Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent ß-amyloid generation.

Assemblies of ß-amyloid (Aß) peptides are pathological mediators of Alzheimer's Disease (AD) and are produced by the sequential cleavages of amyloid precursor protein (APP) by ß-secretase (BACE1) and γ-secretase. The generation of Aß is coupled to neuronal activity, but the molecular basis is unknown. Here, we report that the immediate early gene Arc is required for activity-dependent generation of Aß. Arc is a postsynaptic protein that recruits endophilin2/3 and dynamin to early/recycling endosomes that traffic AMPA receptors to reduce synaptic strength in both hebbian and non-hebbian forms of plasticity. The Arc-endosome also traffics APP and BACE1, and Arc physically associates with presenilin1 (PS1) to regulate γ-secretase trafficking and confer activity dependence. Genetic deletion of Arc reduces Aß load in a transgenic mouse model of AD. In concert with the finding that patients with AD can express anomalously high levels of Arc, we hypothesize that Arc participates in the pathogenesis of AD.

The Use of Wearable Devices in Oncology Patients: A Systematic Review.

INTRODUCTION: The aim of this systematic review was to summarize the current literature on wearable technologies in oncology patients for the purpose of prognostication, treatment monitoring, and rehabilitation planning. METHODS: A search was conducted in Medline ALL, Cochrane Central Register of Controlled Trials, Embase, Emcare, CINAHL, Scopus, and Web of Science, up until February 2022. Articles were included if they reported on consumer grade and/or non-commercial wearable devices in the setting of either prognostication, treatment monitoring or rehabilitation. RESULTS: We found 199 studies reporting on 18 513 patients suitable for inclusion. One hundred and eleven studies used wearable device data primarily for the purposes of rehabilitation, 68 for treatment monitoring, and 20 for prognostication. The most commonly-reported brands of wearable devices were ActiGraph (71 studies; 36%), Fitbit (37 studies; 19%), Garmin (13 studies; 7%), and ActivPAL (11 studies; 6%). Daily minutes of physical activity were measured in 121 studies (61%), and daily step counts were measured in 93 studies (47%). Adherence was reported in 86 studies, and ranged from 40% to 100%; of these, 63 (74%) reported adherence in excess of 80%. CONCLUSION: Wearable devices may provide valuable data for the purposes of treatment monitoring, prognostication, and rehabilitation. Future studies should investigate live-time monitoring of collected data, which may facilitate directed interventions.

MRI-based Neuropathy Score Reporting And Data System (NS-RADS): multi-institutional wider-experience usability study of peripheral neuropathy conditions among 32 radiology readers.

OBJECTIVE: To determine the inter-reader reliability and diagnostic performance of classification and severity scales of Neuropathy Score Reporting And Data System (NS-RADS) among readers of differing experience levels after limited teaching of the scoring system. METHODS: This is a multi-institutional, cross-sectional, retrospective study of MRI cases of proven peripheral neuropathy (PN) conditions. Thirty-two radiology readers with varying experience levels were recruited from different institutions. Each reader attended and received a structured presentation that described the NS-RADS classification system containing examples and reviewed published articles on this subject. The readers were then asked to perform NS-RADS scoring with recording of category, subcategory, and most likely diagnosis. Inter-reader agreements were evaluated by Conger's kappa and diagnostic accuracy was calculated for each reader as percent correct diagnosis. A linear mixed model was used to estimate and compare accuracy between trainees and attendings. RESULTS: Across all readers, agreement was good for NS-RADS category and moderate for subcategory. Inter-reader agreement of trainees was comparable to attendings (0.65 vs 0.65). Reader accuracy for attendings was 75% (95% CI 73%, 77%), slightly higher than for trainees (71% (69%, 72%), p = 0.0006) for nerves and comparable for muscles (attendings, 87.5% (95% CI 86.1-88.8%) and trainees, 86.6% (95% CI 85.2-87.9%), p = 0.4). NS-RADS accuracy was also higher than average accuracy for the most plausible diagnosis for attending radiologists at 67% (95% CI 63%, 71%) and for trainees at 65% (95% CI 60%, 69%) (p = 0.036). CONCLUSION: Non-expert radiologists interpreted PN conditions with good accuracy and moderate-to-good inter-reader reliability using the NS-RADS scoring system. CLINICAL RELEVANCE STATEMENT: The Neuropathy Score Reporting And Data System (NS-RADS) is an accurate and reliable MRI-based image scoring system for practical use for the diagnosis and grading of severity of peripheral neuromuscular disorders by both experienced and general radiologists. KEY POINTS: • The Neuropathy Score Reporting And Data System (NS-RADS) can be used effectively by non-expert radiologists to categorize peripheral neuropathy. • Across 32 different experience-level readers, the agreement was good for NS-RADS category and moderate for NS-RADS subcategory. • NS-RADS accuracy was higher than the average accuracy for the most plausible diagnosis for both attending radiologists and trainees (at 75%, 71% and 65%, 65%, respectively).

