Cutaneous melioidosis: An updated review and primer for the dermatologist.

Melioidosis is an emerging infection with increasing endemic foci and global distribution. It is underrecognized and underdiagnosed because of factors including limited awareness of the disease, nonspecific clinical presentation, lack of diagnostic facilities in some locations, misidentification in laboratories inexperienced with culture, and identification of Burkholderia pseudomallei. Cutaneous findings are reported in approximately 10% to 20% of melioidosis cases and dermatologists may play a significant role in its recognition and management. The most dynamic situation of melioidosis recognition and/or expansion currently is in the United States. Global modeling had predicted that B. pseudomallei were potentially endemic in the southern United States and endemicity with local cases of melioidosis was confirmed in 2022. With the distribution and prevalence of melioidosis increasing globally and with this recent recognition that melioidosis is now endemic in the southern United States, it is important for dermatologists to maintain high clinical suspicion in appropriate patients and be familiar with its diagnosis and treatment. Here we review the available literature on cutaneous melioidosis to evaluate its epidemiology, etiology, pathophysiology and clinical presentation and provide guidance for diagnosis and management in dermatology practice.

Recent Advances in mmWave-Radar-Based Sensing, Its Applications, and Machine Learning Techniques: A Review.

Human gesture detection, obstacle detection, collision avoidance, parking aids, automotive driving, medical, meteorological, industrial, agriculture, defense, space, and other relevant fields have all benefited from recent advancements in mmWave radar sensor technology. A mmWave radar has several advantages that set it apart from other types of sensors. A mmWave radar can operate in bright, dazzling, or no-light conditions. A mmWave radar has better antenna miniaturization than other traditional radars, and it has better range resolution. However, as more data sets have been made available, there has been a significant increase in the potential for incorporating radar data into different machine learning methods for various applications. This review focuses on key performance metrics in mmWave-radar-based sensing, detailed applications, and machine learning techniques used with mmWave radar for a variety of tasks. This article starts out with a discussion of the various working bands of mmWave radars, then moves on to various types of mmWave radars and their key specifications, mmWave radar data interpretation, vast applications in various domains, and, in the end, a discussion of machine learning algorithms applied with radar data for various applications. Our review serves as a practical reference for beginners developing mmWave-radar-based applications by utilizing machine learning techniques.

Adverse cutaneous reaction to hydroxychloroquine in a patient with anti-SAE-1-positive dermatomyositis and a history of diffuse large B-cell lymphoma.

This case report details the cutaneous findings of a patient with a history of diffuse B-cell lymphoma and SAE-1-positive dermatomyositis who developed an adverse cutaneous reaction after initiation of treatment with hydroxychloroquine. This adds to the sparse literature available detailing the correlation between anti-SAE-1 autoantibodies in dermatomyositis and the unique adverse cutaneous reactions in patients taking hydroxychloroquine. Additionally, our patient developed dermatomyositis years after a diagnosis of lymphoma. This report highlights the utility of the myositis-specific antibody panel to guide diagnosis and management, as well as the potential for developing dermatomyositis years after a lymphoma diagnosis.

Urethroplasty Methods for Stricture Repair After Gender Affirming Phalloplasty: High Failure Rates in a Hostile Surgical Field.

OBJECTIVE: To report our experience with 71 postphalloplasty urethral strictures in order to discuss the performance characteristics of different urethroplasty techniques in urethral stricture after phalloplasty. METHODS: We conducted a retrospective chart review of 85 urethroplasties performed for stricture repair in 71 patients with phalloplasty for gender affirmation between August 2017 and May 2020. Stricture location, urethroplasty type, complication rate, and recurrence rate were recorded. RESULTS: The most common stricture type was distal anastomotic (40/71, 56%). The most common initial repair type was excision and primary anastomosis (EPA) (33/85, 39%), followed by first-stage Johanson urethroplasty (32/85, 38%). The stricture recurrence rate after initial repair of all types was 52% (44/85). The recurrence rate of stricture after EPA was 58% (19/33). The recurrence rate after staged urethroplasty was 25% (2/8) for patients who successfully completed a first and second stage. 30% (3/10) of patients who completed a first stage and opted out of a second stage required a revision to achieve successful lifetime voiding from the surgical urethrostomy. CONCLUSION: EPA after phalloplasty has a high failure rate. Nontransecting anastomotic urethroplasty has slightly lower failure rate, and staged Johanson-type surgeries have the highest success rates after phalloplasty.

