A critical appraisal of clinical practice guidelines for the diagnosis and management of benign paroxysmal positional vertigo.

BACKGROUND: Delays in the diagnosis and therapy of benign paroxysmal positional vertigo can greatly impact quality of life and increase healthcare costs for patients. This study aimed to appraise the quality of clinical practice guidelines for the diagnosis and management of benign paroxysmal positional vertigo. METHODS: A comprehensive database search of clinical practice guidelines was completed up to 30 October 2021. Four independent reviewers used the Appraisal of Guidelines for Research and Evaluation II instrument in the quality appraisal. RESULTS: The highest score was in 'clarity and presentation' (58.33 ± 22.7). The lowest score was in 'applicability' (13.96 ± 30.1). Overall, four clinical practice guidelines were 'low quality' and only one guideline was 'high quality'. CONCLUSION: This review identified a significant lack of quality in clinical practice guideline development for benign paroxysmal positional vertigo, highlighting the need for a more rigorous approach for future guideline development.

Physical exam is not an accurate predictor of injury in geriatric patients with low-energy blunt trauma - A retrospective cohort study.

Background: When evaluating trauma patients, many centers perform computed tomography of the head, cervical spine, chest, abdomen, and pelvis, the so-called "pan-scan." Here, we evaluate the utility of physical exam against pan-scan in geriatric patients who sustained ground-level falls. Methods: We performed a single-centered retrospective cohort review of consecutive patients from the trauma registry of a large, urban Level 1 trauma center. Inclusion criteria were registration during the 2019 calendar year, age ≥65, mechanism of fall from either sitting or standing, and performance of "pan-scan" at time of assessment. The sensitivity, specificity, positive and negative predictive values of the physical exam for significant injuries were calculated. The effect of such injuries on disposition from the emergency department and hospital were determined. Results: An initial query for patients age ≥65 yielded 1280 patients. After exclusion of patients who did not undergo pan-scan or who had GCS <14, 751 patients were included in analysis. Median age was 84 years old. 351 patients had at least one injury identified on pan-scan. Physical exam was determined to have a sensitivity of 0.69 when compared to pan-scan as a gold standard. Patients with injury identified on CT scan had significantly more admissions, mortalities, and ICU and OR requirements. Conclusion: Approximately half of all patients were found to have at least one injury on pan-scan. Physical examination was insensitive at identifying such injuries which ultimately altered patient management, disposition, and outcomes. Pan-scan is recommended in this vulnerable population.

Evidence of Association of CYP1A1 Expression in Blood Lymphocytes and Clinicopathological Variables in Oral Cancer.

Association of smokeless tobacco (SLT) with oral cancer is well documented. The nitrosamines of SLT are metabolically bioactivated by CYP1A1. Therefore, in this pilot study, we investigated association of CYP1A1 expression with polymorphism, clinicopathological variables and outcome in exclusive SLT chewers. Semiquantitative RT-PCR analysis on RNA isolated from peripheral blood lymphocytes of 65 histopathologically confirmed cases revealed increased CYP1A1 mRNA expression in Msp I (CYP1A1*2A) and Ile/Val (CYP1A1*2C) polymorphic variants. A higher trend of CYP1A1 mRNA levels in invasive and recurrent tumors which also associated with shorter disease free and overall survival was seen. Odds ratio analysis indicated the association of higher CYP1A1 mRNA levels with disease aggressiveness i.e. metastasis and invasion. Study revealed wider oncogenic role of CYP1A1 in oral cancer patients and justifies further studies and analysis in a large cohort.

A proposed "Radiological Evaluation Score for Bone Tumors" (REST): An objective system for assessment of a radiograph in patients with suspected bone tumor.