Presenilin Is Essential for ApoE Secretion, a Novel Role of Presenilin Involved in Alzheimer's Disease Pathogenesis.

Alzheimer's disease (AD) is a debilitating dementia characterized by progressive memory loss and aggregation of amyloid-ß (Aß) protein into amyloid plaques in patient brains. Mutations in presenilin (PS) lead to abnormal generation of Aß, which is the major cause of familial AD (FAD), and apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) onset. However, whether dysfunction of PS is involved in the pathogenesis of SAD is largely unknown. We found that ApoE secretion was completely abolished in PS-deficient cells and markedly decreased by inhibition of γ-secretase activity. Blockade of γ-secretase activity by a γ-secretase inhibitor, DAPT, decreased ApoE secretion, suggesting an important role of γ-secretase activity in ApoE secretion. Reduced ApoE secretion is also observed in nicastrin-deficient cells with reduced γ-secretase activity. PS deficiency enhanced nuclear translocation of ApoE and binding of ApoE to importin α4, a nuclear transport receptor. Moreover, the expression of PS mutants in PS-deficient cells suppressed the restoration effects on ApoE secretion compared with the expression of wild-type PS. Plasma ApoE levels were lower in FAD patients carrying PS1 mutations compared with normal control subjects. Our findings suggest a novel role of PS contributing to the pathogenesis of SAD by regulating ApoE secretion.SIGNIFICANCE STATEMENT Familial AD (FAD) typically results from mutations in the genes encoding amyloid precursor protein, presenilin 1 (PS1), or PS2. Many PS mutants have been found to exert impaired γ-secretase activity and increased amyloid-ß 42 (Aß42)/Aß40 ratio, which induce early amyloid deposition and FAD. On the other hand, apolipoprotein E4 (ApoE4) is the major genetic risk factor for sporadic AD (SAD) and contributes to AD pathogenesis because it has reduced Aß clearance capability compared with ApoE3 and ApoE2. FAD and SAD have long been considered to be caused by these two independent mechanisms; however, for the first time, we demonstrated that PS is essential for ApoE secretion and PS mutants affected ApoE secretion in vitro and in human samples, suggesting a novel mechanism by which PS is also involved in SAD pathogenesis.

Human brain sialoglycan ligand for CD33, a microglial inhibitory Siglec implicated in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by accumulation of misfolded proteins. Genetic studies implicate microglia, brain-resident phagocytic immune cells, in AD pathogenesis. As positive effectors, microglia clear toxic proteins, whereas as negative effectors, they release proinflammatory mediators. An imbalance of these functions contributes to AD progression. Polymorphisms of human CD33, an inhibitory microglial receptor, are linked to AD susceptibility; higher CD33 expression correlates with increased AD risk. CD33, also called Siglec-3, is a member of the sialic acid-binding immunoglobulin-type lectin (Siglec) family of immune regulatory receptors. Siglec-mediated inhibition is initiated by binding to complementary sialoglycan ligands in the tissue environment. Here, we identify a single sialoglycoprotein in human cerebral cortex that binds CD33 as well as Siglec-8, the most abundant Siglec on human microglia. The ligand, which we term receptor protein tyrosine phosphatase zeta (RPTPζ)S3L, is composed of sialylated keratan sulfate chains carried on a minor isoform/glycoform of RPTPζ (phosphacan) and is found in the extracellular milieu of the human brain parenchyma. Brains from human AD donors had twofold higher levels of RPTPζS3L than age-matched control donors, raising the possibility that RPTPζS3L overexpression limits misfolded protein clearance contributing to AD pathology. Mice express the same structure, a sialylated keratan sulfate RPTPζ isoform, that binds mouse Siglec-F and crossreacts with human CD33 and Siglec-8. Brains from mice engineered to lack RPTPζ, the sialyltransferase St3gal4, or the keratan sulfate sulfotransferase Chst1 lacked Siglec binding, establishing the ligand structure. The unique CD33 and Siglec-8 ligand, RPTPζS3L, may contribute to AD progression.

