What predicts durable symptom relief of uterine fibroids treated with MRI-guided focused ultrasound? A multicenter trial in 8 academic centers.

OBJECTIVE: To identify variables predictive of durable clinical success after MRI-guided focused ultrasound (MRgFUS) treatment of uterine fibroids. MATERIALS AND METHODS: In this prospective, multicenter trial, 99 women with symptomatic uterine fibroids were treated using MRgFUS. Pelvic MRI was obtained at baseline and treatment day. The Uterine Fibroid Symptom-Quality of Life questionnaire was used to calculate a symptom severity score (SSS) at baseline and 6, 12, 24, and 36 months following treatment. Clinical, imaging, and treatment variables were correlated with symptom reduction sustained through the 12- and 24-month time points using univariable and multivariable logistic regression analyses. A novel parameter, the ratio of non-perfused volume to total fibroid load (NPV/TFL), was developed to determine association with durable outcomes. RESULTS: Post-treatment, mean symptom severity decreased at the 6-, 12-, 24-, and 36-month follow-ups (p < 0.001, all time points). In univariable analysis, three variables predicted treatment success (defined by ≥ 30-point improvement in SSS) sustained at both the 12-month and 24-month time points: increasing ratio of NPV/TFL (p = 0.002), decreasing total fibroid load (p = 0.04), and the absence of T2-weighted Funaki type 2 fibroids (p = 0.02). In multivariable analysis, the NPV/TFL was the sole predictor of durable clinical success (p = 0.01). Patients with ratios below 30% had less improvement in SSS and lacked durable clinical response compared with those between 30-79 (p = 0.03) and ≥ 80% (p = 0.01). CONCLUSION: Increased non-perfused volume relative to total fibroid volume was significantly associated with durable reduction of symptoms of abnormal uterine bleeding and bulk bother. CLINICAL RELEVANCE STATEMENT: Patient selection for sustained clinical benefit should emphasize those with likelihood of achieving high ablation ratios, as determined by imaging (e.g., device access, Funaki type) and by considering the total fibroid load, not just the primary symptomatic fibroid. TRIAL REGISTRATION: Clinical trial ID: NCT01285960. KEY POINTS: • Patient selection/treatment approach associated with durable symptom relief in MRI-guided focused ultrasound ablation of uterine fibroids remains unclear. • The ablation ratio, non-perfused volume/total fibroid volume, was positively associated with sustained symptom relief in both bleeding and bulk bother at 1- and 2-year follow-ups. • Selecting patients with imaging features that favor a high ratio of ablation to total fibroid load (including non-targeted fibroids) is the main factor in predicting durability of symptom relief after uterine fibroid treatment.

Comparison of the impact of skull density ratio with alternative skull metrics on magnetic resonance-guided focused ultrasound thalamotomy for tremor.

OBJECTIVE: One of the key metrics that is used to predict the likelihood of success of MR-guided focused ultrasound (MRgFUS) thalamotomy is the overall calvarial skull density ratio (SDR). However, this measure does not fully predict the sonication parameters that would be required or the technical success rates. The authors aimed to assess other skull characteristics that may also contribute to technical success. METHODS: The authors retrospectively studied consecutive patients with essential tremor who were treated by MRgFUS at their center between 2017 and 2021. They evaluated the correlation between the different treatment parameters, particularly maximum power and energy delivered, with a range of patients' skull metrics and demographics. Machine learning algorithms were applied to investigate whether sonication parameters could be predicted from skull density metrics alone and whether including combined local transducer SDRs with overall calvarial SDR would increase model accuracy. RESULTS: A total of 62 patients were included in the study. The mean age was 77.1 (SD 9.2) years, and 78% of treatments (49/63) were performed in males. The mean SDR was 0.51 (SD 0.10). Among the evaluated metrics, SDR had the highest correlation with the maximum power used in treatment (ρ = -0.626, p < 0.001; proportion of local SDR values ≤ 0.8 group also had ρ = +0.626, p < 0.001) and maximum energy delivered (ρ = -0.680, p < 0.001). Machine learning algorithms achieved a moderate ability to predict maximum power and energy required from the local and overall SDRs (accuracy of approximately 80% for maximum power and approximately 55% for maximum energy), and high ability to predict average maximum temperature reached from the local and overall SDRs (approximately 95% accuracy). CONCLUSIONS: The authors compared a number of skull metrics against SDR and showed that SDR was one of the best indicators of treatment parameters when used alone. In addition, a number of other machine learning algorithms are proposed that may be explored to improve its accuracy when additional data are obtained. Additional metrics related to eventual sonication parameters should also be identified and explored.

