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Background Surgical excision is the paradigm treatment option for non-melanoma skin cancer (NMSC), however intralesional fluorouracil (IL 5-FU) is an efficacious alternative and superior to other chemotherapy agents in NMSC. Yet, little summative data exists on the topic. Objective To assess the efficacy of IL 5-FU in the treatment of NMSC. Methods and materials A systematic review was performed using PubMed, Embase and Web of Science databases. 19 studies were included. ANOVA test was used to compare the duration of lesion prior to therapy and resolution time following IL 5-FU treatment. A two-way proportion test was performed to compare the clearance rate between squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and keratoacanthoma (KA). Results There was no significant difference between the clearance rate of SCC and BCC after IL 5-FU therapy (87 % vs 91.4%, respectively; P=0.2); however, the clearance rate of both SCC and BCC was significantly greater than that of KA (74.5%; Pl0.007); 95% CI [2.56%n19.1%]. Lesion duration and resolution time did not significantly differ across SCC, BCC, and KA (Pg0.3). Conclusion While majority of data is derived from individual cases, IL 5-FU achieved higher clearance rate in SCC and BCC groups than in KA group. J Drugs Dermatol. 2021;20(2):192-198. doi:10.36849/JDD.2021.5518.

Background Photograph editing has become popular for individuals using social media like Instagram. However, it is unknown if the use of social media and photograph editing applications by young adults has an association with seeking dermatologic care. Aims To assess the frequency of photograph editing among a cohort of young adults using Instagram and the association with seeking dermatologic care. Methods A population-based survey was administered to undergraduate students from April 2019 to May 2019 through an online platform. Results Of the 257 responses, 228 (88.7%) reported that they edited a photograph prior to posting on Instagram. Of those who reported editing a photograph, 145 (63.6%) edited a skin lesion, 104 (45.6%) whitened teeth, and 70 (30.7%) altered the size of their body. Of those who edited skin lesions, 128 (88.3%) edited acne/acne scars. Those who felt the editing made them more aware of their skin lesions were significantly more likely to feel they needed to see a dermatologist (P = .02, 95% CI). Conclusion Photograph editing is common among young adults using Instagram, especially in individuals with acne/acne scars. The effect of this behavior may be a motivating factor for individuals seeking dermatologic care.

OBJECTIVE Our objective was to determine the role of vaginal and/or vestibular microbiota disturbance as an associated factor of symptom characteristic of provoked vestibulodynia (PVD). STUDY DESIGN In an observational case-control study, the bacterial microbiomes in the vagina and vestibule from 20 women with PVD and 18 healthy controls were compared using a 16S rRNA gene-based molecular analysis. Clinical data were recorded through a 0- to 10-point visual analog scale related to dyspareunia and vulvovaginal pain/burning. RESULTS Comparative assessment of the bacterial taxa (cutoff ≥15%) revealed 105 genera in the vaginal samples of PVD patients and 113 genera in the vestibular samples. Similarly, 120 genera were detected in the vaginal samples and 151 in the vestibular samples of the control group. Bacterial complexity was higher in the vestibular samples than in vaginal samples in both groups, without statistically significant differences. The following 3 dominant taxonomic units were found: Lactobacillus, Gardnerella, and Atopobium in PVD patients and Lactobacillus, Gardnerella, and Bifidobacterium in the control group. Lactobacillus gasseri was dominant only in women with PVD, showing a significant correlation with burning/pain intensity and dyspareunia severity (0.255 and 0.357, respectively, p < .001). CONCLUSIONS Our data suggest that bacterial communities in vaginal discharge are an important contributor to the vestibular microbiota. Lactobacillus gasseri may be an element of vulnerability toward the development of vaginal dysbiosis. We can postulate its association as a potential etiologic organism in some individuals, either by itself or in some combination with other trigger factors.

Background. Palmitoylethanolamide is reported to solve pain and neuroinflammation in different models of chronic and neurodegenerative diseases. Some concerns have been illustrated for cautiously interpreting the available literature on the topic. Specifically, there is a lack of evidence about palmitoylethanolamide and female chronic pelvic pain. Concerns will be best solved by randomized trials. The present study was aimed at finding the best responders to micronized palmitoylethanolamide in female patient with chronic pelvic pain, using the existing literature at individual patient level, to help further randomized trial planning. Methods. After a systematic research, eligible studies (the ones enrolled female patients treated for chronic pelvic pain or for dyspareunia, dysuria, dyschezia, and dysmenorrhea with or without chronic pelvic pain) were assessed at individual patient data level. Conditional probabilities were calculated to assess variables conditioning the rates of good responders (pain score points more or equal to 3 reduction), poor responders (2 pain score reduction), and nonresponders at a three-month follow-up. Results. Only cases treated with palmitoylethanolamide comicronized with polydatin for a short period can be assessed. Good responders are more than 50%. In chronic pelvic pain, there is a 19.0% conditional probability to find good responders among patients with pain score at enrolment of 6 to 8 and of 6.8% to find poor responders among patients with a pain score at enrolment of 6 to 8. Painful disease does not matter on responders’ rates. Conclusion. Best responders to comicronized palmitoylethanolamide/polydatin are patients with pain score higher than 6 at enrolment, irrespective of other variables.