Splenomegaly is a marker of advanced chronic liver disease and portal hypertension in HIV infection.

OBJECTIVES: To evaluate the clinical significance of splenomegaly as a marker of underlying liver disease in people with HIV (PWH). METHODS: We included consecutive PWH from a prospective cohort from 2010 to 2020 with available liver stiffness measurement (LSM) and liver imaging to define splenomegaly (> 13 cm) within 1 year. Cut-offs of LSM > 10 kPa and > 21 kPa were used to identify advanced chronic liver disease (ACLD) and portal hypertension, respectively. Logistic regression multivariable analysis was employed to identify independent predictors of ACLD. RESULTS: In all, 331 PWH were included, 76% of them men, with a median (interquartile range) age of 51.3 (45-58) years, all receiving antiretroviral treatment, and 53% were HIV monoinfected. The PWH with splenomegaly exhibited a higher prevalence of ACLD compared with those with normal spleen size, as per LSM (26% vs. 9%; p = 0.009). Portal hypertension diagnosed by LSM was also more prevalent in PWH with splenomegaly than in those without (15% vs. 2%; p < 0.001). Independent predictors of ACLD were viral hepatitis coinfection [adjusted odds ratio (aOR) = 3.15, 95% confidence interval (CI): 1.65-6.0], lower platelets (aOR = 0.99, 95% CI: 0.99-0.99) and splenomegaly (aOR = 2.41, 95% CI: 1.17-4.99). In patients with available oesophagogastroduodenoscopy, splenomegaly was also associated with higher prevalence of oesophageal varices and other endoscopic findings of portal hypertension (38% vs. 17%; p = 0.027). CONCLUSIONS: Splenomegaly identified on routine imaging may have utility as a marker of ACLD and portal hypertension, prompting further investigations.

Loss of TDP-43 splicing repression occurs early in the aging population and is associated with Alzheimer's disease neuropathologic changes and cognitive decline.

LATE-NC, the neuropathologic changes of limbic-predominant age-related TAR DNA-binding protein 43 kDa (TDP-43) encephalopathy are frequently associated with Alzheimer's disease (AD) and cognitive impairment in older adults. The association of TDP-43 proteinopathy with AD neuropathologic changes (ADNC) and its impact on specific cognitive domains are not fully understood and whether loss of TDP-43 function occurs early in the aging brain remains unknown. Here, using a large set of autopsies from the Baltimore Longitudinal Study of Aging (BLSA) and another younger cohort, we were able to study brains from subjects 21-109 years of age. Examination of these brains show that loss of TDP-43 splicing repression, as judged by TDP-43 nuclear clearance and expression of a cryptic exon in HDGFL2, first occurs during the 6th decade, preceding by a decade the appearance of TDP-43+ neuronal cytoplasmic inclusions (NCIs). We corroborated this observation using a monoclonal antibody to demonstrate a cryptic exon-encoded neoepitope within HDGFL2 in neurons exhibiting nuclear clearance of TDP-43. TDP-43 nuclear clearance is associated with increased burden of tau pathology. Age at death, female sex, high CERAD neuritic plaque score, and high Braak neurofibrillary stage significantly increase the odds of LATE-NC. Faster rates of cognitive decline on verbal memory (California Verbal Learning Test immediate recall), visuospatial ability (Card Rotations Test), mental status (MMSE) and semantic fluency (Category Fluency Test) were associated with LATE-NC. Notably, the effects of LATE-NC on verbal memory and visuospatial ability are independent of ADNC. However, the effects of TDP-43 nuclear clearance in absence of NCI on the longitudinal trajectories and levels of cognitive measures are not significant. These results establish that loss of TDP-43 splicing repression is an early event occurring in the aging population during the development of TDP-43 proteinopathy and is associated with increased tau pathology. Furthermore, LATE-NC correlates with high levels of ADNC but also has an impact on specific memory and visuospatial functions in aging that is independent of AD.

