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Background: SMA is characterized by reduced levels of survival of motor neuron (SMN) protein from deletions and/or mutations of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces low levels of functional SMN protein. Risdiplam (RG7916/RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates pre-mRNA splicing of SMN2 to increase SMN protein levels. Methods: SUNFISH (NCT02908685) is an ongoing multicenter, double-blind, placebo-controlled, operationally seamless study (randomized 2:1, risdiplam:placebo) in patients aged 2–25 years, with Type 2/3 SMA. Part 1 (n=51) assesses safety, tolerability, pharmacokinetics and pharmacodynamics of different risdiplam dose levels. Pivotal Part 2 (n=180) assesses safety and efficacy of the risdiplam dose level selected based on Part 1 results. Results: Part 1 results showed a sustained, >2-fold increase in median SMN protein versus baseline following 1 year of treatment. Adverse events were mostly mild, resolved despite ongoing treatment and reflected underlying disease. No drug-related safety findings have led to withdrawal (data-cut 06/17/18). SUNFISH Part 1 exploratory endpoint results and Part 2 study design will also be presented. Conclusions: To date, no drug-related safety findings have led to withdrawal. Risdiplam led to sustained increases in SMN protein levels.
Introduction: Acute migraine headaches are common causes of presentation to the emergency department (ED). There is great variability in the efficacy of the available parenteral agents to manage pain, though triptans are among the recommended treatments. The objective of this systematic review was to update a previous review examining the effectiveness of parenteral agents for the treatment of acute migraine in the ED or equivalent acute care setting; our review examined pain management in emergency settings and assessed the effectiveness of triptan agents. Methods: A comprehensive search of 10 electronic databases and grey literature was conducted to supplement the previous systematic review. Two independent reviewers completed study selection, quality assessment, and data extraction. Any discrepancies were resolved by third party adjudication. Pain scale scores were analyzed using standardized mean difference (SMD) with 95% confidence intervals (CIs) calculated using a random effects model; heterogeneity (I2) was reported. Results: Titles and abstracts of 5039 unique studies were reviewed, of which, 51 studies were included. Sixty-four studies from the original review were included, resulting in a total of 115 included studies. Pain was measured within the ED or equivalent acute care setting using a variety of pain scales, most commonly the 0-10 cm or 100 mm visual analog scale. Four studies compared pain scores between patients receiving sumatriptan vs. other agents, of which, patients receiving sumatriptan reported higher pain scale scores (SMD = 0.53; 95% CI: 0.04, 1.02; I2 = 80%). In particular, patients receiving sumatriptan reported higher pain scale scores than patients receiving metoclopramide (SMD = 0.68; 95% CI: 0.31, 1.04; n = 1) or ketorolac (SMD = 1.39; 95% CI: 0.56, 2.21; n = 1). Overall, studies comparing anti-inflammatory agents (i.e., ketorolac or dexketoprofen) to other agents reported improved pain scale scores among patients receiving anti-inflammatory agents (SMD = -0.38; 95% CI: -0.73, -0.03; I2 = 66%; n = 5). Conclusion: Limited evidence suggests that patients treated with metoclopramide or anti-inflammatory agents experience greater pain reduction compared to patients treated with sumatriptan. This review will conduct a network analysis of parenteral agents to examine the comparative effectiveness of parenteral agents to manage pain among patients with acute migraine. Further analysis will also consider the balance between efficacy and adverse events.
