Disruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells.

Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1α) signaling as the use of an IRE1α inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1α signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis.

Optimizing Screening for Intrastriatal Interventions in Huntington's Disease Using Predictive Models.

BACKGROUND: Intrastriatal delivery of potential therapeutics in Huntington's disease (HD) requires sufficient caudate and putamen volumes. Currently, volumetric magnetic resonance imaging is rarely done in clinical practice, and these data are not available in large research cohorts such as Enroll-HD. OBJECTIVE: The objective of this study was to investigate whether predictive models can accurately classify HD patients who exceed caudate and putamen volume thresholds required for intrastriatal therapeutic interventions. METHODS: We obtained and merged data for 1374 individuals across three HD cohorts: IMAGE-HD, PREDICT-HD, and TRACK-HD/TRACK-ON. We imputed missing data for clinical variables with >72% non-missing values and used the model-building algorithm BORUTA to identify the 10 most important variables. A random forest algorithm was applied to build a predictive model for putamen volume >2500 mm3 and caudate volume >2000 mm3 bilaterally. Using the same 10 predictors, we constructed a logistic regression model with predictors significant at P < 0.05. RESULTS: The random forest model with 1000 trees and minimal terminal node size of 5 resulted in 83% area under the curve (AUC). The logistic regression model retaining age, CAG repeat size, and symbol digit modalities test-correct had 85.1% AUC. A probability cutoff of 0.8 resulted in 5.4% false positive and 66.7% false negative rates. CONCLUSIONS: Using easily obtainable clinical data and machine learning-identified initial predictor variables, random forest, and logistic regression models can successfully identify people with sufficient striatal volumes for inclusion cutoffs. Adopting these models in prescreening could accelerate clinical trial enrollment in HD and other neurodegenerative disorders when volume cutoffs are necessary enrollment criteria. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Cholinergic Nucleus 4 Degeneration and Cognitive Impairment in Isolated Rapid Eye Movement Sleep Behavior Disorder.

BACKGROUND: Cholinergic nucleus 4 (Ch4) degeneration is associated with cognitive impairment in Parkinson's disease and dementia with Lewy bodies, but it is unknown if Ch4 degeneration is also present in isolated rapid eye movement sleep behavior disorder (iRBD). OBJECTIVE: The aim was to determine if there is evidence of Ch4 degeneration in patients with iRBD and if it is associated with cognitive impairment. METHODS: We analyzed the clinical and neuropsychological data of 35 iRBD patients and 35 age- and sex-matched healthy controls. Regional gray matter density (GMD) was calculated for Ch4 using probabilistic maps applied to brain magnetic resonance imaging (MRI). RESULTS: Ch4 GMD was significantly lower in the iRBD group compared to controls (0.417 vs. 0.441, P = 0.02). Ch4 GMD was also found to be a significant predictor of letter number sequencing (ß-coefficient = 58.31, P = 0.026, 95% confidence interval [7.47, 109.15]), a measure of working memory. CONCLUSIONS: iRBD is associated with Ch4 degeneration, and Ch4 degeneration in iRBD is associated with impairment in working memory. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

One Minute of EEG Data Provides Sufficient and Reliable Data for Identifying Lewy Body Dementia.

OBJECTIVE: To determine the minimum duration of electroencephalography (EEG) data necessary to differentiate EEG features of Lewy body dementia (LBD), that is, dementia with Lewy bodies and Parkinson disease dementia, from non-LBD patients, that is, Alzheimer disease and Parkinson disease. METHODS: We performed quantitative EEG analysis for 16 LBD and 14 non-LBD patients. After artifact removal, a fast Fourier transform was performed on 90, 60, and thirty 2-second epochs to derive dominant frequency; dominant frequency variability; and dominant frequency prevalence. RESULTS: In LBD patients, there were no significant differences in EEG features derived from 90, 60, and thirty 2-second epochs (all P >0.05). There were no significant differences in EEG features derived from 3 different groups of thirty 2-second epochs (all P >0.05). When analyzing EEG features derived from ninety 2-second epochs, we found that LBD had significantly reduced dominant frequency, reduced dominant frequency variability, and reduced dominant frequency prevalence alpha compared with the non-LBD group (all P <0.05). These same differences were observed between the LBD and non-LBD groups when analyzing thirty 2-second epochs. CONCLUSIONS: There were no differences in EEG features derived from 1 minute versus 3 minutes of EEG data, and both durations of EEG data equally differentiated LBD from non-LBD.

