Extending the Hoyle-State Paradigm to

Carbon burning is a key step in the evolution of massive stars, Type 1a supernovae and superbursts in x-ray binary systems. Determining the ^{12}C+^{12}C fusion cross section at relevant energies by extrapolation of direct measurements is challenging due to resonances at and below the Coulomb barrier. A study of the ^{24}Mg(α,α^{'})^{24}Mg reaction has identified several 0^{+} states in ^{24}Mg, close to the ^{12}C+^{12}C threshold, which predominantly decay to ^{20}Ne(ground state)+α. These states were not observed in ^{20}Ne(α,α_{0})^{20}Ne resonance scattering suggesting that they may have a dominant ^{12}C+^{12}C cluster structure. Given the very low angular momentum associated with sub-barrier fusion, these states may play a decisive role in ^{12}C+^{12}C fusion in analogy to the Hoyle state in helium burning. We present estimates of updated ^{12}C+^{12}C fusion reaction rates.

Diabetes-induced microvascular complications at the level of the spinal cord: a contributing factor in diabetic neuropathic pain.

KEY POINTS: Diabetes is thought to induce neuropathic pain through activation of dorsal horn sensory neurons in the spinal cord. Here we explore the impact of hyperglycaemia on the blood supply supporting the spinal cord and chronic pain development. In streptozotocin-induced diabetic rats, neuropathic pain is accompanied by a decline in microvascular integrity in the dorsal horn. Hyperglycaemia-induced degeneration of the endothelium in the dorsal horn was associated with a loss in vascular endothelial growth factor (VEGF)-A165 b expression. VEGF-A165 b treatment prevented diabetic neuropathic pain and degeneration of the endothelium in the spinal cord. Using an endothelial-specific VEGFR2 knockout transgenic mouse model, the loss of endothelial VEGFR2 signalling led to a decline in vascular integrity in the dorsal horn and the development of hyperalgesia in VEGFR2 knockout mice. This highlights that vascular degeneration in the spinal cord could be a previously unidentified factor in the development of diabetic neuropathic pain. ABSTRACT: Abnormalities of neurovascular interactions within the CNS of diabetic patients is associated with the onset of many neurological disease states. However, to date, the link between the neurovascular network within the spinal cord and regulation of nociception has not been investigated despite neuropathic pain being common in diabetes. We hypothesised that hyperglycaemia-induced endothelial degeneration in the spinal cord, due to suppression of vascular endothelial growth factor (VEGF)-A/VEGFR2 signalling, induces diabetic neuropathic pain. Nociceptive pain behaviour was investigated in a chemically induced model of type 1 diabetes (streptozotocin induced, insulin supplemented; either vehicle or VEGF-A165 b treated) and an inducible endothelial knockdown of VEGFR2 (tamoxifen induced). Diabetic animals developed mechanical allodynia and heat hyperalgesia. This was associated with a reduction in the number of blood vessels and reduction in Evans blue extravasation in the lumbar spinal cord of diabetic animals versus age-matched controls. Endothelial markers occludin, CD31 and VE-cadherin were downregulated in the spinal cord of the diabetic group versus controls, and there was a concurrent reduction of VEGF-A165 b expression. In diabetic animals, VEGF-A165 b treatment (biweekly i.p., 20 ng g-1 ) restored normal Evans blue extravasation and prevented vascular degeneration, diabetes-induced central neuron activation and neuropathic pain. Inducible knockdown of VEGFR2 (tamoxifen treated Tie2CreERT2 -vegfr2flfl mice) led to a reduction in blood vessel network volume in the lumbar spinal cord and development of heat hyperalgesia. These findings indicate that hyperglycaemia leads to a reduction in the VEGF-A/VEGFR2 signalling cascade, resulting in endothelial dysfunction in the spinal cord, which could be an undiscovered contributing factor to diabetic neuropathic pain.

Periaqueductal Grey EP3 Receptors Facilitate Spinal Nociception in Arthritic Secondary Hypersensitivity.

