Purpose: Vestibuloocular reflex (VOR) may be helpful in the diagnosis of Benign Paroxysmal Positional Vertigo (BPPV). Video Head Impulse Test (vHIT) can effectively diagnose VOR deficits in vestibular disorders. Aims: The aim of this study is to investigate the significance of vHIT in determining the efficacy of therapeutic maneuvers in individuals with posterior semicircular canal BPPV. Materials and Methods: The study included 25 patients with posterior SCC BPPV (Study Group) between the ages of 19-65 years, 30 healthy individuals (Control Group). All individuals underwent otorhinolaryngologic examination, audiological evaluation with, videonystagmography and vHIT. The Dizziness Handicap Inventory (DHI) and Visual Analogue Scale (VAS) were administered to the individuals with posterior SCC BPPV for the intensity of dizziness and Modified Epley maneuver was performed 3 times at an interval of 3 days. The vHIT, DHI and VAS were re-administered to these individuals 1 week after improvement was detected in positional nystagmus. Results: There was no significant difference between the study and control groups in terms of vHIT gains for all bilateral SCCs before therapeutic maneuver (p>0.05). In the study group, there was no significant difference between vHIT gains of all bilateral SSCs before and after therapeutic maneuvers (p>0.05). No asymmetry or refixation saccades (overt and covert) were observed in any of the individuals in both groups during all measurements. Compared to before therapeutic maneuvers, there was a significant decrease in dizziness-related disability level assessed by DHI and intensity of dizziness assessed by VAS in the study group after the improvement (p<0.001). Conclusion: It was found that vHIT was not a diagnostic test in BPPV and in terms of evaluating the efficacy of therapeutic maneuvers. Subjective evaluations determining the intensity of dizziness and level of dizziness-related disability in BPPV provided supportive information in diagnosis and in determining the efficacy of therapeutic maneuvers.

Purpose: The aim of this study was to evaluate the diagnostic accuracy of 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) and positron emission tomography/computed tomography (PET/CT) in imaging primary and metastatic lesions in Ewing sarcoma (ES). Methods: PubMed, Cochrane, Scopus, and Web of Science were searched for relevant studies. Data concerning 18F-FDG-PET/CT diagnostic accuracy were extracted and then analysed using Open Meta-analyst software. Reported diagnostic accuracy outcomes included sensitivity, specificity, negative likelihood ratio (NLR), positive likelihood ratio (PLR), and diagnostic odds ratio. Results: 31 studies with a total of 735 patients were included in this meta-analysis. The sensitivity and specificity of 18F-FDG PET/CT were: 92.6% and 74.1% for total ES lesions, 96.7% and 68.3% for ES primary lesions, 76.1% and 92.4% for lung metastasis, 83.9% and 93.2% for bone metastasis and 89.9% and 92.6% for ES recurrence respectively. Conclusion: 18F-FDG PET/CT is sensitive and accurate in diagnosing, staging, and detecting the recurrence of ES compared to non-PET imaging. It has high specificity for diagnosing recurrence of ES as well as lung and bone metastases.

Background: Primary immunodeficiency diseases (PIDs) comprise more than 400 rare diseases with potential life-threatening conditions. Clinical manifestations and genetic defects are heterogeneous and diverse among populations. Here, we aimed to characterize the clinical, immunological and genetic features of Thai pediatric patients with PIDs. The use of whole exome sequencing (WES) in diagnosis and clinical decision making was also assessed. Methods: 36 unrelated patients with clinical and laboratory findings consistent with PIDs were recruited from January 2010 to December 2020. WES was performed to identify the underlying genetic defects. Results: The median age of disease onset was 4 months (range; 1 month to 13 years) and 24 were male (66.7%). Recurrent sinopulmonary tract infection was the most common clinical presentation followed by septicemia, and severe pneumonia. Using WES, we successfully identified the underlying genetic defects in 18 patients (50%). Of the 20 variants identified, six have not been previously described (30%). According to the International Union of Immunological Societies (IUIS), 38.9% of these detected cases (7/18) were found to harbor variants associated with genes in combined immunodeficiencies with associated or syndromic features (Class II). Conclusion: The diagnostic yield of WES in this patient cohort was 50%. Six novel genetic variants in PID genes were identified. The clinical usefulness of WES in PIDs was demonstrated, emphasizing it as an effective diagnostic strategy in these genetically heterogeneous disorders.