Challenges in heart failure care in four European countries: a comparative study.

BACKGROUND: In Europe, more than 15 million people live with heart failure (HF). It imposes an enormous social, organizational and economic burden. As a reaction to impending impact on healthcare provision, different country-specific structures for HF-care have been established. The aim of this report is to provide an overview and compare the HF-care approaches of Germany, Ireland, the Netherlands and the UK, and to open the possibility of learning from each other's experience. METHODS: A mixed methods approach was implemented that included a literature analysis, interviews and questionnaires with HF-patients and caregivers, and expert interviews with representatives from healthcare, health service research and medical informatics. RESULTS: The models of HF-care in all countries analyzed are based on the European Society of Cardiology guidelines for diagnosis and treatment of HF. Even though the HF-models differed in design and implementation in practice, key challenges were similar: (i) unequal distribution of care between urban and rural areas, (ii) long waiting times, (iii) unequal access to and provision of healthcare services, (iv) information and communication gaps and (v) inadequate implementation and financing of digital applications. CONCLUSION: Although promising approaches exist to structure and improve HF-care, across the four countries, implementation was reluctant to embrace novel methods. A lack of financial resources and insufficient digitalization making it difficult to adopt new concepts. Integration of HF-nurses seems to be an effective way of improving current models of HF-care. Digital solutions offer further opportunities to overcome communication and coordination gaps and to strengthen self-management skills.

Prodromal Dementia With Lewy Bodies: Evolution of Symptoms and Predictors of Dementia Onset.

BACKGROUND: Research criteria for prodromal dementia with Lewy bodies (DLB) were published in 2020, but little is known regarding prodromal DLB in clinical settings. METHODS: We identified non-demented participants without neurodegenerative disease from the National Alzheimer's Coordinating Center Uniform Data Set who converted to DLB at a subsequent visit. Prevalence of neuropsychiatric and motor symptoms were examined up to 5 years prior to DLB diagnosis. RESULTS: The sample included 116 participants clinically diagnosed with DLB and 348 age and sex-matched (1:3) Healthy Controls. Motor slowing was present in approximately 70% of participants 3 years prior to DLB diagnosis. In the prodromal phase, 50% of DLB participants demonstrated gait disorder, 70% had rigidity, 20% endorsed visual hallucinations, and over 50% of participants endorsed REM sleep behavior disorder. Apathy, depression, and anxiety were common prodromal neuropsychiatric symptoms. The presence of 1+ core clinical features of DLB in combination with apathy, depression, or anxiety resulted in the greatest AUC (0.815; 95% CI: 0.767, 0.865) for distinguishing HC from prodromal DLB 1 year prior to diagnosis. The presence of 2+ core clinical features was also accurate in differentiating between groups (AUC = 0.806; 95% CI: 0.756, 0.855). CONCLUSION: A wide range of motor, neuropsychiatric and other core clinical symptoms are common in prodromal DLB. A combination of core clinical features, neuropsychiatric symptoms and cognitive impairment can accurately differentiate DLB from normal aging prior to dementia onset.

Clinical effectiveness of patellar resurfacing, no resurfacing and selective resurfacing in primary total knee replacement: systematic review and meta-analysis of interventional and observational evidence.

