Mechanistic convergence across initiation sites for RAN translation in fragile X associated tremor ataxia syndrome.

Repeat associated non-AUG (RAN) translation of CGG repeats in the 5'UTR of FMR1 produces toxic proteins that contribute to fragile X-associated tremor/ataxia syndrome (FXTAS) pathogenesis. The most abundant RAN product, FMRpolyG, initiates predominantly at an ACG upstream of the repeat. Accurate FMRpolyG measurements in FXTAS patients are lacking. We used data-dependent acquisition and parallel reaction monitoring (PRM) mass spectrometry coupled with stable isotope labeled standard peptides to identify signature FMRpolyG fragments in patient samples. Following immunoprecipitation, PRM detected FMRpolyG signature peptides in transfected cells, and FXTAS tissues and cells, but not in controls. We identified two amino-terminal peptides: an ACG-initiated Ac-MEAPLPGGVR and a GUG-initiated Ac-TEAPLPGGVR, as well as evidence for RAN translation initiation within the CGG repeat itself in two reading frames. Initiation at all sites increased following cellular stress, decreased following eIF1 overexpression and was eIF4A and M7G cap-dependent. These data demonstrate that FMRpolyG is quantifiable in human samples and FMR1 RAN translation initiates via similar mechanisms for near-cognate codons and within the repeat through processes dependent on available initiation factors and cellular environment.

An Apple a Day to Keep the Parkinson's Disease Doctor Away?

It is challenging to reliably assess the motor features of Parkinson's disease in real-time. This has motivated the search for new digital outcomes that can objectively and remotely measure the severity of parkinsonian motor impairments over an extended period of time. The United States Food and Drug Administration (FDA) has recently granted a 510(k) clearance to the Rune Labs Kinematics System, an ambulatory, smartwatch-based monitoring system to remotely track tremor and dyskinesias in persons with Parkinson's disease. The FDA clearance means that this new digital approach can be regarded as being safe for use in daily practice, with acceptable correlations to clinically based measures. However, the immediate implications for clinicians are limited, because it remains to be demonstrated whether the digital signals correlate well to clinically meaningful outcomes at patient level. The impact on research is also restricted for now, as more validation studies are needed before this new digital approach can be used as primary or secondary endpoint in clinical trials. ANN NEUROL 2023;93:681-685.

The out-of-pocket expenses of people with tinnitus in Europe.

BACKGROUND: Despite the high frequency of tinnitus and its impact on wellbeing, little is known about its economic burden and no data to our knowledge are available on out-of-pocket (OOP) expenses. METHODS: In 2022 a survey was conducted on OOP costs of tinnitus. We enrolled 679 participants with slight, moderate and severe tinnitus in Italy, United Kingdom, Netherlands, Germany and Spain. We estimated annual OOP expenses for tinnitus-related healthcare visits, treatments, medications and alternative medicine practices. Prevalence of tinnitus in the general population, obtained from a representative survey we conducted in Europe in 2017-2018, was used to generalise costs for people with any tinnitus at the national level. RESULTS: OOP expenses were 368€ (95% confidence intervals (CI), 78€-690€), 728€ (95% CI, 316€-1,288€), and 1,492€ (95% CI, 760€-2,688€) for slight, moderate, and severe tinnitus, respectively, with annual expenditure of 565€ for people with any tinnitus: 209€ for healthcare visits, 93€ for treatments, 16€ for drugs, 64€ for hearing supporting systems and 183€ for acupuncture, homeopathy and osteopathy. Individuals with slight, moderate, and severe tinnitus expressed a willingness to invest 1.6, 4.3, and 7.0 times their monthly income, respectively, to achieve complete relief from tinnitus. CONCLUSIONS: This study offers for the first time insights into the OOP expenses incurred by individuals with tinnitus. OOP expenses exhibited substantial variations based on severity status, accounting for more than 17 thousand million€ in the countries considered. In terms of financial burden, these findings align tinnitus to the recognised leading disabilities, including back pain and migraine.

On the Concerning Early Failure of a Short Stem Press-Fit Humeral Component.