Introduction: Although a variety of parenteral agents exist for the treatment of acute migraine, relapse after an emergency department (ED) visit is still a common occurrence. The objective of this systematic review was to update a previous review examining the effectiveness of parenteral agents for the treatment of acute migraine in the ED or equivalent acute care setting; our review focused on those studies aiming a reduction in relapse after an ED visit. Methods: A comprehensive search of 10 electronic databases and grey literature was conducted to identify comparative studies to supplement the previous systematic review. Two independent reviewers completed study selection, quality assessment, and data extraction. Any discrepancies were resolved by third party adjudication. Relative risks (RR) with 95% confidence intervals (CIs) were calculated using a random effects model and heterogeneity (I2) was reported. Results: Titles and abstracts of 5039 unique studies were reviewed, of which, 51 studies were included. Sixty-four studies from the original review were included, resulting in a total of 115 included studies. Relapse was reported in 44 (38%) included studies and occurred commonly in patients receiving placebo or no interventions (median = 39%; IQR: 14%, 47%). Overall, no differences in headache relapse were found between patients receiving sumatriptan or placebo (RR = 1.09; 95% CI: 0.55, 2.17; I2 = 93%; n = 8). Conversely, patients receiving neuroleptic agents experienced fewer relapses compared to placebo (RR = 0.27; 95% CI: 0.12, 0.58; I2 = 0%; n = 3); however, patients receiving neuroleptics reported an increase in adverse events (RR = 1.87; 95% CI: 1.17, 3.00; I2 = 0%; n = 3). Compared to placebo, patients receiving dexamethasone were less likely to experience a headache recurrence (RR = 0.71; 95% CI: 0.53, 0.95; I2 = 60%, n = 9); however, no differences were found in reported adverse events (RR = 1.09; 95% CI: 0.81, 1.47; I2 = 0%; n = 3). Conclusion: Relapse is a common occurrence for patients with migraine headaches. This review found patients receiving neuroleptics or dexamethasone experienced fewer headache recurrences. Conversely, triptan agents appear to have minimal effect on reducing the risk for headache recurrence following discharge from an acute care setting. Limited available data on adverse events is an important limitation to inform decision-making. Guidelines should be revised to reflect these results.
To describe the use of balloon dilation with non-invasive ventilation in the treatment of pregnant patients with idiopathic subglottic stenosis.
The medical charts of four consecutive patients who underwent jet ventilation or high-flow nasal cannula oxygenation with balloon dilation for the treatment of idiopathic subglottic stenosis during pregnancy were reviewed.
Objective improvement of subglottic stenosis was seen in all four cases, with end-result Myer–Cotton grade 1 lesions down from pre-procedure grade 3 lesions. Patients also reported subjective improvements in symptomatology, with no further airway issues. All patients delivered normally, at term.
Laryngeal dilation with continuous radial expansion pulmonary balloons using non-invasive ventilation for the treatment of idiopathic subglottic stenosis in pregnant patients is safe and efficacious, and should be the first line treatment option for this patient population. The improvement in symptoms, and lack of labour and pregnancy complications, distinguish this method of treatment from others reported in the literature.
Objectives: Studies of neurocognitively elite older adults, termed SuperAgers, have identified clinical predictors and neurobiological indicators of resilience against age-related neurocognitive decline. Despite rising rates of older persons living with HIV (PLWH), SuperAging (SA) in PLWH remains undefined. We aimed to establish neuropsychological criteria for SA in PLWH and examined clinically relevant correlates of SA. Methods: 734 PLWH and 123 HIV-uninfected participants between 50 and 64 years of age underwent neuropsychological and neuromedical evaluations. SA was defined as demographically corrected (i.e., sex, race/ethnicity, education) global neurocognitive performance within normal range for 25-year-olds. Remaining participants were labeled cognitively normal (CN) or impaired (CI) based on actual age. Chi-square and analysis of variance tests examined HIV group differences on neurocognitive status and demographics. Within PLWH, neurocognitive status differences were tested on HIV disease characteristics, medical comorbidities, and everyday functioning. Multinomial logistic regression explored independent predictors of neurocognitive status. Results: Neurocognitive status rates and demographic characteristics differed between PLWH (SA=17%; CN=38%; CI=45%) and HIV-uninfected participants (SA=35%; CN=55%; CI=11%). In PLWH, neurocognitive groups were comparable on demographic and HIV disease characteristics. Younger age, higher verbal IQ, absence of diabetes, fewer depressive symptoms, and lifetime cannabis use disorder increased likelihood of SA. SA reported increased independence in everyday functioning, employment, and health-related quality of life than non-SA. Conclusions: Despite combined neurological risk of aging and HIV, youthful neurocognitive performance is possible for older PLWH. SA relates to improved real-world functioning and may be better explained by cognitive reserve and maintenance of cardiometabolic and mental health than HIV disease severity. Future research investigating biomarker and lifestyle (e.g., physical activity) correlates of SA may help identify modifiable neuroprotective factors against HIV-related neurobiological aging. (JINS, 2019, 25, 507–519)
A number of procedures for fluorescent X-ray analysis have been introduced to accommodate the samples that are produced from research on the recovery of values from secondary metal sources. For some applications, standards are conveniently available such as those that can be purchased from the National Bureau of Standards. For other applications, secondary standards must be prepared and analyzed by independent methods. The sample preparation procedures vary considerably. For monitoring process efficiency, sample preparation is often kept at a minimum such as simply pouring loose powders into disposable cups. For the most accurate analyses, sample preparatton requires casting the alloys and finishing the surfaces. Matrix correction procedures are employed where concentrations of major constituents vary over wide ranges.