SRC is a nonreceptor tyrosine kinase with key roles in breast cancer development and progression. Despite this, SRC tyrosine kinase inhibitors have so far failed to live up to their promise in clinical trials, with poor overall response rates. We aimed to identify possible synergistic gene–drug interactions to discover new rational combination therapies for SRC inhibitors. An unbiased genome-wide CRISPR-Cas9 knockout screen in a model of triple-negative breast cancer revealed that loss of integrin-linked kinase (ILK) and its binding partners α-Parvin and PINCH-1 sensitizes cells to bosutinib, a clinically approved SRC/ABL kinase inhibitor. Sensitivity to bosutinib did not correlate with ABL dependency; instead, bosutinib likely induces these effects by acting as a SRC tyrosine kinase inhibitor. Furthermore, in vitro and in vivo models showed that loss of ILK enhanced sensitivity to eCF506, a novel and highly selective inhibitor of SRC with a unique mode of action. Whole-genome RNA sequencing following bosutinib treatment in ILK knockout cells identified broad changes in the expression of genes regulating cell adhesion and cell–extracellular matrix. Increased sensitivity to SRC inhibition in ILK knockout cells was associated with defective adhesion, resulting in reduced cell number as well as increased G1 arrest and apoptosis. These findings support the potential of ILK loss as an exploitable therapeutic vulnerability in breast cancer, enhancing the effectiveness of clinical SRC inhibitors. Significance: A CRISPR-Cas9 screen reveals that loss of integrin-linked kinase synergizes with SRC inhibition, providing a new opportunity for enhancing the clinical effectiveness of SRC inhibitors in breast cancer.

BACKGROUND The incarcerated population may have variable access to specialty care that may affect the detection and diagnosis of skin cancer. OBJECTIVE The purpose of the study was to characterize skin cancers in the incarcerated population and determine time to treatment initiation (TTI) after biopsy. METHODS A retrospective cohort study was performed using data from a single-center referral hospital of incarcerated patients with biopsy-proven basal cell carcinoma (BCC), squamous cell carcinoma (SCC), or melanoma between January 2009 and December 2019. The main outcome measured was TTI after biopsy. RESULTS One hundred thirteen patients, majority men (96.5%) and of Caucasian race (89.4%), were diagnosed and/or treated for 191 skin cancers. Of these 191 skin cancers, 118 were BCC (61.8%), 58 were SCC (30.4%), and 15 were melanomas (7.9%). The average TTI after biopsy for melanoma was 57 days (range: 21-136, median: 51, 95% confidence interval: 39.89-74.10) with an average Breslow depth of 1.57 mm. CONCLUSION The average TTI of melanoma in the incarcerated population in this study was greater than 30 days, which may have increased mortality risk.

OBJECTIVES The purpose of this cross-sectional study was to prepare a reliable and easy-to-use architectural classification for vulvar lichen sclerosus (VLS) aimed at defining the morphological patterns of this condition. MATERIALS AND METHODS An expert panel composed by 7 physicians with expertise in clinical care of vulvar conditions outlined the architectural criteria for the definition of VLS severity (phimosis of the clitoris, involvement of the interlabial sulci, narrowing of the vulvar introitus), identifying 5 grades to build up a classification. Thirteen physicians with 2-30 years expertise in vulvar diseases (nonexpert group) were asked to evaluate 3-5 pictures from 137 patients. Each physician individually assigned a grade to each case, according to the previously mentioned criteria. Interrater reliability was analyzed by means of intraclass correlation coefficient (ICC). The reliability concerning the 2 classifications of each rater was analyzed by means of κ statistic. Intraobserver and interobserver reliability in vivo was analyzed by means of κ index. RESULTS This study provides a new classification of VLS, based on defined anatomical criteria and graded into mutually exclusive progressive classes.The ICC analysis showed a substantial interrater reliability of the classification, ICC = 0.89 (0.87-0.91), both in the expert panel and in the nonexpert group (ICC = 0.92 and 0.87, respectively). An "almost perfect" intraobserver and interobserver reliability was achieved among physicians in vivo (κ = 0.93). CONCLUSIONS Our classification showed a high reliability. It is easy to use, and it can be applied in clinical practice and eventually, in the evaluation of regenerative and cosmetic surgery.

Millennial learners have educational needs and preferences that differ from those of prior generations. They prefer learning from online resources, appreciate interactive didactic sessions, and desire frequent feedback and guidance. Understanding and adapting to these learner attributes may allow for optimization of the educational environment for members of this generation. The following recommendations were developed to advance a dermatology residency program’s curriculum to accommodate the modern learner. Although the efficacy of these teaching tips has yet to be fully established, they are grounded by theory and are evidence-informed. Medical educators who are able to employ these strategies are likely to be successful in teaching and engaging the millennial learner.

Recently, there have been calls to improve diversity among the dermatology workforce, with emphasis placed on the resident selection process and trainee pipeline. However, there is limited data on the perspectives of dermatology applicants, especially among UIM trainees, and the support that they need and want to successfully apply in dermatology.To assess trainee perspectives, we disseminated a survey to medical students, interns (matched into dermatology), and dermatology residents asking how dermatology residency programs can best support trainees through the dermatology application process. We developed a codebook drawing upon grounded theory methodology, and consensus coded all qualitative responses.We received 224 qualitative responses from underrepresented in medicine (UIM) (65, 29.0%) and non-UIM trainees (159, 70.9%). UIM trainees were more likely to mention diversity and inclusion initiatives (46.2% vs 3.8%, Plt;0.001), transparency in program information (40.0% vs 24.5%, P=0.021), holistic review (30.8% vs 6.3%, Plt;0.001), UIM student outreach/pipeline programs (23.1% vs 0.6%, Plt;0.001), and mentorship (21.5% vs 8.2%, P=0.009).Improving programmatic efforts to address unique challenges UIM trainees face when applying into dermatology is instrumental to mitigating barriers. We highlight opportunities for dermatology residency programs to create a more fair and equitable dermatology application process and support a more diverse pipeline of future dermatologists. J Drugs Dermatol. 2021;20(7):795-797. doi:10.36849/JDD.6043.

