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Atrial fibrillation (AF), which is characterized by chaotic patterns of electrical activation of the atria, affects over 4 million people in the US alone. We previously identified nanoscale structural abnormalities in the hearts of AF patients. Specifically, they displayed swelling of gap junction (GJ) –adjacent perinexi, specialized nanodomains rich in cardiac sodium channels (NaV1.5) and located within intercalated disks (IDs; sites of electromechanical contact between adjacent cells). However, the functional consequences of these nanoscale structural changes remain unclear.
We assessed the structural and functional impacts of selectively disrupting different NaV1.5-rich ID nanodomains.
Methods and Results:
We utilized peptide mimetics of adhesion domains to selectively inhibit adhesion within different ID nanodomains: 1) Nadp1 (target: N-cadherin), 2) dadp1 (target: Desmoglein-2), and 3) βadp1 (target: sodium channel β1 subunit [SCN1b]). Each active peptide was compared against a corresponding inactive control peptide (Nadp1-c, dadp1-c, βadp1-scr). Sub-diffraction confocal imaging revealed ID enrichment of active peptides, but not inactive controls. Furthermore, each active peptide was preferentially localized in ID regions rich in its corresponding protein target. Peptide treatment (100 μM; 60 minutes) of ex vivo mouse hearts revealed profound widening of perinexi by βadp1 and of mechanical junctions by Nadp1. Dadp1 also induced widening of mechanical junctions albeit to a lower degree. STORM single molecule localization microscopy identified about 50&per; of ID-localized NaV1.5 within GJ-adjacent perinexi, while an additional ∼35&per; was located within N-cad-rich ID sites. Nadp1 and βadp1 induced redistribution of ID localized NaV1.5 away from perinexi and mechanical junctions respectively. Dadp1, again, had similar but milder effects compared to Nadp1. Western blot revealed the expression levels of NaV1.5, connexin 43 (Cx43), connexin 40 (Cx40), β1 in peptide treated hearts to be within 10&per; of levels in untreated controls. Optical mapping revealed atrial conduction slowing in hearts treated with Nadp1 (17cm/s, 70.83&per; of control) and βadp1 (13 cm/s, 54.17&per; of control), but not inactive control peptides (24 cm/s). Volume-conducted electrocardiograms (ECG) revealed P wave prolongation in active peptide treated hearts (Nadp1: 26.5ms, βadp1: 31ms), consistent with conduction slowing compared to the inactive control peptides (16ms). Importantly, burst pacing elicited atrial arrhythmias in all hearts treated with Nadp1 and βadp1. Arrhythmia burden (duration, number of arrhythmias) was highest with βadp1.
These results suggest that disruption of NaV1.5-rich ID nanodomains impairs electrical impulse propagation and promotes arrhythmias in the atria. Furthermore, the magnitude of functional impacts are likely determined by the amount of sodium channels contained within the nanodomains disrupted.
Although the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke caused by intracranial anterior circulation large vessel occlusion (LVO) is proven, demonstration of local effectiveness is critical for health system planning and resource allocation because of the complexity and cost of this treatment.
Using our prospective registry, we identified all patients who underwent EVT for out-of-hospital LVO stroke from February 1, 2013 through January 31, 2017 (n = 44), and matched them 1:1 in a hierarchical fashion with control patients not treated with EVT based on age (±5 years), prehospital functional status, stroke syndrome, severity, and thrombolysis administration. Demographics, in-hospital mortality, discharge disposition from acute care, length of hospitalization, and functional status at discharge from acute care and at follow-up were compared between cases and controls.
For EVT-treated patients (median age 66, 50% women), the median onset-to-recanalization interval was 247 min, and successful recanalization was achieved in 30/44 (91%). Alteplase was administered in 75% of cases and 57% of controls (p = 0.07). In-hospital mortality was 11% among the cases and 36% in the control group (p = 0.006); this survival benefit persisted during follow-up (p = 0.014). More EVT patients were discharged home from acute care (50% vs. 18%, p = 0.002). Among survivors, there were nonsignificant trends in favor of EVT for median length of hospitalization (14 vs. 41 days, p = 0.11) and functional independence at follow-up (51% vs. 32%, p = 0.079).
