Service delivery approaches related to hearing aids in low- and middle-income countries or resource-limited settings: A systematic scoping review.

Hearing loss is an important global public health issue which can be alleviated through treatment with hearing aids. However, most people who would benefit from hearing aids do not receive them, in part due to challenges in accessing hearing aids and related services, which are most salient in low- and middle-income countries (LMIC) and other resource-limited settings. Innovative approaches for hearing aid service delivery can overcome many of the challenges related to access, including that of limited human resources trained to provide ear and hearing care. The purpose of this systematic scoping review is to synthesize evidence on service delivery approaches for hearing aid provision in LMIC and resource-limited settings. We searched 3 databases (PubMed, Scopus, Ovid MEDLINE) for peer-reviewed articles from 2000 to 2022 that focused on service delivery approaches related to hearing aids in LMIC or resource-limited settings. Fifteen peer-reviewed articles were included, which described hospital-based (3 studies), large-scale donation program (1 studies), community-based (7 studies), and remote (telehealth; 4 studies) service delivery approaches. Key findings are that hearing aid services can be successfully delivered in hospital- and community-based settings, and remotely, and that both qualified hearing care providers and trained non-specialists can provide quality hearing aid services. Service delivery approaches focused on community-based and remote care, and task sharing among qualified hearing care providers and trained non-specialists can likely improve access to hearing aids worldwide, thereby reducing the burden of untreated hearing loss.

Visualizing Mitochondrial Importability of a Protein Using the Yeast Bi-Genomic Mitochondrial-Split-GFP Strain and an Ordinary Fluorescence Microscope.

Proving with certainty that a GFP-tagged protein is imported inside mitochondria by visualizing its fluorescence emission with an epifluorescence microscope is currently impossible using regular GFP-tagging. This is particularly true for proteins dual localized in the cytosol and mitochondria, which have been estimated to represent up to one third of the established mitoproteomes. These proteins are usually composed of a surpassingly abundant pool of the cytosolic isoform compared to the mitochondrial isoform. As a consequence, when tagged with a regular GFP, the fluorescence emission of the cytosolic isoform will inevitably eclipse that of the mitochondrial one and prevent the detection of the mitochondrial echoform. To overcome this technical limit, we engineered a yeast strain expressing a new type of GFP called Bi-Genomic Mitochondrial-Split-GFP (BiG Mito-Split-GFP). In this strain, one moiety of the GFP is encoded by the mitochondrial DNA while the second moiety of the GFP can be tagged to any nuclear-encoded protein (suspected to be dual localized or bona fide mitochondrial). By doing so, only mitochondrial proteins or echoforms of dual localized proteins, regardless of their organismal origin, trigger GFP reconstitution that can be visualized by regular fluorescence microscopy. The strength of the BiG Mito-Split-GFP system is that proof of the mitochondrial localization of a given protein rests on a simple and effortless microscopy observation.

Age-stratified adeno-associated virus serotype 3 neutralizing and total antibody prevalence in hemophilia A patients from India.

Gene therapy using an adeno-associated virus (AAV) vector offers a new treatment option for individuals with monogenetic disorders. The major bottleneck is the presence of pre-existing anti-AAV antibodies, which impacts its use. Even very low titers of neutralizing antibodies (NAb) to capsids from natural AAV infections have been reported to inhibit the transduction of intravenously administered AAV in animal models and are associated with limited efficacy in human trials. Assessing the level of pre-existing NAb is important for determining the primary eligibility of patients for AAV vector-based gene therapy clinical trials. Techniques used to screen AAV-antibodies include AAV capsid enzyme-linked immunosorbent assay (ELISA) and transduction inhibition assay (TIA) for detecting total capsid-binding (TAb) and Nab, respectively. In this study, we screened 521 individuals with hemophilia A from India for TAb and NAb using ELISA and TIA, respectively. The prevalence of TAb and NAb in hemophilia A patients from India were 96% and 77.5%, respectively. There was a significant increase in anti-AAV3 NAb prevalence with age in the hemophilia A patient group from India. There was a trend in anti-AAV3 TAb positivity between the pediatric age group (94.4%) and the adult age group (97.4%).

