Population pharmacokinetics-based recommendations for a single delayed or missed dose of nusinersen

Nusinersen is an antisense oligonucleotide approved for the treatment of spinal muscular atrophy. The drug is given intrathecally at 12 mg, beginning with 3 loading doses at 2-week intervals, a fourth loading dose 30 days thereafter, and maintenance doses at 4-month intervals. This population pharmacokinetic model was developed to clarify how to maintain targeted nusinersen exposure after an unforeseen one-time delay or missed dose. Simulations demonstrated that the impact of a one-time delay in dosing or a missed dose on median cerebrospinal fluid exposures depended on duration of interruption and the regimen phase in which it occurred. Delays in loading doses delayed reaching the peak trough concentration by approximately the duration of the interruption. Resumption of the regimen as soon as possible resulted in achieving steady state trough concentration upon completion of the loading phase. A short delay (30-90 days) during the maintenance phase led to prolonged lower median cerebrospinal fluid concentration if all subsequent doses were shifted by the same 4-month interval. However, administration of the delayed dose, followed by the subsequent dose as originally scheduled, rapidly restored trough concentration. If a dose must be delayed, patients should return to the original dosing schedule as soon as possible

The fitness of dispersing spotted hyaena sons is influenced by maternal social status

Life history theory predicts that mothers should provide their offspring with a privileged upbringing if this enhances their offspring's and their own fitness. In many mammals, high-ranking mothers provide their offspring with a privileged upbringing. Whether dispersing sons gain fitness benefits during adulthood from such privileges (a 'silver spoon' effect) has rarely been examined. In this paper, we show that in the complex, female-dominated society of spotted hyaenas, high-born sons grew at higher rates, were more likely to disperse to clans offering the best fitness prospects, started reproducing earlier and had a higher reproductive value than did lower-born sons. This illustrates the evolutionary importance of maternal effects even in societies in which male size or fighting ability does not influence fitness. By demonstrating for the first time in a non-human mammal that maternal status influences immigration patterns, the study also advances our understanding of two key ecological and evolutionary processes, dispersal and habitat selection

Extension of ELM suppression window using n=4 RMPs in EAST

The q95 window for Type-I Edge Localized Modes (ELMs) suppression using n=4 even parity Resonant Magnetic Perturbations (RMPs) has been significantly expanded to a range from 3.9 to 4.8, which is demonstrated to be reliable and repeatable in EAST over the last two years. This window is significantly wider than the previous one, which is around q95=3.7pm0.1, and is achieved using n=4 odd parity RMPs. Here, n represents the toroidal mode number of the applied RMPs and q95 is the safety factor at the 95% normalized poloidal magnetic flux. During ELM suppression, there is only a slight drop in the stored energy (<=10%). The comparison of pedestal density profiles suggests that ELM suppression is achieved when the pedestal gradient is kept lower than a threshold. This wide q95 window for ELM suppression is consistent with the prediction made by MARS-F modeling prior to the experiment, in which it is located at one of the resonant q95 windows for plasma response. The Chirikov parameter taking into account plasma response near the pedestal top, which measures the plasma edge stochasticity, significantly increases when q95 exceeds 4, mainly due to denser neighboring rational surfaces. Modeling of plasma response by the MARS-F code shows a strong coupling between resonant and non-resonant components across the pedestal region, which is characteristic of the kink-peeling like response observed during RMP-ELM suppression in previous studies on EAST. These promising results show the reliability of ELM suppression using the n=4 RMPs and expand the physical understanding on ELM suppression mechanism.Comment: 25 pages, 11 figure

Prognostic implications of negative dobutamine stress echocardiography in African Americans compared to Caucasians

This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens

An outreach intervention to implement evidence based practice in residential care: a randomized controlled trial [ISRCTN67855475]

BACKGROUND: The aim of this project was to assess whether outreach visits would improve the implementation of evidence based clinical practice in the area of falls reduction and stroke prevention in a residential care setting. METHODS: Twenty facilities took part in a randomized controlled trial with a seven month follow-up period. Two outreach visits were delivered by a pharmacist. At the first a summary of the relevant evidence was provided and at the second detailed audit information was provided about fall rates, psychotropic drug prescribing and stroke risk reduction practices (BP monitoring, aspirin and warfarin use) for the facility relevant to the physician. The effect of the interventions was determined via pre- and post-intervention case note audit. Outcomes included change in percentage patients at risk of falling who fell in a three month period prior to follow-up and changes in use of psychotropic medications. Chi-square tests, independent samples t-test, and logistic regression were used in the analysis. RESULTS: Data were available from case notes at baseline (n = 897) and seven months follow-up (n = 902), 452 residential care staff were surveyed and 121 physicians were involved with 61 receiving outreach visits. Pre-and post-intervention data were available for 715 participants. There were no differences between the intervention and control groups for the three month fall rate. We were unable to detect statistically significant differences between groups for the psychotropic drug use of the patients before or after the intervention. The exception was significantly greater use of "as required" antipsychotics in the intervention group compared with the control group after the pharmacy intervention (RR = 4.95; 95%CI 1.69–14.50). There was no statistically significant difference between groups for the numbers of patients "at risk of stroke" on aspirin at follow-up. CONCLUSIONS: While the strategy was well received by the physicians involved, there was no change in prescribing patterns. Patient care in residential settings is complex and involves contributions from the patient's physician, family and residential care staff. The project highlights challenges of delivering evidence based care in a setting in which there is a paucity of well controlled trial evidence but where significant health outcomes can be attained