EVT improved survival and decreased disability. This demonstration of single-center effectiveness may help facilitate expansion of EVT services in similar health-care jurisdictions.
Endovascular thrombectomy (EVT) is efficacious for ischemic stroke caused by proximal intracranial large-vessel occlusion involving the anterior cerebral circulation. However, evidence of its cost-effectiveness, especially in a real-world setting, is limited. We assessed whether EVT ± tissue plasminogen activator (tPA) was cost-effective when compared with standard care ± tPA at our center.
We identified patients treated with EVT ± tPA after the Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing computed tomography to recanalization times trial from our prospective stroke registry from February 1, 2013 to January 31, 2017. Patients admitted before February 2013 and treated with standard care ± tPA constitute the controls. The sample size was 88. Cost-effectiveness was assessed using the net monetary benefit (NMB). Differences in average costs and quality-adjusted life years (QALYs) were estimated using the augmented inverse probability weighted estimator. We accounted for sampling and methodological uncertainty in sensitivity analyses.
Patients treated with EVT ± tPA had a net gain of 2.89 [95% confidence interval (CI): 0.93–4.99] QALYs at an additional cost of $22,200 (95% CI: −28,902–78,244) per patient compared with the standard care ± tPA group. The NMB was $122,300 (95% CI: −4777–253,133) with a 0.85 probability of being cost-effective. The expected savings to the healthcare system would amount to $321,334 per year.
EVT ± tPA had higher costs and higher QALYs compared with the control, and is likely to be cost-effective at a willingness-to-pay threshold of $50,000 per QALY.
Despite knowing for many decades that depressive psychopathology is common in first-episode schizophrenia spectrum disorders (FES), there is limited knowledge regarding the extent and nature of such psychopathology (degree of comorbidity, caseness, severity) and its demographic, clinical, functional and treatment correlates. This study aimed to determine the pooled prevalence of depressive disorder and caseness, and the pooled mean severity of depressive symptoms, as well as the demographic, illness, functional and treatment correlates of depressive psychopathology in FES.
This systematic review, meta-analysis and meta-regression was prospectively registered (CRD42018084856) and conducted in accordance with PRISMA and MOOSE guidelines.
Forty studies comprising 4041 participants were included. The pooled prevalence of depressive disorder and caseness was 26.0% (seven samples, N = 855, 95% CI 22.1–30.3) and 43.9% (11 samples, N = 1312, 95% CI 30.3–58.4), respectively. The pooled mean percentage of maximum depressive symptom severity was 25.1 (38 samples, N = 3180, 95% CI 21.49–28.68). Correlates of depressive psychopathology were also found.
At least one-quarter of individuals with FES will experience, and therefore require treatment for, a full-threshold depressive disorder. Nearly half will experience levels of depressive symptoms that are severe enough to warrant diagnostic investigation and therefore clinical intervention – regardless of whether they actually fulfil diagnostic criteria for a depressive disorder. Depressive psychopathology is prominent in FES, manifesting not only as superimposed comorbidity, but also as an inextricable symptom domain.
Planning for the preterm birth of a fetus with known anomalies can raise complex ethical issues. This is particularly true of multiple pregnancies, where the interests of each fetus and of the expectant parent(s) can conflict. In these complex situations, parental wishes and values can also conflict with the recommendations of treating clinicians. In this article, we consider the case of a dichorionic twin pregnancy complicated by the diagnosis of vein of Galen aneurysmal malformation (VGAM) in one of the twins at 28 weeks’ gestation. Subsequent deterioration of the affected twin prompted the parents to request preterm delivery to prevent the imminent in-utero demise of the affected twin. However, given the associated risks of prematurity, complying with the parents’ request may have disadvantaged the health and wellbeing of the unaffected twin. This article canvases the complex ethical issues raised when parents request preterm delivery of a multiple pregnancy complicated by a fetal anomaly in one twin, and the various ethical tools and frameworks that clinicians can draw on to guide their decision-making in such cases.