BACKGROUND: Although radiographs have been widely used in the evaluation of patients with suspected bone tumors, the lack of an objective radiological assessment method leads to a challenge in reaching correct diagnosis. The study aimed to propose a Radiological Evaluation Score for Bone Tumors (REST) which includes eight radiological factors [characteristics, content, cortical breach, distinctiveness, distribution, periosteal reaction, fracture, and soft tissue swelling] to form a single score along with its validation by multidisciplinary observers. METHODS: We reviewed the radiographs of 100 patients with a primary bone tumor which were selected at random from the database between January 2017 and January 2019 of a tertiary cancer center. Four reviewers (two orthopedic oncologists and two surgical oncologists) independently assessed the radiographs, based on the reporting system of REST. We constituted two groups according to the probable diagnosis of bone tumor (suspected benign tumor and suspected malignant tumor). RESULTS: The mean score in the suspected benign tumor group was 1.1 (range 0-3, 95% CI 0.8-1.3) and in malignant tumor group was 6.1 (range 2-8, 95% CI 5.8-6.4). A receiver operator characteristic (ROC) curve for REST was with a cutoff of 3.5, with the most diagnostic value area under curve (AUC) of 0.99. The sensitivity was 98% and specificity was 100% with a positive predictive value of 100% and a negative predictive value of 98%. The inter-observer correlation coefficient was 0.985 (p value < 0.05), and Fleiss kappa value for the prediction of the benign or malignant lesion was 0.97 (p value < 0.05). The characteristics and content of tumor, cortical erosion, distinctiveness, distribution, periosteal reaction, and soft tissue mass had a significant correlation with the aggressiveness of bone lesion p value < 0.05. CONCLUSIONS: The Radiological Evaluation Score for Bone Tumors (REST) is a structured reporting and objective method for the assessment of radiographs in patients with suspected bone tumors. This method is a reliable and helpful tool for clinicians in their outdoor patient department to differentiate a radiograph of a suspected benign tumor from a malignant bone tumor.

Neoadjuvant weekly paclitaxel and carboplatin with trastuzumab and pertuzumab in HER2-positive breast cancer: a Brown University Oncology Research Group (BrUOG) study.

PURPOSE: In HER2-positive breast cancer (HER2+ BC), neoadjuvant chemotherapy (NACT) with dual HER2-targeted therapy achieves high pathologic complete response (pCR) rates. Anthracycline-free NACT regimens avoid toxicities associated with anthracyclines, but every 3-week TCHP also has substantial side effects. We hypothesized that a weekly regimen might have equivalent efficacy with less toxicity; we also investigated whether poorly responding patients would benefit from switching to AC. METHODS: Patients with clinical stage II-III HER2+ BC received weekly paclitaxel 80 mg/m2 and carboplatin AUC2 with every 3-week trastuzumab and pertuzumab (wPCbTP), with the option of splitting the pertuzumab loading dose. After 12 weeks, responding patients continued wPCbTP for another 6 weeks, while non-responders switched to AC. Dose modifications and post-op therapy were at investigator discretion. RESULTS: In 30 evaluable patients, the pCR rate was 77% (95% CI 58-90%); 12/14 (86%) in ER-negative and 11/16 (69%) in ER-positive. Only two patients transitioned to AC for non-response, of which one achieved pCR. There were no episodes of febrile neutropenia or grade ≥ 3 peripheral neuropathy, though several patients who continued wPCbTP stopped before week 18. Split-dose pertuzumab was associated with less grade ≥ 2 diarrhea (40%) than the standard loading dose (60%). CONCLUSION: pCR rates with our regimen were as high as reported with TCHP with fewer grade ≥ 3 toxicities, though diarrhea remains a concern. Too few patients had a suboptimal response to adequately test switching to AC. The wPCbTP regimen should be considered an alternative to TCHP as neoadjuvant therapy for HER2+ BC. TRAIL REGISTRATION: ClinicalTrials.gov identifier: NCT02789657.

A proposed ''A to Z RAM (Radiograph Assessment Method)'' for triage of patients with a suspected bone tumour.

