Longevinex ® Improves Human Atrophic Aged-related Macular Degeneration (AMD) Photoreceptor / Retinal Pigment Epithelium Mediated Dark Adaptation*

Aim: Gradual photoreceptor/ RPE deterioration/ vision loss in AMD is common, irrespective of US NEI AREDS I/II supplement risk reduction, or intra-vitreal anti-VEGF pharmacology. We evaluated dark adaptation (DA), a broad measure of photoreceptor / RPE health, with / without epigenetic modulation using a resveratrol–based caloric-restriction mimic (Longevinex ®www.longevinex.com). Study Design: Case series, bi-ocular, clinical DA evaluation in deteriorating AMD, before and after supplementation, under medical center compassionate use guidelines. Place and Duration of Study: Captain James A Lovell Federal Health Care Center, Illinois, USA, Optometry/Ophthalmology Departments between 4/2015 and 8/2016. Methods: Baseline clinical DA threshold (log DB), time (min), and fixation (%) were taken for patients with established atrophic AMD (n=14 eyes; 6 M / 1 F; ages 64 - 89 years), using the AdaptDx ® (www.maculogix.com), with pupil dilation and best refraction. Following prescription of Longevinex® 1 capsule qd AM, DA was repeated, with each eye’s response considered independent. Results: All but 2 eyes improved in one or more DA parameters, with 3 cases showing improvement by retinal macula SD OCT. Expected vs. actual (worse vs. same/better), by eye, was significant by Chi Square, P < .01. Additional factors affecting DA: smoking, alcohol, elevated CRP and statins were retrospectively evaluated. Conclusion: These first cases of epigenetic-induced DA stability / improvement are consistent with previous beneficial effects of Longevinex® such as enhanced choriocapillaris circulation. DA is the earliest functional AMD sign and a prime candidate for “AMD prevention”. This work merits expansion to controlled studies

Correction to: A novel preference-informed complementary trial (PICT) design for clinical trial research influenced by strong patient preferences (Trials, (2021), 22, 1, (206), 10.1186/s13063-021-05164-1)

Following the publication of the original article [1], we were notified that the Acknowledgements section needs to accommodate additional collaborators. The original article has been corrected

Familial Recurrence of Cerebral Palsy with Multiple Risk Factors

The recurrence of cerebral palsy in the same family is uncommon. We, however, report on two families with two or more affected siblings. In both families, numerous potential risk factors were identified including environmental, obstetric, and possible maternal effects. We hypothesize that multiple risk factors may lead to the increased risk of recurrence of cerebral palsy in families. Intrinsic and maternal risk factors should be investigated in all cases of cerebral palsy to properly counsel families on the risk of recurrence. Recent studies of genetic polymorphisms associated with cerebral palsy are considered with reference to our observations in these two families

The very bright SCUBA galaxy count: looking for SCUBA galaxies with the Mexican Hat Wavelet

We present the results of a search for bright high-redshift galaxies in two large SCUBA scan-maps of Galactic regions. A Mexican Hat Wavelet technique was used to locate point sources in these maps, which suffer high foreground contamination as well as typical scan-map noise signatures. A catalogue of point source objects was selected and observed again in the submillimetre continuum, and in HCO+ (3->2) at zero redshift to rule out Galactic sources. No extragalactic sources were found. Simulations show that the survey was sensitive to sources with fluxes > 50 mJy, depending on the local background. These simulations result in upper limits on the 850-micron counts of SCUBA galaxies of 53 per square degree at 50 mJy and 2.9 per square degree at 100 mJy.Comment: Accepted by MNRA

Innovative approaches to investigator-initiated, multicentre paediatric clinical trials in Canada

Data from clinical trials are needed to guide the safe and effective use of medicines in children. Clinical trials are challenging to design and implement in all populations, and children present additional considerations. Several regions including the UK, USA and Europe have established clinical trial infrastructure to capitalise on expertise and promote clinical trials enrolling children. Our objective is to describe the partnerships and operational considerations for the development of paediatric clinical trials infrastructure in Canada. We describe the design and conduct of four emergency room paediatric trials, with four separate sponsors, across four provinces in parallel. Operations discussed include multisite contract development, centralised risk-based data monitoring, ethical review and patient engagement. We conclude with lessons learnt, additional challenges and potential solutions to facilitate drug development for children in Canada