INTRODUCTION: Anatomic total shoulder arthroplasty (TSA) is a common surgical intervention for various shoulder pathologies, predominantly glenohumeral osteoarthritis. While generally considered safe and effective, complications remain a challenge. Short stem implants, aim to preserve bone stock and reduce complications. However, concerns about a specific short stem implant (Univers Apex; Arthrex, Naples, FL, USA) have surfaced due to high reported rates relatively early aseptic loosening. METHODS: This retrospective study analyzed 116 consecutive TSA patients with Univers Apex implants from 2004 to 2022. 15 revision cases were assessed for radiographic loosening, and explanted implants were examined for damage using a 0-3 scale. Histopathological analysis evaluated cellular responses to wear debris. RESULTS: Of the patients, 13% (15/116) required revision at 23.2 months on average. A distinct radiographic loosening pattern was identified, with humeral component subsidence and thinning of the proximal humeral cortex. Histopathology revealed a robust inflammatory response to wear debris, with a potential association between macrophage infiltration, hinge damage, and polyethylene wear. CONCLUSION: This study reveals a notable rate of early aseptic humeral loosening with the Univers Apex short stem implant, emphasizing concerns raised in previous reports and providing a potential explanation for the high rate of early failure. Surgeons should exercise caution and closely monitor patients with this implant design.

Fretting and Tribocorrosion of Modular Dual Mobility Liners: Role of Design, Microstructure, and Malseating.

BACKGROUND: Modular dual mobility (DM) bearings have a junction between a cobalt chrome alloy (CoCrMo) liner and titanium shell, and the risk of tribocorrosion at this interface remains a concern. The purpose of this study was to determine whether liner malseating and liner designs are associated with taper tribocorrosion. METHODS: We evaluated 28 retrieved modular DM implants with a mean in situ duration of 14.6 months (range, 1 to 83). There were 2 manufacturers included (12 and 16 liners, respectively). Liners were considered malseated if a distinct divergence between the liner and shell was present on postoperative radiographs. Tribocorrosion was analyzed qualitatively with the modified Goldberg Score and quantitatively with an optical coordinate-measuring machine. An acetabular shell per manufacturer was sectioned for metallographic analysis. RESULTS: There were 6 implants (22%) that had severe grade 4 corrosion, 6 (22%) had moderate grade 3, 11 (41%) had mild grade 2, and 5 (18.5%) had grade 1 or no visible corrosion. The average volumetric material loss at the taper was 0.086 ± 0.19 mm3. There were 7 liners (25%) that had radiographic evidence of malseating, and all were of a single design (P = .01). The 2 liner designs were fundamentally different from one another with respect to the cobalt chrome alloy type, taper surface finish, and shape deviations. Malseating was an independent risk factor for increased volumetric material loss (P = .017). CONCLUSIONS: DM tribocorrosion with quantifiable material loss occurred more commonly in malseated liners. Specific design characteristics may make liners more prone to malseating, and the interplay between seating mechanics, liner characteristics, and patient factors likely contributes to the shell/liner tribocorrosion environment. LEVEL OF EVIDENCE: Level III.

Potential Prodromal Digital Postural Sway Markers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS) Detected via Dual-Tasking and Sensory Manipulation.

FXTAS is a neurodegenerative disorder occurring in some Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene premutation carriers (PMCs) and is characterized by cerebellar ataxia, tremor, and cognitive deficits that negatively impact balance and gait and increase fall risk. Dual-tasking (DT) cognitive-motor paradigms and challenging balance conditions may have the capacity to reveal markers of FXTAS onset. Our objectives were to determine the impact of dual-tasking and sensory and stance manipulation on balance in FXTAS and potentially detect subtle postural sway deficits in FMR1 PMCs who are asymptomatic for signs of FXTAS on clinical exam. Participants with FXTAS, PMCs without FXTAS, and controls underwent balance testing using an inertial sensor system. Stance, vision, surface stability, and cognitive demand were manipulated in 30 s trials. FXTAS participants had significantly greater total sway area, jerk, and RMS sway than controls under almost all balance conditions but were most impaired in those requiring vestibular control. PMCs without FXTAS had significantly greater RMS sway compared with controls in the feet apart, firm, single task conditions both with eyes open and closed (EC) and the feet together, firm, EC, DT condition. Postural sway deficits in the RMS postural sway variability domain in asymptomatic PMCs might represent prodromal signs of FXTAS. This information may be useful in providing sensitive biomarkers of FXTAS onset and as quantitative balance measures in future interventional trials and longitudinal natural history studies.

Parkinson Disease and Subthalamic Nucleus Deep Brain Stimulation: Cognitive Effects in GBA Mutation Carriers.