High Surgical Complication Rates after Silicone Implant Use for Improvement of Glans Ridge Appearance.

Background: Construction of the glans is an important aspect of gender-affirming phalloplasty. In these surgeries, the glans ridge is commonly constructed using the Norfolk technique or a similar technique. In cases of glans ridge flattening after creation, we generally recommend a redo/revision glansplasty, which is often curative. However, in situations when the glans ridge flattens again, we developed a silicone glans implant technique in an effort to create a satisfactory and lasting glans ridge. Methods: We conducted a pilot study of our first 12 glans implant cases. A retrospective chart review and brief, ad-hoc patient survey measured patient demographics, implant status, and patient satisfaction. Results: A total of 12 patients received a silicone glans implant between November 2017 and February 2020. One patient had the glans implant removed before the survey, and also could not be contacted. Three patients did not respond to the survey. Of the eight patients who responded, only five (5/8, 63%) patients still had the silicone implant at the time of the survey. The average satisfaction score was 3.25 (range 1 = very satisfied and 5 = very dissatisfied). Common complaints cited included dissatisfaction with implant appearance, as well as infection, discomfort, and pain. Conclusions: Patients and surgeons should be aware of the possibility of a novel silicone implant technique to create a glansplasty in those with failed/flattened previous glansplasty surgery. However, the technique is in development: patient satisfaction remains spotty and complication rates are high, although technical improvements may increase future success rates.

Predicting efficacy of viloxazine extended-release treatment in adults with ADHD using an early change in ADHD symptoms: Machine learning Post Hoc analysis of a phase 3 clinical trial.

Early response to viloxazine extended-release (viloxazine ER, Qelbree®) treatment predicted efficacy outcome in pediatric subjects with attention-deficit/hyperactivity disorder (ADHD). This study sought to determine whether the machine learning lasso model used in the pediatric study would predict response to viloxazine ER in an adult population based on early improvements in ADHD symptoms. We used data from a double-blind, placebo-controlled, flexible-dose (200-600 mg) study of viloxazine ER (N = 354; 18 to 60 years old). Area under the Receiver Operating Characteristic Curve (ROC AUC) statistics were computed using the lasso model from pediatric data to predict responder status in adults. Response was defined as ≥50% reduction from baseline in the Adult ADHD Investigator Symptoms Rating Scale (AISRS) Total score at Week 6. The adult study sample included 127 viloxazine ER-treated subjects with Week 6 data. Fifty-one subjects (40.2%) were categorized as responders. The ROC curves indicated that data collected up to Week 2 were sufficient to accurately predict treatment response at Week 6 with 68% positive predictive power, 80% sensitivity, and 74% specificity. This analysis demonstrated that the predictive model estimated from the child data generalizes to adults with ADHD, further supporting the consistency of viloxazine ER treatment across age groups.