BACKGROUND: Patellar resurfacing is optional during total knee replacement (TKR). Some surgeons always resurface the patella, some never resurface, and others selectively resurface. Which resurfacing strategy provides optimal outcomes is unclear. We assessed the effectiveness of patellar resurfacing, no resurfacing, and selective resurfacing in primary TKR. METHODS: A systematic review and meta-analysis was performed. MEDLINE, Embase, Web of Science, The Cochrane Library, and bibliographies were searched to November 2021 for randomised-control trials (RCTs) comparing outcomes for two or more resurfacing strategies (resurfacing, no resurfacing, or selective resurfacing) in primary TKR. Observational studies were included if limited or no RCTs existed for resurfacing comparisons. Outcomes assessed were patient reported outcome measures (PROMs), complications, and further surgery. Study-specific relative risks [RR] were aggregated using random-effects models. Quality of the evidence was assessed using GRADE. RESULTS: We identified 33 RCTs involving 5,540 TKRs (2,727 = resurfacing, 2,772 = no resurfacing, 41 = selective resurfacing). One trial reported on selective resurfacing. Patellar resurfacing reduced anterior knee pain compared with no resurfacing (RR = 0.65 (95% CI = 0.44-0.96)); there were no significant differences in PROMs. Resurfacing reduced the risk of revision surgery (RR = 0.63, CI = 0.42-0.94) and other complications (RR = 0.54, CI = 0.39-0.74) compared with no resurfacing. Quality of evidence ranged from high to very low. Limited observational evidence (5 studies, TKRs = 215,419) suggested selective resurfacing increased the revision risk (RR = 1.14, CI = 1.05-1.22) compared with resurfacing. Compared with no resurfacing, selective resurfacing had a higher risk of pain (RR = 1.25, CI = 1.04-1.50) and lower risk of revision (RR = 0.92, CI = 0.85-0.99). CONCLUSIONS: Level 1 evidence supports TKR with patellar resurfacing over no resurfacing. Resurfacing has a reduced risk of anterior knee pain, revision surgery, and complications, despite PROMs being comparable. High-quality RCTs involving selective resurfacing, the most common strategy in the UK and other countries, are needed given the limited observational data suggests selective resurfacing may not be effective over other strategies.

Functional and Clinical Outcomes of Combined Simultaneous Bilateral Anterior Distal Femoral Plate Hemiepiphysiodesis and Hamstrings Release in Management of Knee Flexion Contractures in Children With Neuromuscular Disorders.

BACKGROUND: We examined the clinical and functional outcomes of the simultaneous anterior distal femoral 8-plate hemiepiphysiodesis (ADF8PH) and hamstring release, for fixed knee flexion deformity in children with neuromuscular disease. To our knowledge, no published evidence is available that reports the outcomes of this combined techniques. METHODS: Electronic medical records were retrospectively reviewed for 19 consecutive children who underwent bilateral ADF8PH and concomitant hamstrings release in our institution from 2012 to 2019. Relevant demographics, Gross Motor Functional Classification Score and preoperative and postoperative knee flexion contractures and popliteal angles were documented. RESULTS: The average age at the time of operation was 12±2.1 years. There were 15 males and 4 females. Diagnoses included cerebral palsy (n=16), Cornelia de Lange syndrome (n=1), hereditary spastic paraplegia type 56 (n=1) and fructose-1,6 bisphosphonate aldose B deficiency (n=1). Mean length of follow-up was 3.8 years (range: 1.5 to 7 y). Mean fixed knee flexion deformity improved from 28.9 to 13.4 degrees (P<0.001) at an average correction rate of 0.94 degrees per month. Mean popliteal angle improved from 81.8 to 44.4 degrees (P<0.001) in the early postoperative phase and to 51.8 degrees (P<0.001) in latest clinic review. Mean time to correction was 18.9 months. The agreed treatment goals of maintaining or promoting the use of standing frame and spinal/postural symmetry was attained in 18 patients (94.7%). Postoperative knee pain was reported in 2 cases (10.5%). We report 2 complications; 1 case of neurapraxia and 1 case of sepsis because of respiratory infection. CONCLUSION: Simultaneous bilateral ADF8PH with hamstrings release is a promising effective technique for correction of knee flexion contractures in skeletally immature individuals with neuromuscular disabilities. Our findings demonstrate improvement in clinical outcomes and maintaining functional outcomes, indicating the validity of this approach as a satisfactory, less invasive alternative in the management of this deformity. LEVEL OF EVIDENCE: Level IV-therapeutic study.

Randomized, Controlled Trial of Exercise on Objective and Subjective Sleep in Parkinson's Disease.

