New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Health-related quality of life in 794 patients with a peripheral facial palsy using the FaCE Scale: a retrospective cohort study.

Item does not contain fulltextOBJECTIVES: To describe the health-related quality of life of patients visiting a tertiary referral centre for facial palsy, and to analyse factors associated with health-related quality of life, using the FaCE Scale instrument. DESIGN: Retrospective cohort study. SETTING: The Facial Nerve Center at the Massachusetts Eye and Ear Infirmary, a tertiary referral centre. PARTICIPANTS: Patients with a peripheral facial palsy visiting the centre for an initial consultation between August 2007 and June 2012. MAIN OUTCOME MEASURES: The total FaCE score and the FaCE social function subdomain. Multiple regression models were developed to identify factors associated with the total FaCE score and FaCE social function score. RESULTS: A total of 794 patients with a mean age of 47.0 +/- 16.0 years were analysed in this study, of which 59.9% were female. The mean House-Brackmann, Sunnybrook, total FaCE and FaCE social function scores were 3.6 +/- 1.5, 48.2 +/- 21.2, 47.3 +/- 19.3 and 55.5 +/- 19.2, respectively. Increasing age (r = -0.229, P < 0.001) was associated with a lower total FaCE score. Female gender (r = -4.422, P = 0.033) and increased duration of palsy (r = -0.018, P = 0.041) were associated with lower FaCE social function scores. CONCLUSIONS: While counselling patients on what to expect during the recovery process after facial paralysis is an important part of any clinical visit, FaCE score correlations suggest that female patients with chronic facial palsy and increased age constitute a patient category that may require additional time and attention to prevent or mitigate psychosocial dysfunction.1 december 201

Electrical stimulation of eye blink in individuals with acute facial palsy : progress toward a bionic blink

Background: Elicitation of eye closure and other movements via electrical stimulation may provide effective treatment for facial paralysis. The authors performed a human feasibility study to determine whether transcutaneous neural stimulation can elicit a blink in individuals with acute facial palsy and to obtain feedback from participants regarding the tolerability of surface electrical stimulation for daily blink restoration. Methods: Forty individuals with acute unilateral facial paralysis, HB grades 4 through 6, were prospectively studied between 6 and 60 days of onset. Unilateral stimulation of zygomatic facial nerve branches to elicit eye blink was achieved with brief bipolar, charge-balanced pulse trains, delivered transcutaneously by adhesive electrode placement; results were recorded on a high-speed video camera. The relationship between stimulation parameters and cutaneous sensation was analyzed using the Wong-Baker Faces Pain Rating Scale. Results: Complete eye closure was achieved in 55 percent of participants using stimulation parameters reported as tolerable. In those individuals, initial eye twitch was observed at an average current of 4.6 mA (\ub11.7; average pulse width of 0.7 ms, 100 to 150 Hz), with complete closure requiring a mean of 7.2 mA (\ub12.6). Conclusions: Transcutaneous facial nerve stimulation may artificially elicit eye blink in a majority of patients with acute facial paralysis. Although individuals varied widely in their reported degrees of discomfort from blink-eliciting stimulation, most of them indicated that such stimulation would be tolerable if it could restore eye closure. These patients would therefore benefit from a biomimetic device to facilitate eye closure until the recovery process is complete