Within the larger ABC superfamily of ATPases, ABCF family members eEF3 in Saccharomyces cerevisiae and EttA in Escherichia coli have been found to function as ribosomal translation factors. Several other ABCFs including biochemically characterized VgaA, LsaA and MsrE confer resistance to antibiotics that target the peptidyl transferase center and exit tunnel of the ribosome. However, the diversity of ABCF subfamilies, the relationships among subfamilies and the evolution of antibiotic resistance (ARE) factors from other ABCFs have not been explored. To address this, we analyzed the presence of ABCFs and their domain architectures in 4505 genomes across the tree of life. We find 45 distinct subfamilies of ABCFs that are widespread across bacterial and eukaryotic phyla, suggesting that they were present in the last common ancestor of both. Surprisingly, currently known ARE ABCFs are not confined to a distinct lineage of the ABCF family tree, suggesting that ARE can readily evolve from other ABCF functions. Our data suggest that there are a number of previously unidentified ARE ABCFs in antibiotic producers and important human pathogens. We also find that ATPase-deficient mutants of all four E. coli ABCFs (EttA, YbiT, YheS and Uup) inhibit protein synthesis, indicative of their ribosomal function, and demonstrate a genetic interaction of ABCFs Uup and YheS with translational GTPase BipA involved in assembly of the 50S ribosome subunit. Finally, we show that the ribosome-binding resistance factor VmlR from Bacillus subtilis is localized to the cytoplasm, ruling out a role in antibiotic efflux., Graphical Abstract Unlabelled Image, Highlights • We present a comprehensive classification of known and novel ABCFs across all life. • We predict multiple novel subfamilies of antibiotic resistance ABCFs in pathogens. • ATPase-deficient mutants of the four Escherichia coli ABCFs disrupt protein synthesis. • Two E. coli ABCFs interact genetically with the ribosome assembly GTPase BipA. • ARE ABCF VmlR is localized to the cytoplasm, ruling out a role in antibiotic efflux.

This cohort study examines the demographic characteristics associated with the incidence of cutaneous T-cell lymphoma from 2000 to 2018 in Louisiana.

BACKGROUND The effectiveness of a new vaginal medical device, which contains polycarbophil, 0.04% lauryl glucoside and glycerides (Polybactum®, Effik Italia Spa, Cinisello Balsamo, Milan, Italy), in reducing BV recurrence rate was investigated. METHODS This was a multicenter, open label, not comparative study. Women over 18 years old affected by recurrent BV were included. The latest episode was diagnosed by Amsel criteria 6-9 days before the start of the study and treated with vaginal metronidazole (gel 0.75% mg for 5 days or ovules 500 mg for 7 days). The recurrence was defined by at least 2 episodes in the previous 12 months. Polybactum® vaginal ovules, day 1-4-7, were started within the 12th and the 24th hour after the end of metronidazole therapy and repeated monthly for 3 cycles. RESULTS The first 41 patients enrolled were evaluated for an interim analysis 6 months after the study started; 2 patients interrupted the trial, leaving 39 evaluable subjects. The recurrence rate was significantly reduced compared to previous published data (10.26% vs. 40% P

Most women experience a urinary tract infection (UTI) at least once in their lifetime. The present study determined the efficacy and safety of a combination ofThis single-centre study enrolled premenopausal women aged 18-50 years with an acute UTI and a history of recurrent uncomplicated UTIs. Patients were first treated with fosfomycin (3 g once a day for 2 days) to eliminate any underlying infection, followed by treatment with Lactoflorene CistA total of 55 women (mean age 39.3 years; range: 20-46) were enrolled in the study. A significantly higher proportion of patients in the control group experienced UTIs during the study period compared with the two treatment groups (52.9% vs 16.0% in Group 1 and 15.5% in group 2;Prophylactic treatment with Lactoflorene Cist

Lasers are being used in ever-expanding roles in dermatology. As our understanding of laser energy grew, the need for safety guidelines became apparent. The US Food and Drug Administration (FDA) published the first safety guidelines in 1984, which are updated on a regular basis. However, these are just guidelines, and their implementation is voluntary by the laser practitioner. In this article, we discuss the 4 regulatory entities for laser safety in the United States, laser principles in general, ocular hazards, laser-generated airborne contaminants (LGACs), fires, and unintended laser beam injuries. We also review the use of checklists in reducing adverse outcomes and the need for safety protocols for laser practitioners. We provide a modifiable checklist, which pertains specifically to lasers and can be customized to meet the needs of the individual laser practitioner.

Objective Cervicovaginal decubitus ulceration is a complication of advanced pelvic organ prolapse that is very difficult to manage. Here, we report on the effectiveness of fractional CO2 laser treatment for a wide decubitus ulcer over an apical vaginal vault prolapse. Methods We report a case of a postmenopausal woman with a wide decubitus ulcer over a vaginal vault prolapse. A fractional microablative CO2 Pixel laser system (Alma Lasers, Cesarea, Israel), equipped with an appropriate probe for the vulva, was used to treat the ulceration of a 78-year-old patient across three laser sessions with 30-day intervals. Results A significant improvement in the decubitus ulcer was noted in a check-up held 2 months after the final laser session, with approximately 95% wound healing observed. No side effects were reported during or after the laser therapy. Conclusions This case demonstrates that fractional Pixel CO2 laser treatment is a viable option for managing decubitus ulcers before definitive surgery in postmenopausal women with advanced pelvic organ prolapse.