RNA-dependent synthesis of ergosteryl-3ß-O-glycine in Ascomycota expands the diversity of steryl-amino acids.

A wide range of bacteria possess virulence factors such as aminoacyl-tRNA transferases (ATTs) that are capable of rerouting aminoacyl-transfer RNAs away from protein synthesis to conjugate amino acids onto glycerolipids. We recently showed that, although these pathways were thought to be restricted to bacteria, higher fungi also possess ergosteryl-3ß-O-L-aspartate synthases (ErdSs), which transfer the L-Asp moiety of aspartyl-tRNAAsp onto the 3ß-OH group of ergosterol (Erg), yielding ergosteryl-3ß-O-L-aspartate (Erg-Asp). Here, we report the discovery, in fungi, of a second type of fungal sterol-specific ATTs, namely, ergosteryl-3ß-O-glycine (Erg-Gly) synthase (ErgS). ErgS consists of a freestanding DUF2156 domain encoded by a gene distinct from and paralogous to that of ErdS. We show that the enzyme only uses Gly-tRNAGly produced by an independent glycyl-tRNA synthetase (GlyRS) to transfer glycine onto the 3ß-OH of Erg, producing Erg-Gly. Phylogenomics analysis also show that the Erg-Gly synthesis pathway exists only in Ascomycota, including species of biotechnological interest, and more importantly, in human pathogens, such as Aspergillus fumigatus. The discovery of a second type of Erg-aa not only expands the repertoire of this particular class of fungal lipids but suggests that Erg-aa synthases might constitute a genuine subfamily of lipid-modifying ATTs.

Assembly-dependent translation of subunits 6 (Atp6) and 9 (Atp9) of ATP synthase in yeast mitochondria.

The yeast mitochondrial ATP synthase is an assembly of 28 subunits of 17 types of which 3 (subunits 6, 8, and 9) are encoded by mitochondrial genes, while the 14 others have a nuclear genetic origin. Within the membrane domain (FO) of this enzyme, the subunit 6 and a ring of 10 identical subunits 9 transport protons across the mitochondrial inner membrane coupled to ATP synthesis in the extra-membrane structure (F1) of ATP synthase. As a result of their dual genetic origin, the ATP synthase subunits are synthesized in the cytosol and inside the mitochondrion. How they are produced in the proper stoichiometry from two different cellular compartments is still poorly understood. The experiments herein reported show that the rate of translation of the subunits 9 and 6 is enhanced in strains with mutations leading to specific defects in the assembly of these proteins. These translation modifications involve assembly intermediates interacting with subunits 6 and 9 within the final enzyme and cis-regulatory sequences that control gene expression in the organelle. In addition to enabling a balanced output of the ATP synthase subunits, these assembly-dependent feedback loops are presumably important to limit the accumulation of harmful assembly intermediates that have the potential to dissipate the mitochondrial membrane electrical potential and the main source of chemical energy of the cell.

Task Demands Differentially Affect Processing of Intrinsic and Extrinsic Object Features in Working Memory.

Some argue that visual working memory operates on integrated object representations. Here, we contend that obligatory feature integration occurs with intrinsic but not extrinsic object features. Working memory for shapes and colors was assessed using a change-detection task with a central test probe, while recording event-related potentials (ERPs). Color was either an intrinsic surface feature of a shape or connected to the shape via a proximal but spatially disjunct extrinsic frame. There were two types of test: The direct test required memory for shape and color; the indirect test required only shape memory. Study-test changes of color were therefore either task-relevant or task-irrelevant. We assessed performance costs and event-related potential (ERP) effects arising from color changes. In the direct test, performance was poorer for extrinsic than intrinsic stimuli; task-relevant color changes elicited enhanced frontal negativity (N2, FN400) for both intrinsic and extrinsic stimuli. In the indirect test, performance costs and ERP effects associated with irrelevant color change were larger for intrinsic than extrinsic stimuli. This suggests intrinsic information is more readily integrated into the working-memory representation and evaluated against the test probe. Findings imply that feature integration is not obligatory under all conditions but influenced by stimulus-driven and task-related focus of attention.