During the past two decades, it has been amply documented that neuropsychiatric disorders (NPDs) disproportionately account for burden of illness attributable to chronic non-communicable medical disorders globally. It is also likely that human capital costs attributable to NPDs will disproportionately increase as a consequence of population aging and beneficial risk factor modification of other common and chronic medical disorders (e.g., cardiovascular disease). Notwithstanding the availability of multiple modalities of antidepressant treatment, relatively few studies in psychiatry have primarily sought to determine whether improving cognitive function in MDD improves patient reported outcomes (PROs) and/or is cost effective. The mediational relevance of cognition in MDD potentially extrapolates to all NPDs, indicating that screening for, measuring, preventing, and treating cognitive deficits in psychiatry is not only a primary therapeutic target, but also should be conceptualized as a transdiagnostic domain to be considered regardless of patient age and/or differential diagnosis.
The aim of this study was to describe patient level costing methods and develop a database of healthcare resource use and cost in patients with AHF receiving ventricular assist device (VAD) therapy.
Patient level micro-costing was used to identify documented activity in the years preceding and following VAD implantation, and preceding heart transplant for a cohort of seventy-seven consecutive patients listed for heart transplantation (2009–12). Clinician interviews verified activity, established time resource required for each activity, and added additional undocumented activities. Costs were sourced from the general ledger, salary, stock price, pharmacy formulary data, and from national medical benefits and prostheses lists. Linked administrative data analyses of activity external to the implanting institution, used National Weighted Activity Units (NWAU), 2014 efficient price, and admission complexity cost weights and were compared with micro-costed data for the implanting admission.
The database produced includes patient level activity and costs associated with the seventy-seven patients across thirteen resource areas including hospital activity external to the implanting center. The median cost of the implanting admission using linked administrative data was $246,839 (interquartile range [IQR] $246,839–$271,743), versus $270,716 (IQR $211,740–$378,482) for the institutional micro-costing (p = .08).
Linked administrative data provides a useful alternative for imputing costs external to the implanting center, and combined with institutional data can illuminate both the pathways to transplant referral and the hospital activity generated by patients experiencing the terminal phases of heart failure in the year before transplant, cf-VAD implant, or death.
Palliative care for nursing home residents with advanced dementia is often sub-optimal due to poor communication and limited care planning. In a cluster randomized controlled trial, registered nurses (RNs) from 10 nursing homes were trained and funded to work as Palliative Care Planning Coordinators (PCPCs) to organize family case conferences and mentor staff. This qualitative sub-study aimed to explore PCPC and health professional perceptions of the benefits of facilitated case conferencing and identify factors influencing implementation.
Semi-structured interviews were conducted with the RNs in the PCPC role, other members of nursing home staff, and physicians who participated in case conferences. Analysis was conducted by two researchers using a thematic framework approach.
Interviews were conducted with 11 PCPCs, 18 other nurses, eight allied health workers, and three physicians. Perceived benefits of facilitated case conferencing included better communication between staff and families, greater multi-disciplinary involvement in case conferences and care planning, and improved staff attitudes and capabilities for dementia palliative care. Key factors influencing implementation included: staffing levels and time; support from management, staff and physicians; and positive family feedback.
The facilitated approach explored in this study addressed known barriers to case conferencing. However, current business models in the sector make it difficult for case conferencing to receive the required levels of nursing qualification, training, and time. A collaborative nursing home culture and ongoing relationships with health professionals are also prerequisites for success. Further studies should document resident and family perceptions to harness consumer advocacy.