OBJECTIVE: This study was undertaken to compare the rate of change in cognition between glucocerebrosidase (GBA) mutation carriers and noncarriers with and without subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson disease. METHODS: Clinical and genetic data from 12 datasets were examined. Global cognition was assessed using the Mattis Dementia Rating Scale (MDRS). Subjects were examined for mutations in GBA and categorized as GBA carriers with or without DBS (GBA+DBS+, GBA+DBS-), and noncarriers with or without DBS (GBA-DBS+, GBA-DBS-). GBA mutation carriers were subcategorized according to mutation severity (risk variant, mild, severe). Linear mixed modeling was used to compare rate of change in MDRS scores over time among the groups according to GBA and DBS status and then according to GBA severity and DBS status. RESULTS: Data were available for 366 subjects (58 GBA+DBS+, 82 GBA+DBS-, 98 GBA-DBS+, and 128 GBA-DBS- subjects), who were longitudinally followed (range = 36-60 months after surgery). Using the MDRS, GBA+DBS+ subjects declined on average 2.02 points/yr more than GBA-DBS- subjects (95% confidence interval [CI] = -2.35 to -1.69), 1.71 points/yr more than GBA+DBS- subjects (95% CI = -2.14 to -1.28), and 1.49 points/yr more than GBA-DBS+ subjects (95% CI = -1.80 to -1.18). INTERPRETATION: Although not randomized, this composite analysis suggests that the combined effects of GBA mutations and STN-DBS negatively impact cognition. We advise that DBS candidates be screened for GBA mutations as part of the presurgical decision-making process. We advise that GBA mutation carriers be counseled regarding potential risks associated with STN-DBS so that alternative options may be considered. ANN NEUROL 2022;91:424-435.

Scales for Antipsychotic-Associated Movement Disorders: Systematic Review, Critique, and Recommendations.

BACKGROUND: Antipsychotic-associated movement disorders remain common and disabling. Their screening and assessment are challenging due to clinical heterogeneity and different use of nomenclature between psychiatrists and neurologists. OBJECTIVE: An International Parkinson and Movement Disorder Society subcommittee aimed to rate psychometric quality of severity and screening instruments for antipsychotic-associated movement disorders. METHODS: Following the methodology adopted by previous International Parkinson and Movement Disorders Society subcommittee papers, instruments for antipsychotic-associated movement disorders were reviewed, applying a classification as "recommended," "recommended with caveats," "suggested," or "listed." RESULTS: Our review identified 23 instruments. The highest grade of recommendation reached is "recommended with caveats," assigned to seven severity rating instruments (Extrapyramidal Symptoms Rating Scale, Barnes Akathisia Rating Scale, Abnormal Involuntary Movements Scale, Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre involuntary movements scale, Simpson Angus Scale, and Matson Evaluation of Drug Side effects). Only three of these seven (Drug-Induced Extra-Pyramidal Symptoms Scale, Maryland Psychiatric Research Centre, Matson Evaluation of Drug Side effects) were also screening instruments. Their main caveats are insufficient demonstration of psychometric properties (internal consistency, skewing, responsiveness to change) and long duration of administration. Eight "suggested" instruments did not meet requirements for the "recommended" grade also because of insufficient psychometric validation. Other limitations shared by several instruments are lack of comprehensiveness in assessing the spectrum of antipsychotic-associated movement disorders and ambiguous nomenclature. CONCLUSIONS: The high number of instruments "recommended with caveats" does not support the need for developing new instruments for antipsychotic-associated movement disorders. However, addressing the caveats with new psychometric studies and revising existing instruments to improve the clarity of their nomenclature are recommended next steps. © 2023 International Parkinson and Movement Disorder Society.

Integrated Multi-Cohort Analysis of the Parkinson's Disease Gut Metagenome.