Study protocol for two complementary trials of non-steroidal or opioid analgesia use for children aged 6 to 17 years with musculoskeletal injuries (the No OUCH study)

Introduction Musculoskeletal (MSK) injuries are a frequent cause for emergency department (ED) visits in children. MSK injuries are associated with moderate-to-severe pain in most children, yet recent research confirms that the management of children\u27s pain in the ED remains inadequate. Clinicians are seeking better oral analgesic options for MSK injury pain with demonstrated efficacy and an excellent safety profile. This study aims to determine the efficacy and safety of adding oral acetaminophen or oral hydromorphone to oral ibuprofen and interpret this information within the context of parent/caregiver preference. Methods and analysis Using a novel preference-informed complementary trial design, two simultaneous trials are being conducted. Parents/caregivers of children presenting to the ED with acute limb injury will be approached and they will decide which trial they wish to participate in: an opioid-inclusive trial or a non-opioid trial. Both trials will follow randomised, double-blind, placebo-controlled, superiority-trial methodology and will enrol a minimum of 536 children across six Canadian paediatric EDs. Children will be eligible if they are 6 to 17 years of age and if they present to the ED with an acute limb injury and a self-reported verbal Numerical Rating Scale pain score ≥5. The primary objective is to determine the effectiveness of oral ibuprofen+oral hydromorphone versus oral ibuprofen+oral acetaminophen versus oral ibuprofen alone. Recruitment was launched in April 2019. Ethics and dissemination This study has been approved by the Health Research Ethics Board (University of Alberta), and by appropriate ethics boards at all recruiting centres. Informed consent will be obtained from parents/guardians of all participants, in conjunction with assent from the participants themselves. Study data will be submitted for publication regardless of results. This study is funded through a Canadian Institutes of Health Research grant. Trial registration number NCT03767933, first registered on 07 December 2018

The Use of Long-Acting Injectable Antipsychotic Therapy for Schizophrenia

Introduction Antipsychotic medications form the cornerstone of schizophrenia treatment. However, only a minority of patients adhere to their initial antipsychotic regimen. It’s expected that Long-Acting Injectable (LAI) antipsychotics improves patient adherence to treatment, however previous research comparing the use of first generation LAI’s against oral antipsychotics reported results that were inconclusive. Objectives and Approach Explore the effectiveness of the use of LAI’s in the delivery of mental health services in Alberta. Using linked data from AHS Analytics: • Physician claims • National Ambulatory Care Reporting System (NACRS), • Discharge Abstract database (DAD) • Pharmacy Information Network (PIN) • Alberta Provincial Registry data • Define a cohort of patients on antipsychotic medications. • Explore and contrast outcomes related to the use of LAIs against other antipsychotic medication types. Specifically using linked data to define: • Treatment Adherence • Utilization of LAI vs. other medication • Demographic differences • Outcomes pre- and post-LAI treatment Results A patient cohort was established containing only cases from April 1, 2013 to March 31, 2015. Additional data was used to perform a two year washout and a one year follow-up. Case and medication definitions were determined by a team of psychiatric clinicians. Patient comorbidity information was extracted using previously validated methods. Overall, 6349 incident cases were identified. Preliminary analysis indicate: • Overall patient cohort is older than expected • Use of additional medication types is correlated with greater health services utilization after diagnosis • Patients on only oral medications appear to have lower treatment adherence • Males seem to have higher treatment adherence than females • No significant differences were found between patients with rural vs. urban postal codes Conclusion/Implications We faced significant challenges when defining cases, medication use and outcomes. However, the linkage of a large number of data sources gives us powerful and multi-faceted insight into the use of antipsychotic medication use in Alberta. Future work will include work on definition validations and deeper analysis of outcomes

The remnants of galaxy formation from a panoramic survey of the region around M31