Objectives This study set out to investigate the epidemiological characteristics and comorbidities of chronic vulvar pain. Secondary goals were to identify the preferred approaches for managing vulvodynia in Italy. Study Design A cross-sectional study (the VuNet -Vulvodynia Network project) was performed in consecutive female patients with chronic vulvar pain attending 21 Italian medical centers (public hospitals, university clinics and private outpatient services) in the period December 2016 to November 2018. Study data were entered by healthcare professionals in a special web-based medical record system (PRIDE- Progetto Rete Italiana Dolore vulvarE). These data covered epidemiological aspects, demographic characteristics, obstetric and gynecological history, presence and duration of current and/or past symptoms, associated disorders, details of physical examination and treatment approaches. Results A total of 1183 subjects with a diagnosis of chronic vulvar pain were included in the study. The main reason for consultation was superficial dyspareunia, present in 64.2 % of the women. 43.4 % of the sample reported comorbid sexual disorders (of desire in 22.1 % and arousal in 21.3 %). 48.3 % of the patients reported prolonged pain lasting between one and five years. Factors associated with vulvar pain included a relatively high family history of diabetes mellitus (father = 8.6 %; mother = 8.4 %), recurrent vulvovaginal candidiasis (32 %), and urinary tract infections (37.4 %: recurrent cystitis in 19.5 % and post-coital cystitis in 17.9 %). Irritable bowel syndrome (28 %), constipation (23.5 %), headache (25.7 %: migraine in 18.0 % and menstrual headache in 7.7 %), allergies (17.5 %: food allergies in 10.1 %, respiratory allergies in 7.4 %), anxiety (15.0 %), dyschezia (11.7 %), invalidating dysmenorrhea/endometriosis (11.1 %), and major depression (7.6 %) were also reported. Vestibulodynia was diagnosed in 837 of the 1183 patients (70.8 %) and generalized vulvodynia in 323 (27.3 %). Notably, 69.1 % of the patients stated that previous therapies had not changed their pain. Conclusions The diagnoses of vestibulodynia and vulvodynia must be considered in patients with chronic vulvar pain. The VuNet study contributes to a more comprehensive reading of the predisposing, precipitating and maintaining factors that contribute to vulvar pain, and of the key comorbidities.

Monitoring glycemic control in diabetes includes daily measurements of glucose levels at home, along with periodic monitoring of glycemia indicators on the whole. The main purpose of monitoring glycemic control is to accurately and authentically assess the glycemic level reached by each patient in order to ensure the glycemic goals achievement. Glycemic control assessment at a certain point in time is best achieved by self-monitoring the level of glucose in the blood, in that allows you to assess the presence of hyperglycemia and hypoglycemia to optimize the treatment strategy.Accuracy assessment of a medical devicelaquo;Portable blood glucose concentration meter with electrochemical single-use strip PKG-03laquo;Satellite Expressraquo; for glycemic control of children with diabetes.In a group of children with diabetes (n=105, age from 1 month to 17 years), simultaneously was taken capillary blood from one drop to assess the accuracy of glycemia levels on thelaquo;Satellite Expressraquo; glucose meter and on the laboratory glucose and lactate analyzer SUPER GL.In a comparative analysis of 660 blood samples on the Clark error scale, was found that all deviations of glycemia values obtained with thelaquo;Satellite Expressraquo; glucose meter were in zones A (99.7%mdash; clinically correct values) and B (0.3%mdash; safe deviations). The limits of permissible systematic error of measurements that meet the requirements of the National Standard of Russian Federation GOST R ISO 15197-2015 in terms of clause 6.3 System Accuracy amounted to 96.8% of deviations of glucose meter indications from reference values, which matches to areas of clinically correct and safe deviations.Using thelaquo;Satellite Expressraquo; glucose meter in clinical practice makes it possible to control glycemia qualitatively and it is safe for children aged from 1 month to 17 years.

Physician gender may impact their exposure to genital dermatoses during residency. The purpose of this study was to survey current dermatology residents regarding their comfort in diagnosing and managing lichen sclerosus. As residents progress through training, confidence improves in diagnosing and managing both male and female lichen sclerosus. However, residents overall feel less comfortable with male genital lichen sclerosus, with female residents displaying the greatest confidence discrepancy. This study highlights gender discrepancies with dermatology resident confidence and practice habits and may serve to further guide curricula to address these disparities.