Resin-loaded papers composed of approximately 50% cellulose and 50% ion-exchange or chelating resin provide an ideal matrix for many X-ray spectrographic analyses. Standards are prepared by multiple filtration of solutions of known composition through the paper to achieve quantitative collection or by the use of a radiotracer as a monitor for nonquantitative collection. Solutions prepared fram unknown samples are processed in the same manner as the standards.
Advantages of the resin-loaded papers are: reduction of interelement effects because standards and unknowns are present in a similar low X-ray absorbing matrix; physical parameters such as metallurgical history, grain size, and surface preparation are eliminated; and sampling errors are significantly reduced and sensitivity greatly increased by concentrating trace elements separated from large samples.
Application of these papers to a variety of metallurgical, geological, and water samples will be summarized. The possible use of resin-loaded papers as standards for air pollution monitoring will be examined.
X-ray fluorescence induced by charged particles has been employed in trace element analysis of both animal and human blood, tissue and bone samples. Preparation techniques included microtome slicing and wet digestion in nitric acid, internal chemical standards being used in the latter case.
Most of the specimens arose from a study of interactions between the toxic elements lead and zinc in growing foals; this was motivated by reports of sickness and death in foals raised near lead-zinc smelters. The cause of toxicity in animals from environmental pollution is often attributed to Single factors, whereas in reality interactions among many factors, including a variety of toxic and nutrient trace elements, should be considered.
A variety of spectra are presented and elemental concentrations derived. Agreement between the X-ray data and atomic absorption spectrophotometry is encouraging. The results demonstrate the potential of particle-excited X-ray fluorescenee as a broad-range analytical technique for the study of trace element interactions.
Indigenous women and children experience some of the most profound health disparities globally. These disparities are grounded in historical and contemporary trauma secondary to colonial atrocities perpetuated by settler society. The health disparities that exist for chronic diseases may have their origins in early-life exposures that Indigenous women and children face. Mechanistically, there is evidence that these adverse exposures epigenetically modify genes associated with cardiometabolic disease risk. Interventions designed to support a resilient pregnancy and first 1000 days of life should abrogate disparities in early-life socioeconomic status. Breastfeeding, prenatal care and early child education are key targets for governments and health care providers to start addressing current health disparities in cardiometabolic diseases among Indigenous youth. Programmes grounded in cultural safety and co-developed with communities have successfully reduced health disparities. More works of this kind are needed to reduce inequities in cardiometabolic diseases among Indigenous women and children worldwide.
The effect of transportation and lairage on the faecal shedding and post-slaughter contamination of carcasses with Escherichia coli O157 and O26 in young calves (4–7-day-old) was assessed in a cohort study at a regional calf-processing plant in the North Island of New Zealand, following 60 calves as cohorts from six dairy farms to slaughter. Multiple samples from each animal at pre-slaughter (recto-anal mucosal swab) and carcass at post-slaughter (sponge swab) were collected and screened using real-time PCR and culture isolation methods for the presence of E. coli O157 and O26 (Shiga toxin-producing E. coli (STEC) and non-STEC). Genotype analysis of E. coli O157 and O26 isolates provided little evidence of faecal–oral transmission of infection between calves during transportation and lairage. Increased cross-contamination of hides and carcasses with E. coli O157 and O26 between co-transported calves was confirmed at pre-hide removal and post-evisceration stages but not at pre-boning (at the end of dressing prior to chilling), indicating that good hygiene practices and application of an approved intervention effectively controlled carcass contamination. This study was the first of its kind to assess the impact of transportation and lairage on the faecal carriage and post-harvest contamination of carcasses with E. coli O157 and O26 in very young calves.