Genital ulcer disease: A review.

Genital ulcer disease (GUD) continues to be an important cause of morbidity and mortality worldwide. It is an important risk factor for the acquisition of HIV. GUD is mainly caused by five sexually transmitted infections. Three pathogens most frequently associated with GUD are herpes simplex virus 2 (HSV-2), Treponema pallidum, and Haemophilus ducreyi. Although their prevalence varies among different geographical regions, HSV-2 is the leading cause of this syndrome globally. In recent years, there has been an epidemiological transition of HSV-1 with a growing role of this virus as a causative agent of GUD. GUD may present with unique features depending on the etiological agent that can help clinicians identify the etiology and start treatment. However, owing to atypical presentations and co-infections, an accurate clinical diagnosis is often a challenge without confirmatory laboratory tests. Standard methods used to detect the causative pathogens of GUD have limitations. Molecular methods can provide a more sensitive and rapid microbiological diagnosis, with detection of the pathogen from the clinical sample directly. In situations where no laboratory support is available, the syndromic approach for management should be followed. The current scenario, clinical presentation (typical and atypical), laboratory diagnosis, and management of GUD will be discussed in this review. We searched PubMed literature and Google search engine using the terms "genital ulcer disease," "epidemiology of genital ulcer disease," and "clinical features of genital ulcer disease and atypical presentations" and relevant literature was selected to provide current perspectives of GUD.

Mycoplasma genitalium: A new superbug.

Mycoplasma genitalium (MG) is an emerging sexually transmitted pathogen. It is an important cause of nongonococcal urethritis in men and is associated with cervicitis and pelvic inflammatory disease in women, putting them at risk of infertility. Multiple factors that aid pathogenesis of MG include its ability of adhesion, gliding motility, and intracellular invasion by means of the tip organelle. Through intracellular localization and antigenic variation, MG could result in treatment-resistant chronic infection. There are limited data on the prevalence of MG in Indian patients with urogenital syndromes. Recently, a high prevalence of extra genital infection with MG has been reported. Molecular assays are the major diagnostic techniques of MG infection. Antimicrobial agents such as macrolides, along with fluoroquinolones, are the treatment of choice for MG infections. The issue of drug resistance to azithromycin and fluoroquinolones in MG is rising globally. As molecular tests are becoming available for MG, both for the diagnosis and the detection of antimicrobial resistance, any patient with MG infection should then be tested for antimicrobial resistance. Consideration of MG as a cause of sexually transmitted disease in the Indian population is crucial in diagnostic algorithms and treatment strategies. The purpose of this review is to understand the prevalence of MG in different clinical scenarios, molecular mechanisms of pathogenesis, current status of antimicrobial resistance, and its impact on MG treatment.

Mycoplasma hominis: An under recognized pathogen.

Mycoplasma hominis, a commensal of the genital tract, is a potential underestimated pathogen causing both genitourinary and extragenital infections including neonatal infections. Septic arthritis, prosthetic joint infection, central nervous system (CNS) infections, infective endocarditis and abscess formation are common extragenital infections associated mainly with immunocompromised patients. Mycoplasma hominis lipoproteins play an important role in pathogenicity and directly interact with the host immune system. Polymerase chain reaction (PCR) is the mainstay of diagnosis. Increasing resistance to tetracyclines and quinolones which are used for treatment, is a matter of global concern. We reviewed PubMed literature and Google search engine on the recent developments of association of Mycoplasma hominis with various diseases, pathogenesis, diagnosis and treatment.