The observation that BRCA1- and BRCA2-deficient cells are sensitive to inhibitors of poly(ADP–ribose) polymerase (PARP) has spurred the development of cancer therapies that use these inhibitors to target deficiencies in homologous recombination. The cytotoxicity of PARP inhibitors depends on PARP trapping, the formation of non-covalent protein–DNA adducts composed of inhibited PARP1 bound to DNA lesions of unclear origins. To address the nature of such lesions and the cellular consequences of PARP trapping, we undertook three CRISPR (clustered regularly interspersed palindromic repeats) screens to identify genes and pathways that mediate cellular resistance to olaparib, a clinically approved PARP inhibitor. Here we present a high-confidence set of 73 genes, which when mutated cause increased sensitivity to PARP inhibitors. In addition to an expected enrichment for genes related to homologous recombination, we discovered that mutations in all three genes encoding ribonuclease H2 sensitized cells to PARP inhibition. We establish that the underlying cause of the PARP-inhibitor hypersensitivity of cells deficient in ribonuclease H2 is impaired ribonucleotide excision repair. Embedded ribonucleotides, which are abundant in the genome of cells deficient in ribonucleotide excision repair, are substrates for cleavage by topoisomerase 1, resulting in PARP-trapping lesions that impede DNA replication and endanger genome integrity. We conclude that genomic ribonucleotides are a hitherto unappreciated source of PARP-trapping DNA lesions, and that the frequent deletion of RNASEH2B in metastatic prostate cancer and chronic lymphocytic leukaemia could provide an opportunity to exploit these findings therapeutically.

Hidradenitis suppurativa is characterized by chronic follicular occlusion that presents with recurrent nodules, inflamed abscesses, and scarring. Research has shown that these patients have a decreased quality of life. In addition to its psychosocial effects, hidradenitis suppurativa has recently been associated with joint pathology. In this study, we distributed a survey consisting of the Short Form 12 Health Survey, used for assessing health outcomes, along with additional questions about joint pain to an online hidradenitis suppurativa support group in order to understand the effect of comorbid arthralgia on quality of life in this disease. The respondents in this study had significantly reduced physical health composite scores-12 (PCS-12), (35.8 versus 50, Plt;0.001) and mental health composite scores-12 (MCS-12), (33.7 versus 50, Plt;0.001) scores compared to the general population. Additionally, patients reporting severe arthralgia had significantly lower PCS-12 (32.3 versus 36.5; Plt;0.05) and MCS-12 (33.3 versus 40.5; Plt;0.001) scores compared to those with mild arthralgia. Despite the effect of comorbid arthralgia on quality of life, only 11% reported having been asked about joint pain by their dermatologist. Routine screening questions concerning associated arthralgia and diminished quality of life may be helpful during clinician assessment and treatment of hidradenitis suppurativa patients.

This study is a single-center, retrospective analysis of postmenopausal women presenting with dyspareunia and vulvar pain, aiming to evaluate relative effectiveness of vestibular CO

Background Inappropriate feminine hygiene practices are related to vulvar unpleasant symptoms (such as skin changes, lesions, burning, pruritus, fissures, and dyspareunia). Aims We assessed the daily use effects of intimate cleansers on vulvar skin by comparing two specific products for intimate care: Saugella Hydraserum (SIS), based on natural extracts, and a standard product based on lactic acid, such as Lactacyd Feminine Hygiene (LTC). Forty healthy women were enrolled in this double-blind controlled study. Methods After randomization, the cleansers were used twice daily for 30 days. The hydration level was determined using the Corneometer® CM 825, the pH using the Skin-pH-Meter PH 905® and the sebum level using the Sebumeter SM815® . Measurements were performed at baseline and on day 30 on the labia majora and labia minora. Results Both cleansers showed a reduction in the hydration level, but this was much less evident in the SIS group (-6.3% SIS vs -23,7% LTC). The pH values of the SIS group were lower than those of the LTC group, especially on the labia minora (5.27 ± 0.08 and 5.6 ± 0.1, respectively, P = .025). The sebum increased in both groups, but in the LTC group, it was higher on the labia majora (+96.2% vs +46.8%, respectively, P = .003), while on the labia minora, it was higher in the SIS group (+24.7% vs +17.1%, respectively P = NS). Conclusions Both cleansers tested showed high performance for safety and tolerability on vulvar skin, but SIS showed better efficacy than LTC on some parameters.

At present, the majority of the proposed Deep Learning (DL) methods provide point predictions without quantifying the models uncertainty. However, a quantification of the reliability of automated image analysis is essential, in particular in medicine when physicians rely on the results for making critical treatment decisions. In this work, we provide an entire framework to diagnose ischemic stroke patients incorporating Bayesian uncertainty into the analysis procedure. We present a Bayesian Convolutional Neural Network (CNN) yielding a probability for a stroke lesion on 2D Magnetic Resonance (MR) images with corresponding uncertainty information about the reliability of the prediction. For patient-level diagnoses, different aggregation methods are proposed and evaluated, which combine the single image-level predictions. Those methods take advantage of the uncertainty in image predictions and report model uncertainty at the patient-level. In a cohort of 511 patients, our Bayesian CNN achieved an accuracy of 95.33% at the image-level representing a significant improvement of 2% over a non-Bayesian counterpart. The best patient aggregation method yielded 95.89% of accuracy. Integrating uncertainty information about image predictions in aggregation models resulted in higher uncertainty measures to false patient classifications, which enabled to filter critical patient diagnoses that are supposed to be closer examined by a medical doctor. We therefore recommend using Bayesian approaches not only for improved image-level prediction and uncertainty estimation but also for the detection of uncertain aggregations at the patient-level., Comment: 21 pages, 13 figures