A prompt radio burst has been observed from the supernova 1987a in the Large Magellanic Cloud. Observations were made at 0.843, 1.415, 2.29, and 8.41 GHz. At frequencies around 1 GHz, the peak flux density reached about 150 mJy and occurred within four days of the supernova. This event may be a weak precursor to a major radio outburst of the type previously observed in other extragalactic supernovae. Radio monitoring of the supernova is continuing at each of the above frequencies, and coordination is underway of a southern hemisphere VLBI array to map the radio outburst region as it expands. Differential astrometry carried out on prime-focus plates taken with the Anglo-Australian telescope indicates that the component, star 1, of Sanduleak's star SK-69202 is within 0.05 ± 0.13 arcsec of the supernova.
Free-range laying hen systems are increasing within Australia. The pullets for these systems are typically reared indoors before being provided first range access around 21 to 26 weeks of age. Thus, the rearing and laying environments are disparate and hens may not adapt well to free-range housing. In this study, we reared 290 Hy-Line® Brown day-old chicks divided into two rooms each with feed, water and litter. In the enriched room, multiple structural, manipulable, visual and auditory stimuli were also provided from 4 to 21 days, the non-enriched room had no additional objects or stimuli. Pullets were transferred to the laying facility at 12 weeks of age and divided into six pens (three enriched-reared, three non-enriched-reared) with identical indoor resources and outdoor range area. All birds were first provided range access at 21 weeks of age. Video observations of natural disturbance behaviours on the range at 22 to 23 and 33 to 34 weeks of age showed no differences in frequency of disturbance occurrences between treatment groups (P=0.09) but a decrease in disturbance occurrences over time (P<0.0001). Radio-frequency identification tracking of individually tagged birds from 21 to 37 weeks of age showed enriched birds on average, spent less time on the range each day (P<0.04) but with a higher number of range visits than non-enriched birds from 21 to 24 weeks of age (P=0.01). Enriched birds accessed the range on more days (P=0.03) but over time, most birds in both treatment groups accessed the range daily. Basic external health scoring showed minimal differences between treatment groups with most birds in visibly good condition. At 38 weeks of age all birds were locked inside for 2 days and from 40 to 42 weeks of age the outdoor range was reduced to 20% of its original size to simulate stressful events. The eggs from non-enriched birds had higher corticosterone concentrations following lock-in and 2 weeks following range reduction compared with the concentrations within eggs from enriched birds (P<0.0001). Correspondingly, the enriched hens showing a greater increase in the number of visits following range area reduction compared to non-enriched hens (P=0.02). Only one rearing room per treatment was used but these preliminary data indicate 3 weeks of early enrichment had some long-term effects on hen ranging behaviour and enhanced hen’s adaptability to environmental stressors.
Introduction: Understanding factors that influence laboratory test ordering in emergency departments (EDs) can help to improve current laboratory test ordering practices. The aim of this study is to compare patterns and influences in laboratory test ordering between emergency physicians and nurses at two ED sites, Halifax Infirmary (HI) and Dartmouth General (DG). Methods: A mixed-methods approach involving administrative data and telephone interviews was employed. Data from 211,279 patients at HI and DG EDs were analyzed. Chi-square analysis and binary logistic regression were used to determine significant factors influencing whether a test was ordered, as well as significant factors predicting likelihood of a nurse or a physician ordering a test. All significant associations had a p-value of <0.0001. Interviews were conducted (n=25) with doctors and nurses in order to explore areas of potential influence in a clinician’s decision-making process, and discuss what makes decision making difficult or inconsistent in the ED. These interviews were analyzed according to the Theoretical Domains Framework. The interviews were coded by two individuals using a consensus methodology in order to ensure accuracy of coding. Results: Overall, laboratory tests were more likely to be ordered at DG than at HI (OR=1.52, 95% CI: [1.48, 1.55]). Laboratory tests were more likely to be ordered by nurses at DG than at HI (OR=1.58, 95% CI: [1.54, 1.62]). Laboratory tests were more likely to be ordered if the ED was not busy, if the patient was over 65, had a high acuity, had a long stay in the ED, required consults, or was admitted to hospital. Doctors were more likely to order a laboratory test in patients over 65, requiring consults or hospital admission, whereas nurses were more likely to order laboratory tests in patients with high acuity or long stays in the ED. Data from the interviews suggested differing influences on decision making between nurses and doctors, especially in the areas of social influence and knowledge. Conclusion: Currently, there is limited research that investigates behaviour of both emergency physicians and nurses. By determining barriers that are most amenable to behaviour change in emergency physicians and nurses, findings from this work may be used to update practice guidelines, ensuring more consistency and efficiency in laboratory test ordering in the ED.