UNLABELLED: Descending controls on spinal nociceptive processing play a pivotal role in shaping the pain experience after tissue injury. Secondary hypersensitivity develops within undamaged tissue adjacent and distant to damaged sites. Spinal neuronal pools innervating regions of secondary hypersensitivity are dominated by descending facilitation that amplifies spinal inputs from unsensitized peripheral nociceptors. Cyclooxygenase-prostaglandin (PG) E2 signaling within the ventrolateral periaqueductal gray (vlPAG) is pronociceptive in naive and acutely inflamed animals, but its contributions in more prolonged inflammation and, importantly, secondary hypersensitivity remain unknown. In naive rats, PG EP3 receptor (EP3R) antagonism in vlPAG modulated noxious withdrawal reflex (EMG) thresholds to preferential C-nociceptor, but not A-nociceptor, activation and raised thermal withdrawal thresholds in awake animals. In rats with inflammatory arthritis, secondary mechanical and thermal hypersensitivity of the hindpaw developed and was associated with spinal sensitization to A-nociceptor inputs alone. In arthritic rats, blockade of vlPAG EP3R raised EMG thresholds to C-nociceptor activation in the area of secondary hypersensitivity to a degree equivalent to that evoked by the same manipulation in naive rats. Importantly, vlPAG EP3R blockade also affected responses to A-nociceptor activation, but only in arthritic animals. We conclude that vlPAG EP3R activity exerts an equivalent facilitation on the spinal processing of C-nociceptor inputs in naive and arthritic animals, but gains in effects on spinal A-nociceptor processing from a region of secondary hypersensitivity. Therefore, the spinal sensitization to A-nociceptor inputs associated with secondary hypersensitivity is likely to be at least partly dependent on descending prostanergic facilitation from the vlPAG. SIGNIFICANCE STATEMENT: After tissue damage, sensitivity to painful stimulation develops in undamaged areas (secondary hypersensitivity). This is found in many painful conditions, particularly arthritis. The periaqueductal gray (PAG) is an important center that controls spinal nociceptive processing, on which secondary hypersensitivity depends. Prostaglandins (PGs) are mediators of inflammation with pronociceptive actions within the PAG under normal conditions. We find that secondary hindpaw hypersensitivity in arthritic rats results from spinal sensitization to peripheral A-nociceptor inputs. In the PAG of arthritic, but not naive, rats, there is enhanced control of spinal A-nociceptor processing through PG EP3 receptors. The descending facilitatory actions of intra-PAG PGs play a direct and central role in the maintenance of inflammatory secondary hypersensitivity, particularly relating to the processing of A-fiber nociceptive information.

Test of the Brink-Axel Hypothesis for the Pygmy Dipole Resonance.

The gamma strength function and level density of 1^{-} states in ^{96}Mo have been extracted from a high-resolution study of the (p[over →], p[over →]^{'}) reaction at 295 MeV and extreme forward angles. By comparison with compound nucleus γ decay experiments, this allows a test of the generalized Brink-Axel hypothesis in the energy region of the pygmy dipole resonance. The Brink-Axel hypothesis is commonly assumed in astrophysical reaction network calculations and states that the gamma strength function in nuclei is independent of the structure of the initial and final state. The present results validate the Brink-Axel hypothesis for ^{96}Mo and provide independent confirmation of the methods used to separate gamma strength function and level density in γ decay experiments.

The use of technology enhanced learning in health research capacity development: lessons from a cross country research partnership.

BACKGROUND: With the recognition of the need for research capacity strengthening for advancing health and development, this research capacity article explores the use of technology enhanced learning in the delivery of a collaborative postgraduate blended Master's degree in Malawi. Two research questions are addressed: (i) Can technology enhanced learning be used to develop health research capacity?, and: (ii) How can learning content be designed that is transferrable across different contexts? METHODS: An explanatory sequential mixed methods design was adopted for the evaluation of technology enhanced learning in the Masters programme. A number of online surveys were administered, student participation in online activities monitored and an independent evaluation of the programme conducted. RESULTS: Remote collaboration and engagement are paramount in the design of a blended learning programme and support was needed for selecting the most appropriate technical tools. Internet access proved problematic despite developing the content around low bandwidth availability and training was required for students and teachers/trainers on the tools used. Varying degrees of engagement with the tools used was recorded, and the support of a learning technologist was needed to navigate through challenges faced. CONCLUSION: Capacity can be built in health research through blended learning programmes. In relation to transferability, the support required institutionally for technology enhanced learning needs to be conceptualised differently from support for face-to-face teaching. Additionally, differences in pedagogical approaches and styles between institutions, as well as existing social norms and values around communication, need to be embedded in the content development if the material is to be used beyond the pilot resource-intensive phase of a project.