To evaluate the efficacy of different methods of antivirus therapy of tick-borne encephalitis (TBE) in children in the acute period and during chronic infections.During 1 year, 130 children, aged 7-17 years, with TBEV received therapy in the acute period (an average in 3.5±1.3 days) in groups 1 (n=84) and 2 (n=20), and in the chronic infection in groups 3 (n=15) and 4 (n=11). Ribavirin orally, recombinant interferon-α2 (IFN-α2) i/m or in suppositories and anaferon orally were prescribed to children of groups 1 and 3. Children of groups 2 and 4 received tick-borne immunoglobulin (IgG)i/m and ribonuclease i/m. At admission, all patients received infusions of cytoflavin in the drip at the rate of 0.6 ml/kg per day. Etiological diagnosis included ELISA (IgM, G, viral antigen), and virus RNA by PCR in the blood and CSF. MRI of the brain and cervical spinal cord using standard programs was performed. All studies were performed prior to and in the course of treatment.In patients of group 1, the period of increase in symptoms was reduced by ~ 4 days, and the duration of impairment of consciousness and pleocytosis in CSF ~ by 5 days, which was accompanied by a faster clearance of the virus in CSF, compared with group 2. In group 1, recovery without neurological deficit was observed in 83.3% (n=70), all patients had no progression of infection. In group 2, 30% of children (n=6) acquired TBEV chronic infection, and in 55% (n=11) there was a neurological deficit without progression. In patients of group 3 with chronic TBEV, the improvement was observed in 86.7% of cases, and complete regression of symptoms occurred in 1 patient, and replication of the virus was arrested in all of them. In group 4, symptoms increased in 72.7%, while virus replication was preserved and atrophic changes in the CNS increased on MRI. Antiviral therapy (ribavirin, IFN-α2 and release of active antibodies to gamma interferon -anaferon children) has the highest efficacy when prescribed for the first 5 days, while IgG and ribonuclease have insufficient efficacy in TBEV.Цель исследования. Оценка эффективности разных схем этиотропной терапии очаговых форм клещевого энцефалита (КЭ) у детей в остром периоде и при хроническом течении. Материал и методы. Обследовали 130 детей 8—17 лет с очаговыми формами КЭ. В остром периоде инфекции были 84 ребенка (1-я группа) и 20 (2-я группа); с хроническим течением КЭ — 15 детей (3-я группа) и 11 (4-я группа). Пациенты 1-й и 3-й групп получали рибавирин, рекомбинантный интерферон-α2 (ИФН-α2) и анаферон детский; дети 2-й и 4-й групп — противоклещевой иммуноглобулин (ПКГ) и рибонуклеазу. Всем пациентам при поступления назначали 10 инфузий цитофлавина и комплекс нейрометаболических препаратов. Этиологическая диагностика включала ИФА с определением IgM, IgG, антигена и РНК вируса методом ПЦР в крови и ЦСЖ. Всем пациентам проводилась МРТ головного мозга и шейного отдела спинного мозга. Исследования выполнялись до начала терапии и в процессе лечения. Результаты и заключение. У пациентов 1-й группы по сравнению со 2-й группой сокращался период нарастания симптомов на 4 сут, а длительность нарушения сознания и плеоцитоза в ЦСЖ — на 5 сут, что сопровождалось более быстрым клиренсом вируса в ЦСЖ. В 1-й группе выздоровление без неврологического дефицита наблюдалось у 70 (83,3%) детей, у всех отсутствовало прогрессирование инфекции. Во 2-й группе у 6 (30%) детей КЭ приобрел хроническое течение, а у 11 (55%) был выявлен неврологический дефицит без прогрессирования. При хроническом течении КЭ у детей 3-й группы в 86,7% отмечалось улучшение, а у 1 ребенка — полный регресс симптомов, у всех была остановлена репликация вируса КЭ. У пациентов 4-й группы симптомы нарастали в 72,7% случаев при сохранении репликации вируса и прогрессировании атрофических изменений в ЦНС по данным МРТ. Таким образом, противовирусная терапия (рибавирин, ИФН-α2 и релиз-активные антитела к интерферону-γ — анаферон детский) имеет наибольшую эффективность в первые 5 сут от начала инфекции, а применение ПКГ и рибонуклеазы при очаговых формах КЭ малоэффективно.

To establish an effect of alcohol dependence on the cognitive functions of patients with schizophrenia.One hundred patients with paranoid schizophrenia were examined. Half of them had a co-occurring diagnosis of alcohol dependence syndrome. Memory, attention, thinking were studied. Comparisons were made between groups, depending on the presence of the addictive disorder.Attention and short-term memory are at the low border of normal values in both groups. No significant between-group differences were found. In Benton test, errors characteristic of schizophrenia were more frequent in the main group. 'Organic' errors were prevalent in the control group. Mild thinking disorders of organic type were significantly more frequent in the main group.Co-occurring alcohol dependence does not significantly influence intelligence but significant organic stigmas contribute to the structure of the cognitive profile of patients. The prevalence of organic disturbances in the structure of thinking in patients with co-occurring alcohol abuse was revealed. The best indicators of attention were demonstrated by patients with attack-like schizophrenia without substance abuse. This suggests that the influence of the alcohol factor differs in continuous and attack-like progressive schizophrenia.Цель исследования. Установление особенностей влияния алкоголизации на когнитивные функции больных шизофренией. Материал и методы. Обследованы 100 пациентов, страдающих параноидной шизофренией. Выделены основная группа (ОГ), имеющая сопутствующий диагноз синдрома зависимости от алкоголя (n=50), и контрольная (n=50). Изучены особенности памяти, внимания, мышления, проведено сопоставление групп сравнения по наличию сопутствующей аддиктивной патологии. Результаты. Внимание и краткосрочная память находились на пограничном уровне, между группами сравнения статистически значимо не различались. В тесте Бентона в основной группе преобладали ошибки по шизофреническому типу, тогда как в контрольной группе превалирующими являлись 'органические' ошибки. Прослеживалось статистически значимое преобладание легкого уровня снижения мышления в ОГ. Заключение. Сопутствующая алкогольная зависимость не является определяющим фактором когнитивного поражения больных шизофренией, однако привносит значимые органические стигмы в структуру когнитивного профиля пациентов. Выявлено превалирование 'органических' нарушений структуры мышления у пациентов с сопутствующей зависимостью от алкоголя. Наилучшие показатели внимания отличали пациентов, страдающих шубообразной шизофренией, здоровых в наркологическом плане. Это заставляет полагать, что влияние алкогольного фактора имеет различное значение при непрерывной и приступообразно-прогредиентной шизофрении.