Non-invasive mid-term electrocardiogram patch monitoring is effective in detecting atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is a cause of serious morbidity such as stroke. Early detection and treatment of AF is important. Current guidelines recommend screening via opportunistic pulse taking or 12­lead electrocardiogram. Mid-term ECG patch monitors increases the sensitivity of AF detection. METHODS: The Singapore Atrial Fibrillation Study is a prospective multi-centre study aiming to study the incidence of AF in patients with no prior AF and a CHA2DS2-VASc score of at least 1, with the use of a mid-term continuous ECG monitoring device (Spyder ECG). Consecutive patients from both inpatient and outpatient settings were recruited from 3 major hospitals from May 2016 to December 2019. RESULTS: Three hundred and fifty-five patients were monitored. 6 patients (1.7%) were diagnosed with AF. There were no significant differences in total duration of monitoring between the AF and non-AF group (6.39 ± 3.19 vs 5.42 ± 2.46 days, p = 0.340). Patients with newly detected AF were more likely to have palpitations (50.0% vs 11.8%, p = 0.027). Half of the patients (n = 3, 50.0%) were diagnosed on the first day of monitoring and the rest were diagnosed after 24 h. On univariate analysis, only hyperlipidemia was associated with reduced odds of being diagnosed with AF (OR HR 0.08 CI 0.01-0.74, p = 0.025). In a group of 128 patients who underwent coronary artery bypass grafting and had post-operative ECG monitoring, 9 patients (7.0%) were diagnosed with post-operative AF. CONCLUSIONS: The use of non-invasive mid-term patch-based ECG monitoring is an effective modality for AF screening.

Loss of TDP-43 in male germ cells causes meiotic failure and impairs fertility in mice.

Meiotic arrest is a common cause of human male infertility, but the causes of this arrest are poorly understood. Transactive response DNA-binding protein of 43 kDa (TDP-43) is highly expressed in spermatocytes in the preleptotene and pachytene stages of meiosis. TDP-43 is linked to several human neurodegenerative disorders wherein its nuclear clearance accompanied by cytoplasmic aggregates underlies neurodegeneration. Exploring the functional requirement for TDP-43 for spermatogenesis for the first time, we show here that conditional KO (cKO) of the Tardbp gene (encoding TDP-43) in male germ cells of mice leads to reduced testis size, depletion of germ cells, vacuole formation within the seminiferous epithelium, and reduced sperm production. Fertility trials also indicated severe subfertility. Spermatocytes of cKO mice showed failure to complete prophase I of meiosis with arrest at the midpachytene stage. Staining of synaptonemal complex protein 3 and γH2AX, markers of the meiotic synaptonemal complex and DNA damage, respectively, and super illumination microscopy revealed nonhomologous pairing and synapsis defects. Quantitative RT-PCR showed reduction in the expression of genes critical for prophase I of meiosis, including Spo11 (initiator of meiotic double-stranded breaks), Rec8 (meiotic recombination protein), and Rad21L (RAD21-like, cohesin complex component), as well as those involved in the retinoic acid pathway critical for entry into meiosis. RNA-Seq showed 1036 upregulated and 1638 downregulated genes (false discovery rate <0.05) in the Tardbp cKO testis, impacting meiosis pathways. Our work reveals a crucial role for TDP-43 in male meiosis and suggests that some forms of meiotic arrest seen in infertile men may result from the loss of function of TDP-43.

Haemoglobin S testing using HEA BeadChip™ technology: Lifeblood comparison with clinical diagnosis.