BACKGROUND: The gut microbiome is altered in several neurologic disorders, including Parkinson's disease (PD). OBJECTIVES: The aim is to profile the fecal gut metagenome in PD for alterations in microbial composition, taxon abundance, metabolic pathways, and microbial gene products, and their relationship with disease progression. METHODS: Shotgun metagenomic sequencing was conducted on 244 stool donors from two independent cohorts in the United States, including individuals with PD (n = 48, n = 47, respectively), environmental household controls (HC, n = 29, n = 30), and community population controls (PC, n = 41, n = 49). Microbial features consistently altered in PD compared to HC and PC subjects were identified. Data were cross-referenced to public metagenomic data sets from two previous studies in Germany and China to determine generalizable microbiome features. RESULTS: We find several significantly altered taxa between PD and controls within the two cohorts sequenced in this study. Analysis across global cohorts returns consistent changes only in Intestinimonas butyriciproducens. Pathway enrichment analysis reveals disruptions in microbial carbohydrate and lipid metabolism and increased amino acid and nucleotide metabolism in PD. Global gene-level signatures indicate an increased response to oxidative stress, decreased cellular growth and microbial motility, and disrupted intercommunity signaling. CONCLUSIONS: A metagenomic meta-analysis of PD shows consistent and novel alterations in functional metabolic potential and microbial gene abundance across four independent studies from three continents. These data reveal that stereotypic changes in the functional potential of the gut microbiome are a consistent feature of PD, highlighting potential diagnostic and therapeutic avenues for future research. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

The International Fragile X Premutation Registry: building a resource for research and clinical trial readiness.

FMR1 premutation cytosine-guanine-guanine repeat expansion alleles are relatively common mutations in the general population that are associated with a neurodegenerative disease (fragile X-associated tremor/ataxia syndrome), reproductive health problems and potentially a wide range of additional mental and general health conditions that are not yet well-characterised. The International Fragile X Premutation Registry (IFXPR) was developed to facilitate and encourage research to better understand the FMR1 premutation and its impact on human health, to facilitate clinical trial readiness by identifying and characterising diverse cohorts of individuals interested in study participation, and to build community and collaboration among carriers, family members, researchers and clinicians around the world. Here, we describe the development and content of the IFXPR, characterise its first 747 registrants from 32 countries and invite investigators to apply for recruitment support for their project(s). With larger numbers, increased diversity and potentially the future clinical characterisation of registrants, the IFXPR will contribute to a more comprehensive and accurate understanding of the fragile X premutation in human health and support treatment studies.

Why is tinnitus a problem? A large-scale qualitative evaluation of problems reported by tinnitus patients in mainland China.

Objectives: The lived experience of tinnitus has biopsychosocial characteristics which are influenced by sociocultural factors. The main purpose of this study is to investigate how tinnitus affects people in their everyday life in China. A deductive qualitative analysis examined whether an a priori Western-centric conceptual framework could extend to an Asian context.Design: A large-scale prospective survey collected patient-reported problems associated with tinnitus in 485 adults attending four major ENT clinics in Eastern and Southern mainland China.Results: The evidence suggests that patients in China express a narrower range of problem domains associated with the lived experience of tinnitus. While 13 tinnitus-related problem domains were confirmed, culture-specific adaptations included the addition uncomfortable (a novel concept not previously reported), and the potential exclusion of concepts such as intrusiveness, loss of control, loss of peace and loss of sense of self.Conclusions: The sociocultural context of patients across China plays an important role in defining the vocabulary used to describe the patient-centred impacts of tinnitus. Possible explanatory factors include cultural differences in the meaning and relevance of certain concepts relating to self and in help-seeking behaviour, low health literacy and a different lexicon in Chinese compared to English to describe tinnitus-related problems.

Has Wrought Cobalt-Chromium-Molybdenum Alloy Changed for the Worse Over Time?

BACKGROUND: Total hip arthroplasty (THA) failure due to tribocorrosion of modular junctions and resulting adverse local tissue reactions to corrosion debris have seemingly increased over the past few decades. Recent studies have found that chemically-induced column damage seen on the inner head taper is enabled by banding in the alloy microstructure of wrought cobalt-chromium-molybdenum alloy femoral heads, and is associated with more material loss than other tribocorrosion processes. It is unclear if alloy banding represents a recent phenomenon. The purpose of this study was to examine THAs implanted in the 1990s, 2000s, and 2010s to determine if alloy microstructure and implant susceptibility to severe damage has increased over time. METHODS: Five hundred and forty-five modular heads were assessed for damage severity and grouped based on decade of implantation to serve as a proxy measure for manufacturing date. A subset of heads (n = 120) was then processed for metallographic analysis to visualize alloy banding. RESULTS: We found that damage score distribution was consistent over the time periods, but the incidence of column damage significantly increased between the 1990s and 2000s. Banding also increased from the 1990s to 2000s, but both column damage and banding levels appear to recover slightly in the 2010s. CONCLUSION: Banding, which provides preferential corrosion sites enabling column damage, has increased over the last 3 decades. No difference between manufacturers was seen, which may be explained by shared suppliers of bar stock material. These findings are important as banding can be avoidable, reducing the risk of severe column damage to THA modular junctions and failure due to adverse local tissue reactions.