An examination of factors influencing the choice of therapy for patients with coronary artery disease

BACKGROUND: A diverse range of factors influence clinicians' decisions regarding the allocation of patients to different treatments for coronary artery disease in routine cardiology clinics. These include demographic measures, risk factors, co-morbidities, measures of objective cardiac disease, symptom reports and functional limitations. This study examined which of these factors differentiated patients receiving angioplasty from medication; bypass surgery from medication; and bypass surgery from angioplasty. METHODS: Univariate and multivariate logistic regression analyses were conducted on patient data from 214 coronary artery disease patients who at the time of recruitment had been received a clinical assessment and were reviewed by their cardiologist in order to determine the form of treatment they were to undergo: 70 would receive/continue medication, 71 were to undergo angioplasty and 73 were to undergo bypass surgery. RESULTS: Analyses differentiating patients receiving angioplasty from medication produced 9 significant univariate predictors, of which 5 were also multivariately significant (left anterior descending artery disease, previous coronary interventions, age, hypertension and frequency of angina). The analyses differentiating patients receiving surgery from angioplasty produced 12 significant univariate predictors, of which 4 were multivariately significant (limitations in mobility range, circumflex artery disease, previous coronary interventions and educational level). The analyses differentiating patients receiving surgery from medication produced 14 significant univariate predictors, of which 4 were multivariately significant (left anterior descending artery disease, previous cerebral events, limitations in mobility range and circumflex artery disease). CONCLUSION: Variables emphasised in clinical guidelines are clearly involved in coronary artery disease treatment decisions. However, variables beyond these may also be important factors when therapy decisions are undertaken thus their roles require further investigation

Institutional capacity for health systems research in East and Central Africa schools of public health: enhancing capacity to design and implement teaching programs

BACKGROUND: The role of health systems research (HSR) in informing and guiding national programs and policies has been increasingly recognized. Yet, many universities in sub-Saharan African countries have relatively limited capacity to teach HSR. Seven schools of public health (SPHs) in East and Central Africa undertook an HSR institutional capacity assessment, which included a review of current HSR teaching programs. This study determines the extent to which SPHs are engaged in teaching HSR-relevant courses and assessing their capacities to effectively design and implement HSR curricula whose graduates are equipped to address HSR needs while helping to strengthen public health policy. METHODS: This study used a cross-sectional study design employing both quantitative and qualitative approaches. An organizational profile tool was administered to senior staff across the seven SPHs to assess existing teaching programs. A self-assessment tool included nine questions relevant to teaching capacity for HSR curricula. The analysis triangulates the data, with reflections on the responses from within and across the seven SPHs. Proportions and average of values from the Likert scale are compared to determine strengths and weaknesses, while themes relevant to the objectives are identified and clustered to elicit in-depth interpretation. RESULTS: None of the SPHs offer an HSR-specific degree program; however, all seven offer courses in the Master of Public Health (MPH) degree that are relevant to HSR. The general MPH curricula partially embrace principles of competency-based education. Different strengths in curricula design and staff interest in HSR at each SPH were exhibited but a number of common constraints were identified, including out-of-date curricula, face-to-face delivery approaches, inadequate staff competencies, and limited access to materials. Opportunities to align health system priorities to teaching programs include existing networks. CONCLUSIONS: Each SPH has key strengths that can be leveraged to design and implement HSR teaching curricula. We propose networking for standardizing HSR curricula competencies, institutionalizing sharing of teaching resources, creating an HSR eLearning platform to expand access, regularly reviewing HSR teaching content to infuse competency-based approaches, and strengthening staff capacity to deliver such curricula.DFI

Investigation of the direct effects of salmon calcitonin on human osteoarthritic chondrocytes