Utility of surgical lung biopsy in critically ill patients with diffuse pulmonary infiltrates: a retrospective review.

BACKGROUND: There are conflicting reports regarding the role of surgical lung biopsies in patients who present to the intensive care unit (ICU) with unexplained respiratory failure and diffuse pulmonary infiltrates on imaging. AIM: To describe the utility of surgical lung biopsies in patients presenting to the ICU with unexplained respiratory failure and diffuse pulmonary infiltrates. METHODS: A retrospective cohort study was performed. All patients admitted to the ICU who underwent a surgical lung biopsy for the investigation of respiratory failure and unexplained pulmonary infiltrates between 1998 and 2012 were included. The primary outcome measures for this descriptive study were the biopsy histopathology, changes in patient management following biopsy and in-hospital mortality. RESULTS: A total of 30 patients was included in the review. Biopsies in 22 patients (73%) demonstrated diffuse alveolar damage (DAD), with 15 of these biopsies (50%) suggesting a specific underlying aetiology. In 73% of cases (n = 22), the biopsy finding was associated with a change in management, although this generally involved the escalation of an existing therapy rather than initiation of a new treatment. Biopsies were performed at a median 10 days after admission (interquartile range 5-17 days), with the majority of patients being treated empirically prior to the biopsy with systemic steroids and broad-spectrum antimicrobials. Mortality was 53%. CONCLUSION: In this series, DAD was the most frequent pathology. The biopsy result was associated with a change in management in a majority of the subjects, most frequently an escalation of prior empiric therapy. Mortality was high.

Detection of wood cell wall porosity using small carbohydrate molecules and confocal fluorescence microscopy.

A novel approach to nanoscale detection of cell wall porosity using confocal fluorescence microscopy is described. Infiltration of cell walls with a range of nitrophenyl-substituted carbohydrates of different molecular weights was assessed by measuring changes in the intensity of lignin fluorescence, in response to the quenching effect of the 4-nitrophenyl group. The following carbohydrates were used in order of increasing molecular weight; 4-nitrophenyl ß-D-glucopyrano-side (monosaccharide), 4-nitrophenyl ß-D-lactopyranoside (disaccharide), 2-chloro-4-nitrophenyl ß-D-maltotrioside (trisaccharide), and 4-nitrophenyl α-D-maltopentaoside (pentasaccharide). This technique was used to compare cell wall porosity in wood which had been dewatered to 40% moisture content using supercritical CO2, where cell walls remain fully hydrated, with kiln dried wood equilibrated to 12% moisture content. Infiltration of cell walls as measured by fluorescence quenching, was found to decrease with increasing molecular weight, with the pentasaccharide being significantly excluded compared to the monosaccharide. Porosity experiments were performed on blocks and sections to assess differences in cell wall accessibility. Dewatered and kiln dried wood infiltrated as blocks showed similar results, but greater infiltration was achieved by using sections, indicating that not all pores were easily accessible by infiltration from the lumen surface. In wood blocks infiltrated with 4-nitrophenyl α-D-maltopentaoside, quenching of the secondary wall was quite variable, especially in kiln dried wood, indicating limited connectivity of pores accessible from the lumen surface.

Regulation of alternative VEGF-A mRNA splicing is a therapeutic target for analgesia.