We agree with Bracken, Rose, and Church (2016) and others that a critical design feature of any 360° feedback process is accountability, where the goal is “creation of sustainable individual, group, and/or organizational change in behaviors valued by the organization” (p. 764). Though we acknowledge the important roles that the organization and raters play in holding leaders accountable for their development, the goal of our commentary is to expand on how the leader's boss and other key individuals can serve as powerful sources of accountability in the 360° feedback process and throughout a leader's development journey. We also want to note that although the Center for Creative Leadership (CCL) encourages leaders to share what they have learned from their 360° feedback with their bosses and other accountability partners (e.g., peers), it is the leader's choice as to whether he or she shares key feedback with others. This practice ensures confidentiality of the data, helping leaders trust the process and increasing the likelihood that individuals accept difficult feedback and use it for performance improvement (Fleenor, Taylor, & Chappelow, 2008; King & Santana, 2010).
Twenty one samples of relatively pure tubular halloysites (HNTs) from localities in Australia, China, New Zealand, Scotland, Turkey and the USA have been investigated by X-ray diffraction (XRD), infrared spectroscopy (IR) and electron microscopy. The halloysites occur in cylindrical tubular forms with circular or elliptical cross sections and curved layers and also as prismatic tubular forms with polygonal cross sections and flat faces. Measurements of particle size indicate a range from 40 to 12,700 nm for tube lengths and from 20 to 600 nm for diameters. Size distributions are positively skewed with mean lengths ranging from 170 to 950 nm and mean diameters from 50 to 160 nm. Cylindrical tubes are systematically smaller than prismatic ones. Features related to order/ disorder in XRD patterns e.g. as measured by a ‘cylindrical/prismatic’ (CP) index and IR spectra as measured by an ‘OH-stretching band ratio’ are related to the proportions of cylindrical vs. prismatic tubes and correlated with other physical measurements such as specific surface area and cation exchange capacity. The relationships of size to geometric form, along with evidence for the existence of the prismatic form in the hydrated state and the same 2M1 stacking sequence irrespective of hydration state (i.e. 10 vs. 7 Å) or form, suggests that prismatic halloysites are the result of continued growth of cylindrical forms.
1) To evaluate whether transient ischemic attack (TIA) management in emergency departments (EDs) of the Nova Scotia Capital District Health Authority followed Canadian Best Practice Recommendations, and 2) to assess the impact of being followed up in a dedicated outpatient neurovascular clinic.
Retrospective chart review of all patients discharged from EDs in our district from January 1, 2011 to December 31, 2012 with a diagnosis of TIA. Cox proportional hazards models, Kaplan-Meier survival curve, and propensity matched analyses were used to evaluate 90-day mortality and readmission.
Of the 686 patients seen in the ED for TIA, 88.3% received computed tomography (CT) scanning, 86.3% received an electrocardiogram (ECG), 35% received vascular imaging within 24 hours of triage, 36% were seen in a neurovascular clinic, and 4.2% experienced stroke, myocardial infarction, or vascular death within 90 days. Rates of antithrombotic use were increased in patients seen in a neurovascular clinic compared to those who were not (94% v. 86.3%, p<0.0001). After adjustment for age, sex, vascular disease risk factors, and stroke symptoms, the risk of readmission for stroke, myocardial infarction, or vascular death was lower for those seen in a neurovascular clinic compared to those who were not (adjusted hazard ratio 0.28; 95% confidence interval 0.08–0.99, p=0.048).
The majority of patients in our study were treated with antithrombotic agents in the ED and investigated with CT and ECG within 24 hours; however, vascular imaging and neurovascular clinic follow-up were underutilized. For those with neurovascular clinic follow-up, there was an association with reduced risk of subsequent stroke, myocardial infarction, or vascular death.
