Differentiation and characterization of healthy versus pathological tau using chemical exchange saturation transfer.

Neurofibrillary tangles of tau constitute one of the key biological hallmarks of Alzheimer's disease. Currently, the assessment of regional tau accumulation requires intravenous administration of radioactive tracers for PET imaging. A noninvasive MRI-based solution would have significant clinical implications. Herein, we utilized an MRI technique known as chemical exchange saturation transfer (CEST) to determine the imaging signature of tau in both its monomeric and pathologic fibrillated conformations. Three sets of purified recombinant full-length (4R) tau protein were prepared for collection of CEST spectra using a 9.4 T NMR spectrometer at varying temperatures (25, 37, and 42 °C) and RF intensities (0.7, 1.0, 1.5, and 2.2 µT). Monomeric and fibrillated tau were readily distinguished based on their Z-spectrum profiles. Fibrillated tau demonstrated a less prominent peak at 3.5 ppm with additional peaks near 0.5 and 1.5 ppm. No significant differences were identified between fibrillated tau prepared using heparin versus seed-competent tau. In conclusion, monomeric and fibrillated tau can be readily detected and distinguished based on their CEST-derived Z-spectra, pointing to the potential utility of CEST-MRI as a noninvasive biomarker of regional pathologic tau accumulation in the brain. Further testing and validation in vitro and in vivo will be necessary before this can be applied clinically.

Detection of Hybrid Fusion Transcripts, Aberrant Transcript Expression, and Specific Single Nucleotide Variants in Acute Leukemia and Myeloid Disorders with Recurrent Gene Rearrangements.

INTRODUCTION: A variety of gene rearrangements and molecular alterations are key drivers in the pathobiology of acute leukemia and myeloid disorders; current classification systems increasingly incorporate these findings in diagnostic algorithms. Therefore, clinical laboratories require versatile tools, which can detect an increasing number and variety of molecular and cytogenetic alterations of clinical significance. METHODS: We validated an RNA-based next-generation sequencing (NGS) assay that enables the detection of: (i) numerous hybrid fusion transcripts (including rare/novel gene partners), (ii) aberrantly expressed EVI1 (MECOM) and IKZF1 (Del exons 4-7) transcripts, and (iii) hotspot variants in KIT, ABL1, NPM1 (relevant in the context of gene rearrangement status). RESULTS: For hybrid fusion transcripts, the assay showed 98-100% concordance for known positive and negative samples, with an analytical sensitivity (i.e., limit of detection) of approximately 0.8% cells. Samples with underlying EVI1 (MECOM) translocations demonstrated increased EVI1 (MECOM) expression. Aberrant IKZF1 (Del exons 4-7) transcripts detectable with the assay were also present on orthogonal reverse transcription PCR. Specific hotspot mutations in KIT, ABL1, and NPM1 detected with the assay showed 100% concordance with orthogonal testing. Lastly, several illustrative samples are included to highlight the assay's clinically relevant contributions to patient workup. CONCLUSION: Through its ability to simultaneously detect various gene rearrangements, aberrantly expressed transcripts, and hotspot mutations, this RNA-based NGS assay is a valuable tool for clinical laboratories to supplement other molecular and cytogenetic methods used in the diagnostic workup and in clinical research for patients with acute leukemia and myeloid disorders.

Imaging Guide to Inner Ear Malformations: An Illustrative Review.

Inner ear malformation (IEM) with associated sensoryneural hearing loss (SNHL) is a major cause of childhood disability. Computed tomography (CT) and magnetic resonance imaging (MRI) imaging play important and often complementary roles in diagnosing underlying structural abnormalities and surgical planning allows for direct visualization of the cochlear nerve and is the preferred imaging modality prior to cochlear implantation. CT is helpful to assess osseous anatomy and when evaluating children with mixed hearing loss or syndromic associations. When reviewing these cases, it is important for the radiologist to be familiar with the key imaging features. In this article, we will present the imaging findings associated with different inner ear malformations associated with congenital sensorineural hearing loss.

Brain on fire: an imaging-based review of autoimmune encephalitis.

Autoimmune encephalitis represents an increasingly recognized group of immune-mediated disorders the affect the central nervous system. The purpose of this article is to highlight the characteristic MR imaging findings associated with autoimmune encephalitis, describe the pathophysiology, review antibodies that have been identified and their patterns of CNS involvement, and discuss approaches to management. Familiarity with the imaging and clinical features of autoimmune encephalitis will prompt the radiologist to suggest the diagnosis which can facilitate appropriate management.

