control group). Participants were free to use any other services or interventions during the study period. The primary outcomes were self-reported STI testing at 6 weeks, verified by patient record checks, and self-reported STI diagnosis at 6 weeks, verified by patient record checks. Secondary outcomes were the proportion of participants prescribed treatment for an STI, time from randomisation to completion of an STI test, and time from randomisation to treatment of an STI. Participants were sent a £10 cash incentive on submission of self-reported data. We completed all follow-up, including patient record checks, by 17 June 2016. Uptake of STI testing was increased in the intervention group at 6 weeks (50.0% versus 26.6%, relative risk RR 1.87, 95% CI 1.63 to 2.15, P < 0.001). The proportion of participants diagnosed was 2.8% in the intervention group versus 1.4% in the control group (RR 2.10, 95% CI 0.94 to 4.70, P = 0.079). No evidence of heterogeneity was observed for any of the pre-specified subgroup analyses. The proportion of participants treated was 1.1% in the intervention group versus 0.7% in the control group (RR 1.72, 95% CI 0.71 to 4.16, P = 0.231). Time to test, was shorter in the intervention group compared to the control group (28.8 days versus 36.5 days, P < 0.001, test for difference in restricted mean survival time RMST), but no differences were observed for time to treatment (83.2 days versus 83.5 days, P = 0.51, test for difference in RMST). We were unable to recruit the planned 3,000 participants and therefore lacked power for the analyses of STI diagnoses and STI cases treated.
The e-STI testing service increased uptake of STI testing for all groups including high-risk groups. The intervention required people to attend clinic for treatment and did not reduce time to treatment. Service innovations to improve treatment rates for those diagnosed online are required and could include e-treatment and postal treatment services. e-STI testing services require long-term monitoring and evaluation.
ISRCTN Registry ISRCTN13354298.
Great efforts and expense have been expended in attempts to detect genetic polymorphisms contributing to susceptibility to complex human disease. Concomitantly, technology for detection and scoring ...of single nucleotide polymorphisms (SNPs) has undergone rapid development, extensive catalogues of SNPs across the genome have been constructed, and SNPs have been increasingly used as a means for investigation of the genetic causes of complex human diseases. For many diseases, population-based studies of unrelated individuals—in which case-control and cohort studies serve as standard designs for genetic association analysis—can be the most practical and powerful approach. However, extensive debate has arisen about optimum study design, and considerable concern has been expressed that these approaches are prone to population stratification, which can lead to biased or spurious results. Over the past decade, a great shift has been noted, away from case-control and cohort studies, towards family-based association designs. These designs have fewer problems with population stratification but have greater genotyping and sampling requirements, and data can be difficult or impossible to gather. We discuss past evidence for population stratification on genotype-phenotype association studies, review methods to detect and account for it, and present suggestions for future study design and analysis.
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