To characterize the clinical picture, infectious etiology and MRI results of panencephalitis (PANE) in children, depending on the duration of the disease.Children (n=32) with PANE at the age from 3 months up to 17 years were examined for a group of actual viral and bacterial infections. The inclusion criterion was a diffuse lesion of white matter hemispheres on MRI. MRI of the brain and spinal cord, CSF study (pleocytosis, oligoclonal IgG, the main myelin protein (MBP) were performed. The follow-up was 5-10 years. The complex therapy included etiotropic (antiviral) and pathogenetic agents, with priority given to cytoflavin as a drug with a multimodal effect.In 84.4% of cases, PANE in children are recorded under the age of 3 years and in 71.9% of cases, are associated with congenital infections with the prevalence of herpes viruses, especially cytomegalovirus (37,8%) and herpes type 6 (21.9%). In 78.3% of cases, PANE have chronic gradual development more often with a delay in the formation of motor and speech/prespeech skills, and manifested with pyramidal, cerebellar and other symptoms in the future. PANE is accompanied by a lesion of the white matter of the hemispheres inIn almostЦель исследования - охарактеризовать клинико-этиологическую и МРТ-картину панэнцефалитов у детей в зависимости от продолжительности заболевания. Материал и методы. Обследованы 32 ребенка с панэнцефалитом (ПАНЭ) в возрасте от 3 мес до 17 лет на группу актуальных вирусных и бактериальных инфекций. Критерием включения явилось поражение белого вещества полушарий головного мозга диффузного характера на МРТ. Проводились МРТ головного и спинного мозга, исследование цереброспинальной жидкости (цитоз, олигоклональные IgG, основной белок миелина (ОБМ). Катамнез составил 5-10 лет. Пациентам проводилась комплексная терапия, включающая этиотропные (противовирусные) и патогенетические средства, среди последних приоритетное значение имело применение цитофлавина как препарата с мультимодальным действием. Результаты. ПАНЭ у детей в 84,4% случаев регистрируются в возрасте до 3 лет и связаны с врожденными инфекциями в 71,9%, с доминированием в этиологии цитомегаловируса (37,8%) и вируса герпеса 6-го типа (21,9%). В 78,3% случаев ПАНЭ имеют хроническое постепенное развитие, чаще с задержкой формирования двигательных и речевых/предречевых навыков, а в дальнейшем проявляются развитием пирамидных, мозжечковых и других симптомов. Сопровождаются поражением белого вещества полушарий, в

Microcephalic primordial dwarfism (MPD) is a group of rare single‐gene disorders characterized by the extreme reduction in brain and body size from early development onwards. Proteins encoded by MPD‐associated genes play important roles in fundamental cellular processes, notably genome replication and repair. Here we report the identification of four MPD individuals with biallelic variants in DNA2, which encodes an adenosine triphosphate (ATP)‐dependent helicase/nuclease involved in DNA replication and repair. We demonstrate that the two intronic variants (c.1764‐38_1764‐37ins(53) and c.74+4A>C) found in these individuals substantially impair DNA2 transcript splicing. Additionally, we identify a missense variant (c.1963A>G), affecting a residue of the ATP‐dependent helicase domain that is highly conserved between humans and yeast, with the resulting substitution (p.Thr655Ala) predicted to directly impact ATP/ADP (adenosine diphosphate) binding by DNA2. Our findings support the pathogenicity of these variants as biallelic hypomorphic mutations, establishing DNA2 as an MPD disease gene.

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycleprogression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitinligase, in patients with microcephalic primordial dwarfism/Seckel syndrome. We establish that TRAIPrelocalizes to sites of DNA damage where it is required for optimal phosphorylation of H2AX andRPA2 during S-phase in response to UV irradiation, as well as fork progression through UV-inducedDNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP thereforelimit cellular proliferation, providing a potential mechanism for microcephaly and dwarfismphenotypes. Human genetics thus identifies TRAIP as a novel component of the DNA damageresponse to replication-blocking DNA lesions.