INTRODUCTION: We propose a ''A to Z RAM (Radiograph Assessment Method)'' for evaluation of Radiograph of patients with a suspected bone tumour. METHODS: In the current study, ten radiological features with letters 'A, B, C, D, E, F and Z' were used and which included the age of the patient, involved part of the bone, characteristics, content, distinctiveness, the exterior of the bone, fracture, and zone of transition. Four independent observers (orthopaedic oncologists and surgical oncologists) evaluated a set of 30 radiographs of bone tumour selected at random from our hospital database based on A to Z RAM. We classified the lesions into two groups according to the traffic signal system; Green (suspected benign lesion) and Red (suspected malignant lesion). RESULTS: There were 18 (60%) benign bone lesions and 12 (40%) malignant lesions in the current study. 91.6% of malignant tumours and 88.8% of the benign tumours were identified correctly by the four observers. The inter-observer variability with Fleiss kappa was 0.884 (95% CI 0.7-1.03 p-value < 0.05), suggestive of agreement not by chance. These radiographs were again reassessed by the four observers after 3 months. The interobserver variability by Fleiss kappa was 1.0 (95% CI 0.8-1.1) suggesting complete agreement amongst the observers. Both orthopaedic oncologists had intra-observer kappa as 1.0 each and both surgical oncologists had 0.795 and 0.930 respectively. CONCLUSION: The proposed A to Z RAM is an easy to use and reproducible method for reviewing radiographs in the out-patient department along with clinical findings for better management of patients with suspected bone lesions. The A to Z RAM can be a medical triage tool and subdivide bone lesions into two subgroups i.e. suspected benign lesion with a suggestion of further investigations with MRI and biopsy and suspected malignant lesion with a suggestion of MRI or early referral to a tertiary cancer center with expertise in orthopaedic oncology. IMPLICATIONS FOR PRACTICE: The A to Z RAM (Radiologic Assessment Method) is a reproducible method for reviewing radiographs in the out-patient department and can be an aid for better management of patients. A to Z RAM is useful as a medical triage system, subdividing patients according to the probable diagnosis into a suspected benign lesion and suspected malignant lesion.

Quantitative Susceptibility Mapping of Time-Dependent Susceptibility Changes in Multiple Sclerosis Lesions.

BACKGROUND AND PURPOSE: MR imaging studies have demonstrated that magnetic susceptibility in multiple sclerosis lesions is dependent on lesion age. The objective of this study was to use quantitative susceptibility mapping to determine whether lesions with a hyperintense rim, indicative of iron-laden inflammatory cells (rim+), follow a unique time-dependent trajectory of susceptibility change compared with those without (rim-). MATERIALS AND METHODS: We studied patients with MS with at least 1 new gadolinium-enhancing lesion and at least 3 longitudinal quantitative susceptibility mapping scans obtained between 1.1 and 6.1 years. Lesions were classified as rim+ if a hyperintense rim appeared on quantitative susceptibility mapping at any time. A multilevel growth curve model compared longitudinal susceptibility among rim+ and rim- lesions. RESULTS: Thirty-two new gadolinium-enhancing lesions from 19 patients with MS were included, and 16 lesions (50%) were identified as rim+. Quantitative susceptibility mapping rim+ lesions were larger than rim- lesions with gadolinium enhancement (P < .001). Among all lesions, susceptibility increased sharply after enhancement to a peak between 1 and 2 years followed by a decrease. The overall susceptibility curve height for rim- lesions was 4.27 parts per billion lower than that for rim+ lesions (P = .01). Rim- lesions demonstrated a higher linear slope relative to rim+ lesions (P = .023) but faster cubic decay relative to rim+ lesions (P = .005). Rim- lesions started decaying approximately 2 years earlier compared with rim+ lesions. CONCLUSIONS: There was a marked difference in the susceptibility temporal trajectory between rim+ and rim- lesions during the first 6 years of lesion formation. Most rim+ lesions retain iron for years after the initial lesion appearance.