Gut microbial metabolites in Parkinson's disease: Association with lifestyle, disease characteristics, and treatment status.

There is growing appreciation of the importance of the intestinal microbiota in Parkinson's disease (PD), and one potential mechanism by which the intestinal microbiota can communicate with the brain is via bacteria-derived metabolites. In this study, plasma levels of bacterial-derived metabolites including trimethylamine-N-oxide (TMAO), short chain fatty acids (SCFA), the branched chain fatty acid isovalerate, succinate, and lactate were evaluated in PD subjects (treatment naïve and treated) which were compared to (1) population controls, (2) spousal / household controls (similar lifestyle to PD subjects), and (3) subjects with multiple system atrophy (MSA). Analyses revealed an increase in the TMAO pathway in PD subjects which was independent of medication status, disease characteristics, and lifestyle. Lactic acid was decreased in treated PD subjects, succinic acid positively correlated with disease severity, and the ratio of pro-inflammatory TMAO to the putative anti-inflammatory metabolite butyric acid was significantly higher in PD subjects compared to controls indicating a pro-inflammatory shift in the metabolite profile in PD subjects. Finally, acetic and butyric acid were different between PD and MSA subjects indicating that metabolites may differentiate these synucleinopathies. In summary, (1) TMAO is elevated in PD subjects, a phenomenon independent of disease characteristics, treatment status, and lifestyle and (2) metabolites may differentiate PD and MSA subjects. Additional studies to understand the potential of TMAO and other bacterial metabolites to serve as a biomarker or therapeutic targets are warranted.

Characterization of the Cerebrospinal Fluid Proteome in Patients with Fragile X-Associated Tremor/Ataxia Syndrome.

Fragile X-associated tremor/ataxia syndrome (FXTAS), first described in 2001, is a neurodegenerative and movement disorder, caused by a premutation in the fragile X mental retardation 1 (FMR1) gene. To date, the biological mechanisms causing this condition are still not well understood, as not all premutation carriers develop FXTAS. To further understand this syndrome, we quantitatively compared the cerebrospinal fluid (CSF) proteome of FXTAS patients with age-matched controls using mass spectrometry. We identified 415 proteins of which 97 were altered in FXTAS patients. These proteins suggest changes in acute phase response signaling, liver X receptor/ retinoid X receptor (LXR/RXR) activation, and farnesoid X receptor (FXR)/RXR activation, which are the main pathways found to be affected. Additionally, we detected changes in many other proteins including amyloid-like protein 2, contactin-1, afamin, cell adhesion molecule 4, NPC intracellular cholesterol transporter 2, and cathepsin B, that had been previously noted to hold important roles in other movement disorders. Specific to RXR pathways, several apolipoproteins (APOA1, APOA2, APOA4, APOC2, and APOD) showed significant changes in the CSF of FXTAS patients. Lastly, CSF parameters were analyzed to investigate abnormalities in blood brain barrier function. Correlations were observed between patient albumin quotient values, a measure of permeability, and CGG repeat length as well as FXTAS rating scale scores.

Gut-Brain Communication in Parkinson's Disease: Enteroendocrine Regulation by GLP-1.

PURPOSE OF REVIEW: Defective gut-brain communication has recently been proposed as a promoter of neurodegeneration, but mechanisms mediating communication remain elusive. In particular, the Parkinson's disease (PD) phenotype has been associated with both dysbiosis of intestinal microbiota and neuroinflammation. Here, we review recent advances in the PD field that connect these two concepts, providing an explanation based on enteroendocrine signaling from the gut to the brain. RECENT FINDINGS: There have been several recent accounts highlighting the importance of the microbiota-gut-brain axis in PD. The objective of this review is to discuss the role of the neuroendocrine system in gut-brain communication as it relates to PD pathogenesis, as this system has not been comprehensively considered in prior reviews. The incretin hormone glucagon-like peptide 1 (GLP-1) is secreted by enteroendocrine cells of the intestinal epithelium, and there is evidence that it is neuroprotective in animal models and human subjects with PD. Agonists of GLP-1 receptors used in diabetes appear to be useful for preventing neurodegeneration. New tools and models have enabled us to study regulation of GLP-1 secretion by intestinal microbiota, to understand how this process may be defective in PD, and to develop methods for therapeutically modifying disease development or progression using the enteroendocrine system. GLP-1 secretion by enteroendocrine cells may be a key mediator of neuroprotection in PD, and new findings in this field may offer unique insights into PD pathogenesis and therapeutic strategies.