Immunohistochemical Characterization of 120 Testicular Sex Cord-Stromal Tumors With an Emphasis on the Diagnostic Utility of SOX9, FOXL2, and SF-1.

Sex cord-stromal tumors (SCSTs) account for the second most common category of testicular neoplasms and include several entities that may show overlapping morphologies and present diagnostic challenges. We analyzed a cohort of 120 testicular SCSTs and investigated the diagnostic utility of SRY-box transcription factor 9 (SOX9), forkhead box protein L2 (FOXL2), and steroidogenic factor 1 (SF-1) immunohistochemical stains. The results were compared with the more commonly used SCST markers, inhibin α, calretinin, and Wilms' tumor 1 (WT1). SF-1 was overall the most sensitive stain (91%), followed by inhibin α (70%), calretinin (52%), FOXL2 (50%), SOX9 (47%), and WT1 (37%), but sensitivities varied by tumor type. SOX9 and calretinin were more commonly positive in sex cord elements versus stromal elements (62% vs. 27% and 47% vs. 9%, respectively), whereas FOXL2 was more commonly positive in stromal elements versus sex cord elements (100% vs. 55%) when excluding Leydig cell tumors from the stromal category. Although no individual stain was diagnostically specific, some immunophenotypic patterns were noted that may help in the subclassification of SCSTs. We conclude that SOX9, FOXL2, and SF-1 are useful immunohistochemical stains for confirming sex cord-stromal differentiation in testicular tumors and provide increased sensitivity as well as additional diagnostic information, especially when combined with the more commonly used inhibin α, calretinin, and WT1 immunostains. Although morphology is paramount for subclassification of SCSTs, knowledge of certain immunohistochemical patterns may be helpful for diagnostically challenging cases.

Synthesis of aminoacylated ergosterols: A new lipid component of fungi.

Aminoacylated ergosterol such as 1-ergosteryl aspartate (Erg-Asp) is a new lipid component recently discovered in fungi. In order to study physiological functions of this novel sterol derivative and to develop potential antifungal agents, we established the method to synthesize aminoacylated ergosterol derivatives. Herein, we report the synthesis of Erg-Asp as well as some other aminoacylated ergosterols (Erg-Gly, Erg-Ala, Erg-Leu, Erg-Ile, and Erg-Val) using Boc protected amino acids.

Cex1 is a component of the COPI intracellular trafficking machinery.

COPI (coatomer complex I) coated vesicles are involved in Golgi-to-ER and intra-Golgi trafficking pathways, and mediate retrieval of ER resident proteins. Functions and components of the COPI-mediated trafficking pathways, beyond the canonical set of Sec/Arf proteins, are constantly increasing in number and complexity. In mammalian cells, GORAB, SCYL1 and SCYL3 proteins regulate Golgi morphology and protein glycosylation in concert with the COPI machinery. Here, we show that Cex1, homologous to the mammalian SCYL proteins, is a component of the yeast COPI machinery, by interacting with Sec27, Sec28 and Sec33 (Ret1/Cop1) proteins of the COPI coat. Cex1 was initially reported to mediate channeling of aminoacylated tRNA outside of the nucleus. Our data show that Cex1 localizes at membrane compartments, on structures positive for the Sec33 α-COP subunit. Moreover, the Wbp1 protein required for N-glycosylation and interacting via its di-lysine motif with the Sec27 ß'-COP subunit is mis-targeted in cex1Δ deletion mutant cells. Our data point to the possibility of developing Cex1 yeast-based models to study neurodegenerative disorders linked to pathogenic mutations of its human homologue SCYL1.

Prevalence of Adeno-Associated Virus 3 Capsid Binding and Neutralizing Antibodies in Healthy and Hemophilia B Individuals from India.