Kinetic control of tunable multi-state switching in ferroelectric thin films.

Deterministic creation of multiple ferroelectric states with intermediate values of polarization remains challenging due to the inherent bi-stability of ferroelectric switching. Here we show the ability to select any desired intermediate polarization value via control of the switching pathway in (111)-oriented PbZr0.2Ti0.8O3 films. Such switching phenomena are driven by kinetic control of the volume fraction of two geometrically different domain structures which are generated by two distinct switching pathways: one direct, bipolar-like switching and another multi-step switching process with the formation of a thermodynamically-stable intermediate twinning structure. Such control of switching pathways is enabled by the competition between elastic and electrostatic energies which favors different types of ferroelastic switching that can occur. Overall, our work demonstrates an alternative approach that transcends the inherent bi-stability of ferroelectrics to create non-volatile, deterministic, and repeatedly obtainable multi-state polarization without compromising other important properties, and holds promise for non-volatile multi-state functional applications.

Predictive model of spread of Parkinson's pathology using network diffusion.

Growing evidence suggests that a "prion-like" mechanism underlies the pathogenesis of many neurodegenerative disorders, including Parkinson's disease (PD). We extend and tailor previously developed quantitative and predictive network diffusion model (NDM) to PD, by specifically modeling the trans-neuronal spread of alpha-synuclein outward from the substantia nigra (SN). The model demonstrated the spatial and temporal patterns of PD from neuropathological and neuroimaging studies and was statistically validated using MRI deformation of 232 Parkinson's patients. After repeated seeding simulations, the SN was found to be the most likely seed region, supporting its unique lynchpin role in Parkinson's pathology spread. Other alternative spread models were also evaluated for comparison, specifically, random spread and distance-based spread; the latter tests for Braak's original caudorostral transmission theory. We showed that the distance-based spread model is not as well supported as the connectivity-based model. Intriguingly, the temporal sequencing of affected regions predicted by the model was in close agreement with Braak stages III-VI, providing what we consider a "computational Braak" staging system. Finally, we investigated whether the regional expression patterns of implicated genes contribute to regional atrophy. Despite robust evidence for genetic factors in PD pathogenesis, NDM outperformed regional genetic expression predictors, suggesting that network processes are far stronger mediators of regional vulnerability than innate or cell-autonomous factors. This is the first finding yet of the ramification of prion-like pathology propagation in Parkinson's, as gleaned from in vivo human imaging data. The NDM is potentially a promising robust and clinically useful tool for diagnosis, prognosis and staging of PD.

Maternal critical care in resource-limited settings. Narrative review.

Maternal critical care reflects interdisciplinary care in any hospital area according to the severity of illness of the pregnant woman. The admission rate to intensive care units is below 1% (0.08-0.76%) of deliveries in high-income countries, and ranges from 0.13% to 4.6% in low- and middle-income countries. Mortality in these patients is high and varies from 0% to 4.9% of admissions in high-income countries, and from 2% to 43.6% in low- and middle-income countries. Obstetric haemorrhage, sepsis, preeclampsia, human immunodeficiency virus complications and tropical diseases are the main reasons for intensive care unit admission in low middle-income countries. Bedside assessment tools, such as early warning scores, may help to identify critically ill patients and those at risk of deterioration. There is a lack of uniformity in definitions, identification and treatment of critically ill pregnant patients, especially in resource-limited settings. Our aims were to (i) propose a more practical definition of maternal critical care, (ii) discuss maternal mortality in the setting of limited accessibility of critical care units, (iii) provide some accessible tools to improve identification of obstetric patients who may become critically ill, and (iv) confront challenges in providing maternal critical care in resource-limited settings. To improve maternal critical care, training programmes should embrace modern technological educational aids and incorporate new tools and technologies that assist prediction of critical illness in the pregnant patient. The goal must be improved outcomes following early interventions, early initiation of resuscitation, and early transfer to an appropriate level of care, whenever possible.