A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Efficacy and Safety of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND AND OBJECTIVE: Attention-deficit/hyperactivity disorder is a neurodevelopmental disorder that typically begins in childhood and often persists into adulthood. Recent phase III trials have demonstrated the efficacy and safety of viloxazine extended-release capsules (viloxazine ER; Qelbree®) in pediatrics (6-17 years of age). The aim of this study was to evaluate the efficacy and safety of viloxazine ER in adults with attention-deficit/hyperactivity disorder. METHODS: This was a phase III, randomized, double-blind, placebo-controlled, two-arm trial in adults (18-65 years of age) with attention-deficit/hyperactivity disorder. Eligible subjects were randomized 1:1 to viloxazine ER (flexible dose of 200-600 mg/day) or matched placebo. The primary efficacy endpoint was the change from baseline at end of study (week 6) in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score. The key secondary endpoint was the change from baseline at end of study in the Clinical Global Impressions-Severity of Illness (CGI-S) score. Additional secondary outcome measures included the AISRS Inattention and Hyperactivity/Impulsivity subscales, the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), the Generalized Anxiety Disorder-7 Item (GAD-7), and the Clinical Global Impressions-Improvement (CGI-I); each was analyzed at end of study. Responder rates on CGI scales and the AISRS were also assessed. RESULTS: A total of 374 subjects were randomized. At end of study, the mean viloxazine ER dose was 504 mg. The reduction in the change from baseline at end of study AISRS total score (least-square means ± standard error) was significantly greater in subjects treated with viloxazine ER (-15.5 ± 0.91) compared with placebo (-11.7 ± 0.90), p = 0.0040. The reduction in the CGI-S score was also significantly greater in subjects treated with viloxazine ER (-1.4 ± 0.10) compared with placebo (-1.0 ± 0.10), p = 0.0023. The viloxazine ER group demonstrated significantly greater improvements in the AISRS Inattention (p = 0.0015) and Hyperactivity/Impulsivity (p = 0.0380) subscales, the CGI-I (p = 0.0076), and the BRIEF-A Global Executive Composite (p = 0.0468) and Metacognition Index (p = 0.0100). Analysis of categorical secondary endpoints revealed that the viloxazine ER group had a significantly higher AISRS 30% response rate compared with placebo (p = 0.0395); all other comparisons were not significant. Many treatment effects (including the primary and key secondary endpoints) were significant by week 2. The most common treatment-related adverse events that occurred in ≥5% of subjects receiving viloxazine ER were insomnia (14.8%), fatigue (11.6%), nausea (10.1%), decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). Viloxazine ER was well tolerated, with a 9.0% discontinuation rate due to adverse events compared with 4.9% in the placebo group. CONCLUSIONS: Treatment with viloxazine ER resulted in a statistically significant improvement in primary and key secondary endpoints, indicating improvements in attention-deficit/hyperactivity disorder symptomology, executive function, and overall clinical illness severity in adults. Viloxazine ER was well tolerated at the tested doses in adults with attention-deficit/hyperactivity disorder. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04016779.

Attention-deficit/hyperactivity disorder (ADHD) is a condition characterized by inattention (difficulty maintaining focus), and/or impulsiveness/hyperactivity. In 2021, a nonstimulant medication called viloxazine ER (brand name: Qelbree^®) received US FDA-approval for ADHD in children and adolescents (aged 6 to 17 years), based on efficacy and safety demonstrated in clinical trials. Here we present results of a phase 3, randomized, double-blind, placebo-controlled, clinical trial that enrolled 374 adults with ADHD. In this trial, half the patients received viloxazine ER, and half received placebo (identical capsule without active ingredient). Medication doses ranged from 200­600 mg/day, based on symptom response and presence of side effects. To reduce bias, patients and investigators did not know which medication the patient was receiving. The primary measure of efficacy was the Adult ADHD Investigator Symptom Rating Scale (AISRS), a standardized questionnaire rating presence and severity of patient-reported ADHD symptoms. At the end of the 6-week trial, participants receiving viloxazine ER showed greater improvement in ADHD symptoms according to AISRS than those receiving placebo. Improvement was seen in both the Inattentive and Impulsive/Hyperactive components of ADHD and in other study measures, including a measure of behaviors called Executive Function. Viloxazine ER was generally safe and well-tolerated in the trial. The most common side effects were insomnia (14.8%), fatigue (11.6%), and nausea (10.1%). Overall, 9.0% of patients receiving viloxazine and 5% receiving placebo left the trial because of side effects. Due to these positive results, the US FDA recently approved viloxazine ER to treat adults with ADHD.

Optimization of Second-stage Metoidioplasty.