Rapid simultaneous acquisition of macromolecular tissue volume, susceptibility, and relaxometry maps.

PURPOSE: A major obstacle to the clinical implementation of quantitative MR is the lengthy acquisition time required to derive multi-contrast parametric maps. We sought to reduce the acquisition time for QSM and macromolecular tissue volume by acquiring both contrasts simultaneously by leveraging their redundancies. The joint virtual coil concept with GRAPPA (JVC-GRAPPA) was applied to reduce acquisition time further. METHODS: Three adult volunteers were imaged on a 3 Tesla scanner using a multi-echo 3D GRE sequence acquired at 3 head orientations. Macromolecular tissue volume, QSM, R2∗ , T1 , and proton density maps were reconstructed. The same sequence (GRAPPA R = 4) was performed in subject 1 with a single head orientation for comparison. Fully sampled data was acquired in subject 2, from which retrospective undersampling was performed (R = 6 GRAPPA and R = 9 JVC-GRAPPA). Prospective undersampling was performed in subject 3 (R = 6 GRAPPA and R = 9 JVC-GRAPPA) using gradient blips to shift k-space sampling in later echoes. RESULTS: Subject 1's multi-orientation and single-orientation macromolecular tissue volume maps were not significantly different based on RMSE. For subject 2, the retrospectively undersampled JVC-GRAPPA and GRAPPA generated similar results as fully sampled data. This approach was validated with the prospectively undersampled images in subject 3. Using QSM, R2∗ , and macromolecular tissue volume, the contributions of myelin and iron content to susceptibility were estimated. CONCLUSION: We have developed a novel strategy to simultaneously acquire data for the reconstruction of 5 intrinsically coregistered 1-mm isotropic resolution multi-parametric maps, with a scan time of 6 min using JVC-GRAPPA.

Novel Strategies for Evaluating and Improving Plastic Surgery Applicant Selection.

SUMMARY: Residency applicant evaluation and selection is a critical part of developing and maintaining a high-quality plastic surgery residency program. Currently, many programs rely on objective measures such as the United States Medical Licensing Exam scores, number of research publications, grade point average, Alpha Omega Alpha Honor Medical Society status, or a combination of these objective metrics. However, there is a growing body of literature suggesting that the current means of residency applicant evaluation and selection may not be the best predictive factors of future resident success. The aim of this study was to identify nontraditional means of evaluating plastic surgery residency candidates and discuss how these means have been implemented at the authors' institution. After reviewing industry hiring practices, the authors propose that standardized interviewing and personality testing can help evaluate some of the previously intangible parts of an applicant that may play a role in teamwork, commitment, and dedication to patient care.

Uremic Leontiasis Ossea.

While renal osteodystrophy is a common complication of chronic renal failure which is caused by secondary hyperparathyroidism, it is rare that the bony changes result in a severe progressive overgrowth of the bones of the face such that the patient is at risk for breathing and feeding difficulties. When this occurs, it is called uremic leontiasis ossea and patients who suffer from this rare, severe complication of renal osteodystrophy may go undiagnosed or be misdiagnosed resulting improper management due to its limited discussion in the literature. We report a case of a 42-year-old man with end-stage renal disease who was unable to receive dialysis consistently for many years who was found to have a large hard mass on the palate and palate ulcers.

Predicting Parkinson's disease trajectory using clinical and neuroimaging baseline measures.

INTRODUCTION: Predictive biomarkers of Parkinson's Disease progression are needed to expedite neuroprotective treatment development and facilitate prognoses for patients. This work uses measures derived from resting-state functional magnetic resonance imaging, including regional homogeneity (ReHo) and fractional amplitude of low frequency fluctuations (fALFF), to predict an individual's current and future severity over up to 4 years and to elucidate the most prognostic brain regions. METHODS: ReHo and fALFF are measured for 82 Parkinson's Disease subjects and used to train machine learning predictors of baseline clinical and future severity at 1 year, 2 years, and 4 years follow-up as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Predictive performance is measured with nested cross-validation, validated on an external dataset, and again validated through leave-one-site-out cross-validation. Important predictive features are identified. RESULTS: The models explain up to 30.4% of the variance in current MDS-UPDRS scores, 55.8% of the variance in year 1 scores, and 47.1% of the variance in year 2 scores (p < 0.0001). For distinguishing high and low-severity individuals at each timepoint (MDS-UPDRS score above or below the median, respectively), the models achieve positive predictive values up to 79% and negative predictive values up to 80%. Higher ReHo and fALFF in several regions, including components of the default motor network, predicted lower severity across current and future timepoints. CONCLUSION: These results identify an accurate prognostic neuroimaging biomarker which may be used to better inform enrollment in trials of neuroprotective treatments and enable physicians to counsel their patients.