Dimensions of adversity in association with adolescents' depression symptoms: Distinct moderating roles of cognitive and autonomic function.

Exposure to adverse events is prevalent among youths and robustly associated with risk for depression, particularly during adolescence. The Dimensional Model of Adversity and Psychopathology (DMAP) distinguishes between adverse events that expose youths to deprivation versus threat, positing unique mechanisms of risk (cognitive functioning deficits for deprivation, and altered fear and emotion learning for threat) that may require different approaches to intervention. We examined whether deprivation and threat were distinctly associated with behavioral measures of cognitive processes and autonomic nervous system function in relation to depression symptom severity in a community sample of early adolescents (n = 117; mean age 12.73 years; 54.7% male). Consistent with DMAP, associations between threat and depression symptoms, and between economic deprivation and depression symptoms, were distinctly moderated by physiological and cognitive functions, respectively, at baseline but not follow-up. Under conditions of greater cognitive inhibition, less exposure to deprivation was associated with lower symptom severity. Under conditions of blunted resting-state autonomic response (electrodermal activity and respiratory sinus arrhythmia), greater exposure to threat was associated with higher symptom severity. Our findings support the view that understanding risk for youth depression requires parsing adversity: examining distinct roles played by deprivation and threat, and the associated cognitive and biological processes.

Copper-dependent amino oxidase 3 governs selection of metabolic fuels in adipocytes.

Copper (Cu) has emerged as an important modifier of body lipid metabolism. However, how Cu contributes to the physiology of fat cells remains largely unknown. We found that adipocytes require Cu to establish a balance between main metabolic fuels. Differentiating adipocytes increase their Cu uptake along with the ATP7A-dependent transport of Cu into the secretory pathway to activate a highly up-regulated amino-oxidase copper-containing 3 (AOC3)/semicarbazide-sensitive amine oxidase (SSAO); in vivo, the activity of SSAO depends on the organism's Cu status. Activated SSAO oppositely regulates uptake of glucose and long-chain fatty acids and remodels the cellular proteome to coordinate changes in fuel availability and related downstream processes, such as glycolysis, de novo lipogenesis, and sphingomyelin/ceramide synthesis. The loss of SSAO-dependent regulation due to Cu deficiency, limited Cu transport to the secretory pathway, or SSAO inactivation shifts metabolism towards lipid-dependent pathways and results in adipocyte hypertrophy and fat accumulation. The results establish a role for Cu homeostasis in adipocyte metabolism and identify SSAO as a regulator of energy utilization processes in adipocytes.

Bilayer mucoadhesive microparticles for the delivery of metoprolol succinate: Formulation and evaluation.

Metoprolol succinate is a very potent drug for the treatment of hypertension but suffers from poor bioavailability due to its erratic absorption in lower GI tract. Therefore, in the present study, it was hypothesized that by formulating mucoadhesive particles, the residence time in the GIT and release of drug may be prolonged that will enhance the bioavailability of metoprolol succinate. Metoprolol succinate loaded chitosan microparticles were prepared by ionic gelation method. The optimized microparticles were coated with sodium alginate to form a layer over chitosan microparticles to increase the mucoadhesive strength and to release the drug in controlled manner. Coated and uncoated microparticles were evaluated for particle size, zeta potential, morphology, entrapment efficiency, drug loading and in vitro drug release. The coated microparticles showed comparatively less drug release in the 0.1 N HCl while sustained release in PBS (pH 6.8) as compared to uncoated microparticles. The in vivo study on albino rats demonstrated an increase in bioavailability of the coated microparticles as compared to marketed formulation. From the study it can be concluded that alginate coated chitosan microparticles could be a useful carrier for the oral delivery of metoprolol succinate.

N-succinyl chitosan as buccal penetration enhancer for delivery of herbal agents in treatment of oral mucositis.