Supply Chain Management in practice : A Case study of McDonald’s Sweden

Although much discussed in theory, supply chain management (SCM) is often problematic to carry out in practice. One exception is McDonald’s Sweden, which since its establishment has worked with suppliers and restaurants (franchisees) in a way that reminds of what SCM literature recommends. The purpose of this report is to describe and analyse the supply chain of McDonald’s Sweden from suppliers to franchisees. Based on interviews with McDonald’s Sweden, suppliers and franchisees, McDonald’s supply chain is described and analysed according to SCM literature. Cooper and Ellram’s (1993) framework of SCM characteristics is used complemented with several other writers. The study describes a supply chain where its members to a large extent collaborate as described in SCM literature. The report identifies and describes how significant SCM characteristics, such as information sharing, joint planning, and the sharing of risks and rewards are managed in the case. Finally, the report identifies market saturation and the search for economies of scale outside the primary supply chain as a challenge for future SCM practices. The case constitutes an interesting showcase where the ways in which the studied features are managed can inspire others businesses in succeeding in SCM.Trots att supply chain management (SCM) är väl diskuterat i teorin så är det ofta problematiskt att genomföra i praktiken. Ett undantag är McDonalds Sverige, som sedan starten arbetat med leverantörer och restauranger (franchisetagare) på ett sätt som påminner om vad litteratur inom SCM rekommenderar. Syftet med denna rapport är att beskriva och analysera McDonalds Sveriges supply chain från leverantörer till franchisetagare. Baserat på intervjuer med McDonalds Sverige, leverantörer och franchisetagare är McDonalds försörjningskedja beskriven och analyserad utifrån SCM-litteratur. Cooper och Ellrams (1993) teorier inom SCM och dess olika egenskaper används kompletterat med flera andra författare. Studien beskriver en försörjningskedja där medlemmarna i stor utsträckning samarbetar enligt SCM-litteraturen. I rapporten identifieras och beskrivs hur viktiga egenskaper inom SCM, såsom utbyte av information, gemensam planering och riskdelning hanteras. Slutligen identifierar rapporten marknadsmättnad och sökandet efter stordriftsfördelar utanför den primära försörjningskedjan som en utmaning för framtida SCM-praxis. Studien hur SCM fungerar i praktiken och kan inspirera andra företag i att lyckas inom området

Rat whisker movement after facial nerve lesion: Evidence for autonomic contraction of skeletal muscle.

Item does not contain fulltextVibrissal whisking is often employed to track facial nerve regeneration in rats; however, we have observed similar degrees of whisking recovery after facial nerve transection with or without repair. We hypothesized that the source of non-facial nerve-mediated whisker movement after chronic denervation was from autonomic, cholinergic axons traveling within the infraorbital branch of the trigeminal nerve (ION). Rats underwent unilateral facial nerve transection with repair (N=7) or resection without repair (N=11). Post-operative whisking amplitude was measured weekly across 10weeks, and during intraoperative stimulation of the ION and facial nerves at 18weeks. Whisking was also measured after subsequent ION transection (N=6) or pharmacologic blocking of the autonomic ganglia using hexamethonium (N=3), and after snout cooling intended to elicit a vasodilation reflex (N=3). Whisking recovered more quickly and with greater amplitude in rats that underwent facial nerve repair compared to resection (P<0.05), but individual rats overlapped in whisking amplitude across both groups. In the resected rats, non-facial-nerve-mediated whisking was elicited by electrical stimulation of the ION, temporarily diminished following hexamethonium injection, abolished by transection of the ION, and rapidly and significantly (P<0.05) increased by snout cooling. Moreover, fibrillation-related whisker movements decreased in all rats during the initial recovery period (indicative of reinnervation), but re-appeared in the resected rats after undergoing ION transection (indicative of motor denervation). Cholinergic, parasympathetic axons traveling within the ION innervate whisker pad vasculature, and immunohistochemistry for vasoactive intestinal peptide revealed these axons branching extensively over whisker pad muscles and contacting neuromuscular junctions after facial nerve resection. This study provides the first behavioral and anatomical evidence of spontaneous autonomic innervation of skeletal muscle after motor nerve lesion, which not only has implications for interpreting facial nerve reinnervation results, but also calls into question whether autonomic-mediated innervation of striated muscle occurs naturally in other forms of neuropathy

New insights into the genetic etiology of Alzheimer’s disease and related dementias

Characterization of the genetic landscape of Alzheimer’s disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/‘proxy’ AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele. © 2022, The Author(s)