BACKGROUND AND OBJECTIVES: Red cell antigen genotyping is commonly performed on patients requiring chronic transfusion support, such as sickle cell disease and thalassaemia. The Immucor HEA BeadChip™ test, in addition to assessing red cell antigen expression, can also detect the haemoglobin S (HbS) mutation. Our aim was to compare HbS results using HEA BeadChip™ performed at the Australian Red Cross Lifeblood with conventional haemoglobin studies. MATERIALS AND METHODS: Patients with thalassaemia and sickle cell trait (SCT) or disease (SCD) referred for red cell genotyping between 2017 and 2019 were assessed. The HbS result obtained from HEA BeadChip™ was compared with that obtained from high-performance liquid chromatography (HPLC) performed by the referring pathology provider. RESULTS: One-hundred and nineteen cases had comparable HPLC and HEA BeadChip™ results. On HEA BeadChip™ testing, 40 cases showed a negative HbS result, 31 cases showed HbS+ and 47 cases showed HbS++. There was one case with 'low signal' result. Of the negative HbS cases, there was none with SCT. The HbS+ group comprised a mixture of SCT and SCD due to compound heterozygosity for HbS and ß-thalassaemia mutations. The HbS++ group comprised predominantly SCD due to homozygosity for HbS. CONCLUSION: HEA BeadChip™ is an accurate screening test for the detection of HbS. There were no false positives or false negatives. The identification of donors with the HbS mutation through the targeted genotyping programme would enable early intervention, improved donor management and reduced wastage.

Neuropathy Score Reporting and Data System: A Reporting Guideline for MRI of Peripheral Neuropathy With a Multicenter Validation Study.

BACKGROUND. A standardized guideline and scoring system would improve evaluation and reporting of peripheral neuropathy (PN) on MRI. OBJECTIVE. The objective of this study was to create and validate a neuropathy classification and grading system, which we named the Neuropathy Score Reporting and Data System (NS-RADS). METHODS. This retrospective study included 100 patients with nerve imaging studies and known clinical diagnoses. Experts crafted NS-RADS using mutually agreed-on qualitative criteria for the classification and grading of PN. Different classes were created to account for the spectrum of underlying pathologies: unremarkable (U), injury (I), neoplasia (N), entrapment (E), diffuse neuropathy (D), not otherwise specified (NOS), and postintervention state (PI). Subclasses were established to describe the severity or extent of the lesions. Validation testing was performed by 11 readers from 10 institutions with experience levels ranging from 3 to 18 years after residency. After initial reader training, cases were presented to readers who were blinded to the final clinical diagnoses. Interobserver agreement was assessed using correlation coefficients and the Conger kappa, and accuracy testing was performed. RESULTS. Final clinical diagnoses included normal (n = 5), nerve injury (n = 25), entrapment (n = 15), neoplasia (n = 33), diffuse neuropathy (n = 18), and persistent neuropathy after intervention (n = 4). The miscategorization rate for NS-RADS classes was 1.8%. Final diagnoses were correctly identified by readers in 71-88% of cases. Excellent inter-reader agreement was found on the NS-RADS pathology categorization (κ = 0.96; 95% CI, 0.93-0.98) as well as muscle pathology categorization (κ = 0.76; 95% CI, 0.68-0.82). The accuracy for determining milder versus more severe categories per radiologist ranged from 88% to 97% for nerve lesions and from 86% to 94% for muscle abnormalities. CONCLUSION. The proposed NS-RADS classification is accurate and reliable across different reader experience levels and a spectrum of PN conditions. CLINICAL IMPACT. NS-RADS can be used as a standardized guideline for reporting PN and improved multidisciplinary communications.

Cooled Radiofrequency Ablation for Chronic Joint Pain Secondary to Hip and Shoulder Osteoarthritis.

Osteoarthritis (OA) of the shoulder and hip is a leading cause of physical disability and mental distress. Traditional nonsurgical management alone is often unable to completely address the associated chronic joint pain. Moreover, a large number of patients are not eligible for joint replacement surgery owing to comorbidities or cost. Radiofrequency ablation (RFA) of articular sensory nerve fibers can disrupt the transmission of nociceptive signals by neurolysis, thereby providing long-term pain relief. A subtype of RFA, cooled RFA (CRFA), utilizes internally cooled electrodes to generate larger ablative zones compared with standard RFA techniques. Given the complex variable innervation of large joints such as the glenohumeral and hip joints, a larger ablative treatment zone, such as that provided by CRFA, is desired to capture a greater number of afferent nociceptive fibers. The suprascapular, axillary, and lateral pectoral nerve articular sensory branches are targeted during CRFA of the glenohumeral joint. The obturator and femoral nerve articular sensory branches are targeted during CRFA of the hip. CRFA is a promising tool in the interventionalist's arsenal for management of OA-related pain and symptoms, particularly in patients who cannot undergo, have long wait times until, or have persistent pain following joint replacement surgery. An invited commentary by Tomasian is available online. ©RSNA, 2022.