Vascular endothelial growth factor-A (VEGF-A) is best known as a key regulator of the formation of new blood vessels. Neutralization of VEGF-A with anti-VEGF therapy e.g. bevacizumab, can be painful, and this is hypothesized to result from a loss of VEGF-A-mediated neuroprotection. The multiple vegf-a gene products consist of two alternatively spliced families, typified by VEGF-A165a and VEGF-A165b (both contain 165 amino acids), both of which are neuroprotective. Under pathological conditions, such as in inflammation and cancer, the pro-angiogenic VEGF-A165a is upregulated and predominates over the VEGF-A165b isoform. We show here that in rats and mice VEGF-A165a and VEGF-A165b have opposing effects on pain, and that blocking the proximal splicing event - leading to the preferential expression of VEGF-A165b over VEGF165a - prevents pain in vivo. VEGF-A165a sensitizes peripheral nociceptive neurons through actions on VEGFR2 and a TRPV1-dependent mechanism, thus enhancing nociceptive signaling. VEGF-A165b blocks the effect of VEGF-A165a. After nerve injury, the endogenous balance of VEGF-A isoforms switches to greater expression of VEGF-Axxxa compared to VEGF-Axxxb, through an SRPK1-dependent pre-mRNA splicing mechanism. Pharmacological inhibition of SRPK1 after traumatic nerve injury selectively reduced VEGF-Axxxa expression and reversed associated neuropathic pain. Exogenous VEGF-A165b also ameliorated neuropathic pain. We conclude that the relative levels of alternatively spliced VEGF-A isoforms are critical for pain modulation under both normal conditions and in sensory neuropathy. Altering VEGF-Axxxa/VEGF-Axxxb balance by targeting alternative RNA splicing may be a new analgesic strategy.

Fluorescence lifetime imaging of lignin autofluorescence in normal and compression wood.

Wood cell walls fluoresce as a result of UV and visible light excitation due to the presence of lignin. Fluorescence spectroscopy has revealed characteristic spectral differences in various wood types, notably normal and compression wood. In order to extend this method of characterising cell walls we examined the fluorescence lifetime of wood cell walls using TCSPC (Time-Correlated Single Photon Counting) as a method of potentially detecting differences in lignin composition and measuring the molecular environment within cell walls. The fluorescence decay curves of both normal and compression wood from pine contain three exponential decay components with a mean lifetime of τm = 473 ps in normal wood and 418 ps in compression wood. Lifetimes are spatially resolved to different cell wall layers or cell types where individual lifetimes are shown to have a log-normal distribution. The differences in fluorescence lifetime observed in pine compression wood compared to normal wood, are associated with known differences in cell wall composition such as increased p-hydroxyphenyl content in lignin as well as novel deposition of ß(1,4)-Galactan. Our results indicate increased deposition of lignin fluorophores with shorter lifetimes in the outer secondary wall of compression wood. We have demonstrated the usefulness of fluorescence lifetime imaging for characterising wood cell walls, offering some advantages over conventional fluorescence imaging/spectroscopy. For example, we have measured significant changes in fluorescence lifetime resulting from changes to lignin composition as a result of compression wood formation that complement similar changes in fluorescence intensity.

Spontaneous firing in C-fibers and increased mechanical sensitivity in A-fibers of knee joint-associated mechanoreceptive primary afferent neurones during MIA-induced osteoarthritis in the rat.

OBJECTIVE: Osteoarthritis (OA) pain mechanisms are poorly understood. We used the monosodium iodoacetate (MIA) model of knee OA to characterize changes in excitability during the course of OA in different classes of mechanosensitive afferents projecting to joint-associated tissues, and examine whether these afferent responses and pain behavior are correlated. METHODS: Rats were injected intra-articularly with MIA (1mg in 50 µl). Hind-limb weight bearing was studied 3 (MIA3) and 14 (MIA14) days after MIA, followed by deep anesthesia and teased-nerve-fiber recordings. Spontaneous activity (SA) and mechanically evoked responses of A- and C-mechanosensitive fibers (AM and CM respectively, probably nociceptive) innervating tissues associated with the ipsilateral knee joint were examined. RESULTS: MIA3 and MIA14 rats exhibited reduced ipsilateral weight bearing. SA (>0.02 impulses/s) occurred in ∼50% of CMs from MIA rats vs 0% in normals. SA firing rates in CMs were significantly higher than normal; decreased weight bearing was correlated with increased CM SA rates. Neither percentages of AMs with SA (20%) nor their firing rates (0-0.01 impulses/s) significantly increased after MIA. In contrast, in MIA rats AMs, but not CMs, exhibited decreased mechanical thresholds and increased firing rates in response to suprathreshold mechanical stimulation. CONCLUSIONS: These findings of increased SA firing rate in CMs but not AMs and increased mechanical sensitivity of AMs, but not CMs, have not previously been reported. These are two distinct important physiological mechanisms that may underpin spontaneous pain (CMs) and stimulus-evoked pain (AMs) in OA. Our data contribute to a mechanism-based understanding of OA pain.