Combining Quantitative Susceptibility Mapping with Automatic Zero Reference (QSM0) and Myelin Water Fraction Imaging to Quantify Iron-Related Myelin Damage in Chronic Active MS Lesions.

BACKGROUND AND PURPOSE: A hyperintense rim on susceptibility in chronic MS lesions is consistent with iron deposition, and the purpose of this study was to quantify iron-related myelin damage within these lesions as compared with those without rim. MATERIALS AND METHODS: Forty-six patients had 2 longitudinal quantitative susceptibility mapping with automatic zero reference scans with a mean interval of 28.9 ± 11.4 months. Myelin water fraction mapping by using fast acquisition with spiral trajectory and T2 prep was obtained at the second time point to measure myelin damage. Mixed-effects models were used to assess lesion quantitative susceptibility mapping and myelin water fraction values. RESULTS: Quantitative susceptibility mapping scans were on average 6.8 parts per billion higher in 116 rim-positive lesions compared with 441 rim-negative lesions (P < .001). All rim-positive lesions retained a hyperintense rim over time, with increasing quantitative susceptibility mapping values of both the rim and core regions (P < .001). Quantitative susceptibility mapping scans and myelin water fraction in rim-positive lesions decreased from rim to core, which is consistent with rim iron deposition. Whole lesion myelin water fractions for rim-positive and rim-negative lesions were 0.055 ± 0.07 and 0.066 ± 0.04, respectively. In the mixed-effects model, rim-positive lesions had on average 0.01 lower myelin water fraction compared with rim-negative lesions (P < .001). The volume of the rim at the initial quantitative susceptibility mapping scan was negatively associated with follow-up myelin water fraction (P < .01). CONCLUSIONS: Quantitative susceptibility mapping rim-positive lesions maintained a hyperintense rim, increased in susceptibility, and had more myelin damage compared with rim-negative lesions. Our results are consistent with the identification of chronic active MS lesions and may provide a target for therapeutic interventions to reduce myelin damage.

Relationships among Cortical Glutathione Levels, Brain Amyloidosis, and Memory in Healthy Older Adults Investigated In Vivo with 1H-MRS and Pittsburgh Compound-B PET.

BACKGROUND AND PURPOSE: Oxidative stress has been implicated as an important pathologic mechanism in the development of Alzheimer disease. The purpose of this study was to assess whether glutathione levels, detected noninvasively with proton MR spectroscopy, are associated with brain amyloidosis and memory in a community-dwelling cohort of healthy older adults. MATERIALS AND METHODS: Fifteen cognitively healthy subjects were prospectively enrolled in this study. All subjects underwent 1H-MR spectroscopy of glutathione, a positron-emission tomography scan with an amyloid tracer, and neuropsychological testing by using the Repeatable Battery for the Assessment of Neuropsychological Status. Associations among glutathione levels, brain amyloidosis, and memory were assessed by using multivariate regression models. RESULTS: Lower glutathione levels were associated with greater brain amyloidosis in the temporal (P = .03) and parietal (P = .05) regions, adjusted for apolipoprotein E ε4 carrier status. There were no significant associations between glutathione levels and cognitive scores. CONCLUSIONS: This study found an association between cortical glutathione levels and brain amyloidosis in healthy older adults, suggesting a potential role for 1H-MR spectroscopy measures of glutathione as a noninvasive biomarker of early Alzheimer disease pathogenesis.

A Case of Refractory Pulmonary Coccidioidomycosis Successfully Treated with Posaconazole Therapy.

Coccidioidomycosis is an endemic fungal infection caused by the inhalation of the spores of Coccidioides species. Patients with underlying immunosuppressive illness can contract chronic or disseminated disease which requires prolonged systemic therapy. Pulmonary coccidioidomycosis remains as an illusory and abstruse disease, with increased prevalence that poses as a challenge for clinicians in developing an effective strategy for treatment. Here, we report successful treatment of a refractory case of chronic relapsing pulmonary coccidioidomycosis in a 50-year old woman with a thin-walled cavitary lung lesion who was ultimately treated with posaconazole.