Critical thermal limits (CTmax and CTmin) are predicted to decrease with elevation, with greater change in CTmin, and the risk to suffer heat and cold stress increasing at the gradient ends. A central prediction is that populations will adapt to the prevailing climatic conditions. Yet, reliable support for such expectation is scant because of the complexity of integrating phenotypic and molecular divergence. We propose that phenotypic plasticity and breeding phenology may hinder local adaptation cancelling the appearance of adaptive patterns. We examined intraspecific variation of CTmax/CTmin in 11 populations of an amphibian across an elevational gradient, and assessed (1) the existence of local adaptation through a PST-FST comparison, (2) the acclimation scope in both thermal limits, and (3) the vulnerability to suffer acute heat (CTmax–tmax) and cold (tmin–CTmin) thermal stress, measured at both macro- and microclimatic scales. Our study revealed significant microgeographic variation in CTmax/CTmin, and unexpected elevation gradients in pond temperatures. However, variation in CTmax/CTmin could not be attributed to selection because critical thermal limits were not correlated to elevation or temperatures. Differences in breeding phenology among populations resulted in exposure to higher and more variable temperatures at mid and high elevations. Accordingly, mid- and high-elevation populations had higher CTmax and CTmin plasticities than lowland populations, but not more extreme CTmax/CTmin. Thus, we confirm our prediction that plasticity and phenological shifts may hinder local adaptation, promoting thermal niche conservatism and a higher vulnerability to climate change. This contradicts some of the existing predictions on adaptive thermal clines.

Behcet's Disease is a rare systemic vasculitis characterized by recurrent episodes of acute inflammation affecting blood vessels of all sizes. Symptoms include orogenital apthosis, cutaneous skin lesions, and uveitis. We present the case of a 38-year-old Nepalese man with Behcet's Disease. In Nepal, Behcet's Disease may still be under-reported.

Perimedullary spinal AVM is a rare type of spinal arteriovenous malformations. We present a case of 70 yrs female who presented with motor weakness in her bilateral limbs. Initial MRI was misinterpreted as ependymal myxoma; however, histopathology revealed spinal AVM. MRA or DSA should be conducted if AVM is suspected.

Objective: Characterize the presentation of vulvar lichen scleorsus (LS) among premenopausal women. Design: Cross-sectional study. Setting: An international web-based survey distributed on social media support groups and in two urban gynecology offices specializing in LS. Population: A total of 503 premenopausal women with biopsy-confirmed vulvar LS between the ages of 18-50. Methods: Participants completed an anonymous 28-question web-based survey between January to March 2021. Main Outcome Measures: Symptoms, timing and accuracy of diagnosis, and presence of concomitant autoimmune conditions. Results: Symptoms reported to be most present and affect the individual were dyspareunia (68%; 44%) and tearing with intercourse or vaginal insertion (63%; 39%). Symptoms that most frequently prompted patients to seek medical attention were dyspareunia (35%), pruritus (31%), and tearing with intercourse or vaginal insertion (26%). Most common skin changes included hypopigmentation (81%), vulvar fissures (72%) and labial resorption (60%), with fissures affecting the individual the most (48%). There was a 4-year delay in diagnosis with an average age of symptom onset of 27 years and average age of diagnosis of 32 years. Sixty-six percent of respondents initially received an alternative diagnosis, most commonly vulvovaginal yeast infection (49%). There is an increased incidence of hypothyroidism, vitiligo, pernicious anemia, and celiac disease. Conclusion: Premenopausal women with vulvar LS more commonly present with dyspareunia and tearing with intercourse, less often than vulvar pruritis. This condition should be considered and evaluated in women of all ages presenting with vulvar symptoms and sexual pain. Funding: None Keywords: lichen sclerosus; vulvar dermatoses; vulvar pruritis; dyspareunia

Machine learning (ML) models are valuable research tools for making accurate predictions. However, ML models often unreliably extrapolate outside their training data. We propose an uncertainty quantification method for ML models (and generally for other nonlinear models) with parameters trained by least squares regression. The uncertainty measure is based on the multiparameter delta method from statistics, which gives the standard error of the prediction. The uncertainty measure requires the gradient of the model prediction and the Hessian of the loss function, both with respect to model parameters. Both the gradient and Hessian can be readily obtained from most ML software frameworks by automatic differentiation. We show that the uncertainty measure is larger for input space regions that are not part of the training data. Therefore this method can be used to identify extrapolation and to aid in selecting training data or assessing model reliability.