Ovarian VEGF(165)b expression regulates follicular development, corpus luteum function and fertility.

Angiogenesis and vascular regression are critical for the female ovulatory cycle. They enable progression and regression of follicular development, and corpora lutea formation and regression. Angiogenesis in the ovary occurs under the control of the vascular endothelial growth factor-A (VEGFA) family of proteins, which are generated as both pro-(VEGF(165)) and anti(VEGF(165)b)-angiogenic isoforms by alternative splicing. To determine the role of the VEGF(165)b isoforms in the ovulatory cycle, we measured VEGF(165)b expression in marmoset ovaries by immunohistochemistry and ELISA, and used transgenic mice over-expressing VEGF(165)b in the ovary. VEGF(165)b was expressed in the marmoset ovaries in granulosa cells and theca, and the balance of VEGF(165)b:VEGF(165) was regulated during luteogenesis. Mice over-expressing VEGF(165)b in the ovary were less fertile than wild-type littermates, had reduced secondary and tertiary follicles after mating, increased atretic follicles, fewer corpora lutea and generated fewer embryos in the oviduct after mating, and these were more likely not to retain the corona radiata. These results indicate that the balance of VEGFA isoforms controls follicle progression and luteogenesis, and that control of isoform expression may regulate fertility in mammals, including in primates.

Mortality due to pandemic (H1N1) 2009 influenza in England: a comparison of the first and second waves.

Deaths in England attributable to pandemic (H1N1) 2009 deaths were investigated through a mandatory reporting system. The pandemic came in two waves. The second caused greater population mortality than the first (5·4 vs. 1·6 deaths per million, P<0·001). Mortality was particularly high in those with chronic neurological disease, chronic heart disease and immune suppression (450, 100, and 94 deaths per million, respectively); significantly higher than in those with chronic respiratory disease (39 per million) and those with no risk factors (2·4 per million). Greater mortality in the second wave has been observed in all previous influenza pandemics. This time, the explanation appears to be behavioural. This emphasizes the importance of maintaining public and clinical awareness of risks associated with pandemic influenza beyond the initial high-profile period.

Influenza A(H1N1)pdm09 in England, 2009 to 2011: a greater burden of severe illness in the year after the pandemic than in the pandemic year.

Influenza pandemics are often perceived as single-year events, but the burden of previous influenza pandemics has in reality been spread over a number of years. The aim of this paper is to compare the burden of influenza in the pandemic year 2009/10 with that in the year immediately after (2010/11) in England. We compared four measures of disease. There was a greater burden of severe illness in 2010/11 compared with 2009/10: more deaths (474 vs 361), more critical care admissions (2,200 vs 1,700), and more hospital admissions (8,797 vs 7,879). In contrast, there were fewer general practice consultations in 2010/11 compared with 2009/10 (370,000 vs 580,000). There was also much less public interest in influenza, as assessed by number of Google searches. This is a worrying finding, as by the time of the second influenza season, much had been learnt about the potential impact of the influenza A(H1N1)pdm09 virus and an effective vaccine developed. We suggest that a widespread assumption of 'mildness' led to insufficient ongoing action to prevent influenza and hence to avoidable influenza-related deaths. This offers a lesson to all countries, both for future influenza seasons and for pandemic preparedness planning.

Hospitalization in two waves of pandemic influenza A(H1N1) in England.