Acquired Hemophilia A following Pfizer-BioNTech SARS CoV-2 mRNA vaccine, successfully treated with prednisolone and rituximab.

INTRODUCTION: Acquired haemophilia A (AHA) is a rare bleeding disorder, characterised by the presence of autoantibodies to clotting factor VIII (FVIII). AHA can be idiopathic or occur in the context of malignancy, autoimmune disease, drugs, or pregnancy. Recently, cases of AHA following both COVID-19 infection and vaccination have been reported. CASE REPORT: We report the case of a 95-year-old female who was immunised with the Pfizer-BioNTech SARS CoV-2 mRNA vaccine, with doses given three weeks apart. Spontaneous bruising over her extremities appeared one week after the initial dose, with hospital admission occurring three weeks after the second. Examination revealed a large haematoma on the dorsum of the right hand with resultant bleeding and widespread ecchymoses. Investigations confirmed a diagnosis of AHA. MANAGEMENT AND OUTCOME: Initial management included high dose prednisolone, recombinant Factor VIII and tranexamic acid. There was no significant clinical improvement after three days, so intravenous rituximab 100 mg weekly for four weeks was commenced. The activated partial thromboplastin time (aPTT) normalised after two doses and Factor VIII level reached 0.68U/ml on day + 22. The patient was successfully discharged from hospital after 37 days. DISCUSSION: Four cases of AHA following administration of COVID mRNA vaccines (Pfizer and Moderna) have been documented. AHA should be a differential in patients presenting with bleeding following COVID-19 vaccination, in the presence of a normal platelet count. Rapid recognition, prompt initiation of immunosuppressive treatment and rigorous supportive cares are required to minimise morbidity and mortality.

Alternative treatment of hip pain from advanced hip osteoarthritis utilizing cooled radiofrequency ablation: single institution pilot study.

OBJECTIVE: To establish the effectiveness of cooled radiofrequency ablation in managing hip pain from osteoarthritis at 6 months after receiving treatment in patients who failed conservative treatments and are not surgical candidates due to comorbidities or unwillingness to undergo arthroplasty surgery by targeting the femoral and obturator branches and assessing the degree of hip pain relief and change of function. MATERIALS AND METHODS: This prospective pilot study includes a total of 11 consecutive patients experiencing persistent chronic hip pain in the setting of advanced osteoarthritis. Patients initially underwent anesthetic blocks of the obturator and femoral nerve branches to determine cooled radiofrequency ablation candidacy. After adequate response to the anesthetic blocks (> 50% immediate pain relief), patients were subjected to the procedures 2-3 weeks later. Treatment response was evaluated utilizing clinically validated questionnaires and visual analog score in order to assess impact on pain severity, stiffness, and functional activities of daily living. Follow-up outcome scores were collected up to 6 months after cooled radiofrequency ablation procedure. RESULTS: A total of 11 hips were treated consecutively between August 2019 and March 2020 (mean patient age 61.4 years; 8 M:3F). The mean total HOOS score improved significantly from baseline at 17.0 ± 6.0 to 52.9 ± 5.4 at a mean of 6.2 months after treatment (p < 0.0001), with significant improvement in mean pain score from 16.1 ± 6.6 to 53.4 ± 7.4 (p < 0.0001) and mean stiffness score from 15.0 ± 8.1 to 53.6 ± 11.0 (p < 0.0001). No major complications were encountered. No patients went on to re-treatment, surgery, or other intervention. CONCLUSION: Image-guided obturator and femoral nerve cooled radiofrequency ablation is effective and safe in treating chronic hip pain/stiffness in the setting of advanced osteoarthritis.

Management of uncomplicated total knee arthroplasty chronic pain and stiffness utilizing cooled radiofrequency ablation: a single institution pilot study.