Adeno-associated virus (AAV) vector-based gene therapy offers a new treatment option for individuals with hemophilia. Pre-existing anti-AAV antibodies significantly impact the use of AAV vectors. Even relatively low titers of AAV neutralizing antibodies (NAb) from natural AAV infections against the capsid have been shown to inhibit the transduction of intravenously administered AAV in animal models and were associated with limited efficacy in human trials. This is important for determining the primary eligibility of patients for AAV vector-based gene therapy clinical trials. Current techniques to screen AAV antibodies include AAV capsid enzyme-linked immunosorbent assay (ELISA) for total antibodies and a transduction inhibition assay (TIA) for NAb. This study developed and screened total capsid binding anti-AAV3 antibodies by using ELISA and determined NAb levels by TIA using mCherry flow cytometry in healthy individuals with hemophilia B in India. One hundred and forty-three apparently healthy controls and 92 individuals with hemophilia B were screened. The prevalence of total and NAb in healthy controls was 79.7% and 65%, respectively; the prevalence of total and NAb in patients with hemophilia B for AAV3 was 92.4% and 91.3%, respectively.

Unitization of internal and external features contributes to associative recognition for faces: Evidence from modulations of the FN400.

Associative recognition requires discriminating between old items and conjunction lures constructed by recombining elements from two different study items. This task can be solved not only by recollection but also by familiarity if the to-be-remembered stimuli are perceived as a unitized representation. In two event-related potential (ERP) studies, we provide evidence for the integration of internal and external facial features by showing that the early frontal old-new effect (considered a correlate of familiarity) is modulated by the specific combination of facial features. Participants studied faces consisting of internal features (eyes, eyebrows, nose, and mouth) paired with external features (hair, head shape, and ears). During the testing phase, intact, recombined, and new faces were presented. Recombined faces consisted of internal and external features taken from two different studied faces. The results showed that at the frontal sites, during the time window from 300 to 500 ms, ERPs to intact faces were more positive than those to new and recombined faces; the latter two did not differ from one another. The late parietal effect was observed only after a more extended study phase in Experiment 2. We take the modulation of the early frontal old-new effect as evidence for the contribution of familiarity to associative recognition for combinations of internal and external facial features.

Metastatic squamous cell carcinoma transformed from prostatic adenocarcinoma following androgen deprivation therapy: A case report with clinicopathologic and molecular findings.

Squamous cell carcinoma (SCC) of the prostate is a rare and clinically aggressive entity that may arise de novo or through transformation of prostatic adenocarcinoma, typically following hormonal or radiation therapy. Confirmation of prostatic origin, especially when evaluating a metastatic focus, often requires correlation with clinical and imaging findings, as the morphologic and immunohistochemical features of SCC are not organ-specific. Comprehensive genomic profiling (CGP) may provide additional information useful for confirming the primary site and for identifying potential targeted therapy options. CGP data may also contribute to our understanding of the molecular basis of squamous differentiation in prostatic malignancies. However, these data are limited, and to our knowledge, there are only three previously published cases of prostatic SCC with reported CGP findings. Herein, we report a case of metastatic keratinizing SCC diagnosed by core needle biopsy in a 68-year-old man with a history of prostatic adenocarcinoma status post radical prostatectomy and androgen deprivation therapy (ADT). NKX3.1 immunohistochemistry was negative. CGP was performed, and a TMPRSS2-ERG fusion, among other genetic alterations, was detected, supporting a diagnosis of metastatic SCC transformed from prostatic adenocarcinoma following ADT. This case supports the use of CGP or other molecular techniques not only to query potential targeted therapy options but also to refine the diagnosis and confirm the primary site of disease in cases with non-specific morphologic and immunophenotypic features, such as SCC.

RNA-dependent sterol aspartylation in fungi.