A stabilizer-free method based on segmented flow for the continuous synthesis of TiO2 supported noble metal nanoparticles (M/TiO2-MR, M = Pd, Pt or Au) was proposed. Due to the enhanced mixing performance arising from the internal convection in the discrete plugs, the particle size of noble metal nanoparticles could be well controlled by reducing the metal precursors with NaBH4 just in the presence of TiO2 without using any stabilizer. In comparison with the batch method, the as-prepared M/TiO2-MR had smaller noble metal particle size and better dispersity. Experimental results showed that adjusting the oil-to-water phase ratio or increasing the total volume flow rate and synthetic temperature could lead to smaller average particle size with narrower distribution. The as-prepared M/TiO2-MR possessed higher catalytic activities in the hydrolysis of ammonia borane than those prepared by the batch method, which could be ascribed to smaller noble metal nanoparticles, exposing more active sites.

Background: Bicuspid aortic valve is the most common congenital heart defect and predisposes patients to developing aortic stenosis more frequently and at a younger age than the general population. However, the influence of bicuspid aortic valve on the rate of progression of aortic stenosis remains unclear. Methods: In 236 patients (177 tricuspid aortic valve, 59 bicuspid aortic valve) matched by initial severity of mild or moderate aortic stenosis, we retrospectively analyzed baseline echocardiogram at diagnosis with latest available follow-up echocardiogram. Baseline comorbidities, annualized progression rate of hemodynamic parameters, and hazard of aortic valve replacement were compared between valve phenotypes. Results: Median echocardiographic follow-up was 2.6 (IQR 1.6-4.2) years. Patients with tricuspid aortic stenosis were significantly older with more frequent comorbid hypertension and congestive heart failure. Median annualized progression rate of mean gradient was 2.3 (IQR 0.6-5.0) mmHg/year vs. 1.5 (IQR 0.5-4.1) mmHg/year (p=0.5), and that of peak velocity was 0.14 (IQR 0-0.31) m/s/year vs. 0.10 (IQR 0.04-0.26) m/s/year (p=0.7) for tricuspid vs. bicuspid aortic valve, respectively. On multivariate analyses, bicuspid aortic valve was not significantly associated with more rapid progression of aortic stenosis. In a stepwise Cox proportional hazards model adjusted for baseline mean gradient, bicuspid aortic valve was associated with increased hazard of aortic valve replacement (HR: 1.7, 95% CI [1.0, 3.0], p=0.049). Conclusion: Bicuspid aortic valve may not significantly predispose patients to more rapid progression of mild or moderate aortic stenosis. Guidelines for echocardiographic surveillance of aortic stenosis need not be influenced by valve phenotype.

Background: For diseases with a genetic cause genomics can deliver improved diagnostics and facilitate access to targeted treatments. Drug pharmacodynamics and pharmacokinetics are often dependent on genetic variation underlying these processes. As pharmacogenomics comes of age it may be the first way in which genomics is utilised at a population level. Still required is guidance and standards of how genomic information can be communicated within the health record, and how clinicians should be alerted to variation impacting the use of medicines. Methods: The Professional Record Standards Body commissioned by National Health Service England developed guidance on using pharmacogenomics information in clinical practice. We conducted research with those implementing pharmacogenomics in England and internationally to produce guidance and recommendations for a systems-based approach. Results: A consensus viewpoint is that systems need to be in place to ensure the safe provision of pharmacogenomics information that is curated, actionable and up-to-date. Standards should be established with respect to notification and information exchange, which could impact new or existing prescribing and these must be in keeping with routine practice. Alerting systems should contribute to safer practices. Conclusion: Ensuring pharmacogenetics information is available to make use of medicines safer will require major effort of which this guidance is a beginning. Standards are required to ensure useful genomic information within the health record can be communicated to clinicians in the right format and times to be actioned successfully. A multidisciplinary group of stakeholders must be engaged in developing pharmacogenomic standards to support the most appropriate prescribing.