BACKGROUND: Sleep dysfunction is common and disabling in persons with Parkinson's Disease (PD). Exercise improves motor symptoms and subjective sleep quality in PD, but there are no published studies evaluating the impact of exercise on objective sleep outcomes. The goal of this study was to to determine if high-intensity exercise rehabilitation combining resistance training and body-weight interval training, compared with a sleep hygiene control improved objective sleep outcomes in PD. METHODS: Persons with PD (Hoehn & Yahr stages 2-3; aged ≥45 years, not in a regular exercise program) were randomized to exercise (supervised 3 times a week for 16 weeks; n = 27) or a sleep hygiene, no-exercise control (in-person discussion and monthly phone calls; n = 28). Participants underwent polysomnography at baseline and post-intervention. Change in sleep efficiency was the primary outcome, measured from baseline to post-intervention. Intervention effects were evaluated with general linear models with measurement of group × time interaction. As secondary outcomes, we evaluated changes in other aspects of sleep architecture and compared the effects of acute and chronic training on objective sleep outcomes. RESULTS: The exercise group showed significant improvement in sleep efficiency compared with the sleep hygiene group (group × time interaction: F = 16.0, P < 0.001, d = 1.08). Other parameters of sleep architecture also improved in exercise compared with sleep hygiene, including total sleep time, wake after sleep onset, and slow-wave sleep. Chronic but not acute exercise improved sleep efficiency compared with baseline. CONCLUSIONS: High-intensity exercise rehabilitation improves objective sleep outcomes in PD. Exercise is an effective nonpharmacological intervention to improve this disabling nonmotor symptom in PD. © 2020 International Parkinson and Movement Disorder Society.

Red blood cells stabilize flow in brain microvascular networks.

Capillaries are the prime location for oxygen and nutrient exchange in all tissues. Despite their fundamental role, our knowledge of perfusion and flow regulation in cortical capillary beds is still limited. Here, we use in vivo measurements and blood flow simulations in anatomically accurate microvascular network to investigate the impact of red blood cells (RBCs) on microvascular flow. Based on these in vivo and in silico experiments, we show that the impact of RBCs leads to a bias toward equating the values of the outflow velocities at divergent capillary bifurcations, for which we coin the term "well-balanced bifurcations". Our simulation results further reveal that hematocrit heterogeneity is directly caused by the RBC dynamics, i.e. by their unequal partitioning at bifurcations and their effect on vessel resistance. These results provide the first in vivo evidence of the impact of RBC dynamics on the flow field in the cortical microvasculature. By structural and functional analyses of our blood flow simulations we show that capillary diameter changes locally alter flow and RBC distribution. A dilation of 10% along a vessel length of 100 µm increases the flow on average by 21% in the dilated vessel downstream a well-balanced bifurcation. The number of RBCs rises on average by 27%. Importantly, RBC up-regulation proves to be more effective the more balanced the outflow velocities at the upstream bifurcation are. Taken together, we conclude that diameter changes at capillary level bear potential to locally change the flow field and the RBC distribution. Moreover, our results suggest that the balancing of outflow velocities contributes to the robustness of perfusion. Based on our in silico results, we anticipate that the bi-phasic nature of blood and small-scale regulations are essential for a well-adjusted oxygen and energy substrate supply.

Host-related factors for venous thromboembolism following total joint replacement: A meta-analysis of 89 observational studies involving over 14 million hip and knee replacements.

BACKGROUND: Venous thromboembolism, a potential complication of total joint replacement, is associated with preventable mortality and morbidity and is likely to be influenced by host-related factors such as sociodemographic characteristics, body mass index, medical and surgical histories, as well as circulating biomarkers. We conducted a systematic review and meta-analysis to assess the associations between host-related factors and venous thromboembolism risk following total hip and knee replacements. METHODS: We searched MEDLINE, Embase, Web of Science, and Cochrane Library to March 2018 for longitudinal studies reporting these associations. Summary measures of association were relative risks (95% confidence intervals). RESULTS: We identified 89 studies with data on 14,763,963 joint replacements and 150,086 venous thromboembolism events. Comparing males to females, age ≥70 to <70 years, and blacks to whites, relative risks for venous thromboembolism were 0.83 (0.75-0.91), 1.24 (1.03-1.50), and 1.26 (1.20-1.31) respectively. Comparing body mass indices ≥25 vs. <25; ≥30 vs. <30; and ≥50 vs. <50 kg/m2, relative risks were 1.40 (1.24-1.57); 1.65 (1.23-2.22); and 1.72 (1.10-2.67) respectively. Histories of venous thromboembolism; cardiovascular disease; congestive heart failure; cardiac arrhythmia; chronic pulmonary disease; renal disease; neurological disease; fluid & electrolyte imbalance; bariatric surgery; and comorbidity indices were associated with increased venous thromboembolism risk. Comparing a total knee with a hip replacement, the relative risk for venous thromboembolism was 1.69 (1.32-2.15). CONCLUSIONS: Enhanced venous thromboembolism prophylaxis should be considered in those with nonmodifiable risk factors such as older black female knee replacement patients. Modifiable risk factors such as high body mass index and fluid & electrolyte imbalance should be addressed prior to elective surgery. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2018: CRD42018089625.