Diverting aminoacyl-transfer RNAs (tRNAs) from protein synthesis is a well-known process used by a wide range of bacteria to aminoacylate membrane constituents. By tRNA-dependently adding amino acids to glycerolipids, bacteria change their cell surface properties, which intensifies antimicrobial drug resistance, pathogenicity, and virulence. No equivalent aminoacylated lipids have been uncovered in any eukaryotic species thus far, suggesting that tRNA-dependent lipid remodeling is a process restricted to prokaryotes. We report here the discovery of ergosteryl-3ß-O-l-aspartate (Erg-Asp), a conjugated sterol that is produced by the tRNA-dependent addition of aspartate to the 3ß-OH group of ergosterol, the major sterol found in fungal membranes. In fact, Erg-Asp exists in the majority of "higher" fungi, including species of biotechnological interest, and, more importantly, in human pathogens like Aspergillus fumigatus We show that a bifunctional enzyme, ergosteryl-3ß-O-l-aspartate synthase (ErdS), is responsible for Erg-Asp synthesis. ErdS corresponds to a unique fusion of an aspartyl-tRNA synthetase-that produces aspartyl-tRNAAsp (Asp-tRNAAsp)-and of a Domain of Unknown Function 2156, which actually transfers aspartate from Asp-tRNAAsp onto ergosterol. We also uncovered that removal of the Asp modifier from Erg-Asp is catalyzed by a second enzyme, ErdH, that is a genuine Erg-Asp hydrolase participating in the turnover of the conjugated sterol in vivo. Phylogenomics highlights that the entire Erg-Asp synthesis/degradation pathway is conserved across "higher" fungi. Given the central roles of sterols and conjugated sterols in fungi, we propose that this tRNA-dependent ergosterol modification and homeostasis system might have broader implications in membrane remodeling, trafficking, antimicrobial resistance, or pathogenicity.

Visual Working Memory of Chinese Characters and Expertise: The Expert's Memory Advantage Is Based on Long-Term Knowledge of Visual Word Forms.

People unfamiliar with Chinese characters show poorer visual working memory (VWM) performance for Chinese characters than do literates in Chinese. In a series of experiments, we investigated the reasons for this expertise advantage. Experiments 1 and 2 showed that the advantage of Chinese literates does not transfer to novel material. Experts had similar resolution as novices for material outside of their field of expertise, and the memory of novices and experts did not differ when detecting a big change, e.g., when a character's color was changed. Memorizing appears to function as a rather abstract representation of word forms because memory for characters' fonts was poor independently of expertise (Experiment 3), though still visual. Distractors that were highly similar conceptually did not increase memory errors, but visually similar distractors impaired memory (Experiment 4). We hypothesized that literates in Chinese represent characters in VWM as tokens of visual word forms made available by long-term memory. In Experiment 5, we provided novices with visual word form knowledge. Participants subsequently performed a change detection task with trained and novel characters in a functional magnetic resonance experiment. We analyzed set size- and training-dependent effects in the intraparietal sulcus (IPS) and the visual word form area. VWM for trained characters was better than for novel characters. Neural activity increased with set size and at a slower rate for trained than for novel characters. All conditions approached the same maximum, but novel characters reached the maximum at a smaller set size than trained characters. The time course of the bold response depended on set size and knowledge status. Starting from the same initial maximum, neural activity at small set sizes returned to baseline more quickly for trained characters than for novel characters. Additionally, high performers showed generally more neural activity in the IPS than low performers. We conclude that experts' better performance in working memory (WM) is caused by the availability of visual long-term representations (word form types) that allow a sparse representation of the perceived stimuli and make even small changes big because they cause a type change that is easily detected.