The stress sensitization theory hypothesizes that individuals exposed to childhood adversity will be more vulnerable to mental disorders from proximal stressors. We aimed to test this theory with respect to risk of 30-day major depressive episode (MDE) and generalized anxiety disorder (GAD) among new US Army soldiers.
The sample consisted of 30 436 new soldier recruits in the Army Study to Assess Risk and Resilience (Army STARRS). Generalized linear models were constructed, and additive interactions between childhood maltreatment profiles and level of 12-month stressful experiences on the risk of 30-day MDE and GAD were analyzed.
Stress sensitization was observed in models of past 30-day MDE (χ28 = 17.6, p = 0.025) and GAD (χ28 = 26.8, p = 0.001). This sensitization only occurred at high (3+) levels of reported 12-month stressful experiences. In pairwise comparisons for the risk of 30-day MDE, the risk difference between 3+ stressful experiences and no stressful experiences was significantly greater for all maltreatment profiles relative to No Maltreatment. Similar results were found with the risk for 30-day GAD with the exception of the risk difference for Episodic Emotional and Sexual Abuse, which did not differ statistically from No Maltreatment.
New soldiers are at an increased risk of 30-day MDE or GAD following recent stressful experiences if they were exposed to childhood maltreatment. Particularly in the military with an abundance of unique stressors, attempts to identify this population and improve stress management may be useful in the effort to reduce the risk of mental disorders.
Ross Ice Shelf (RIS) is known to experience transient thickness change due to changes in the flow of its tributary ice streams and glaciers and this may complicate identification of external, climate-forced signals in contemporary observations of ice shelf thinning and thickening. Flux changes at the lateral boundaries produce both instantaneous and longer timescale adjustments in the coupled velocity and thickness fields. Here, we adapt a statistical approach to output from a numerical model of ice shelf flow to identify characteristic patterns (spatial response surfaces) associated with stepped and cyclic perturbations to boundary fluxes. Once known, characteristic patterns identified in observational data may be attributed to specific sources. An example involving discharge of Byrd Glacier into RIS is described. We find that spatial response surfaces for thickness and velocity generated in individual flow model experiments appear to be independent of flux perturbation shape and magnitude. Additionally, recent acceleration of Byrd Glacier is apparent in ICESat-detected change in RIS thickness.
Migrants are considered a key group at risk for HIV infection. This study describes differences between migrants and the Spanish-born population as they progress through the HIV care cascade in Catalonia, Spain. This study found that among people reached by prevention activities, migrants had a higher number of barriers to access HIV testing services than Spanish-born people, driven primarily by shared risk factors. Between 2001 and 2013, 9829 new HIV diagnoses were reported in Catalonia, the proportion of migrants increasing from 24% in 2001 to 41% in 2013. Compared with Spanish-born people, migrants had a higher proportion of women at diagnosis (24·6% vs. 16·7%), and were younger (median age of 33 vs. 37). The most frequent at-risk population was MSM (men who have sex with men) in both migrants and Spanish-born people, (40% and 43%, respectively), although there were significant differences by region of origin. People from sub-Saharan Africa had the highest proportion of late diagnosis (63·7%). Compared with the Spanish-born population, migrants on follow-up had a lower proportion of people on antiretroviral therapy (ART) (93·7% vs. 90·8%, P < 0·001) and with viral suppression (87·2% vs. 82·9%, P < 0·001). Migrants have higher number of barriers to access HIV testing services, lower retention rates and proportions on ART as compared with Spanish-born people, these differences not being uniform between migrants from different regions.