OBJECTIVE: The objective of this study is to introduce cooled radiofrequency ablation technical feasibility as an alternative percutaneous image-guided treatment of chronic pain and stiffness in the setting of uncomplicated total knee arthroplasty. MATERIAL AND METHOD: This retrospective pilot study includes a total of 19 consecutive patients experiencing persistent chronic pain after total knee arthroplasty, without underlying hardware complications who had failed conservative care. Patients initially underwent anesthetic blocks of the genicular nerve branches to determine C-RFA candidacy. After adequate response to the anesthetic blocks (> 50% immediate pain relief), patients were subjected to cooled radiofrequency ablations 2-3 weeks later. Treatment response was evaluated utilizing clinically validated questionnaires (KOOS, the Knee Injury and Osteoarthritis Outcome Score) and visual analog scale (VAS) to assess pain severity, stiffness, functional activities of daily living, and use of pain medication. Follow-up outcome scores were collected up to 1 year after C-RFA procedure. RESULT: A total of 21 knees were treated consecutively between 4/2019 and 1/2020 (mean age 70.5 years; 5 M:14F). The mean total KOOS score improved significantly from baseline at 35.0 ± 14.0 to 64.2 ± 14.7 at a mean of 10.2 months after treatment (p < 0.0001), with significant improvement in mean stiffness score from 44.8 ± 16.7 to 68.8 ± 20 (p < 0.0001). The mean VAS score improved significantly from baseline at 8.30 ± 1.1 to 2.45 ± 1.8 (p < 0.0001). No major complications were encountered. No patients went on to receive re-treatment, surgical revision, or other intervention. CONCLUSION: Image-guided genicular nerve cooled radiofrequency ablation offers a promising alternative in treating chronic pain/stiffness in the setting of uncomplicated TKA.

Brain Activity During Experimental Knee Pain and Its Relationship With Kinesiophobia in Patients With Patellofemoral Pain: A Preliminary Functional Magnetic Resonance Imaging Investigation.

CONTEXT: The etiology of patellofemoral pain has remained elusive, potentially due to an incomplete understanding of how pain, motor control, and kinesiophobia disrupt central nervous system functioning. OBJECTIVE: To directly evaluate brain activity during experimental knee pain and its relationship to kinesiophobia in patients with patellofemoral pain. DESIGN: Cross-sectional. METHODS: Young females clinically diagnosed with patellofemoral pain (n = 14; 14.4 [3.3] y; body mass index = 22.4 [3.8]; height = 1.61 [0.1] m; body mass = 58.4 [12.7] kg). A modified Clarke test (experimental pain condition with noxious induction via patella pressure and quadriceps contraction) was administered to the nondominant knee (to minimize limb dominance confounds) of patients during brain functional magnetic resonance imaging (fMRI) acquisition. Patients also completed a quadriceps contraction without application of external pressure (control contraction). Kinesiophobia was measured using the Tampa Scale of Kinesiophobia. The fMRI analyses assessed brain activation during the modified Clarke test and control contraction and assessed relationships between task-induced brain activity and kinesiophobia. Standard processing for neuroimaging and appropriate cluster-wise statistical thresholds to determine significance were applied to the fMRI data (z > 3.1, P < .05). RESULTS: The fMRI revealed widespread neural activation in the frontal, parietal, and occipital lobes, and cerebellum during the modified Clarke test (all zs > 4.4, all Ps < .04), whereas neural activation was localized primarily to frontal and cerebellar regions during the control contraction test (all zs > 4.4, all Ps < .01). Greater kinesiophobia was positively associated with greater activity in the cerebello-frontal network for the modified Clarke test (all zs > 5.0, all Ps < .01), but no relationships between kinesiophobia and brain activity were observed for the control contraction test (all zs < 3.1, all Ps > .05). CONCLUSIONS: Our novel experimental knee pain condition was associated with alterations in central nociceptive processing. These findings may provide novel complementary pathways for targeted restoration of patient function.

Early detection of Alzheimer's disease using creatine chemical exchange saturation transfer magnetic resonance imaging.

Detecting Alzheimer's disease (AD) at an early stage brings a lot of benefits including disease management and actions to slow the progression of the disease. Here, we demonstrate that reduced creatine chemical exchange saturation transfer (CrCEST) contrast has the potential to serve as a new biomarker for early detection of AD. The results on wild type (WT) mice and two age-matched AD models, namely tauopathy (Tau) and Aß amyloidosis (APP), indicated that CrCEST contrasts of the cortex and corpus callosum in the APP and Tau mice were significantly reduced compared to WT counterpart at an early stage (6-7 months) (p < 0.011). Two main causes of the reduced CrCEST contrast, i.e. cerebral pH and creatine concentration, were investigated. From phantom and hypercapnia experiments, CrCEST showed excellent sensitivity to pH variations. From MRS results, the creatine concentration in WT and AD mouse brain was equivalent, which suggests that the reduced CrCEST contrast was dominated by cerebral pH change involved in the progression of AD. Immunohistochemical analysis revealed that the abnormal cerebral pH in AD mice may relate to neuroinflammation, a known factor that can cause pH reduction.