A document by Lillian D. Parker, Ph.D., written on Authorea.

A document by Lillian D. Parker, Ph.D., written on Authorea.

Primary bladder amyloidosis is a rare pathological finding. The clinical importance of this finding is that it may clinically mimic bladder cancer. The only accurate diagnostic method available till now is the histopathologic examination of tissue samples usually obtained through transurethral resection.

Respiratory Syncytial Virus (RSV) is a common seasonal respiratory virus and an important cause of illness among infants, but the burden of RSV disease is not well described among the older population. The objective of this study was to estimate the age-specific incidence of hospital admission among over 65s due to respiratory illnesses attributable to RSV in England to inform optimal vaccine and therapeutic interventions. We used linear multiple regression to examine the effect of changes in weekly counts of respiratory pathogens on the weekly counts of respiratory hospital admissions. The study population was all patients aged 65 years or over admitted to English hospitals between 2nd August 2010 and 30th July 2017. RSV was estimated to account for a seasonal annual average of 71 (95% CI 52-90) respiratory admissions per 100,000 in adults age 65-74 and 251 (95% CI 186-316) admissions per 100,000 adults age 75+. Pneumococcus was the pathogen responsible for highest annual average respiratory admission with 448 (95% CI 310-587) admissions per 100,000 adults age 65-74 and 1010 (95%CI 527-1493) admissions per 100,000 adults aged 75+. This study shows that RSV continues to exert a significant burden of disease among older adults in England. These findings will support development of policy for the use of RSV therapeutics and vaccines in this age group.

Species with broader niches may have the opportunity to occupy larger geographic areas, assuming no limitations on dispersal and a relatively homogeneous environmental space. While there is general support for positive \textit{geographic range size – climatic niche area} relationships, a great deal of variation exists across taxonomic and spatial gradients. Here, we use data on a large set of mammal ($n$ = 1225), bird ($n$ = 1829), and tree ($n$ = 341) species distributed across the Americas to examine the \textbf{1}) relationship between geographic range size and climatic niche area, \textbf{2}) influence of species traits on species departures from the best fit geographic range size – climatic niche area relationship, and \textbf{3}) how detection of these relationships is sensitive to how species range size and climatic niche area are estimated. We find positive \textit{geographic range size – climatic niche area} relationships for all taxa. Residual variation in this relationship contained a strong latitudinal signal. Subsampling the occurrence data to create a null expectation, we found that residual variation did not strongly deviate from the null expectation. Together, we provide support for the generality of \textit{geographic range size – climatic niche area} relationships, which may be constrained by latitude but are agnostic to species identity, suggesting that species traits are far less responsible than geographic barriers and the distribution of land area and available environmental space.

We report an uncommon case of late infective endocarditis, in a patient with a history of intravenous drug abuse and HIV positivity, 9 years after a percutaneous closure of a patent foramen ovale. Despite a target and prolonged intravenous antibiotic therapy, he was then referred for surgical device and vegetation removal. Given the high risk associated with drug addiction lifestyle, especially in HIV positive cases, it is mandatory to observe this group of patients with lifelong follow-up and support. Furthermore, it may be considered a multidisciplinary-team approach to find the best option for these patients, also evaluating a surgical correction.