Human CtIP is a decisive factor in DNA double-strand break repair pathway choice by enabling DNA-end resection, the first step that differentiates homologous recombination (HR) from non-homologous end-joining (NHEJ). To coordinate appropriate and timely execution of DNA-end resection, CtIP function is tightly controlled by multiple protein–protein interactions and post-translational modifications. Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway. A tripeptide motif (FRY) conserved across vertebrate CtIP proteins is essential for KLHL15-binding; its mutation blocks KLHL15-dependent CtIP ubiquitination and degradation. Consequently, DNA-end resection is strongly attenuated in cells overexpressing KLHL15 but amplified in cells either expressing a CtIP-FRY mutant or lacking KLHL15, thus impacting the balance between HR and NHEJ. Collectively, our findings underline the key importance and high complexity of CtIP modulation for genome integrity., Nature Communications, 7, ISSN:2041-1723

The aim of this non-interventional, observational, multicentre, open-label study was to assess the effectiveness of a vaginal gel containing extracts of Thymus vulgaris and Eugenia caryophyllus in conjunction with two specific lactobacilli strains (Lactobacillus fermentum LF10 and Lactobacillus plantarum LP02) specifically formulated in slow-release vaginal capsules, in treating bacterial vaginosis (BV), vulvovaginal candidiasis (VVC) or recurrent vulvovaginal candidiasis disease (RVVC) [Estromineral Probiogel (EPB) in Italy, or Saugella Probiogel; Meda Pharma - Mylan Group]. There was a statistically significant improvement in pruritus, burning, vulvovaginal oedema and erythema, dyspareunia and vaginal secretions in all diagnostic groups. At the end of the study, the microbiological evaluation was normal in 80.0% of cases with BV, 62.5% of cases with VVC and 100.0% with RVVC. The clinical data allow EPB to be recommended in the acute treatment of VVC and BV, suggesting that EPB is a useful maintenance treatment if there are recurrent episodes. Controlled studies are needed to confirm the efficacy of EPB in the treatment of recurrences and to identify the most appropriate dosage regimen.

To assess the effectiveness of vaginal diazepam in addition to transcutaneous electrical nerve stimulation (TENS) in the treatment of vestibulodynia (VBD).This study was a randomized, double-blind, placebo-controlled trial. Forty-two patients with VBD were randomized, 21 underwent diazepam and TENS (diazepam group) and 21 received placebo and TENS (placebo group). Vulvar pain was assessed on a on a 10-cm visual analogue scale (VAS) and dyspareunia according to the Marinoff dyspareunia scale. Vaginal surface electromyography (EMG) and vestibular current perception threshold (CPT) testing were performed at baseline and 60 days after treatment. The primary endpoints included the change in pain and dyspareunia from baseline to 60 days of pain and dyspareunia. The secondary endpoints was the variation in objectivity of pelvic floor muscle (PFM) function and vestibular nerve fiber current perception threshold (CPT).The VAS scores for pain from basal values of 7.5 and 7.2 for the diazepam and placebo, respectively, showed significant (p 0.01) decreases from 4.7 to 4.3, but this difference was not statistically significant. The Marinoff dyspareunia scores in the diazepam group showed a significant difference (p 0.05) from values measured in the placebo group. The ability to relax the PFM after contraction (difference between maximal contraction and rest tone) was significantly greater for the diazepam group versus the placebo group (3.8 μv and 2.4 μv, respectively, p 0.01). The CPT values for all of the nerve fibers increased after the treatment, but this increase was significant in the diazepam group only for the values at a 5-Hz stimulation (C fibers) with a change of 47.8% vs 26.9% (p 0.05). Only two patients reported a mild drowsiness in the diazepam group.The present study provided indications that vaginal diazepam plus TENS is useful to improve pain and PFM instability in women with VBD.

The study aimed to assess the effects of ospemifene on vulvar vestibule in postmenopausal women with vulvar pain and dyspareunia. Fifty-five postmenopausal women used oral ospemifene 60 mg/d for 60 d. Symptoms of dryness, burning, and dyspareunia were evaluated on a 10 cm visual analog scale. Visual examination of the vulvar vestibule was also conducted. Patients also underwent current perception threshold (CPT) testing obtained from the vulvar vestibule. Fifty-five patients (94.6%) completed the treatment. Hot flashes were the most frequent adverse effects, but this led to a discontinuation of therapy in three patients (5.4%). After therapy, there was a statistically significant decrease from the baseline in the mean scores for dryness, burning, and dyspareunia and reduction of vestibular trophic score (baseline value of 11.2-4.2 after the therapy, p ≤ 002) and cotton swab test scores (2.81 compared with 1.25, p = .001). There was a difference in CPT values for all nerve fibers and more consistent for C fibers (-38% of sensitivity). These results confirm the efficacy of ospemifene on postmenopausal vestibular symptoms and signs; moreover, the drug was effective in normalizing vestibular innervation sensitivity.

DNA is strictly compartmentalized within the nucleus to prevent autoimmunity; despite this, cyclic GMP-AMP synthase (cGAS), a cytosolic sensor of double-stranded DNA, is activated in autoinflammatory disorders and by DNA damage. Precisely how cellular DNA gains access to the cytoplasm remains to be determined. Here, we report that cGAS localizes to micronuclei arising from genome instability in a mouse model of monogenic autoinflammation, after exogenous DNA damage and spontaneously in human cancer cells. Such micronuclei occur after mis-segregation of DNA during cell division and consist of chromatin surrounded by its own nuclear membrane. Breakdown of the micronuclear envelope, a process associated with chromothripsis, leads to rapid accumulation of cGAS, providing a mechanism by which self-DNA becomes exposed to the cytosol. cGAS is activated by chromatin, and consistent with a mitotic origin, micronuclei formation and the proinflammatory response following DNA damage are cell-cycle dependent. By combining live-cell laser microdissection with single cell transcriptomics, we establish that interferon-stimulated gene expression is induced in micronucleated cells. We therefore conclude that micronuclei represent an important source of immunostimulatory DNA. As micronuclei formed from lagging chromosomes also activate this pathway, recognition of micronuclei by cGAS may act as a cell-intrinsic immune surveillance mechanism that detects a range of neoplasia-inducing processes.