Novel Negative Pressure Protective Box in Upper Digestive Endoscopy: A Prospective Case Series.

In the context of the Severe Acute Respiratory Syndrome Coronavirus 2 pandemic, we have developed a novel negative pressure aerosol protector for upper endoscopy (TRACEY). TRACEY is the first endoscopic enclosure to have passed stringent testing for aerosol protection. The following describes its clinical use in a single-center prospective case series. Overall, 15 patients were included. All endoscopic procedures were successful without premature removal of TRACEY. In addition, its use did not lead to significant patient discomfort, technical hinderance, or adverse events. TRACEY seems to offer a safe and easy to use aerosol protection for upper endoscopy and a potential Severe Acute Respiratory Syndrome Coronavirus 2 mitigation strategy in endoscopy.

Distinct Hepatitis B and HIV co-infected populations in Canada.

Due to shared modes of exposure, HIV-HBV co-infection is common worldwide. Increased knowledge of the demographic and clinical characteristics of the co-infected population will allow us to optimize our approach to management of both infections in clinical practice. The Canadian Hepatitis B Network Cohort was utilized to conduct a cross-sectional evaluation of the demographic, biochemical, fibrotic and treatment characteristics of HIV-HBV patients and a comparator HBV group. From a total of 5996 HBV-infected patients, 335 HIV-HBV patients were identified. HIV-HBV patients were characterized by older median age, higher male and lower Asian proportion, more advanced fibrosis and higher anti-HBV therapy use (91% vs. 30%) than the HBV-positive / HIV seronegative comparator group. A history of reported high-risk exposure activities (drug use, high-risk sexual contact) was more common in HIV-HBV patients. HIV-HBV patients with reported high-risk exposure activities had higher male proportion, more Caucasian ethnicity and higher prevalence of cirrhosis than HIV-HBV patients born in an endemic country. In the main cohort, age ≥60 years, male sex, elevated ALT, the presence of comorbidity and HCV seropositivity were independent predictors of significant fibrosis. HIV seropositivity was not an independent predictor of advanced fibrosis (adj OR 0.75 [95%CI: 0.34-1.67]). In conclusion, Canadian co-infected patients differed considerably from those with mono-infection. Furthermore, HIV-HBV-infected patients who report high-risk behaviours and those born in endemic countries represent two distinct subpopulations, which should be considered when engaging these patients in care.

Effectiveness and Renal Safety of Tenofovir Alafenamide Fumarate among Chronic Hepatitis B Patients: Real-World Study.

Tenofovir alafenamide fumarate (TAF) has high plasma stability resulting in fewer renal adverse events compared to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. We aimed to study the effectiveness and renal safety of TAF in a real-world setting, in patients with or without compromised kidney function. CHB patients (Nucleos(t)ide Analogue [NA]-naïve or experienced) who received TAF >1 year from 11 academic institutions as part of the Canadian Hepatitis B Network (CanHepB) were included. Kidney function was measured by estimated glomerular filtration rate (eGFR) as per Cockcroft-Gault. Patients were followed for up to 160 weeks. Of 176 patients receiving TAF, 143 switched from NA (88% TDF), and 33(19%) were NA naïve. Majority of NA-naïve patients (75%) achieved undetectable HBV DNA after one year of TAF treatment. Majority of patients with eGFR <60 mL/min who had renal deterioration during TDF (76%) reversed to eGFR increase after one year of TAF (p=0.009). Among patients with stage 2 chronic kidney disease (CKD) (eGFR 60-89), the estimated eGFR decline during TDF was halted after switching to TAF (p=0.09). NA-experienced patients with abnormal ALT before TAF showed a significant decline after switching to TAF: -0.005 [-0.006 - -0.004] log10 ULN U/L/month, p<0.001). In CHB patients, TAF was safe, well-tolerated and effective in this real-world cohort. Switching to TAF led to improved kidney function, particularly in those with stage 2 CKD, which suggests that the indication for TAF in the guidelines could be extended to patients with an eGFR higher than 60 mL/min.