Clinical Effectiveness of Treatment Strategies for Prosthetic Joint Infection Following Total Ankle Replacement: A Systematic Review and Meta-analysis.

Prosthetic joint infection (PJI) after total ankle replacement (TAR) is a challenging complication, which often requires debridement and implant retention (DAIR) with or without polyethylene exchange, revision surgery, implantation of a cement spacer, conversion to arthrodesis, or even amputation. The optimum treatment for ankle PJI is not well established. We conducted a systematic review and meta-analysis to compare the clinical effectiveness of various treatment strategies for infected ankle prostheses. We searched MEDLINE, Embase, Web of Science, and the Cochrane Library up to December 2018 for studies evaluating the impact of treatment in patient populations with infected ankle prostheses following TAR. Binary data were pooled after arcsine transformation. Six citations comprising 17 observational design comparisons were included. The reinfection rates (95% confidence intervals) for DAIR with or without polyethylene exchange, 1-stage revision, 2-stage revision, cement spacer, and arthrodesis were 39.8% (24.4 to 56.1), 0.0% (0.0 to 78.7), 0.0% (0.0 to 8.5), 0.2% (0.0 to 17.9), and 13.6% (0.0 to 45.8), respectively. Rates of amputation for DAIR with or without polyethylene exchange and cement spacer were 5.6% (0.0 to 16.9) and 22.2% (6.3 to 54.7), respectively. Measures of function, pain, and satisfaction could not be compared because of limited data. One- and 2-stage revision strategies seem to be associated with the lowest reinfection rates, but these findings are based on limited data. Arthrodesis and DAIR with or without polyethylene exchange appear to be commonly used in treating infected ankle prosthesis, but are associated with poor infection control. Clear gaps exist in the literature, and further research is warranted to evaluate treatment strategies for infected ankle prosthesis.

A membrane-associated, fluorogenic reporter for mammalian phospholipase C isozymes.

A diverse group of cell-surface receptors, including many G protein-coupled receptors and receptor tyrosine kinases, activate phospholipase C (PLC) isozymes to hydrolyze phosphatidylinositol 4,5-bisphosphate into the second messengers diacylglycerol and 1,4,5-inositol trisphosphate. Consequently, PLCs control various cellular processes, and their aberrant regulation contributes to many diseases, including cancer, atherosclerosis, and rheumatoid arthritis. Despite the widespread importance of PLCs in human biology and disease, it has been impossible to directly monitor the real-time activation of these enzymes at membranes. To overcome this limitation, here we describe XY-69, a fluorogenic reporter that preferentially partitions into membranes and provides a selective tool for measuring the real-time activity of PLCs as either purified enzymes or in cellular lysates. Indeed, XY-69 faithfully reported the membrane-dependent activation of PLC-ß3 by Gαq Therefore, XY-69 can replace radioactive phosphatidylinositol 4,5-bisphosphate used in conventional PLC assays and will enable high-throughput screens to identify both orthosteric and allosteric PLC inhibitors. In the future, cell-permeable variants of XY-69 represent promising candidates for reporting the activation of PLCs in live cells with high spatiotemporal resolution.

Vascular density and distribution in neocortex.

An amazingly wide range of complex behavior emerges from the cerebral cortex. Much of the information processing that leads to these behaviors is performed in neocortical circuits that span throughout the six layers of the cortex. Maintaining this circuit activity requires substantial quantities of oxygen and energy substrates, which are delivered by the complex yet well-organized and tightly-regulated vascular system. In this review, we provide a detailed characterization of the most relevant anatomical and functional features of the cortical vasculature. This includes a compilation of the available data on laminar variation of vascular density and the topological aspects of the microvascular system. We also review the spatio-temporal dynamics of cortical blood flow regulation and oxygenation, many aspects of which remain poorly understood. Finally, we discuss some of the important implications of vascular density, distribution, oxygenation and blood flow regulation for (laminar) fMRI.

Accelerated, first-pass cardiac perfusion pulse sequence with radial k-space sampling, compressed sensing, and k-space weighted image contrast reconstruction tailored for visual analysis and quantification of myocardial blood flow.