Vertebrate colonization of land occurred multiple times, including over 50 origins of terrestrial eggs in frogs. Some environmental factors and phenotypic responses that facilitated these transitions are known, but responses to water constraints and risk of ammonia toxicity during early development are poorly understood. We tested if ammonia accumulation and dehydration risk induce a shift from ammonia to urea excretion during in early stages of four anurans, from three origins of terrestrial development. We quantified ammonia and urea concentrations during early development on land, under well-hydrated and dry conditions. Where we found urea excretion, we tested for a plastic increase under dry conditions and with ammonia accumulation in developmental environments. We assessed the potential adaptive role of urea excretion by comparing ammonia tolerance measured in 96h-LC50 tests with ammonia levels in developmental environments. Ammonia accumulated in foam nests and perivitelline fluid, increasing over development and reaching higher concentrations under dry conditions. All four species showed high ammonia tolerance, compared to fishes and aquatic-breeding frogs. Both nest-dwelling larvae of Leptodactylus fragilis and late embryos of Hyalinobatrachium fleischmanni excreted urea, showing a plastic increase under dry conditions. These two species can develop the longest on land and urea excretion appears adaptive, preventing their exposure to potentially lethal levels of ammonia. Neither late embryos of Agalychnis callidryas nor nest-dwelling larvae of Engystomops pustulosus risked toxic ammonia levels under dry conditions, and neither excreted urea. Our results suggests that an early onset of urea excretion, its increase under dry conditions, and elevated ammonia tolerance, can all help prevent ammonia toxicity during terrestrial development. High ammonia represents a general risk for development that can be exacerbated as climate change increases dehydration risk for terrestrial-breeding frogs. It may also be a cue that elicits adaptive physiological responses during early development.

Introduction: Raynaud phenomenon (RP) is a multifactorial disorder. If any underlying disease cannot be detected responsible for RP then it considered as primary RP (pRP). We aimed to investigate the differences between laboratory markers and impaired endothelial function in pRP. Material and Methods: Forty-two pRP patients included as study and control groups were created from 30 healthy individuals. The endothelial function was evaluated with flow-mediated dilatation (FMD) of the brachial artery. The blood samples were obtained both groups and white blood cell [WBC], hemoglobin, platelet, mean platelet volume [MPV], creatinine, alanine aminotransferase [ALT], aspartate aminotransferase[AST], D-dimer, fibrinogen, albumin, fibrinogen to albumin ratio [FAR], Neutrophil to Lymphocyte ratio [NLR], D-dimer to albumin ratio [DDAR] and monocyte chemo-attractant protein-1 [MCP-1]. Obtained blood parameters and FMD values were compared between groups. Results: The groups were found as similar in regards to age, gender, smoking history (p<0.05). There was no difference between the two groups in regards to hemoglobin, platelet, MPV, creatinine, ALT, D-dimer, albumin, FAR, NLR, DDAR levels (p<0.05). AST levels were slightly higher in pRP group (p=0.027). Markedly increased WBC, fibrinogen, MPV and MCP-1 values were detected in pRP group (p=0.000). Additionally, higher abnormal FMD responses were detected in pRP group (p=0.000). There was a direct correlation between abnormal FMD response and serum MCP-1 values in patients with pRP (R: 0.308, R2: 0.095, p: 0.044). Conclusion: It seems to be that MCP-1 levels are higher in patients with pRP and increased values of MCP-1 levels seem to be related to impaired endothelial functions

Time series data are often observed in ecological monitoring. Frequently such data exhibit nonlinear trends over time potentially due to complex relationships between observed and auxiliary variables, and there may also be sudden declines over time due to major disturbances. This poses substantial challenges for modelling such data and also for model-based adaptive monitoring. We propose novel methods for finding adaptive designs for monitoring when historical data show such nonlinear patterns and sudden declines over time. This work is motivated by a coral reef monitoring program that has been established at Scott Reef; a coral reef off the Western coast of Australia. Data collected for monitoring the health of Scott Reef are considered, and semiparametric and interrupted time series modelling approaches are adopted to describe how these data vary over time. New methods are then proposed that enable adaptive monitoring designs to be found based on such modelling approaches. These methods are then applied to find future monitoring designs at Scott Reef and form a set of recommendations for future monitoring. Through applying the proposed methods, it was found that future information gain is expected to be similar across a variety of different sites, suggesting that no particular location needed to be prioritised at Scott Reef for the next monitoring phase. In addition, it was found that omitting some sampling sites/reef locations was possible without substantial loss in expected information gain, depending upon the disturbances that were observed. The resulting adaptive designs are used to provide recommendations for future monitoring in this region, and for reefs where changes to the current monitoring practices are being sought. Furthermore, as the methods used and developed throughout this study are generic in nature, this research has the potential to improve ecological monitoring more broadly where complex data are being collected over time.