Uncertainties exist regarding the population risks of hospitalization due to pandemic influenza A(H1N1). Understanding these risks is important for patients, clinicians and policy makers. This study aimed to clarify these uncertainties. A national surveillance system was established for patients hospitalized with laboratory-confirmed pandemic influenza A(H1N1) in England. Information was captured on demographics, pre-existing conditions, treatment and outcomes. The relative risks of hospitalization associated with pre-existing conditions were estimated by combining the captured data with population prevalence estimates. A total of 2416 hospitalizations were reported up to 6 January 2010. Within the population, 4·7 people/100,000 were hospitalized with pandemic influenza A(H1N1). The estimated hospitalization rate of cases showed a U-shaped distribution with age. Chronic kidney disease, chronic neurological disease, chronic respiratory disease and immunosuppression were each associated with a 10- to 20-fold increased risk of hospitalization. Patients who received antiviral medication within 48 h of symptom onset were less likely to be admitted to critical care than those who received them after this time (adjusted odds ratio 0·64, 95% confidence interval 0·44-0·94, P=0·024). In England the risk of hospitalization with pandemic influenza A(H1N1) has been concentrated in the young and those with pre-existing conditions. By quantifying these risks, this study will prove useful in planning for the next winter in the northern and southern hemispheres, and for future pandemics.

Republished paper: The WHO patient safety curriculum guide for medical schools.

BACKGROUND: The urgent need for patient safety education for healthcare students has been recognised by many accreditation bodies, but to date there has been sporadic attention to undergraduate/graduate medical programmes. Medical students themselves have identified quality and safety of care as an important area of instruction; as future doctors and healthcare leaders, they must be prepared to practise safe healthcare. Medical education has yet to fully embrace patient safety concepts and principles into existing medical curricula. Universities are continuing to produce graduate doctors lacking in the patient safety knowledge, skills and behaviours thought necessary to deliver safe care. A significant challenge is that patient safety is still a relatively new concept and area of study; thus, many medical educators are unfamiliar with the literature and unsure how to integrate patient safety learning into existing curriculum. DESIGN: To address this gap and provide a foothold for medical schools all around the world, the WHO's World Alliance for Patient Safety sponsored the development of a patient safety curriculum guide for medical students. The WHO Patient Safety Curriculum Guide for Medical Schools adopts a 'one-stop-shop' approach in that it includes a teacher's manual providing a step-by-step guide for teachers new to patient safety learning as well as a comprehensive curriculum on the main patient safety areas. This paper establishes the need for patient safety education of medical students, describes the development of the WHO Patient Safety Curriculum Guide for Medical Schools and outlines the content of the Guide.

Impact of caloric test asymmetry on response to treatment in vestibular migraine.

OBJECTIVE: This study aimed to examine the association between caloric asymmetry and response to treatment in patients with vestibular migraine. METHOD: Dizziness Handicap Inventory scores were compared between patients with less than and more than 25 per cent asymmetry (using Cohen effect size) in a cohort of definite vestibular migraine patients who underwent caloric testing between August 2016 and March 2019. RESULTS: A total of 31 patients (mean age: 48.7 ± 20.0 years; mean follow up: 9.1 ± 8.1 months) were included. Mean caloric asymmetry was 15.1 ± 15.6 per cent, with 6 (19.4 per cent) patients having asymmetry more than 25 per cent. Overall, patients experienced significant improvement in Dizziness Handicap Inventory total (d = 0.623 (95 per cent confidence interval, 0.007, 1.216)), emotional domain (d = 0.635 (95 per cent confidence interval, 0.019, 1.229)) and functional domain (d = 0.769 (95 per cent confidence interval, 0.143, 1.367)) but not physical domain (d = 0.227 (95 per cent confidence interval, -0.370, 0.815)) scores. Patients with more than 25 per cent asymmetry had no significant improvement in Dizziness Handicap Inventory scores, whereas those with less than 25 per cent asymmetry had significant improvement in Dizziness Handicap Inventory functional domain scores only (d = 0.636 (95 per cent confidence interval, 0.004, 1.244)). CONCLUSION: Vestibular migraine patients with peripheral vestibular weakness on caloric testing may be less likely to improve after treatment compared with those without.

Surgical fires, a clear and present danger.