MRI Features of Free Liquid Silicone in the Transgender Female Breast.

OBJECTIVE: To define MRI features of free liquid silicone injection (FLSI) of the breast in transgender women considering surgical management. METHODS: This study was IRB-approved. MRI images from transgender women with FLSI imaged between 2009 and 2019 were reviewed. Presence and location of fibrotic masses (FMs) in the breast(s) and pectoralis muscle and patterns of granulomas were correlated with clinicopathologic findings. Background enhancement was quantified. Comparisons were performed using two-tailed Fisher exact and Student's t test. RESULTS: Of 21 transgender women with FLSI (mean age 46.8 years), 13/21 (61.9%) had a dominant FM measuring over 4 cm; these were limited to breast and pectoralis in 6/21 (28.6%), breast in 9/21 (42.9%), and pectoralis only in 2/21 (9.5%). Four of 21 patients (19.0%) had no FMs, and 4/21 (19.0%) had masses under 4 cm. Mean size of the dominant FM was 7.4 cm (range 4-12 cm). FMs were enhancing in 5/13 (38.5%) and contained T2 high signal granulomas in 8/13 (61.5%). While 18/21 (85.8%) of cases showed mild to moderate overall background enhancement, the majority 7/13 (61.5%) of dominant FM were non-enhancing. About half of cases (11/21, 52.4%) had diffuse foci, and half (10/21, 47.6%) had diffuse foci and masses throughout the breast and pectoralis muscle. These foci and masses displayed T2 high signal in 13/21 (61.9%). There were no occult carcinomas observed. CONCLUSION: MRI performed on symptomatic FLSI patients considering surgical treatment is helpful in assessing the extent of silicone infiltration and fibrotic reaction of the breast and pectoralis muscle.

Impact of increasing age on functioning free muscle transplantation for facial palsy reconstruction.

BACKGROUND: Management of facial paralysis in older patients is controversial. The purpose of this study is to evaluate the impact of increasing age on functioning free muscle transplantation (FFMT). PATIENTS AND METHODS: Twenty-nine facial paralysis patients over 50 years old received FFMT. A separate group of patients aged 41-50 years old were included as control. Outcome assessments included use of the SMILE evaluation system for excursion, a cortical adaptation scoring system for brain plasticity, and a subjective satisfaction assessment score. Meta-analysis of literature over the past 50 years was also performed to examine the impact of older age. RESULTS: The mean change in excursion movement was 13.39 ± 5.49 mm. Weakest excursion was found in the oldest age group (11.74 ± 4.84 mm, p = .097), in concordance with the meta-analysis. There was significant difference between the three different neurotizers (p = .036). Excursion and satisfaction score were significantly worse in the older cohort with the cross face-nerve graft FFMT. CONCLUSIONS: FFMT is a viable option in the elderly patient group but performs weaker in excursion. The choice of neurotizer is dependent on the patient's goals and the suitable age at which the benefits outweigh the risks.

Correction to: HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction induced injury.

Following publication of the original article [1], the authors flagged that there is a discrepancy with the Availability of data and materials statement on page 12 of the article.

HIF prolyl hydroxylase inhibition protects skeletal muscle from eccentric contraction-induced injury.

