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JNPL3 transgenic mice expressing a mutant tau protein, which develop neurofibrillary tangles and progressive motor disturbance, were crossed with Tg2576 transgenic mice expressing mutant β-amyloid precursor protein (APP), thus modulating the APP-Aβ (β-amyloid peptide) environment. The resulting double mutant (tau/APP) progeny and the Tg2576 parental strain developed Aβ deposits at the same age; however, relative to JNPL3 mice, the double mutants exhibited neurofibrillary tangle pathology that was substantially enhanced in the limbic system and olfactory cortex. These results indicate that either APP or Aβ influences the formation of neurofibrillary tangles. The interaction between Aβ and tau pathologies in these mice supports the hypothesis that a similar interaction occurs in Alzheimer's disease.

Study design Retrospective cohort study. Objectives Same-day discharge is widely used in many surgical specialities. If carefully planned, it can improve patient outcomes whilst using resources efficiently. We aimed to investigate the safety of same-day discharge following a posterior lumbar decompression and/or discectomy (PLDD). Methods This was a retrospective analysis of administrative data. We extracted data from the Hospital Episodes Statistics database for the 5 years from 1st April 2014 to 31st March 2019. Patients undergoing an elective one or two level PLDD aged 19-54 years during the index stay were included. The primary exposure variable was same-day discharge or post-surgery overnight stay and the primary outcome was emergency hospital readmission within 90 days post-discharge. Results Data were available for 45,814 PLDD performed across 103 hospital trusts of which 7914 (17.3%) were performed as same-day discharge. Same-day discharge rates varied from 87.7% to 0% across the 90 hospital trusts that operated on more than 50 patients during the study period. Fourteen (15.6%) trusts had same-day discharge rates above 30% and 57 (63.3%) trusts had same-day discharge rates below 10%. The odds of emergency hospital readmission within 90 days were lower for same-day discharge patients (odds ratio .72 (95% confidence interval .61 to .85). There was no difference in outcomes for patients seen at trusts with a same-day discharge rate of ≥30% compared to trusts with a same-day discharge rate of ≤10%. Conclusions Same-day discharge low-complexity elective PLDD is safe in adult patients below the age of 55 years. There is potential for many providers to substantially increase their rates of same-day discharge.

Study Design Retrospective analysis of an administrative dataset. Objective This study aims to investigate changing practice over a six-year period in the use of repeated lumbar facet joint injections/medial branch blocks in England. Methods Patient data were extracted from the Hospital Episodes Statistics database for the period 1st April 2015 to 31st March 2021 for the index lumbar injection and for repeat lumbar injections performed within one year of the first. The exposure of interest was two injections within 180 days or three within one year. Patients aged <17 years and where the body site was listed as cervical, thoracic or sacral were excluded. Results Data were available for 134,249 patients of which, 8,922 (6.6%) had either two injections within 180 days or three injections within one year. First injections fell from 42,511 in 2015/16 to 13,368 in 2019/20 as did the number of repeat injections: 4,018 to 424 for the same period. If all years had the same carbon footprint as 2019/20, 2.8 kilotons of CO2e would have been saved over the five years, enough to power 2,575 average UK homes for 1 year. The financial cost of injections decreased from £27.6 million in 2015/16 to £7.9 million in 2019/20. Conclusions The number of patients having repeated lumbar injections has decreased over time but has not been eliminated. More work is needed to educate patients and clinicians regarding alternative and more effective treatments.

Study Design: Systematic review. Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, ultimately resulting in paralysis and death. The condition is considered to be caused by a complex interaction between environmental and genetic factors. Although vast genetic research has deciphered many of the molecular factors in ALS pathogenesis, the environmental factors have remained largely unknown. Recent evidence suggests that participation in certain types of sporting activities are associated with increased risk for ALS. Objective: To test the hypothesis that competitive sports at the highest level that involve repetitive concussive head and cervical spinal trauma result in an increased risk of ALS compared with the general population or nonsport controls. Methods: Electronic databases from inception to November 22, 2017 and reference lists of key articles were searched to identify studies meeting inclusion criteria. Results: Sixteen studies met the inclusion criteria. Sports assessed (professional or nonprofessional) included soccer (n = 5), American football (n = 2), basketball (n = 1), cycling (n = 1), marathon or triathlon (n = 1), skating (n = 1), and general sports not specified (n = 11). Soccer and American football were considered sports involving repetitive concussive head and cervical spinal trauma. Professional sports prone to repetitive concussive head and cervical spinal trauma were associated with substantially greater effects (pooled rate ratio [RR] 8.52, 95% CI 5.18-14.0) compared with (a) nonprofessional sports prone to repetitive concussive head and cervical spinal trauma (pooled RR 0.60, 95% CI 0.12-3.06); (b) professional sports not prone to repetitive head and neck trauma (pooled RR 1.35, 95% CI 0.67-2.71); or (c) nonprofessional sports not prone to repetitive concussive head and cervical spinal trauma (pooled RR 1.17, 95% CI 0.79-1.71). Conclusions: Our review suggests that increased susceptibility to ALS is significantly and independently associated with 2 factors: professional sports and sports prone to repetitive concussive head and cervical spinal trauma. Their combination resulted in an additive effect, further increasing this association to ALS.

Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration 1 (CBD). Mutations in the gene ( Mtapt ) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration 2 . Expression of human tau containing the most common 3 , 4 , 5 FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.

The clinical disorders associated with frontotemporal lobar degeneration (FTLD) are increasingly recognized as an important cause of early-onset dementia. Patients usually present with progressive changes in personality, behavior, or language, progressing to general cognitive impairment and ultimately death. In the past decade, improved clinical and histopathologic characterization uncovered extensive heterogeneity, and multiple clinical and pathologic FTLD subtypes were defined. Simultaneously, the discovery of four causal FTLD genes emphasized the genetic complexity associated with FTLD. More recently, the field of FTLD has gained increased attention as a result of two major findings. First, mutations in the progranulin gene (PGRN) were recognized as a major cause of FTLD with ubiquitin-positive and tau-negative inclusions (FTLD-U), and subsequently the TAR DNA-binding protein-43 (TDP-43) was identified as a key protein within the ubiquitinated inclusions in FTLD-U and amyotrophic lateral sclerosis (ALS). In this report, we outline the progress made in the study of the genetic etiologies and neuropathologic substrates in FTLD.

Argyrophilic grain disease (AGD) was first reported as an adult-onset dementia, but recent studies have emphasized personality change, emotional imbalance, and memory problems as clinical features of AGD. AGD is characterized by spindle- or comma-shaped argyrophilic grains in the neuropil of entorhinal cortex, hippocampus, and amygdala. Immunohistochemistry with monoclonal antibodies specific to tau isoforms with four (4R) or three (3R) repeats in the microtubule-binding domain showed immunostaining of grains with 4R, but not 3R, tau antibodies, suggesting that AGD was a 4R tauopathy. The tau isoform composition of AGD was confirmed with densitometric analysis of Western blots of sarkosyl-insoluble tau from the medial temporal lobe of AGD brains with a range of concurrent neurofibrillary pathology and compared with Alzheimer controls. The 4R/3R ratio was 1 or less for Alzheimer disease; the 4R/3R ratio was more than 1 for AGD, decreasing with increasing neurofibrillary pathology and demonstrating that insoluble tau in AGD was enriched in 4R tau. The frequency of the extended tau haplotype was not different in AGD compared to other sporadic 4R tauopathies, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Furthermore, AGD occurred in PSP and CBD more frequently than in dementia controls, including Alzheimer disease. These results suggest that AGD, PSP and CBD are 4R tauopathies that share common pathologic, biochemical, and genetic characteristics.

MUTATIONS in the genes encoding amyloid-β precursor protein ( APP ) 1 presenilin 1 ( PS1 ) 2 and presenilin 2 ( PS2 ) 3,4 are known to cause early-onset, autosomal dominant Alzheimer's disease. Studies of plasma and fibroblasts from subjects with these mutations have established that they all alter amyloid β-protein (βAPP) processing, which normally leads to the secretion of amyloid-β protein (relative molecular mass 4,000; M r 4K; ∼90% Aβ1–40, ∼10% Aβ1–42(43)), so that the extracellular concentration of Aβ42(43) is increased 5 . This increase in Aβ42(43) is believed to be the critical change that initiates Alzheimer's disease pathogenesis because Aβ42(43) is deposited early and selectively in the senile plaques that are observed in the brains of patients with all forms of the disease. To establish that the presenilin mutations increase the amount of Aβ42(43) in the brain and to test whether presenilin mutations act as true (gain of function) dominants, we have now constructed mice expressing wild-type and mutant presenilin genes. Analysis of these mice showed that overexpression of mutant, but not wild-type, PS1 selectively increases brain Aβ42(43). These results indicate that the presenilin mutations probably cause Alzheimer's disease through a gain of deleterious function that increases the amount of Aβ42(43) in the brain.

Regulatory-quality outcomes and statistical validity depend on participants staying until endpoint assessments are completed.1 When large proportions of patients drop out, the study loses power to detect treatment effects, wasting the efforts of those who did participate and often forcing costly extensions or protocol amendments. The reasons are diverse- disease burden, adverse events, lack of perceived benefit, logistical and personal hardships can all play a role.2 Surveys of trial participants consistently find that burdens and inconveniences are top drivers of dropout.2 For instance, travel to the study site is often cited as the No. 1 burden contributing to discontinuation, especially when participants must travel long distances or take time offwork repeatedly.2 Complex visit schedules, long waits at clinics, language barriers, and cumbersome trial procedures can all erode a participant's motivation to continue. Trials increasingly span global populations, and even within one country there may be substantial language diversity.1 Providing study materials, app interfaces, and support in each participant's preferred language is not just a regulatory box-check -it's fundamental to retention. [...]a retention-focused trial design embraces flexibility: offering remote visit options, local labs or healthcare provider visits, and in-home services when feasible.4 The COVID-19 pandemic accelerated the acceptance of decentralized trial elements, and now we see their lasting benefit for retention.â For example, if a participant can do a telemedicine visit for a routine check-in or have a home health nurse come to draw blood, they are less likely to withdraw due to travel burden or schedule conflicts. †Integrated reminders and participant support Forgetfulness and feeling \"out of the loop\" are common contributors to non-compliance and drop-out .3 Participant-centric trials, therefore, proactively support participants with integrated reminder systems and open lines of communication.