Background: Computed tomography perfusion (CTP) is increasingly being used in the setting of acute ischemic stroke (AIS). The aim of the current study was to compare the prognostic utility of, and inter-observer variation between, baseline appearances on non-contrast CT (using Alberta Stroke Program Early CT score(ASPECTS)) and on CTP for predicting final infarct volume. We also assessed impact of training on interpretation of these images. Methods: Retrospectively, plain head computed tomography (CT) and CTP images at presentation and CT or diffusion imaging on follow up of patients with AIS were analyzed. The lesion volume on different CTP parameters was then correlated with the final infarct volume. This analysis was done by a Neuroradiologist, a stroke Neurologist and a medical student. Kappa statistics and Intra-class correlation coefficients were used for agreement between readers. Pearson correlation coefficients were used.Results: Thirty eight patients with AIS met all inclusion criteria. There was very good agreement among all readers for the CTP parameters. There was only fair agreement for ASPECT score. Correlation coefficient (r-square) between CTP parameters and final infarct volume showed that cerebral blood volume was the best parameter to predict the final infarct volume followed by cerebral blood flow and time to peak. The best reader to predict the final infarct volume on the initial CT perfusion study was the neuroradiologist followed by medical student and stroke neurologist. Conclusions: Cerebral blood volume defect correlated the best with the final infarct volume. There was a very good inter-observer agreement for all the CTP maps in predicting the final infarct volume despite the wide variation in the experience of the readers.
The aim of this study was to examine whether people differed in change in performance across the first five blocks of an online flanker task and whether those trajectories of change were associated with self-reported aerobic or resistance exercise frequency according to age. A total of 8752 men and women aged 13–89 completed a lifestyle survey and five 45-s games (each game was a block of ~46 trials) of an online flanker task. Accuracy of the congruent and incongruent flanker stimuli was analyzed using latent class and growth curve modeling adjusting for time between blocks, whether the blocks occurred on the same or different days, education, smoking, sleep, caffeinated coffee and tea use, and Lumosity training status (“free play” or part of a “daily brain workout”). Aerobic and resistance exercise were unrelated to first block accuracies. For the more cognitively demanding incongruent flanker stimuli, aerobic activity was positively related to the linear increase in accuracy [B=0.577%, 95% confidence interval (CI), 0.112 to 1.25 per day above the weekly mean of 2.8 days] and inversely related to the quadratic deceleration of accuracy gains (B=−0.619% CI, −1.117 to −0.121 per day). An interaction of aerobic activity with age indicated that active participants younger than age 45 had a larger linear increase and a smaller quadratic deceleration compared to other participants. Age moderates the association between self-reported aerobic, but not self-reported resistance, exercise and changes in cognitive control that occur with practice during incongruent presentations across five blocks of a 45-s online, flanker task. (JINS, 2015, 21, 802–815)
Volcanic eruptions commonly produce buoyant ash-laden plumes that rise through the stratified atmosphere. On reaching their level of neutral buoyancy, these plumes cease rising and transition to horizontally spreading intrusions. Such intrusions occur widely in density-stratified fluid environments, and in this paper we develop a shallow-layer model that governs their motion. We couple this dynamical model to a model for particle transport and sedimentation, to predict both the time-dependent distribution of ash within volcanic intrusions and the flux of ash that falls towards the ground. In an otherwise quiescent atmosphere, the intrusions spread axisymmetrically. We find that the buoyancy-inertial scalings previously identified for continuously supplied axisymmetric intrusions are not realised by solutions of the governing equations. By calculating asymptotic solutions to our model we show that the flow is not self-similar, but is instead time-dependent only in a narrow region at the front of the intrusion. This non-self-similar behaviour results in the radius of the intrusion growing with time
, rather than
as suggested previously. We also identify a transition to drag-dominated flow, which is described by a similarity solution with radial growth now proportional to
. In the presence of an ambient wind, intrusions are not axisymmetric. Instead, they are predominantly advected downstream, while at the same time spreading laterally and thinning vertically due to persistent buoyancy forces. We show that close to the source, this lateral spreading is in a buoyancy-inertial regime, whereas far downwind, the horizontal buoyancy forces that drive the spreading are balanced by drag. Our results emphasise the important role of buoyancy-driven spreading, even at large distances from the source, in the formation of the flowing thin horizontally extensive layers of ash that form in the atmosphere as a result of volcanic eruptions.