BACKGROUND: In muscular dystrophy and old age, skeletal muscle repair is compromised leading to fibrosis and fatty tissue accumulation. Therefore, therapies that protect skeletal muscle or enhance repair would be valuable medical treatments. Hypoxia-inducible factors (HIFs) regulate gene transcription under conditions of low oxygen, and HIF target genes EPO and VEGF have been associated with muscle protection and repair. We tested the importance of HIF activation following skeletal muscle injury, in both a murine model and human volunteers, using prolyl hydroxylase inhibitors that stabilize and activate HIF. METHODS: Using a mouse eccentric limb injury model, we characterized the protective effects of prolyl hydroxylase inhibitor, GSK1120360A. We then extended these studies to examine the impact of EPO modulation and infiltrating immune cell populations on muscle protection. Finally, we extended this study with an experimental medicine approach using eccentric arm exercise in untrained volunteers to measure the muscle-protective effects of a clinical prolyl hydroxylase inhibitor, daprodustat. RESULTS: GSK1120360A dramatically prevented functional deficits and histological damage, while accelerating recovery after eccentric limb injury in mice. Surprisingly, this effect was independent of EPO, but required myeloid HIF1α-mediated iNOS activity. Treatment of healthy human volunteers with high-dose daprodustat reduced accumulation of circulating damage markers following eccentric arm exercise, although we did not observe any diminution of functional deficits with compound treatment. CONCLUSION: The results of these experiments highlight a novel skeletal muscle protective effect of prolyl hydroxylase inhibition via HIF-mediated expression of iNOS in macrophages. Partial recapitulation of these findings in healthy volunteers suggests elements of consistent pharmacology compared to responses in mice although there are clear differences between these two systems.

MORAb-202, an Antibody-Drug Conjugate Utilizing Humanized Anti-human FRα Farletuzumab and the Microtubule-targeting Agent Eribulin, has Potent Antitumor Activity.

Microtubule-targeting agents (MTA) have been investigated for many years as payloads for antibody-drug conjugates (ADC). In many cases, these ADCs have shown limited benefits due to lack of efficacy or significant toxicity, which has spurred continued investigation into novel MTA payloads for next-generation ADCs. In this study, we have developed ADCs using the MTA eribulin, a derivative of the macrocyclic polyether natural product halichondrin B, as a payload. Eribulin ADCs demonstrated in vitro potency and specificity using various linkers and two different conjugation approaches. MORAb-202 is an investigational agent that consists of the humanized anti-human folate receptor alpha (FRA) antibody farletuzumab conjugated via reduced interchain disulfide bonds to maleimido-PEG2-valine-citrulline-p-aminobenzylcarbamyl-eribulin at a drug-to-antibody ratio of 4.0. MORAb-202 displayed preferable biophysical properties and broad potency across a number of FRA-positive tumor cell lines as well as demonstrated improved specificity in vitro compared with farletuzumab conjugated with a number of other MTA payloads, including MMAE, MMAF, and the reducible maytansine linker-payload sulfo-SPDB-DM4. A single-dose administration of MORAb-202 in FRA-positive human tumor cell line xenograft and patient-derived tumor xenograft models elicited a robust and durable antitumor response. These data support further investigation of MORAb-202 as a potential new treatment modality for FRA-positive cancers, using the novel MTA eribulin as a payload.

Thoracic Outlet Syndrome: Past and Present-88 Surgeries in 30 Years at Chang Gung.

BACKGROUND: Thoracic outlet syndrome (TOS) is a highly controversial clinical entity. There is much debate on its terminology, existence, diagnosis, and treatment. The purpose of this study was to describe our opinions about these controversial topics of TOS and the treatment of TOS over the past 30 years. METHODS: From 1985 to 2014, a total of 80 patients underwent decompressive surgery for TOS. Eight patients requested a second surgery on the contralateral limb. They all had at least 1-year follow-up. Preoperative evaluation included provocative tests, plain X-ray, magnetic resonance angiography/computed tomography angiography, and electromyography. Surgical intervention for each patient involved a supraclavicular approach and near-total resection of the anterior scalene muscle and the first rib and of any cervical rib if it was present. Rib resection was performed with the use of Kerrison bone punch forceps. The operative time was typically 2 hours. RESULTS: Major postoperative complications were rare. Nearly all patients (98%) experienced significant symptom relief, with improvement in soreness and tightness of the shoulder, neck, and arm immediately on the first postoperative day or within a few weeks thereafter. There were no cases with symptoms recurring. CONCLUSIONS: It is evident that decompressive surgery through a supraclavicular approach for TOS not only is an effective and safe procedure but also provides a diagnosis of the cause of TOS. For a patient who meets the criteria for surgical indication, decompressive surgery usually results in resolution of symptoms and no recurrence.

The effect of systemic injury score on the decision making of mangled lower extremities.