OBJECTIVE: To describe a planned 2-staged metoidioplasty. Metoidioplasty is a genital gender-affirmation surgery aimed at creating a neophallus, scrotum (if desired), and flat male-type perineum (if desired) from natal tissues. It generally requires a planned second-stage to place testes prostheses, address complications, and perform additional surgical steps to maximally lengthen the phallus. The details of this procedure are sparsely mentioned in the literature. We found that phallus length can be optimized in the second-stage by applying surgical principles already established in the surgical treatment of adult acquired buried penis. MATERIAL AND METHODS: We conducted a retrospective chart review of patients after metoidioplasty between August 2015 and June 2020, and isolated those that underwent second-stage metoidioplasty. Each procedure was done by 1 of 4 surgeons in a single practice in 2 locations, San Francisco, CA, and Austin, TX. Details of procedures required, complications, and demographic information were recorded. RESULTS: Out of the 75 patients that had undergone metoidioplasty, 37 (37 of 75, 49%) underwent a second-stage metoidioplasty. Reduction of upper scrotal blocking tissue was the most common procedure performed during a second-stage metoidioplasty (31 of 37, 84%), followed by escutcheonectomy/penile lift (30 of 37, 81%), bilateral implant placement (20 of 37, 54%), chordee repair (13 of 37, 35%), and unilateral implant placement (1 of 37, 3%). 6 of the 37 patients (16%) developed major complications. 5 of the 37 (5 of 37, 15%) second-stage patients required a redo second-stage metoidioplasty. CONCLUSION: Second-stage metoidioplasties are commonly performed on patients to optimize results of phallic lengthening and release, and to repair complications that arise after single-stage metoidioplasty. Escutcheonectomy/penile lift, placement of scrotal implants, repair of chordee, and upper scrotal blocking tissue reduction are procedures that are often performed during a second-stage metoidioplasty.

Frequent and recent retrotransposition of orthologous genes plays a role in the evolution of sperm glycolytic enzymes.

BACKGROUND: The central metabolic pathway of glycolysis converts glucose to pyruvate, with the net production of 2 ATP and 2 NADH per glucose molecule. Each of the ten reactions in this pathway is typically catalyzed by multiple isozymes encoded by a multigene family. Several isozymes in this pathway are expressed only during spermatogenesis, and gene targeting studies indicate that they are essential for sperm function and male fertility in mouse. At least three of the novel glycolytic isozymes are encoded by retrogenes (Pgk2, Aldoart1, and Aldoart2). Their restricted expression profile suggests that retrotransposition may play a significant role in the evolution of sperm glycolytic enzymes. RESULTS: We conducted a comprehensive genomic analysis of glycolytic enzymes in the human and mouse genomes and identified several intronless copies for all enzymes in the pathway, except Pfk. Within each gene family, a single orthologous gene was typically retrotransposed frequently and independently in both species. Several retroposed sequences maintained open reading frames (ORFs) and/or provided evidence of alternatively spliced exons. We analyzed expression of sequences with ORFs and <99% sequence identity in the coding region and obtained evidence for the expression of an alternative Gpi1 transcript in mouse spermatogenic cells. CONCLUSIONS: Our analysis detected frequent, recent, and lineage-specific retrotransposition of orthologous glycolytic enzymes in the human and mouse genomes. Retrotransposition events are associated with LINE/LTR and genomic integration is random. We found evidence for the alternative splicing of parent genes. Many retroposed sequences have maintained ORFs, suggesting a functional role for these genes.

Genome-wide expression profiling identifies deregulated miRNAs in malignant astrocytoma.

Malignant astrocytoma includes anaplastic astrocytoma (grade III) and glioblastoma (grade IV). Among them, glioblastoma is the most common primary brain tumor with dismal responses to all therapeutic modalities. We performed a large-scale, genome-wide microRNA (miRNA) (n=756) expression profiling of 26 glioblastoma, 13 anaplastic astrocytoma and 7 normal brain samples with an aim to find deregulated miRNA in malignant astrocytoma. We identified several differentially regulated miRNAs between these groups, which could differentiate glioma grades and normal brain as recognized by PCA. More importantly, we identified a most discriminatory 23-miRNA expression signature, by using PAM, which precisely distinguished glioblastoma from anaplastic astrocytoma with an accuracy of 95%. The differential expression pattern of nine miRNAs was further validated by real-time RT-PCR on an independent set of malignant astrocytomas (n=72) and normal samples (n=7). Inhibition of two glioblastoma-upregulated miRNAs (miR-21 and miR-23a) and exogenous overexpression of two glioblastoma-downregulated miRNAs (miR-218 and miR-219-5p) resulted in reduced soft agar colony formation but showed varying effects on cell proliferation and chemosensitivity. Thus we have identified the miRNA expression signature for malignant astrocytoma, in particular glioblastoma, and showed the miRNA involvement and their importance in astrocytoma development.

Impact of somatic copy number alterations on the glioblastoma miRNome: miR-4484 is a genomically deleted tumour suppressor.