<p>Abstract</p> <p>Background</p> <p>Calcitonin has been demonstrated to have chondroprotective effects under pre-clinical settings. It is debated whether this effect is mediated through subchondral-bone, directly on cartilage or both in combination. We investigated possible direct effects of salmon calcitonin on proteoglycans and collagen-type-II synthesis in osteoarthritic (OA) cartilage.</p> <p>Methods</p> <p>Human OA cartilage explants were cultured with salmon calcitonin [100 pM-100 nM]. Direct effects of calcitonin on articular cartilage were evaluated by 1) measurement of proteoglycan synthesis by incorporation of radioactive labeled ³⁵SO₄[5 μCi] 2) quantification of collagen-type-II formation by pro-peptides of collagen type II (PIINP) ELISA, 3) QPCR expression of the calcitonin receptor in OA chondrocytes using four individual primer pairs, 4) activation of the cAMP signaling pathway by EIA and, 5) investigations of metabolic activity by AlamarBlue.</p> <p>Results</p> <p>QPCR analysis and subsequent sequencing confirmed expression of the calcitonin receptor in human chondrocytes. All doses of salmon calcitonin significantly elevated cAMP levels (P < 0.01 and P < 0.001). Calcitonin significantly and concentration-dependently [100 pM-100 nM] induced proteoglycan synthesis measured by radioactive ³⁵SO₄incorporation, with a 96% maximal induction at 10 nM (P < 0.001) corresponding to an 80% induction of 100 ng/ml IGF, (P < 0.05). In alignment with calcitonin treatments [100 pM-100 nM] resulted in 35% (P < 0.01) increased PIINP levels.</p> <p>Conclusion</p> <p>Calcitonin treatment increased proteoglycan and collagen synthesis in human OA cartilage. In addition to its well-established effect on subchondral bone, calcitonin may prove beneficial to the management of joint diseases through direct effects on chondrocytes.</p

Narrow band imaging for the detection of gastric intestinal metaplasia and dysplasia during surveillance endoscopy

Background: Surveillance of premalignant gastric lesions relies mainly on random biopsy sampling. Narrow band imaging (NBI) may enhance the accuracy of endoscopic surveillance of intestinal metaplasia (IM) and dysplasia. We aimed to compare the yield of NBI to white light endoscopy (WLE) in the surveillance of patients with IM and dysplasia. Methods: Patients with previously identified gastric IM or dysplasia underwent a surveillance endoscopy. Both WLE and NBI were performed in all patients during a single procedure. The sensitivity of WLE and NBI for the detection of premalignant lesions was calculated by correlating endoscopic findings to histological diagnosis. Results: Forty-three patients (28 males and 15 females, mean age 59 years) were included. IM was diagnosed in 27 patients; 20 were detected by NBI and WLE, four solely by NBI and three by random biopsies only. Dysplasia was detected in seven patients by WLE and NBI and in two patients by random biopsies only. Sixty-eight endoscopically detected lesions contained IM: 47 were detected by WLE and NBI, 21 by NBI only. Nine endoscopically detected lesions demonstrated dysplasia: eight were detected by WLE and NBI, one was detected by NBI only. The sensitivity, specificity, positive and negative predictive values for detection of premalignant lesions were 71, 58, 65 and 65% for NBI and 51, 67, 62 and 55% for WLE, respectively. Conclusions: NBI increases the diagnostic yield for detection of advanced premalignant gastric lesions compared to routine WLE

Urokinase Plasminogen Receptor and the Fibrinolytic Complex Play a Role in Nerve Repair after Nerve Crush in Mice, and in Human Neuropathies

Remodeling of extracellular matrix (ECM) is a critical step in peripheral nerve regeneration. In fact, in human neuropathies, endoneurial ECM enriched in fibrin and vitronectin associates with poor regeneration and worse clinical prognosis. Accordingly in animal models, modification of the fibrinolytic complex activity has profound effects on nerve regeneration: high fibrinolytic activity and low levels of fibrin correlate with better nerve regeneration. The urokinase plasminogen receptor (uPAR) is a major component of the fibrinolytic complex, and binding to urokinase plasminogen activator (uPA) promotes fibrinolysis and cell movement. uPAR is expressed in peripheral nerves, however, little is known on its potential function on nerve development and regeneration. Thus, we investigated uPAR null mice and observed that uPAR is dispensable for nerve development, whereas, loss of uPAR affects nerve regeneration. uPAR null mice showed reduced nerve repair after sciatic nerve crush. This was a consequence of reduced fibrinolytic activity and increased deposition of endoneurial fibrin and vitronectin. Exogenous fibrinolysis in uPAR null mice rescued nerve repair after sciatic nerve crush. Finally, we measured the fibrinolytic activity in sural nerve biopsies from patients with peripheral neuropathies. We showed that neuropathies with defective regeneration had reduced fibrinolytic activity. On the contrary, neuropathies with signs of active regeneration displayed higher fibrinolytic activity. Overall, our results suggest that enforced fibrinolysis may facilitate regeneration and outcome of peripheral neuropathies