PURPOSE: Mangled lower extremity with Mangled extremity severity score (MESS) more than 7 are considered unsalvageable. We are looking for a factor helps us predicting the salvage potential in the patient with MESS score between 7 and 9. MATERIALS AND METHODS: We reviewed the patients with lower extremities open fracture type IIIB or IIIC and received salvaged procedure or amputation in CGMH between 2002/01 and 2010/09. The patients are subgroup according to their MESS score. ISS score, Gustilo open fracture classification were compared between patient with successful salvage and patient with delay amputation. Logistic regression and stepwise modeling were used to determine the effect of each covariate. RESULTS: 242 patients were enrolled in the study. 33 patients had primary amputation, 160 patients had successfully salvaged limbs and 49 patients received delay amputation. Among patients with MESS score less than 7, 116 patients had successful salvage limbs and 7 patients received delay amputation. Among patient with MESS between 7 and 9, 44 patients discharged with salvaged limbs and 39 patients were failed to salvage their limbs. Successful salvaged patients in this group had significant lower ISS score in compare to delay amputated patients. Patients with ISS score more than 18 in this group has higher delay amputated rate (P value=0.01). CONCLUSION: Systemic injury severity score can help us tell potentially salvaged patient from potentially amputated patient. In patients with MESS score between 7 and 9 concurrently have ISS score less then 17 are potentially salvageable. Level of Evidence & Study Type: Level 3 Retrospective cohort study/prognostic study.

A case of astroblastoma: Radiological and histopathological characteristics and a review of current treatment options.

BACKGROUND: Astroblastoma is a rare neuroepithelial tumor that often originates in the cerebral hemisphere of children and young adults. Diagnosis of this obscure neoplasm can be difficult because these tumors are so infrequently encountered and share common radiological and neuropathological features of other glial neoplasms. As such, it should be included in the differential diagnosis of astrocytoma and ependymoma if the clinical and radiographic features suggest it. Standardized treatment of astroblastomas remains under dispute because of the lack of knowledge regarding the tumor and a paucity of studies in the literature. CASE DESCRIPTION: We present a case of a low-grade astroblastoma diagnosed in a 30-year-old female with seizures, headache, and vision changes. She underwent gross total resection and, without evidence of high-grade features, adjuvant therapy was not planned postoperatively. Post-operative surveillance suggested early recurrence, warranting referral to radiation therapy. Patient ended up expiring despite adjuvant therapy secondary to extensive recurrence and tumor metastasis. CONCLUSIONS: Astroblastoma must be considered in the differential of supratentorial tumors in children and young adults. Treatment of such, as suggested by most recent literature, includes gross total resection and adjuvant radiotherapy for lesions exhibiting high-grade features.

Proximal versus Distal Nerve Transfer for Biceps Reinnervation-A Comparative Study in a Rat's Brachial Plexus Injury Model.

BACKGROUND: The exact role of proximal and distal nerve transfers in reconstruction strategies of brachial plexus injury remains controversial. We compared proximal with distal nerve reconstruction strategies in a rat model of brachial plexus injury. METHODS: In rats, the C6 spinal nerve with a nerve graft (proximal nerve transfer model, n = 30, group A) and 50% of ulnar nerve (distal nerve transfer model, n = 30, group B) were used as the donor nerves. The targets were the musculocutaneous nerve and the biceps muscle. Outcomes were recorded at 4, 8, 12, and 16 weeks postoperatively. Outcome parameters included grooming test, biceps muscle weight, compound muscle action potentials, tetanic contraction force, and axonal morphology of the donor and target nerves. RESULTS: The axonal morphology of the 2 donor nerves revealed no significant difference. Time interval analysis in the proximal nerve transfer group showed peak axon counts at 12 weeks and a trend of improvement in all functional and physiologic parameters across all time points with statistically significant differences for grooming test, biceps compound action potentials, tetanic muscle contraction force, and muscle weight at 16 weeks. In contrast, in the distal nerve transfer group, the only statistically significant difference was observed between the 4 and 8 week time points, followed by a plateau from 8 to 16 weeks. CONCLUSIONS: Outcomes of proximal nerve transfers are ultimately superior to distal nerve transfers in our experimental model. Possible explanations for the superior results include a reduced need for cortical adaptation and higher proportions of motor units in the proximal nerve transfers.

An evolutionary perspective on the history of flap reconstruction in the upper extremity.

Examining the evolution of flap reconstruction of the upper extremity is similar to studying the evolution of biological species. This analogy provides a perspective to appreciate the contributing factors that led to the development of the current arsenal of techniques. It shows the trajectory for the future and provides a glimpse of the factors that that will be influential in the future.