PURPOSE: To develop an accelerated cardiac perfusion pulse sequence and test whether it is capable of increasing spatial coverage, generating high-quality images, and enabling quantification of myocardial blood flow (MBF). METHODS: We implemented an accelerated first-pass cardiac perfusion pulse sequence by combining radial k-space sampling, compressed sensing (CS), and k-space weighted image contrast (KWIC) filtering. The proposed and clinical standard pulse sequences were evaluated in a randomized order in 13 patients at rest. For visual analysis, 3 readers graded the conspicuity of wall enhancement, artifact, and noise level on a 5-point Likert scale (overall score index = sum of 3 individual scores). Resting MBF was calculated using a Fermi function model with and without KWIC filtering. Mean visual scores and MBF values were compared between sequences using appropriate statistical tests. RESULTS: The proposed pulse sequence produced greater spatial coverage (6-8 slices) with higher spatial resolution (1.6 × 1.6 × 8 mm3 ) and shorter readout duration (78 ms) compared to clinical standard (3-4 slices, 3 × 3 × 8 mm3 , 128 ms, respectively). The overall image score index between accelerated (11.1 ± 1.3) and clinical standard (11.2 ± 1.3) was not significantly different (P = 0.64). Mean resting MBF values with KWIC filtering (0.9-1.2 mL/g/min across different slices) were significantly lower (P < 0.0001) than those without KWIC filtering (3.1-4.3 mL/g/min) and agreed better with values reported in literature. CONCLUSION: An accelerated, first-pass cardiac perfusion pulse sequence with radial k-space sampling, CS, and KWIC filtering is capable of increasing spatial coverage, generating high-quality images, and enabling quantification of MBF.

Lower volume, more impairment: reduced cholinergic basal forebrain grey matter density is associated with impaired cognition in Parkinson disease.

OBJECTIVE: A major contributor to dementia in Parkinson disease (PD) is degeneration of the cholinergic basal forebrain. This study determined whether cholinergic nucleus 4 (Ch4) density is associated with cognition in early and more advanced PD. METHODS: We analysed brain MRIs and neuropsychological test scores for 228 newly diagnosed PD participants from the Parkinson's Progression Markers Initiative (PPMI), 101 healthy controls from the PPMI and 125 more advanced PD patients from a local retrospective cohort. Cholinergic basal forebrain nuclei densities were determined by applying probabilistic maps to MPRAGE T1 sequences processed using voxel-based morphometry methods. Relationships between grey matter densities and cognitive scores were analysed using correlations and linear regression models. RESULTS: In more advanced PD, greater Ch4 density was associated with Montreal Cognitive Assessment (MoCA) score (ß=14.2; 95% CI=1.5 to 27.0; p=0.03), attention domain z-score (ß=3.2; 95% CI=0.8 to 5.5; p=0.008) and visuospatial domain z-score (ß=7.9; 95% CI=2.0 to 13.8; p=0.009). In the PPMI PD cohort, higher Ch4 was associated with higher scores on MoCA (ß=9.2; 95% CI=1.9 to 16.5; p=0.01), Judgement of Line Orientation (ß=20.4; 95% CI=13.8 to 27.0; p<0.001), Letter Number Sequencing (ß=16.5; 95% CI=9.5 to 23.4; p<0.001) and Symbol Digit Modalities Test (ß=41.8; 95% CI=18.7 to 65.0; p<0.001). These same relationships were observed in 97 PPMI PD participants at 4 years. There were no significant associations between Ch4 density and cognitive outcomes in healthy controls. CONCLUSION: In de novo and more advanced PD, lower Ch4 density is associated with impaired global cognition, attention and visuospatial function.

Long-term In Vivo Calcium Imaging of Astrocytes Reveals Distinct Cellular Compartment Responses to Sensory Stimulation.

Localized, heterogeneous calcium transients occur throughout astrocytes, but the characteristics and long-term stability of these signals, particularly in response to sensory stimulation, remain unknown. Here, we used a genetically encoded calcium indicator and an activity-based image analysis scheme to monitor astrocyte calcium activity in vivo. We found that different subcellular compartments (processes, somata, and endfeet) displayed distinct signaling characteristics. Closer examination of individual signals showed that sensory stimulation elevated the number of specific types of calcium peaks within astrocyte processes and somata, in a cortical layer-dependent manner, and that the signals became more synchronous upon sensory stimulation. Although mice genetically lacking astrocytic IP3R-dependent calcium signaling (Ip3r2-/-) had fewer signal peaks, the response to sensory stimulation was sustained, suggesting other calcium pathways are also involved. Long-term imaging of astrocyte populations revealed that all compartments reliably responded to stimulation over several months, but that the location of the response within processes may vary. These previously unknown characteristics of subcellular astrocyte calcium signals provide new insights into how astrocytes may encode local neuronal circuit activity.