A Clinicopathologic and Molecular Analysis of Fumarate Hydratase-deficient Renal Cell Carcinoma in 32 Patients.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare and recently described entity associated with hereditary leiomyomatosis and RCC syndrome. FH-deficient RCC may show variable clinical and pathologic findings, but commonly presents with locally advanced and metastatic disease and carries a poor prognosis. We identified 32 patients with FH-deficient RCC, confirmed by FH immunohistochemistry (IHC) and/or FH mutation analysis, and performed a retrospective review of the clinical and pathologic features. Median age at presentation was 43 years (range, 18 to 69 y), and the M:F ratio was 2.2:1. Median tumor size was 6.5 cm (range, 2.5 to 28 cm), and 71% presented at stage ≥pT3a. After a median follow-up of 16 months (range, 1 to 118 mo) in 26 patients, 19% showed no evidence of disease, 31% were alive with disease, and 50% were dead of disease. The vast majority of cases showed multiple histologic growth patterns, with papillary (52%) being the most common predominant pattern, followed by solid (21%), cribriform/sieve-like (14%), sarcomatoid (3%), tubular (3%), cystic (3%), and low-grade oncocytic (3%). Viral inclusion-like macronucleoli with perinucleolar clearing were present in almost all cases (96%). All cases were evaluated using FH IHC, and 3 cases (9%) showed retained FH expression. Nineteen cases had germline or tumor mutation analysis confirming a FH mutation, with 79% (11/14) of cases showing mutations within coding regions and 21% (3/14) showing mutations within intronic splice-sites. By IHC, 97% (32/33) of cases were negative for CK7, 93% (27/29) were negative for p63, and 52% (15/29) were negative for GATA3. All cases stained were positive for PAX8 and showed retained succinate dehydrogenase B expression. Our overall findings show that FH-deficient RCC is considerably heterogenous in morphology and frequently behaves aggressively. Suspicion for this entity should be raised even in the absence of predominantly papillary architecture and characteristic nucleolar features. We have included cases with uncommonly seen features, including 4 cases with predominantly cribriform/sieve-like architecture as well as one case with pure low-grade oncocytic morphology (9 y of clinical follow-up without evidence of disease). Although FH IHC is a useful tool for identifying cases of FH-deficient RCC, not all cases of FH-deficient RCC show loss of FH staining, and FH mutation analysis should be considered for patients with suspicious clinical or pathologic features, even in cases with retained FH IHC expression.

Targeted deep sequencing of cell-free DNA in serous body cavity fluids with malignant, suspicious, and benign cytology.

BACKGROUND: Liquid biopsy using cell-free DNA (cfDNA) presents new opportunities for solid tumor genotyping. While studies have demonstrated the utility of cfDNA from plasma, cfDNA from other body fluids remains underexplored. METHODS: We evaluated the molecular features and clinicopathologic correlates of cfDNA from serous body cavity fluids by performing hybrid capture-based next-generation sequencing (NGS) on cfDNA isolated from residual effusion supernatants. Twenty-one serous effusions from pleural (n = 15), peritoneal (n = 5), and pericardial (n = 1) cavity were analyzed. RESULTS: The supernatants provided a median cfDNA concentration of 10.3 ng/µL. Notably, all effusions were sequenced successfully to a median depth >1000×, revealing a broad range of genetic alterations including single nucleotide variants, small insertions and deletions, amplifications, and fusions. Specifically, pathogenic alterations were identified in all malignant fluids (13/13), all fluids suspicious for malignancy (2/2), and 1 benign fluid (1/6) from a patient with metastatic cancer. To validate our findings, we examined matching results from 11 patients who underwent additional testing using formalin-fixed, paraffin-embedded (FFPE) specimens. In 8 patients, the paired results between FFPE and supernatant testing were concordant, whereas in the remaining 3 patients, supernatant analysis identified additional variants likely associated with resistance to targeted therapies. Additional comparison between FFPE and supernatant testing showed no difference in DNA concentration (P = .5), depth of coverage (P = .6), or allele frequency of pathogenic mutations (P = .7). CONCLUSION: cfDNA isolated from serous body cavity fluids represents a promising source of genomic input for targeted NGS.

Spatio-Temporal Neural Changes After Task-Switching Training in Old Age.