Oral mucositis is one of the major side effects of cancer chemotherapy (30-76%) and radiotherapy (over 50%). Current palliative treatments of oral mucositis include specialized agents like pelifermin, platelet derived factors etc. or oral hygienic agents which suffered from various drawbacks like systemic side effect, least effect owing to fast wash out of buccal mucosa, patient unfriendly delivery systems, and mere symptomatic relief. In this research work, N-succinyl chitosan gel delivery system of microemulsified eugenol, honey and sodium hyaluronate was prepared to explore their multiple and synergistic effects on various pathological factors of oral mucositis. N-succinyl chitosan was synthesized in our laboratory and loaded with microemulsified eugenol (10% v/v), honey (10% v/v) and sodium hyaluronate (0.2% w/v) to prepare orogel with optimum pH, spreadability, mucoadhesion strength, and viscosity. In vitro eugenol release from N-succinyl chitosan gel after 8 hours in PBS (pH-6.4) was found to be 87.45±0.14%, which was better in comparison to that released from chitosan gel. Ex vivo penetration studies using rat buccal mucosal tissue also suggested better J-efflux of eugenol through N-succinyl chitosan in comparison to chitosan gel with enhancement ratio (ER) of 1.71. The antimicrobial effect of N-succinyl chitosan based orogel against S. aureus and C. albicans efficacy was found to be statistically high in comparison to chitosan based orogel as well as marketed formulation of chlorhexidine (p<0.05). The N-succinyl chitosan orogel in 5-fluoro uracil induced oral mucositis animal (Wistar rats) model showed enhanced survival ratio, weight gain and high tissue regeneration activity than chitosan gel formulation within 15 days. The formulation was successful in elevating the survival and reducing the inflammation in the oral mucosa of animals compared to disease control (p<0.05) and hence suggesting the potential of N-succinyl chitosan orogel in the treatment of oral mucositis.

Bioadhesive polymers: novel tool for drug delivery.

Mucoadhesive drug delivery systems came into picture in the early 1980s and are one of the most studied novel delivery systems. Several researchers have focused on the investigations of the interfacial phenomena of mucoadhesion with the mucus. Mucoadhesion can be defined as a state in which two components, of which one is of biological origin, are held together for an extended period of time by the help of interfacial forces. A number of polymers have shown characteristics of bioadhesion and have been used in the formulation of various conventional and novel drug delivery systems. Studies demonstrated that these carriers not only increase the local therapeutic activity, but also increase the systemic availability of the drugs by increasing the residence time at the site of application. The current review is an attempt to throw some light on the basics of the mucoadhesion: the mechanism of bioadhesion and the polymers that are used in the design of the bioadhesive delivery system with their properties that affect the bioadhesion.

Effect of Exercise Program and Calcium Supplements on Low Bone Mass among Young Indian Women- A Comparative Study.

PURPOSE: Low bone mass is a major health concern among young women nowadays due to sedentary lifestyle and lack of calcium rich food intake. Therefore there is an increase in the incidence of LBM among young university women so our main purpose of study was to compare effects of exercise program and calcium supplements on bone mass in young women. METHODS: This single blinded, cross sectional study included data collection in the form of SOS T-scores at distal radius for 104 young university women of mean age 22.3 years using Sunlight Omnisense Bone Sonometer 7000S. Of these, 62 women with low bone mass were included in a 3 month study but 60 subjects completed the study. They were randomly divided into 3 groups: exercise group (n=21), calcium supplementation group (n=21) and control group (n=20). All participants were evaluated pre and post protocol for T-score distal radius and midshaft tibia. RESULTS: After measuring SOS T-score of 104 subjects; we found that 60.57% had low bone mass and remaining 39.43% had normal bone mass. After 3 months, the exercise group showed significant improvement in distal radius SOS T-score (t=5.10, P<0.001), at midshaft tibia (t=3.71, P<0.001) followed by improvement in calcium group at distal radius (t=6.28, P<0.001), midshaft tibia (t=2.33, P<0.05) as compared to control group which showed a marginal increase. CONCLUSIONS: Exercise group showed more improvement in T-scores than calcium and control group. Exercise is important modifiable factor to improve bone accretion at this age and reduce risk of developing osteoporosis related debilitating conditions later in life.