As social media becomes an ever-increasing staple of everyday life and a growing percentage of people turn to community driven platforms as a primary source of information, the data created from these posts can provide a new source of information from which to better understand an event in near real-time. The 2018-2020 outbreak of virulent Newcastle Disease (vND) in Southern California is the third outbreak of vND in Southern California within a 50-year time span. These outbreaks are thought to be primarily driven by non-commercial poultry (i.e. backyard and game fowl) in the region. Here we employed a commercial “web crawling” tool between June of 2018 and July of 2020 which encompassed the majority of the outbreak in order to collect all available online mentions of virulent Newcastle Disease (vND) in relation to the outbreak. A total of 2,498 posts in English and Spanish were returned using a Boolean logic-based string search. While the number of posts was relatively small, their impact as measured by the number of visitors to the website and the number of people viewing the post (where provided) was much larger. Using views as a metric, Twitter was identified as the most significant source of comments over blogs, forums and other news sites. Posts with negative sentiment were found to have a larger audience relative to posts with a positive sentiment. In addition, posts with negative sentiment peaked in May of 2019 which preceded the formation of the anti-depopulation group Save Our Birds (SOB). As the usage and impact of social media grows, the ability to utilize tools to analyze social media may improve both response and outreach-based strategies for various disease outbreaks including vND in Southern California which has a large non-commercial poultry population.

Objectives. Fifteen potentially low value practices in adult orthopaedic trauma care were previously identified in a scoping review. The aim of this study was to synthesize the evidence on these practices. Methods. We searched four databases for systematic reviews, randomized controlled trials (RCTs), cohort studies and case series that assessed the effectiveness of selected practices. Methodological quality was evaluated using the Measurement Tool to Assess Systematic Reviews version 2 (AMSTAR-2) for systematic reviews and the Critical Appraisal Checklist for Case Series. We evaluated risk of bias with the Cochrane revised tool for RCTs and the risk of bias in non-randomized studies of interventions tool for observational studies. We summarized findings with measures of frequency and association for primary outcomes. Results. Of the 30,670 records screened, 70 studies were retained. We identified high-level evidence of lack of effectiveness or harm for routine initial imaging of ankle injury, orthosis for A0-A3 thoracolumbar burst fracture in patients < 60 years of age, cast or splint immobilization for suspected scaphoid fracture negative on MRI or confirmed fifth metacarpal neck fracture, and routine follow-up imaging for distal radius and ankles fractures. However, evidence was mostly based on studies of low methodological quality or high risk of bias. Conclusion. In this review, we identified clinical practices in orthopedic injury care which are not supported by current evidence and whose use may be questioned. In future research we should measure their frequency, assess practice variations and evaluate root causes to identify practices that could be targeted for de-implementation.

Perioperative management of congenital tracheal stenosis (CTS) is challenging. Objectives: We investigated the effect of closed-pediatric intensive care unit (PICU) perioperative management by pediatric intensivists, compared with open-PICU management by surgeons, on the ventilator-free days (VFD) and length of postoperative PICU stay in children with CTS. Methods: This retrospective cohort study was conducted in a PICU in Japan. Children with CTS who underwent slide tracheoplasty were grouped according to whether they were perioperatively managed in an open (January 2015 to April 2016) or a closed (May 2016 to July 2019) PICU. Data were extracted from patient medical records. Results: In total, 13 and 38 patients were included in the open- and closed-PICU groups, respectively. Compared to the open-PICU group, the closed-PICU group had shorter durations of muscle relaxant administration (median: 4 vs. 5 days; P < 0.001); earlier initiation of enteral feeding (median: postoperative day 1 vs. postoperative day 7; P < 0.001); more 28-day VFD (median: 21 vs. 20 days; P = 0.04); and shorter duration of postoperative PICU stay (median: 16 vs. 36 days; P = 0.002), but the mortality did not differ significantly (0/38 [0%] vs. 1/13 [8%]; P = 0.25). Conclusions: Closed-PICU perioperative management with pediatric intensivists’ participation significantly increased 28-day VFD and reduced the length of postoperative PICU stay in patients with CTS.

We report a rare case of postoperative recurrence of MLS in the left thigh with ectopic and metachronous pericardial metastases. He was found to have a cardiac abnormality that was initially thought to be a pericardial cyst, but was later pathologically confirmed to be MLS metastasis.