Design and characterization of a prototype divertor viewing infrared video bolometer for NSTX-U.

The InfraRed Video Bolometer (IRVB) is a powerful tool to measure radiated power in magnetically confined plasmas due to its ability to obtain 2D images of plasma emission using a technique that is compatible with the fusion nuclear environment. A prototype IRVB has been developed and installed on NSTX-U to view the lower divertor. The IRVB is a pinhole camera which images radiation from the plasma onto a 2.5 µm thick, 9 × 7 cm2 Pt foil and monitors the resulting spatio-temporal temperature evolution using an IR camera. The power flux incident on the foil is calculated by solving the 2D+time heat diffusion equation, using the foil's calibrated thermal properties. An optimized, high frame rate IRVB, is quantitatively compared to results from a resistive bolometer on the bench using a modulated 405 nm laser beam with variable power density and square wave modulation from 0.2 Hz to 250 Hz. The design of the NSTX-U system and benchtop characterization are presented where signal-to-noise ratios are assessed using three different IR cameras: FLIR A655sc, FLIR A6751sc, and SBF-161. The sensitivity of the IRVB equipped with the SBF-161 camera is found to be high enough to measure radiation features in the NSTX-U lower divertor as estimated using SOLPS modeling. The optimized IRVB has a frame rate up to 50 Hz, high enough to distinguish radiation during edge-localized-modes (ELMs) from that between ELMs.

Highly mobile ferroelastic domain walls in compositionally graded ferroelectric thin films.

Domains and domain walls are critical in determining the response of ferroelectrics, and the ability to controllably create, annihilate, or move domains is essential to enable a range of next-generation devices. Whereas electric-field control has been demonstrated for ferroelectric 180° domain walls, similar control of ferroelastic domains has not been achieved. Here, using controlled composition and strain gradients, we demonstrate deterministic control of ferroelastic domains that are rendered highly mobile in a controlled and reversible manner. Through a combination of thin-film growth, transmission-electron-microscopy-based nanobeam diffraction and nanoscale band-excitation switching spectroscopy, we show that strain gradients in compositionally graded PbZr1-xTixO3 heterostructures stabilize needle-like ferroelastic domains that terminate inside the film. These needle-like domains are highly labile in the out-of-plane direction under applied electric fields, producing a locally enhanced piezoresponse. This work demonstrates the efficacy of novel modes of epitaxy in providing new modalities of domain engineering and potential for as-yet-unrealized nanoscale functional devices.

Neurological and endocrine phenotypes of fragile X carrier women.

Women who carry fragile X mental retardation 1 (FMR1)gene premutation expansions frequently report neurological or endocrine symptoms and prior studies have predominantly focused on questionnaire report of medical issues. Premutation carrier (PMC) women (n = 33) and non-carrier controls (n = 13) were recruited and evaluated by a neurologist, neuropsychologist, and endocrinologist. Blood and skin biopsies were collected for molecular measures. Scales for movement disorders, neuropathy, cognitive function, psychiatric symptoms, sleep, and quality of life were completed. The average age of the women was 51 years (n = 46) and average CGG repeat size was 91 ± 24.9 in the FMR1 PMC women. Seventy percent of the PMC women had an abnormal neurological examination. PMC women had significantly higher scores on the Fragile X-Associated Tremor Ataxia Syndrome (FXTAS) rating scale, more neuropathy, and difficulty with tandem gait compared to controls. Central sensitivity syndromes, a neuroticism profile on the NEO Personality Profile, and sleep disorders were also prevalent. Discrepancies between subject report and examination findings were also seen. This pilot study suggests that women with the FMR1 premutation may have a phenotype that overlaps with that seen in FXTAS. Additional research with larger sample sizes is warranted to better delineate the clinical features.