Alloys Used in Different Temporomandibular Joint Reconstruction Replacement Prostheses Exhibit Variable Microstructures and Electrochemical Properties.

PURPOSE: Metallic temporomandibular joint replacement (TMJR) systems vary depending on design, material composition, and manufacturing methods such as casting, forging, and additive manufacturing. Therefore, the purpose of this study was to measure the association between manufacturing process of TMJR systems in terms of microstructure and electrochemical properties. MATERIALS AND METHODS: The sample was composed of new or surgically retrieved TMJ replacement devices of either titanium alloy (Ti6Al4V) or cobalt-chromium-molybdenum (CoCrMo) alloy from 8 different manufacturers. The primary predictor variable was alloy type, according to its manufacturing process (wrought, cast, additively manufactured [AM]). The primary outcome variables were 1) microstructure (grain size, aspect ratio, and phase content) and 2) corrosion potential and current, polarization resistance, and capacitance. Differences between alloy groups were determined by t tests, Kruskal-Wallis, and Mann-Whitney tests. RESULTS: We demonstrated that the TMJR CoCrMo and Ti6Al4V alloy microstructures can vary broadly within American Society for Testing and Materials specifications, where the components made of Ti6Al4V had 3 types of microstructures (equiaxial, bimodal, and martensitic) out of 10 samples, and the components made of CoCrMo had 2 types of microstructure (equiaxial and dendritic) out of 16 samples. Some CoCrMo alloys exhibited preferential corrosion sites, while wrought Ti6Al4V alloys trended toward a superior corrosion behavior (corrosion rate: 2 × 10-9 A/cm2, polarization resistance: 5,000,000 kΩcm2, and capacitance: 10 µSsa/cm2) compared with AM alloys (39 × 10-9 A/cm2, 1676 kΩcm2, 36 µSsa/cm2, respectively), where 4 samples of each group were tested and repeated 5 times. Among four AM devices, two exhibited a significantly inferior corrosion behavior. CONCLUSIONS: Although AM is an exciting emerging new technology that allows manufacturing of custom-made TMJR, their corrosion behavior is still inferior in comparison to that of traditional wrought alloys. Preventing corrosion is crucial because it can cause surface defects that may lead to implant fracture.

An Albanian translation of a questionnaire for self-reported tinnitus assessment.

OBJECTIVE: To our knowledge, there is no published study investigating the characteristics of people experiencing tinnitus in Albania. Such a study would be important, providing the basis for further research in this region and contributing to a wider understanding of tinnitus heterogeneity across different geographic locations. The main objective of this study was to develop an Albanian translation of a standardised questionnaire for tinnitus research, namely the European School for Interdisciplinary Tinnitus Research-Screening Questionnaire (ESIT-SQ). A secondary objective was to assess its applicability and usefulness by conducting an exploratory survey on a small sample of the Albanian tinnitus population. DESIGN AND STUDY SAMPLE: Three translators were recruited to create the Albanian ESIT-SQ translation following good practice guidelines. Using this questionnaire, data from 107 patients attending otolaryngology clinics in Albania were collected. RESULTS: Participants reporting various degrees of tinnitus symptom severity had distinct phenotypic characteristics. Application of a random forest approach on this preliminary dataset showed that self-reported hearing difficulty, and tinnitus duration, pitch and temporal manifestation were important variables for predicting tinnitus symptom severity. CONCLUSIONS: Our study provided an Albanian translation of the ESIT-SQ and demonstrated that it is a useful tool for tinnitus profiling and subgrouping.

Do total shoulder arthroplasty implants corrode?