The outcomes of total knee arthroplasty in morbidly obese patients: a systematic review of the literature.

INTRODUCTION: The increasing prevalence of obesity has led to an increase in total knee arthroplasties (TKAs) being undertaken in patients with a higher body mass index (BMI). TKA in morbidly obese patients can be technically challenging due to numerous anatomical factors and patient co-morbidities. The long-term outcomes in this patient group are unclear. This systematic review aims to compare the long-term revision rates, functional outcomes and complication rates of TKAs in morbidly obese versus non-obese patients. METHODS: A search of PubMed, EMBASE and PubMed Central was conducted to identify studies that reported revision rates in a cohort of morbidly obese patients (BMI ≥ 40 kg/m2) that underwent primary TKA, compared to non-obese patients (BMI ≤ 30 kg/m2). Secondary outcomes included Knee Society Objective Scores (KSOS), Knee Society Functional Scores (KSFS), and complication rates between the two groups. The difference in revision rates was assessed using the Chi-squared test. The Wilcoxon signed-rank test was used to compare pre-operative and post-operative functional scores for each group. KSOS and KSFS for morbidly obese and non-obese patients were compared using the Mann-Whitney test. Statistical significance was defined as p ≤ 0.05. RESULTS: Nine studies were included in this review. There were 624 TKAs in morbidly obese patients and 9,449 TKAs in non-obese patients, average BMI values were 45.0 kg/m2 (range 40-66 kg/m2) and 26.5 kg/m2 (range 11-30 kg/m2) respectively. The average follow-up time was 4.8 years (range 0.5-14.1) and 5.2 years (range 0.5-13.2) respectively, with a revision rate of 7% and 2% (p < 0.001) respectively. All functional scores improved after TKA (p < 0.001). Pre- and post-operative KSOS and KSFS were poorer in morbidly obese patients, however, mean improvement in KSOS was the same in both groups and comparable between groups for KSFS (p = 0.78). Overall complication rates,  including infection, were higher in morbidly obese patients. CONCLUSIONS: This review suggests an increased mid to long-term revision rate following primary TKA in morbidly obese patients, however, these patients have a functional recovery which is comparable to non-obese individuals. There is also an increased risk of perioperative complications, such as superficial wound infection. Morbidly obese patients should be fully informed of these issues prior to undergoing primary TKA.

Transient perceived back pain induced by prolonged sitting in a backless office chair: are biomechanical factors involved?

It is not currently known if biomechanical factors contribute to low back pain (LBP) during prolonged sitting. Thus, this study recruited 90 participants (61 with no history of LBP, and 29 with) to sit for 1 hour where back electromyography, spine posture, and perceived pain ratings (PPR) were collected. Participants were classified as Pain Developers (PD) or Non-Pain Developers (NPD) based on their maximum PPR. PDs had significantly higher PPR (p = 0.000) and lower number of spine fidgets (p = 0.004) than NPDs. There was a significant interaction between clinical health history and pain group (p = 0.037) for PPR. Besides fidget frequency, there were no biomechanical differences between pain groups. Therefore, sitting-induced back pain does not appear to be due to posture or muscle activity; however, it may be related to micro-movement strategies. Future work should explore fidgeting further and whether healthy PDs are at risk for clinical LBP in the future. Practitioner summary: We have replicated the differential transient sitting-induced pain response observed in previous studies. Pain developers do not sit differently than non-pain developers, although they do appear to move less. More research is warranted to better understand these groups and the relationship between pain developers and future cases of back pain. Abbreviations: LBP: low back pain; PG: pain group; PD: pain developer; NPD: non-pain developer; +veHx: positive clinical history for low back pain; -veHx: negative clinical history for low back pain; RTS: right thoracic erector spinae; LTS: left thoracic erector spine; RLM: right lumbar multifidus; LLM: left lumbar multifidus; MVC: maximum voluntary contraction; Pelvic N: normalized pelvic angle; ANOVA: analysis of variance; SD: standard deviation.