Glioblastoma (GBM) is the most frequent and most malignant primary brain tumour in adults. GBMs have a unique landscape of somatic copy number alterations (SCNAs), with the concomitant appearance of numerous driver amplifications and deletions. Here, we examined the genomic regions harbouring SCNAs and their impact on the GBM miRNome. We found that 40% of SCNA events covering 70-88% of the genomically altered regions, as identified by GISTIC and RAE algorithms, carried miRNA genes. Of 1426 annotated mature miRNAs analysed, ~ 14% (n = 198) were mapped to such fragile loci. Further, we identified an intragenic miRNA, miR-4484 located on chromosome-10, as a deleted and downregulated miRNA in GBM. miR-4484 exhibited a strong positive correlation with the expression of its host gene uroporphyrinogen III synthase (UROS), thereby indicating that the loss of miR-4484 is a codeletion event in GBM. Overexpression of miR-4484 reduced the colony-forming ability and suppressed the migratory capacity of glioma cells. Analysis of the RNA-seq-derived transcriptome upon exogenous miR-4484 overexpression in conjunction with an integrative bioinformatics approach revealed several putative targets of miR-4484. Unbiased functional enrichment of these targets through DAVID identified a cohort of important gene ontology terms, which possibly explain the functional role of miR-4484 in gliomagenesis. Selected targets were validated and, importantly, were found to be upregulated in GBM. In brief, our study identified a panel of miRNAs that are likely to be regulated by genomic deletions and amplifications. Further, miR-4484 was found to be deleted and acts as a tumour suppressor miRNA in GBM.

Src and STAT3 inhibitors synergize to promote tumor inhibition in renal cell carcinoma.

The intracytoplasmic tyrosine kinase Src serves both as a conduit and a regulator for multiple processes required for the proliferation and survival cancer cells. In some cancers, Src engages with receptor tyrosine kinases to mediate downstream signaling and in other cancers, it regulates gene expression. Src therefore represents a viable oncologic target. However, clinical responses to Src inhibitors, such as dasatinib have been disappointing to date. We identified Stat3 signaling as a potential bypass mechanism that enables renal cell carcinoma (RCC) cells to escape dasatinib treatment. Combined Src-Stat3 inhibition using dasatinib and CYT387 (a JAK/STAT inhibitor) synergistically reduced cell proliferation and increased apoptosis in RCC cells. Moreover, dasatinib and CYT387 combine to suppress YAP1, a transcriptional co-activator that promotes cell proliferation, survival and organ size. Importantly, this combination was well tolerated, and caused marked tumor inhibition in RCC xenografts. These results suggest that combination therapy with inhibitors of Stat3 signaling may be a useful therapeutic approach to increase the efficacy of Src inhibitors.

Tapia's syndrome after repair of a fractured mandible.

A 41-year-old gentleman underwent surgical repair of the fractured right parasymphisis and left condyle of his mandible. Post-operatively he developed hoarseness of voice and dyspnoea during speech, with deviation of the tongue on protrusion. After excluding intracranial and surgical causes, a clinical diagnosis of Tapia's syndrome was made.

Three male germline-specific aldolase A isozymes are generated by alternative splicing and retrotransposition.

Enzymes in the glycolytic pathway of mammalian sperm are modified extensively and are localized in the flagellum, where several are tightly bound to the fibrous sheath. This study provides the first evidence for three novel aldolase isozymes in mouse sperm, two encoded by Aldoart1 and Aldoart2 retrogenes on different chromosomes and another by Aldoa_v2, a splice variant of Aldoa. Phylogenetic analyses and comparative genomics indicate that the retrogenes and splice variant have remained functional and have been under positive selection for millions of years. Their expression is restricted to the male germline and is tightly regulated at both transcriptional and translational levels. All three isozymes are present only in spermatids and sperm and have distinctive features that may be important for localization in the flagellum and/or altered metabolic regulation. Both ALDOART1 and ALDOA_V2 have unusual N-terminal extensions not found in other aldolases. The N-terminal extension of ALDOA_V2 is highly conserved in mammals, suggesting a conserved function in sperm. We hypothesize that the N-terminal extensions are responsible for localizing components of the glycolytic pathway to the fibrous sheath and that this localization is required to provide sufficient ATP along the length of the flagellum to support sperm motility.