BACKGROUND: Total shoulder arthroplasty (TSA) has become the gold-standard treatment to relieve joint pain and disability in patients with glenohumeral osteoarthritis who do not respond to conservative treatment. An adverse reaction to metal debris released due to fretting corrosion has been a major concern in total hip arthroplasty. To date, it is unclear how frequently implant corrosion occurs in TSA and whether it is a cause of implant failure. This study aimed to characterize and quantify corrosion and fretting damage in a single anatomic TSA design and to compare the outcomes to the established outcomes of total hip arthroplasty. METHODS: We analyzed 21 surgically retrieved anatomic TSAs of the same design (Tornier Aequalis Pressfit). The retrieved components were microscopically examined for taper corrosion, and taper damage was scored. Head and stem taper damage was quantitatively measured with a non-contact optical coordinate-measuring machine. In selected cases, damage was further characterized at high magnifications using scanning electron microscopy. Energy-dispersive x-ray spectroscopy and metallographic evaluations were performed to determine underlying alloy microstructure and composition. Comparisons between groups with different damage features were performed with independent-samples t tests; Mann-Whitney tests and multivariate linear regression were conducted to correlate damage with patient factors. The level of statistical significance was set at P < .05. RESULTS: The average material loss for head and stem tapers was 0.007 mm3 and 0.001 mm3, respectively. Material loss was not correlated with sex, age, previous implant, or time in situ (P > .05). We observed greater volume loss in head tapers compared with stem tapers (P = .002). Implants with evidence of column damage had larger volumetric material loss than those without such evidence (P = .003). Column damage aligned with segregation bands within the alloy (preferential corrosion sites). The average angular mismatch was 0.03° (standard deviation, 0.0668°), with negative values indicating distal engagement and positive values indicating proximal engagement. Implants with proximal engagement were significantly more likely to have column damage than those with distal engagement (P = .030). DISCUSSION: This study has shown not only that the metal components of TSA implants can corrode but also that the risk of corrosion can be reduced by (1) eliminating preferential corrosion sites and (2) ensuring distal engagement to prevent fluid infiltration into the modular junction.

Exosomal microRNAs in the development of essential hypertension and its potential as biomarkers.

MicroRNAs (miRNAs) are small regulatory molecules that are involved in posttranscriptional modifications. These noncoding RNAs are usually ferried by extracellular carriers such as exosomes or other protein and lipid carriers inside a range of body fluids including plasma and urine. Due to their ability to withstand harsh external conditions, exosomal miRNAs possess enormous potential as noninvasive disease biomarkers for, notably hypertension, whereby exosomal miRNAs have been implicated in its pathophysiological processes. More importantly, alterations in the microenvironment as a result of disease progression can induce active and selective loading of miRNAs into exosomes. In this paper, we first review the mechanisms of miRNA loading into exosomes, followed by the roles of exosomal miRNAs in the development of hypertension, and the potentials of exosomal miRNAs as biomarkers in comparison with other free circulating miRNAs. Finally, challenges and future research surrounding exosomal miRNAs will also be discussed. This review will aid in the understanding of noninvasive biomarkers for the early diagnosis of hypertension and for probing therapeutic efficacy.

Comparison of continuous sampling with active noise cancelation and sparse sampling for cortical and subcortical auditory functional MRI.

PURPOSE: Detecting sound-related activity using functional MRI requires the auditory stimulus to be more salient than the intense background scanner acoustic noise. Various strategies can reduce the impact of scanner acoustic noise, including "sparse" temporal sampling with single/clustered acquisitions providing intervals without any background scanner acoustic noise, or active noise cancelation (ANC) during "continuous" temporal sampling, which generates an acoustic signal that adds destructively to the scanner acoustic noise, substantially reducing the acoustic energy at the participant's eardrum. Furthermore, multiband functional MRI allows multiple slices to be collected simultaneously, thereby reducing scanner acoustic noise in a given sampling period. METHODS: Isotropic multiband functional MRI (1.5 mm) with sparse sampling (effective TR = 9000 ms, acquisition duration = 1962 ms) and continuous sampling (TR = 2000 ms) with ANC were compared in 15 normally hearing participants. A sustained broadband noise stimulus was presented to drive activation of both sustained and transient auditory responses within subcortical and cortical auditory regions. RESULTS: Robust broadband noise-related activity was detected throughout the auditory pathways. Continuous sampling with ANC was found to give a statistically significant advantage over sparse sampling for the detection of the transient (onset) stimulus responses, particularly in the auditory cortex (P < .001) and inferior colliculus (P < .001), whereas gains provided by sparse over continuous ANC for detecting offset and sustained responses were marginal (p ~ 0.05 in superior olivary complex, inferior colliculus, medial geniculate body, and auditory cortex). CONCLUSIONS: Sparse and continuous ANC multiband functional MRI protocols provide differing advantages for observing the transient (onset and offset) and sustained stimulus responses.