BACKGROUND: A surgical fire is potentially devastating for a patient. Fire has been recognised as a potential complication of surgery for many years. Surgical fires continue to happen with alarming frequency. We present a review of the literature and an examination of possible solutions to this problem. METHODS: The PubMed and Medline databases from 1948 onwards were searched using the subject headings "operating rooms", "fire", "safety" and "safety management". "Surgical fire" was also searched as a keyword. Relevant references from articles were obtained. RESULTS: Fire occurs when the three elements of the fire triad, fuel, oxidiser and ignition coincide. Surgical fires are unusual in the absence of an oxygen-enriched atmosphere. The ignition source is most commonly diathermy but lasers carry a relatively greater risk. The majority of fires occur during head and neck surgery. This is due to the presence of oxygen and the extensive use of lasers. The risk of fire can be reduced with an awareness of the risk and good communication. CONCLUSIONS: Surgery will always carry a risk of fire. Reducing this risk requires a concerted effort from all team members.

Intensive care unit occupancy and premature discharge rates: A cohort study assessing the reporting of quality indicators.

PURPOSE: ICU occupancy fluctuates. High levels may disadvantage patients. Currently, occupancy is benchmarked annually which may inaccurately reflect strained units. Outcomes potentially sensitive to occupancy include premature (early) ICU discharge and non-clinical transfer (NCT). This study assesses the association between daily occupancy and these outcomes, and evaluates benchmarking care across Scotland using daily occupancy. MATERIALS AND METHODS: Population: all Scottish ICU patients, 2006-2014. EXPOSURE: bed occupancy per unit-day; Outcomes: proportion of early discharges and NCTs. DESIGN: Retrospective cohort study. Outcome rates were calculated above various occupancy thresholds. Polynomial regression visualised associations, and inflection points between occupancy and outcomes. Spearman's rho correlations between occupancy measures and outcomes were reported. RESULTS: 65,472 discharges occurred over 57,812 unit-days. 1954(3.0%) discharges were early; 429 (0.7%) were NCTs. Early discharge rates above 70%, 80% and 90% occupancy were 3.9%, 5.0% and 7.5% respectively. Occupancies at which outcome rates greatly increased were near 80% for early discharge, and 90% for NCT. Mean annual occupancy was not correlated with outcomes; annual proportion of days ≥90% occupancy correlated most strongly (early discharge rho = 0.46,p < .001; NCT rho = 0.31, p < .001). CONCLUSIONS: We demonstrate a clear association between daily ICU occupancy and early discharge/NCT. Daily occupancy may better benchmark care quality than mean annual occupancy.

Pharmacotherapy failure and progression to botulinum toxin injection in vestibular migraine.

OBJECTIVE: Given the lack of evidence on patients with medically refractory vestibular migraine, this study aimed to identify factors associated with pharmacotherapy failure and progression to botulinum toxin injection in vestibular migraine. METHODS: A retrospective cohort study was conducted on definite vestibular migraine patients from September 2015 to July 2019 who completed the Dizziness Handicap Inventory at least six weeks apart.. RESULTS: The study comprised 47 patients (mean age = 50.2 ± 15.8 years), with a mean follow-up time of 6.0 ± 6.0 months. The mean pre-treatment Dizziness Handicap Inventory score was 57.5 ± 23.5, with a mean reduction of 17.3 ± 25.2 (p < 0.001) at last follow up. Oscillopsia (r = 0.458, p = 0.007), failure of first medication (r = 0.518, p = 0.001) and pre-treatment Dizziness Handicap Inventory question 15 (an emotional domain question) score (r = 0.364, p = 0.019) were the only variables significantly correlated with progression to botulinum toxin injection. CONCLUSION: Motion hypersensitivity, failure of first medication, and fear of social stigmatisation suggest a decreased treatment response. These symptoms may require more aggressive treatment at an earlier stage.

Modulation of transcription factor Ets-1 DNA binding: DNA-induced unfolding of an alpha helix.

Conformational changes, including local protein folding, play important roles in protein-DNA interactions. Here, studies of the transcription factor Ets-1 provided evidence that local protein unfolding also can accompany DNA binding. Circular dichroism and partial proteolysis showed that the secondary structure of the Ets-1 DNA-binding domain is unchanged in the presence of DNA. In contrast, DNA allosterically induced the unfolding of an alpha helix that lies within a flanking region involved in the negative regulation of DNA binding. These findings suggest a structural basis for the intramolecular inhibition of DNA binding and a mechanism for the cooperative partnerships that are common features of many eukaryotic transcription factors.