In the present study, we aimed at examining selective neural changes after task-switching training in old age by not only considering the spatial location but also the timescale of brain activation changes (i.e., sustained/block-related or transient/trial-related timescales). We assigned a sample of 50 older adults to a task-switching training or an active single-task control group. We administered two task paradigms, either sensitive to transient (i.e., a context-updating task) or sustained (i.e., a delayed-recognition working-memory task) dynamics of cognitive control. These dynamics were captured by utilizing an appropriate event-related or block-related functional magnetic resonance imaging design. We captured selective changes in task activation during the untrained tasks after task-switching training compared to an active control group. Results revealed changes at the neural level that were not evident from only behavioral data. Importantly, neural changes in the transient-sensitive context updating task were found on the same timescale but in a different region (i.e., in the left inferior parietal lobule) than in the task-switching training task (i.e., ventrolateral PFC, inferior frontal junction, superior parietal lobule), only pointing to temporal overlap, while neural changes in the sustained-sensitive delayed-recognition task overlapped in both timescale and region with the task-switching training task (i.e., in the basal ganglia), pointing to spatio-temporal overlap. These results suggest that neural changes after task-switching training seem to be critically supported by the temporal organization of neural processing.

Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.

Mutations in genes encoding aminoacyl-tRNA synthetases have been reported in several neurological disorders. KARS is a dual localized lysyl-tRNA synthetase and its cytosolic isoform belongs to the multiple aminoacyl-tRNA synthetase complex (MSC). Biallelic mutations in the KARS gene were described in a wide phenotypic spectrum ranging from nonsyndromic deafness to complex impairments. Here, we report on a patient with severe neurological and neurosensory disease investigated by whole-exome sequencing and found to carry biallelic mutations c.683C>T (p.Pro228Leu) and c.871T>G (p.Phe291Val), the second one being novel, in the KARS gene. The patient presented with an atypical clinical presentation with an optic neuropathy not previously reported. At the cellular level, we show that cytoplasmic KARS was expressed at a lower level in patient cells and displayed decreased interaction with MSC. In vitro, these two KARS variants have a decreased aminoacylation activity compared with wild-type KARS, the p.Pro228Leu being the most affected. Our data suggest that dysfunction of cytoplasmic KARS resulted in a decreased level of translation of the nuclear-encoded lysine-rich proteins belonging to the respiratory chain complex, thus impairing mitochondria functions.

Evaluation of diagnostic accuracy and a practical algorithmic approach for the diagnosis of renal masses by FNA.

BACKGROUND: The classification of renal neoplasms is essential for oncologic risk stratification and clinical management, and an accurate pretreatment pathologic diagnosis can provide useful guidance for active surveillance, minimally invasive ablative therapy, or surgical resection and can reduce the incidence of overtreatment. Previous studies evaluating the diagnostic accuracy of fine-needle aspiration (FNA) and core-needle biopsy (CNB) for renal masses are limited and show variable results. METHODS: Two hundred forty-seven renal FNA cases with or without concurrent CNB performed and/or reviewed at the Stanford University School of Medicine over the course of 20 years were identified. Cytohistopathologic correlation was performed for 77 cases with subsequent resection specimens. All available case materials were reviewed, and select cases were worked up further and reclassified as necessary. RESULTS: Cytohistopathologic correlation showed 96% diagnostic specificity and 83% sensitivity for renal FNA with or without concurrent CNB. Discordant cases were mostly attributed to sampling errors or suboptimal specimens (79%) and also included 2 non-renal cell carcinoma entities (1 case of angiomyolipoma and 1 case of a benign peripheral nerve sheath tumor) and 1 case involving misclassification of the renal cell carcinoma subtype. CONCLUSIONS: There is considerable value in FNA/CNB for the initial diagnosis of renal masses because of the high diagnostic specificity and sensitivity. Sensitivity is predominantly dependent on sufficient sampling, and additional potential diagnostic pitfalls include nonepithelial and rare entities. Judicious use of ancillary techniques is encouraged, especially when one is presented with a limited specimen, and this article presents a practical algorithmic approach to the diagnosis of renal masses using salient morphologic features and results from ancillary studies. Fine-needle aspiration is an accurate method for the diagnosis of renal masses. A practical diagnostic algorithm, based on salient morphologic and ancillary findings, is presented.