In hierarchical cosmological models, galaxies grow in mass through the continual accretion of smaller ones. The tidal disruption of these systems is expected to result in loosely bound stars surrounding the galaxy, at distances that reach $10 - 100$ times the radius of the central disk. The number, luminosity and morphology of the relics of this process provide significant clues to galaxy formation history, but obtaining a comprehensive survey of these components is difficult because of their intrinsic faintness and vast extent. Here we report a panoramic survey of the Andromeda galaxy (M31). We detect stars and coherent structures that are almost certainly remnants of dwarf galaxies destroyed by the tidal field of M31. An improved census of their surviving counterparts implies that three-quarters of M31's satellites brighter than $M_V < -6$ await discovery. The brightest companion, Triangulum (M33), is surrounded by a stellar structure that provides persuasive evidence for a recent encounter with M31. This panorama of galaxy structure directly confirms the basic tenets of the hierarchical galaxy formation model and reveals the shared history of M31 and M33 in the unceasing build-up of galaxies.Comment: Published in Nature. Supplementary movie available at https://www.astrosci.ca/users/alan/PANDAS/Latest%20news%3A%20movie%20of%20orbit.htm

A novel preference-informed complementary trial (PICT) design for clinical trial research influenced by strong patient preferences

Background: Patients and their families often have preferences for medical care that relate to wider considerations beyond the clinical effectiveness of the proposed interventions. Traditionally, these preferences have not been adequately considered in research. Research questions where patients and families have strong preferences may not be appropriate for traditional randomized controlled trials (RCTs) due to threats to internal and external validity, as there may be high levels of drop-out and non-adherence or recruitment of a sample that is not representative of the treatment population. Several preference-informed designs have been developed to address problems with traditional RCTs, but these designs have their own limitations and may not be suitable for many research questions where strong preferences and opinions are present. Methods: In this paper, we propose a novel and innovative preference-informed complementary trial (PICT) design which addresses key weaknesses with both traditional RCTs and available preference-informed designs. In the PICT design, complementary trials would be operated within a single study, and patients and/or families would be given the opportunity to choose between a trial with all treatment options available and a trial with treatment options that exclude the option which is subject to strong preferences. This approach would allow those with strong preferences to take part in research and would improve external validity through recruiting more representative populations and internal validity. Here we discuss the strengths and limitations of the PICT design and considerations for analysis and present a motivating example for the design based on the use of opioids for pain management for children with musculoskeletal injuries. Conclusions: PICTs provide a novel and innovative design for clinical trials with more than two arms, which can address problems with existing preference-informed trial designs and enhance the ability of researchers to reflect shared decision-making in research as well as improving the validity of trials of topics with strong preferences

Loss-of-function mutations in the X-linked biglycan gene cause a severe syndromic form of thoracic aortic aneurysms and dissections.

Thoracic aortic aneurysm and dissection (TAAD) is typically inherited in an autosomal dominant manner, but rare X-linked families have been described. So far, the only known X-linked gene is FLNA, which is associated with the periventricular nodular heterotopia type of Ehlers-Danlos syndrome. However, mutations in this gene explain only a small number of X-linked TAAD families. We performed targeted resequencing of 368 candidate genes in a cohort of 11 molecularly unexplained Marfan probands. Subsequently, Sanger sequencing of BGN in 360 male and 155 female molecularly unexplained TAAD probands was performed. We found five individuals with loss-of-function mutations in BGN encoding the small leucine-rich proteoglycan biglycan. The clinical phenotype is characterized by early-onset aortic aneurysm and dissection. Other recurrent findings include hypertelorism, pectus deformity, joint hypermobility, contractures, and mild skeletal dysplasia. Fluorescent staining revealed an increase in TGF-β signaling, evidenced by an increase in nuclear pSMAD2 in the aortic wall. Our results are in line with those of prior reports demonstrating that Bgn-deficient male BALB/cA mice die from aortic rupture. In conclusion, BGN gene defects in humans cause an X-linked syndromic form of severe TAAD that is associated with preservation of elastic fibers and increased TGF-β signaling.Genet Med 19 4, 386-395